Compound based on corydalmine structure and application thereof

Abstract

The invention relates to a compound as shown in a general formula (A) and a pharmaceutical composition of the compound, and the compound as shown in the general formula (A) can be used for preventing and / or treating diseases related to a central nervous system, such as pain, drug addiction and depression. The invention also relates to preparation and application of the compound. # imgabs0 #

Description

Compounds based on corydaline structure and uses thereof

[0001] The present invention claims priority to Chinese application No. 202211273550.1 filed on October 18, 2022 and Chinese application No. 202311089455.0 filed on August 25, 2023, which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to a compound based on the structure of corydaline and uses thereof. Background Art

[0003] L-orydalmine (l-DL) is a known compound with analgesic, detoxification, and anti-drug addiction effects. Its chemical name is (S)-2,3,9-trimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinolin-10-ol, and it has the following structure:

[0004] As one of the effective alkaloid components in the traditional Chinese medicine Corydalis yanhusuo, the natural content of corydalis yanhusuo is extremely small, which limits its application in the pharmaceutical field. Therefore, there is an urgent need to develop other active compounds based on the structure of corydalis yanhusuo.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a compound based on the structure of corydaline, which has a good analgesic effect and can be used to prepare analgesic drugs.

[0007] In one aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0008] Wherein, L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-;

[0009] L2 is selected from a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 1-6 Alkylene), C 3-10Cycloalkylene (preferably C 3-8 Cycloalkylene, more preferably C 3-6 Cycloalkylene), C 6-30 Arylene (preferably C 6-18 Arylene, more preferably C 6-12 Arylene), C 3-30 Heteroarylene (preferably C 3-18 Heteroarylene, more preferably C 3-12 Heteroarylene), -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-), -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 Heteroarylene-O-)-C(O)-C 1-18 Alkyl-, C 1-30 Alkoxy or -X1-PRa(O)-X2-; said Ra are each independently selected from hydrogen, hydroxyl, halogen (preferably F, Cl or Br), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), C 1-30 Hydrocarbyl (preferably C 1-30 Alkyl, more preferably C 1-18 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 1-30 Alkoxy (preferably C 1-18 Alkoxy, more preferably C 1-6 Alkoxy), C 6-30 Aryl-O-(preferably C 6-18 Aryl-O-, more preferably C 6-12 Aryl-O-), C 3-30 Heteroaryl-O-(preferably C 3-18 Heteroaryl-O-, more preferably C 3-12 Heteroaryl-O-), C 6-30 Aryl-C 1-18 Alkylene-O-(preferably C6-18 Aryl-C 1-12 Alkylene-O-, more preferably C 6-12 Aryl-C 1-6 Alkylene-O-), C 3-30 Heteroaryl-C 1-18 Alkylene-O-(preferably C 3-18 Heteroaryl-C 1-12 Alkylene-O-, more preferably C 3-12 Heteroaryl-C 1-6 Alkylene-O-), -OC 6-30 Aryl-C 1-18 Alkylene-(preferably -OC 6-18 Aryl-C 1-12 Alkylene-) or -OC 3-30 Heteroaryl-C 1-18 Alkylene-(preferably -OC 3-18 Heteroaryl-C 1-12 Alkylene-); said Ra and X2 can be connected to form a ring;

[0010] The X1 is selected from a single bond, -O-, -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-) or -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 heteroarylene-O-);

[0011] The X2 is selected from a single bond, -O-- or -NR*-; wherein R* is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy;

[0012] R 1 is absent or is selected from hydrogen, hydroxyl, amine which is not substituted or substituted by Rb, C which is not substituted or substituted by Rb 1-30 Hydrocarbyl (preferably C 1-30 Alkyl or C 2-30 Alkenyl, more preferably C 1-18 Alkyl or C 2-18 Alkenyl, more preferably C 1-6 Alkyl or C 2-12 Alkenyl, the number of double bonds in the alkenyl is 1-10, preferably 1-6), unsubstituted or substituted C 3-10Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 cycloalkyl), unsubstituted or substituted C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 alkoxy), unsubstituted or Rb-substituted C 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 tetra-fused ring group), unsubstituted or C substituted with Rc on the hydrogen atom of the alkyl group 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-(preferably C 1-12 Alkyl-C 6-18 Arylene-C 1-12 Alkyl-), unsubstituted or C 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-(preferably C 6-18 Aryl-C 1-12 Alkylene-), -OC(O)-Y1, unsubstituted or -C in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ;

[0013] where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl,

[0014] -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0015] R 2is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-;

[0016] The Rb are each independently selected from C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl) or C 1-30 Alkyl (preferably C 1-18 Alkyl, more preferably C 1-6 alkyl);

[0017] The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, more preferably cyclopentyl);

[0018] The Rd are each independently selected from C which is unsubstituted or substituted by halogen (preferably F, Cl or Br). 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl);

[0019] Said Y1 is selected from C 1-30 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C3-6 Cycloalkyl), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl); each of Re is independently selected from C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl);

[0020] Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 The Rf are each independently selected from C unsubstituted or substituted by halogen (preferably F, Cl or Br) 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 aryl);

[0021] Said Y3 is selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -OC 1-18 Alkyl (preferably -OC 1-12 Alkyl, more preferably -OC 1-6 alkyl);

[0022] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), each of the Rg groups is independently selected from hydroxyl or C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C1-12 Alkoxy, more preferably C 1-3 alkoxy);

[0023] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 3-6 alkylene);

[0024] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number in the range of 2-20 (preferably any natural number in the range of 2-10);

[0025] Said Y7 is selected from amino, C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy) or hydroxyl;

[0026] When both L1 and L2 are selected from single bonds, R 1 Not hydroxyl group;

[0027] U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O- or -O-; preferably -O-; or the available ring atoms on U2 and the available ring atoms on U3 are connected through a Z group to form a 4-8 membered ring, preferably a 5-6 membered ring,

[0028] Z is selected from: single bond; NR 3 ; C 1-3 Alkylene, wherein 1 or 2 CH2 are optionally independently selected from O, S and NR 3 and C 2-3 Alkenylene, wherein any CH forming a C=C double bond is optionally replaced by N;

[0029] W1, W2 and W3 are each independently selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -(OC 2-6 alkylene) p (Preferably -(OC 2-4 alkylene) p , more preferably -(O-CH2-CH2) p ), wherein p is selected from any natural number between 1 and 18 (preferably any natural number between 1 and 10).

[0030] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted at each occurrence with 1, 2, 3 or more R 3 Substituted, wherein the R 3 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl; and wherein with respect to the substituent R 3 The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by 1, 2, 3 or more substituents independently selected from the following: halogen, OH, oxo, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl.

[0031] In the present invention, the number of substituents such as Ra, Rb, Rc, Rd, Re, Rf, Rg, methoxy, halogen, amino, etc. can be one or more, and the present invention does not limit this.

[0032] In some embodiments of the present invention, in the compound of formula I, the heteroaryl group, the heteroarylene group, the C containing at least one heteroatom 12-17 The heteroatoms in the fused ring group are each independently selected from O, N or S, preferably N;

[0033] Preferably, the heteroaryl group, the heteroarylene group, the C 12-17 The number of heteroatoms in the fused ring group is 1-3, preferably 1-2;

[0034] Preferably, the C containing at least one heteroatom 12-17 The four fused ring groups are

[0035] In a second aspect, the present invention provides a composition comprising the aforementioned compound or its stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs.

[0036] In a third aspect, the present invention provides the use of the aforementioned compound or its stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs, or the aforementioned compositions in the preparation of drugs for preventing and / or treating central nervous system-related diseases.

[0037] In a fourth aspect, the present invention provides the use of the aforementioned compound or its stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs, or the composition of claim 42 in the preparation of drugs for analgesia, antidepression or anti-addiction.

[0038] In some preferred embodiments of the present invention, the drug is used for pain caused by postoperative trauma, postoperative incision or cancer organ metastasis.

[0039] In a fifth aspect, the present invention provides a method for analgesia, antidepression or anti-drug addiction, which comprises administering to a subject in need thereof an effective dose of the aforementioned compound or its stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs or the aforementioned compositions, wherein the administration is carried out orally, rectally, nasally, topically or parenterally.

[0040] definition

[0041] Chemical definition

[0042] Definitions of specific functional groups and chemical terms are described in more detail below.

[0043] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes 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.

[0044] “C 1-30"Hydrocarbon" refers to a group containing only carbon and hydrogen atoms, which can be saturated or unsaturated. For example, "C 1-30 Alkyl", "C 2-30 Alkenyl" and "C 2-30 Alkynyl".

[0045] “C 1-30 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 30 carbon atoms. In some embodiments, C 1-18 Alkyl and C 1-12 Alkyl is preferred. In some embodiments, C 1-6 Alkyl and C 1-4 Alkyl is more preferred. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are more preferred. 1-6 Examples 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 1-6 "Alkyl" also includes heteroalkyl groups 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 alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0046] “C 2-30 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 30 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-18 Alkenyl and C 2-12 Alkenyl is preferred. In some embodiments, C 2-6 Alkenyl, C 2-4 Alkenyl and C 2-3 Alkenyl is more preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6"Alkenyl" also includes heteroalkenyl groups 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). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0047] “C 2-30 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 30 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-18 Alkynyl and C 2-12 Alkynyl is preferred. In some embodiments, C 2-6 Alkynyl and C 2-4 Alkynyl is more preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups 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). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] “C 1-30 Alkylene", "C 2-30 Alkenylene" and "C 2-30 "Alkynylidene" refers to the group with the C 1-30 Alkyl, C 2-30 Alkenyl and C 2-30 In some embodiments, C 2-8 Alkylene, C 3-7 Alkylene, C 1-6 Alkylene, C 4-6 Alkylene, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. In some embodiments, C 2-18 Alkenylene, C 2-12 Alkenylene, C 2-6 Alkenylene, C 2-4 Alkenylene is preferred. In some embodiments, C 2-18 Alkynylidene, C 2-12 Alkynylidene, C 2-6 Alkynylidene, C 2-4Alkyne is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes 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-), and the like.

[0049] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0050] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] “C 1-30 "Alkoxy" refers to an -OR group, wherein R is a C 1-30 In some embodiments, C 1-18 Alkoxy, C 1-12 Alkoxy is preferred. In some embodiments, C 1-6 Alkoxy, C 1-4 Alkoxy groups are more preferred.

[0052] “C 1-30 "Alkyleneoxy" refers to the removal of "C 1-30The divalent group is formed by the other hydrogen of the "alkoxy" and may be substituted or unsubstituted. In some embodiments, C 1-18 Alkyleneoxy, C 1-12 Alkyleneoxy is preferred. In some embodiments, C 1-6 Alkyleneoxy, C 1-4 Alkyleneoxy groups are more preferred.

[0053] “C 1-6 "Haloalkoxy" refers to the above-mentioned "C 1-6 Alkoxy", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Haloalkoxy is particularly preferred, more preferably C 1-2 Halogenated alkoxy. Exemplary haloalkoxy groups include, but are not limited to, -OCF3, -OCH2F, -OCHF2, -OCHFCH2F, -OCH2CHF2, -OCF2CF3, -OCCl3, -OCH2Cl, -OCHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, and the like. The haloalkoxy group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0054] “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 3-8 Cycloalkyl, C 3-7 Cycloalkyl and C 3-5 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls 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), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0055] "3-10 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 4- to 8-membered heterocyclyl groups are preferred, which are 4- to 8-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; in other embodiments, 4- to 7-membered heterocyclyl groups are preferred, which are 4- to 7-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; and more preferably 5- to 6-membered heterocyclyl groups are 5- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiidine. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, 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 thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.Heterocyclyl also includes the above-mentioned heterocyclyl and a cycloalkyl, heterocyclyl, aryl or heteroaryl group sharing one or two atoms to form a bridged ring or spirocycle. As long as the valence permits, the shared atom can be a carbon or nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups that may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0056] “C 6-30 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-30 ring carbon atoms and zero heteroatoms. In some embodiments, C 6-18 Aryl, C 6-12 Aryl is preferred, C 6-10 Aryl is more preferred. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0057] “C 3-30 "Heteroaryl" refers to a monocyclic or bicyclic 4n+2 aromatic ring system (for example, having 6 or 10 π electrons shared in a cyclic arrangement) containing 3-30 ring carbon atoms and at least one ring heteroatom, and "5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system containing ring carbon atoms and 1-5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, C 3-18 Heteroaryl, C 3-12 Heteroaryl is preferred, C 3-10 Heteroaryl and C 3-6Heteroaryl is more preferred. Exemplary 5-membered heteroaryl groups containing one heteroatom (i.e., C4 heteroaryl) include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms (i.e., C3 heteroaryl) include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms (i.e., C2 heteroaryl) include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms (i.e., C1 heteroaryl) include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom (i.e., C5 heteroaryl) 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 tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom (i.e., C6 heteroaryl groups) include, but are not limited to, azacycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0058] “C 3-10 Cycloalkylene", "3-10 membered heterocyclylene", "C 6-30 Arylene" and "C 3-30 "Heteroarylene" refers to a group with the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-30 Aryl and C 3-30 The other hydrogen atom of the heteroaryl group forms a divalent group, and may be substituted or unsubstituted.

[0059] The cycloalkyl, heterocyclyl, aryl and heteroaryl groups defined above that form a ring are collectively referred to as "cyclic groups".

[0060] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0061] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa 、-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)SRaa 、-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, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0062] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R 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 replace;

[0063] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two Raa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0064] R bb Each of the following 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, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0065] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0066] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(Rff )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 、-OCO2R ee 、-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)(ORee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0067] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0068] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0069] R gg Each of the independently: 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), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6alkyl), -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 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -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), -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, -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 1-6Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0070] Exemplary substituents on nitrogen atoms include, but are not limited to, 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 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, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0071] Other definitions

[0072] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0074] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0075] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0076] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. 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, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0077] A "subject in need" of administration includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," "subject in need," and "subject" are used interchangeably herein.

[0078] "Disease," "disorder," and "condition" are used interchangeably herein.

[0079] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0080] Generally, an "effective dose" or "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0081] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a 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 an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0082] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0083] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0084] As used herein, the term "compound of the present invention" refers to the following compounds of formula (A) or formula (I) (including sub-formulas), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, or prodrugs thereof.

[0085] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0086] In some embodiments, the present invention relates to a compound of formula A, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0087] in,

[0088] * indicates a chiral center, selected from (S) configuration or (R) configuration;

[0089] L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-;

[0090] L2 is selected from a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, -C(O)NH-, -OC(O-

[0091] C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 1-6 alkylene),

[0092] C 3-10 Cycloalkylene (preferably C 3-8 Cycloalkylene, more preferably C 3-6 Cycloalkylene),

[0093] C 6-30 Arylene (preferably C 6-18 Arylene, more preferably C 6-12 arylene),

[0094] C 3-30 Heteroarylene (preferably C 3-18 Heteroarylene, more preferably C 3-12 Heteroarylene),

[0095] -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-),

[0096] -C 6-30Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-),

[0097] -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 Heteroarylene-O-),

[0098] -C(O)-C 1-18 Alkylene-,

[0099] -C(O)-C 1-18 Alkylene-NHC(O)-C 1-18 Alkylene-,

[0100] -C(O)-C 1-18 Alkylene-C(O)NH-C 1-18 Alkylene-,

[0101] C 1-30 Alkyleneoxy or

[0102] -X1-PRa(O)-X2-; the Ra are each independently selected from hydrogen, hydroxyl, halogen (preferably F, Cl or Br), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), C 1-30 Hydrocarbyl (preferably C 1-30 Alkyl, more preferably C 1-18 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 1-30 Alkoxy (preferably C 1-18 Alkoxy, more preferably C 1-6 Alkoxy), C 6-30 Aryl-O-(preferably C 6-18 Aryl-O-, more preferably C 6-12 Aryl-O-), C 3-30 Heteroaryl-O-(preferably C 3-18 Heteroaryl-O-, more preferably C 3-12 Heteroaryl-O-), C 6-30 Aryl-C 1-18 Alkylene-O-(preferably C6-18 Aryl-C 1-12 Alkylene-O-, more preferably C 6-12 Aryl-C 1-6 Alkylene-O-), C 3-30 Heteroaryl-C 1-18 Alkylene-O-(preferably C 3-18 Heteroaryl-C 1-12 Alkylene-O-, more preferably C 3-12 Heteroaryl-C 1-6 Alkylene-O-), -OC 6-30 Aryl-C 1-18 Alkylene-(preferably -OC 6-18 Aryl-C 1-12 Alkylene-) or -OC 3-30 Heteroaryl-C 1-18 Alkylene-(preferably -OC 3-18 Heteroaryl-C 1-12 Alkylene-); said Ra and X2 can be connected to form a ring;

[0103] The X1 is selected from a single bond, -O-, -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-) or -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 heteroarylene-O-);

[0104] The X2 is selected from a single bond, -O- or -NR*-; wherein R* is selected from H, C 1-6 Alkyl, C 1-6 alkoxy;

[0105] The L2 is optionally replaced by 1, 2, 3, 4 or 5 selected from halogen, OH, CN, C(O)OH, C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Substitution of haloalkoxy substituents;

[0106] R 1 is selected from the group consisting of: hydrogen, hydroxy, amine which is not substituted or substituted with 1 or 2 Rb, C which is not substituted or substituted with Rb 1-30Hydrocarbyl (preferably C 1-30 Alkyl or C 2-30 Alkenyl, more preferably C 1-18 Alkyl or C 2-18 Alkenyl, more preferably C 1-6 Alkyl or C 2-12 alkenyl, the number of double bonds in the alkenyl is 1-10, preferably 1-6), unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 cycloalkyl), unsubstituted or substituted C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 alkoxy), unsubstituted or substituted by 1, 2, 3, 4 or 5 Rb 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 tetra-fused ring group), unsubstituted or C substituted with Rc on the hydrogen atom of the alkyl group 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-(preferably C 1-12 Alkyl-C 6-18 Arylene-C 1-12 Alkylene-), unsubstituted or C substituted with Rd as the hydrogen atom on the alkyl group 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-(preferably C 6-18 Aryl-C 1-12 Alkylene-), -OC(O)-Y1, unsubstituted or -C in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## , -ZC optionally substituted by x A 6-30 Aryl (preferably -ZC 6-18 Aryl, more preferably -ZC 6-12 aryl, such as -Z-phenyl); wherein R # and R ##Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl,

[0107] -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0108] R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-;

[0109] The Rb are each independently selected from C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl) or C 1-30 Alkyl (preferably C 1-18 Alkyl, more preferably C 1-6 alkyl);

[0110] The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, more preferably cyclopentyl);

[0111] The Rd are each independently selected from C which is unsubstituted or substituted by halogen (preferably F, Cl or Br). 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl);

[0112] Said Y1 is selected from C 1-30 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl); each of Re is independently selected from C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl);

[0113] Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 The Rf are each independently selected from C unsubstituted or substituted by halogen (preferably F, Cl or Br) 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 aryl);

[0114] Said Y3 is selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -OC 1-18 Alkyl (preferably -OC 1-12Alkyl, more preferably -OC 1-6 alkyl);

[0115] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), each of the Rg groups is independently selected from hydroxyl or C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy);

[0116] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 3-6 alkylene);

[0117] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number in the range of 2-20 (preferably any natural number in the range of 2-10);

[0118] Said Y7 is selected from amino, C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy) or hydroxyl;

[0119] x is selected from 0, 1, 2, 3, 4 or 5;

[0120] Z is selected from chemical bonds, -O-, -NH-, -C 1-12 Alkylene-, -C 1-12 Alkylene-OC 1-12 Alkylene-, -C 1-12 Alkylene-NH-C 1-12 Alkylene-, -C 1-18 Alkylene-C(O)-C 1-12 Alkylene-, -C 1-10 Alkylene-C(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)-C 1-10 Alkylene-, -C 1-10Alkylene-NHC(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-C(O)NH-C 1-10 Alkylene- or -C 1-10 Alkylene-OC(O)NH-C 1-10 Alkylene-, preferably a chemical bond or -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-;

[0121] The Z is optionally replaced by 1, 2, 3, 4 or 5 selected from halogen, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups;

[0122] A is independently selected from H, halogen, OH, -L A -C 3-10 Cycloalkyl, -L A -3-10 membered heterocyclic group, -L A -C 6-12 Aryl or -L A -5-12 membered heteroaryl, preferably halogen, C 6-10 Aryl or -NH-C 6-10 aryl;

[0123] L A is selected from a chemical bond, -NH-, -O-, -C(O)-, -C(O)O-, -NHC(O)-, -NHC(O)O-, -OC(O)NH- or -C(O)NH-;

[0124] Said A is optionally further replaced by halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0125] When both L1 and L2 are selected from single bonds, R 1 Not hydroxyl group;

[0126] U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O-, -O-, or the available ring atoms on U2 and the available ring atoms on U3 are connected through a Q group to form a 4-8 membered ring, preferably a 5-6 membered ring,

[0127] Q is selected from: single bond; NR 3 ; C 1-3 Alkylene, wherein 1 or 2 CH2 are optionally independently selected from O, S and NR3 and C 2-3 Alkenylene, wherein any CH forming a C=C double bond is optionally replaced by N;

[0128] W1, W2 and W3 are each independently selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -(OC 2-6 alkylene) p (Preferably -(OC 2-4 alkylene) p , more preferably -(O-CH2-CH2) p ), wherein p is selected from any natural number between 1 and 18, and preferably any natural number between 1 and 10;

[0129] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted at each occurrence with 1, 2, 3 or more R 3 Substituted, wherein the R 3 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl; and wherein with respect to the substituent R 3 The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by 1, 2, 3 or more substituents independently selected from the following: halogen, OH, oxo, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl.

[0130] In some embodiments, the present invention relates to compounds of formula A-1, A-2, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof:

[0131] Wherein, each variable is as defined herein.

[0132] L1

[0133] In one embodiment, L1 is a single bond; in another embodiment, L1 is -O-; in another embodiment, L1 is -NH-; in another embodiment, L1 is -S-; in another embodiment, L1 is -P(O)OH-.

[0134] L2

[0135] In one embodiment, L2 is a single bond; in another embodiment, L2 is -O-; in another embodiment, L2 is -NH-; in another embodiment, L2 is -C(O)-; in another embodiment, L2 is -C(O)-O-; in another embodiment, L2 is -C(O)NH-; in another embodiment, L2 is -OC(O)-; in another embodiment, L2 is C 1-18 Alkylene; in another embodiment, L2 is C 1-12 Alkylene; in another embodiment, L2 is C 1-6 Alkylene; in another embodiment, L2 is C 3-10 In another embodiment, L2 is C 3-8 In another embodiment, L2 is C 3-6 In another embodiment, L2 is C 6-30 Arylene; in another embodiment, L2 is C 6-18 Arylene; in another embodiment, L2 is C 6-12 Arylene; in another embodiment, L2 is C 3-30 Heteroarylene; In another embodiment, L2 is C 3-18 Heteroarylene; In another embodiment, L2 is C 3-12 Heteroarylene; In another embodiment, L2 is -C 1-18 Alkylene-O-; in another embodiment, L2 is -C 1-12 Alkylene-O-; in another embodiment, L2 is -C 1-6 Alkylene-O-; in another embodiment, L2 is -C 6-30 Arylene-O-; in another embodiment, L2 is -C 6-18 Arylene-O-; in another embodiment, L2 is -C 6-12 Arylene-O-; in another embodiment, L2 is -C 3-30 Heteroarylene-O-; In another embodiment, L2 is -C 3-18 Heteroarylene-O; In another embodiment, L2 is -C 3-12 Heteroarylene-O-, such as -C 3-6Heteroarylene-O-; In another embodiment, L2 is -C(O)-C 1-18 Alkylene-; In another embodiment, L2 is -C(O)-C 1-12 Alkylene-; In another embodiment, L2 is -C(O)-C 1-6 Alkylene-; In another embodiment, L2 is -C(O)-C 1-18 Alkylene-NHC(O)-C 1-18 Alkylene-; In another embodiment, L2 is -C(O)-C 1-12 Alkylene-NHC(O)-C 1-12 Alkylene-; In another embodiment, L2 is -C(O)-C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-; In another embodiment, L2 is -C(O)-C 1-18 Alkylene-C(O)NH-C 1-18 Alkylene-; In another embodiment, L2 is -C(O)-C 1-12 Alkylene-C(O)NH-C 1-12 Alkylene-; In another embodiment, L2 is -C(O)-C 1-6 Alkylene-C(O)NH-C 1-6 Alkylene-; In another embodiment, L2 is C 1-30 Alkyleneoxy; in another embodiment, L2 is C 1-18 Alkyleneoxy; in another embodiment, L2 is C 1-12 Alkyleneoxy; in another embodiment, L2 is C 1-6 Alkyleneoxy; in another embodiment, L2 is -X1-PRa(O)-X2-.

[0136] In one embodiment, L2 is unsubstituted; in another embodiment, L2 is optionally substituted with 1, 2, 3, 4 or 5 substituted halogens, OH, CN, C(O)OH, C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The substituents of the haloalkoxy group are substituted.

[0137] In a specific embodiment, L2 is -C 1-12 Alkylene-, the alkylene may be further C 1-6 Alkyl substitution.

[0138] In one specific embodiment, L2 is -CH2-; in another specific embodiment, L2 is -CH(CH3)-; in another specific embodiment, L2 is

[0139] L3

[0140] In one embodiment, L3 is a chemical bond; in another embodiment, L3 is C 1-12 Alkylene; in another embodiment, L3 is -C 1-6 -alkylene-; in another embodiment, L3 is -CH2-; in another embodiment, L3 is -CH2CH2CH2-; in another embodiment, L3 is -CH2CH2CH2CH2CH2CH2-.

[0141] X1

[0142] In one embodiment, X1 is a single bond; in another embodiment, X1 is -O-; in another embodiment, X1 is -C 1-18 Alkylene-O-, preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-; in another embodiment, X1 is -C 6-30 Arylene-O-, preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-; In another embodiment, X1 is -C 3-30 Heteroarylene-O-, preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 Heteroarylene-O-.

[0143] X2

[0144] In one embodiment, X2 is a single bond; in another embodiment, X2 is -O-; in another embodiment, X2 is -NR*-.

[0145] In one embodiment, R* is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy.

[0146] Ra

[0147] In one embodiment, Ra is hydrogen; in another embodiment, Ra is hydroxy; in another embodiment, Ra is halogen, preferably F, Cl or Br; in another embodiment, Ra is C 6-30 Aryl, preferably C 6-18 Aryl, more preferably C 6-12Aryl; In another embodiment, Ra is C 3-30 Heteroaryl, preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl; in another embodiment, Ra is C 1-30 Hydrocarbyl, preferably C 1-30 Alkyl, more preferably C 1-18 Alkyl, more preferably C 1-6 Alkyl, such as methyl or ethyl; in another embodiment, Ra is C 3-10 Cycloalkyl, preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl; in another embodiment, Ra is C 1-30 Alkoxy, preferably C 1-18 Alkoxy, more preferably C 1-6 Alkoxy; in another embodiment, Ra is C 6-30 Aryl-O-, preferably C 6-18 Aryl-O-, more preferably C 6-12 Aryl-O-; in another embodiment, Ra is C 3-30 Heteroaryl-O-, preferably C 3-18 Heteroaryl-O-, more preferably C 3-12 heteroaryl-O-; in another embodiment, Ra is C 6-30 Aryl-C 1-18 Alkylene-O-, preferably C 6-18 Aryl-C 1-12 Alkylene-O-, more preferably C 6-12 Aryl-C 1-6 Alkylene-O-; in another embodiment, Ra is C 3-30 Heteroaryl-C 1-18 Alkylene-O-, preferably C 3-18 Heteroaryl-C 1-12 Alkylene-O-, more preferably C 3-12 Heteroaryl-C 1-6 Alkylene-O-; in another embodiment, Ra is -OC 6-30 Aryl-C 1-18 Alkylene-, preferably -OC 6-18 Aryl-C 1-12 Alkylene-; in another embodiment, Ra is -OC 3-30 Heteroaryl-C 1-18 Alkylene-, preferably -OC 3-18 Heteroaryl-C 1-12 Alkylene-; In another embodiment, Ra is said Ra and X2 can be connected to form a ring.

[0148] R 1

[0149] In one embodiment, R 1 Not present; in another embodiment, R 1 is hydrogen; in another embodiment, R 1 is hydroxy; in another embodiment, R 1 is an amino group which is unsubstituted or substituted with 1 or 2 Rb; in another embodiment, R 1 C is unsubstituted or substituted with Rb 1-30 In another embodiment, R 1 C 1-30 Alkyl or C 2-30 alkenyl; in another embodiment, R 1 C 1-18 Alkyl or C 2-18 alkenyl; in another embodiment, R 1 C 1-6 Alkyl or C 2-12 alkenyl, the number of double bonds in the alkenyl is 1-10, preferably 1-6; in another embodiment, R 1 C is unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb 3-10 Cycloalkyl, preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl; in another embodiment, R 1 C is unsubstituted or substituted with Rb 1-30 Alkoxy, preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy; in another embodiment, R 1 C is unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb 12-30 Condensed ring group, preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 Four fused ring groups, such as In another embodiment, R 1 Cyclopentanone-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-; in another embodiment, R 1 Cyclopentanol-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-; in another embodiment, R 1C is unsubstituted or the hydrogen atom on the alkyl group is replaced by Rc 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-, preferably C 1-12 Alkyl-C 6-18 Arylene-C 1-12 Alkylene-; in another embodiment, R 1 is unsubstituted or the hydrogen atom on the alkyl group is replaced by Rd 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-; in another embodiment, R 1 C 6-30 Aryl-C 1-18 Alkylene-, preferably C 6-18 Aryl-C 1-12 Alkylene-; in another embodiment, R 1 is -OC(O)-Y1; in another embodiment, R 1 -C is unsubstituted or the hydrogen atom on the alkylene group is replaced by Rd 1-12 Alkylene-C(O)-O-Y2; in another embodiment, R 1 -OC is unsubstituted or the hydrogen atom on the alkylene group is replaced by Rd 1-12 Alkylene-OC(O)-Y3; in another embodiment, R 1 is -C=CH-Y4; in another embodiment, R 1 is -Y5-Y6-Y7; in another embodiment, R 1 -CHR # R ## In another embodiment, R 1 is -ZC optionally substituted by x A 6-30 Aryl, preferably -ZC 6-18 Aryl, more preferably -ZC 6-12 Aryl, for example -Z-phenyl.

[0150] Among them, R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0151] In one embodiment, when L1 and L2 are both single bonds, R 1 Not a hydroxyl group.

[0152] In a specific embodiment, R 1 is H; in another specific embodiment, R 1 is -OH; in another specific embodiment, R 1 is -NH2; in another specific embodiment, R 1 is -OCH3; in another specific embodiment, R 1 is methyl; in another specific embodiment, R 1 is ethyl; in another specific embodiment, R 1 isopropyl; in another specific embodiment, R 1 is cyclopropyl; in another specific embodiment, R 1 -(CH2) p CH3; In another specific embodiment, R 1 -(CH2) p OCH3; In another specific embodiment, R 1 -(CH2) p NH2; In another specific embodiment, R 1 -(CH2) p OH; In another specific embodiment, R 1 is -(OCH2CH2)qCH3; in another specific embodiment, R 1 is -(OCH2CH2)qOCH3; in another specific embodiment, R 1 is -(OCH2CH2)qOH; in another specific embodiment, R 1 is -(OCH2CH2)qNH2; in another specific embodiment, R 1 is phenyl; in another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for (like ); In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for (like ); In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 is -CH2-phenyl; in another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 is C7 alkyl; in another specific embodiment, R 1 is C8 alkyl; in another specific embodiment, R 1 is C9 alkyl; in another specific embodiment, R 1 C 10 Alkyl; in another specific embodiment, R 1 C 11 Alkyl; in another specific embodiment, R 1 C 12 Alkyl; in another specific embodiment, R 1 C 13 Alkyl; in another specific embodiment, R 1 C 14 Alkyl; in another specific embodiment, R 1 C 15 Alkyl; in another specific embodiment, R 1 C 16 Alkyl; in another specific embodiment, R 1 C 17 Alkyl; in another specific embodiment, R 1 C 18 Alkyl; in another specific embodiment, R 1 C 19 Alkyl; in another specific embodiment, R 1 C 20 Alkyl; in another specific embodiment, R 1 C 21 Alkyl; in another specific embodiment, R 1 C 22 Alkyl; in another specific embodiment, R 1 C 23 Alkyl; in another specific embodiment, R 1 C 24 Alkyl; in another specific embodiment, R 1 C 25 Alkyl; in another specific embodiment, R1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for In another specific embodiment, R 1 for

[0153] R 2

[0154] In one embodiment, R 2 is H; in another embodiment, R 2 is hydroxy; in another embodiment, R 2 is an amino group; in another embodiment, R 2 is halogen; in another embodiment, R 2 is alkyl; in another embodiment, R 2 is cycloalkyl; in another embodiment, R 2 is aryl; in another embodiment, R 2 is heteroaryl; in another embodiment, R 2 C is unsubstituted or substituted with Rb 12-30 In another embodiment, R 2 It is -NHC(NH)NH-.

[0155] Rb

[0156] In one embodiment, Rb is C 1-30Alkoxy; in another embodiment, Rb is C 1-20 Alkoxy; in another embodiment, Rb is C 1-12 Alkoxy; in another embodiment, Rb is C 1-3 Alkoxy; in another embodiment, Rb is C 6-30 Aryl; in another embodiment, Rb is C 6-18 Aryl; in another embodiment, Rb is C 6-12 Aryl; in another embodiment, Rb is C 3-30 Heteroaryl; In another embodiment, Rb is C 3-18 Heteroaryl; In another embodiment, Rb is C 3-12 Heteroaryl; In another embodiment, Rb is C 1-30 Alkyl; in another embodiment, Rb is C 1-18 Alkyl; in another embodiment, Rb is C 1-6 alkyl.

[0157] In one embodiment, Rb is unsubstituted; in another embodiment, Rb is substituted with halogen (preferably F, Cl, or Br).

[0158] Rc

[0159] In one embodiment, Rc is C 3-10 Cycloalkyl; in another embodiment, Rc is C 3-8 Cycloalkyl; in another embodiment, Rc is C 3-6 Cycloalkyl; in another embodiment, Rc is cyclopentyl.

[0160] In one embodiment, Rc is unsubstituted; in another embodiment, Rc is substituted with hydroxy; in another embodiment, Rc is oxo or thio.

[0161] Rd

[0162] In one embodiment, Rd is C 1-18 Alkyl; in another embodiment, Rd is C 1-12 Alkyl; in another embodiment, Rd is C 1-6 Alkyl; in another embodiment, Rd is C 1-30 Alkoxy; in another embodiment, Rd is C 1-20 Alkoxy; in another embodiment, Rd is C 1-12 Alkoxy; in another embodiment, Rd is C 1-3 Alkoxy; in another embodiment, Rd is C 6-30 Aryl; in another embodiment, Rd is C6-18 Aryl; in another embodiment, Rd is C 6-12 Aryl; in another embodiment, Rd is C 3-30 Heteroaryl; In another embodiment, Rd is C 3-18 Heteroaryl; In another embodiment, Rd is C 3-12 Heteroaryl.

[0163] In one embodiment, Rd is unsubstituted; in another embodiment, Rd is substituted with halogen (preferably F, Cl, or Br).

[0164] Y1

[0165] In one embodiment, Y1 is C 1-30 Alkyl; in another embodiment, Y1 is C 1-12 Alkyl; in another embodiment, Y1 is C 1-6 Alkyl; in another embodiment, Y1 is C 3-10 In another embodiment, Y1 is C 3-8 In another embodiment, Y1 is C 3-6 In another embodiment, Y1 is C 6-30 Aryl; In another embodiment, Y1 is C 6-18 Aryl; In another embodiment, Y1 is C 6-12 Aryl; In another embodiment, Y1 is C 3-30 Heteroaryl; In another embodiment, Y1 is C 3-18 Heteroaryl; In another embodiment, Y1 is C 3-12 Heteroaryl.

[0166] In one embodiment, Y1 is unsubstituted; in another embodiment, Y1 is substituted with Re; in another embodiment, Y1 is substituted with C 1-6 Alkyl substitution.

[0167] Re

[0168] In one embodiment, Re is C 6-30 Aryl; in another embodiment, Re is C 6-18 Aryl; in another embodiment, Re is C 6-12 Aryl; in another embodiment, Re is C 3-30 heteroaryl; in another embodiment, Re is C 3-18 heteroaryl; in another embodiment, Re is C 3-12 Heteroaryl.

[0169] In one embodiment, Re is unsubstituted; in another embodiment, Re is substituted with halogen (preferably F, Cl, or Br).

[0170] Y2

[0171] In one embodiment, Y2 is C 12-30 In another embodiment, Y2 is C 12-17 In another embodiment, Y2 is a C containing at least one heteroatom 12-17 In another embodiment, Y2 is a C containing at least one heteroatom 12-17 Four fused ring groups, such as

[0172] In one embodiment, Y2 is unsubstituted; in another embodiment, Y2 is substituted with Rf.

[0173] Rf

[0174] In one embodiment, Rf is C 1-30 Alkoxy; in another embodiment, Rf is C 1-20 Alkoxy; in another embodiment, Rf is C 1-12 Alkoxy; in another embodiment, Rf is C 1-3 Alkoxy; in another embodiment, Rf is C 6-30 In another embodiment, Rf is C 6-18 Aryl; In another embodiment, Rf is C 6-12 Aryl.

[0175] In one embodiment, Rf is unsubstituted; in another embodiment, Rf is substituted with halogen (preferably F, Cl, or Br).

[0176] Y3

[0177] In one embodiment, Y3 is C 1-18 Alkyl; in another embodiment, Y3 is C 1-12 Alkyl; in another embodiment, Y3 is C 1-6 Alkyl; in another embodiment, Y3 is -OC 1-18 Alkyl; in another embodiment, Y3 is -OC 1-12 Alkyl; in another embodiment, Y3 is -OC 1-6 alkyl.

[0178] Y4

[0179] In one embodiment, Y4 is C 6-30 Aryl; In another embodiment, Y4 is C6-18 Aryl; In another embodiment, Y4 is C 6-12 Aryl; In another embodiment, Y4 is C 3-30 Heteroaryl; In another embodiment, Y4 is C 3-18 Heteroaryl; In another embodiment, Y4 is C 3-12 Heteroaryl; In another embodiment, Y4 is C 3-6 Heteroaryl.

[0180] In one embodiment, Y4 is unsubstituted; in another embodiment, Y4 is substituted with Rg.

[0181] Rg

[0182] In one embodiment, Rg is hydroxy; in another embodiment, Rg is C 1-30 Alkoxy; in another embodiment, Rg is C 1-20 Alkoxy; in another embodiment, Rg is C 1-12 Alkoxy; in another embodiment, Rg is C 1-3 Alkoxy.

[0183] Y5

[0184] In one embodiment, Y5 is a single bond; in another embodiment, Y5 is C 1-18 In another embodiment, Y5 is C 1-12 In another embodiment, Y5 is C 3-6 Alkylene.

[0185] Y6

[0186] In one embodiment, Y6 is a single bond; in another embodiment, Y6 is -NH-C(NH)-; in another embodiment, Y6 is -(O-CH2-CH2) m -; In another embodiment, Y6 is -CH2-(O-CH2-CH2) n -.

[0187] m and n are each independently selected from any natural number between 2 and 20, preferably any natural number between 2 and 10.

[0188] Y7

[0189] In one embodiment, Y7 is an amine group; in another embodiment, Y7 is C 1-30 Alkoxy; in another embodiment, Y7 is C 1-20 Alkoxy; in another embodiment, Y7 is C1-12 Alkoxy; in another embodiment, Y7 is C 1-3 Alkoxy; in another embodiment, Y7 is hydroxy.

[0190] Z

[0191] In one embodiment, Z is a chemical bond; in another embodiment, Z is -O-; in another embodiment, Z is -NH-; in another embodiment, Z is C 1-30 Alkylene; in another embodiment, Z is C 1-18 Alkylene; in another embodiment, Z is -C 1-12 Alkylene-; in another embodiment, Z is -C 1-6 Alkylene-; in another embodiment, Z is -C 1-12 Alkylene-OC 1-12 Alkylene-; in another embodiment, Z is -C 1-12 Alkylene-NH-C 1-12 Alkylene-; in another embodiment, Z is -C 1-6 Alkylene-NH-C 1-6 Alkylene-; in another embodiment, Z is -C 1-18 Alkylene-C(O)-C 1-12 Alkylene-; in another embodiment, Z is -C 1-10 Alkylene-C(O)OC 1-10 Alkylene-; in another embodiment, Z is -C 1-10 Alkylene-NHC(O)-C 1-10 Alkylene-; in another embodiment, Z is -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-; in another embodiment, Z is -C 1-4 Alkylene-NHC(O)-C 1-4 Alkylene-; in another embodiment, Z is -C 1-10 Alkylene-NHC(O)OC 1-10 Alkylene-; in another embodiment, Z is -C 1-10 Alkylene-C(O)NH-C 1-10 Alkylene-; in another embodiment, Z is -C 1-6 Alkylene-C(O)NH-C 1-6 Alkylene-; in another embodiment, Z is -C 1-4 Alkylene-C(O)NH-C 1-4 Alkylene-; in another embodiment, Z is -C 1-10 Alkylene-OC(O)NH-C1-10 Alkylene-; in another embodiment, Z is C 3-10 Cycloalkylene; in another embodiment, Z is C 6-30 Arylene; in another embodiment, Z is C 3-30 Heteroarylene; in another embodiment, Z is -C=CH-.

[0192] In one embodiment, Z is unsubstituted; in another embodiment, Z is optionally substituted with 1, 2, 3, 4 or 5 substituted or unsubstituted moieties selected from halogen, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-4 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 The substituents of the haloalkyl group are substituted.

[0193] A

[0194] In one embodiment, A is H; in another embodiment, A is halogen; in another embodiment, A is OH; in another embodiment, A is -L A -C 3-10 Cycloalkyl; in another embodiment, A is -L A -3-10 membered heterocyclyl; in another embodiment, A is -L A -C 6-12 Aryl; in another embodiment, A is -L A -5-12 membered heteroaryl; in another embodiment, A is C 6-10 Aryl; in another embodiment, A is -NH-C 6-10 Aryl; In another embodiment, A is C substituted with Rc 1-18 alkyl.

[0195] In one specific embodiment, A is F; in another specific embodiment, A is OH; in another specific embodiment, A is phenyl; in another specific embodiment, A is In another specific embodiment, A is

[0196] In one embodiment, A is unsubstituted; in another embodiment, A is optionally further substituted with halogen, C 1-6 Alkyl or C 1-6 Haloalkyl substitution.

[0197] B

[0198] In one embodiment, B is H; in another embodiment, B is halogen; in another embodiment, B is OH; in another embodiment, B is -L A -C 3-10 Cycloalkyl; in another embodiment, B is -L A -3-10 membered heterocyclyl; In another embodiment, B is C 6-30 Aryl; in another embodiment, B is -L A -C 6-12 Aryl; in another embodiment, B is -L A -5-12 membered heteroaryl; In another embodiment, B is C 6-10 Aryl; in another embodiment, B is -NH-C 6-10 Aryl.

[0199] B is optionally further substituted with halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0200] x and y

[0201] In one embodiment, x is selected from 0, 1, 2, 3, 4 or 5.

[0202] In one embodiment, y is selected from 0, 1 or 2.

[0203] In one embodiment, x+y is not zero.

[0204] L A

[0205] In one embodiment, L A is a chemical bond; in another embodiment, L A is -NH-; in another embodiment, L A is -O-; in another embodiment, L A is -C(O)-; in another embodiment, L A is -C(O)O-; in another embodiment, L A is -NHC(O)-; in another embodiment, L A is -NHC(O)O-; in another embodiment, L A is -OC(O)NH-; in another embodiment, L A It is -C(O)NH-.

[0206] U1, U2, and U3

[0207] In one embodiment, U1 is -OC(O)-; in another embodiment, U1 is -NH-C(O)-; in another embodiment, U1 is -O-CH2-O-; in another embodiment, U1 is -O-.

[0208] In one embodiment, U2 is -OC(O)-; in another embodiment, U2 is -NH-C(O)-; in another embodiment, U2 is -O-CH2-O-; in another embodiment, U2 is -O-.

[0209] In one embodiment, U3 is -OC(O)-; in another embodiment, U3 is -NH-C(O)-; in another embodiment, U3 is -O-CH2-O-; in another embodiment, U3 is -O-.

[0210] In one embodiment, the available ring atoms on U2 and the available ring atoms on U3 are linked via the Q group to form a 4-8 membered ring, preferably a 5-6 membered ring.

[0211] Q

[0212] In one embodiment, Q is a single bond; in another embodiment, Q is NR 3 In another embodiment, Q is C 1-3 Alkylene, wherein 1 or 2 CH2 are optionally independently selected from O, S and NR 3 In another embodiment, Q is C 2-3 Alkenylene, wherein any CH forming a C=C double bond is optionally replaced by N.

[0213] W1, W2, and W3

[0214] In one embodiment, W1 is C 1-18 Alkyl; in another embodiment, W1 is C 1-12 Alkyl; in another embodiment, W1 is C 1-6 Alkyl; in another embodiment, W1 is C1-4 alkyl, preferably methyl; in another embodiment, W1 is -(OC 2-6 alkylene) p In another embodiment, W1 is -(OC 2-4 alkylene) p In another embodiment, W1 is -(O-CH2-CH2) p .

[0215] p is selected from any natural number between 1 and 18, and preferably any natural number between 1 and 10.

[0216] M1

[0217] In one embodiment, M1 is a single bond; in another embodiment, M1 is -C(O)-.

[0218] M4

[0219] In one embodiment, M4 is a chemical bond; in another embodiment, M4 is -O-; in another embodiment, M4 is -NH-; in another embodiment, M4 is -C(O)-; in another embodiment, M4 is -C(O)O-, -OC(O)-; in another embodiment, M4 is -NHC(O)O-; in another embodiment, M4 is -OC(O)NH-; in another embodiment, M4 is -C 1-10 Alkylene-; in another embodiment, M4 is -C 1-6 Alkylene-; in another embodiment, M4 is -C 1-4 Alkylene-.

[0220] Ring G

[0221] In one embodiment, ring G is C 6-12 Aryl; In another embodiment, Ring G is C 6-10 Aryl; in another embodiment, Ring G is phenyl.

[0222] r, t, s, k, m, and n

[0223] In one embodiment, r is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0224] In one embodiment, t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0225] In one embodiment, s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0226] In one embodiment, k is selected from 0, 1, 2, 3, 4 or 5.

[0227] In one embodiment, m is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, preferably 6, 7, 8, 9 or 10, more preferably 7, 8 or 9.

[0228] In one embodiment, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, preferably 6, 7, 8, 9 or 10, more preferably 7, 8 or 9.

[0229] In one embodiment, n is selected from any natural number between 2 and 20, preferably any natural number between 2 and 10.

[0230] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted at each occurrence with 1, 2, 3 or more R 3 replace.

[0231] R 3

[0232] In one embodiment, R 3 is halogen; in another embodiment, R 3 is cyano; in another embodiment, R 3 is nitro; in another embodiment, R 3 C 1-6 Alkyl; in another embodiment, R 3 C 3-10 Cycloalkyl; in another embodiment, R 3 is a 3-10 membered heterocyclyl; in another embodiment, R 3 C 6-10 Aryl; in another embodiment, R 3 is a 5-14 membered heteroaryl; in another embodiment, R 3 C 6-12 Aralkyl.

[0233] In one embodiment, R 3 The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by 1, 2, 3 or more substituents independently selected from the following: halogen, OH, oxo, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl.

[0234] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of L1 can be combined with L2, L3, X1, X2, R 1 -R 3 ,Ra-Rg,Y1-Y7,Z,A,B,x,y,L A, U1-U3, W1-W3, Q, M1, M4, ring G, r, t, s, k, m and n, etc., or any combination thereof. The present invention is intended to include combinations of all these technical solutions, which are not listed one by one due to space limitations.

[0235] In some embodiments, the present invention relates to a compound of Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0236] in,

[0237] L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-;

[0238] L2 is selected from a single bond, -O-, -NH-, -C(O)-, -C(O)-O-,

[0239] C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 1-6 alkylene),

[0240] C 3-10 Cycloalkylene (preferably C 3-8 Cycloalkylene, more preferably C 3-6 Cycloalkylene),

[0241] C 6-30 Arylene (preferably C 6-18 Arylene, more preferably C 6-12 arylene),

[0242] C 3-30 Heteroarylene (preferably C 3-18 Heteroarylene, more preferably C 3-12 Heteroarylene),

[0243] -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-),

[0244] -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-),

[0245] -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C3-12 Heteroarylene-O-),

[0246] -C(O)-C 1-18 alkyl-,

[0247] C 1-30 Alkoxy or

[0248] -X1-PRa(O)-X2-; the Ra are each independently selected from hydrogen, hydroxyl, halogen (preferably F, Cl or Br), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), C 1-30 Hydrocarbyl (preferably C 1-30 Alkyl, more preferably C 1-18 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 1-30 Alkoxy (preferably C 1-18 Alkoxy, more preferably C 1-6 Alkoxy), C 6-30 Aryl-O-(preferably C 6-18 Aryl-O-, more preferably C 6-12 Aryl-O-), C 3-30 Heteroaryl-O-(preferably C 3-18 Heteroaryl-O-, more preferably C 3-12 Heteroaryl-O-), C 6-30 Aryl-C 1-18 Alkylene-O-(preferably C 6-18 Aryl-C 1-12 Alkylene-O-, more preferably C 6-12 Aryl-C 1-6 Alkylene-O-), C 3-30 Heteroaryl-C 1-18 Alkylene-O-(preferably C 3-18 Heteroaryl-C 1-12 Alkylene-O-, more preferably C 3-12 Heteroaryl-C 1-6 Alkylene-O-), -OC 6-30 Aryl-C 1-18 Alkylene-(preferably -OC 6-18 Aryl-C 1-12 Alkylene-) or -OC 3-30Heteroaryl-C 1-18 Alkylene-(preferably -OC 3-18 Heteroaryl-C 1-12 Alkylene-); said Ra and X2 can be connected to form a ring;

[0249] The X1 is selected from a single bond, -O-, -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-) or -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 heteroarylene-O-);

[0250] The X2 is selected from a single bond, -O- or -NR*-; wherein R* is selected from H, C 1-6 Alkyl, C 1-6 alkoxy;

[0251] R 1 is absent or selected from hydrogen, hydroxyl, amine which is not substituted or substituted by Rb, C which is not substituted or substituted by Rb 1-30 Hydrocarbyl (preferably C 1-30 Alkyl or C 2-30 Alkenyl, more preferably C 1-18 Alkyl or C 2-18 Alkenyl, more preferably C 1-6 Alkyl or C 2-12 Alkenyl, the number of double bonds in the alkenyl is 1-10, preferably 1-6), unsubstituted or substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 cycloalkyl), unsubstituted or substituted C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 alkoxy), unsubstituted or Rb-substituted C 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 tetra-fused ring group), unsubstituted or C substituted with Rc on the hydrogen atom of the alkyl group 1-18 Alkyl-C 6-30 Arylene-C 1-18Alkylene-(preferably C 1-12 Alkyl-C 6-18 Arylene-C 1-12 Alkylene-), unsubstituted or C substituted with Rd as the hydrogen atom on the alkyl group 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-(preferably C 6-18 Aryl-C 1-12 Alkylene-), -OC(O)-Y1, unsubstituted or -C in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ;

[0252] where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl,

[0253] -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0254] R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-;

[0255] The Rb are each independently selected from C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12heteroaryl) or C 1-30 Alkyl (preferably C 1-18 Alkyl, more preferably C 1-6 alkyl);

[0256] The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, more preferably cyclopentyl);

[0257] The Rd are each independently selected from C which is unsubstituted or substituted by halogen (preferably F, Cl or Br). 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl);

[0258] Said Y1 is selected from C 1-30 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl); each of Re is independently selected from C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl);

[0259] Said Y2 is selected from C which is unsubstituted or substituted by Rf12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 The Rf are each independently selected from C unsubstituted or substituted by halogen (preferably F, Cl or Br) 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 aryl);

[0260] Said Y3 is selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -OC 1-18 Alkyl (preferably -OC 1-12 Alkyl, more preferably -OC 1-6 alkyl);

[0261] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), each of the Rg groups is independently selected from hydroxyl or C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy);

[0262] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 3-6 alkylene);

[0263] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number in the range of 2-20 (preferably any natural number in the range of 2-10);

[0264] Said Y7 is selected from amino, C1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy) or hydroxyl;

[0265] When both L1 and L2 are selected from single bonds, R 1 Not hydroxyl group;

[0266] U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O-, -O-, or the available ring atoms on U2 and the available ring atoms on U3 are connected through a Q group to form a 4-8 membered ring, preferably a 5-6 membered ring,

[0267] Q is selected from: single bond; NR 3 ; C 1-3 Alkylene, wherein 1 or 2 CH2 are optionally independently selected from O, S and NR 3 and C 2-3 Alkenylene, wherein any CH forming a C=C double bond is optionally replaced by N;

[0268] W1, W2 and W3 are each independently selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -(OC 2-6 alkylene) p (Preferably -(OC 2-4 alkylene) p , more preferably -(O-CH2-CH2) p ), wherein p is selected from any natural number between 1 and 18, and preferably any natural number between 1 and 10;

[0269] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted at each occurrence with 1, 2, 3 or more R 3 Substituted, wherein the R 3 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl; and wherein with respect to the substituent R 3 The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by 1, 2, 3 or more substituents independently selected from the following: halogen, OH, oxo, amino, cyano, nitro, C 1-6Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl.

[0270] In some embodiments of the present invention, the compound is selected from the compound of formula II:

[0271] The L2 is selected from a single bond, -C(O)-, -C(O)-O-, C 1-18 Alkylene, -C 1-18 Alkylene-O-, -C(O)-C 1-18 Alkyl-, C 1-30 Alkoxy or -X1-PRa(O)-X2-; said Ra are each independently selected from hydrogen, hydroxyl, halogen, C 6-30 Aryl, C 3-30 Heteroaryl, C 1-30 Hydrocarbon, C 3-10 Cycloalkyl, C 1-30 Alkoxy, C 6-30 Aryl-O-, C 3-30 Heteroaryl-O-, C 6-30 Aryl-C 1-18 Alkylene-O-, C 3-30 Heteroaryl-C 1-18 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC 3-30 Heteroaryl-C 1-18 Alkylene-; said Ra and X2 can be connected to form a ring;

[0272] The X1 is selected from a single bond or -C 1-18 Alkylene-O-;

[0273] Said X2 is selected from a single bond, -O- or -NR*- (e.g. -NH-);

[0274] The R 1 Selected from hydrogen, hydroxyl, amino, C 1-30 Hydrocarbon, C 1-30 Alkoxy, unsubstituted or Rb-substituted C 12-30 Condensed ring group, unsubstituted or alkyl group with hydrogen atoms replaced by Rc 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-, C 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ;

[0275] where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl,

[0276] -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0277] R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-;

[0278] The Rb are each independently selected from unsubstituted or halogen-substituted C 1-30 Alkoxy, C 6-30 Aryl, C 3-30 Heteroaryl or C 1-30 alkyl;

[0279] The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl;

[0280] Said Y1 is selected from C 1-30 Alkyl, C 3-10 Cycloalkyl, C 6-30 Aryl or C 3-30 Heteroaryl; said Re are each independently selected from unsubstituted or halogen-substituted C 6-30 aryl;

[0281] Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group; the Rf are each independently selected from C 1-30 alkoxy;

[0282] Said Y3 is selected from C 1-18 Alkyl or -OC 1-18alkyl;

[0283] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl or C 3-30 Heteroaryl, said Rg are each independently selected from hydroxyl or C 1-30 alkoxy;

[0284] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 alkylene;

[0285] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 20;

[0286] Said Y7 is selected from amino, C 1-30 Alkoxy or hydroxy.

[0287] In some embodiments of the present invention, the compound is selected from the compound of formula I-1:

[0288] Wherein, L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-;

[0289] The L2 is selected from a single bond, -C(O)-, -C(O)-O-, -C 1-18 Alkylene-, -C 1-18 Alkylene-O-(such as -(CH2) 1-5 -O-), -C(O)-C 1-18 Alkyl-, C 1-30 Alkoxy (such as -(OCH2CH2) 2-8 -) or -X1-PRa(O)-X2-;

[0290] Said Ra are independently selected from hydrogen, hydroxyl, halogen, C 6-30 Aryl, C 3-30 Heteroaryl, C 1-30 Hydrocarbon, C 3-10 Cycloalkyl, C 1-30 Alkoxy, C 6-30 Aryl-O-, C 3-30 Heteroaryl-O-, C 6-30 Aryl-C 1-18 Alkylene-O-, C 3-30 Heteroaryl-C 1-18 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC3-30 Heteroaryl-C 1-18 Alkylene-; wherein the available ring atoms on Ra can be directly connected to X2 to form a 4-7 membered ring, preferably a 5-6 membered ring;

[0291] The X1 is selected from a single bond, -O- or -C 1-18 Alkylene-O-; preferably a single bond, -O-, or -(CH2) 1-3 O- (such as -CH2O-);

[0292] The X2 is selected from a single bond, -O- or -NR*-; wherein R* is selected from H, or C 1-6 Alkyl (such as methyl, ethyl, isopropyl, etc.);

[0293] The R 1 Not present, or selected from hydrogen, hydroxyl, amino, C 1-30 Hydrocarbyl (wherein the C 1-30 The hydrocarbon group contains 0-10 double bonds or triple bonds, preferably 0-6 double bonds or triple bonds), C 1-30 Alkoxy, unsubstituted or Rb-substituted C 12-30 Condensed ring group, unsubstituted or alkyl group with hydrogen atoms replaced by Rc 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-, C 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -CH=CH-Y4 or -Y5-Y6-Y 7、 -CHR # R ## ;

[0294] where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl,

[0295] -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0296] R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-;

[0297] The Rb are each independently selected from unsubstituted or halogen-substituted C 1-30 Alkoxy, C 6-30 Aryl, C 3-30 Heteroaryl or C 1-30 alkyl;

[0298] The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl;

[0299] Said Y1 is selected from C 1-30 Alkyl, C 3-10 Cycloalkyl, C 6-30 Aryl or C 3-30 Heteroaryl; said Re are each independently selected from unsubstituted or halogen-substituted C 6-30 aryl;

[0300] Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group; the Rf are each independently selected from C 1-30 alkoxy;

[0301] Said Y3 is selected from C 1-18 Alkyl or -OC 1-18 alkyl;

[0302] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl or C 3-30 Heteroaryl, said Rg are each independently selected from hydroxyl or C 1-30 alkoxy;

[0303] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 alkylene;

[0304] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 20;

[0305] Said Y7 is selected from amino, C 1-30 Alkoxy or hydroxy.

[0306] In some embodiments of the present invention, in the compound of formula II, L2 is selected from a single bond, -C(O)-, -C(O)-O-, C 1-6 Alkylene, -C 1-6 Alkylene-O- or -X1-PRa(O)-X2-; said Ra are each independently selected from hydrogen, hydroxyl, C 6-12 Aryl-O- or C 6-12 Aryl-C 1-6 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC 3-30 Heteroaryl-C 1-18 Alkylene-; said Ra and X2 can be connected to form a ring;

[0307] The X1 is selected from a single bond or -C 1-6 Alkylene-O-;

[0308] Said X2 is selected from a single bond, -O-, -NH-;

[0309] The R 1 Selected from absent, hydrogen, hydroxyl, amine, C 1-30 Alkyl, C 1-30 Alkoxy, unsubstituted or methoxy-substituted C containing at least one heteroatom 12-17 Tetra-fused ring, cyclopentanone-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-, cyclopentanol-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-, C 1-6 Alkyl-OC(O)-C 1-6 Alkylene-imino-, C 6-12 Aryl-C 1-6 Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y 7、 -CHR # R ## ;

[0310] where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl,

[0311] -C(O)-OR 2 、-OC(O)-OR 2 、-C1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl;

[0312] R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-;

[0313] Said Y1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-12 Aryl; said Re are each independently selected from unsubstituted or halogen-substituted C 6-12 aryl;

[0314] Said Y3 is selected from C 1-6 Alkyl or -OC 1-6 alkyl;

[0315] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-12 Aryl, said Rg are each independently selected from hydroxyl or methoxy;

[0316] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-6 alkylene;

[0317] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 10;

[0318] Said Y7 is selected from amino, C 1-6 Alkoxy or hydroxy.

[0319] In some embodiments, the R 1 Selected from absent, hydrogen, hydroxyl, amino, aromatic (such as benzene), C 1-30 Alkyl, C 1-30 Alkoxy (such as -OCH3), unsubstituted or Rb substituted C 12-30 fused ring group, -(CH2) 1-10 -C(O)-OC 12-30 Condensed ring group, -OC(O)-Y1, -C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## , preferably the following structures H, -OH, -NH2, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -(CH2) p CH3, -(CH2) p OCH3, -(CH2) p NH2, -(CH2) p OH, -(OCH2CH2)qCH 3、 -(OCH2CH2)qOCH3, -(OCH2CH2)qOH, -(OCH2CH2)qNH2, phenyl, (like ), (like );

[0320] Where p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;

[0321] q choose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0322] The cyclopentanone group of the present invention refers to The cyclopentanol group of the present invention refers to

[0323] In some embodiments of the present invention, in the compound of formula II, L2 is selected from a single bond, -C(O)-, -C(O)-O-, C 1-6 Alkylene, -C 1-6 Alkylene-O- or -X1-PH(O)-X2-; the hydrogen atoms on the -X1-PH(O)-X2- may be replaced by Ra, wherein Ra are independently selected from hydroxyl, C 6-12 Aryl-O- or C 6-12 Aryl-C 1-6 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC 3-30 Heteroaryl-C 1-18 Alkylene-; said Ra and X2 can be connected to form a ring;

[0324] The X1 is selected from a single bond or -C 1-6 Alkylene-O-;

[0325] Said X2 is selected from a single bond or -O-;

[0326] The R 1 Selected from hydrogen, hydroxyl, amino, C 1-30 Hydrocarbon, C 1-30 Alkoxy, unsubstituted or methoxy-substituted C containing at least one heteroatom 12-17 Tetra-fused ring, cyclopentanone-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-, cyclopentanol-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-, C 1-6 Alkyl-OC(O)-C 1-6 Alkylene-imino-, C 6-12 Aryl-C 1-6 Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7;

[0327] Said Y1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-12 Aryl; said Re are each independently selected from unsubstituted or halogen-substituted C 6-12 aryl;

[0328] Said Y3 is selected from C 1-6 Alkyl or -OC 1-6 alkyl;

[0329] Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-12 Aryl, said Rg are each independently selected from hydroxyl or methoxy;

[0330] The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-6 alkylene;

[0331] The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 10;

[0332] Said Y7 is selected from amino, C 1-6 Alkoxy or hydroxy.

[0333] In some embodiments of the present invention, the compound is selected from the compound of formula III: Wherein, the definitions of each group are as shown in the compound of formula II.

[0334] In some embodiments of the present invention, in the compound of formula III, the Ra are each independently selected from hydroxyl, C 6-12 Aryl-O-, C 6-12 Aryl-C 1-6 Alkylene-O- or -OC 6-12 Aryl-C 1-6 Alkylene-; said Ra and X2 can be connected to form a ring;

[0335] The X1 is selected from a single bond or -C 1-6 Alkylene-O-;

[0336] Said X2 is selected from a single bond, -O-, -NH-;

[0337] The R 1 Selected from absent, hydrogen, hydroxyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkylene-imino-, C 6-12 Aryl-C 1-6 Alkylene- or -OC 1-12 Alkylene-OC(O)-Y3; wherein Y3 is selected from -OC 1-6 alkyl.

[0338] In some embodiments of the present invention, the compound is selected from the group consisting of Formula IVa, Formula IVb, and Formula IVc:

[0339] Wherein, the G ring in formula IVc is C 6-12 Aryl ring; the definitions of each group are as shown in the compound of formula III.

[0340] In some embodiments of the present invention, the compound is selected from compounds of Formula V:

[0341] Wherein, the definitions of each group are as shown in the compound of formula II.

[0342] In some embodiments of the present invention, the compound is selected from the compound of Formula VIa or Formula VIb:

[0343] Wherein, r and t in Formula VIa and Formula VIb are each independently selected from any natural number from 0 to 10, and s is each independently selected from any natural number from 0 to 9 (preferably any natural number from 1 to 6); r, s and t are not 0 at the same time; and the definitions of each group are as shown in the compound of Formula V.

[0344] In some embodiments of the present invention, the compound is selected from the compound of formula VII:

[0345] Wherein, n is selected from any natural number between 2 and 20, preferably any natural number between 2 and 10; and the definitions of each group are as shown in the compound of formula V.

[0346] In some embodiments of the present invention, the compound is selected from the group consisting of compounds of Formula VIII:

[0347] Among them, Z is selected from C 1-30 Alkylene, C 3-10 Cycloalkylene, C 6-30 Arylene, C 3-30 heteroarylene or -C=CH-;

[0348] A is selected from hydroxy, halogen, C 6-30 Aryl or C substituted by Rc 1-18 Alkyl, wherein Rc is independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl;

[0349] B is selected from hydroxy, halogen or C 6-30 aryl;

[0350] x is selected from 0 or 1, y is selected from 0, 1 or 2, and x+y is not 0;

[0351] The definitions of the groups are as shown for the compounds of formula V.

[0352] In some embodiments of the present invention, the compound is selected from the compound of formula IX:

[0353] A is selected from C substituted by Rc 1-18 Alkyl, the Rc are each independently selected from C 3-10 Cycloalkyl;

[0354] B is selected from halogen or C 6-30 aryl;

[0355] x is selected from 1, y is selected from 0 or 1;

[0356] The definitions of the groups are as shown for the compound of formula VIII.

[0357] In some embodiments of the present invention, the compound is selected from compounds of formula X:

[0358] wherein M1 is each independently selected from a single bond or -C(O)-;

[0359] L3 is selected from C 1-12 alkylene;

[0360] The definitions of the groups are as shown for the compounds of formula I.

[0361] In some embodiments of the present invention, the compound is selected from compounds of formula XI:

[0362] Wherein, L3 is selected from C 1-12 alkylene;

[0363] Preferably, U1, U2 and U3 are each independently selected from -O-, and W1, W2 and W3 are each independently selected from methyl.

[0364] In some embodiments of the present invention, the compound is selected from the group consisting of compounds of Formula XII:

[0365] Wherein, the definitions of each group are as shown in the compound of formula I.

[0366] In some embodiments of the present invention, in the compound of formula XII, the L2 is selected from a single bond or -O-; the R 1 is selected from hydrogen, amine or -Y5-Y6-Y7; wherein Y5 is selected from a single bond, unsubstituted or amine-substituted C 3-12 Alkylene.

[0367] In some embodiments of the present invention, the compound is selected from compounds of Formula XIII:

[0368] Preferably, the Y5 is selected from C 3-12 Alkylene, preferably unsubstituted or substituted by amino C 3-6 Alkylene; the definitions of each group are as shown in the compound of formula XII.

[0369] In some embodiments of the present invention, the compound is selected from the group consisting of compounds of Formula XIV:

[0370] Wherein, the definitions of each group are as shown in the compound of formula I.

[0371] In some embodiments of the present invention, in the compound of formula XIV: the L1 is selected from -O- or -NH-; the L2 is selected from -C(O)- or C 1-18 Alkylene; said Y7 is selected from amino, C 1-30 Alkyl, C 1-30 Alkoxy or hydroxy.

[0372] In some embodiments of the present invention, the compound is selected from the compound of Formula XVa or Formula XVb:

[0373] Preferably, Y7 is selected from methoxy or hydroxy; the definitions of each group are as shown in the compound of formula XIV.

[0374] In some embodiments of the present invention, in the compounds of Formula I to Formula XIV, U1, U2 and U3 are each independently selected from -O-;

[0375] W1, W2 and W3 are each independently selected from C 1-18 Alkyl, preferably C 1-12 Alkyl, more preferably C 1-6 The alkyl group is more preferably a methyl group.

[0376] In some embodiments of the present invention, the compound is selected from the group consisting of compounds of formula Ia: Preferred

[0377] or

[0378] Among them, L1, L2, W1, R 1 , R* are as defined in the compound of formula I.

[0379] In some embodiments, the present invention relates to a compound of Formula XVI, XVI-1, XVI-2, XVI-3 or XVI-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0380] in,

[0381] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0382] W1, W2 and W3 are independently selected from C 1-18 alkyl;

[0383] M4 is selected from a chemical bond, -O-, -NH-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)O-, -OC(O)NH- or -C 1-10 Alkylene-.

[0384] In some embodiments, the present invention relates to a compound of the above formula XVI, XVI-1, XVI-2, XVI-3 or XVI-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0385] U1, U2 and U3 are independently selected from -OC(O)- or -O-;

[0386] W1, W2 and W3 are independently selected from C 1-12 Alkyl, preferably C 1-6 alkyl;

[0387] M4 is selected from a chemical bond, -NH-, -C(O)O-, -OC(O)-, -NHC(O)O- or -OC(O)NH-.

[0388] In some embodiments, the present invention relates to the above-mentioned compounds of formula XVI, XVI-1, XVI-2, XVI-3 or XVI-4, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein,

[0389] U1, U2 and U3 are -O-;

[0390] W1, W2 and W3 are independently selected from C 1-6 Alkyl, preferably C1-4 alkyl, more preferably methyl;

[0391] M4 is selected from -NHC(O)O- or -OC(O)NH-.

[0392] In some embodiments, the present invention relates to a compound of Formula VIII, VIII-1 or VIII-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0393] in,

[0394] U1, U2 and U3 are independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O- or -O;

[0395] W1, W2 and W3 are independently selected from C 1-12 alkyl;

[0396] Z is selected from chemical bonds, -O-, -NH-, -C 1-12 Alkylene-, -C 1-12 Alkylene-OC 1-12Alkylene-, -C 1-12 Alkylene-NH-C 1-12 Alkylene-, -C 1-18 Alkylene-C(O)-C 1-12 Alkylene-, -C 1-10 Alkylene-C(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)-C 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-C(O)NH-C 1-10 Alkylene- or -C 1-10 Alkylene-OC(O)NH-C 1-10 Alkylene-, preferably a chemical bond or -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-;

[0397] The Z is optionally replaced by 1, 2, 3, 4 or 5 selected from halogen, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups;

[0398] A and B are independently selected from H, halogen, OH, -L A -C 3-10 Cycloalkyl, -L A -3-10 membered heterocyclic group, -L A -C 6-12 Aryl or -L A -5-12 membered heteroaryl, preferably halogen, C 6-10 Aryl or -NH-C 6-10 aryl;

[0399] L A is selected from a chemical bond, -NH-, -O-, -C(O)-, -C(O)O-, -NHC(O)-, -NHC(O)O-, -OC(O)NH- or -C(O)NH-;

[0400] The A and B are optionally further substituted with halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0401] x is 0, 1, or 2;

[0402] y is 0, 1, 2, or 3.

[0403] In some embodiments, the present invention relates to the above-mentioned compounds of formula VIII, VIII-1 or VIII-2, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0404] U1, U2 and U3 are independently selected from -OC(O)- or -O-;

[0405] W1, W2 and W3 are independently selected from C 1-6 alkyl;

[0406] Z is selected from chemical bonds, -O-, -NH-, -C 1-6 Alkylene-, -C 1-6 Alkylene-C(O)-C 1-6 Alkylene-, -C 1-6 Alkylene-C(O)OC 1-6 Alkylene-, -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-, -C 1-6 Alkylene-C(O)NH-C 1-6 Alkylene-, preferably a chemical bond, -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene- or -C 1-6 Alkylene-C(O)NH-C 1-6 Alkylene-;

[0407] The Z is optionally replaced by 1, 2 or 3 selected from halogen, C(O)OH, C(O)OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups;

[0408] A and B are independently selected from H, halogen, C 6-10 Aryl, -NH-C 6-10 Aryl, -OC 6-10 Aryl, -C(O)-C 6-10 Aryl, -C(O)OC 6-10 Aryl, preferably halogen, C 6-10 Aryl or -NH-C 6-10 aryl;

[0409] The A and B are optionally further substituted with halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution;

[0410] x is 0, 1, or 2;

[0411] y is 0, 1, 2, or 3.

[0412] In some embodiments, the present invention relates to the above-mentioned compounds of formula VIII, VIII-1 or VIII-2, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0413] U1, U2 and U3 are -O-;

[0414] W1, W2 and W3 are independently selected from C1-4 alkyl, preferably methyl;

[0415] Z is selected from chemical bonds, -C 1-4 Alkylene-NHC(O)-C 1-4 Alkylene- or -C 1-4 Alkylene-C(O)NH-C 1-4 Alkylene-, preferably a chemical bond or -C 1-4 Alkylene-NHC(O)-C 1-4 Alkylene-;

[0416] The Z is optionally replaced by 1, 2 or 3 selected from halogen, C(O)OH, C(O)OC 1-4 Alkyl or C 1-4 Alkyl substituent substitution;

[0417] A and B are independently selected from H, halogen, phenyl or -NH-phenyl, preferably F, phenyl or NH-phenyl;

[0418] Said A and B are optionally further substituted by halogen;

[0419] x, y are 0, 1, or 2.

[0420] In some embodiments, the present invention relates to a compound of Formula II, II-1, II-2, Formula I-1, I-2 or Formula I-3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0421] in,

[0422] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0423] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0424] L1 is selected from a single bond, -O- or -NH-;

[0425] L2 is -C 1-12 Alkylene-, the alkylene may be further C 1-6 Alkyl substitution;

[0426] R 1 Selected from -OC(O)-Y1;

[0427] Y1 is selected from C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-18 Aryl or C 3-18 Heteroaryl, said Y1 may be further C 1-6 Alkyl substitution;

[0428] Y1 is preferably C 1-6 Alkyl, more preferably CH3.

[0429] In some embodiments, the present invention relates to compounds of formula II, II-1, II-2, formula I-1, I-2 or formula I-3, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0430] U1, U2, U3 are selected from -O- or -OC(O)-;

[0431] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0432] L1 is selected from -O- or -NH-;

[0433] L2 is -C 1-6 Alkylene-, the alkylene may be further C 1-6 Alkyl substitution;

[0434] R 1 Selected from -OC(O)-Y1;

[0435] Y1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-12 Aryl, said Y1 may be further C 1-6 Alkyl substitution;

[0436] Y1 is preferably CH3.

[0437] In some embodiments, the present invention relates to compounds of formula II, II-1, II-2, formula I-1, I-2 or formula I-3, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0438] U1, U2, and U3 are -O-;

[0439] W1, W2, and W3 are CH3;

[0440] L1 is -O-;

[0441] L2 is -CH2-, -CH(CH3)-,

[0442] R 1 Selected from

[0443] In some embodiments, the present invention relates to a compound of formula III, III-1 or III-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0444] in,

[0445] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0446] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0447] X1 is selected from a chemical bond or -C 1-6 Alkylene-O-;

[0448] X2 is a chemical bond, -O- or -C(O)-;

[0449] R 1 Not present, or selected from H, -NH-C 1-12 Alkylene-C(O)-OC 1-12 Alkyl, -C 1-12 Alkylene-C 6-18 Aryl, -OC 1-12 Alkylene-OC(O)-Y3, wherein R 1 The hydrogen atoms on the alkylene group are optionally substituted by Rd;

[0450] Y3 is -OC 1-6 Alkyl, the C 1-6 The alkyl group may be C1-6 The alkyl group is further substituted;

[0451] Ra is selected from OH, -OC 6-18 Aryl, -OC 1-12 Alkylene-C 6-18 Aryl or -OC 6-18 Aryl-C 1-12 alkyl;

[0452] Alternatively, Ra and X2 are connected to form a ring;

[0453] Rd is selected from C 1-12 Alkyl or C 1-12 Alkoxy.

[0454] In some embodiments, the present invention relates to the above-mentioned compound of formula III, III-1 or III-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0455] U1, U2, U3 are selected from -O- or -OC(O)-;

[0456] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0457] X1 is selected from a chemical bond or -C 1-6 Alkylene-O-;

[0458] X2 is a chemical bond, -O- or -C(O)-;

[0459] R 1 Not present, or selected from H, -NH-C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, -C 1-6 Alkylene-C 6-10 Aryl, -OC 1-6 Alkylene-OC(O)-Y3, wherein R 1 The hydrogen atoms on the alkylene group are optionally substituted by Rd;

[0460] Y3 is -OC 1-6 Alkyl, the C 1-6 The alkyl group may be C 1-6 The alkyl group is further substituted;

[0461] Ra is selected from OH, -OC 6-12 Aryl, -OC 1-6 Alkylene-C 6-12 Aryl or -OC 6-12 Aryl-C 1-6 alkyl;

[0462] Alternatively, Ra and X2 are connected to form a ring;

[0463] Rd is C 1-6 alkyl.

[0464] In some embodiments, the present invention relates to the above-mentioned compound of formula III, III-1 or III-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0465] U1, U2, and U3 are 0;

[0466] W1, W2, and W3 are CH3;

[0467] X1 is selected from a chemical bond or -CH2-O-;

[0468] X2 is a chemical bond or -O-;

[0469] R 1 Not present, or selected from H, -CH2-phenyl or

[0470] Ra is selected from OH, -O-phenyl or -O-CH2-phenyl or -O-phenyl-CH3;

[0471] Alternatively, Ra and X2 are linked to form a ring.

[0472] In some embodiments, the present invention relates to a compound of Formula IVa, IVa-1, IVa-2, IVb, IVb-1, IVb-2, IVc, IVc-1 or IVc-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0473] Among them, ring G is C 6-12 Aryl, preferably C 6-10 Aryl, more preferably phenyl;

[0474] The other variables are as defined above.

[0475] In some embodiments, the present invention relates to a compound of Formula V, V-1 or V-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0476] in,

[0477] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0478] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0479] R 1 Selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 1-20 -OC in which the hydrogen atom on an alkoxy group, an unsubstituted group, or an alkylene group is replaced by Rd 1-12 Alkylene-OC(O)-Y3;

[0480] Rd is selected from C 1-12 alkyl;

[0481] R 1 Preferably C 6-10 Alkyl or C 10-30 alkenyl;

[0482] Y3 is selected from C 1-12 Alkyl or OC 1-12 alkyl.

[0483] In some embodiments, the present invention relates to a compound of formula V, V-1 or V-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0484] U1, U2, U3 are selected from -O- or -OC(O)-;

[0485] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0486] R 1 Selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 1-6 -OC in which the hydrogen atom on an alkoxy group, an unsubstituted group, or an alkylene group is replaced by Rd 1-6 Alkylene-OC(O)-Y3;

[0487] Rd is selected from C 1-6 alkyl;

[0488] R 1 Preferably C 6-10 Alkyl or C 10-30 alkenyl;

[0489] Y3 is C 1-6 alkyl.

[0490] In some embodiments, the present invention relates to a compound of formula V, V-1 or V-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0491] U1, U2, and U3 are 0;

[0492] W1, W2, and W3 are CH3;

[0493] R 1 Selected from CH3, C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 19 Alkyl, C 21 Alkyl, C 23 Alkyl, C 25 alkyl,

[0494] In some embodiments, the present invention relates to a compound of Formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0495] in,

[0496] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0497] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0498] r, t are selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0499] s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0500] k is selected from 0, 1, 2, 3, 4 or 5.

[0501] In some embodiments, the present invention relates to a compound of Formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0502] U1, U2, U3 are selected from -O- or -OC(O)-;

[0503] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0504] r, t are selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0505] s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0506] k is selected from 0, 1, 2 or 3.

[0507] In some embodiments, the present invention relates to a compound of Formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0508] U1, U2, and U3 are 0;

[0509] W1, W2, and W3 are CH3;

[0510] r is 0, 2, 3, 6, or 7;

[0511] s is 1, 2, 4, 5, or 6

[0512] t is 0, 2, 5, 6, or 8

[0513] k is 0 or 1.

[0514] In some embodiments, the present invention relates to a compound of Formula VII, VII-1, VII-2, XIV, XIV-1 or XIV-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0515] in,

[0516] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0517] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0518] m and n are selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, preferably 6, 7, 8, 9 or 10, more preferably 7, 8 or 9;

[0519] L1 is a chemical bond, -O- or -NH-;

[0520] L2 is -C(O)-, -C(O)O-, -C(O)-C 1-18 Alkylene- or -OC 1-18 Alkylene-;

[0521] Y7 is C 1-12 Alkoxy.

[0522] In some embodiments, the present invention relates to a compound of the above formula VII, VII-1, VII-2, XIV, XIV-1 or XIV-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0523] U1, U2, U3 are selected from -O- or -OC(O)-;

[0524] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0525] m, n are selected from 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 7, 8 or 9;

[0526] L1 is -O- or -NH-, preferably -O-;

[0527] L2 is -C(O)-, -C(O)-C 1-6 Alkylene-;

[0528] Y7 is C 1-3 Alkoxy.

[0529] In some embodiments, the present invention relates to a compound of the above formula VII, VII-1, VII-2, XIV, XIV-1 or XIV-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0530] U1, U2, and U3 are 0;

[0531] W1, W2, and W3 are CH3;

[0532] m and n are 3, 4, 5, 6, 7, or 8, preferably 3 or 8;

[0533] L1 is O;

[0534] L2 is -C(O)- or -C(O)-C 1-4 Alkylene-, preferably -C(O)-;

[0535] Y7 is C 1-3 Alkoxy, preferably OCH3.

[0536] In some embodiments, the present invention relates to a compound of Formula VIII, VIII-1 or VIII-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0537] in,

[0538] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0539] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0540] Z is selected from C 1-30 Alkylene or C 2-30 Alkenylene, said Z is optionally replaced by 1, 2 or 3 R 3 replace;

[0541] R 3 C 1-6 alkyl;

[0542] A is selected from halogen, OH, C optionally substituted by Rc 1-18 Alkyl or C 6-30 Aryl, preferably OH, C optionally substituted by Rc 1-18 Alkyl or C 6-30 Aryl, more preferably C 6-30 aryl;

[0543] B is selected from halogen, OH or C 6-30 Aryl, preferably halogen or OH, more preferably halogen;

[0544] Rc is selected from C optionally substituted by OH, oxo or thio 3-10 Cycloalkyl, preferably oxo-substituted C3-10 Cycloalkyl;

[0545] x is 0, 1, or 2;

[0546] y is 0, 1, 2, or 3.

[0547] In some embodiments, the present invention relates to the above-mentioned compounds of formula VIII, VIII-1 or VIII-2, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0548] U1, U2, U3 are selected from -O- or -OC(O)-;

[0549] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0550] Z is selected from C 1-6 Alkylene or C 2-6 Alkenylene, preferably C 1-3 Alkylene; said Z is optionally replaced by 1, 2 or 3 R 3 replace;

[0551] R 3 C 1-6 alkyl;

[0552] A is selected from halogen, OH, C optionally substituted by Rc 1-6 Alkyl or C 6-12 Aryl, preferably OH, C optionally substituted by Rc 1-6 Alkyl or C 6-12 Aryl, more preferably C 6-12 aryl;

[0553] B is selected from halogen, OH or C 6-12 Aryl, preferably halogen or OH, more preferably halogen;

[0554] Rc is selected from C optionally substituted by OH or oxo 3-10 Cycloalkyl;

[0555] x is 0, 1, or 2;

[0556] y is 0, 1, 2, or 3.

[0557] In some embodiments, the present invention relates to the above-mentioned compounds of formula VIII, VIII-1 or VIII-2, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0558] U1, U2, and U3 are 0;

[0559] W1, W2, and W3 are CH3;

[0560] Z is selected from -CH(CH3)-, -CH=CH- or -CH2-CH2-;

[0561] A is selected from F, OH, phenyl, Preferably OH, phenyl, More preferably, it is phenyl;

[0562] B is selected from F, OH or phenyl, preferably F or OH, more preferably F;

[0563] x, y are 0, 1, or 2.

[0564] In some embodiments, the present invention relates to a compound of Formula IX, IX-1 or IX-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0565] in,

[0566] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0567] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0568] A is selected from H or C substituted by Rc 1-18 alkyl;

[0569] B is selected from halogen or C 6-30 Aryl, preferably halogen or C 6-12 aryl;

[0570] Rc is selected from C optionally substituted by OH, oxo or thio 3-10 Cycloalkyl, preferably oxo-substituted C 3-10 Cycloalkyl;

[0571] x is 0, 1, or 2;

[0572] y is 0, 1, 2, or 3.

[0573] In some embodiments, the present invention relates to a compound of Formula IX, IX-1 or IX-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0574] U1, U2, U3 are selected from -O- or -OC(O)-;

[0575] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0576] A is selected from H or C substituted by Rc 1-6 Alkyl, preferably H;

[0577] B is selected from halogen or C 6-10 Aryl, preferably F or phenyl;

[0578] Rc is selected from C substituted by oxo or OH 3-10 Cycloalkyl, preferably oxo-substituted C 3-10 Cycloalkyl;

[0579] x is 0, 1, or 2;

[0580] y is 0, 1, 2, or 3.

[0581] In some embodiments, the present invention relates to a compound of Formula IX, IX-1 or IX-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0582] U1, U2, and U3 are -O-;

[0583] W1, W2, and W3 are CH3;

[0584] A is selected from

[0585] B is selected from F or phenyl;

[0586] x is 0 or 1;

[0587] y is either 0 or 1.

[0588] In some embodiments, the present invention relates to a compound of formula X, X-1, X-2, X-3 or X-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0589] in,

[0590] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0591] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0592] Each M1 is independently a chemical bond or -C(O)-, preferably, both M1 are not chemical bonds;

[0593] L3 is a chemical bond or -C 1-18 -Alkylene-, preferably a chemical bond.

[0594] In some embodiments, the present invention relates to a compound of the above formula X, X-1, X-2, X-3 or X-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0595] U1, U2, U3 are selected from -O- or -OC(O)-;

[0596] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0597] Each M1 is independently a chemical bond or -C(O)-, preferably, both M1 are not chemical bonds;

[0598] L3 is selected from a chemical bond or -C 1-12 -Alkylene-, preferably a chemical bond.

[0599] In some embodiments, the present invention relates to a compound of the above formula X, X-1, X-2, X-3 or X-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0600] U1, U2, and U3 are -O-;

[0601] W1, W2, and W3 are CH3;

[0602] Each M1 is independently a chemical bond or -C(O)-, preferably, both M1 are not chemical bonds;

[0603] L3 is selected from a chemical bond or -C 1-6 -Alkylene-, such as a chemical bond, -CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-, is preferably a chemical bond.

[0604] In some embodiments, the present invention relates to a compound of Formula XI, XI-1, XI-2, XI-3 or XI-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0605] in,

[0606] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0607] W1, W2, W3 are independently selected from C 1-12 alkyl;

[0608] L3 is -C 1-18 -alkylene-.

[0609] In some embodiments, the present invention relates to compounds of formula XI, XI-1, XI-2, XI-3 or XI-4, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0610] U1, U2, U3 are selected from -O- or -OC(O)-;

[0611] W1, W2, W3 are independently selected from C 1-6 alkyl;

[0612] L3 is -C 1-12 -alkylene-.

[0613] In some embodiments, the present invention relates to compounds of formula XI, XI-1, XI-2, XI-3 or XI-4, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, and mixtures thereof, wherein:

[0614] U1, U2, and U3 are 0;

[0615] W1, W2, and W3 are CH3;

[0616] L3 is -C 1-6 -alkylene-, for example -CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2CH2-.

[0617] In some embodiments, the present invention relates to a compound of Formula XII, XII-1 or XII-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0618] in,

[0619] U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-;

[0620] W1, W2, W3 are C 1-12 alkyl;

[0621] L2 is a chemical bond, -C(O)- or -C(O)O-;

[0622] R 1 Selected from H, OH or -Y5-Y6-Y7

[0623] Y5 is unsubstituted or substituted with NH2 C 1-12 alkylene;

[0624] Y6 is a single bond or -NH-C(NH)-;

[0625] Y7 is NH2, OH or C 1-12 Alkoxy.

[0626] In some embodiments, the present invention relates to the compound of formula XII, XII-1 or XII-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0627] U1, U2, U3 are selected from -O- or -OC(O)-;

[0628] W1, W2, W3 are C 1-6 alkyl;

[0629] L2 is a chemical bond or -C(O)-;

[0630] R 1 is selected from H, OH or -Y5-Y6-Y7;

[0631] Y5 is unsubstituted or substituted with NH2 C 3-6 alkylene;

[0632] Y6 is a single bond or -NH-C(NH)-;

[0633] Y7 is NH2 or OH.

[0634] In some embodiments, the present invention relates to the compound of formula XII, XII-1 or XII-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein:

[0635] U1, U2, and U3 are 0;

[0636] W1, W2, and W3 are CH3;

[0637] L2 is a chemical bond or -C(O)-;

[0638] R 1 Selected from H,

[0639] In some embodiments, the present invention relates to a compound of Formula XIII, XIII-1 or XIII-2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof:

[0640] in,

[0641] The variables are as defined above.

[0642] In some embodiments of the present invention, the compound is selected from the following compounds:

[0643] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0644] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0645] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0646] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0647] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0648] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0649] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A) and formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C.14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of Formula (A) and Formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or Examples and Preparations.

[0650] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted into its active form having a medical effect in vivo, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0651] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can cleave to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (A) and formula (I). In addition, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0652] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (A), formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0653] The second aspect of the present invention provides a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug of the compound described in the first aspect of the present invention.

[0654] The third aspect of the present invention provides a composition comprising the compound described in the first aspect of the present invention and / or the stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug described in the second aspect of the present invention.

[0655] The composition of the present invention may further comprise pharmaceutically acceptable carriers, adjuvants, excipients, and the like.

[0656] Use of the compounds of the present invention and their stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs, or compositions containing the above compounds in the preparation of medicaments for preventing and / or treating central nervous system-related diseases.

[0657] Use of the compounds of the present invention and their stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs, or compositions thereof in the preparation of analgesic, antidepressant or anti-addiction drugs.

[0658] In some embodiments of the present invention, the drug is used for pain caused by postoperative trauma, postoperative incision, or cancer organ metastasis.

[0659] The fifth aspect of the present invention provides a method for analgesia, antidepression or anti-drug addiction, which comprises administering to a subject in need thereof an effective dose of the compound of the first aspect of the present invention, the stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs of the second aspect of the present invention, or the composition of the third aspect of the present invention, wherein the administration is carried out orally, rectally, nasally, topically or parenterally.

[0660] In some embodiments of the present invention, the effective dose is 0.1 mg / day to 1000 mg / day, preferably 3 mg / day to 300 mg / day, and more preferably 5 mg / day to 50 mg / day, calculated as the compound.

[0661] The sixth aspect of the present invention provides a compound according to the first aspect of the present invention, a stereoisomer, a pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug according to the second aspect of the present invention, or a composition according to the third aspect of the present invention for use as a medicine or for treatment.

[0662] The present invention modifies different active sites of the parent structure of s-corydalin to obtain compounds of formula I, stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, inclusion compounds or prodrugs thereof. These compounds can be used to prevent and / or treat central nervous system-related diseases, such as pain, drug addiction, depression, etc., have excellent analgesic, antidepressant and anti-addiction effects, and can be used to prepare analgesic, antidepressant and anti-addiction drugs.

[0663] Of course, it is not necessary to achieve all of the advantages described above simultaneously in order to implement any product or method of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0664] In order to more clearly illustrate the technical solutions of the present invention and the prior art, the following briefly introduces the embodiments and the drawings required for use in the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other embodiments can be obtained based on these drawings without paying any creative work.

[0665] FIG1 is a graph showing the mechanical pain threshold results in a mechanical pain test in a complete Freund's adjuvant-induced inflammatory pain model in mice;

[0666] FIG2 is a graph showing the results of plantar thickness in a mechanical pain test in a mouse inflammatory pain model induced by complete Freund's adjuvant;

[0667] FIG3 is a graph showing the time at which each group of mice began to twist in an analgesic test of the acetic acid writhing model in mice;

[0668] FIG4 is a graph showing the total number of writhing times of mice in each group in the analgesia test of the acetic acid writhing model in mice.

[0669] DETAILED DESCRIPTION

[0670] The following will be combined with the accompanying drawings to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field based on the present invention are within the scope of protection of the present invention.

[0671] Abbreviations: PE: petroleum ether; EA: ethyl acetate; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; DCC: dicyclohexylcarbodiimide; EDCI, EDC: 1-ethyl-(3-dimethylaminopropyl)carbodiimide; DIPEA, DIEA: N,N-diisopropylethylamine; EtOH: ethanol; Et3N: triethylamine; ACN: acetonitrile; TBAB: tetrabutylammonium bromide; NMP: N-methylpyrrolidone; THF: tetrahydrofuran; rt: room temperature; LCMS: liquid chromatography-mass spectrometry; TLC: thin-layer chromatography; Chemical Formula: chemical formula; Molecular Weight: relative molecular weight; Exact Mass: exact mass. Yield calculation: Yield = actual mass of synthesized product / theoretical mass of synthesized product × 100%.

[0672] The present invention is described in detail below with reference to specific examples. The synthesis method of the compound of the present invention is not particularly limited and can be synthesized by any method known to those skilled in the art.

[0673] Example 1: Synthesis of Compound A7

[0674] A10-0 34 mg, NaOH 20 mg, and DCM 0.5 mL were added to a reaction flask. In another vial, chloromethyl pivalate 45 mg and DCM 0.5 mL were added. After mixing, the mixture was slowly added dropwise to the reaction flask at room temperature. After stirring at room temperature overnight, the mixture was monitored by LCMS. The peak corresponding to 695 nm was the main peak. TLC separation was performed with PE / EA (3 / 1, v / v) as the developing solvent to obtain a light yellow oil. After lyophilization, A7 (24 mg) was obtained as a light yellow solid.

[0675] 1 H-NMR (400MHz, CDCl-d3) δ7.103(d,J=8.4Hz,2H),6.879(d,J=8.4Hz,2H),6.723(s,2H),6.625(s,2H),5.755(d,2H),4.265(d,J=16.0Hz, 2H),3.890(s,6H),3.873(s,6H),3.826(s,6H),3.707~3.575(m,4H),3.314~3.231(m,6H),2.922~2.865(m,2H),2.709(d,J=10.4Hz,4H).

[0676] Example 2: Synthesis of Compound A10

[0677] Step 1: Add 1.52 g of loxoprofen sodium and 5 mL of water to a reaction flask. Add 1N (i.e., 1 mol / L) hydrochloric acid dropwise to the reaction flask with stirring to adjust the pH to 2. The reaction solution is extracted with EA, and the organic phase is dried, filtered, and concentrated to dryness under reduced pressure to obtain a colorless oil A10-1 (1.3 g).

[0678] 1 H-NMR (400MHz, DMSO-d6) 12.234 (s, 1H), 7.188 (d, J = 8.4Hz, 2H), 7.128 (d, J = 8.0Hz, 2H), 3.623 (q, 7.2Hz, 1H), 2.951 (dd, J1 = 13.2Hz, J2 = 3.6Hz, 1H), 2. 463~2.325(m,2H),2.270~2.202(m,1H),2.112~2.018(m,1H),1.966~1.815 (m,2H),1.744~10624(m,1H),1.525~1.426(m,1H),1.336(d,J=7.2Hz,3H).

[0679] Step 2: To a reaction flask, add 360 mg of A10-1, 500 mg of A10-0, and 18 mg of DMAP. Add 44 mL of ultra-dry DCM, and add 604 mg of DCC while stirring at room temperature. Stir at room temperature overnight. The reaction solution was washed three times with water, dried, and filtered. The mother liquor was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain a pale yellow solid. 3 mL of DCM was added, and the mixture was refrigerated for 1 hour. Filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain A10 (596 mg) as a yellow solid.

[0680] 1 H-NMR (400MHz, DMSO-d6) δ5.332(d,J=8.0Hz,2H),7.211(d,J=8.0Hz,2H),6.933(d,J=8.0Hz,1H),6.890~6.860(m,2H), 6.681(s,1H),4.084(q,J=7.2Hz,1H),4.009(dd,J1=15.6Hz,J2=11.2Hz,1H),3.743(s,3H),3.722(s,3H),3.455~3.370( m,3H),3.352(d,J=2.8Hz,3H),3.104~3.086(m,1H),3.004~2.886(m,2H),2.632~3.542(m,2H),2.479~2.390(m,3H),2.2 47(dd,J1=18.0Hz, J2=8.0Hz,1H),2.117~2.024(m,1H),1.954~1.833(m,2H),1.760~1.688(m,1H),1.536~1.466(m,4H).

[0681] Example 3: Synthesis of Compound A12

[0682] Step 1: Add 138 mg of anhydrous ethanol and 237 mg of pyridine to a reaction flask, add 1 mL of DCM, cool in an ice-water bath, and add a solution of triphosgene (bis(trichloromethyl)carbonate, 297 mg) in DCM (1 mL) dropwise to the reaction mixture. Stir for 1.5 hours. Dilute the reaction mixture with DCM, wash the organic phase three times with water, dry, filter, and concentrate the filtrate to dryness under reduced pressure to yield A12 as a colorless oil (with fragrance).

[0683] Step 2: A10-0 (34 mg), triethylamine (20 mg), and DCM (1 mL) were added to a reaction flask, cooled in an ice-water bath, and a solution of A12-1 (12 mg) in DCM (1 mL) was added dropwise to the reaction flask. The mixture was stirred at room temperature. LCMS showed the main peak to be the target compound. The reaction solution was diluted with DCM and purified by column chromatography to obtain 24 mg of a pale yellow oil. This oil was dissolved in a small amount of DCM and purified by TLC using DCM / EA (1 / 1, v / v) as the developing solvent to obtain 17 mg of a pale yellow oil. After lyophilization, A12 (15 mg) was obtained as a pale yellow solid.

[0684] 1 H-NMR (400MHz, DMSO-d6)7.067(d,J=8.4Hz,1H),6.967(d,J=8.4Hz,1H),6. 890(s,1H),6.692(s,1H),4.261(q,J=7.2Hz,2H),4.073(d,J=16.0Hz,1H),3 .752(s,3H),3.737(s,3H),3.729(s,3H),3.489~3.429(m,3H),3.138~3.12 2(m,1H),2.931~2.902(m,1H),2.646~2.562(m,2H),1.296(t,J=7.2Hz,3H).

[0685] Example 4: Synthesis of Compound A14

[0686] A10-0 (34 mg), DCM (1 mL), and triethylamine (20 mg) were added to a reaction flask. A solution of palmitoyl chloride (27 mg) in DCM (1 mL) was added dropwise to the flask at room temperature. TLC was performed until the reaction was complete. The reaction solution was purified by TLC using DCM / EA (1 / 1, v / v) as the developing solvent to obtain a yellow solid, which was lyophilized to afford A14 (56 mg).

[0687] 1 H-NMR(400MHz, CDCl-d3)6.949~6.897(m,2H),6.709(s,1H),6.630(s,1H) ,4.291(m,1H),3.894(s,3H),3.875(s,3H),3.814(s,3H),3.711~3.631(m ,2H),3.350~3.280(m,3H),2.964(s,1H),2.733(s,1H),2.590(t,J=7.2Hz ,2H),1.814~1.739(m,2H),1.360~1.263(m,24H),0.881(t,J=6.8Hz,3H).

[0688] Example 5: Synthesis of Compound A15

[0689] A reaction flask was added with 68 mg of A10-0, 13 mL of glutaric acid, and 12 mg of DMAP. DCM (2 mL) was then added and the mixture was cooled in an ice-water bath. DCC (82 mg) was added to the reaction flask and stirred overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was purified by TLC to obtain a colorless oil, which was lyophilized to afford A15 (61 mg) as a pale yellow solid.

[0690] 1 H-NMR (400MHz, CDCl-d3)6.965~6.917(m,4H),6.715(s,2H),6.631(s,2H),4.284(d,J=14.8Hz,2H),3.897(s,6H),3.8 77(s,6H),3.824(s,6H),3.694(s,4H),3.359~3.256(m,6H),2.956(s,2H),2.816~2.742(m,8H),2.280~2.208(m,2H).

[0691] Example 6: Synthesis of Compound A16

[0692] To a reaction flask, 50 mg of A10-0, 12.7 mg of suberic acid, and 2 mg of DMAP were added. 2 mL of DCM was added and the mixture was cooled in an ice-water bath. 60 mg of DCC was added to the reaction flask and stirring continued overnight. The reaction solution was filtered and the filtrate was purified by TLC using EA as the developing solvent to obtain A16 (42 mg) as a white solid.

[0693] 1 H-NMR (400MHz, CDCl-d3) δ6.953~6.901(m,4H),6.710(s,2H),6.629(s,2H),4.272(d,J=14.0Hz,2H),3.893(s,6H),3.875(s,6H),3.816(s,6 H),3.724~3.633(m,4H),3.349~3.261(m,6H),2.964(s,2H),2.742(s, 4H), 2.621 (t, J=7.2Hz, 4H), 1.824 (t, 6.8Hz, 4H), 1.535~1.500 (m, 4H).

[0694] Example 7: Synthesis of Compound A17

[0695] A10-0 50 mg, triphosgene 7.2 mg, and DCM 1 mL were added to a reaction flask, which was cooled in an ice-water bath. A solution of pyridine (17 mg) in DCM (1 mL) was added dropwise to the flask. The mixture was stirred at room temperature overnight. The reaction was detected by TLC. The insoluble material was removed by filtration, and the filtrate was purified by TLC to obtain a colorless oil, which was lyophilized to obtain solid A17 (42 mg).

[0696] 1 H-NMR (400MHz, CDCl-d3) δ7.117(d,J=8.4Hz,2H),6.967(d,J=8.4Hz,2H),6.711(s,2H),6.634(s,2H),4.306(s,2H) ,3.945(s,6H),3.893(s,6H),3.876(s,6H),3.761~3.636(m,4H),3.373~3.279(m,6H),2.987(s,2H),2.746(s,4H).

[0697] Example 8: Synthesis of Compound A18

[0698] Step 1: 5.0 g of L-alanine and 25 mL of THF were added to a reaction flask. 2.45 g of sodium hydroxide was added to another vial and dissolved in 50 mL of water. After cooling, the sodium hydroxide solution was added to the reaction flask and stirred at room temperature. 13.5 g of (Boc)2O was added dropwise to the flask and stirred at room temperature overnight. The resulting reaction solution was concentrated under reduced pressure to remove THF. The pH of the residue was adjusted to 3 with 1N HCl. The aqueous phase was extracted three times with EA. The organic phases were combined, dried, filtered, and concentrated to dryness under reduced pressure to obtain A18-1 (3.4 g) as a colorless oil.

[0699] 1H-NMR (400MHz, CDCl-d3) δ8.819(s,1H),5.075(s,1H),4.342(s,1H),1.528(s,1.454(s,9H).

[0700] Step 2: Weigh 3.4 g of A18-1, 1.18 g of isopropanol, and 0.22 g of DMAP, add 34 mL of DCM, cool in an ice-water bath, add 4.13 g of EDCI, remove the ice-water bath, and stir at room temperature overnight. TLC analysis confirmed no residual starting material. The reaction mixture was diluted with DCM and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography with EA / PE (1 / 1, v / v) to afford A18-2 (2.1 g) as a colorless oil.

[0701] 1H-NMR (400MHz, CDCl-d3) δ5.090~4.997(m,2H),4.250(s,1H),1.447(s,9H),1.364(d,J=7.2Hz,3H),1.255(t,J=6.8Hz,6H).

[0702] Step 3: Weigh 2.1 g of A18-2, dissolve it in 6 mL of dioxane hydrochloric acid, and stir at room temperature overnight. TLC detection shows that no starting material remains. The reaction solution is concentrated to dryness under reduced pressure to obtain a colorless oil. 10 mL of isopropyl ether is added to the oil and stirred to precipitate a white solid. The solid is filtered and the filter cake is dried in vacuo at 50°C to obtain A18-3 (1.3 g) as a white solid.

[0703] 1 H-NMR (400MHz, CDCl-d3) δ8.708 (s, 2H), 5.089 (hept, J = 6.0Hz, 1H), 4.181 (quint, J = 6.0Hz, 1H), 1.705 (d, J = 7.2Hz, 3H), 1.278 (dd, J1 = 6.4Hz, J2 = 4.4Hz, 6H).

[0704] Step 4: Add 37 mg of A18-3 to a reaction flask, and protect with N2. In another vial, add 46 mg of phenyl dichlorophosphate and 1 mL of DCM. Transfer the phenyl dichlorophosphate solution to the reaction flask and cool to -40°C with stirring. In another vial, weigh 89 mg of triethylamine, dissolve it in 1 mL of DCM, and then slowly add it dropwise to the reaction flask. Stir at room temperature for 10 minutes after addition. Then transfer to -40°C and stir for 1 hour. In another vial, add 68 mg of A10-0, dissolve it in 1 mL of DCM, and then slowly add it dropwise to the reaction flask. Stir at room temperature for 2 hours after addition. Detect by TLC. The mixture was purified by reverse-phase column chromatography to obtain a yellow oil, which was lyophilized to obtain A18 (53 mg) as a light yellow solid.

[0705] 1H-NMR (400MHz, CDCl-d3) δ7.358~7.282(m,5H),7.171(t,J=7.2Hz,1H),6.885(d,J=8.4Hz ,1H),6.707(s,1H),6.623(s,1H),5.502(sext,J=6.4Hz,1H),4.299~4.254(m,1H),4.126~ 4.064(m,1H),3.924~3.871(m,7H),3.808~3.763(m,3H),3.595(s,2H),3.318~3.276(m,3H ), 2.902 (s, 1H), 2.708 (s, 2H), 1.332 (dd, J1=21.2Hz, J2=6.8Hz, 3H), 1.244~1.199 (m, 6H).

[0706] Example 9: Synthesis of Compound A19

[0707] Step 1: To a reaction flask, add 136 mg of A10-0 and 77 mg of DIPEA, followed by 1 mL of ultra-dry DCM. To a separate vial, add 57 mg of 1-chloroethyl chloroformate and 1 mL of DCM to obtain a 1-chloroethyl chloroformate solution. Add the 1-chloroethyl chloroformate solution dropwise to the reaction flask with stirring at room temperature. Stir at room temperature for 3 h. Complete the reaction by TLC. Separate the product by TLC using PE / EA (1 / 1, v / v) as the developing solvent to obtain A19-1 (178 mg) as a pale yellow solid.

[0708] 1 H-NMR (400MHz, CDCl-d3) δ7.029 (dd, J1=8.4Hz, J2=3.2Hz, 1H), 6.946 (d, J=8.4Hz, 1H),6.714(s,1H),6.630(s,1H),6.517(q,J=6.0Hz,1H),4.263(d,J=16.0Hz,1H), 3.894(s,3H),3.875(s,3H),3.857(d,J=2.0Hz,3H),3.711~3.618(m,2H),3.355~3 .165(m,3H),2.975~2.891(m,1H),2.727(d,J=11.6Hz,2H),1.912(d,J=5.6Hz,3H).

[0709] Step 2: A19-1 (45 mg) was added to a vial, along with 0.25 mL of dimethyl carbonate and 0.75 mL of isobutyric acid. 26 mg of DIEA was slowly added dropwise to the vial while stirring in an ice-water bath. The mixture was heated at 80°C overnight and monitored by TLC. The product had the same Rf value as A19. TLC separation was performed using PE / EA (4 / 1, v / v) as the developing solvent to give A19 (22 mg) as a light yellow oil.

[0710] 1 H-NMR (400MHz, CDCl-d3) δ7.016 (d, J=8.4Hz, 1H), 6.926 (d, J=8.0Hz, 1H), 6.824 (td, J1=5.6Hz, J2=2. 8Hz,1H),6.709(s,1H),6.627(s,1H),4.262(d,J=15.2Hz,1H),3.892(s,3H),3.873(s,3H),3.854(s, 3H),3.709~3.592(m,2H),3.321(dd,J1=16.4Hz,J2=3.6Hz,1H),3.276~3.147(m,2H),2.996~2.887(m ,1H),2.735~2.699(m,2H),2.592(sep,J=7.2Hz,1H),1.602(d,J=5.6Hz,3H),1.196(d,J=6.8Hz,6H).

[0711] Example 10: Synthesis of Compound A21

[0712] To a reaction flask, 34 mg of A10-0 and 16 mg of NaOH powder were added, along with 1 mL of DCM. The mixture was stirred at room temperature for 10 minutes, and solids were washed out. Subsequently, 98 mg of dibenzyl chloromethyl phosphate was added, and the mixture was stirred at room temperature overnight. The reaction solution was separated by TLC using a 1:1 PE / EA solvent to afford 39 mg of A21 (a pale yellow solid, which easily turns yellow due to oxidation).

[0713] 1H-NMR (400MHz, CDCl-d3) δ7.328~7.307(m,10H),7.151(d,J=8.4Hz,1H),6.841(d,J= 8.4Hz,1H),6.719(s,1H),6.623(s,1H),5.164~5.133(m,4H),4.213(d,J=16.0Hz,1H) ,3.893(s,3H),3.872(s,3H),3.836(s,3H),3.587~3.511(m,2H),2.375(dd,J2=16.4H z,J2=3.6Hz,1H),3.212~3.120(m,2H),2.853(t,J=13.4Hz,1H),2.706~2.635(m,2H).

[0714] Example 11: Synthesis of Compound A22

[0715] To a reaction flask, 130 mg of A21, 10 mL of ethanol, 5 mL of water, and 13 mg of Pd / C were added. The mixture was replaced with H2 and stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with 5 ml of ethyl acetate × 2. The aqueous phase was lyophilized to obtain A22 (53 mg) as a light yellow solid.

[0716] 1 H-NMR(400MHz,D2O-d2)δ7.300(d,J=8.4Hz,1H),7.020(d,J=8.4Hz,1H),6.941(s,1H),6.899(s,1H),4.783~4.743(m ,2H),4.415(d,J=16.0Hz,1H),3.889~3.790(m,11H),3.556~3.480(m,1H),3.296~3.207(m,1H),3.102~3.004(m,2H).

[0717] Example 12: Synthesis of Compound A1

[0718] Raw material A10-0 was dissolved in 3 mL of acetonitrile, followed by the addition of KCO and 47 mg of 1-chloroethyl acetate. After stirring at 60°C for 2 h, the mixture was diluted with 30 mL of ethyl acetate and washed twice with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to obtain A1 (34 mg) as a light yellow solid. MS: [M+H] 384.

[0719] 1H-NMR (400MHz, DMSO-d6) δ6.95(s,2H),6.89(s,1H),6.69(s,1H),4.06(d,J=15.9Hz,1H),3.74(d,J=9.6Hz,9H) ,3.44(dd,J=16.5,8.2Hz,3H),3.13(dd,J=10.9,3.7Hz,1H),2.97-2.87(m,1H),2.69-2.55(m,2H),2.31(s,3H).

[0720] Example 13: Synthesis of Compound A3

[0721] Step 1: Dissolve 200 mg of the raw material in 10 mL of thionyl chloride, heat to reflux, cool after 4 h, and concentrate to obtain 218 mg of the concentrate T-004-1, which is directly used in the next reaction.

[0722] Step 2: Dissolve 218 mg of A10-0 and 201 mg of T-004-1 in 10 mL of anhydrous acetonitrile, add 176 mg of anhydrous potassium carbonate, and stir at 60°C for 2 h. Then cool and dilute the reaction mixture with 50 mL of ethyl acetate. Wash twice with 30 mL of water and once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify on a silica gel column to obtain A3 (26 mg) as a light yellow solid. MS: [M+H] 568.

[0723] 1 H-NMR (400MHz, DMSO-d6) δ6.95(s,2H),6.89(s,1H),6.69(s,1H),4.06(d,J=15.9Hz,1H),3.74(d,J=9.6Hz,9H) ,3.44(dd,J=16.5,8.2Hz,3H),3.13(dd,J=10.9,3.7Hz,1H),2.97-2.87(m,1H),2.69-2.55(m,2H),2.31(s,3H).

[0724] Example 14: Synthesis of Compound A30

[0725] A reaction flask was weighed with 150 mg of A10-0 and 89 mg of triethylamine, followed by 4 mL of DCM. The mixture was cooled in an ice-water bath. In another vial, 127 mg of palmitoyl chloride and 1 mL of DCM were added dropwise to the reaction flask. After addition, the mixture was stirred at room temperature for 2 h and monitored by TLC. After completion of the reaction, the reaction mixture was separated by column chromatography to obtain 245 mg of a light yellow solid, which was then lyophilized to afford A30 (228 mg, 83.4%) as a light yellow solid. MS: [M+H] 580.

[0726] 1 H-NMR(CDCl3,400MHz)δ6.931(d,J=8.4Hz,1H),6.894(d,J=8.4Hz,1H),6.716(s,1H),6.625(s,1 H),4.234(d,J=15.6Hz,1H),3.894(s,3H),3.873(s,3H),3.806(s,3H),3.711-3.589(m,2H),3.31 1(dd,J1=16.4Hz,J2=3.2Hz,1H),3.231-3.173(m,2H),2.942-2.873(m,1H),2.720-2.688(m,2H) ,2.587(t,J=7.6Hz,2H),1.777(quint,J=7.6Hz,2H),1.461-1.263(m,24H),0.897-0.864(m,3H).

[0727] Example 15: Synthesis of Compound A20

[0728] A10-0 (340 mg) and TBAB (640 mg) were weighed into a reaction flask and dissolved in 5 mL of DCM. In another vial, 200 mg of NaOH was weighed and dissolved in 5 mL of water. The NaOH solution was added dropwise to the reaction flask at room temperature. In another vial, 360 mg of dibenzyl chloromethyl phosphate was weighed and dissolved in 5 mL of DCM. The solution was added dropwise to the reaction flask at room temperature. Stirring was continued overnight. After separation and purification by TLC, A20 (210 mg, 97% purity) was obtained as a pale yellow oil. MS: [M+H]: 632.

[0729] Example 16: Synthesis of Compound A23

[0730] Step 1: A10-0 (341 mg) and sodium hydroxide (160 mg, 4 eq) were weighed into a 20 mL reaction flask, followed by the addition of 6 mL of DCM. In another vial, 490 mg (1.5 eq) of dibenzyl chloromethyl phosphate was weighed and dissolved in 4 mL of DCM. The mixture was stirred at room temperature for 10 min. A solid precipitated from the reaction flask. The dibenzyl chloromethyl phosphate solution was added dropwise to the reaction flask, and the mixture was stirred at room temperature overnight. The aqueous phase was separated and extracted with DCM. The combined organic phases were purified by column chromatography to afford T-025 (462 mg, 77% yield) as a pale yellow solid. MS: [M+H]: 602. 1 H-NMR (400MHz, CDCl-d3) δ7.328~7.307(m,10H),7.151(d,J=8.4Hz,1H),6.841(d,J= 8.4Hz,1H),6.719(s,1H),6.623(s,1H),5.164~5.133(m,4H),4.213(d,J=16.0Hz,1H) ,3.893(s,3H),3.872(s,3H),3.836(s,3H),3.587~3.511(m,2H),2.375(dd,J1=16.4H z,J2=3.6Hz,1H),3.212~3.120(m,2H),2.853(t,J=13.4Hz,1H),2.706~2.635(m,2H).

[0731] Step 2: 462 mg of T-025 was weighed into a 50 mL single-necked bottle, along with 10 mL of anhydrous ethanol, 5 mL of purified water, and 46 mg of 10% Pd / C. The mixture was stirred vigorously, replaced with hydrogen three times, and stirred overnight at room temperature. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was filtered, and the filtrate was extracted twice with EA. The aqueous phase was lyophilized to obtain a pale yellow solid, T-026 (212 mg, 66% yield). MS: [M+H] 422.

[0732] 1 H-NMR(400MHz,D2O-d2)δ7.300(d,J=8.4Hz,1H),7.020(d,J=8.4Hz,1H),6.941(s,1H),6.899(s,1H),4.783~4.743(m ,2H),4.415(d,J=16.0Hz,1H),3.889~3.790(m,11H),3.556~3.480(m,1H),3.296~3.207(m,1H),3.102~3.004(m,2H).

[0733] Step 3: 60 mg of T-026 was weighed into a vial, and 1 mL of NMP was added. The temperature was raised to 45°C, and 60 mg (4 eq) of triethylamine and 48 mg of TBAB were added. The temperature was raised to 50°C, and 114 mg (5 eq) of chloromethyl isopropyl carbonate was added. The mixture was stirred at 50°C overnight. The product was purified by reverse-phase column chromatography, and the fraction was concentrated to dryness under reduced pressure to obtain a yellow solid. The product was dissolved in water and lyophilized to obtain A23 (49 mg, 48.0% yield) as a yellow solid. MS: [M+H] 538.

[0734] 1 H-NMR(CDCl3,400MHz)δ7.198(d,J=8.8Hz,1H),6.686(s,1H),6.648-6.612(m,2H),5.645-5.563(m,2H),4.845(sept,J=6.4Hz,1H),4.531(s, 1H),4.067-3.706(m,13H),3.309(dd,J1=16.4Hz,J2=6.4Hz,1H),3.149(s,3H),2.968(s,1H),2.809(d,J=15.6Hz,1H),1.300(t,J=7.6Hz,6H).

[0735] 31 P-NMR(CDCl3,160MHz)δ-7.7546(s).

[0736] Example 17: Synthesis of Compound A56

[0737] A10-0 (68 mg), octanoic acid (32 mg), and DMAP (2 mg) were weighed into a reaction flask. Dichloromethane (1 mL) was added and stirred at room temperature. EDCI (76 mg, 2 eq) was added and stirred at room temperature overnight. The reaction was confirmed to be complete by TLC. Purification was performed by silica gel column chromatography to obtain a pale yellow oil, which was lyophilized to afford product A56 (65 mg, yield 69.8%). MS: [M+H] 468.

[0738] 1H-NMR(CDCl3,400MHz)δ6.880(d,J=8.4Hz,1H),6.890(d,J=8.4Hz,1H),6.720(s,1H),6.623(s,1H),4.218 (d,J=15.6Hz,1H),3.894(s,3H),3.873(s,3H),3.803(s,3H),3.620-3.565(m,2H),3.304(dd,J1=16.4Hz,J 2=3.2Hz,1H),3.227-3.108(m,2H),2.884(dd,J1=14.8Hz,J2=12.0Hz,1H),2.709-2.850(m,2H),2.589(t, J=7.2Hz,3H),1.781(quint,J=7.6Hz,2H),1.465-1.393(m,2H),1.374-1.313(m,6H),0.914-0.881(m,3H).

[0739] Example 18: Synthesis of Compound A44

[0740] A10-0 (68 mg), oleic acid (57 mg (1.01 eq), and DMAP (3 mg (0.1 eq)) were weighed into a reaction flask, and DCM (1 mL) was added. In another vial, DCC (82 mg (2 eq)) was weighed and dissolved in DCM (1 mL). The DCC solution was added dropwise to the reaction flask with stirring at room temperature. Stirring was continued overnight at room temperature. The reaction was confirmed by TLC to determine completion. Purification afforded a pale yellow oil, which was then lyophilized to afford A44 (60.53 mg) as a pale yellow solid. MS: [M+H]: 606.

[0741] 1 H-NMR(CDCl3,400MHz)δ6.882(d,J=8.0Hz,1H),6.898(d,J=8.4Hz,1H),6.714(s,1H),6.625(s,1H ),5.396-5.312(m,2H),4.254(d,J=15.6Hz,1H),3.893(s,3H),3.873(s,3H),3.807(s,3H),3.701- 3.609(m,2H),3.340-3.183(m,3H),2.960-2.894(m,1H),2.738-2.706(m,2H),2.587(t,J=7.6Hz, 2H),2.025-2.012(m,5H),1.779(quint,J=7.2Hz,2H),1.433-1.271(m,19H),0.897-0.864(m,3H).

[0742] Example 19: Synthesis of Compound A24

[0743] A10-0 (68 mg), DMAP (3 mg), and nonanoic acid (32 mg) were weighed into a reaction flask, along with 1 mL of DCM. In another vial, 82 mg of DCC was weighed, along with 1 mL of DCM. The DCC solution was added dropwise to the reaction flask while stirring at room temperature. Stirring was continued overnight. TLC confirmed the reaction was complete. Purification afforded a colorless oil, which was lyophilized to afford A24 (63.44 mg), a pale yellow solid. MS: [M+H]: 482.

[0744] 1 H-NMR(CDCl3,400MHz)δ6.882(d,J=8.4Hz,1H),6.896(d,J=8.4Hz,1H),6.716(s,1H),6.625(s,1 H),4.242(d,J=16.0Hz,1H),3.893(s,3H),3.872(s,3H),3.807(s,3H),3.710-3.601(m,2H),3.31 3(dd,J1=16.0Hz,J2=3.6Hz,1H),3.245-3.145(m,2H),2.950-2.886(m,1H),2.730-2.697(m,2H) ,2.588(t,J=7.6Hz,2H),1.779(quint,J=7.6Hz,2H),1.362-1.256(m,10H),0.908-0.874(m,3H).

[0745] Example 20: Synthesis of Compound A25

[0746] A reaction flask was charged with 68 mg of A10-0, 3 mg (0.1 eq) of DMAP, and 38 mg of n-decanoic acid, followed by 1 mL of DCM. In another vial, 77 mg of EDCI was weighed and 0.5 mL of DCM was added. The solid did not dissolve. With stirring, the EDCI suspension was added to the reaction flask via syringe, and the solid immediately dissolved. Stirring was continued at room temperature overnight. TLC confirmed the reaction was complete. Purification afforded a pale yellow oil, which was lyophilized to afford A25 (61.91 mg) as a pale yellow solid. MS: [M+H]: 496.

[0747] 1H-NMR(CDCl3,400MHz)δ6.934(d,J=8.4Hz,1H),6.900(d,J=8.0Hz,1H),6.713(s,1H) ,6.627(s,1H),4.252(d,J=15.2Hz,1H),3.893(s,3H),3.873(s,3H),3.810(s,3H),3 .710-3.627(m,2H),3.343-3.160(m,3H),2.937(s,1H),2.723-2.695(m,2H),2.588( t,J=7.6Hz,2H),1.778(quint,7.6Hz,2H),1.448-1.283(m,14),0.904-0.871(m,3H).

[0748] Example 21: Synthesis of Compound A57

[0749] Step 1: 1.8 g of caffeic acid was weighed into a 30 mL bottle, 20 mL of anhydrous ethanol was added, and 5 drops of concentrated sulfuric acid were added dropwise. After the addition, the mixture was heated, stirred, and refluxed overnight. TLC detection showed that no raw material remained. The reaction solution was diluted with water, and the mixture was extracted twice with EA. The organic phases were combined, washed twice with water, dried, filtered, and concentrated to dryness under pressure to obtain a brown solid T-039-1 (2.12 g).

[0750] 1 H-NMR(DMSO-d6,400MHz)δ9.565(s,1H),9.116(s,1H),7.470(d,J=16.0Hz,1H),7.047(d,J=1.6Hz,1H),6.999(dd,J1= 8.0Hz,J2=2.0Hz,1H),6.763(d,J=8.4Hz,1H),6.253(d,J=16.0Hz,1H),4.155(q,J=7.2Hz,2H),1.241(t,J=7.2Hz,3H).

[0751] Step 2: Weigh 1.04 g of T-039-1 and 2.07 g of K2CO3 into a vial, add 15 mL of acetone, stir at room temperature, and add 1.79 g of benzyl bromide dropwise. After completion of the addition, stir at 60°C overnight. TLC detection shows that no starting material remains. Filter the reaction solution, and concentrate the filtrate to dryness under reduced pressure to obtain a colorless oil T-039-2. The crude product is used directly in the next step.

[0752] Step 3: Dissolve T-039-2 obtained in the previous step in 30 mL of THF, add 5.5 mL of water and 1.62 g (8.1 eq) of solid sodium hydroxide, and stir at room temperature for 36 h. LCMS shows that the reaction is complete. The reaction solution is concentrated under reduced pressure, and the pH of the aqueous phase is adjusted to 2. The mixture is extracted once with EA, the EA phase is dried, filtered, and concentrated to dryness under reduced pressure to obtain a beige solid T-039-3 (1.741 g).

[0753] 1 H-NMR(DMSO-d6,400MHz)δ12.202(s,1H),7.516-7.437(m,6H),7.406-7.363(m,4H),7.335-7.301(m,2H),7.1 95(dd,J1=8.4Hz,J2=1.6Hz,1H),7.073(d,J=8.4Hz,1H),6.418(d,J=16.0Hz,1H),5.196(s,2H),5.184(s,2H).

[0754] Step 4: A10-0 (102 mg), T-039-3 (129 mg), and DMAP (3 mg) were weighed into a vial. 3 mL of DCM was added. The solid was not completely dissolved. 115 mg of EDCI was added, and the solid dissolved immediately. The mixture was stirred at room temperature for 48 h. TLC showed that there was almost no residue. The reaction solution was separated by silica gel chromatography with a developing solvent of PE / EA = 1 / 1 to obtain T-039-4 (208 mg) as a yellow oil.

[0755] 1 H-NMR(DMSO-d6,400MHz)δ7.792(d,J=16.0Hz,1H),7.620(s,1H),7.496-7.449(m,4H),7.416-7.375(m,4H ),7.348-7.311(m,3H),7.127(d,J=8.4Hz,1H),7.028-6.947(m,2H),6.899(s,1H),6.826(d,J=16.0Hz,1H ),6.697(s,1H),5.223-5.220(m,4H),4.086(d,J=16.0Hz,1H),3.761(s,3H),3.744(s,3H),3.733(s,3H), 3.497-3.438(m,3H),3.156-3.118(m,1H),2.953-2.913(m,1H),2.653-2.583(m,2H),2.537-2.529(m,1H).

[0756] Step 5: Dissolve 208 mg of T-039-4 in 15 mL of THF, add 20 mg of 10% palladium hydroxide, replace the atmosphere with hydrogen, and stir at room temperature overnight. TLC analysis shows no residual starting material. Filter the reaction mixture and concentrate to dryness under reduced pressure. The residue is separated on a large plate using EA as the developing solvent to obtain A57 (70 mg), an off-white solid. MS: [M+H] 506.

[0757] 1 H-NMR (CDCl3, 400MHz) δ6.941-6.863 (m, 2H), 6.716 (s, 1H), 6.678 (d, J = 8.0Hz, 1H), 6.635 (s, 1H), 6.567(dd,J1=8.0Hz,J2=1.6Hz,1H),6.418(d,J=1.6Hz,1H),4.293(d,J=16.0Hz,1H),3.891(s,3H) ,3.876(s,3H),3.767-3.736(m,1H),3.710(s,3H),3.649(d,J=16.0Hz,1H),3.369(dd,J1=16.4Hz ,J2=3.6Hz,1H),3.312-3.256(m,2H),2.990(dd,J1=16.0Hz,J2=12.0Hz,1H),2.848-2.712(m,6H).

[0758] Example 22: Synthesis of Compound A53

[0759] To a reaction flask, 101 mg of phosphorus oxychloride, 302 mg of triethylamine, and 2 mL of THF were added. The reaction mixture was cooled to -40°C. A solution of 74 mg of 2-hydroxybenzyl alcohol in THF (2 mL) was slowly added dropwise at -40°C. Stirring was continued at -40°C for 1 h, then at room temperature for 2 h. The reaction mixture was then cooled to -40°C. A solution of 102 mg of A10-0 in THF (0.5 mL) was slowly added dropwise at -40°C. Stirring was continued at room temperature overnight. LCMS showed no residual A10-0 and the main peak was 510. The reaction mixture was filtered and the filtrate was separated on a large plate using EA as the developing solvent to give a colorless oil. This was lyophilized to afford A53 (97.78 mg) as a pale yellow solid. MS: [M+H] 510.

[0760] 1H-NMR(CDCl3,400MHz)δ7.369(t,J=7.2Hz,1H),7.265(s,1H),7.195(t,J=7.2Hz,1H),7.140(d,J= 7.6Hz,2H),7.927(d,J=8.4Hz,1H),6.741(s,1H),6.650(s,1H),5.608-5.553(m,1 H),5.499-5.417(m,1H),4.234(d,J=14.8Hz,1H),3.920(d,J=2.0Hz,3H),3.299(d ,J=1.6Hz,3H),3.751(dd,J1=13.6Hz,J2=2.4Hz,3H),3.647-3.566(m,2H),3.320( d,J=16.4Hz,1H),3.243-3.157(m,2H),2.933-2.869(m,1H),2.741-2.707(m,2H).

[0761] 13 P-NMR (CDCl3, 160MHz): δ-15.448(s),-15.548(s).

[0762] Example 23: Synthesis of Compound A43

[0763] A reaction flask was charged with 68 mg of A10-0, 2 mg of DMAP, and 120 mg of all-cis-eicosapentaenoic acid. 2 mL of DCM was added, followed by 153 mg of EDCI at room temperature. The mixture was stirred overnight at room temperature. The reaction was confirmed to be complete by TLC. The product was purified by column chromatography to afford a yellow oil, which was then lyophilized to afford A43 (93.01 mg) as a pale yellow solid. MS: [M+H]: 626.

[0764] 1H-NMR(CDCl3,400MHz)δ6.928(d,J=8.4Hz,1H),6.893(d,J=8.4Hz,1H),6.715(s,1H),6.623(s,1H),5.548-5.2 91(m,10H),4.233(d,J=16.0Hz,1H),3.890(s,3H),3.870(s,3H),3.802(s,3H),3.631-3.593(m,2H),3.308(dd ,J1=16.4Hz, J2=2.8Hz,1H),3.236-3.145(m,2H),2.987-2.815(m,9H),2.724-2.692(m,2H),2.608(t,J=7.2Hz ,2H),2.225(q,J=6.4Hz,2H),2.076(quint,J=7.2Hz,2H),1.862(quint,J=7.2Hz,2H),0.974(t,J=7.2Hz,3H).

[0765] Example 24: Synthesis of Compound A54

[0766] A reaction flask was charged with 68 mg of A10-0, 2 mg of DMAP, and 49 mg of 3,6,9,12-tetraoxotridecanoic acid. 2 mL of DCM was added, followed by 76 mg of EDCI at room temperature. The mixture was stirred overnight at room temperature. TLC analysis indicated no residual starting material. The reaction mixture was separated by column chromatography to afford 75 mg of a colorless oil, which was lyophilized to afford A54 (65 mg) as a pale yellow oil. MS: [M+H] 546.

[0767] 1 H-NMR(DMSO,400MHz)δ6.999(d,J=8.0Hz,1H),6.963(d,J=8.4Hz,1H),6.887(s,1H),6.691(s, 1H),4.282(s,2H),4.069(d,J=16.0Hz,1H),3.753(s,3H),3.729-3.694(s,8H),3.605-3.582(m,2H), 3.554-3.419(m,12H),3.238(s,3H),3.144-3.108(m,1H),2.970-2.891(m,1H),2.640-2.565(m,2H).

[0768] Example 25: Synthesis of Compound A40

[0769] A10-0 (68 mg), DMAP (2 mg), and docosahexaenoic acid (79 mg) were weighed into a reaction flask. DCM (2 mL) was added, and EDCI (76 mg) was added while stirring at room temperature. The mixture was stirred overnight at room temperature. After TLC, the reaction was complete, and the product was purified to obtain a pale yellow oil. The product was lyophilized to obtain A40 (103 mg). MS: [M+H]: 652.

[0770] 1 H-NMR(CDCl3,400MHz)δ6.929(d,J=8.4Hz,1H),6.896(d,J=8.4Hz,1H),6.714(s,1H),6.625(s,1 H),5.484-5.294(m,12H),4.239(m,16.0Hz,1H),3.892(s,3H),3.872(s,3H),3.804(s,3H),3.70 9-3.599(m,2H),3.311(dd,J1=16.0Hz,J2=3.2Hz,1H),3.241-3.142(m,2H),2.995-2.797(m,11H ),2.728-2.644(m,4H),2.566-2.518(m,2H),2.073(quint,J=7.2Hz,2H),0.972(t,J=7.6Hz,3H).

[0771] Example 26: Synthesis of Compound A55

[0772] A reaction flask was charged with 68 mg of A10-0, 2 mg of DMAP, and 101 mg of 2,5,8,11,14,17,20,23,26-nonaoxaoctacosanoic acid-28-oic acid. 2 mL of DCM was added, and 76 mg of EDCI was added while stirring at room temperature. The mixture was stirred overnight at room temperature. TLC confirmed the absence of residual starting material. The mixture was separated and purified by column chromatography to obtain a pale yellow oil, which was lyophilized to afford A55 (135 mg). MS: [M+H] 766.5.

[0773] 1H-NMR(CDCl3,400MHz)δ6.973-3.929(m,2H),6.709(s,1H),6.632(s,1H),4 .459(s,2H),4.308-4.276(m,1H),3.894(s,3H),3.875(s,3H),3.852-3.814 (m,5H),3.747-3.724(m,2H),3.690-3.629(m,27H),3.557-3.533(m,2H),3. 376(s,3H),3.322-3.198(m,2H),2.987(s,1H),2.760(s,2H),1.759(s,2H).

[0774] Example 27: Synthesis of Compound A45

[0775] A10-0 (68 mg), DMAP (2 mg), and elaidic acid (68 mg) were weighed into a reaction flask. DCM (2 mL) was added, and EDCI (76 mg) was added while stirring at room temperature. The mixture was stirred overnight at room temperature. After TLC, the reaction was complete. Column chromatography was used to separate the mixture to obtain 102 mg of a yellow oil, which was lyophilized to afford A45 (95 mg) as a pale yellow solid. MS: [M+H]: 606.

[0776] 1 H-NMR(CDCl3,400MHz)δ6.932(d,J=8.4Hz,1H),6.898(d,J=8.4Hz,1H),6.713(s,1H),6.626 (s,1H),5.390(s,2H),4.251(d,J=15.6Hz,1H),3.892(s,3H),3.873(s,3H),3.808(s,3H),3. 7093.626(m,2H),3.334-3.232(m,3H),2.938(s,1H),2.712(s,2H),2.585(t,J=7.6Hz,2H),2 .019-1.974(m,4H),1.776(quint,J=7.2Hz,2H),1.443-1.265(m,20H),0.895-0.862(m,3H).

[0777] Example 28: Synthesis of Compound A4

[0778] Using 200 mg of s-conformation raw material as the starting material, the steps were the same as compound A3 to finally obtain a light yellow solid A4 (25 mg)

[0779] MS: [M+H]568.

[0780] 1H-NMR (400MHz, DMSO-d6) δ6.95 (s, 2H), 6.89 (s, 1H), 6.69 (s, 1H), 4.06 (d, J = 15.9Hz, 1H), 3.74 (d, J = 9.6Hz, 9H) ,3.44(dd,J=16.5,8.2Hz,3H),3.13(dd,J=10.9,3.7Hz,1H),2.97-2.87(m,1H),2.69-2.55(m,2H),2.31(s,3H).

[0781] Example 29: Synthesis of Compound A48

[0782] 1. Synthesis of A48-1

[0783] Steps: Add 20.0 g (1.0 eq) of A48-SM to a 500 mL bottle, add 200 mL of dichloromethane, and under nitrogen, add 8.88 g of triethylamine. Add 19.8 g of trifluoromethanesulfonic anhydride dropwise to the mixture under an ice bath, and stir overnight at room temperature. LC / MS analysis indicates completion of the reaction. Add 200 mL of purified water to the reaction solution, stir and separate the layers. Extract the aqueous phase with 100 mL of dichloromethane. Combine the dichloromethane phases, wash with 150 mL of saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate. The sample residue is purified on a 330 g silica gel column (PE / EA, 0-30%, 0-40 min, gradient elution). A48-1 yields 26.97 g of a yellow solid in a 94.8% yield. HPLC purity: 98.93%. MS: 474 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ7.30(d,J=8.5Hz,1H),7.11(d,J=8.6Hz,1H),6.89(s,1H),6.70(s,1H),4.13(d,J=16.1Hz,1H),3.83(s,3H) ,3.74(d,J=9.4Hz,6H),3.53(dd,J=16.5,6.6Hz,3H),3.15(dd,J=11.1,3.7Hz,1H),2.99–2.86(m,1H),2.63(dd,J=15.6,9.6Hz,3H).

[0784] 2. Synthesis of A48-2

[0785] To a 1L bottle, add 20.0 g (1.0 eq) of A48-1, tert-butyl carbamate, tripotassium phosphate, tris(dibenzylideneacetone)dipalladium(0), 2-(biphenyl)di-tert-butylphosphine, and 200 mL of 1,4-dioxane. Heat the temperature to 90°C under nitrogen and stir overnight. After LC / MS analysis of the reaction, cool the mixture to room temperature, filter the reaction mixture, and rinse the filter cake with 50 mL of EA. Concentrate to dryness, and purify the residue on a silica gel column to yield 22.0 g of A48-2, a yellow solid (100% yield).

[0786] 3. Synthesis of A48

[0787] Steps: Take a 50ml bottle, add 2.5g of A48-2, 10ml of dichloromethane, add 10ml of hydrochloric acid dioxane solution dropwise, and stir at room temperature overnight. LC / MS detection of the reaction is complete, concentrate to dryness, add 20ml of DCM, and then add 20ml of saturated sodium carbonate solution to adjust the pH to alkaline. Separate the layers, extract the aqueous phase with 20ml of DCM, combine the DCM phases, wash the DCM phases with 20ml of saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate. The sample residue is purified on a silica gel column to obtain 1.05g of A48 as a yellow solid, with a yield of 54.4%.

[0788] MS: [M+H] 326.

[0789] 1 H NMR (400MHz, DMSO-d6) δ6.85 (s, 1H), 6.67 (s, 1H), 6.65 (d, J = 8.0Hz, 1H), 6.55 (d, J = 8.0Hz, 1H),4.65(s,2H),4.05–4.01(m,1H),3.74(s,3H),3.72(s,3H),3.63(s,3H),3.41–3.35(m,2H),3.27(dd,J=16. 0Hz, 4.0Hz, 1H), 3.10 (dd, J=12.0Hz, 4.0Hz, 1H), 2.97–2.89 (m, 1H), 2.60 (d, J=16.0Hz, 1H), 2.48-2.42 (m, 2H).

[0790] Example 30: Synthesis of Compound N12

[0791] Synthesis of N12-1

[0792] N12-SM2 (2 g, 1 eq) was added to a single-necked flask. At room temperature, N12-SM1 (6.47 g, 2 eq), potassium phosphate (8.05 g, 3 eq), and BrettPhos Pd G3 (2.2 g, 0.2 eq) were added. 30 ml of dioxane was added to the system. The system temperature was raised to 80°C and stirred overnight. The reaction was monitored by LCMS. After post-processing, the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and spin-dried. This was prepared under medium pressure to yield 624 mg of product N12-1.

[0793] MS:296, 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.96(dd,J=8.0,1.5Hz,1H),7.55–7.47(m,2H),7.36–7.27(m,3H),6.97(t,J=7.6Hz,1H),3.88(s,3H).

[0794] Synthesis of N12-2

[0795] N12-1 (624 mg, 1.0 eq) was added to 10 mL of MeOH, followed by a 13 mL aqueous solution of sodium hydroxide (140 mg, 1.8 eq). The mixture was stirred at 60°C for 1 h. LCMS analysis revealed no residual starting material. The product was then concentrated, adjusted to pH 3-4, filtered, and the filter cake was collected and lyophilized to yield 540 mg of the product, which was used directly in the next step. MS: 341.

[0796] Synthesis of compound N12

[0797] N12-2 (200 mg, 1 eq) was added to DCM and fully dissolved. Compound A48 (266 mg, 1.1 eq), EDCI (203 mg, 1.5 eq), and DMAP (9 mg, 0.1 eq) were then added and stirred at room temperature for 1 hour to obtain the desired product. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, then concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain 250 mg of compound N12.

[0798] MS:605.

[0799] 1H NMR (400MHz, DMSO-d6) δ9.57 (s, 1H), 8.28 (d, J = 8.0Hz, 1H), 7.62–7.56 (m, 2H), 7.38-7.32(m,3H),7.14(d,J=8.0Hz,1H),7.08–7.02(m,2H),6.91(s,1H),6.70 (s,1H),4.11(d,J=16.0Hz,1H),3.79–3.72(m,9H),3.53–3.46(m,3H),3.14(dd ,J=8.0Hz,4.0Hz,1H),2.99–2.91(m,1H),2.68–2.61(m,2H),2.53–2.48(m,1H).

[0800] Example 31

[0801] Synthesis of N16-1

[0802] S-Flurbiprofen (400 mg, 1 eq) was added to DMF and fully dissolved. HATU (700 mg, 1.1 eq) and DIEA (800 mg, 4 eq) were added and stirred at 40°C for 1 hour. N16-SM (400 mg, 1 eq) was added to the reaction system and stirred for 2 hours. Mass spectrometry analysis was performed to obtain the desired product. Extraction with ethyl acetate was followed by back extraction with water and saturated brine, followed by spin drying and column chromatography with petroleum ether / ethyl acetate to obtain the desired product, N16-1. MS: 464.

[0803] Synthesis of N16-2

[0804] N16-1 (400 mg, 1 eq), A10-0 (400 mg, 1.3 eq), and DMAP (10 mg, 0.1 eq) were dissolved in DCM. EDCI (300 mg, 1.6 eq) was added and stirred for 2 hours. The mixture was extracted with dichloromethane and dried by spin drying. Purification by column chromatography afforded product N16-2. MS: 787.

[0805] Synthesis of compound N16

[0806] N16-2 (400 mg) was dissolved in methanol, palladium hydroxide on carbon was added, and the mixture was stirred for 3 h. Mass spectrometry analysis was performed to obtain the desired product. The crude product was filtered and dried, washed with acid and alkali, and then lyophilized to obtain 400 mg of compound N16. MS: 697.

[0807] Synthesis of compound N17

[0808] Compound N16 was dissolved in ethanol, and thionyl chloride was added dropwise at 0°C. The mixture was stirred for 30 minutes and analyzed by mass spectrometry to obtain the desired product. The mixture was extracted with ethyl acetate and dried by spin drying. Column chromatography afforded the desired crude product, which was then recrystallized from ethanol to obtain the desired product.

[0809] MS:[M+H]725.

[0810] 1 H NMR(400MHz, DMSO-d6)δ8.57(t,J=8.0Hz,1H),7.54–7.36(m,6H),7.29–7.24(m,2H),6.96(s,1H) ,6.93–6.86(m,2H),6.69(s,1H),4.36–4.29(m,1H),4.14–4.01(m,3H),3.83–3.77(m,1H),3.75– 3.71(m,9H),3.60(s,1H),3.48–3.38(m,3H),3.15–3.08(m,1H),2.97–2.89(m,1H),2.75–2.59(m ,4H),2.17–2.11(m,1H),1.99–1.90(m,1H),1.39(d,J=8.0Hz,3H),1.14(dt,J=40Hz,8.0Hz,3H).

[0811] Mechanical pain testing in a complete Freund's adjuvant-induced inflammatory pain model in mice

[0812] 1. Test method

[0813] 1) Animals: Mice (C57BL / 6J, 8-week-old, male, purchased from Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd.; Certificate No.: 20220617Abzz0619000690; License No.: SCXK(Zhe)2019-0001; Issued by: Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd.; 18-22 g) were adaptively housed for one week after purchase and given free access to food.

[0814] 2) Three days before the experiment, the mice were placed on a metal pain test frame to acclimate for 40-60 minutes, and the experimenter had adaptive contact with the animals (stroking the mice for 3-5 minutes on days 1-3) to reduce the experimental animals' stress response to the experimenter;

[0815] 3) After acclimatization (day 4), baseline values ​​of the animals were tested (up-down test) and the animals were randomly divided into four groups: model group (Model), control group 1 (morphine), control group 2 (A10-0, corydaline), and test group (A3); each group consisted of 4 mice (n=4);

[0816] 4) Inducing an inflammatory pain model using complete Freund's adjuvant (CFA) involves the following steps: using a microinjector to draw 20 μL of complete Freund's adjuvant (CFA) solution, inserting a needle into the toe of one hind paw of the animal, and slowly injecting the CFA solution subcutaneously into the palm to form a subcutaneous papule. The needle is then paused for 20 seconds and slowly rotated out to prevent fluid leakage.

[0817] 5) The mechanical pain threshold and plantar thickness of the mice were measured at 0.5 hours, 2 hours, 8 hours, and 24 hours after the first administration (morphine was administered subcutaneously in control group 1, and orally at an interval of 8 hours in the other groups). Among them, the dosage of control group 1 (morphine) was 2 mg / kg, the dosage of control group 2 (A10-0, corydaline) was 5 mg / kg, and the dosage of test group (A3) was 8.4 mg / kg.

[0818] The mechanical pain measurement method (Up-down test method) includes the following steps:

[0819] a. Place the test animal on the mechanical pain metal grid and let it rest for 30-60 minutes. Start the test after the animal stops looking around, exploring, and becomes relatively quiet.

[0820] b. After adaptation, use one of the fibers to stimulate the mid-plantar area of ​​the hind paw;

[0821] The experimenter holds the von Frey fiber perpendicular to the plantar surface of the foot and applies enough force to cause the fiber to slightly flex the paw and maintain this position for about 6-8 seconds.

[0822] c. The contact should be gentle (no thorns) and pressure should be applied slowly until the fiber begins to bend;

[0823] d. In the mouse test, starting with 1.0 g, depending on whether there was a response or not, the researchers then used a lower or higher force filament using the up-down method.

[0824] e. The first data point after the first inflection point is taken as reading 1. Stop the test after obtaining four readings. The maximum force applied in this mouse test is 2.0g, and the minimum force is 0.16g.

[0825] f. If the animal raises its paw, avoids, or licks its paw in response to stimulation, it is marked as positive (×). Paw withdrawal due to physical activity is not counted. If the animal does not show any of the above, it is marked as negative (O).

[0826] g. Fiber weight: Mouse (g): 0.16, 0.40, 0.60, 1.0, 1.4, 2.0. Cut-off value is 2.0g.

[0827] 2. Test results

[0828] The data obtained above were summarized and analyzed using SPSS data statistics software. Graph Pad software was used to draw images based on the SPSS analysis results. The results are shown in Figures 1 and 2.

[0829] Figure 1 shows the mechanical pain threshold results in the mechanical pain test of the complete Freund's adjuvant-induced inflammatory pain model in mice, where: all values ​​are Mean±SEM (mean ± standard error), n=4; *: vs. Model group, *-P<0.05, **-P<0.01, ***-p<0.001, #: vs. Morphine-2 mg / kg, ###-P<0.001.

[0830] Figure 2 shows the results of plantar thickness in the mechanical pain test of the complete Freund's adjuvant-induced inflammatory pain model in mice, where: all values ​​are Mean±SEM (mean±standard error), n=4; *: vs. Model group, *-P<0.05.

[0831] As can be seen from Figures 1 and 2, the complete Freund's adjuvant (CFA)-induced inflammatory pain model was successfully established; the positive drug Morphine (dose of 2 mg / kg) showed a good analgesic effect in the mouse inflammatory pain model, but it could not be maintained for a long time and had no effect on reducing the swelling of the mouse paws; Compound A10-0 (dose of 5 mg / kg) had no obvious analgesic effect in the mouse inflammatory pain model, but had an effect on reducing the swelling of the paws, but the duration of maintenance was short; compared with the positive drug Morphine, there were differences in the analgesic effect and the effect of reducing the swelling of the paws; Compound A3 (dose of 8.4 mg / kg) had a strong analgesic effect in the mouse inflammatory pain model, but the drug effect was short-lived, and it had an effect on reducing the swelling of the paws after multiple drug treatments. Compared with the positive drug Morphine, there were differences in the analgesic effect and the effect of reducing the swelling of the paws.

[0832] Analgesia test of the acetic acid writhing model in mice

[0833] 1. Test method

[0834] 1) Animals (CD-1 mice, age: 6-8 weeks, sex: male, weight: 20-24 g, number: 120, animal provider: Beijing Sibeifu Biotechnology Co., Ltd.) were quarantined for 7 days. Routine health examinations were performed by a veterinarian, and animals with abnormal performance were removed before the experiment.

[0835] Animals and mice were housed in an SPF-grade laminar flow clean room with constant temperature and humidity at the Animal Center of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. (AAALAC-accredited unit), with 5 mice per cage. The temperature in the breeding room was 22±3°C, the humidity was 40-70%, and the lighting was alternating between light and dark for 12 hours. Cages: Made of polycarbonate. Soft corn cob high-pressure sterilized clean bedding was changed twice a week. Feed and drinking water: Clean-grade mouse feed purchased from Beijing Keao Xieli Feed Co., Ltd. Drinking water was sterilized by high pressure, and food was irradiated with cobalt-60 rays. Animals had free access to sterile food and drinking water.

[0836] Each cage has a cage label indicating the number of animals, sex, strain, receipt time, group, and start time of the experiment. Animal number: Each animal has an individual animal number marked on the tail.

[0837] The animals were randomly divided into groups according to their body weight. The specific groups and administration methods are shown in Table 1 below. Fentanyl is a commonly used analgesic drug and is used as a positive control in the present invention.

[0838] Table 1 Animal groups and drug administration

[0839] The mice were fasted for 16 hours before administration. According to Table 1, the administration methods of each group were as follows: positive drug fentanyl: intravenous injection; other drugs and blank group: oral gavage; administration volume: 10 mL / kg; administration frequency: single.

[0840] 2) All mice were weighed before administration and detailed records were kept. Each group was administered according to the dosing method in Table 1. After administration, each group was injected with 0.6% glacial acetic acid. Group 2 was injected 10 minutes after administration, and the remaining groups were injected 2 hours after administration. 0.6% glacial acetic acid was injected into the mouse's abdominal cavity and deposited in the visceral and parietal peritoneum, causing deep, large-area inflammatory pain for a long time. The mice showed a behavioral reaction of abdominal concavity, extension of the trunk and hind limbs, and elevation of the buttocks, which is called a writhing reaction. The number of writhing reactions in mice was used as a pain response indicator to evaluate the analgesic effect of the compound. The writhing reaction occurred more frequently within 30 minutes after the injection of 0.6% glacial acetic acid. The number of "writhing reactions" occurring 5-15 minutes and 15-30 minutes after the injection of 0.6% glacial acetic acid was observed and recorded.

[0841] 2. Test results

[0842] The writhing test results for each group of mice are presented as "mean ± standard deviation." Data were analyzed using SPSS 16.0 software package, using one-way ANOVA. Statistical differences between groups were compared, with a P < 0.05 considered statistically significant. The time at which mice in each group began to writhe is shown in Figure 3. The writhing test results for each group are shown in Table 2. The total number of writhing events for each group is shown in Table 2 and Figure 4.

[0843] Table 2 Test results of writhing test of mice in each group

[0844] According to the results in Table 2, the number of writhing times of mice administered with the compound of the present invention was less than that of the blank group, indicating that the compound of the present invention has a good analgesic effect.

[0845] Activity detection

[0846] Animal mice (CD-1 mice, age: 6-8 weeks, sex: male, weight: 20-24 g, number: 120, animal provider: Beijing Sibeifu Biotechnology Co., Ltd.) were taken for a quarantine period of 7 days. Routine health examinations were completed by a veterinarian, and animals with abnormal performance were eliminated before the experiment.

[0847] Mice were housed in a clean room, with 5 mice per cage. The room temperature was 22±3°C, the humidity was 40-70%, and the lighting was alternating between light and dark for 12 hours. Cages were made of polycarbonate. Soft corn cob bedding was sterilized and cleaned under high pressure and changed twice a week. Feed and water: Clean-grade mouse feed was purchased from Beijing Keao Xieli Feed Co., Ltd. Drinking water was sterilized under high pressure, and food was irradiated with cobalt-60 radiation. Animals had free access to sterile food and water. All mice were weighed and their weights were recorded in detail before dosing.

[0848] Mice were fasted for 16 hours before administration. The drug was administered intravenously in a volume of 10 mL / kg at a dose of 10 mpk. Fifteen minutes after administration, 0.6% glacial acetic acid was injected into the peritoneal cavity of the mice. This acid deposited in the visceral and parietal peritoneum, causing deep, extensive, and prolonged pain. This resulted in a behavioral response, known as a writhing reaction, characterized by abdominal indentation, extension of the trunk and hind limbs, and elevation of the buttocks. The analgesic effect of the compound was evaluated by measuring the number of writhing reactions observed 20 minutes after the 0.6% glacial acetic acid injection and calculating the ratio of the number of writhing reactions observed in the untreated control group. This ratio was subtracted from 100% to obtain the inhibition rate.

[0849] Table 3

[0850] Each embodiment in this specification is described in a related manner. The same or similar parts between the embodiments can be referred to each other. Each embodiment focuses on the differences from other embodiments.

[0851] The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention are included in the scope of protection of the present invention.

Claims

1. A compound of formula A, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof: in, * indicates a chiral center, selected from (S) configuration or (R) configuration; L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-; L2 is selected from a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, -C(O)NH-, -OC(O- C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 1-6 alkylene), C 3-10 Cycloalkylene (preferably C 3-8 Cycloalkylene, more preferably C 3-6 Cycloalkylene), C 6-30 Arylene (preferably C 6-18 Arylene, more preferably C 6-12 arylene), C 3-30 Heteroarylene (preferably C 3-18 Heteroarylene, more preferably C 3-12 Heteroarylene), -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-), -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 Heteroarylene-O-), -C(O)-C 1-18 Alkylene-, -C(O)-C 1-18 Alkylene-NHC(O)-C 1-18 Alkylene-, -C(O)-C 1-18 Alkylene-C(O)NH-C 1-18 Alkylene-, C 1-30 Alkyleneoxy or -X1-PRa(O)-X2-; the Ra are each independently selected from hydrogen, hydroxyl, halogen (preferably F, Cl or Br), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), C 1-30 Hydrocarbyl (preferably C 1-30 Alkyl, more preferably C 1-18 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 1-30 Alkoxy (preferably C 1-18 Alkoxy, more preferably C 1-6 Alkoxy), C 6-30 Aryl-O-(preferably C 6-18 Aryl-O-, more preferably C 6-12 Aryl-O-), C 3-30 Heteroaryl-O-(preferably C 3-18 Heteroaryl-O-, more preferably C 3-12 Heteroaryl-O-), C 6-30 Aryl-C 1-18 Alkylene-O-(preferably C 6-18 Aryl-C 1-12 Alkylene-O-, more preferably C 6-12 Aryl-C 1-6 Alkylene-O-), C 3-30 Heteroaryl-C 1-18 Alkylene-O-(preferably C 3-18 Heteroaryl-C 1-12 Alkylene-O-, more preferably C 3-12 Heteroaryl-C 1-6 Alkylene-O-), -OC 6-30 Aryl-C 1-18 Alkylene-(preferably -OC 6-18 Aryl-C 1-12 Alkylene-) or -OC 3-30 Heteroaryl-C 1-18 Alkylene-(preferably -OC 3-18 Heteroaryl-C 1-12 Alkylene-); said Ra and X2 can be connected to form a ring; The X1 is selected from a single bond, -O-, -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-) or -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 heteroarylene-O-); The X2 is selected from a single bond, -O- or -NR*-; wherein R* is selected from H, C 1-6 Alkyl, C 1-6 alkoxy; The L2 is optionally replaced by 1, 2, 3, 4 or 5 selected from halogen, OH, CN, C(O)OH, C(O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Substitution of haloalkoxy substituents; R 1 is selected from the group consisting of: hydrogen, hydroxy, amine which is not substituted or substituted with 1 or 2 Rb, C which is not substituted or substituted with Rb 1-30 Hydrocarbyl (preferably C 1-30 Alkyl or C 2-30 Alkenyl, more preferably C 1-18 Alkyl or C 2-18 Alkenyl, more preferably C 1-6 Alkyl or C 2-12 alkenyl, the number of double bonds in the alkenyl is 1-10, preferably 1-6), unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 cycloalkyl), unsubstituted or Rb-substituted C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 alkoxy), unsubstituted or substituted by 1, 2, 3, 4 or 5 Rb 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 tetra-fused ring group), unsubstituted or C substituted with Rc on the hydrogen atom of the alkyl group 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-(preferably C 1-12 Alkyl-C 6-18 Arylene-C 1-12 Alkylene-), unsubstituted or C substituted with Rd as the hydrogen atom on the alkyl group 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-(preferably C 6-18 Aryl-C 1-12 Alkylene-), -OC(O)-Y1, unsubstituted or -C in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## , -ZC optionally substituted by x A 6-30 Aryl (preferably -ZC 6-18 Aryl, more preferably -ZC 6-12 aryl, such as -Z-phenyl); wherein R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl; R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-; The Rb are each independently selected from C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl) or C 1-30 Alkyl (preferably C 1-18 Alkyl, more preferably C 1-6 alkyl); The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, More preferably C 3-6 Cycloalkyl, more preferably cyclopentyl); The Rd are each independently selected from C which is unsubstituted or substituted by halogen (preferably F, Cl or Br). 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl); Said Y1 is selected from C 1-30 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl); each of Re is independently selected from C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl); Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 The Rf are each independently selected from C unsubstituted or substituted by halogen (preferably F, Cl or Br) 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 aryl); Said Y3 is selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -OC 1-18 Alkyl (preferably -OC 1-12 Alkyl, more preferably -OC 1-6 alkyl); Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), each of the Rg groups is independently selected from hydroxyl or C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy); The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 3-6 alkylene); The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number in the range of 2-20 (preferably any natural number in the range of 2-10); Said Y7 is selected from amino, C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy) or hydroxyl; x is selected from 0, 1, 2, 3, 4 or 5; Z is selected from chemical bonds, -O-, -NH-, -C 1-12 Alkylene-, -C 1-12 Alkylene-OC 1-12 Alkylene-, -C 1-12 Alkylene-NH-C 1-12 Alkylene-, -C 1-18 Alkylene-C(O)-C 1-12 Alkylene-, -C 1-10 Alkylene-C(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)-C 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-C(O)NH-C 1-10 Alkylene- or -C 1-10 Alkylene-OC(O)NH-C 1-10 Alkylene-, preferably a chemical bond or -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-; The Z is optionally replaced by 1, 2, 3, 4 or 5 selected from halogen, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 alkyl, -OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups; A is independently selected from H, halogen, OH, -L A -C 3-10 Cycloalkyl, -L A -3-10 membered heterocyclic group, -L A -C 6-12 Aryl or -L A -5-12 membered heteroaryl, preferably halogen, C 6-10 Aryl or -NH-C 6-10 aryl; L A is selected from a chemical bond, -NH-, -O-, -C(O)-, -C(O)O-, -NHC(O)-, -NHC(O)O-, -OC(O)NH- or -C(O)NH-; Said A is optionally further replaced by halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution; When both L1 and L2 are selected from single bonds, R 1 Not hydroxyl group; U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O-, -O-, or the available ring atoms on U2 and the available ring atoms on U3 are connected through a Q group to form a 4-8 membered ring, preferably a 5-6 membered ring, Q is selected from: single bond; NR 3 ; C 1-3 Alkylene, wherein 1 or 2 CH2 are optionally independently selected from O, S and NR 3 and C 2-3 Alkenylene, wherein any CH forming a C=C double bond is optionally replaced by N; W1, W2 and W3 are each independently selected from C1- 18 Alkyl (preferably C1- 12 Alkyl, more preferably C1-6 alkyl) or -(OC 2-6 alkylene) p (Preferably -(OC 2-4 alkylene) p , more preferably -(O-CH2-CH2) p ), wherein p is selected from any natural number between 1 and 18, and preferably any natural number between 1 and 10; The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted at each occurrence with 1, 2, 3 or more R 3 Substituted, wherein the R 3 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl; and wherein with respect to the substituent R 3 The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by 1, 2, 3 or more substituents independently selected from the following: halogen, OH, oxo, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl.

2. A compound of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof: in, L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-; L2 is selected from a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 1-6 alkylene), C 3-10 Cycloalkylene (preferably C 3-8 Cycloalkylene, more preferably C 3-6 Cycloalkylene), C 6-30 Arylene (preferably C 6-18 Arylene, more preferably C 6-12 arylene), C 3-30 Heteroarylene (preferably C 3-18 Heteroarylene, more preferably C 3-12 Heteroarylene), -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-), -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 Heteroarylene-O-), -C(O)-C 1-18 alkyl-, C 1-30 Alkoxy or -X1-PRa(O)-X2-; the Ra are each independently selected from hydrogen, hydroxyl, halogen (preferably F, Cl or Br), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), C 1-30 Hydrocarbyl (preferably C 1-30 Alkyl, more preferably C 1-18 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 1-30 Alkoxy (preferably C 1-18 Alkoxy, more preferably C 1-6 Alkoxy), C 6-30 Aryl-O-(preferably C 6-18 Aryl-O-, more preferably C 6-12 Aryl-O-), C 3-30 Heteroaryl-O-(preferably C 3-18 Heteroaryl-O-, more preferably C 3-12 Heteroaryl-O-), C 6-30 Aryl-C 1-18 Alkylene-O-(preferably C 6-18 Aryl-C 1-12 Alkylene-O-, more preferably C 6-12 Aryl-C 1-6 Alkylene-O-), C 3-30 Heteroaryl-C 1-18 Alkylene-O-(preferably C 3-18 Heteroaryl-C 1-12 Alkylene-O-, more preferably C 3-12 Heteroaryl-C 1-6 Alkylene-O-), -OC 6-30 Aryl-C 1-18 Alkylene-(preferably -OC 6-18 Aryl-C 1-12 Alkylene-) or -OC 3-30 Heteroaryl-C 1-18 Alkylene-(preferably -OC 3-18 Heteroaryl-C 1-12 Alkylene-); said Ra and X2 can be connected to form a ring; The X1 is selected from a single bond, -O-, -C 1-18 Alkylene-O-(preferably -C 1-12 Alkylene-O-, more preferably -C 1-6 Alkylene-O-), -C 6-30 Arylene-O-(preferably -C 6-18 Arylene-O-, more preferably -C 6-12 Arylene-O-) or -C 3-30 Heteroarylene-O-(preferably -C 3-18 Heteroarylene-O-, more preferably -C 3-12 heteroarylene-O-); The X2 is selected from a single bond, -O- or -NR*-; wherein R* is selected from H, C 1-6 Alkyl, C 1-6 alkoxy; R 1 is absent or selected from hydrogen, hydroxyl, amine which is not substituted or substituted by Rb, C which is not substituted or substituted by Rb 1-30 Hydrocarbyl (preferably C 1-30 Alkyl or C 2-30 Alkenyl, more preferably C 1-18 Alkyl or C 2-18 Alkenyl, more preferably C 1-6 Alkyl or C 2-12 Alkenyl, the number of double bonds in the alkenyl is 1-10, preferably 1-6), unsubstituted or substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 cycloalkyl), unsubstituted or Rb-substituted C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 alkoxy), unsubstituted or Rb-substituted C 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 tetra-fused ring group), unsubstituted or C substituted with Rc on the hydrogen atom of the alkyl group 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-(preferably C 1-12 Alkyl-C 6-18 Arylene-C 1-12 Alkylene-), unsubstituted or C substituted with Rd as the hydrogen atom on the alkyl group 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-(preferably C 6-18 Aryl-C 1-12 Alkylene-), -OC(O)-Y1, unsubstituted or -C in which the hydrogen atom on the alkylene is replaced by Rd 1-12 Alkylene-C(O)-O-Y2, unsubstituted or the hydrogen atom on the alkylene is replaced by Rd -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ; where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl; R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-; The Rb are each independently selected from C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl), C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl) or C 1-30 Alkyl (preferably C 1-18 Alkyl, more preferably C 1-6 alkyl); The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, more preferably cyclopentyl); The Rd are each independently selected from C which is unsubstituted or substituted by halogen (preferably F, Cl or Br). 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl); Said Y1 is selected from C 1-30 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 Alkyl), C 3-10 Cycloalkyl (preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl); each of Re is independently selected from C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 heteroaryl); Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group (preferably C 12-17 A fused ring group, more preferably a C 12-17 The fused ring group is more preferably a C 12-17 The Rf are each independently selected from C unsubstituted or substituted by halogen (preferably F, Cl or Br) 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 Alkoxy), C 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 aryl); Said Y3 is selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -OC 1-18 Alkyl (preferably -OC 1-12 Alkyl, more preferably -OC 1-6 alkyl); Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl (preferably C 6-18 Aryl, more preferably C 6-12 Aryl) or C 3-30 Heteroaryl (preferably C 3-18 Heteroaryl, more preferably C 3-12 Heteroaryl), each of the Rg groups is independently selected from hydroxyl or C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy); The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 Alkylene (preferably C 1-12 Alkylene, more preferably C 3-6 alkylene); The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number in the range of 2-20 (preferably any natural number in the range of 2-10); Said Y7 is selected from amino, C 1-30 Alkoxy (preferably C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, more preferably C 1-3 alkoxy) or hydroxyl; When both L1 and L2 are selected from single bonds, R 1 Not hydroxyl group; U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O-, -O-, or the available ring atoms on U2 and the available ring atoms on U3 are connected through a Q group to form a 4-8 membered ring, preferably a 5-6 membered ring, Q is selected from: single bond; NR 3 ; C 1-3 Alkylene, wherein 1 or 2 CH2 are optionally independently selected from O, S and NR 3 and C 2-3 Alkenylene, wherein any CH forming a C=C double bond is optionally replaced by N; W1, W2 and W3 are each independently selected from C 1-18 Alkyl (preferably C 1-12 Alkyl, more preferably C 1-6 alkyl) or -(OC 2-6 alkylene) p (Preferably -(OC 2-4 alkylene) p , more preferably -(O-CH2-CH2) p ), wherein p is selected from any natural number between 1 and 18, and preferably any natural number between 1 and 10; The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted at each occurrence with 1, 2, 3 or more R 3 Substituted, wherein the R 3 is independently selected at each occurrence from: halogen, cyano, nitro, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl; and wherein with respect to the substituent R 3 The alkyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted by 1, 2, 3 or more substituents independently selected from the following: halogen, OH, oxo, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The heteroaryl group, the heteroarylene group, the C 12-17 The heteroatoms in the fused ring group are each independently selected from O, N or S, preferably N; Preferably, the heteroaryl group, the heteroarylene group, the C 12-17 The number of heteroatoms in the fused ring group is 1-3, preferably 1-2; Preferably, the C containing at least one heteroatom 12-17 The four fused ring groups are 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the compounds of formula II: The L2 is selected from a single bond, -C(O)-, -C(O)-O-, C 1-18 Alkylene, -C 1-18 Alkylene-O-, -C(O)-C 1-18 Alkyl-, C 1-30 Alkoxy or -X1-PRa(O)-X2-; said Ra are each independently selected from hydrogen, hydroxyl, halogen, C 6-30 Aryl, C 3-30 Heteroaryl, C 1-30 Hydrocarbon, C 3-10 Cycloalkyl, C 1-30 Alkoxy, C 6-30 Aryl-O-, C 3-30 Heteroaryl-O-, C 6-30 Aryl-C 1-18 Alkylene-O-, C 3-30 Heteroaryl-C 1-18 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC 3-30 Heteroaryl-C 1-18 Alkylene-; said Ra and X2 can be connected to form a ring; The X1 is selected from a single bond or -C 1-18 Alkylene-O-; Said X2 is selected from a single bond, -O- or -NR*- (e.g. -NH-); The R 1 Selected from hydrogen, hydroxyl, amino, C 1-30 Hydrocarbon, C 1-30 Alkoxy, unsubstituted or Rb-substituted C 12-30 Condensed ring group, unsubstituted or alkyl group with hydrogen atoms replaced by Rc 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-, C 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ; where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl; R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-; The Rb are each independently selected from unsubstituted or halogen-substituted C 1-30 Alkoxy, C 6-30 Aryl, C 3-30 Heteroaryl or C 1-30 alkyl; The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl; Said Y1 is selected from C 1-30 Alkyl, C 3-10 Cycloalkyl, C 6-30 Aryl or C 3-30 Heteroaryl; said Re are each independently selected from unsubstituted or halogen-substituted C 6-30 aryl; Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group; the Rf are each independently selected from C 1-30 alkoxy; Said Y3 is selected from C 1-18 Alkyl or -OC 1-18 alkyl; Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl or C 3-30 Heteroaryl, said Rg are each independently selected from hydroxyl or C 1-30 alkoxy; The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 alkylene; The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 20; Said Y7 is selected from amino, C 1-30 Alkoxy or hydroxy.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula I-1: Wherein, L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-; preferably a single bond, -O-, -NH-; The L2 is selected from a single bond, -C(O)-, -C(O)-O-, -C 1-18 Alkylene-, -C 1-18 Alkylene-O-(such as -(CH2) 1-5 -O-), -C(O)-C 1-18 Alkyl-, C 1-30 Alkoxy (such as -(OCH2CH2) 2-8 -) or -X1-PRa(O)-X2-; Said Ra are independently selected from hydrogen, hydroxyl, halogen, C 6-30 Aryl, C 3-30 Heteroaryl, C 1-30 Hydrocarbon, C 3-10 Cycloalkyl, C 1-30 Alkoxy, C 6-30 Aryl-O-, C 3-30 Heteroaryl-O-, C 6-30 Aryl-C 1-18 Alkylene-O-, C 3-30 Heteroaryl-C 1-18 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC 3-30 Heteroaryl-C 1-18 Alkylene-; wherein the available ring atoms on Ra can be directly connected to X2 to form a 4-7 membered ring, preferably a 5-6 membered ring; The X1 is selected from a single bond, -O- or -C 1-18 Alkylene-O-; preferably a single bond, -O-, or -(CH2) 1-3 O- (such as -CH2O-); X2 is selected from a single bond, -O- or -NR*-; wherein R* is selected from H, or C 1-6 Alkyl (such as methyl, ethyl, isopropyl); The R 1 Not present, or selected from hydrogen, hydroxyl, amino, C 1-30 Hydrocarbyl (wherein the C 1-30 The hydrocarbon group contains 0-10 double bonds or triple bonds, preferably 0-6 double bonds or triple bonds), C 1-30 Alkoxy, unsubstituted or Rb-substituted C 12-30 Condensed ring group, unsubstituted or alkyl group with hydrogen atoms replaced by Rc 1-18 Alkyl-C 6-30 Arylene-C 1-18 Alkylene-, C 1-12 Alkyl-OC(O)-C 1-12 Alkylene-imino-, C 6-30 Aryl-C 1-18 Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -CH=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ; where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl; R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-; The Rb are each independently selected from unsubstituted or halogen-substituted C 1-30 Alkoxy, C 6-30 Aryl, C 3-30 Heteroaryl or C 1-30 alkyl; The Rc are each independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl; Said Y1 is selected from C 1-30 Alkyl, C 3-10 Cycloalkyl, C 6-30 Aryl or C 3-30 Heteroaryl; the Re are each independently is selected from unsubstituted or halogen-substituted C 6-30 aryl; Said Y2 is selected from C which is unsubstituted or substituted by Rf 12-30 Condensed ring group; the Rf are each independently selected from C 1-30 alkoxy; Said Y3 is selected from C 1-18 Alkyl or -OC 1-18 alkyl; Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-30 Aryl or C 3-30 Heteroaryl, said Rg are each independently selected from hydroxyl or C 1-30 alkoxy; The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-18 alkylene; The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 20; Said Y7 is selected from amino, C 1-30 Alkoxy or hydroxy.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The L2 is selected from a single bond, -C(O)-, -C(O)-O-, C 1-6 Alkylene, -C 1-6 Alkylene-O- or -X1-PRa(O)-X2-; wherein Ra are each independently selected from hydrogen, hydroxyl, C 6-12 Aryl-O- or C 6-12 Aryl-C 1-6 Alkylene-O-, -OC 6-30 Aryl-C 1-18 Alkylene- or -OC 3-30 Heteroaryl-C 1-18 Alkylene-; said Ra and X2 can be connected to form a ring; The X1 is selected from a single bond or -C 1-6 Alkylene-O-; Said X2 is selected from a single bond, -O-, -NH-; The R 1 Selected from absent, hydrogen, hydroxyl, amine, C 1-30 Alkyl, C 1-30 Alkoxy, unsubstituted or methoxy-substituted C containing at least one heteroatom 12-17 Tetra-fused ring, cyclopentanone-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-, cyclopentanol-C 1-6 Alkylene-C 6-12 Arylene-C 1-6 Alkylene-, C 1-6 Alkyl-OC(O)-C 1-6 Alkylene-imino-, C 6-12 Aryl-C 1-6 Alkylene-、-OC(O)-Y1、-C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## ; where R # and R ## Each independently selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-OR 2 、-OC(O)-OR 2 、-C 1-18 Alkylene-C(O)-OR 2 、-C 1-18 Alkylene-R 2 or -C 6-10 Aryl-C 1-6 alkyl; R 2 is selected from H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, C 12-30 Fused ring group, -NHC(NH)NH-; Said Y1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-12 Aryl; said Re are each independently selected from unsubstituted or halogen-substituted C 6-12 aryl; Said Y3 is selected from C 1-6 Alkyl or -OC 1-6 alkyl; Said Y4 is selected from C which is unsubstituted or substituted by Rg 6-12 Aryl, said Rg are each independently selected from hydroxyl or methoxy; The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 1-6 alkylene; The Y6 is selected from a single bond, -NH-C(NH)-, -(O-CH2-CH2) m -or -CH2-(O-CH2-CH2) n -, said m and said n are each independently selected from any natural number between 2 and 10; Said Y7 is selected from amino, C 1-6 Alkoxy or hydroxy.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The R 1 Selected from absent, hydrogen, hydroxyl, amino, aromatic (such as benzene), C 1-30 Alkyl, C 1-30 Alkoxy (such as -OCH3), unsubstituted or substituted by 1, 2, 3, 4 or 5 Rb C 12-30 fused ring group, -(CH2) 1-10 -C(O)-OC 12-30 Condensed ring group, -OC(O)-Y1, -C1- 12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## , preferably absent, hydrogen, hydroxyl, amine, aryl (such as benzene), C 1-30 Alkyl, C 1-30 Alkoxy (such as -OCH3), unsubstituted or Rb substituted C 12-30 fused ring group, -(CH2) 1-10 -C(O)-OC 12-30 Condensed ring group, -OC(O)-Y1, -C 1-12 Alkylene-C(O)-O-Y2, -OC 1-12 Alkylene-OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## , Preferred structures are H, -OH, -NH2, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -(CH2) p CH3, -(CH2) p OCH3, -(CH2) p NH2, -(CH2) p OH, -(OCH2CH2)qCH3, -(OCH2CH2)qOCH3, -(OCH2CH2)qOH, -(OCH2CH2)qNH2, phenyl, (like )、 (like )、 Preferred structures are H, -OH, -NH2, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -(CH2) p CH3, -(CH2) p OCH3, -(CH2) p NH2, -(CH2) p OH, -(OCH2CH2)qCH3, -(OCH2CH2)qOCH3, -(OCH2CH2)qOH, -(OCH2CH2)qNH2, phenyl, (like (like )； Where p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula III:

9. The compound of claim 8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: Said Ra are independently selected from hydroxyl, C 6-12 Aryl-O-, C 6-12 Aryl-C 1-6 Alkylene-O- or -OC 6-12 Aryl-C 1-6 Alkylene-; said Ra and X2 can be connected to form a ring; The X1 is selected from a single bond or -C 1-6 Alkylene-O-; Said X2 is selected from a single bond, -O-, -NH-; The R 1 Selected from absent, hydrogen, hydroxyl, C 1-6 Alkyl-OC(O)-C 1-6 Alkylene-imino-, C 6-12 Aryl-C 1-6 Alkylene- or -OC 1-12 Alkylene-OC(O)-Y3; wherein Y3 is selected from -OC 1-6 alkyl.

10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula IVa, IVb, and IVc: Wherein, the G ring in formula IVc is C 6-12 Aryl ring.

11. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula V:

12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the compounds of formula VIa or formula VIb: In Formula VIa and Formula VIb, r and t are each independently selected from any natural number from 0 to 10, and s is each independently selected from any natural number from 0 to 9 (preferably any natural number from 1 to 6); r, s and t are not 0 at the same time.

13. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula VII: Wherein, n is selected from any natural number between 2 and 20, preferably any natural number between 2 and 10.

14. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula VIII: Among them, Z is selected from C 1-30 Alkylene, C 3-10 Cycloalkylene, C 6-30 Arylene, C 3-30 heteroarylene or -C=CH-; A is selected from hydroxy, halogen, C 6-30 Aryl or C substituted by Rc 1-18 Alkyl, wherein Rc is independently selected from unsubstituted, hydroxy-substituted, oxo-substituted or thio-substituted C 3-10 Cycloalkyl; B is selected from hydroxy, halogen or C 6-30 aryl; x is selected from 0 or 1, y is selected from 0, 1 or 2, and x+y is not zero.

15. The compound of claim 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the group consisting of compounds of formula IX: A is selected from C substituted by Rc 1-18 Alkyl, the Rc are each independently selected from C 3-10 Cycloalkyl; B is selected from halogen or C 6-30 aryl; x is selected from 1, and y is selected from 0 or 1.

16. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the compounds of formula X: wherein M1 is each independently selected from a single bond or -C(O)-; L3 is selected from C 1-12 Alkylene.

17. The compound of claim 16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: The compound is selected from the compounds of formula XI: Wherein, L3 is selected from C 1-12 alkylene; Preferably, U1, U2 and U3 are each independently selected from -O-, and W1, W2 and W3 are each independently selected from methyl.

18. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula XII:

19. The compound of claim 16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and a mixture thereof, wherein: Said L2 is selected from a single bond or -O-; The R 1 is selected from hydrogen, amine or -Y5-Y6-Y7; The Y5 is selected from a single bond, an unsubstituted or amino-substituted C 3-12 Alkylene.

20. The compound of claim 16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula XIII: Preferably, the Y5 is selected from C 3-12 Alkylene, preferably unsubstituted or substituted by amino C 3-6 Alkylene.

21. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula XIV:

22. The compound of claim 19, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: Said L1 is selected from -O- or -NH-; The L2 is selected from -C(O)- or C 1-18 alkylene; Said Y7 is selected from amino, C 1-30 Alkyl, C 1-30 Alkoxy or hydroxy.

23. The compound of claim 19, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula XVa or formula XVb: Preferably, Y7 is selected from methoxy or hydroxy.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: U1, U2 and U3 are each independently selected from -O-; W1, W2 and W3 are each independently selected from C 1-18 Alkyl, preferably C 1-12 Alkyl, more preferably C 1-6 The alkyl group is more preferably a methyl group.

25. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula Ia: Preferred or Among them, L1, L2, W1, R 1 , R* as defined in claim 1 or 2.

26. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula XVI, XVI-1, XVI-2, XVI-3, and XVI-4: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently selected from C 1-18 alkyl; M4 is selected from a chemical bond, -O-, -NH-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)O-, -OC(O)NH- or -C 1-10 Alkylene-; Preferably, U1, U2 and U3 are independently selected from -OC(O)- or -O-; W1, W2 and W3 are independently selected from C 1-12 Alkyl, preferably C 1-6 alkyl; M4 is selected from a chemical bond, -NH-, -C(O)O-, -OC(O)-, -NHC(O)O- or -OC(O)NH-; Preferably, U1, U2 and U3 are -O-; W1, W2 and W3 are independently selected from C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably methyl; M4 is selected from -NHC(O)O- or -OC(O)NH-.

27. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula VIII, VIII-1 or VIII-2: in, U1, U2 and U3 are independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O- or -O; W1, W2 and W3 are independently selected from C 1-12 alkyl; Z is selected from chemical bonds, -O-, -NH-, -C 1-12 Alkylene-, -C 1-12 Alkylene-OC 1-12 Alkylene-, -C 1-12 Alkylene-NH-C 1-12 Alkylene-, -C 1-18 Alkylene-C(O)-C 1-12 Alkylene-, -C 1-10 Alkylene-C(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)-C 1-10 Alkylene-, -C 1-10 Alkylene-NHC(O)OC 1-10 Alkylene-, -C 1-10 Alkylene-C(O)NH-C 1-10 Alkylene- or -C 1-10 Alkylene-OC(O)NH-C 1-10 Alkylene-, preferably a chemical bond or -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-; The Z is optionally replaced by 1, 2, 3, 4 or 5 selected from halogen, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups; A and B are independently selected from H, halogen, OH, -L A -C 3-10 Cycloalkyl, -L A -3-10 membered heterocyclic group, -L A -C 6-12 Aryl or -L A -5-12 membered heteroaryl, preferably halogen, C 6-10 Aryl or -NH-C 6-10 aryl; L A is selected from a chemical bond, -NH-, -O-, -C(O)-, -C(O)O-, -NHC(O)-, -NHC(O)O-, -OC(O)NH- or -C(O)NH-; The A and B are optionally further substituted with halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution; x is 0, 1, or 2; y is 0, 1, 2, or 3; Preferably, U1, U2 and U3 are independently selected from -OC(O)- or -O-; W1, W2 and W3 are independently selected from C 1-6 alkyl; Z is selected from chemical bonds, -O-, -NH-, -C 1-6 Alkylene-, -C 1-6 Alkylene-C(O)-C 1-6 Alkylene-, -C 1-6 Alkylene-C(O)OC 1-6 Alkylene-, -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene-, -C 1-6 Alkylene-C(O)NH-C 1-6 Alkylene-, preferably a chemical bond, -C 1-6 Alkylene-NHC(O)-C 1-6 Alkylene- or -C 1-6 Alkylene-C(O)NH-C 1-6 Alkylene-; The Z is optionally replaced by 1, 2 or 3 selected from halogen, C(O)OH, C(O)OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups; A and B are independently selected from H, halogen, C 6-10 Aryl, -NH-C 6-10 Aryl, -OC 6-10 Aryl, -C(O)-C 6-10 Aryl, -C(O)OC 6-10 Aryl, preferably halogen, C 6-10 Aryl or -NH-C 6-10 aryl; The A and B are optionally further substituted with halogen, C 1-6 Alkyl or C 1-6 haloalkyl substitution; x is 0, 1, or 2; y is 0, 1, 2, or 3; More preferably, U1, U2 and U3 are -O-; W1, W2 and W3 are independently selected from C 1-4 an alkyl group, preferably a methyl group; Z is selected from chemical bonds, -C 1-4 Alkylene-NHC(O)-C 1-4 Alkylene- or -C 1-4 Alkylene-C(O)NH-C 1-4 Alkylene-, preferably a chemical bond or -C 1-4 Alkylene-NHC(O)-C 1-4 Alkylene-; The Z is optionally replaced by 1, 2 or 3 selected from halogen, C(O)OH, C(O)OC 1-4 Alkyl or C 1-4 Alkyl substituent substitution; A and B are independently selected from H, halogen, phenyl or -NH-phenyl, preferably F, phenyl or NH-phenyl; Said A and B are optionally further substituted by halogen; x, y are 0, 1, or 2.

28. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula II, II-1, II-2, I-1, I-2, and I-3: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; L1 is selected from a single bond, -O- or -NH-; L2 is -C 1-12 Alkylene-, the alkylene may be further C 1-6 Alkyl substitution; R 1 Selected from -OC(O)-Y1; Y1 is selected from C 1-12 Alkyl, C 3-10 Cycloalkyl, C 6-18 Aryl or C 3-18 Heteroaryl, said Y1 may be further C 1-6 Alkyl substitution; Y1 is preferably C 1-6 Alkyl, more preferably CH3; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; L1 is selected from -O- or -NH-; L2 is -C 1-6 Alkylene-, the alkylene may be further C 1-6 Alkyl substitution; R 1 Selected from -OC(O)-Y1; Y1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or C 6-12 Aryl, said Y1 may be further C 1-6 Alkyl substitution; Y1 is preferably CH3; More preferably, U1, U2, and U3 are -O-; W1, W2, and W3 are CH3; L1 is -O-; L2 is -CH2-, -CH(CH3)-, R 1 Selected from 29. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula III, III-1 or III-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; X1 is selected from a chemical bond or -C 1-6 Alkylene-O-; X2 is a chemical bond, -O- or -C(O)-; R 1 Not present, or selected from H, -NH-C 1-12 Alkylene-C(O)-OC 1-12 Alkyl, -C 1-12 Alkylene-C 6-18 Aryl, -OC 1-12 Alkylene-OC(O)-Y3, wherein R 1 The hydrogen atoms on the alkylene group are optionally substituted by Rd; Y3 is -OC 1-6 Alkyl, the C 1-6 The alkyl group may be C 1-6 The alkyl group is further substituted; Ra is selected from OH, -OC 6-18 Aryl, -OC 1-12 Alkylene-C 6-18 Aryl or -OC 6-18 Aryl-C 1-12 alkyl; Alternatively, Ra and X2 are connected to form a ring; Rd is selected from C 1-12 Alkyl or C 1-12 alkoxy; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; X1 is selected from a chemical bond or -C 1-6 Alkylene-O-; X2 is a chemical bond, -O- or -C(O)-; R 1 Not present, or selected from H, -NH-C 1-6 Alkylene-C(O)-OC 1-6 Alkyl, -C 1-6 Alkylene-C 6-10 Aryl, -OC 1-6 Alkylene-OC(O)-Y3, wherein R 1 The hydrogen atoms on the alkylene group are optionally substituted by Rd; Y3 is -OC 1-6 Alkyl, the C 1-6 The alkyl group may be C 1-6 The alkyl group is further substituted; Ra is selected from OH, -OC 6-12 Aryl, -OC 1-6 Alkylene-C 6-12 Aryl or -OC 6-12 Aryl-C 1-6 alkyl; Alternatively, Ra and X2 are connected to form a ring; Rd is C 1-6 alkyl; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; X1 is selected from a chemical bond or -CH2-O-; X2 is a chemical bond or -O-; R 1 Not present, or selected from H, -CH2-phenyl or Ra is selected from OH, -O-phenyl or -O-CH2-phenyl or -O-phenyl-CH3; Alternatively, Ra and X2 are linked to form a ring.

30. The compound of claim 29, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula IVa, IVa-1, IVa-2, IVb, IVb-1, IVb-2, IVc, IVc-1 or IVc-2: Among them, ring G is C 6-12 Aryl, preferably C 6-10 Aryl, more preferably phenyl; The other variables are as defined in claim 29.

31. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula V, V-1 or V-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; R 1 Selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 1-20 -OC in which the hydrogen atom on an alkoxy group, an unsubstituted group, or an alkylene group is replaced by Rd 1-12 Alkylene-OC(O)-Y3; Rd is selected from C 1-12 alkyl; R 1 Preferably C 6-10 Alkyl or C 10-30 alkenyl; Y3 is selected from C 1-12 Alkyl or OC 1-12 alkyl; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; R 1 Selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 1-6 -OC in which the hydrogen atom on an alkoxy group, an unsubstituted group, or an alkylene group is replaced by Rd 1-6 Alkylene-OC(O)-Y3; Rd is selected from C 1-6 alkyl; R 1 Preferably C 6-10 Alkyl or C 10-30 alkenyl; Y3 is C 1-6 alkyl; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; R 1 Selected from CH3, C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 12 Alkyl, C 13 Alkyl, C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 19 Alkyl, C 21 Alkyl, C 23 Alkyl, C 25 alkyl, 32. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of Formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; r, t are selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; k is selected from 0, 1, 2, 3, 4 or 5; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; r, t are selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; k is selected from 0, 1, 2 or 3; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; r is 0, 2, 3, 6, or 7; s is 1, 2, 4, 5, or 6 t is 0, 2, 5, 6, or 8 k is 0 or 1.

33. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula VII, VII-1, VII-2, XIV, XIV-1 or XIV-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; m and n are selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, preferably 6, 7, 8, 9 or 10, more preferably 7, 8 or 9; L1 is a chemical bond, -O- or -NH-; L2 is -C(O)-, -C(O)O-, -C(O)-C 1-18 Alkylene- or -OC 1-18 Alkylene-; Y7 is C 1-12 alkoxy; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; m, n are selected from 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 7, 8 or 9; L1 is -O- or -NH-, preferably -O-; L2 is -C(O)-, -C(O)-C 1-6 Alkylene-; Y7 is C 1-3 alkoxy; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; m and n are 3, 4, 5, 6, 7, or 8, preferably 3 or 8; L1 is O; L2 is -C(O)- or -C(O)-C 1-4 Alkylene-, preferably -C(O)-; Y7 is C 1-3 Alkoxy, preferably OCH3.

34. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula VIII, VIII-1 or VIII-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; Z is selected from C 1-30 Alkylene or C 2-30 Alkenylene, said Z is optionally replaced by 1, 2 or 3 R 3 replace; R 3 C 1-6 alkyl; A is selected from halogen, OH, C optionally substituted by Rc 1-18 Alkyl or C 6-30 Aryl, preferably OH, C optionally substituted by Rc 1-18 Alkyl or C 6-30 Aryl, more preferably C 6-30 aryl; B is selected from halogen, OH or C 6-30 Aryl, preferably halogen or OH, more preferably halogen; Rc is selected from C optionally substituted by OH, oxo or thio 3-10 Cycloalkyl, preferably oxo-substituted C 3-10 Cycloalkyl; x is 0, 1, or 2; y is 0, 1, 2, or 3; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; Z is selected from C 1-6 Alkylene or C 2-6 Alkenylene, preferably C 1-3 Alkylene; said Z is optionally replaced by 1, 2 or 3 R 3 replace; R 3 C 1-6 alkyl; A is selected from halogen, OH, C optionally substituted by Rc 1-6 Alkyl or C 6-12 Aryl, preferably OH, C optionally substituted by Rc 1-6 Alkyl or C 6-12 Aryl, more preferably C 6-12 aryl; B is selected from halogen, OH or C 6-12 Aryl, preferably halogen or OH, more preferably halogen; Rc is selected from C optionally substituted by OH or oxo 3-10 Cycloalkyl; x is 0, 1, or 2; y is 0, 1, 2, or 3; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; Z is selected from -CH(CH3)-, -CH=CH- or -CH2-CH2-; A is selected from F, OH, phenyl, Preferably OH, phenyl, More preferably, it is phenyl; B is selected from F, OH or phenyl, preferably F or OH, more preferably F; x, y are 0, 1, or 2.

35. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula IX, IX-1, or IX-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; A is selected from H or C substituted by Rc 1-18 alkyl; B is selected from halogen or C 6-30 Aryl, preferably halogen or C 6-12 aryl; Rc is selected from C optionally substituted by OH, oxo or thio 3-10 Cycloalkyl, preferably oxo-substituted C 3-10 Cycloalkyl; x is 0, 1, or 2; y is 0, 1, 2, or 3; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; A is selected from H or C substituted by Rc 1-6 Alkyl, preferably H; B is selected from halogen or C 6-10 Aryl, preferably F or phenyl; Rc is selected from C substituted by oxo or OH 3-10 Cycloalkyl, preferably oxo-substituted C 3-10 Cycloalkyl; x is 0, 1, or 2; y is 0, 1, 2, or 3; More preferably, U1, U2, and U3 are -O-; W1, W2, and W3 are CH3; A is selected from B is selected from F or phenyl; x is 0 or 1; y is either 0 or 1.

36. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula X, X-1, X-2, X-3, and X-4: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; Each M1 is independently a chemical bond or -C(O)-, preferably, both M1 are not chemical bonds; L3 is a chemical bond or -C 1-18 -alkylene-, preferably a chemical bond; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; Each M1 is independently a chemical bond or -C(O)-, preferably, both M1 are not chemical bonds; L3 is selected from a chemical bond or -C 1-12 -alkylene-, preferably a chemical bond; More preferably, U1, U2, and U3 are -O-; W1, W2, and W3 are CH3; Each M1 is independently a chemical bond or -C(O)-, preferably, both M1 are not chemical bonds; L3 is selected from a chemical bond or -C 1-6 -Alkylene-, such as a chemical bond, -CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-, is preferably a chemical bond.

37. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the group consisting of compounds of formula XI, XI-1, XI-2, XI-3, and XI-4: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are independently selected from C 1-12 alkyl; L3 is -C 1-18 -alkylene-; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are independently selected from C 1-6 alkyl; L3 is -C 1-12 -alkylene-; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; L3 is -C 1-6 -alkylene-, for example -CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2CH2-.

38. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula XII, XII-1 or XII-2: in, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2, W3 are C 1-12 alkyl; L2 is a chemical bond, -C(O)- or -C(O)O-; R 1 Selected from H, OH or -Y5-Y6-Y7 Y5 is unsubstituted or substituted with NH2 C 1-12 alkylene; Y6 is a single bond or -NH-C(NH)-; Y7 is NH2, OH or C 1-12 alkoxy; Preferably, U1, U2, U3 are selected from -O- or -OC(O)-; W1, W2, W3 are C 1-6 alkyl; L2 is a chemical bond or -C(O)-; R 1 is selected from H, OH or -Y5-Y6-Y7; Y5 is unsubstituted or substituted with NH2 C 3-6 alkylene; Y6 is a single bond or -NH-C(NH)-; Y7 is NH2 or OH; More preferably, U1, U2, and U3 are 0; W1, W2, and W3 are CH3; L2 is a chemical bond or -C(O)-; R 1 Selected from H, 39. The compound of claim 38, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the compounds of formula XIII, XIII-1 or XIII-2: in, The variables are as defined in claim 38.

40. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and mixtures thereof, wherein: The compound is selected from the following compounds:

41. A stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug of the compound of any one of claims 1-40.

42. A composition comprising the compound of any one of claims 1 to 40 and / or the stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, inclusion compound or prodrug of claim 41.

43. A pharmaceutical composition comprising the compound of any one of claims 1 to 40 and / or the stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, inclusion compound or prodrug of claim 41, and optionally a pharmaceutically acceptable carrier or excipient.

44. Use of the compound of any one of claims 1 to 40, the stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug of claim 41, or the composition of claim 42 in the preparation of a medicament for preventing and / or treating central nervous system-related diseases.

45. Use of the compound of any one of claims 1 to 40, the stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug of claim 41, or the composition of claim 42 in the preparation of a medicament for analgesia, antidepression or anti-addiction.

46. ​​The use according to claim 44, wherein The medicine is used for pain caused by postoperative trauma, postoperative incision or cancer organ metastasis.

47. A method for analgesia, antidepression or anti-drug addiction, comprising administering to a subject in need thereof an effective dose of the compound of any one of claims 1 to 40, the stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, inclusion compound or prodrug of claim 41, or the composition of claim 42, wherein the administration is performed orally, rectally, nasally, topically or parenterally.

48. The method of claim 47, wherein The effective dose is 0.1 mg / day to 1000 mg / day, preferably 3 mg / day to 300 mg / day, more preferably 5 mg / day to 50 mg / day, based on the compound.

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