Compounds based on the corydalmine structure and uses thereof

Abstract

The present invention relates to a compound of general formula (A) and a pharmaceutical composition thereof. The compound of formula (A) provided by the present invention can be used to prevent and / or treat diseases related to the central nervous system, such as pain, drug addiction, and depression. The present invention also relates to the preparation and use of the compound. [C1] TIFF2025534778000200.tif48156

Description

[Technical Field]

[0001] This disclosure claims priority to Chinese Patent Application No. 202211273550.1, filed on October 18, 2022, and Chinese Patent Application No. 202311089455.0, filed on August 25, 2023, both of which are incorporated herein by reference in their entireties.

[0002] <Technical field> The present disclosure relates to the field of medicine, and in particular to compounds based on the corydalmine structure and uses thereof. [Background technology]

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

[0004] Corydalmine, one of the active alkaloids in the traditional Chinese herb Rhizoma corydalis, has an extremely low natural content, limiting its use in pharmaceutical applications. Therefore, there is an urgent need to develop other active compounds based on the corydalmine structure. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure aims to provide compounds based on the corydalmine structure that have good analgesic effects and can be used to prepare analgesics. [Means for solving the problem]

[0006] In one aspect, the present disclosure provides a compound of formula I: [ka] A compound of the formula wherein L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-, alternatively a single bond, -O- and -NH-; L2 is a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, C 1~18 Alkylene (alternatively, C 1~12 Alkylene, more alternatively C 1~6 alkylene), C 3~10 Cycloalkylene (alternatively, C 3~8 Cycloalkylene, more alternatively, C 3~6 Cycloalkylene), C 6~30 Arylene (alternatively, C 6~18 Arylene, more alternatively, C 6~12 arylene), C 3~30 Heteroarylene (alternatively, C 3~18 Heteroarylene, more alternatively C 3~12 heteroarylene), -C 1~18 Alkylene-O-(alternatively, -C 1~12 Alkylene-O-, more alternatively, -C 1~6 alkylene-O-), -C 6~30 Arylene-O-(alternatively, -C 6~18 arylene-O-, more alternatively, -C 6~12 arylene-O-), -C 3~30 Heteroarylene-O-(alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -C 3~12 Heteroarylene-O-), -C(O)-C 1~18 Alkyl-, C 1~30 alkoxy or -X1-PRa(O)-X2-, where each R is independently selected from hydrogen, hydroxyl, halogen (alternatively F, Cl, or Br), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), C 3~30Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 Heteroaryl), C 1~30 Hydrocarbon groups (alternatively, C 1~30 Alkyl, more alternatively, C 1~18 Alkyl, and alternatively, C 1~6 alkyl), C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), C 1~30 Alkoxy (alternatively, C 1~18 Alkoxy, more alternatively, C 1~6 Alkoxy), C 6~30 Aryl-O-(alternatively, C 6~18 Aryl-O-, more alternatively, C 6~12 Aryl-O-), C 3~30 Heteroaryl-O-(alternatively, C 3~18 Heteroaryl-O-, more alternatively, C 3~12 Heteroaryl-O-), C 6~30 Aryl-C 1~18 Alkylene-O-(alternatively, C 6~18 Aryl-C 1~12 alkylene-O-, more alternatively C 6~12 Aryl-C 1~6 alkylene-O-), C 3~30 Heteroaryl-C 1~18 Alkylene-O-(alternatively, C 3~18 Heteroaryl-C 1~12 alkylene-O-, more alternatively C 3~12 Heteroaryl-C 1~6 Alkylene-O-), -OC 6~30 Aryl-C 1~18 Alkylene-(alternatively, -OC 6~18 Aryl-C 1~12 Alkylene-) or -OC 3~30 Heteroaryl-C 1~18 Alkylene-(alternatively, -OC 3~18 Heteroaryl-C 1~12alkylene-), wherein Ra and X2 may be connected to form a ring; The above X1 is a single bond, -O-, -C 1~18 Alkylene-O-(alternatively, -C 1~12 Alkylene-O-, more alternatively, -C 1~6 alkylene-O-), -C 6~30 Arylene-O-(alternatively, -C 6~18 arylene-O-, more alternatively, -C 6~12 arylene-O-) or -C 3~30 Heteroarylene-O-(alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -C 3~12 heteroarylene-O-), The above X2 is a single bond, -O- or -NR * - selected from, where R * is H, C 1~6 Alkyl or C 1~6 alkoxy; R 1 is absent or is selected from hydrogen, hydroxyl, unsubstituted or Rb-substituted amino, unsubstituted or Rb-substituted C 1~30 Hydrocarbon groups (alternatively, C 1~30 Alkyl or C 2~30 alkenyl, more alternatively C 1~18 Alkyl or C 2~18 alkenyl, and alternatively, C 1~6 Alkyl or C 2~12 alkenyl, wherein the alkenyl has 1 to 10, alternatively 1 to 6, double bonds, unsubstituted or Rb-substituted C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), unsubstituted or Rb-substituted C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 alkoxy), unsubstituted or Rb-substituted C 12~30 A fused ring group (alternatively, C 12~17fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 tetra-fused ring group), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rc 1~18 Alkyl-C 6~30 Arylene-C 1~18 Alkylene-(alternatively, C 1~12 Alkyl-C 6~18 Arylene-C 1~12 alkyl-), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rd 1~12 Alkyl-OC(O)-C 1~12 Alkylene-imino-, C 6~30 Aryl-C 1~18 Alkylene-(alternatively, C 6~18 Aryl-C 1~12 alkylene-), -OC(O)-Y, unsubstituted or -C in which a hydrogen atom in the alkylene is replaced by Rd 1~12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which a hydrogen atom in the alkylene is replaced by Rd 1~12 Alkylene -OC(O)-Y, -C=CH-Y, -Y-Y-Y or -CHR # R ## is selected from where R # and R ## are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C12~30 a fused ring group, or -NHC(NH)NH-; Each Rb is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br). 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 Alkoxy), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 Heteroaryl) or C 1~30 Alkyl (alternatively, C 1~18 Alkyl, more alternatively, C 1~6 alkyl), Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl, and alternatively, cyclopentyl; Each Rd is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br). 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl), C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 Alkoxy), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein Y1 is unsubstituted or substituted with Re; 1~30 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl), C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein each Re is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br); 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), The above Y2 is unsubstituted or Rf-substituted C 12~30 A fused ring group (alternatively, C 12~17 fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 tetra-fused ring groups), wherein each Rf is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy) or C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), The above Y3 is C1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl) or -OC 1~18 Alkyl (alternatively, -OC 1~12 Alkyl, more alternatively, -OC 1~6 alkyl), Y4 is unsubstituted or substituted with Rg, 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein each Rg is independently selected from hydroxyl and C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy), The above Y5 is a single bond, an unsubstituted or amino-substituted C 1~18 Alkylene (alternatively, C 1~12 Alkylene, more alternatively C 3~6 alkylene), The above Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 20 (alternatively, any natural number from 2 to 10); The above Y7 is amino, C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy) or hydroxyl; When both L1 and L2 are selected from single bonds, R 1 is not hydroxyl, U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O- or -O-, alternatively -O-, or an available ring atom on U2 and an available ring atom on U3 are connected via a Z group to form a 4-8 membered ring, alternatively a 5-6 membered ring; Z is a single bond; NR 3 1 or 2 CH2 are O, S and NR 3 C optionally independently replaced with a group selected from 1~3 alkylene; and C in which any CH to form a C=C double bond is optionally replaced with N. 2~3 alkenylene; W1, W2 and W3 are each independently C 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl) or -(OC 2~6 alkylene) p (Alternatively, -(OC 2~4 alkylene) p , or more alternatively, -(O-CH2-CH2) p ), wherein p is selected from any natural number from 1 to 18 (alternatively, any natural number from 1 to 10); The compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, and mixtures thereof are provided.

[0007] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl, and aralkyl, when present in each occurrence, may each be present in one, two, three, or more R 3 where R is optionally substituted with 3 represents, independently at each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12aralkyl, and the substituent R 3 The above alkyl, alkylene, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl and aralkyl related to the above may independently be halogen, OH, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with 1, 2, 3 or more substituents selected from aralkyl.

[0008] In the present disclosure, the number of substituents such as Ra, Rb, Rc, Rd, Re, Rf, Rg, methoxy, halogen, amino, etc. may be one or more, and is not limited in the present disclosure.

[0009] In some embodiments of the present disclosure, in the compounds of formula I, heteroaryl, heteroarylene, and C containing at least one heteroatom are 12~17 the heteroatoms in the fused ring group are each independently selected from O, N, and S, alternatively N; Alternatively, heteroaryl, heteroarylene, and C containing at least one heteroatom are also included. 12~17 the number of heteroatoms in the fused ring group is 1 to 3, alternatively 1 to 2; Alternatively, a C containing at least one heteroatom 12~17 The tetra-fused ring group is [ka] is.

[0010] In a second aspect, the present disclosure provides a composition comprising the compound described above, or a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate, or prodrug thereof.

[0011] In a third aspect, the present disclosure provides the use of the above compound, or a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug thereof, or the above composition, in the manufacture of a medicament for preventing and / or treating a central nervous system (CNS) related disease.

[0012] In a fourth aspect, the present disclosure provides use of the compound, or a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug thereof, or the composition of claim 42, in the manufacture of a medicament for analgesia, antidepressant or anti-addiction.

[0013] In some alternative embodiments of the present disclosure, the medicament is used for pain caused by post-surgical trauma, post-surgical incision, or organ metastasis of cancer.

[0014] In a fifth aspect, the present disclosure provides a method for analgesia, antidepressant or anti-drug addiction, comprising administering to a subject in need thereof an effective dose of the compound, or a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug thereof, or a composition as described above, wherein said administration is by oral, rectal, nasal, topical or parenteral administration.

[0015] definition chemical definition Definitions of certain functional groups and chemical terms are described in more detail herein below.

[0016] When a range of numerical values ​​is listed, it is intended to encompass any and all values ​​and subranges within that range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C1~2 , 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 Contains alkyl.

[0017] "C 1~30 A "hydrocarbon group" is a group that contains only carbon and hydrogen atoms, which may be saturated or unsaturated, e.g., "C 1~30 Alkyl," "C 2~30 alkenyl" and "C 2~30 It refers to "alkynyl".

[0018] "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 an alternative. 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 is a further alternative. 1~6 Examples of alkyl 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). 1~6The term "alkyl" further includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). Alkyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0019] "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 an alternative. In some embodiments, C 2~6 Alkenyl, C 2~4 Alkenyl and C 2~3 Alkenyl is more alternative. 2~6 Examples of alkenyl 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. 2~6 The term "alkenyl" further includes heteroalkenyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). Alkenyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0020] "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 2~12Alkynyl is an alternative. In some embodiments, C 2~6 Alkynyl and C 2~4 Alkynyl is more alternative. 2~6 Examples of alkynyl 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. 2~6 The term "alkynyl" further includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0021] "C 1~30 alkylene," "C 2~30 alkenylene" and "C 2~30 "Alkynylene" is C 1~30 Alkyl, C 2~30 Alkenyl and C 2~30 It refers to a divalent group formed by removing another hydrogen from an alkynyl, which may be substituted or unsubstituted. 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 an alternative. In some embodiments, C 2~18 Alkenylene, C 2~12 Alkenylene, C 2~6 Alkenylene and C 2~4 Alkenylene is an alternative. In some embodiments, C 2~18 Alkynylene, C 2~12 Alkynylene, C 2~6 Alkynylene and C 2~4Alkynylene is an alternative. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., those substituted with one or more alkyl(methyl), 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)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0022] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0023] Therefore, "C 1~6 Haloalkyl is a group consisting of a C substituted with one or more halogen groups. 1~6 In some embodiments, C 1~4 Haloalkyl is a particular alternative, C 1~2 Haloalkyl is more alternative. Exemplary haloalkyl groups include, but are not limited to, -CF, -CHF, -CHFCHF, -CHCHF, -CFCF, -CCl, -CHCl, -CHCl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Haloalkyl groups can be optionally substituted at any available point of attachment with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0024] "C 1~30 "Alkoxy" refers to the group -OR, where R is C as defined above. 1~30 In some embodiments, C1~18 Alkoxy and C 1~12 Alkoxy is an alternative. In some embodiments, C 1~6 Alkoxy and C 1~4 Alkoxy is a more preferred alternative.

[0025] "C 1~30 "Alkyleneoxy" is C 1~30 It refers to a divalent group formed by removing another hydrogen from alkoxy, and may be substituted or unsubstituted. In some embodiments, C 1~18 Alkyleneoxy and C 1~12 Alkyleneoxy is an alternative. In some embodiments, C 1~6 Alkyleneoxy and C 1~4 Alkyleneoxy is a more alternative.

[0026] "C 1~6 Haloalkoxy is a group consisting of alkoxy groups substituted with one or more halogen groups. 1~6 In some embodiments, C 1~4 Haloalkoxy is a particular alternative, C 1~2 Haloalkoxy is more alternative. Exemplary haloalkoxy groups include, but are not limited to, -OCF, -OCHF, -OCHF, -OCHFCHF, -OCHCHF, -OCFCF, -OCCl, -OCHCl, -OCHCl, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, and the like. Haloalkoxy groups can be optionally substituted at any available point of attachment with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "C 3~10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, C 3~8 Cycloalkyl, C 3~7 Cycloalkyl and C 3~5 Cycloalkyl is a particular alternative, C 5~6Cycloalkyl is more alternative. Cycloalkyl groups also include ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups and the point of attachment is on the cycloalkyl ring; in such cases, the number of carbon atoms still refers to the number of carbon atoms in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), cycloheptyl (C), cycloheptenyl (C), cycloheptadienyl (C), cycloheptatrienyl (C), and the like. Cycloalkyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] "3- to 10-membered heterocyclyl" refers to a group of 3- to 10-membered saturated or unsaturated non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each of which 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 atom or a nitrogen atom, valence permitting. In some embodiments, a 4- to 8-membered heterocyclyl is an alternative that is a 4- to 8-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms; in some other embodiments, a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms is an alternative; and a 5- to 6-membered heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms is even more alternative. Heterocyclyl also includes ring systems in which the above-described heterocyclyl is fused to one or more cycloalkyl groups, with the point of attachment being on the cyclylalkyl ring, or the above-described heterocyclyl is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl (thiorenyl). Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused with a C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused with C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include bridged or spiro rings formed by the above heterocyclyl groups and cycloalkyl, heterocyclyl, aryl, or heteroaryl groups sharing one or two atoms, where the shared atom may be a carbon atom or a nitrogen atom, as permitted by valence. Heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] "C 6~30 "Aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring systems having 6 to 30 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared π electrons in the ring arrangement). In some embodiments, C 6~18 Aryl and C 6~12 Aryl is alternative and C 6~10Aryl is more alternative. In some embodiments, aryl has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, aryl has 10 ring carbon atoms ("C 10 Aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl groups also include ring systems in which an aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, the point of attachment of which is on the aryl ring; in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Aryl groups may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] "C 3~30 "Heteroaryl" refers to a group of monocyclic or bicyclic 4n+2 aromatic ring systems containing 3 to 30 ring carbon atoms and at least one ring heteroatom (e.g., having 6 or 10 shared π electrons in the ring arrangement), and "5- to 14-membered heteroaryl" refers to a group of 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring systems containing ring carbon atoms and 1 to 5 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic systems may contain one or more heteroatoms on one or both of the rings. Heteroaryl groups further include ring systems in which a heteroaryl ring is fused to one or more cycloalkyls or heterocyclyls, and the point of attachment is on the heteroaryl ring; in such cases, the number of carbon atoms still represents the number of carbon atoms in the heteroaryl ring system. In some embodiments, C 3~18 Heteroaryl and C 3~12 Heteroaryl is an alternative, C 3~10 Heteroaryl and C 3~6Heteroaryl is more alternative. Exemplary 5-membered heteroaryl groups containing one heteroatom (i.e., C4 heteroaryl) include, but are not limited to, pyrrolyl, furyl, 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, pyridyl. 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) include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "C 3~10 "Cycloalkylene", "3- to 10-membered heterocyclylene", "C 6~30 arylene" and "C 3~30 "Heteroarylene" is C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~30 Aryl and C 3~30 It refers to a divalent group formed by removing another hydrogen from a heteroaryl, and may be substituted or unsubstituted.

[0032] Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl defined above are collectively referred to as "cyclic groups."

[0033] Groups such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.

[0034] Exemplary substituents on carbon atoms include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc) R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)Raa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NRbb )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 of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, Or, two geminal hydrogens on a carbon atom are =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 is replaced by a group, R aa are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb each independently represents hydrogen, —OH, —OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(Rcc )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 groups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups linked to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X- 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-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)(OR ee)2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd the substituents may combine to form =O or =S; R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups linked to form a heterocyclyl or heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC1~6 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 1~6 alkyl), -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(C1~6 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 1~6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclyl or C5-C 10 Heteroaryl or two geminal R gg The substituents may be linked to form =O or =S, where X - is the counterion.

[0035] Exemplary substituents on a nitrogen atom include 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)(NRcc ) 2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bonded to a nitrogen atom cc groups are joined to form a heterocyclyl or heteroaryl ring, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as described herein.

[0036] Other definitions As used herein, the term "treating" refers to reversing, alleviating, or inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the noun "treatment" refers to the act of treating, which is a verb, as just defined.

[0037] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate and amino acid addition salts of compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for contact with patient tissues and do not cause undue toxicity, irritation, allergy, etc., that are commensurate with a reasonable benefit / risk ratio and are effective for their intended use. The term also includes, to the extent possible, zwitterionic forms of compounds of the present disclosure.

[0038] 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, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0039] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the necessary base to form the salt in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner, followed by isolation of the free acid. The free acid form will have somewhat different physical properties, such as solubility in polar solvents, from its salt form. However, for purposes of this disclosure, the salt is still equivalent to its free acid.

[0040] Salts can be prepared from inorganic acids and include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, and iodide. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucoheptanoate, lactobionate, laurylsulfonate, and isethionate. Salts can also be prepared from organic acids, including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids such as arginine salts, gluconates, galacturonates, etc. are also included (see, for example, Berge, S. M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, for reference).

[0041] A "subject in need" to which administration is contemplated includes, but is not limited to, a human (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or the elderly)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. 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" may be used interchangeably herein.

[0042] "Disease," "disorder," and "condition" may be used interchangeably herein.

[0043] Unless otherwise specified, as used herein, the term "treatment" includes an effect on a subject suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"). The term also includes an effect that occurs before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0044] In general, an "effective dose" or "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of a compound of the present disclosure may vary depending on the following factors: the desired biological endpoint, 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 a therapeutically effective amount and a prophylactically effective amount.

[0045] Unless otherwise specified, as used herein, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in treating a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0046] Unless otherwise specified, as used herein, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of the disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of 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 another prophylactic agent.

[0047] "Combination" and related terms refer to simultaneous or sequential administration of a compound of the present disclosure and another therapeutic agent. For example, the compound of the present disclosure can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosages, or simultaneously with the other therapeutic agent in a single unit dosage. DETAILED DESCRIPTION OF THE INVENTION

[0048] In this disclosure, "a compound of the disclosure" refers to a compound of Formula (A) or Formula (I) below (including subgeneric formulae), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0049] In this disclosure, compounds are named using standard nomenclature. For compounds with asymmetric centers, unless otherwise specified, it should be understood that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomeric compounds and carbon-carbon double bonds included in this disclosure can exist in Z and E forms. For compounds that can exist in different tautomeric forms, the compounds described are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0050] In some embodiments, the present disclosure provides a compound of formula A: [ka] A compound of the formula: During the ceremony, * represents a chiral center and is selected from the (S)-configuration or the (R)-configuration; L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-, alternatively a single bond, -O-, -NH-; L2 is a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, -C(O)NH-, -OC(O)-, C 1~18 Alkylene (alternatively, C 1~12 Alkylene, more alternatively C 1~6 alkylene), C 3~10 Cycloalkylene (alternatively, C 3~8 Cycloalkylene, more alternatively, C 3~6 cycloalkylene), C 6~30 Arylene (alternatively, C 6~18 Arylene, more alternatively, C 6~12 arylene), C 3~30 Heteroarylene (alternatively, C 3~18 Heteroarylene, more alternatively C 3~12 heteroarylene), -C 1~18 Alkylene-O-(alternatively, -C 1~12Alkylene-O-, more alternatively, -C 1~6 alkylene-O-), -C 6~30 Arylene-O-(alternatively, -C 6~18 Arylene-O-, more alternatively, -C 6~12 arylene-O-), -C 3~30 Heteroarylene-O-(alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -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-, where each Ra is independently selected from hydrogen, hydroxyl, halogen (alternatively F, Cl, or Br), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 Heteroaryl), C 1~30 Hydrocarbon groups (alternatively, C 1~30 Alkyl, more alternatively, C 1~18 Alkyl, and alternatively, C 1~6 alkyl), C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), C 1~30 Alkoxy (alternatively, C 1~18 Alkoxy, more alternatively, C 1~6 Alkoxy), C 6~30 Aryl-O-(alternatively, C 6~18Aryl-O-, more alternatively, C 6~12 Aryl-O-), C 3~30 Heteroaryl-O-(alternatively, C 3~18 Heteroaryl-O-, more alternatively, C 3~12 Heteroaryl-O-), C 6~30 Aryl-C 1~18 Alkylene-O-(alternatively, C 6~18 Aryl-C 1~12 alkylene-O-, more alternatively C 6~12 Aryl-C 1~6 alkylene-O-), C 3~30 Heteroaryl-C 1~18 Alkylene-O-(alternatively, C 3~18 Heteroaryl-C 1~12 alkylene-O-, more alternatively C 3~12 Heteroaryl-C 1~6 Alkylene-O-), -OC 6~30 Aryl-C 1~18 Alkylene-(alternatively, -OC 6~18 Aryl-C 1~12 Alkylene-) or -OC 3~30 Heteroaryl-C 1~18 Alkylene-(alternatively, -OC 3~18 Heteroaryl-C 1~12 alkylene-), wherein Ra and X2 may be connected to form a ring; The above X1 is a single bond, -O-, -C 1~18 Alkylene-O-(alternatively, -C 1~12 Alkylene-O-, more alternatively, -C 1~6 alkylene-O-), -C 6~30 Arylene-O-(alternatively, -C 6~18 Arylene-O-, more alternatively, -C 6~12 arylene-O-) or -C 3~30 Heteroarylene-O-(alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -C 3~12 heteroarylene-O-), The above X2 is a single bond, -O- or -NR *- selected from, where R * is H, C 1~6 Alkyl and C 1~6 alkoxy; The above L2 is halogen, OH, CN, C(O)OH, C(O)OC 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 optionally substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkoxy; R 1 is absent or hydrogen, hydroxyl, amino unsubstituted or substituted with 1 or 2 Rb, C unsubstituted or substituted with Rb 1~30 Hydrocarbon groups (alternatively, C 1~30 Alkyl or C 2~30 alkenyl, more alternatively C 1~18 Alkyl or C 2~18 alkenyl, and alternatively, C 1~6 Alkyl or C 2~12 alkenyl, wherein the alkenyl has 1 to 10, alternatively 1 to 6, double bonds, unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb; 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), unsubstituted or Rb-substituted C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 alkoxy), unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb 12~30 A fused ring group (alternatively, C 12~17 fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 tetra-fused ring group), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rc 1~18 Alkyl-C 6~30 Arylene-C 1~18 Alkylene-(alternatively, C1~12 Alkyl-C 6~18 Arylene-C 1~12 alkylene-), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rd 1~12 Alkyl-OC(O)-C 1~12 Alkylene-imino-, C 6~30 Aryl-C 1~18 Alkylene-(alternatively, C 6~18 Aryl-C 1~12 alkylene-), -OC(O)-Y, unsubstituted or -C in which a hydrogen atom in the alkylene is replaced by Rd 1~12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which a hydrogen atom in the alkylene is replaced by Rd 1~12 Alkylene -OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## , -ZC optionally substituted with xA 6~30 Aryl (alternatively, -ZC 6~18 Aryl, more alternatively, -ZC 6~12 aryl, e.g., -Z-phenyl), where R # and R ## are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C 12~30 a fused ring group, or -NHC(NH)NH-; Each Rb is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br). 1~30Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 Alkoxy), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 Heteroaryl) or C 1~30 Alkyl (alternatively, C 1~18 Alkyl, more alternatively, C 1~6 alkyl), Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl, and alternatively, cyclopentyl; Each Rd is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br). 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl), C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 Alkoxy), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein Y1 is unsubstituted or substituted with Re; 1~30 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl), C3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein each Re is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br); 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), The above Y2 is unsubstituted or Rf-substituted C 12~30 A fused ring group (alternatively, C 12~17 fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 tetra-fused ring groups), wherein each Rf is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy) or C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), The above Y3 is C 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl) or -OC 1~18 Alkyl (alternatively, -OC 1~12Alkyl, more alternatively, -OC 1~6 alkyl), Y4 is unsubstituted or substituted with Rg, 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein each Rg is independently selected from hydroxyl and C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy), The above Y5 is a single bond, an unsubstituted or amino-substituted C 1~18 Alkylene (alternatively, C 1~12 Alkylene, more alternatively C 3~6 alkylene), The above Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 20 (alternatively, any natural number from 2 to 10); The above Y7 is amino, C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy) or hydroxyl; x is selected from 0, 1, 2, 3, 4 or 5; Z is a chemical bond, -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)-C1~12 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 -, alternatively a chemical bond or -C 1~6 Alkylene-NHC(O)-C 1~6 alkylene-, The above Z is 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 optionally substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl; A is independently H, halogen, OH, -L A -C 3~10 Cycloalkyl, -L A -3 to 10-membered heterocyclyl, -L A -C 6~12 Aryl or -L A -5 to 12 membered heteroaryl, alternatively 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—; A above is halogen, C 1~6 Alkyl or C 1~6 optionally further substituted with haloalkyl; When both L1 and L2 are selected from single bonds, R 1 is not hydroxyl, U1, U2 and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O- and -O-, or an available ring atom on U2 and an available ring atom on U3 are connected through a Q group to form a 4- to 8-membered ring, alternatively a 5- or 6-membered ring; Q is a single bond; NR 3 1 or 2 CH2 are O, S and NR 3 C optionally independently replaced with a group selected from 1~3 alkylene; and C in which any CH to form a C=C double bond is optionally replaced with N. 2~3 alkenylene; W1, W2 and W3 are each independently C 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl) or -(OC 2~6 alkylene) p (Alternatively, -(OC 2~4 alkylene) p , or more alternatively, -(O-CH2-CH2) p ), wherein p is selected from any natural number from 1 to 18, alternatively any natural number from 1 to 10; The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl, and aralkyl, when present in each occurrence, may each be present in one, two, three, or more R 3 where R is optionally substituted with 3 represents, independently at each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 aralkyl, and the substituent R 3 The above alkyl, alkylene, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl and aralkyl related to the above may independently be halogen, OH, oxo, amino, cyano, nitro, C 1~6 Alkyl, C1~6 Haloalkyl, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 optionally further substituted with 1, 2, 3 or more substituents selected from aralkyl; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0051] In some embodiments, the present disclosure provides compounds of formula A-1 or A-2: [ka] A compound of the formula: wherein the various variables are as defined herein. The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0052] L1 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-, and in another embodiment, L1 is -P(O)OH-.

[0053] L2 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)-; 1~18 alkylene, and in another embodiment, L2 is C 1~12 alkylene, and in another embodiment, L2 is C 1~6 alkylene, and in another embodiment, L2 is C3~10 In another embodiment, L is C 3~8 In another embodiment, L is C 3~6 In another embodiment, L is C 6~30 arylene, and in another embodiment, L2 is C 6~18 arylene, and in another embodiment, L2 is C 6~12 arylene, and in another embodiment, L2 is C 3~30 In another embodiment, L2 is C 3~18 In another embodiment, L2 is C 3~12 In another embodiment, L2 is -C 1~18 In another embodiment, L2 is -C 1~12 In another embodiment, L2 is -C 1~6 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 In another embodiment, L2 is -C 3~18 In another embodiment, L2 is -C 3~12 Heteroarylene-O-, e.g., -C 3~6 In another embodiment, L2 is -C(O)-C 1~18 In another embodiment, L2 is -C(O)-C 1~12 In another embodiment, L2 is -C(O)-C 1~6 In another embodiment, L2 is -C(O)-C 1~18 Alkylene-NHC(O)-C 1~18 In another embodiment, L2 is -C(O)-C 1~12 Alkylene-NHC(O)-C 1~12 In another embodiment, L2 is -C(O)-C1~6 Alkylene-NHC(O)-C 1~6 In another embodiment, L2 is -C(O)-C 1~18 Alkylene-C(O)NH-C 1~18 In another embodiment, L2 is -C(O)-C 1~12 Alkylene-C(O)NH-C 1~12 In another embodiment, L2 is -C(O)-C 1~6 Alkylene-C(O)NH-C 1~6 alkylene-, and in another embodiment, L2 is C 1~30 alkyleneoxy, and in another embodiment, L2 is C 1~18 alkyleneoxy, and in another embodiment, L2 is C 1~12 alkyleneoxy, and in another embodiment, L2 is C 1~6 In another embodiment, L2 is -X1-PRa(O)-X2-.

[0054] In one embodiment, L2 is unsubstituted, and in another embodiment, L2 is halogen, OH, CN, C(O)OH, C(O)OC 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 and optionally substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkoxy.

[0055] In certain embodiments, L2 is -C 1~12 alkylene-, where alkylene is C 1~6 It may be further substituted with alkyl.

[0056] In certain embodiments, L2 is -CH2-, in another particular embodiment, L2 is -CH(CH3)-, and in another particular embodiment, L2 is [ka] is.

[0057] L3 In one embodiment, L3 is a chemical bond, and in another embodiment, L3 is C 1~12 alkylene, and in another embodiment, L3 is -C 1~6 In another embodiment L3 is -alkylene-; in another embodiment L3 is -CH2-; in another embodiment L3 is -CH2CH2CH2-; in another embodiment L3 is -CH2CH2CH2CH2CH2CH2-.

[0058] X1 In one embodiment, X1 is a single bond, in another embodiment, X1 is -O-, and in another embodiment, X1 is -C 1~18 Alkylene-O-, alternatively -C 1~12 Alkylene-O-, more alternatively, -C 1~6 alkylene-O—, and in another embodiment, X1 is —C 6~30 arylene-O-, alternatively, -C 6~18 arylene-O-, more alternatively, -C 6~12 arylene-O-; in another embodiment, X1 is -C 3~30 Heteroarylene-O-, alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -C 3~12 It is heteroarylene-O-.

[0059] X2 In one embodiment, X2 is a single bond, in another embodiment, X2 is -O-, and in another embodiment, X2 is -NR * -It is.

[0060] In one embodiment, R * is H, C 1~6 Alkyl, C 1~6 Alkoxy is selected from:

[0061] Ra In one embodiment, Ra is hydrogen; in another embodiment, Ra is hydroxyl; in another embodiment, Ra is halogen, alternatively, F, Cl, or Br; in another embodiment, Ra is C 6~30 aryl, alternatively C6~18 Aryl, more alternatively, C 6~12 aryl, and in another embodiment, Ra is C 3~30 Heteroaryl, alternatively C 3~18 Heteroaryl, more alternatively, C 3~12 In another embodiment, Ra is C 1~30 Hydrocarbon radical, alternatively C 1~30 Alkyl, more alternatively C 1~18 Alkyl, and alternatively C 1~6 alkyl, for example, methyl or ethyl; in another embodiment, Ra is C 3~10 cycloalkyl, alternatively C 3~8 Cycloalkyl, more alternatively, C 3~6 In another embodiment, Ra is C 1~30 Alkoxy, alternatively C 1~18 Alkoxy, more alternatively, C 1~6 In another embodiment, Ra is C 6~30 Aryl-O-, alternatively C 6~18 Aryl-O-, more alternatively, C 6~12 aryl-O—, and in another embodiment, Ra is C 3~30 Heteroaryl-O-, alternatively C 3~18 Heteroaryl-O-, more alternatively, C 3~12 In another embodiment, Ra is C 6~30 Aryl-C 1~18 alkylene-O-, alternatively C 6~18 Aryl-C 1~12 alkylene-O-, more alternatively C 6~12 Aryl-C 1~6 alkylene-O-, and in another embodiment, Ra is C 3~30 Heteroaryl-C 1~18 alkylene-O-, alternatively C 3~18 Heteroaryl-C 1~12 alkylene-O-, more alternatively C 3~12 Heteroaryl-C 1~6 alkylene-O-, and in another embodiment, Ra is -OC 6~30Aryl-C 1~18 Alkylene-, alternatively -OC 6~18 Aryl-C 1~12 alkylene-, and in another embodiment, Ra is -OC 3~30 Heteroaryl-C 1~18 Alkylene-, alternatively -OC 3~18 Heteroaryl-C 1~12 In another embodiment, Ra is alkylene-, and Ra and X2 may be connected to form a ring.

[0062] R 1 In one embodiment, R 1 is absent, and in another embodiment, R 1 is hydrogen, and in another embodiment, R 1 is hydroxyl, and in another embodiment, R 1 is amino unsubstituted or substituted with one or two Rb, and in another embodiment, R 1 is unsubstituted or Rb-substituted C 1~30 In another embodiment, R 1 is C 1~30 Alkyl or C 2~30 alkenyl, and in another embodiment, R 1 is C 1~18 Alkyl or C 2~18 alkenyl, and in another embodiment, R 1 is C 1~6 Alkyl or C 2~12 alkenyl, where the alkenyl has 1 to 10, alternatively 1 to 6, double bonds; in another embodiment, R 1 is unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb; 3~10 cycloalkyl, alternatively C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl, and in another embodiment, R 1 is unsubstituted or Rb-substituted C 1~30 Alkoxy, alternatively C 1~20 Alkoxy, more alternatively, C 1~12In another embodiment, R 1 is unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb; 12~30 A fused ring group, alternatively C 12~17 fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 Tetra-fused ring groups, for example: [ka] and in another embodiment, R 1 is oxocyclopentyl-C 1~6 Alkylene-C 6~12 Arylene-C 1~6 alkylene-, and in another embodiment, R 1 is hydroxycyclopentyl-C 1~6 Alkylene-C 6~12 Arylene-C 1~6 alkylene-, and in another embodiment, R 1 is unsubstituted or a hydrogen atom in the alkyl is replaced by Rc, C 1~18 Alkyl-C 6~30 Arylene-C 1~18 alkylene-, alternatively C 1~12 Alkyl-C 6~18 Arylene-C 1~12 alkylene-, and in another embodiment, R 1 is unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rd 1~12 Alkyl-OC(O)-C 1~12 alkylene-imino-, and in another embodiment, R 1 is C 6~30 Aryl-C 1~18 alkylene-, alternatively C 6~18 Aryl-C 1~12 alkylene-, and in another embodiment, R 1 is —OC(O)—Y; in another embodiment, R 1 is unsubstituted or -C in which a hydrogen atom in the alkylene is replaced by Rd 1~12alkylene-C(O)-O-Y; in another embodiment, R 1 is unsubstituted or -OC in which a hydrogen atom in the alkylene is replaced by Rd 1~12 alkylene-OC(O)-Y; in another embodiment, R 1 is -C=CH-Y4, and in another embodiment, R 1 is -Y-Y-Y, and in another embodiment, R 1 Ha-CHR # R ## and in another embodiment, R 1 Ha-ZC 6~30 aryl, alternatively -ZC 6~18 Aryl, more alternatively, -ZC 6~12 Aryl, for example -Z-phenyl, optionally substituted with xA.

[0063] In particular, R # and R ## are each independently 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.

[0064] In one embodiment, when both L and L are selected from a single bond, R 1 is not a hydroxyl.

[0065] In certain embodiments, R 1 is H, and in another particular embodiment, R 1 is —OH, and in another particular embodiment, R 1 is —NH, and in another particular embodiment, R 1 is —OCH3, and in another particular embodiment R 1 is methyl, and in another particular embodiment, R 1is ethyl, and in another particular embodiment, R 1 is isopropyl, and in another particular embodiment, R 1 is cyclopropyl, and in another particular embodiment, R 1 Ha-(CH2) p CH3, and in another particular embodiment, R 1 Ha-(CH2) p OCH3, and in another particular embodiment, R 1 Ha-(CH2) p NH2, and in another particular embodiment, R 1 Ha-(CH2) p OH, and in another particular embodiment, R 1 is —(OCH2CH2)qCH3, and in another particular embodiment, R 1 is —(OCH2CH2)qOCH3, and in another particular embodiment, R 1 is —(OCHCH)OH, and in another particular embodiment, R 1 is —(OCHCH)NH, and in another particular embodiment, R 1 is phenyl, and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 is —CH-phenyl, and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 is C alkyl, and in another particular embodiment, R 1 is C alkyl, and in another particular embodiment, R 1 is C alkyl, and in another particular embodiment, R 1 is C 10 alkyl, and in another particular embodiment, R 1 is C 11 alkyl, and in another particular embodiment, R 1 is C 12alkyl, and in another particular embodiment, R 1 is C 13 alkyl, and in another particular embodiment, R 1 is C 14 alkyl, and in another particular embodiment, R 1 is C 15 alkyl, and in another particular embodiment, R 1 is C 16 alkyl, and in another particular embodiment, R 1 is C 17 alkyl, and in another particular embodiment, R 1 is C 18 alkyl, and in another particular embodiment, R 1 is C 19 alkyl, and in another particular embodiment, R 1 is C 20 alkyl, and in another particular embodiment, R 1 is C 21 alkyl, and in another particular embodiment, R 1 is C 22 alkyl, and in another particular embodiment, R 1 is C 23 alkyl, and in another particular embodiment, R 1 is C 24 alkyl, and in another particular embodiment, R 1 is C 25 alkyl, and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] and in another particular embodiment, R 1 teeth [ka] is.

[0066] R 2 In one embodiment, R 2 is H, and in another embodiment, R 2 is hydroxyl, and in another embodiment, R 2 is amino, and in another embodiment, R 2 is halogen, and in another embodiment, R 2 is alkyl, and in another embodiment, R 2 is cycloalkyl, and in another embodiment, R 2 is aryl, and in another embodiment, R 2 is heteroaryl, and in another embodiment, R 2 is unsubstituted or Rb-substituted C 12~30 In another embodiment, R 2 is -NHC(NH)NH-.

[0067] Rb In one embodiment, Rb is C 1~30 In another embodiment, Rb is C 1~20 In another embodiment, Rb is C 1~12 In another embodiment, Rb is C 1~3 In another embodiment, Rb is C 6~30 aryl, and in another embodiment, Rb is C 6~18 aryl, and in another embodiment, Rb is C 6~12 aryl, and in another embodiment, Rb is C 3~30 heteroaryl, and in another embodiment, Rb is C 3~18 heteroaryl, and in another embodiment, Rb is C 3~12 heteroaryl, and in another embodiment, Rb is C 1~30 alkyl, and in another embodiment, Rb is C 1~18 alkyl, and in another embodiment, Rb is C 1~6 It is alkyl.

[0068] In one embodiment, Rb is unsubstituted, and in another embodiment, Rb is substituted with a halogen (alternatively, F, Cl, or Br).

[0069] Rc In one embodiment, Rc is C 3~10 In another embodiment, Rc is C 3~8 In another embodiment, Rc is C 3~6 In another embodiment, Rc is cyclopentyl.

[0070] In one embodiment, Rc is unsubstituted, in another embodiment, Rc is substituted with hydroxyl, and in another embodiment, Rc is substituted with oxo or thioxo.

[0071] Road In one embodiment, Rd is C 1~18 alkyl, and in another embodiment, Rd is C 1~12 alkyl, and in another embodiment, Rd is C 1~6 alkyl, and in another embodiment, Rd is C 1~30 In another embodiment, Rd is C 1~20 In another embodiment, Rd is C 1~12 In another embodiment, Rd is C 1~3 In another embodiment, Rd is C 6~30 aryl, and in another embodiment, Rd is C 6~18 aryl, and in another embodiment, Rd is C 6~12 aryl, and in another embodiment, Rd is C 3~30 heteroaryl, and in another embodiment, Rd is C 3~18 heteroaryl, and in another embodiment, Rd is C 3~12 It is heteroaryl.

[0072] In one embodiment, Rd is unsubstituted, and in another embodiment, Rd is substituted with halogen (alternatively, F, Cl, or Br).

[0073] Y1 In one embodiment, Y is C 1~30 alkyl, and in another embodiment, Y is C 1~12alkyl, and in another embodiment, Y is C 1~6 alkyl, and in another embodiment, Y is C 3~10 In another embodiment, Y is C 3~8 In another embodiment, Y is C 3~6 In another embodiment, Y is C 6~30 aryl, and in another embodiment, Y is C 6~18 aryl, and in another embodiment, Y is C 6~12 aryl, and in another embodiment, Y is C 3~30 heteroaryl, and in another embodiment, Y is C 3~18 heteroaryl, and in another embodiment, Y is C 3~12 It is heteroaryl.

[0074] In one embodiment, Y is unsubstituted, in another embodiment, Y is substituted with Re, and in another embodiment, Y is C 1~6 It is substituted with alkyl.

[0075] Re In one embodiment, Re is C 6~30 aryl, and in another embodiment, Re is C 6~18 aryl, and in another embodiment, Re is C 6~12 aryl, and in another embodiment, Re is C 3~30 In another embodiment, Re is C 3~18 In another embodiment, Re is C 3~12 It is heteroaryl.

[0076] In one embodiment, Re is unsubstituted, and in another embodiment, Re is substituted with a halogen (alternatively, F, Cl, or Br).

[0077] Y2 In one embodiment, Y2 is C 12~30 In another embodiment, Y2 is C 12~17In another embodiment, Y2 is a C 12~17 In another embodiment, Y2 is a C 12~17 Tetrafused ring groups, such as [ka] is.

[0078] In one embodiment, Y2 is unsubstituted, and in another embodiment, Y2 is substituted with Rf.

[0079] Rf In one embodiment, Rf is C 1~30 In another embodiment, Rf is C 1~20 In another embodiment, Rf is C 1~12 In another embodiment, Rf is C 1~3 In another embodiment, Rf is C 6~30 aryl, and in another embodiment, Rf is C 6~18 aryl, and in another embodiment, Rf is C 6~12 It is aryl.

[0080] In one embodiment, Rf is unsubstituted, and in another embodiment, Rf is substituted with a halogen (alternatively, F, Cl, or Br).

[0081] Y3 In one embodiment, Y3 is C 1~18 alkyl, and in another embodiment, Y is C 1~12 alkyl, and in another embodiment, Y is C 1~6 alkyl, and in another embodiment, Y3 is -OC 1~18 alkyl, and in another embodiment, Y3 is -OC 1~12 alkyl, and in another embodiment, Y3 is -OC 1~6 It is alkyl.

[0082] Y4 In one embodiment, Y4 is C6~30 aryl, and in another embodiment, Y is C 6~18 aryl, and in another embodiment, Y is C 6~12 aryl, and in another embodiment, Y is C 3~30 heteroaryl, and in another embodiment, Y is C 3~18 heteroaryl, and in another embodiment, Y is C 3~12 heteroaryl, and in another embodiment, Y is C 3~6 It is heteroaryl.

[0083] In one embodiment, Y4 is unsubstituted, and in another embodiment, Y4 is substituted with Rg.

[0084] Rg In one embodiment, Rg is hydroxyl, and in another embodiment, Rg is C 1~30 In another embodiment, Rg is C 1~20 In another embodiment, Rg is C 1~12 In another embodiment, Rg is C 1~3 It is an alkoxy.

[0085] Y5 In one embodiment, Y5 is a single bond, and in another embodiment, Y5 is an unsubstituted or amino-substituted C 1~18 In another embodiment, Y is an unsubstituted or amino-substituted C 1~12 In another embodiment, Y is an unsubstituted or amino-substituted C 3~6 It is alkylene.

[0086] Y6 In one embodiment, Y6 is a single bond, in another embodiment, Y6 is -NH-C(NH)-, and in another embodiment, Y6 is -(O-CH2-CH2) m -, and in another embodiment, Y6 is -CH2-(O-CH2-CH2) n -It is.

[0087] m and n are each independently selected from any natural number from 2 to 20, alternatively any natural number from 2 to 10.

[0088] Y7 In one embodiment, Y7 is amino, and in another embodiment, Y7 is C 1~30 In another embodiment, Y7 is C 1~20 In another embodiment, Y7 is C 1~12 In another embodiment, Y7 is C 1~3 In another embodiment, Y7 is alkoxy, and in another embodiment, Y7 is hydroxyl.

[0089] Z 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, and in another embodiment, Z is C 1~18 alkylene, and in another embodiment, Z is -C 1~12 alkylene-, and in another embodiment, Z is -C 1~6 alkylene-, and in another embodiment, Z is -C 1~12 Alkylene-OC 1~12 alkylene-, and in another embodiment, Z is -C 1~12 Alkylene-NH-C 1~12 alkylene-, and in another embodiment, Z is -C 1~6 Alkylene-NH-C 1~6 alkylene-, and in another embodiment, Z is -C 1~18 Alkylene-C(O)-C 1~12 alkylene-, and in another embodiment, Z is -C 1~10 Alkylene-C(O)OC 1~10 alkylene-, and in another embodiment, Z is -C 1~10 Alkylene-NHC(O)-C 1~10 alkylene-, and in another embodiment, Z is -C 1~6 Alkylene-NHC(O)-C 1~6 alkylene-, and in another embodiment, Z is -C 1~4 Alkylene-NHC(O)-C1~4 alkylene-, and in another embodiment, Z is -C 1~10 Alkylene-NHC(O)OC 1~10 alkylene-, and in another embodiment, Z is -C 1~10 Alkylene-C(O)NH-C 1~10 alkylene-, and in another embodiment, Z is -C 1~6 Alkylene-C(O)NH-C 1~6 alkylene-, and in another embodiment, Z is -C 1~4 Alkylene-C(O)NH-C 1~4 alkylene-, and in another embodiment, Z is -C 1~10 Alkylene-OC(O)NH-C 1~10 alkylene-, and in another embodiment, Z is C 3~10 In another embodiment, Z is C 6~30 arylene, and in another embodiment, Z is C 3~30 heteroarylene, in another embodiment, Z is -C=CH-.

[0090] In one embodiment, Z is unsubstituted, and in another embodiment, Z is 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 and optionally substituted with 1, 2, 3, 4, or 5 substituents selected from haloalkyl.

[0091] A 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 In another embodiment, A is -L A -3 to 10-membered heterocyclyl, and in another embodiment, A is -L A -C 6~12 In another embodiment, A is -L A-5 to 12 membered heteroaryl, and in another embodiment, A is C 6~10 aryl, and in another embodiment, A is -NH-C 6~10 aryl, and in another embodiment, A is C substituted with R 1~18 It is alkyl.

[0092] In certain embodiments, A is F; in another particular embodiment, A is OH; in another particular embodiment, A is phenyl; in another particular embodiment, A is [ka] and in another particular embodiment, A is [ka] is.

[0093] In one embodiment, A is unsubstituted, and in another embodiment, A is halogen, C 1~6 Alkyl or C 1~6 Optionally further substituted with haloalkyl.

[0094] B 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 In another embodiment, B is -L A -3 to 10-membered heterocyclyl, and in another embodiment, B is C 6~30 In another embodiment, B is -L A -C 6~12 In another embodiment, B is -L A -5 to 12 membered heteroaryl, and in another embodiment, B is C 6~10 aryl, and in another embodiment, B is —NH—C 6~10 It is aryl.

[0095] B is halogen, C 1~6 Alkyl or C 1~6Optionally further substituted with haloalkyl.

[0096] x and y In one embodiment, x is selected from 0, 1, 2, 3, 4 and 5.

[0097] In one embodiment, y is selected from 0, 1 and 2.

[0098] In one embodiment, x+y is not zero.

[0099] L A In one embodiment, L A is a chemical bond, and in another embodiment, L A is —NH—, and in another embodiment, L A is —O—, and in another embodiment, L A is —C(O)—, and in another embodiment, L A is —C(O)O—, and in another embodiment, L A is —NHC(O)—, and in another embodiment, L A is —NHC(O)O—, and in another embodiment, L A is —OC(O)NH—, and in another embodiment, L A is -C(O)NH-.

[0100] U1, U2 and U3 In one embodiment, U1 is -OC(O)-, in another embodiment, U1 is -NH-C(O)-, in another embodiment, U1 is -O-CH2-O-, and in another embodiment, U1 is -O-.

[0101] In one embodiment, U2 is -OC(O)-, in another embodiment, U2 is -NH-C(O)-, in another embodiment, U2 is -O-CH2-O-, and in another embodiment, U2 is -O-.

[0102] In one embodiment, U3 is -OC(O)-, in another embodiment, U3 is -NH-C(O)-, in another embodiment, U3 is -O-CH2-O-, and in another embodiment, U3 is -O-.

[0103] In one embodiment, an available ring atom on U2 and an available ring atom on U3 are connected through a Q group to form a 4-8 membered ring, alternatively a 5-6 membered ring.

[0104] Q In one embodiment, Q is a single bond, and in another embodiment, Q is NR 3 and in another embodiment, Q is selected from the group consisting of O, S, and NR 3 C optionally substituted with a group selected from 1~3 In another embodiment, Q is a C═C double bond, optionally with any CH replaced with N. 2~3 It is alkenylene.

[0105] W1, W2 and W3 In one embodiment, W1 is C 1~18 alkyl, and in another embodiment, W is C 1~12 alkyl, and in another embodiment, W is C 1~6 In another embodiment, W is C 1~4 alkyl, alternatively methyl, and in another embodiment W is -(OC 2~6 alkylene) p and in another embodiment, W1 is -(OC 2~4 alkylene) p and in another embodiment, W1 is -(O-CH2-CH2) p is.

[0106] p is selected from any natural number from 1 to 18, alternatively from any natural number from 1 to 10.

[0107] M1 In one embodiment, M1 is a single bond, and in another embodiment, M1 is -C(O)-.

[0108] M4 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-, and in another embodiment, M4 is -C 1~6 alkylene-, and in another embodiment, M4 is -C 1~4 It is alkylene.

[0109] Ring G In one embodiment, ring G is C 6~12 aryl, and in another embodiment, ring G is C 6~10 In another embodiment, ring G is aryl, and in another embodiment, ring G is phenyl.

[0110] r, t, s, k, m and n In one embodiment, r is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0111] In one embodiment, t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0112] In one embodiment, s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 and 9.

[0113] In one embodiment, k is selected from 0, 1, 2, 3, 4 and 5.

[0114] In one embodiment, m is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; alternatively, 6, 7, 8, 9 or 10; more alternatively, 7, 8 or 9.

[0115] In one embodiment, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; alternatively, 6, 7, 8, 9 or 10; more alternatively, 7, 8 or 9.

[0116] In one embodiment, n is selected from any natural number from 2 to 20, alternatively from any natural number from 2 to 10.

[0117] The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl, and aralkyl, when present in each occurrence, may each be present in one, two, three, or more R 3 is optionally replaced by

[0118] R 3 In one embodiment, R 3 is halogen, and in another embodiment, R 3 is cyano, and in another embodiment, R 3 is nitro, and in another embodiment, R 3 is C 1~6 alkyl, and in another embodiment, R 3 is C 3~10 In another embodiment, R 3 is 3-10 membered heterocyclyl, and in another embodiment, R 3 is C 6~10 aryl, and in another embodiment, R 3 is a 5- to 14-membered heteroaryl, and in another embodiment, R 3 is C 6~12 It is aralkyl.

[0119] In one embodiment, R 3 The alkyl, alkylene, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl and aralkyl are independently selected from halogen, OH, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with 1, 2, 3 or more substituents selected from aralkyl.

[0120] Any technical solution or any combination thereof of any specific embodiment above can be combined with any technical solution or any combination thereof of 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 to U3, W1 to W3, Q, M1, M4, ring G, r, t, s, k, m, n, etc., or any combination thereof. Although these technical solutions are not listed one by one due to space limitations, the present disclosure is intended to encompass all combinations of these technical solutions.

[0121] In some embodiments, the present disclosure provides a compound of formula I: [ka] A compound of the formula: During the ceremony, L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-, alternatively a single bond, -O-, -NH-; L2 is a single bond, -O-, -NH-, -C(O)-, -C(O)-O-, C 1~18 Alkylene (alternatively, C 1~12 Alkylene, more alternatively C 1~6 alkylene), C 3~10 Cycloalkylene (alternatively, C 3~8 Cycloalkylene, more alternatively, C 3~6 cycloalkylene), C 6~30 Arylene (alternatively, C 6~18 Arylene, more alternatively, C 6~12arylene), C 3~30 Heteroarylene (alternatively, C 3~18 Heteroarylene, more alternatively C 3~12 heteroarylene), -C 1~18 Alkylene-O-(alternatively, -C 1~12 Alkylene-O-, more alternatively, -C 1~6 alkylene-O-), -C 6~30 Arylene-O-(alternatively, -C 6~18 arylene-O-, more alternatively, -C 6~12 arylene-O-), -C 3~30 Heteroarylene-O-(alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -C 3~12 heteroarylene-O-), -C(O)-C 1~18 Alkyl-, C 1~30 Alkoxy or -X1-PRa(O)-X2-, where each Ra is independently selected from hydrogen, hydroxyl, halogen (alternatively F, Cl, or Br), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 Heteroaryl), C 1~30 Hydrocarbon groups (alternatively, C 1~30 Alkyl, more alternatively, C 1~18 Alkyl, and alternatively, C 1~6 alkyl), C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), C 1~30 Alkoxy (alternatively, C 1~18 Alkoxy, more alternatively, C 1~6 Alkoxy), C 6~30Aryl-O-(alternatively, C 6~18 Aryl-O-, more alternatively, C 6~12 Aryl-O-), C 3~30 Heteroaryl-O-(alternatively, C 3~18 Heteroaryl-O-, more alternatively, C 3~12 Heteroaryl-O-), C 6~30 Aryl-C 1~18 Alkylene-O-(alternatively, C 6~18 Aryl-C 1~12 alkylene-O-, more alternatively C 6~12 Aryl-C 1~6 alkylene-O-), C 3~30 Heteroaryl-C 1~18 Alkylene-O-(alternatively, C 3~18 Heteroaryl-C 1~12 alkylene-O-, more alternatively C 3~12 Heteroaryl-C 1~6 Alkylene-O-), -OC 6~30 Aryl-C 1~18 Alkylene-(alternatively, -OC 6~18 Aryl-C 1~12 Alkylene-) or -OC 3~30 Heteroaryl-C 1~18 Alkylene-(alternatively, -OC 3~18 Heteroaryl-C 1~12 alkylene-), wherein Ra and X2 may be connected to form a ring; The above X1 is a single bond, -O-, -C 1~18 Alkylene-O-(alternatively, -C 1~12 Alkylene-O-, more alternatively, -C 1~6 alkylene-O-), -C 6~30 Arylene-O-(alternatively, -C 6~18 Arylene-O-, more alternatively, -C 6~12 arylene-O-) or -C 3~30 Heteroarylene-O-(alternatively, -C 3~18 Heteroarylene-O-, more alternatively, -C 3~12 heteroarylene-O-), The above X2 is a single bond, -O- or -NR * - selected from, where R * is H, C 1~6 Alkyl and C 1~6 alkoxy; R 1 is absent or hydrogen, hydroxyl, unsubstituted or Rb-substituted amino, unsubstituted or Rb-substituted C 1~30 Hydrocarbon groups (alternatively, C 1~30 Alkyl or C 2~30 alkenyl, more alternatively C 1~18 Alkyl or C 2~18 alkenyl, and alternatively, C 1~6 Alkyl or C 2~12 alkenyl, wherein the alkenyl has 1 to 10, alternatively 1 to 6, double bonds, unsubstituted or Rb-substituted C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), unsubstituted or Rb-substituted C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 alkoxy), unsubstituted or Rb-substituted C 12~30 A fused ring group (alternatively, C 12~17 fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 tetra-fused ring group), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rc 1~18 Alkyl-C 6~30 Arylene-C 1~18 Alkylene-(alternatively, C 1~12 Alkyl-C 6~18 Arylene-C 1~12 alkylene-), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rd 1~12 Alkyl-OC(O)-C 1~12 Alkylene-imino-, C 6~30 Aryl-C 1~18Alkylene-(alternatively, C 6~18 Aryl-C 1~12 alkylene-), -OC(O)-Y, unsubstituted or -C in which a hydrogen atom in the alkylene is replaced by Rd 1~12 Alkylene-C(O)-O-Y2, unsubstituted or -OC in which a hydrogen atom in the alkylene is replaced by Rd 1~12 Alkylene -OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## is selected from where R # and R ## are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C 12~30 a fused ring group, or -NHC(NH)NH-; Each Rb is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br). 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 Alkoxy), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 Heteroaryl) or C 1~30Alkyl (alternatively, C 1~18 Alkyl, more alternatively, C 1~6 alkyl), Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl, and alternatively, cyclopentyl; Each Rd is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br). 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl), C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 Alkoxy), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), wherein Y1 is unsubstituted or substituted with Re; 1~30 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl), C 3~10 Cycloalkyl (alternatively, C 3~8 Cycloalkyl, more alternatively, C 3~6 cycloalkyl), C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12heteroaryl), wherein each Re is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br); 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C 3~12 heteroaryl), The above Y2 is unsubstituted or Rf-substituted C 12~30 A fused ring group (alternatively, C 12~17 fused ring groups, more alternatively C containing at least one heteroatom 12~17 fused ring groups, and alternatively, C containing at least one heteroatom 12~17 tetra-fused ring groups), wherein each Rf is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy) or C 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl), The above Y3 is C 1~18 Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl) or -OC 1~18 Alkyl (alternatively, -OC 1~12 Alkyl, more alternatively, -OC 1~6 alkyl), Y4 is unsubstituted or substituted with Rg, 6~30 Aryl (alternatively, C 6~18 Aryl, more alternatively, C 6~12 aryl) or C 3~30 Heteroaryl (alternatively, C 3~18 Heteroaryl, more alternatively, C3~12 heteroaryl), wherein each Rg is independently selected from hydroxyl and C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy), The above Y5 is a single bond, an unsubstituted or amino-substituted C 1~18 Alkylene (alternatively, C 1~12 Alkylene, more alternatively C 3~6 alkylene), The above Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 20 (alternatively, any natural number from 2 to 10); The above Y7 is amino, C 1~30 Alkoxy (alternatively, C 1~20 Alkoxy, more alternatively, C 1~12 Alkoxy, and alternatively, C 1~3 alkoxy) or hydroxyl; When both L1 and L2 are selected from single bonds, R 1 is not hydroxyl, U1, U2, and U3 are each independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O-, and -O-, or an available ring atom on U2 and an available ring atom on U3 are connected through a Q group to form a 4- to 8-membered ring, alternatively a 5- or 6-membered ring; Q is a single bond; NR 3 1 or 2 CH2 are O, S and NR 3 C optionally independently replaced with a group selected from 1~3 alkylene; and C in which any CH to form a C=C double bond is optionally replaced with N. 2~3 alkenylene; W1, W2 and W3 are each independently C 1~18Alkyl (alternatively, C 1~12 Alkyl, more alternatively, C 1~6 alkyl) or -(OC 2~6 alkylene) p (Alternatively, -(OC 2~4 alkylene) p , or more alternatively, -(O-CH2-CH2) p ), wherein p is selected from any natural number from 1 to 18, alternatively any natural number from 1 to 10; The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl, and aralkyl, when present in each occurrence, may each be present in one, two, three, or more R 3 where R is optionally substituted with 3 represents, independently at each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 aralkyl, and the substituent R 3 The above alkyl, alkylene, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl and aralkyl related to the above may independently be halogen, OH, oxo, amino, cyano, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 optionally further substituted with 1, 2, 3 or more substituents selected from aralkyl; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0122] In some embodiments of the present disclosure, the compound has Formula II: [ka] is selected from the compounds The above L2 is 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-, wherein each Ra is independently hydrogen, hydroxyl, halogen, C 6~30 Aryl, C 3~30 Heteroaryl, C 1~30 Hydrocarbon group, 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 Ra and X2 may be connected to form a ring; The above X1 is a single bond or -C 1~18 alkylene-O-; The above X2 is a single bond, -O- or -NR * - (e.g., -NH-), Above R 1 is hydrogen, hydroxyl, amino, C 1~30 Hydrocarbon group, C 1~30 Alkoxy, unsubstituted or Rb-substituted C 12~30 A fused ring group, unsubstituted or a C in which a hydrogen atom in the alkyl is 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)-Y, -C 1~12 Alkylene-C(O)-O-Y2, -OC 1~12 Alkylene -OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## is selected from where R # and R ## are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C 12~30 a fused ring group, or -NHC(NH)NH-; Each Rb is independently unsubstituted or substituted with halogen. 1~30 Alkoxy, C 6~30 Aryl, C 3~30 Heteroaryl or C 1~30 alkyl, Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. 3~10 cycloalkyl; wherein Y1 is unsubstituted or substituted with Re; 1~30 Alkyl, C 3~10 Cycloalkyl, C 6~30 Aryl or C 3~30 heteroaryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C 6~30 aryl; The above Y2 is unsubstituted or Rf-substituted C 12~30fused ring groups, wherein each Rf is independently selected from C 1~30 alkoxy; The above Y3 is C 1~18 Alkyl or -OC 1~18 alkyl, Y4 is unsubstituted or substituted with Rg, 6~30 Aryl or C 3~30 heteroaryl, wherein each Rg is independently hydroxyl or C 1~30 alkoxy; The above Y5 is a single bond, an unsubstituted or amino-substituted C 1~18 alkylene; The above Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 20; The above Y7 is amino, C 1~30 It is selected from alkoxy or hydroxyl.

[0123] In some embodiments of the present disclosure, the compound has formula I-1: [ka] is selected from the compounds wherein L1 is selected from a single bond, -O-, -NH-, -S- or -P(O)OH-, alternatively a single bond, -O- and -NH-; The above L2 is a single bond, -C(O)-, -C(O)-O-, -C 1~18 Alkylene-, -C 1~18 Alkylene-O- (e.g., -(CH2) 1~5 -O-), -C(O)-C 1~18 Alkyl-, C 1~30 Alkoxy (e.g., -(OCH2CH2) 2~8 -) or -X1-PRa(O)-X2-, Each of the Ra groups independently represents hydrogen, hydroxyl, halogen, or C. 6~30Aryl, C 3~30 Heteroaryl, C 1~30 Hydrocarbon group, 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-, and the available ring atoms on Ra may be directly connected to X2 to form a 4- to 7-membered ring, alternatively a 5- or 6-membered ring; The above X1 is a single bond, —O— or —C 1~18 Alkylene -O-, alternatively a single bond, -O- or -(CH2) 1~3 O— (e.g., —CHO—), The above X2 is a single bond, -O- or -NR * - selected from, where R * is H or C 1~6 alkyl (e.g., methyl, ethyl, isopropyl, etc.); Above R 1 is absent or is hydrogen, hydroxyl, amino, C 1~30 Hydrocarbon group (C above) 1~30 The hydrocarbon group has 0 to 10 double or triple bonds, alternatively 0 to 6 double or triple bonds), C 1~30 Alkoxy, unsubstituted or Rb-substituted C 12~30 A fused ring group, unsubstituted or a C in which a hydrogen atom in the alkyl is 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)-Y, -C1~12 Alkylene-C(O)-O-Y2, -OC 1~12 Alkylene -OC(O)-Y3, -CH=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## is selected from where R # and R ## are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C 12~30 a fused ring group, or -NHC(NH)NH-; Each Rb is independently unsubstituted or substituted with halogen. 1~30 Alkoxy, C 6~30 Aryl, C 3~30 Heteroaryl or C 1~30 alkyl, Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. 3~10 cycloalkyl; wherein Y1 is unsubstituted or substituted with Re; 1~30 Alkyl, C 3~10 Cycloalkyl, C 6~30 Aryl or C 3~30 heteroaryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C 6~30 aryl; The above Y2 is unsubstituted or Rf-substituted C 12~30fused ring groups, wherein each Rf is independently selected from C 1~30 alkoxy; The above Y3 is C 1~18 Alkyl or -OC 1~18 alkyl, Y4 is unsubstituted or substituted with Rg, 6~30 Aryl or C 3~30 heteroaryl, wherein each Rg is independently hydroxyl or C 1~30 alkoxy; The above Y5 is a single bond, an unsubstituted or amino-substituted C 1~18 alkylene; The above Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 20; The above Y7 is amino, C 1~30 It is selected from alkoxy or hydroxyl.

[0124] In some embodiments of the present disclosure, in the compound of formula II, L2 is a single bond, -C(O)-, -C(O)-O-, C 1~6 Alkylene, -C 1~6 alkylene-O- or -X1-PRa(O)-X2-, each R is independently 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-, and Ra and X2 may be connected to form a ring; X1 is a single bond or -C 1~6 alkylene-O-; X2 is selected from a single bond, —O—, and —NH—; R 1is absent, hydrogen, hydroxyl, amino, C 1~30 Alkyl, C 1~30 Alkoxy, unsubstituted or methoxy-substituted C containing at least one heteroatom 12~17 Tetra-fused ring group, oxocyclopentyl-C 1~6 Alkylene-C 6~12 Arylene-C 1~6 Alkylene-, hydroxycyclopentyl-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)-Y, -C 1~12 Alkylene-C(O)-O-Y2, -OC 1~12 Alkylene -OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7, -CHR # R ## is selected from where R # and R ## are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C 12~30 a fused ring group, or -NHC(NH)NH-; Y1 is unsubstituted or substituted with Re; C 1~6 Alkyl, C 3~6 Cycloalkyl or C 6~12aryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C 6~12 aryl; Y3 is C 1~6 Alkyl or -OC 1~6 alkyl, Y4 is unsubstituted or Rg-substituted C 6~12 aryl, wherein each Rg is independently selected from hydroxyl or methoxy; Y5 is a single bond, an unsubstituted or amino-substituted C 1~6 alkylene; Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 10; Y7 is amino, C 1~6 It is selected from alkoxy or hydroxyl.

[0125] In some embodiments, R 1 is absent, hydrogen, hydroxyl, amino, aryl (e.g., phenyl), C 1~30 Alkyl, C 1~30 Alkoxy (e.g., -OCH), unsubstituted or Rb-substituted C 12~30 Fused cyclic group, -(CH2) 1~10 -C(O)-OC 12~30 Fused cyclic 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 ## Alternatively, H, -OH, -NH2, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -(CH2) p CH3, -(CH2) p OCH3, -(CH2) p NH 2、 -(CH2) p OH 、-(OCH2CH2)qCH3, -(OCH2CH2)qOCH3, -(OCH2CH2)qOH, -(OCH2CH2)qNH2, phenyl, [ka] is selected from the structure wherein 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.

[0126] The oxocyclopentyl of the present disclosure is [ka] In the present disclosure, hydroxycyclopentyl refers to [ka] Refers to...

[0127] In some embodiments of the present disclosure, in the compound of formula II, L2 is a single bond, -C(O)-, -C(O)-O-, C 1~6 Alkylene, -C 1~6 alkylene -O- or -X1-PH(O)-X2-, wherein a hydrogen atom on -X1-PH(O)-X2- may be replaced by Ra, where each Ra is independently 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-, and Ra and X2 may be connected to form a ring; X1 is a single bond or -C 1~6 alkylene-O-; X2 is selected from a single bond or -O-; R 1 is hydrogen, hydroxyl, amino, C 1~30 Hydrocarbon group, C 1~30 Alkoxy, unsubstituted or methoxy-substituted C containing at least one heteroatom 12~17 Tetra-fused ring group, oxocyclopentyl-C 1~6 Alkylene-C 6~12 Arylene-C 1~6 Alkylene-, hydroxycyclopentyl-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)-Y, -C 1~12 Alkylene-C(O)-O-Y2, -OC 1~12 alkylene -OC(O)-Y3, -C=CH-Y4 or -Y5-Y6-Y7; Y1 is unsubstituted or substituted with Re; C 1~6 Alkyl, C 3~6 Cycloalkyl or C 6~12 aryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C 6~12 aryl; Y3 is C 1~6 Alkyl or -OC 1~6 alkyl, Y4 is unsubstituted or Rg-substituted C 6~12 aryl, wherein each Rg is independently selected from hydroxyl or methoxy; Y5 is a single bond, an unsubstituted or amino-substituted C 1~6 alkylene; Y6 is a single bond, -NH-C(NH)-, -(O-CH2-CH2) m - or -CH2-(O-CH2-CH2) n wherein m and n are each independently selected from any natural number from 2 to 10; Y7 is amino, C 1~6 It is selected from alkoxy or hydroxyl.

[0128] In some embodiments of the present disclosure, the compound has formula III: [ka] is selected from the compounds wherein the various groups are as defined for the groups of compounds of formula II.

[0129] In some embodiments of the present disclosure, in the compound of formula III, each R is independently hydroxyl, C 6~12 Aryl-O-, C 6~12 Aryl-C 1~6 Alkylene -O- or -OC 6~12 Aryl-C 1~6 alkylene-, and Ra and X2 may be connected to form a ring; X1 is a single bond or -C 1~6 alkylene-O-; X2 is selected from a single bond, —O—, and —NH—; R 1 is 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.

[0130] In some embodiments of the present disclosure, the compound has Formula IVa, Formula IVb, or Formula IVc: [ka] is selected from the compounds wherein ring G in formula IVc is C 6~12 is an aryl ring, and the various groups are as defined for the groups of the compound of formula III.

[0131] In some embodiments of the present disclosure, the compound has formula V: [ka] is selected from the compounds wherein the various groups are as defined for the groups of compounds of formula II.

[0132] In some embodiments of the present disclosure, the compound has Formula VIa or Formula VIb: [ka] is selected from the compounds wherein r and t in Formula VIa and Formula VIb are each independently selected from any natural number from 0 to 10, s is each independently selected from any natural number from 0 to 9 (alternatively, any natural number from 1 to 6), r, s, and t are not simultaneously 0, and the various groups are as defined for the groups of the compound of Formula V.

[0133] In some embodiments of the present disclosure, the compound has formula VII: [ka] is selected from the compounds wherein n is selected from any natural number from 2 to 20, alternatively from 2 to 10, and the various groups are as defined for the groups of the compound of formula V.

[0134] In some embodiments of the present disclosure, the compound has Formula VIII: [ka] is selected from the compounds In the formula, Z is C 1~30 Alkylene, C 3~10 Cycloalkylene, C 6~30 Arylene, C 3~30 selected from heteroarylene or -C=CH-; A is hydroxyl, halogen, C 6~30 Aryl or C substituted with Rc 1~18 alkyl, wherein each Rc is independently selected from C unsubstituted or substituted with hydroxyl, oxo, or thioxo. 3~10 cycloalkyl; B is hydroxyl, 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 0; The various groups are as defined for the groups of the compound of formula V.

[0135] In some embodiments of the present disclosure, the compound has formula IX: [ka] is selected from the compounds A is C substituted with Rc 1~18 alkyl, wherein each Rc is independently selected from C substituted with oxo. 3~10 cycloalkyl; B is halogen or C 6~30 aryl; x is selected from 1 and y is selected from 0 or 1; The various groups are as defined for the groups of the compound of formula VIII.

[0136] In some embodiments of the present disclosure, the compound has formula X: [ka] is selected from the compounds wherein each M1 is independently selected from a single bond or —C(O)—; L3 is C 1~12 alkylene; The various groups are as defined for the groups of compounds of formula I.

[0137] In some embodiments of the present disclosure, the compound has formula XI: [ka] is selected from the compounds In the formula, L3 is C 1~12 alkylene; Alternatively, U1, U2, and U3 are each independently selected from -O-, and W1, W2, and W3 are each independently selected from methyl.

[0138] In some embodiments of the present disclosure, the compound has formula XII: [ka] is selected from the compounds wherein the various groups are as defined for the groups of compounds of formula I.

[0139] In some embodiments of the present disclosure, in the compound of formula XII, L2 is selected from a single bond or —O—; and R 1 is selected from hydrogen, amino, or -Y5-Y6-Y7, where Y5 is a single bond, an unsubstituted or amino-substituted C 3~12 alkylene.

[0140] In some embodiments of the present disclosure, the compound has formula XIII: [ka] is selected from the compounds Alternatively, Y5 is an unsubstituted or amino-substituted C 3~12 alkylene, alternatively unsubstituted or amino-substituted C 3~6 alkylene, wherein the various groups are as defined for the groups of the compound of formula XII.

[0141] In some embodiments of the present disclosure, the compound has formula XIV: [ka] is selected from the compounds wherein the various groups are as defined for the groups of compounds of formula I.

[0142] In some embodiments of the present disclosure, in the compound of formula XIV, L is selected from -O- or -NH-, and L is -C(O)- or -C 1~18 alkylene; Y7 is selected from amino, C 1~30 Alkyl, C 1~30 It is selected from alkoxy or hydroxyl.

[0143] In some embodiments of the present disclosure, the compound has Formula XVa or Formula XVb: [ka] is selected from the compounds Alternatively, Y7 is selected from methoxy or hydroxyl, and the various groups are as defined for the groups of the compound of formula XIV.

[0144] In some embodiments of the present disclosure, in compounds of Formulae I-XIV, U1, U2, and U3 are each independently selected from -O-; W1, W2 and W3 are each independently C 1~18 Alkyl, alternatively C 1~12 Alkyl, more alternatively, C 1~6 alkyl, and more alternatively, methyl.

[0145] In some embodiments of the present disclosure, the compound has formula Ia: [ka] , alternatively, [ka] is selected from the compounds In the formula, L1, L2, W1, R 1 and R *is as defined for the radicals of compounds of formula I.

[0146] In some embodiments, the present disclosure provides compounds of formula XVI, XVI-1, XVI-2, XVI-3, or XVI-4: [ka] A compound of the formula: During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~18 alkyl, M4 is a chemical bond, -O-, -NH-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)O-, -OC(O)NH- or -C 1~10 alkylene-, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0147] In some embodiments, the present disclosure provides a compound of formula XVI, XVI-1, XVI-2, XVI-3, or XVI-4, wherein: U1, U2, and U3 are independently selected from -OC(O)- or -O-; W1, W2 and W3 are independently C 1~12 Alkyl, alternatively C 1~6 alkyl, M4 is selected from a chemical bond, -NH-, -C(O)O-, -OC(O)-, -NHC(O)O- or -OC(O)NH-; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0148] In some embodiments, the present disclosure provides a compound of formula XVI, XVI-1, XVI-2, XVI-3, or XVI-4, wherein: U1, U2 and U3 are -O-; W1, W2 and W3 are independently C 1~6 Alkyl, alternatively C 1~4 alkyl, and more alternatively, methyl; M4 is selected from -NHC(O)O- or -OC(O)NH-; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0149] In some embodiments, the present disclosure provides compounds of formula VIII, VIII-1, or VIII-2: [ka] A compound of the formula: During the ceremony, U1, U2 and U3 are independently selected from -OC(O)-, -NH-C(O)-, -O-CH2-O- or -O; W1, W2 and W3 are independently C 1~12 alkyl, Z is a chemical bond, -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 1~10Alkylene- or -C 1~10 Alkylene-OC(O)NH-C 1~10 Alkylene -, alternatively a chemical bond or -C 1~6 Alkylene-NHC(O)-C 1~6 alkylene-, The above Z is 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 optionally substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl; A and B are independently H, halogen, OH, -L A -C 3~10 Cycloalkyl, -L A -3 to 10-membered heterocyclyl, -L A -C 6~12 Aryl or -L A -5 to 12 membered heteroaryl, alternatively 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 above A and B are halogen, C 1~6 Alkyl or C 1~6 optionally further substituted with haloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0150] In some embodiments, the present disclosure provides a compound of formula VIII, VIII-1, or VIII-2, wherein: U1, U2, and U3 are independently selected from -OC(O)- or -O-; W1, W2 and W3 are independently C 1~6 alkyl, Z is a chemical bond, -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 -, alternatively 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 above Z is halogen, C(O)OH, C(O)OC 1~6 Alkyl, C 1~6 Alkyl or C 1~6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; A and B are independently H, halogen, C 6~10 Aryl, -NH-C 6~10 Aryl, -OC 6~10 Aryl, -C(O)-C 6~10 Aryl and -C(O)OC 6~10 aryl, alternatively halogen, C 6~10 Aryl or -NH-C 6~10 aryl; The above A and B are halogen, C 1~6 Alkyl or C 1~6 optionally further substituted with haloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0151] In some embodiments, the present disclosure provides a compound of formula VIII, VIII-1, or VIII-2, wherein: U1, U2 and U3 are -O-; W1, W2 and W3 are independently C 1~4 alkyl, alternatively methyl; Z is a chemical bond, -C 1~4 Alkylene-NHC(O)-C 1~4 Alkylene- or -C 1~4 Alkylene-C(O)NH-C 1~4 Alkylene -, alternatively a chemical bond or -C 1~4 Alkylene-NHC(O)-C 1~4 alkylene-, The above Z is halogen, C(O)OH, C(O)OC 1~4 Alkyl or C 1~4 optionally substituted with 1, 2 or 3 substituents selected from alkyl; A and B are independently selected from H, halogen, phenyl, or —NH-phenyl, alternatively F, phenyl, or NH-phenyl; wherein A and B are optionally further substituted with halogen; x and y are 0, 1 or 2; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0152] In some embodiments, the present disclosure provides compounds of formula II, II-1, II-2, I-1, I-2, or I-3: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, L1 is selected from a single bond, —O— or —NH—; L2 is -C 1~12 alkylene-, wherein the alkylene is C 1~6 may be further substituted with alkyl, R 1 is selected from -OC(O)-Y1; Y1 is C 1~12 Alkyl, C 3~10 Cycloalkyl, C 6~18 Aryl or C 3~18 heteroaryl, wherein Y is selected from C 1~6 may be further substituted with alkyl, Y1 may alternatively be C 1~6 alkyl, more alternatively CH3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0153] In some embodiments, the present disclosure provides a compound of formula II, II-1, II-2, I-1, I-2, or I-3, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, L1 is selected from -O- or -NH-; L2 is -C 1~6 alkylene-, wherein the alkylene is C 1~6 may be further substituted with alkyl, R 1 is selected from -OC(O)-Y1; Y1 is C 1~6 Alkyl, C 3~6 Cycloalkyl or C 6~12aryl, wherein Y is selected from C 1~6 may be further substituted with alkyl, Y1 is alternatively CH3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0154] In some embodiments, the present disclosure provides a compound of formula II, II-1, II-2, I-1, I-2, or I-3, wherein: U1, U2 and U3 are -O-; W1, W2 and W3 are CH3; L1 is -O-; L2 is -CH2-, -CH(CH3)-, [ka] and R 1 teeth, [ka] Selected from: The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0155] In some embodiments, the present disclosure provides compounds of formula III, III-1, or III-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, X1 is a chemical bond or -C 1~6alkylene-O-; X2 is a chemical bond, —O— or —C(O)—; R 1 is absent or 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, where R 1 a hydrogen atom in the alkylene is optionally substituted with Rd; Y3-OC 1~6 alkyl, and the C 1~6 Alkyl is C 1~6 may be further substituted with alkyl, Ra, OH, -OC 6~18 Aryl, -OC 1~12 Alkylene-C 6~18 Aryl or -OC 6~18 Aryl-C 1~12 alkyl; or Ra and X2 are connected to form a ring; Rd, C 1~12 Alkyl or C 1~12 alkoxy, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0156] In some embodiments, the present disclosure provides a compound of formula III, III-1, or III-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, X1 is a chemical bond or -C 1~6 alkylene-O-; X2 is a chemical bond, —O— or —C(O)—; R 1is absent or 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, where R 1 a hydrogen atom in the alkylene is optionally substituted with Rd; Y3-OC 1~6 alkyl, and the C 1~6 Alkyl is C 1~6 may be further substituted with alkyl, Ra, OH, -OC 6~12 Aryl, -OC 1~6 Alkylene-C 6~12 Aryl or -OC 6~12 Aryl-C 1~6 alkyl; or Ra and X2 are connected to form a ring; Rd is C 1~6 is alkyl, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0157] In some embodiments, the present disclosure provides a compound of formula III, III-1, or III-2, wherein: U1, U2 and U3 are O; 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 is non-existent or H, [ka] , -CH2-phenyl or [ka] is selected from Ra is selected from OH, —O-phenyl or —O—CH2-phenyl or —O-phenyl-CH3; or Ra and X2 are connected to form a ring; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0158] In some embodiments, the present disclosure provides compounds of formula IVa, IVa-1, IVa-2, IVb, IVb-1, IVb-2, IVc, IVc-1, or IVc-2: [ka] A compound of the formula In the formula, ring G is C 6~12 aryl, alternatively C 6~10 aryl, more alternatively phenyl; Various other variables are as defined above. The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0159] In some embodiments, the present disclosure provides compounds of formula V, V-1, or V-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, R 1 is C 1~30 Alkyl, C 2~30 Alkenyl, C 1~20Alkoxy, and —OC which is unsubstituted or in which a hydrogen atom in the alkylene is replaced by Rd 1~12 alkylene-OC(O)-Y3; Rd, C 1~12 alkyl, R 1 Alternatively, C 6~10 Alkyl or C 10~30 is alkenyl, Y3 is C 1~12 Alkyl or OC 1~12 selected from alkyl, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0160] In some embodiments, the present disclosure provides a compound of formula V, V-1, or V-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, R 1 is C 1~30 Alkyl, C 2~30 Alkenyl, C 1~6 Alkoxy, and —OC which is unsubstituted or in which a hydrogen atom in the alkylene is replaced by Rd 1~6 alkylene-OC(O)-Y3; Rd, C 1~6 alkyl, R 1 Alternatively, C 6~10 Alkyl or C 10~30 is alkenyl, Y3 is C 1~6 is alkyl, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0161] In some embodiments, the present disclosure provides a compound of formula V, V-1, or V-2, wherein: U1, U2 and U3 are O; W1, W2 and W3 are CH3; R 1 is CH3, [ka] , 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, [ka] Selected from: The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0162] In some embodiments, the present disclosure provides compounds of formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, r and 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; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0163] In some embodiments, the disclosure provides a compound of formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, r and 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; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0164] In some embodiments, the disclosure provides a compound of formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1, or VIc-2, wherein: U1, U2 and U3 are O; 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; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0165] In some embodiments, the present disclosure provides compounds of formula VII, VII-1, VII-2, XIV, XIV-1, or XIV-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently 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, alternatively 6, 7, 8, 9 or 10, more alternatively 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 is an alkoxy, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0166] In some embodiments, the present disclosure provides a compound of formula VII, VII-1, VII-2, XIV, XIV-1, or XIV-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, m and n are selected from 2, 3, 4, 5, 6, 7, 8, 9 or 10, alternatively 7, 8 or 9; L1 is -O- or -NH-, alternatively -O-; L2 is -C(O)- or -C(O)-C 1~6 alkylene-, Y7 is C 1~3 is an alkoxy, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0167] In some embodiments, the present disclosure provides a compound of formula VII, VII-1, VII-2, XIV, XIV-1, or XIV-2, wherein: U1, U2 and U3 are O; W1, W2 and W3 are CH3; m and n are 3, 4, 5, 6, 7, 8, alternatively 3 or 8; L1 is O, L2 is -C(O)- or -C(O)-C 1~4 alkylene-, alternatively -C(O)-; Y7 is C 1~3 Alkoxy, alternatively OCH3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0168] In some embodiments, the present disclosure provides compounds of formula VIII, VIII-1, or VIII-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, Z is C 1~30 Alkylene or C 2~30 alkenylene, wherein Z is selected from 1, 2 or 3 R 3 is optionally replaced by R 3is C 1~6 is alkyl, A is optionally substituted with halogen, OH, or Rc; C 1~18 Alkyl or C 6~30 aryl, optionally substituted with OH, Rc, C 1~18 Alkyl or C 6~30 Aryl, more alternatively, C 6~30 aryl; B is halogen, OH or C 6~30 aryl, alternatively halogen or OH, more alternatively halogen; Rc is C optionally substituted with OH, oxo, or thioxo. 3~10 Cycloalkyl, alternatively C substituted with oxo 3~10 cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0169] In some embodiments, the present disclosure provides a compound of formula VIII, VIII-1, or VIII-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, Z is C 1~6 Alkylene or C 2~6 Alkenylene, alternatively C 1~3 alkylene, wherein Z is selected from 1, 2 or 3 R 3 is optionally replaced by R 3 is C 1~6 is alkyl, A is optionally substituted with halogen, OH, or Rc; C 1~6 Alkyl or C 6~12 aryl, optionally substituted with OH, Rc, C1~6 Alkyl or C 6~12 Aryl, more alternatively, C 6~12 aryl; B is halogen, OH or C 6~12 aryl, alternatively halogen or OH, more alternatively halogen; Rc is C optionally substituted with OH or oxo. 3~10 cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0170] In some embodiments, the present disclosure provides a compound of formula VIII, VIII-1, or VIII-2, wherein: U1, U2 and U3 are O; W1, W2 and W3 are CH3; Z is selected from -CH(CH3)-, -CH=CH- or -CH2-CH2-; A is F, OH, phenyl, [ka] , alternatively OH, phenyl or [ka] and more alternatively selected from phenyl; B is selected from F, OH or phenyl, alternatively F or OH, more alternatively F; x and y are 0, 1 or 2; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0171] In some embodiments, the present disclosure provides compounds of formula IX, IX-1, or IX-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, A is H or C substituted with Rc 1~18 alkyl, B is halogen or C 6~30 aryl, alternatively halogen or C 6~12 aryl; Rc is C optionally substituted with OH, oxo, or thioxo. 3~10 Cycloalkyl, alternatively C substituted with oxo 3~10 cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0172] In some embodiments, the present disclosure provides a compound of formula IX, IX-1, or IX-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, A is H or C substituted with Rc 1~6 alkyl, alternatively selected from H; B is halogen or C 6~10 aryl, alternatively selected from F or phenyl; Rc is C substituted with oxo or OH 3~10Cycloalkyl, alternatively C substituted with oxo 3~10 cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0173] In some embodiments, the present disclosure provides a compound of formula IX, IX-1, or IX-2, wherein: U1, U2 and U3 are -O-; W1, W2 and W3 are CH3; A is, [ka] is selected from B is selected from F or phenyl; x is 0 or 1, y is 0 or 1; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0174] In some embodiments, the present disclosure provides compounds of formula X, X-1, X-2, X-3, or X-4: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, Each M is independently a chemical bond or —C(O)—; alternatively, neither of the two M is a chemical bond; L3 is a chemical bond or -C1~18 -alkylene-, alternatively a chemical bond; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0175] In some embodiments, the present disclosure provides a compound of formula X, X-1, X-2, X-3, or X-4, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, Each M is independently a chemical bond or —C(O)—; alternatively, neither of the two M is a chemical bond; L3 is a chemical bond or -C 1~12 -alkylene-; alternatively, a chemical bond; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0176] In some embodiments, the present disclosure provides a compound of formula X, X-1, X-2, X-3, or X-4, wherein: U1, U2 and U3 are -O-; W1, W2 and W3 are CH3; Each M is independently a chemical bond or —C(O)—; alternatively, neither of the two M is a chemical bond; L3 is a chemical bond or -C 1~6 -alkylene-, for example a chemical bond, -CH-, -CHCHCH- or -CHCHCHCHCHCHCH-, alternatively selected from a chemical bond, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0177] In some embodiments, the present disclosure provides compounds of formula XI, XI-1, XI-2, XI-3, or XI-4: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are independently C 1~12 alkyl, L3 is -C 1~18 -alkylene-, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0178] In some embodiments, the present disclosure provides a compound of formula XI, XI-1, XI-2, XI-3, or XI-4, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are independently C 1~6 alkyl, L3 is -C 1~12 -alkylene-, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0179] In some embodiments, the present disclosure provides a compound of formula XI, XI-1, XI-2, XI-3, or XI-4, wherein: U1, U2 and U3 are O; W1, W2 and W3 are CH3; L3 is -C 1~6 -alkylene-, for example -CH2CH2CH2- or -CH2CH2CH2CH2CH2CH2-, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0180] In some embodiments, the present disclosure provides compounds of formula XII, XII-1, or XII-2: [ka] A compound of the formula During the ceremony, U1, U2 and U3 are independently selected from -O-, -OC(O)-, -NH-C(O)- or -O-CH2-O-; W1, W2 and W3 are C 1~12 is alkyl, L2 is a chemical bond, —C(O)— or —C(O)O—; R 1 is selected from H, OH or -Y5-Y6-Y7; Y5 is an unsubstituted or NH2-substituted C 1~12 is alkylene, Y6 is a single bond or -NH-C(NH)-; Y7 is NH2, OH or C 1~12 is an alkoxy, The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0181] In some embodiments, the present disclosure provides a compound of formula XII, XII-1, or XII-2, wherein: U1, U2 and U3 are selected from -O- or -OC(O)-; W1, W2 and W3 are C 1~6 is alkyl, L2 is a chemical bond or -C(O)-; R 1 is selected from H, OH or -Y5-Y6-Y7; Y5 is an unsubstituted or NH2-substituted C 3~6is alkylene, Y6 is a single bond or -NH-C(NH)-; Y7 is NH2 or OH; The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0182] In some embodiments, the present disclosure provides a compound of formula XII, XII-1, or XII-2, wherein: U1, U2 and U3 are O; W1, W2 and W3 are CH3; L2 is a chemical bond or -C(O)-; R 1 H, [ka] Selected from: The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0183] In some embodiments, the present disclosure provides compounds of formula XIII, XIII-1, or XIII-2: [ka] A compound of the formula During the ceremony, The various variables are as defined above. The present invention relates to the compound or its pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, and mixtures thereof.

[0184] In some embodiments of the present disclosure, the compound is the following compound: [ka] [ka] [ka] [ka] [ka] is selected from.

[0185] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of an individual enantiomer, diastereomer, or geometric isomer (e.g., cis- and trans-isomers), or may be in the form of a mixture of stereoisomers, such as a racemic mixture or a mixture enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or alternative isomers can be prepared by asymmetric synthesis.

[0186] The compounds of the present disclosure may exist in tautomeric forms. Tautomers are functional group isomers that arise from the rapid movement of atoms between two positions in a molecule. Tautomers are special functional group isomers. A pair of tautomers can be converted into each other, but the relatively stable isomer is usually the predominant form. The most important examples are enol and keto tautomers.

[0187] Those skilled in the art will understand that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates." When the solvent is water, the complex is known as a "hydrate." The present disclosure encompasses all solvates of the compounds of the present disclosure.

[0188] The term "solvate" refers to a compound or a salt form thereof associated with a solvent, usually by solvolysis. This physical association may involve hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0189] The term "hydrate" refers to a compound associated with water. Generally, the number of water molecules contained in a hydrate of a compound is a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, including monohydrates (x is 1), lower hydrates (x is a number greater than 0 but less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0190] The compounds of the present disclosure may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Thus, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0191] The present disclosure also includes compounds labeled with isotopes (isotopic variants) equivalent to those described in formula (A) or (I), but in which one or more atoms have been replaced by atoms whose atomic mass or mass number differs from that of atoms common in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 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 Compounds of the present disclosure, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the above isotopes and / or other isotopes of other atoms are all within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, for example, compounds containing radioactive isotopes (e.g., 3 H and 14 C) can be used to measure drug and / or substrate distribution within tissues. 3 H, tritium, and 14 The C isotope, carbon-14, is a better alternative because it is easier to prepare and detect.2 Substitution of heavier isotopes, such as deuterium, H, may be an alternative in some cases, as it may confer therapeutic benefits due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of formula (A) or (I) of the present disclosure and prodrugs thereof may generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in the following schemes, and / or procedures disclosed in the Examples and Preparations.

[0192] In addition, prodrugs are also included within the context of the present disclosure. As used herein, the term "prodrug" refers to a compound that is converted into an active form that has medical effects in vivo, for example, by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, 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.

[0193] A prodrug is any covalently bonded compound of the present disclosure that releases the parent compound in vivo when the prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups such that the modification can be cleaved by routine manipulation or degraded in vivo to yield the parent compound. Prodrugs include, for example, compounds of the present disclosure in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that cleaves to form a hydroxyl, amino, or sulfhydryl group when administered to a patient. Thus, representative examples of prodrugs include, but are not limited to, acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives of the hydroxyl, sulfhydryl, or amino functional group of a compound of Formula (A) or (I). Furthermore, in the case of carboxylic acids (—COOH), esters such as methyl and ethyl esters can be employed. The esters themselves may be active in themselves and / or hydrolyzable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.

[0194] The present disclosure also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of Formula (A) or (I), or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof, all of which are within the scope of the present disclosure.

[0195] In a second aspect, the present disclosure provides a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug of a compound according to the first aspect of the disclosure.

[0196] In a third aspect, the present disclosure provides a composition comprising a compound according to the first aspect of the disclosure, and / or a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug according to the second aspect of the disclosure.

[0197] The compositions of the present disclosure may further comprise pharmaceutically acceptable carriers, adjuvants, excipients, and the like.

[0198] Use of a compound of the present disclosure, and its stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, chelates, complexes, clathrates or prodrugs, or compositions comprising said compounds, in the manufacture of a medicament for preventing and / or treating a CNS-related disease.

[0199] Use of the above compound, or a stereoisomer, pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug thereof, or the above composition, in the manufacture of a medicament for analgesia, antidepressant or anti-addiction.

[0200] In some embodiments of the present disclosure, the medicament is used for pain caused by post-surgical trauma, post-surgical incision, or organ metastasis of cancer.

[0201] In a fifth aspect, the present disclosure provides a method for analgesia, antidepressant or anti-drug addiction, comprising administering to a subject in need thereof an effective dose of a compound according to the first aspect of the disclosure, a stereoisomer, a pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug, or a composition according to the third aspect, wherein said administration is by oral, rectal, nasal, topical or parenteral administration.

[0202] In some embodiments of the present disclosure, the effective dose is from 0.1 mg / day to 1000 mg / day, alternatively from 3 mg / day to 300 mg / day, and more alternatively from 5 mg / day to 50 mg / day of the compound.

[0203] In a sixth aspect, the present disclosure provides a compound according to the first aspect of the disclosure, a stereoisomer according to the second aspect, a pharmaceutically acceptable salt, ester, optical isomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, chelate, complex, clathrate or prodrug, or a composition according to the third aspect of the disclosure, for use as a medicament or for use in therapy.

[0204] In the present disclosure, the compound of formula (I) and its stereoisomers, pharmaceutically acceptable salts, esters, optical isomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, clathrates or prodrugs obtained by modifying various active sites of the s-coridalmine parent structure can be used to prevent and / or treat CNS-related diseases such as pain, drug addiction and depression, and exhibit good analgesic, antidepressant and anti-addiction effects, and can be used in the manufacture of medicines for analgesia, antidepressant or anti-addiction.

[0205] Of course, it is not necessary for all of the above advantages to be achieved simultaneously in any material or method practice of the present disclosure.

[0206] In order to more clearly describe the technical solutions of the present disclosure or the prior art, the drawings required in the embodiments and the prior art are briefly described below. The drawings described below are only some examples of the present disclosure, and it is obvious that those skilled in the art can obtain other examples based on these drawings without creative efforts. [Brief explanation of the drawings]

[0207] [Figure 1] FIG. 1 is a graph showing the results of mechanical pain thresholds in a mechanical pain test in a mouse inflammatory pain model induced by Freund's complete adjuvant. [Figure 2] FIG. 2 is a graph showing the results of paw thickness in a mechanical pain test in a mouse inflammatory pain model induced by Freund's complete adjuvant. [Figure 3] FIG. 3 is a graph showing the results of the time to onset of writhing in mice in various groups in an analgesic test of an acetic acid-induced writhing model in mice. [Figure 4] FIG. 4 is a graph showing the results of the total number of writhing movements of mice in various groups in an analgesic test of an acetic acid-induced writhing model in mice.

[0208] The technical solutions of the present disclosure will be clearly and fully described below with reference to the drawings in the present disclosure. It is clear that the described embodiments are only a part of the embodiments, not all of the embodiments of the present disclosure. Based on the embodiments of the present disclosure, all other embodiments that a person skilled in the art can obtain based on the present disclosure are within the scope of the present disclosure.

[0209] Abbreviation: 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-methylpyrrolidinone; THF: tetrahydrofuran; rt: room temperature LCMS: liquid chromatography-mass spectrometry; TLC: thin layer chromatography; Chemical Formula: chemical formula; Molecular Weight: Relative molecular mass; Exact Mass: Exact mass.

[0210] Yield calculation: Yield = actual quality of synthesized product / theoretical quality of synthesized product*100%.

[0211] The present disclosure will be described in detail below with reference to specific examples. The compounds of the present disclosure are not particularly limited in terms of synthesis method, and can be synthesized by any method known to those skilled in the art.

[0212] Example 1: Synthesis of Compound A7 [ka] A10-0 (34 mg), NaOH (20 mg), and DCM (0.5 mL) were added to a reaction flask. Chloromethyl pivalate (45 mg) and DCM (0.5 mL) were added to a separate vial, mixed thoroughly, and then slowly added dropwise to the reaction flask at room temperature. After the addition, the reaction mixture was stirred overnight at room temperature and monitored by LCMS. The peak at 695 nm was the main peak. The reaction mixture was separated by TLC using PE / EA (3 / 1, v / v) as a developer to give a pale yellow oil, which was lyophilized to give A7 as a pale yellow solid (24 mg). 1 H-NMR(400MHz, CDCl-d3) δ 7.103(d, J = 8.4 Hz, 2H), 6.879(d, J = 8.4 Hz, 2H), 6.723(s, 2H), 6.625(s, 2H), 5.755(d, 2H), 4.265(d, J = 16.0 Hz, 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 = 10.4 Hz, 4H).

[0213] Example 2: Synthesis of Compound A10 [ka] Step 1: Loxoprofen sodium (1.52 g) and water (5 mL) were added to a reaction flask, and the pH was adjusted to 2 by adding 1 N (i.e., 1 mol / L) hydrochloric acid dropwise while stirring. The reaction solution was extracted with EA. The organic phase was dried, filtered, and concentrated to dryness under reduced pressure to obtain A10-1 as a colorless oil (1.3 g). 1 H-NMR(400MHz, DMSO-d6) 12.234(s, 1H), 7.188(d, J = 8.4 Hz, 2H), 7.128(d, J = 8.0 Hz, 2H), 3.623(q, 7.2 Hz, 1H), 2.951(dd, J1= 13.2 Hz, J2= 3.6 Hz, 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 = 7.2 Hz, 3H).

[0214] Step 2: A10-1 (360 mg), A10-0 (500 mg), DMAP (18 mg), and ultra-anhydrous DCM (44 mL) were added to a reaction flask, and DCC (604 mg) was added at room temperature with stirring. The reaction was stirred overnight at room temperature. The reaction solution was washed three times with water, dried, filtered, and the mother liquor was concentrated to dryness under reduced pressure. The residue was purified by column chromatography to give a pale yellow solid. DCM (3 mL) was added, the mixture was cooled in the refrigerator for 1 hour, filtered, and the filtrate was concentrated to dryness under reduced pressure to give A10 as a yellow solid (596 mg). 1H-NMR(400MHz, DMSO-d6) δ 5.332(d, J = 8.0 Hz, 2H), 7.211(d, J = 8.0 Hz, 2H), 6.933(d, J = 8.0 Hz, 1H), 6.890~6.860(m, 2H), 6.681(s, 1H), 4.084(q, J = 7.2 Hz, 1H), 4.009(dd, J1= 15.6 Hz, J2= 11.2 Hz, 1H), 3.743(s, 3H), 3.722(s, 3H), 3.455~3.370(m, 3H), 3.352(d, J = 2.8 Hz, 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), 2.247(dd, J1= 18.0 Hz, J2= 8.0 Hz, 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).

[0215] Example 3: Synthesis of Compound A12 [ka] Step 1: Absolute ethanol (138 mg), pyridine (237 mg), and DCM (1 mL) were added to a reaction flask and cooled in an ice-water bath. A solution of triphosgene (di(trichloromethyl)carbonate, 297 mg) in DCM (1 mL) was added dropwise to the reaction. After the addition, the mixture was stirred for an additional 1.5 hours. The reaction was diluted with DCM. The organic phase was washed three times with water, dried, filtered, and the filtrate was concentrated to dryness under reduced pressure to give A12 as a colorless oil (with an aromatic odor).

[0216] Step 2: A10-0 (34 mg), triethylamine (20 mg), and DCM (1 mL) were added to a reaction flask and cooled in an ice-water bath. A solution of A12-1 (12 mg) in DCM (1 mL) was added dropwise to the reaction flask. After the addition, the mixture was stirred at room temperature. LCMS showed that the main peak was the target product. The reaction solution was diluted with DCM and purified by column chromatography to give a pale yellow oil (24 mg). The oil was dissolved in a small amount of DCM and purified by TLC using a DCM / EA (1 / 1, v / v) eluent to give a pale yellow oil (17 mg), which was lyophilized to give A12 as a pale yellow solid (15 mg). 1 H-NMR(400MHz, DMSO-d6) 7.067(d, J = 8.4 Hz, 1H), 6.967(d, J = 8.4 Hz, 1H), 6.890(s, 1H), 6.692(s, 1H), 4.261(q, J = 7.2 Hz, 2H), 4.073(d, J = 16.0 Hz, 1H), 3.752(s, 3H), 3.737(s, 3H), 3.729(s, 3H), 3.489~3.429(m, 3H), 3.138~3.122(m, 1H), 2.931~2.902(m, 1H), 2.646~2.562(m, 2H), 1.296(t, J = 7.2 Hz, 3H).

[0217] Example 4: Synthesis of Compound A14 [ka] A10-0 (34 mg), DCM (1 mL), and triethylamine (20 mg) were added to a reaction flask, and a solution of palmitoyl chloride (27 mg) in DCM (1 mL) was added dropwise to the reaction flask. The reaction was monitored by TLC until completion. The reaction solution was purified by TLC using a DCM / EA (1 / 1, v / v) developer to give a yellow solid, which was lyophilized to give A14 (56 mg). 1H-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 = 7.2 Hz, 2H), 1.814~1.739(m, 2H), 1.360~1.263(m, 24H), 0.881(t, J = 6.8 Hz, 3H).

[0218] Example 5: Synthesis of Compound A15 [ka] A10-0 (68 mg), glutaric acid (13 mg), DMAP (12 mg), and DCM (2 mL) were added to a reaction flask and cooled in an ice-water bath. DCC (82 mg) was added to the reaction flask. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was purified by TLC to give a colorless oil, which was lyophilized to give A15 as a pale yellow solid (61 mg). 1 H-NMR(400MHz, CDCl-d3) 6.965~6.917(m, 4H), 6.715(s, 2H), 6.631(s, 2H), 4.284(d, J = 14.8 Hz, 2H), 3.897(s, 6H), 3.877(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).

[0219] Example 6: Synthesis of Compound A16 [ka] A10-0 (50 mg), suberic acid (12.7 mg), DMAP (2 mg), and DCM (2 mL) were added to a reaction flask and cooled in an ice-water bath. DCC (60 mg) was added to the reaction flask. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was purified by TLC using EA as a eluent to give A16 as a white solid (42 mg). 1 H-NMR(400MHz, CDCl-d3) δ 6.953~6.901(m, 4H), 6.710(s, 2H), 6.629(s, 2H), 4.272(d, J = 14.0 Hz, 2H), 3.893(s, 6H), 3.875(s, 6H), 3.816(s, 6H), 3.724~3.633(m, 4H), 3.349~3.261(m, 6H), 2.964(s, 2H), 2.742(s, 4H), 2.621(t, J = 7.2 Hz, 4H), 1.824(t, 6.8 Hz, 4H), 1.535~1.500(m, 4H).

[0220] Example 7: Synthesis of Compound A17 [ka] A10-0 (50 mg), triphosgene (7.2 mg), and DCM (1 mL) were added to a reaction flask and cooled in an ice-water bath. A solution of pyridine (17 mg) in DCM (1 mL) was added dropwise to the flask. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC until completion. The reaction mixture was filtered to remove insoluble matter, and the filtrate was purified by TLC to give a colorless oil, which was lyophilized to give A17 as a solid (42 mg). 1H-NMR(400MHz, CDCl-d3) δ 7.117(d, J = 8.4 Hz, 2H), 6.967(d, J = 8.4 Hz, 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).

[0221] Example 8: Synthesis of Compound A18 [ka] Step 1: L-alanine (5.0 g) and THF (25 mL) were added to a reaction flask. Sodium hydroxide (2.45 g) was added to a separate vial and dissolved by the addition of water (50 mL). After cooling, sodium hydroxide solution was added to the reaction flask and stirred at room temperature. (Boc)2O (13.5 g) was added dropwise to the flask. After the addition, the reaction mixture was stirred at room temperature overnight, and the resulting reaction solution was concentrated under reduced pressure to remove THF. The residue was adjusted to pH 3 with 1N HCl, and the aqueous phase was extracted three times with EA. The combined organic phase was dried, filtered, and concentrated to dryness under reduced pressure to give A18-1 as a colorless oil (3.4 g). 1H-NMR(400MHz, CDCl-d3) δ 8.819(s, 1H), 5.075(s, 1H), 4.342(s, 1H), 1.528(s, 1.454(s, 9H).

[0222] Step 2: A18-1 (3.4 g), isopropanol (1.18 g), and DMAP (0.22 g) were added to DCM (34 mL) and cooled in an ice-water bath. EDCI (4.13 g) was added, and then the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. TLC showed that no starting material remained. The reaction mixture was diluted with DCM. The mixture was washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography using EA / PE (1 / 1, v / v) to give A18-2 as a colorless oil (2.1 g). 1 H-NMR(400MHz, CDCl-d3) δ 5.090~4.997(m, 2H), 4.250(s, 1H), 1.447(s, 9H), 1.364(d, J = 7.2 Hz, 3H), 1.255(t, J = 6.8 Hz, 6H).

[0223] Step 3: A18-2 (2.1 g) was dissolved in hydrochloric acid / dioxane (6 mL). The reaction was stirred at room temperature overnight. TLC detected no remaining starting material. The reaction mixture was concentrated to dryness under reduced pressure to give a colorless oil. Isopropyl ether (10 mL) was added to the oil to precipitate a white solid. The reaction mixture was filtered, and the filter cake was dried under vacuum at 50° C. to give A18-3 as a white solid (1.3 g). 1 H-NMR(400MHz, CDCl-d3) δ 8.708(s, 2H), 5.089(hept, J = 6.0 Hz, 1H), 4.181(quint, J = 6.0 Hz, 1H), 1.705(d, J = 7.2 Hz, 3H), 1.278(dd, J1= 6.4 Hz, J2= 4.4 Hz, 6H).

[0224] Step 4: A18-3 (37 mg) was added to the reaction flask under N2 protection. Phenyl dichlorophosphate (46 mg) was added to a separate vial, and DCM (1 mL) was added. The phenyl dichlorophosphate solution was transferred to the reaction flask and cooled to -40 °C with stirring. Triethylamine (89 mg) was added to a separate vial and dissolved by the addition of DCM (1 mL). The solution was slowly added dropwise to the reaction flask. After the addition, the reaction mixture was stirred at room temperature for 10 minutes, then transferred to -40 °C and cooled with stirring for 1 hour. A10-0 (68 mg) was added to a separate vial and dissolved by the addition of DCM (1 mL). The solution was slowly added dropwise to the reaction flask. After the addition, the reaction mixture was transferred to room temperature and stirred for 2 hours, then detected by TLC. The mixture was purified by reverse-phase column chromatography to give a yellow oil, which was lyophilized to give A18 as a pale yellow solid (53 mg). 1 H-NMR(400MHz, CDCl-d3) δ 7.358~7.282(m, 5H), 7.171(t, J = 7.2 Hz, 1H), 6.885(d, J = 8.4 Hz, 1H), 6.707(s, 1H), 6.623(s, 1H), 5.502(sext, J = 6.4 Hz, 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= 21.2 Hz, J2= 6.8 Hz, 3H), 1.244~1.199(m, 6H).

[0225] Example 9: Synthesis of Compound A19 [ka] Step 1: A10-0 (136 mg), DIPEA (77 mg), and ultra-anhydrous DCM (1 mL) were added to a reaction flask. 1-Chloroethyl chloroformate (57 mg) and DCM (1 mL) were added to a separate vial to obtain a solution of 1-chloroethyl chloroformate. The solution of 1-chloroethyl chloroformate was added dropwise to the reaction flask while stirring at room temperature. After the addition, the reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until completion. The reaction mixture was isolated by TLC using PE / EA (1 / 1, v / v) as a developer to obtain A19-1 as a pale yellow solid (178 mg). 1 H-NMR(400MHz, CDCl-d3) δ 7.029 (dd, J1= 8.4 Hz, J2= 3.2 Hz, 1H), 6.946(d, J = 8.4 Hz, 1H), 6.714(s, 1H), 6.630(s, 1H), 6.517(q, J = 6.0 Hz, 1H), 4.263(d, J = 16.0 Hz, 1H), 3.894(s, 3H), 3.875(s, 3H), 3.857(d, J = 2.0 Hz, 3H), 3.711~3.618(m, 2H), 3.355~3.165(m, 3H), 2.975~2.891(m, 1H), 2.727(d, J = 11.6 Hz, 2H), 1.912(d, J = 5.6 Hz, 3H).

[0226] Step 2: A19-1 (45 mg), dimethyl carbonate (0.25 mL), and isobutyric acid (0.75 mL) were added to a vial. DIEA (26 mg) was slowly added dropwise to the vial while stirring in an ice-water bath. After the addition, the reaction was heated at 80°C overnight and monitored by TLC. This product, which had the same Rf value as A19, was isolated by TLC using a PE / EA (4 / 1, v / v) developer to give A19 as a pale yellow oil (22 mg). 1H-NMR(400MHz, CDCl-d3) δ 7.016(d, J = 8.4Hz, 1H), 6.926(d, J = 8.0 Hz, 1H), 6.824(td, J1= 5.6 Hz, J2= 2.8 Hz, 1H), 6.709(s, 1H), 6.627(s, 1H), 4.262(d, J = 15.2 Hz, 1H), 3.892(s, 3H), 3.873(s, 3H), 3.854(s, 3H), 3.709~3.592(m, 2H), 3.321(dd, J1= 16.4 Hz, J2= 3.6 Hz, 1H), 3.276~3.147(m, 2H), 2.996~2.887(m, 1H), 2.735~2.699(m, 2H), 2.592(sep, J = 7.2 Hz, 1H), 1.602(d, J = 5.6 Hz, 3H), 1.196(d, J = 6.8 Hz, 6H).

[0227] Example 10: Synthesis of Compound A21 [ka] A10-0 (34 mg), NaOH powder (16 mg), and DCM (1 mL) were added to a reaction flask and stirred at room temperature for 10 minutes. A solid precipitated in the flask. Dibenzylchloromethyl phosphate (98 mg) was then added and stirred at room temperature overnight. The reaction mixture was purified by TLC using a 1:1 PE / EA developer to give A21 as a pale yellow solid (39 mg; the product tends to turn yellow upon oxidation). 1H-NMR(400MHz, CDCl-d3) δ 7.328~7.307(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 = 16.0 Hz, 1H), 3.893(s, 3H), 3.872(s, 3H), 3.836(s, 3H), 3.587~3.511(m, 2H), 2.375(dd, J2 = 16.4 Hz, J2 = 3.6 Hz, 1H), 3.212~3.120(m, 2H), 2.853(t, J = 13.4 Hz, 1H), 2.706~2.635(m, 2H).

[0228] Example 11: Synthesis of Compound A22 [ka] A21 (130 mg), ethanol (10 mL), water (5 mL), and Pd / C (13 mg) were added to a reaction flask. The reaction mixture was subjected to H2 purge and stirred at room temperature overnight. The reaction was monitored by LCMS until completion. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (5 mL x 2), and the aqueous phase was lyophilized to give A22 as a pale yellow solid (53 mg). 1 H-NMR(400MHz, D2O-d2) δ 7.300(d, J = 8.4 Hz, 1H), 7.020(d, J = 8.4 Hz, 1H), 6.941(s, 1H), 6.899(s, 1H), 4.783~4.743(m, 2H), 4.415(d, J = 16.0 Hz, 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).

[0229] Example 12: Synthesis of Compound A1 [ka] The crude A10-0 was dissolved in acetonitrile (3 mL), and K2CO3 and 1-chloroethyl acetate (47 mg) were added sequentially. After stirring at 60 °C for 2 h, the reaction mixture was diluted with ethyl acetate (30 mL), washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give A1 as a pale yellow solid (34 mg). MS: [M+H] 384. 1 H-NMR(400MHz, DMSO-d6) δ 6.95(s, 2H), 6.89(s, 1H), 6.69(s, 1H), 4.06(d, J = 15.9 Hz, 1H), 3.74(d, J = 9.6 Hz, 9H), 3.44(dd, J = 16.5, 8.2 Hz, 3H), 3.13(dd, J = 10.9, 3.7 Hz, 1H), 2.97-2.87(m, 1H), 2.69-2.55(m, 2H), 2.31(s, 3H).

[0230] Example 13: Synthesis of Compound A3 [ka] Step 1: The starting material (200 mg) was dissolved in thionyl chloride (10 mL) and heated to reflux for 4 hours. The reaction mixture was then cooled and concentrated to give the enriched product T-004-1 (218 mg in total), which was used directly in the next step.

[0231] Step 2: A10-0 (218 mg) and T-004-1 (201 mg) were dissolved in acetonitrile (10 mL), and anhydrous potassium carbonate (176 mg) was added. After stirring at 60 °C for 2 hours, the reaction mixture was cooled. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with water (30 mL) and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column to give A3 as a pale yellow solid (26 mg). MS: [M+H] 568. 1H-NMR(400 MHz, DMSO-d6) δ 6.95(s, 2H), 6.89(s, 1H), 6.69(s, 1H), 4.06(d, J = 15.9 Hz, 1H), 3.74(d, J = 9.6 Hz, 9H), 3.44(dd, J = 16.5, 8.2 Hz, 3H), 3.13(dd, J = 10.9, 3.7 Hz, 1H), 2.97-2.87(m, 1H), 2.69 - 2.55(m, 2H), 2.31(s, 3H).

[0232] Example 14: Synthesis of Compound A30 [ka] A10-0 (150 mg), triethylamine (89 mg), and DCM (4 mL) were added to a reaction flask and cooled in an ice-water bath. Palmitoyl chloride (127 mg) and DCM (1 mL) were added to a separate vial, and the palmitoyl chloride solution was added dropwise to the reaction flask. After the addition, the reaction mixture was stirred at room temperature for 2 hours and detected by TLC. After the reaction was complete, the reaction mixture was isolated and purified by column chromatography to give a pale yellow solid (245 mg), which was lyophilized to give A30 as a pale yellow solid (228 mg, 83.4% yield). MS: [M+H] 580. 1H-NMR(CDCl3, 400 MHz) δ 6.931(d, J = 8.4 Hz, 1H), 6.894(d, J = 8.4 Hz, 1H), 6.716(s, 1H), 6.625(s, 1H), 4.234(d, J = 15.6 Hz, 1H), 3.894(s, 3H), 3.873(s, 3H), 3.806(s, 3H), 3.711-3.589(m, 2H), 3.311(dd, J1= 16.4 Hz, J2= 3.2 Hz, 1H), 3.231-3.173(m, 2H), 2.942-2.873(m, 1H), 2.720-2.688(m, 2H), 2.587(t, J = 7.6 Hz, 2H), 1.777(quint, J = 7.6 Hz, 2H), 1.461-1.263(m, 24H), 0.897-0.864(m, 3H).

[0233] Example 15: Synthesis of Compound A20 [ka] A10-0 (340 mg) and TBAB (640 mg) were added to a reaction flask and dissolved by the addition of DCM (5 mL). NaOH (200 mg) was added to a separate vial and dissolved by the addition of water (5 mL). At room temperature, the NaOH solution was added dropwise to the reaction flask. Dibenzylchloromethyl phosphate (360 mg) was added to a separate vial and dissolved by the addition of DCM (5 mL). At room temperature, the solution was added dropwise to the reaction flask. After the addition, the reaction mixture was kept stirring overnight and purified by TLC isolation to give A20 as a pale yellow oil (210 mg, purity 97%). MS: [M+H] 632.

[0234] Example 16: Synthesis of Compound A23 [ka] Step 1: A10-0 (341 mg), sodium hydroxide (160 mg, 4 equiv.), and DCM (6 mL) were added to a 20 mL reaction flask. Dibenzylchloromethyl phosphate (490 mg, 1.5 equiv.) was added to a separate vial and diluted with DCM (4 mL). The reaction mixture was stirred at room temperature for 10 minutes, causing a solid to precipitate in the reaction flask. The dibenzylchloromethyl phosphate solution was added dropwise to the reaction flask and stirred at room temperature overnight. The separated aqueous phase was extracted with DCM. The combined organic phase was purified by column chromatography to afford T-025 as a pale yellow solid (462 mg, 77% yield). MS: [M+H] 602. 1 H-NMR(400MHz, CDCl-d3) δ 7.328~7.307(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 = 16.0 Hz, 1H), 3.893(s, 3H), 3.872(s, 3H), 3.836(s, 3H), 3.587~3.511(m, 2H), 2.375(dd, J1= 16.4 Hz, J2= 3.6 Hz, 1H), 3.212~3.120(m, 2H), 2.853(t, J = 13.4 Hz, 1H), 2.706~2.635(m, 2H).

[0235] Step 2: T-025 (462 mg), absolute ethanol (10 mL), purified water (5 mL), and Pd / C (46 mg, 10%) were added to a 50 mL one-neck flask and vigorously stirred. The reaction mixture was subjected to hydrogen purge three times and stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered. The filtrate was extracted twice with EA, and the aqueous phase was lyophilized to give T-026 as a pale yellow solid (212 mg, 66% yield). MS: [M+H] 422. 1H-NMR(400MHz, D2O-d2) δ 7.300(d, J = 8.4 Hz, 1H), 7.020(d, J = 8.4 Hz, 1H), 6.941(s, 1H), 6.899(s, 1H), 4.783~4.743(m, 2H), 4.415(d, J = 16.0 Hz, 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).

[0236] Step 3: T-026 (60 mg) and NMP (1 mL) were added to a vial and heated to 45° C. Triethylamine (60 mg, 4 eq.) and TBAB (48 mg) were added and heated to 50° C. Chloromethyl isopropyl carbonate (114 mg, 5 eq.) was added and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was purified by column chromatography. The fractions were concentrated to dryness under reduced pressure to give a yellow solid, which was dissolved in water and then lyophilized to give A23 as a yellow solid (49 mg, 48.0% yield). MS: [M+H] 538. 1 H-NMR (CDCl3, 400 MHz) δ 7.198(d, J = 8.8 Hz, 1H), 6.686(s, 1H), 6.648-6.612(m, 2H), 5.645-5.563(m, 2H), 4.845(sept, J = 6.4 Hz, 1H), 4.531(s, 1H), 4.067-3.706(m, 13H), 3.309(dd, J1= 16.4Hz, J2= 6.4 Hz, 1H), 3.149(s, 3H), 2.968(s, 1H), 2.809(d, J = 15.6 Hz, 1H), 1.300(t, J = 7.6 Hz, 6H). 31 P-NMR (CDCl3, 160 MHz) δ -7.7546(s).

[0237] Example 17: Synthesis of Compound A56 [ka] A10-0 (68 mg), n-caprylic acid (32 mg), DMAP (2 mg), and dichloromethane (1 mL) were added to a reaction flask and stirred at room temperature. EDCI (76 mg, 2 equivalents) was added to the flask, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC until completion. The reaction mixture was purified by silica gel column chromatography to give a pale yellow oil, which was lyophilized to give product A56 (65 mg, 69.8% yield). MS: [M+H] 468. 1 H-NMR(CDCl3, 400 MHz) δ 6.880(d, J = 8.4 Hz, 1H), 6.890(d, J = 8.4 Hz, 1H), 6.720(s, 1H), 6.623(s, 1H), 4.218(d, J = 15.6 Hz, 1H), 3.894(s, 3H), 3.873(s, 3H), 3.803(s, 3H), 3.620-3.565(m, 2H), 3.304(dd, J1= 16.4 Hz, J2= 3.2 Hz, 1H), 3.227-3.108(m, 2H), 2.884(dd, J1= 14.8 Hz, J2= 12.0 Hz, 1H), 2.709-2.850(m, 2H), 2.589(t, J = 7.2 Hz, 3H), 1.781(quint, J = 7.6 Hz, 2H), 1.465-1.393(m, 2H), 1.374-1.313(m, 6H), 0.914-0.881(m, 3H).

[0238] Example 18: Synthesis of Compound A44 [ka] A10-0 (68 mg), oleic acid (57 mg, 1.01 eq.), DMAP (3 mg, 0.1 eq.), and DCM (1 mL) were added to a reaction flask. DCC (82 mg, 2 eq.) was added to a separate vial and diluted with DCM (1 mL). The DCC solution was added dropwise to the reaction flask while stirring at room temperature. After the addition, the reaction mixture was stirred overnight at room temperature. The reaction was detected to be complete by TLC, and the reaction mixture was purified to give a pale yellow oil, which was lyophilized to give A44 as a pale yellow solid (60.53 mg). MS: [M+H] 606. 1 H-NMR(CDCl3, 400 MHz) δ 6.882(d, J = 8.0 Hz, 1H), 6.898(d, J = 8.4 Hz, 1H), 6.714(s, 1H), 6.625(s, 1H), 5.396-5.312(m, 2H), 4.254(d, J = 15.6 Hz, 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 = 7.6 Hz, 2H), 2.025-2.012(m, 5H), 1.779(quint, J = 7.2 Hz, 2H), 1.433-1.271(m, 19H), 0.897-0.864(m, 3H).

[0239] Example 19: Synthesis of Compound A24 [ka] A10-0 (68 mg), DMAP (3 mg), n-nonanoic acid (32 mg), and DCM (1 mL) were added to a reaction flask. DCC (82 mg) and DCM (1 mL) were added to a separate vial, and the DCC solution was added dropwise to the reaction flask while stirring at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction was detected to be complete by TLC, and the reaction mixture was purified to give a colorless oil, which was lyophilized to give A24 as a pale yellow solid (63.44 mg). MS: [M+H] 482. 1 H-NMR(CDCl3, 400 MHz) δ 6.882(d, J = 8.4 Hz, 1H), 6.896(d, J = 8.4 Hz, 1H), 6.716(s, 1H), 6.625(s, 1H), 4.242(d, J = 16.0 Hz, 1H), 3.893(s, 3H), 3.872(s, 3H), 3.807(s, 3H), 3.710-3.601(m, 2H), 3.313(dd, J1= 16.0 Hz, J2= 3.6 Hz, 1H), 3.245-3.145(m, 2H), 2.950-2.886(m, 1H), 2.730-2.697(m, 2H), 2.588(t, J = 7.6 Hz, 2H), 1.779(quint, J = 7.6 Hz, 2H), 1.362-1.256(m, 10H), 0.908-0.874(m, 3H).

[0240] Example 20: Synthesis of Compound A25 [ka] A10-0 (68 mg), DMAP (3 mg, 0.1 equiv.), n-decanoic acid (38 mg), and DCM (1 mL) were added to a reaction flask. EDCI (77 mg) and DCM (0.5 mL) were added to a separate vial, but the solid did not dissolve. With stirring, the EDCI suspension was added to the reaction flask via syringe, and the solid immediately dissolved. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction mixture was purified to give a pale yellow oil, which was lyophilized to give A25 as a pale yellow solid (61.91 mg). MS: [M+H] 496. 1 H-NMR(CDCl3, 400 MHz) δ 6.934(d, J = 8.4 Hz, 1H), 6.900(d, J = 8.0 Hz, 1H), 6.713(s, 1H), 6.627(s, 1H), 4.252(d, J = 15.2 Hz, 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 = 7.6 Hz, 2H), 1.778(quint, 7.6 Hz, 2H), 1.448-1.283(m, 14), 0.904-0.871(m, 3H).

[0241] Example 21: Synthesis of Compound A57 [ka] Step 1: Caffeic acid (1.8 g) and absolute ethanol (20 mL) were added to a 30 mL flask, and concentrated sulfuric acid (5 drops) was added dropwise. After the addition, the reaction mixture was heated and stirred under reflux overnight. TLC detected that no raw material remained. The reaction mixture was diluted by adding water, and the mixture was extracted twice with EA. The combined organic phase was washed twice with water, dried, and filtered. The filtrate was concentrated to dryness under pressure to give T-039-1 as a brown solid (2.12 g). 1H-NMR(DMSO-d6, 400MHz) δ 9.565(s, 1H), 9.116(s, 1H), 7.470(d, J = 16.0 Hz, 1H), 7.047(d, J = 1.6 Hz, 1H), 6.999(dd, J1= 8.0 Hz, J2= 2.0 Hz, 1H), 6.763(d, J = 8.4 Hz, 1H), 6.253(d, J = 16.0 Hz, 1H), 4.155(q, J = 7.2 Hz, 2H), 1.241(t, J = 7.2 Hz, 3H).

[0242] Step 2: T-039-1 (1.04 g), K2CO3 (2.07 g), and acetone (15 mL) were added to a vial and stirred at room temperature. Benzyl bromide (1.79 g) was added dropwise. After the addition, the reaction mixture was stirred at 60 °C overnight. TLC showed that no raw material remained. The reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure to give T-039-2 as a colorless oil. The crude product was used directly in the next step.

[0243] Step 3: T-039-2 obtained in the last step was dissolved in THF (30 mL), and water (5.5 mL) and solid sodium hydroxide (1.62 g, 8.1 equiv.) were added. The reaction mixture was stirred at room temperature for 36 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure, and the aqueous phase was adjusted to pH 2. The mixture was extracted once with EA, and the EA phase was dried, filtered, and concentrated to dryness under reduced pressure to give T-039-3 as a beige solid (1.741 g). 1 H-NMR(DMSO-d6, 400MHz) δ 12.202(s, 1H), 7.516-7.437(m, 6H), 7.406-7.363(m, 4H), 7.335-7.301(m, 2H), 7.195(dd, J1= 8.4 Hz, J2= 1.6 Hz, 1H), 7.073(d, J = 8.4 Hz, 1H), 6.418(d, J = 16.0 Hz, 1H), 5.196(s, 2H), 5.184(s, 2H).

[0244] Step 4: A10-0 (102 mg), T-039-3 (129 mg), DMAP (3 mg), and DCM (3 mL) were added to a vial. The solid did not completely dissolve. EDCI (115 mg) was added, and the solid immediately dissolved. The reaction mixture was stirred at room temperature for 48 hours. TLC showed that essentially no starting material remained. The reaction mixture was isolated by silica gel chromatography using a PE / EA=1 / 1 eluent to give T-039-4 as a yellow oil (208 mg). 1 H-NMR(DMSO-d6, 400MHz) δ 7.792(d, J = 16.0 Hz, 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 = 8.4 Hz, 1H), 7.028-6.947(m, 2H), 6.899(s, 1H), 6.826(d, J = 16.0 Hz, 1H), 6.697(s, 1H), 5.223-5.220(m, 4H), 4.086(d, J = 16.0 Hz, 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).

[0245] Step 5: T-039-4 (208 mg) was dissolved in THF (15 mL) and palladium hydroxide (20 mg, 10%) was added. The reaction mixture was subjected to hydrogen purge and stirred at room temperature overnight. TLC showed no remaining starting material. The reaction mixture was filtered and concentrated to dryness under reduced pressure. The residue was isolated by preparative TLC using EA as a eluent to give A57 as an off-white solid (70 mg). MS: [M+H] 506. 1H-NMR(CDCl3, 400 MHz) δ 6.941-6.863(m, 2H), 6.716(s, 1H), 6.678(d, J = 8.0 Hz, 1H), 6.635(s, 1H), 6.567(dd, J1= 8.0 Hz, J2= 1.6 Hz, 1H), 6.418(d, J = 1.6 Hz, 1H), 4.293(d, J = 16.0 Hz, 1H), 3.891(s, 3H), 3.876(s, 3H), 3.767-3.736(m,1H), 3.710(s, 3H), 3.649(d, J = 16.0 Hz, 1H), 3.369(dd, J1= 16.4 Hz, J2= 3.6 Hz, 1H), 3.312-3.256(m, 2H), 2.990(dd, J1= 16.0 Hz, J2= 12.0 Hz, 1H), 2.848-2.712(m,6H).

[0246] Example 22: Synthesis of Compound A53 [ka] Phosphorus oxychloride (101 mg), triethylamine (302 mg), and THF (2 mL) were added to a reaction flask and cooled to -40 °C. A solution of 2-hydroxybenzyl alcohol (74 mg) in THF (2 mL) was slowly added dropwise at -40 °C. After the addition, the reaction mixture was stirred at -40 °C for 1 hour, then transferred to room temperature and stirred for an additional 2 hours, and then cooled to -40 °C. At -40 °C, a solution of A10-0 (102 mg) in THF (0.5 mL) was slowly added dropwise. After the addition, the reaction mixture was transferred to room temperature and stirred overnight. LCMS showed that no A10-0 remained in the reaction mixture, and the main peak was 510. The reaction mixture was filtered, and the filtrate was isolated by preparative thin-layer chromatography using EA as a eluent to give a colorless oil, which was lyophilized to give A53 as a pale yellow solid (97.78 mg). MS: [M+H] 510. 1H-NMR(CDCl3, 400 MHz) δ 7.369(t, J = 7.2 Hz, 1H), 7.265(s, 1H), 7.195(t, J = 7.2 Hz, 1H), 7.140(d, J = 7.6 Hz, 2H), 7.927(d, J = 8.4 Hz, 1H), 6.741(s, 1H), 6.650(s, 1H), 5.608-5.553(m, 1H), 5.499-5.417(m, 1H), 4.234(d, J = 14.8 Hz, 1H), 3.920(d, J = 2.0 Hz, 3H), 3.299(d, J = 1.6 Hz, 3H), 3.751(dd, J1= 13.6 Hz, J2= 2.4 Hz, 3H), 3.647-3.566(m, 2H), 3.320(d, J = 16.4 Hz, 1H), 3.243-3.157(m, 2H), 2.933-2.869(m, 1H), 2.741-2.707(m, 2H). 13 P-NMR(CDCl3, 160 MHz): δ -15.448(s), -15.548(s).

[0247] Example 23: Synthesis of Compound A43 [ka] A10-0 (68 mg), DMAP (2 mg), all-cis-eicosapentaenoic acid (120 mg), and DCM (2 mL) were added to a reaction flask. EDCI (153 mg) was added at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction was detected to be complete by TLC. The reaction mixture was isolated by column chromatography to give a yellow oil, which was lyophilized to give A43 as a pale yellow solid (93.01 mg). MS: [M+H] 626. 1H-NMR(CDCl3, 400 MHz) δ 6.928(d, J = 8.4 Hz, 1H), 6.893(d, J = 8.4 Hz, 1H), 6.715(s, 1H), 6.623(s, 1H), 5.548-5.291(m, 10 H), 4.233(d, J = 16.0 Hz, 1H), 3.890(s, 3H), 3.870(s, 3H), 3.802(s, 3H), 3.631-3.593(m, 2H), 3.308(dd, J1= 16.4 Hz, J2= 2.8 Hz, 1H), 3.236-3.145(m, 2H), 2.987-2.815(m, 9H), 2.724-2.692(m, 2H), 2.608(t, J = 7.2 Hz, 2H), 2.225(q, J = 6.4 Hz, 2H), 2.076(quint, J = 7.2 Hz, 2H), 1.862(quint, J = 7.2 Hz, 2H), 0.974(t, J = 7.2 Hz, 3H).

[0248] Example 24: Synthesis of Compound A54 [ka] A10-0 (68 mg), DMAP (2 mg), 3,6,9,12-tetraoxotridecanoic acid (49 mg), and DCM (2 mL) were added to a reaction flask. EDCI (76 mg) was added at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. TLC showed that no starting material remained. The reaction mixture was isolated by column chromatography to give a colorless oil (75 mg), which was lyophilized to give A54 as a pale yellow solid (65 mg). MS: [M+H] 546. 1H-NMR(DMSO, 400 MHz) δ 6.999(d, J = 8.0 Hz, 1H), 6.963(d, J = 8.4 Hz, 1H), 6.887(s, 1H), 6.691(s, 1H), 4.282(s, 2H), 4.069(d, J = 16.0 Hz, 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).

[0249] Example 25: Synthesis of Compound A40 [ka] A10-0 (68 mg), DMAP (2 mg), docosahexenoic acid (79 mg), and DCM (2 mL) were added to a reaction flask. EDCI (76 mg) was added at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was detected to be complete by TLC, the reaction mixture was purified to give a pale yellow oil, which was lyophilized to give A40 as a pale yellow oil (103 mg). MS: [M+H] 652. 1H-NMR(CDCl3, 400 MHz) δ 6.929(d, J = 8.4 Hz, 1H), 6.896(d, J = 8.4 Hz, 1H), 6.714(s, 1H), 6.625(s, 1H), 5.484-5.294(m, 12H), 4.239(m, 16.0 Hz, 1H), 3.892(s, 3H), 3.872(s, 3H), 3.804(s, 3H), 3.709-3.599(m, 2H), 3.311(dd, J1= 16.0 Hz, J2= 3.2 Hz, 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 = 7.2 Hz, 2H), 0.972(t, J = 7.6 Hz, 3H).

[0250] Example 26: Synthesis of Compound A55 [ka] A10-0 (68 mg), DMAP (2 mg), 2,5,8,11,14,17,20,23,26-nonaoxaoctacosan-28-oic acid (101 mg), and DCM (2 mL) were added to a reaction flask. EDCI (76 mg) was added at room temperature with stirring. The reaction mixture was stirred overnight at room temperature. TLC showed no remaining starting material. The reaction mixture was isolated by column chromatography to give a pale yellow oil, which was lyophilized to give A55 as a pale yellow solid (135 mg). MS: [M+H] 766.5. 1H-NMR(CDCl3, 400 MHz) δ 6.973-3.929(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).

[0251] Example 27: Synthesis of Compound A45 [ka] A10-0 (68 mg), DMAP (2 mg), elaidic acid (68 mg), and DCM (2 mL) were added to a reaction flask. EDCI (76 mg) was added at room temperature with stirring. The reaction mixture was stirred overnight at room temperature. After the reaction was detected to be complete by TLC, the reaction mixture was purified by column chromatography to give a yellow oil (102 mg), which was lyophilized to give A45 as a pale yellow solid (95 mg). MS: [M+H] 606. 1H-NMR(CDCl3, 400 MHz) δ 6.932(d, J = 8.4 Hz, 1H), 6.898(d, J = 8.4 Hz, 1H), 6.713(s, 1H), 6.626(s, 1H), 5.390(s, 2H), 4.251(d, J = 15.6 Hz, 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 = 7.6 Hz, 2H), 2.019-1.974(m, 4H), 1.776(quint, J = 7.2 Hz, 2H), 1.443-1.265(m, 20H), 0.895-0.862(m, 3H).

[0252] Example 28: Synthesis of Compound A4 [ka] Starting from the S-configuration raw material (200 mg), the same procedure as that for compound A3 was followed to finally obtain A4 as a pale yellow solid (25 mg). MS: [M+H] 568. 1H-NMR(400 MHz, DMSO-d6) δ 6.95(s, 2H), 6.89(s, 1H), 6.69(s, 1H), 4.06(d, J = 15.9 Hz,1H), 3.74(d, J = 9.6 Hz, 9H), 3.44(dd, J = 16.5, 8.2 Hz, 3H), 3.13(dd, J = 10.9, 3.7 Hz, 1H),2.97-2.87(m, 1H), 2.69 - 2.55(m, 2H), 2.31(s, 3H).

[0253] Example 29: Synthesis of Compound A48 [ka] 1.Synthesis of A48-1 Step: A48-SM (20.0 g, 1.0 equiv.) and dichloromethane (200 mL) were added to a 500 mL flask. Under nitrogen protection, triethylamine (8.88 g) was added, and trifluoromethanesulfonic anhydride (19.8 g) was added dropwise in an ice bath. The reaction mixture was warmed and stirred at room temperature overnight. LC / MS showed the reaction was complete. Water (200 mL) was added to the reaction mixture, and the mixture was stirred to separate the layers. The aqueous phase was extracted with dichloromethane (100 mL). The combined dichloromethane phase was washed with saturated chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The sample residue was purified using a 330 g silica gel column (PE / EA, 0-30%, 0-40 min, gradient elution) to give A48-1 as a yellow solid (26.97 g, 94.8% yield). HPLC purity: 98.93%. MS:474[M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 4.13 (d, J = 16.1 Hz, 1H), 3.83 (s, 3H), 3.74 (d, J = 9.4 Hz, 6H), 3.53 (dd, J = 16.5, 6.6 Hz, 3H), 3.15 (dd, J = 11.1, 3.7 Hz, 1H), 2.99 - 2.86 (m, 1H), 2.63 (dd, J = 15.6, 9.6 Hz, 3H).

[0254] 2.Synthesis of A48-2 Step: A48-1 (20.0 g, 1.0 equiv.), tert-butyl carbamate, tripotassium phosphate, tri(dibenzylideneacetone)dipalladium(0), 2-(biphenyl)di-tert-butylphosphine, and 1,4-dioxane (200 mL) were added to a 1 L flask. The reaction mixture was heated to 90° C. under nitrogen protection and stirred overnight. LC / MS showed that the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with EA (50 mL). The liquid was concentrated to dryness. The residue was purified by silica gel column to give A48-2 as a yellow solid (22.0 g, 100% yield).

[0255] 3.Synthesis of A48 Step: A48-2 (2.5 g) and dichloromethane (10 mL) were added to a 50 mL flask, and a solution of hydrochloric acid in dioxane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. LC / MS showed that the reaction was complete. The reaction mixture was concentrated to dryness, and then DCM (20 mL) was added. Saturated sodium carbonate solution (20 mL) was added to adjust the pH to basic. The layers were separated, and the aqueous phase was extracted with DCM (20 mL). The combined DCM phase was washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The sample residue was purified by silica gel column to give A48 as a yellow solid (1.05 g, 54.4% yield). MS: [M+H] 326. 1H NMR (400 MHz, DMSO-d6) δ 6.85 (s, 1H), 6.67(s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 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 = 16.0 Hz, 4.0 Hz, 1H), 3.10 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 2.97 - 2.89 (m, 1H), 2.60 (d, J = 16.0 Hz, 1H), 2.48-2.42 (m, 2H).

[0256] Example 30: Synthesis of Compound N12 [ka]

[0257] Synthesis of N12-1 [ka] N12-SM2 (2 g, 1 eq.) was added to a one-neck flask, and 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 at room temperature. Dioxane (30 mL) was added to the system. The system was heated to 80 °C and stirred overnight. The reaction was monitored by LCMS. The reaction was subjected to workup. The reaction was cooled to room temperature, quenched by the addition of water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and rotary evaporated. Medium pressure separation gave product N12-1 (624 mg). MS: 296, 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.36 - 7.27 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 3.88 (s, 3H).

[0258] Synthesis of N12-2 [ka] N12-1 (624 mg, 1.0 equiv.) was added to MeOH (10 mL) and a solution of sodium hydroxide (140 mg, 1.8 equiv.) in water (13 mL) was added. The reaction mixture was heated and stirred at 60° C. for 1 h. LCMS showed no remaining starting material. The reaction mixture was worked up, concentrated, adjusted to pH 3-4, and filtered. The filter cake was collected and lyophilized to give the product (540 mg), which was used directly in the next step. MS: 341.

[0259] Synthesis of compound N12 [ka] N12-2 (200 mg, 1 equiv.) was added to DCM. After complete dissolution, A48 (266 mg, 1.1 equiv.), EDCI (203 mg, 1.5 equiv.), and DMAP (9 mg, 0.1 equiv.) were added. The reaction mixture was stirred at room temperature for 1 hour to give the desired product. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to give the product, compound N12 (250 mg). MS: 605. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.38-7.32 (m, 3H), 7.14 (d, J = 8.0 Hz, 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 = 8.0 Hz, 4.0 Hz, 1H), 2.99-2.91 (m, 1H), 2.68-2.61 (m, 2H), 2.53-2.48 (m, 1H).

[0260] Example 31 [ka]

[0261] Synthesis of N16-1 [ka] S-Flurbiprofen (400 mg, 1 eq.) was added to DMF and completely dissolved. Then, HATU (700 mg, 1.1 eq.) and DIEA (800 mg, 4 eq.) were added. The reaction mixture was stirred at 40° C. for 1 hour. N16-SM (400 mg, 1 eq.) was added to the reaction mixture. After stirring for 2 hours, the reaction mixture was analyzed by mass spectrometry to obtain the desired product. The reaction mixture was extracted with ethyl acetate, back-extracted with water and saturated brine, spun dry, and subjected to column chromatography using petroleum ether / ethyl acetate to obtain the desired product N16-1. MS: 464.

[0262] Synthesis of N16-2 [ka] N16-1 (400 mg, 1 eq.), A10-0 (400 mg, 1.3 eq.), and DMAP (10 mg, 0.1 eq.) were dissolved in DCM, and EDCI (300 mg, 1.6 eq.) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was extracted with dichloromethane, rotary evaporated, and purified by column chromatography to give product N16-2. MS: 787.

[0263] Synthesis of compound N16 [ka] N16-2 (400 mg) was dissolved in methanol and palladium hydroxide / carbon was added. The reaction mixture was stirred for 3 hours to give the desired product (detected by mass spectrometry). The reaction mixture was filtered and rotary dried to give the crude product, which was subjected to acid and alkali treatment and lyophilized to give compound N16 (400 mg). MS: 697.

[0264] Synthesis of compound N17 [ka] Compound N16 was dissolved in ethanol and thionyl chloride was added dropwise at 0°C. The reaction mixture was stirred for 30 minutes to give the desired product (detected by mass spectrometry). The reaction mixture was extracted with ethyl acetate and rotary evaporated. The residue was subjected to column chromatography to give the desired crude product. The crude product was recrystallized from ethanol to give the desired product. MS: [M+H] 725. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (t, J = 8.0 Hz, 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 = 8.0 Hz, 3H), 1.14(dt, J = 40 Hz, 8.0 Hz, 3H).

[0265] Mechanical pain testing in a Freund's complete adjuvant-induced inflammatory pain model in mice 1. Test Method 1) After purchase, the animal mice (C57BL / 6J, 8-week-old, male, purchased from Zhejiang Charles River Experimental Animal Technology Co., Ltd.; certificate number: 20220617Abzz0619000690; license number: SCXK(Zhejiang)2019-0001; issuer: Zhejiang Charles River Experimental Animal Technology Co., Ltd.; 18-22 g) were housed for one week to allow them to acclimate, and during this time, the mice were allowed to eat ad libitum. 2) During the first three days of the study, the mice were placed in a metal pain measurement rack for 40–60 minutes to acclimate, during which time the experimenter handled the animals to allow them to acclimate (from day 1 to day 3, the mice were touched for 3–5 minutes) to reduce the animals' stress response to the experimenter. 3) After the environmental adaptation was completed (day 4), the baseline values ​​of the animals were tested (up-down test method), and the animals were randomly divided into four groups, including model group (model), control group I (morphine), control group II (A10-0, Corydalmine), and test group (A3), with four mice per group (n=4). 4) The inflammatory pain model was induced using Freund's complete adjuvant. 20 μL of Freund's complete adjuvant (CFA) solution was drawn up with a sample microinjector, and the needle was inserted into the toe of one of the animal's hind paws. The CFA solution was slowly injected subcutaneously in the palm of the hand to form a bulge under the skin. The needle was then held in place for 20 seconds, and slowly rotated to prevent leakage of the liquid before being removed. 5) The mechanical pain threshold and paw thickness of the mice were tested 0.5, 2, 8, and 24 hours after the first administration (morphine was administered subcutaneously in control group I; drugs were administered by oral gavage at 8-hour intervals in the other groups), with the doses being 2 mg / kg in control group I (morphine), 5 mg / kg in control group II (A10-0, coridalmin), and 8.4 mg / kg in test group (A3).

[0266] The method for measuring mechanical pain (up-down test method) includes the following steps. The experimental animals were placed on a metal mesh rack for 30 to 60 minutes. The test began once the animals had stopped observing and exploring and were quiet. b. After acclimation, the mid-plantar hind paw was stimulated with the fiber. The experimenter positioned the von Frey fiber perpendicular to the plantar surface and applied a force that slightly flexed the fiber relative to the paw for approximately 6–8 seconds. c. The contact should be gentle (no punctures) and the force applied slowly until the fiber begins to bend. d. The mouse experiment started at 1.0 g, and then the researcher used the fiber at smaller or larger forces according to the up-down method, depending on whether there was a response. e. The first data point after the first inflection point was designated as reading 1, and the test was stopped after four readings were taken. In mouse experiments, the maximum force applied was 2.0 g and the minimum force was 0.16 g. f. If the animal responded to the stimulus by lifting, hiding, or licking its paw, except for a paw withdrawal response due to physical movement, it was recorded as positive (X); if none of the above behaviors occurred, it was recorded as negative (O). g. Grams of fiber: Grams for mice: 0.16, 0.40, 0.60, 1.0, 1.4, 2.0 (cut-off value 2.0 g).

[0267] 2. Test Results The data obtained above were compiled, counted, and analyzed by SPSS data statistical software, and plotted by Graph Pad software according to the SPSS analysis results. The results are shown in Figures 1 and 2.

[0268] FIG. 1 is a graph showing the results of mechanical pain thresholds in a mechanical pain test of an inflammatory pain model induced by Freund's complete adjuvant in mice; all values ​​are mean ± SEM (mean ± standard error), n=4. * :For the model group, * -P<0.05, ** -P<0.01, *** -p<0.001, #: Morphine-2mg / kg vs. ###-P<0.001.

[0269] Figure 2 is a graph showing the results of the plantar thickness test in a Freund's complete adjuvant-induced inflammatory pain model in mice; all values ​​are mean ± SEM (mean ± standard error), n = 4. * :For the model group, * -P<0.05.

[0270] As can be seen from Figures 1 and 2, we successfully established an inflammatory pain model induced by Freund's adjuvant (CFA). The positive drug morphine (2 mg / kg dose) showed good analgesic effects in the inflammatory pain model in mice, but the effects could not be maintained for a long period of time. The positive drug morphine (2 mg / kg dose) did not show any effect in reducing the degree of plantar swelling in mice. Compound A10-0 (5 mg / kg dose) did not show significant analgesic effects in the inflammatory pain model in mice, and although it did show an effect of reducing the degree of plantar swelling in mice, the effect was only maintained for a short period of time. Compared with the positive drug morphine, compound A10-0 has different effects in terms of analgesic effects and plantar swelling reduction effects. Compound A3 (8.4 mg / kg dose) showed a strong analgesic effect in inflammatory pain models in mice, but the effect was maintained for a short period of time, and compound A3 (8.4 mg / kg dose) reduced the degree of plantar swelling after several drug treatments.Compared with the active drug morphine, compound A3 has different effects in terms of analgesic effect and plantar swelling reduction effect.

[0271] Analgesic test in the acetic acid-induced writhing model 1. Test Method 1) Animals: Mice (CD-1 mice, age: 6-8 weeks, sex: male, weight: 20-24 g, number: 120, animal supplier: SPF (Beijing) Biotechnology Co., Ltd.) underwent a 7-day quarantine period, during which routine health examinations were performed by a veterinarian. Animals with abnormalities were excluded from the study prior to the experiment.

[0272] Mice were housed at Pharmaron (Beijing) New Drug Technology Co., Ltd. Animal Center (AAALAC-accredited facility) in an SPF-grade laminar flow clean room with constant temperature and humidity, with five mice per cage. The feeding room was maintained at 22±3°C and 40-70% humidity, with a 12-hour light / dark cycle. Cages were made of polycarbonate. Autoclaved clean bedding was made from soft corncobs and changed twice weekly. Diet and drinking water: clean-grade rodent diet (purchased from Beijing Keao Xieli Feed Co., Ltd.). Drinking water was autoclaved, and the diet was irradiated with cobalt-60. Animals were provided with free access to sterile diet and drinking water.

[0273] Each cage was labeled with a cage label indicating the animal's number, sex, strain, time of receipt, grouping and start time of the experiment.Animal Number: Each animal was marked with a unique animal number on its tail.

[0274] The animals were randomly divided into groups according to body weight, and the specific groups and modes of administration are listed in Table 1 below; in this disclosure, fentanyl, an existing drug commonly used for analgesia, was used as a positive control.

[0275] [Table 1]

[0276] Before administration, the mice were fasted for 16 hours. According to Table 1, the administration methods in each group were as follows: positive drug fentanyl: intravenous injection; other drugs or blank groups: oral gavage; dose: 10 mL / kg; number of administrations: single.

[0277] 2) Before administration, all mice were weighed and recorded in detail. Each group was administered the drug according to the administration method listed in Table 1. After administration, each group received an injection of 0.6% glacial acetic acid. Group 2 received the injection 10 minutes after administration, while the other groups received the injection 2 hours after administration. The 0.6% glacial acetic acid was injected intraperitoneally into the mice, where it deposited in the visceral and parietal peritoneum, causing deep, widespread, and prolonged inflammatory pain. As a result, the mice exhibited a behavioral response known as a writhing response, which included abdominal depression, extension of the trunk and hind limbs, and lifting of the buttocks. The analgesic effect of the compound was evaluated based on the number of mouse writhing movements as an index of pain response. Writhing responses occurred most frequently within 30 minutes after injection of 0.6% glacial acetic acid. The number of writhing responses was observed and recorded within 5 to 15 minutes and 15 to 30 minutes after injection of 0.6% glacial acetic acid.

[0278] 2. Test Results The results of the writhing test for mice in each group were expressed as "mean ± standard error." Data from each group were subjected to data statistics using the SPSS 16.0 software package, with one-way ANOVA statistical method. Groups were compared to determine whether there was a statistical difference between groups, with P<0.05 indicating a statistical difference. The recorded results of the writhing onset time for mice in each group are shown in Figure 3, and the results of the writhing test for mice in each group are shown in Table 2. The total number of writhing movements for mice in each group is shown in Table 2 and Figure 4.

[0279] [Table 2]

[0280] As can be seen from the results in Table 2, the mice administered with the compound of the present disclosure had fewer writhes than the blank group, indicating that the compound of the present disclosure has a good analgesic effect.

[0281] Activity detection The mice (CD-1 mice, age: 6-8 weeks, sex: male, weight: 20-24 g, number: 120, animal supplier: SPF (Beijing) Biotechnology Co., Ltd.) underwent a 7-day quarantine period during which routine health examinations were performed by a veterinarian. Animals with abnormalities were excluded from the study prior to the experiment.

[0282] Mice were housed in a clean room with five mice per cage. The feeding room was maintained at 22±3°C and 40-70% humidity with a 12-hour light / dark cycle. Cages were made of polycarbonate. Autoclaved clean bedding was made from soft corncobs and replaced twice weekly. Diet and drinking water: clean-grade rodent diet (purchased from Beijing Keao Xieli Feed Co., Ltd.). Drinking water was autoclaved, and the diet was irradiated with cobalt-60. Animals were provided with free access to sterile diet and drinking water. All mice were weighed and recorded in detail before administration.

[0283] Mice were fasted for 16 hours before administration. Administration was performed intravenously at a volume of 10 mL / kg and a dose of 10 mpk. 15 minutes after administration, 0.6% glacial acetic acid was injected intraperitoneally into the mice. It deposited in the visceral and parietal peritoneum, causing deep, widespread, and prolonged inflammatory pain. As a result, the mice exhibited a behavioral response known as a writhing response, including abdominal depression, extension of the trunk and hind limbs, and lifting of the buttocks. The analgesic effect of the compound was evaluated using the number of writhing movements observed in the mice as an index of pain response. The number of "writhing movements" occurring within 20 minutes after injection of 0.6% glacial acetic acid and the number of "writhing movements" in the control group were observed, and the ratio was calculated. The ratio was subtracted from 100% to record the inhibition rate.

[0284] [Table 3]

[0285] The various embodiments in this specification are described in relation to one another, and reference may be made to identical and similar parts between the embodiments, with each embodiment focusing on the differences from the other embodiments.

[0286] The above are merely alternative embodiments of the present disclosure and are not intended to limit the scope of protection of the present disclosure. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present disclosure shall be embraced in the scope of protection of the present disclosure.

Claims

1. Formula A: 【Chemical 1】 A compound of the formula: During the ceremony, ＊ represents a chiral center and is selected from the (S)-configuration or the (R)-configuration; L １ is selected from a single bond, —O—, —NH—, —S— or —P(O)OH—, alternatively a single bond, —O—, —NH—; L ２ Single bonds, -O-, -NH-, -C(O)-, -C(O)-O-, -C(O)NH-, -OC(O)-, C １～１８ Alkylene (alternatively, C １～１２ alkylene, more alternatively C １～６ alkylene), C ３～１０ Cycloalkylene (alternatively, C ３～８ cycloalkylene, more alternatively C ３～６ cycloalkylene), C ６～３０ Arylene (alternatively, C ６～１８ arylene, more alternatively C ６～１２ arylene), C ３～３０ Heteroarylene (alternatively, C ３～１８ heteroarylene, more alternatively C ３～１２ heteroarylene), -C １～１８ Alkylene-O-(alternatively, -C １～１２ Alkylene-O-, more alternatively, -C １～６ alkylene-O-), -C ６～３０ Arylene-O-(alternatively, —C ６～１８ arylene-O-, more alternatively, -C ６～１２ arylene-O-), -C ３～３０ Heteroarylene-O-(alternatively, -C ３～１８ Heteroarylene-O-, more alternatively, -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 -X １ -PRa(O)-X ２ -, wherein each Ra is independently selected from hydrogen, hydroxyl, halogen (alternatively, F, Cl, or Br), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl), C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ Heteroaryl), C １～３０ A hydrocarbon group (alternatively, C １～３０ alkyl, more alternatively C １～１８ alkyl, and alternatively, C １～６ alkyl), C ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl), C １～３０ Alkoxy (alternatively, C １～１８ Alkoxy, more alternatively C １～６ Alkoxy), C ６～３０ Aryl-O—(alternatively, C ６～１８ aryl-O—, more alternatively, C ６～１２ aryl-O-), C ３～３０ Heteroaryl-O—(alternatively, C ３～１８ heteroaryl-O—, more alternatively, C ３～１２ Heteroaryl-O-), C ６～３０ Aryl-C １～１８ Alkylene-O-(alternatively, C ６～１８ Aryl-C １～１２ alkylene-O-, more alternatively C ６～１２ Aryl-C １～６ alkylene-O-), C ３～３０ Heteroaryl-C １～１８ Alkylene-O-(alternatively, C ３～１８ Heteroaryl-C １～１２ alkylene-O-, more alternatively C ３～１２ Heteroaryl-C １～６ alkylene-O-), —O—C ６～３０ Aryl-C １～１８ Alkylene-(alternatively, —O—C ６～１８ Aryl-C １～１２ alkylene-) or —O—C ３～３０ Heteroaryl-C １～１８ Alkylene-(alternatively, —O—C ３～１８ Heteroaryl-C １～１２ alkylene-), and the Ra and X ２ may be connected to form a ring, Above X １ represents a single bond, —O—, —C １～１８ Alkylene-O-(alternatively, -C １～１２ Alkylene-O-, more alternatively, -C １～６ alkylene-O-), -C ６～３０ Arylene-O-(alternatively, —C ６～１８ arylene-O-, more alternatively, -C ６～１２ arylene-O-) or -C ３～３０ Heteroarylene-O-(alternatively, -C ３～１８ Heteroarylene-O-, more alternatively, -C ３～１２ heteroarylene-O-), Above X ２ represents a single bond, —O—, or —NR ＊ -, where R ＊ is H, C １～６ Alkyl and C １～６ alkoxy; The above L ２ is halogen, OH, CN, C(O)OH, C(O)O-C １～６ Alkyl, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy or C １～６ optionally substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkoxy; R １ is absent or hydrogen, hydroxyl, amino unsubstituted or substituted with 1 or 2 Rb, C １～３０ A hydrocarbon group (alternatively, C １～３０ Alkyl or C ２～３０ alkenyl, more alternatively C １～１８ Alkyl or C ２～１８ alkenyl, and alternatively, C １～６ Alkyl or C ２～１２ alkenyl, wherein the alkenyl has 1 to 10, alternatively 1 to 6, double bonds), unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb; ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl), unsubstituted or Rb-substituted C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ alkoxy), unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb １２～３０ A fused ring group (alternatively, C １２～１７ fused cyclic groups, more alternatively C containing at least one heteroatom １２～１７ fused ring groups, and alternatively, C containing at least one heteroatom １２～１７ a tetra-fused ring group), unsubstituted or a C in which a hydrogen atom in the alkyl is replaced by Rc １～１８ Alkyl-C ６～３０ Arylene-C １～１８ Alkylene-(alternatively, C １～１２ Alkyl-C ６～１８ Arylene-C １～１２ alkylene-), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rd １～１２ Alkyl-O—C(O)—C １～１２ Alkylene-imino-, C ６～３０ Aryl-C １～１８ Alkylene-(alternatively, C ６～１８ Aryl-C １～１２ alkylene-), —O—C(O)—Y １ , unsubstituted or -C in which a hydrogen atom in the alkylene is replaced by Rd １～１２ Alkylene—C(O)—O—Y ２ , unsubstituted or —O—C in which a hydrogen atom in the alkylene is replaced by Rd １～１２ Alkylene-O-C(O)-Y ３ , -C=CH-Y ４ or -Y ５ -Y ６ -Y ７ , -CHR ＃ R ＃＃ , -Z-C optionally substituted with xA ６～３０ Aryl (alternatively, -Z-C ６～１８ aryl, more alternatively, -Z-C ６～１２ aryl, for example -Z-phenyl), where R ＃ and R ＃＃ are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C １２～３０ a fused ring group, or —NHC(NH)NH—; Each Rb is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br). １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ Alkoxy), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl), C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ Heteroaryl) or C １～３０ Alkyl (alternatively, C １～１８ alkyl, more alternatively C １～６ alkyl), Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl, and alternatively, cyclopentyl; Each Rd is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br). １～１８ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl), C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ Alkoxy), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl); Above Y １ is unsubstituted or substituted with Re, C １～３０ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl), C ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl), wherein each Re is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl); Above Y ２ is unsubstituted or Rf-substituted C １２～３０ A fused ring group (alternatively, C １２～１７ fused cyclic groups, more alternatively C containing at least one heteroatom １２～１７ fused ring groups, and alternatively, C containing at least one heteroatom １２～１７ tetra-fused ring groups), wherein each Rf is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ alkoxy) or C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl), Above Y ３ is C １～１８ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl) or —O—C １～１８ Alkyl (alternatively, —O—C １～１２ Alkyl, more alternatively, —O—C １～６ alkyl), Above Y ４ is unsubstituted or substituted with Rg, C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl), wherein each Rg is independently selected from hydroxyl and C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ alkoxy), Above Y ５ is a single bond, unsubstituted or amino-substituted C １～１８ Alkylene (alternatively, C １～１２ alkylene, more alternatively C ３～６ alkylene), Above Y ６ represents a single bond, —NH—C(NH)—, —(O—CH ２ -CH ２ ) ｍ - or -CH ２ -(O-CH ２ -CH ２ ) ｎ -, wherein m and n are each independently selected from any natural number from 2 to 20 (alternatively, any natural number from 2 to 10); Above Y ７ is amino, C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ alkoxy) or hydroxyl; x is selected from 0, 1, 2, 3, 4 or 5; Z is a chemical bond, —O—, —NH—, —C １～１２ Alkylene-, -C １～１２ Alkylene -O-C 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)O-C １～１０ Alkylene-, -C １～１０ Alkylene-NHC(O)-C １～１０ Alkylene-, -C １～１０ Alkylene-NHC(O)O-C 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-, alternatively a chemical bond or -C １～６ Alkylene-NHC(O)-C １～６ alkylene-, The above Z is a halogen, —C(O)OH, —C(O)O—C １～６ Alkyl, —C(O)—C １～６ Alkyl, —O—C １～６ Alkyl, C １～６ Alkyl or C １～６ optionally substituted with 1, 2, 3, 4, or 5 substituents selected from haloalkyl; A is independently H, halogen, OH, -L Ａ -C ３～１０ cycloalkyl, -L Ａ -3 to 10-membered heterocyclyl, -L Ａ -C ６～１２ Aryl or -L Ａ - 5 to 12 membered heteroaryl, alternatively 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 above A is halogen, C １～６ Alkyl or C １～６ optionally further substituted with haloalkyl; The above L １ and the above L ２ When both of R １ is not hydroxyl, U １ , U ２ and U ３ are each independently —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O- and -O-, or U ２ Available ring atoms and U on ３ the available ring atoms above are connected via Q groups to form a 4- to 8-membered ring, alternatively a 5- or 6-membered ring; Q is a single bond; NR ３ ; 1 or 2 CH ２ is O, S and NR ３ C optionally independently substituted with a group selected from １～３ alkylene; and C═C in which any CH to form a C═C double bond is optionally replaced with N. ２～３ alkenylene; W １ , W ２ and W ３ are each independently C １～１８ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl) or -(O-C ２～６ alkylene) ｐ (Alternatively, —(O—C ２～４ alkylene) ｐ , or more alternatively, —(O—CH ２ -CH ２ ) ｐ wherein p is selected from any natural number from 1 to 18, alternatively any natural number from 1 to 10; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl, and aralkyl, when present in each occurrence, may each be present in one, two, three, or more R ３ wherein the R ３ is independently, at each occurrence, halogen, cyano, nitro, C １～６ Alkyl, C ３～１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ aralkyl, and the substituent R ３ The alkyl, alkylene, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl and aralkyl related to the above may independently be halogen, OH, oxo, amino, cyano, nitro, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ optionally further substituted with 1, 2, 3 or more substituents selected from aralkyl; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

2. Formula I: 【Chemistry 2】 A compound of the formula: During the ceremony, L １ is selected from a single bond, —O—, —NH—, —S— or —P(O)OH—, alternatively a single bond, —O—, —NH—; L ２ represents a single bond, —O—, —NH—, —C(O)—, —C(O)—O—, C １～１８ Alkylene (alternatively, C １～１２ alkylene, more alternatively C １～６ alkylene), C ３～１０ Cycloalkylene (alternatively, C ３～８ cycloalkylene, more alternatively C ３～６ cycloalkylene), C ６～３０ Arylene (alternatively, C ６～１８ arylene, more alternatively C ６～１２ arylene), C ３～３０ Heteroarylene (alternatively, C ３～１８ heteroarylene, more alternatively C ３～１２ heteroarylene), -C １～１８ Alkylene-O-(alternatively, -C １～１２ Alkylene-O-, more alternatively, -C １～６ alkylene-O-), -C ６～３０ Arylene-O-(alternatively, —C ６～１８ arylene-O-, more alternatively, -C ６～１２ arylene-O-), -C ３～３０ Heteroarylene-O-(alternatively, -C ３～１８ Heteroarylene-O-, more alternatively, -C ３～１２ heteroarylene-O-), -C(O)-C １～１８ Alkyl-, C １～３０ Alkoxy or -X １ -PRa(O)-X ２ -, wherein each Ra is independently selected from hydrogen, hydroxyl, halogen (alternatively, F, Cl, or Br), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl), C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ Heteroaryl), C １～３０ A hydrocarbon group (alternatively, C １～３０ alkyl, more alternatively C １～１８ alkyl, and alternatively, C １～６ alkyl), C ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl), C １～３０ Alkoxy (alternatively, C １～１８ Alkoxy, more alternatively C １～６ Alkoxy), C ６～３０ Aryl-O—(alternatively, C ６～１８ aryl-O—, more alternatively, C ６～１２ aryl-O-), C ３～３０ Heteroaryl-O—(alternatively, C ３～１８ heteroaryl-O—, more alternatively, C ３～１２ Heteroaryl-O-), C ６～３０ Aryl-C １～１８ Alkylene-O-(alternatively, C ６～１８ Aryl-C １～１２ alkylene-O-, more alternatively C ６～１２ Aryl-C １～６ alkylene-O-), C ３～３０ Heteroaryl-C １～１８ Alkylene-O-(alternatively, C ３～１８ Heteroaryl-C １～１２ alkylene-O-, more alternatively C ３～１２ Heteroaryl-C １～６ alkylene-O-), —O—C ６～３０ Aryl-C １～１８ Alkylene-(alternatively, —O—C ６～１８ Aryl-C １～１２ alkylene-) or —O—C ３～３０ Heteroaryl-C １～１８ Alkylene-(alternatively, —O—C ３～１８ Heteroaryl-C １～１２ alkylene-), and the Ra and X ２ may be connected to form a ring, Above X １ represents a single bond, —O—, —C １～１８ Alkylene-O-(alternatively, -C １～１２ Alkylene-O-, more alternatively, -C １～６ alkylene-O-), -C ６～３０ Arylene-O-(alternatively, —C ６～１８ arylene-O-, more alternatively, -C ６～１２ arylene-O-) or -C ３～３０ Heteroarylene-O-(alternatively, -C ３～１８ Heteroarylene-O-, more alternatively, -C ３～１２ heteroarylene-O-), Above X ２ represents a single bond, —O—, or —NR ＊ -, where R ＊ is H, C １～６ Alkyl and C １～６ alkoxy; R １ is absent or hydrogen, hydroxyl, unsubstituted or Rb-substituted amino, unsubstituted or Rb-substituted C １～３０ A hydrocarbon group (alternatively, C １～３０ Alkyl or C ２～３０ alkenyl, more alternatively C １～１８ Alkyl or C ２～１８ alkenyl, and alternatively, C １～６ Alkyl or C ２～１２ alkenyl, where the alkenyl has 1 to 10, alternatively 1 to 6, double bonds), unsubstituted or Rb-substituted C ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl), unsubstituted or Rb-substituted C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ alkoxy), unsubstituted or Rb-substituted C １２～３０ A fused ring group (alternatively, C １２～１７ fused cyclic groups, more alternatively C containing at least one heteroatom １２～１７ fused ring groups, and alternatively, C containing at least one heteroatom １２～１７ a tetra-fused ring group), unsubstituted or a C in which a hydrogen atom in the alkyl is replaced by Rc １～１８ Alkyl-C ６～３０ Arylene-C １～１８ Alkylene-(alternatively, C １～１２ Alkyl-C ６～１８ Arylene-C １～１２ alkylene-), unsubstituted or C in which a hydrogen atom in the alkyl is replaced by Rd １～１２ Alkyl-O—C(O)—C １～１２ Alkylene-imino-, C ６～３０ Aryl-C １～１８ Alkylene-(alternatively, C ６～１８ Aryl-C １～１２ alkylene-), —O—C(O)—Y １ , unsubstituted or -C in which a hydrogen atom in the alkylene is replaced by Rd １～１２ Alkylene—C(O)—O—Y ２ , unsubstituted or —O—C in which a hydrogen atom in the alkylene is replaced by Rd １～１２ Alkylene-O-C(O)-Y ３ , -C=CH-Y ４ , -Y ５ -Y ６ -Y ７ or -CHR ＃ R ＃＃ is selected from Here, R ＃ and R ＃＃ are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C １２～３０ a fused ring group, or —NHC(NH)NH—; Each Rb is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br). １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ Alkoxy), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl), C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ Heteroaryl) or C １～３０ Alkyl (alternatively, C １～１８ alkyl, more alternatively C １～６ alkyl), Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl, and alternatively, cyclopentyl; Each Rd is independently unsubstituted or substituted with halogen (alternatively, F, Cl, or Br). １～１８ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl), C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ Alkoxy), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl); Above Y １ is unsubstituted or substituted with Re, C １～３０ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl), C ３～１０ Cycloalkyl (alternatively, C ３～８ cycloalkyl, more alternatively C ３～６ cycloalkyl), C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl), wherein each Re is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl); Above Y ２ is unsubstituted or Rf-substituted C １２～３０ A fused ring group (alternatively, C １２～１７ fused cyclic groups, more alternatively C containing at least one heteroatom １２～１７ fused ring groups, and alternatively, C containing at least one heteroatom １２～１７ tetra-fused ring groups), wherein each Rf is independently unsubstituted or substituted with a halogen (alternatively, F, Cl, or Br); １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ alkoxy) or C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl), Above Y ３ is C １～１８ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl) or —O—C １～１８ Alkyl (alternatively, —O—C １～１２ Alkyl, more alternatively, —O—C １～６ alkyl), Above Y ４ is unsubstituted or substituted with Rg, C ６～３０ Aryl (alternatively, C ６～１８ aryl, more alternatively C ６～１２ aryl) or C ３～３０ Heteroaryl (alternatively, C ３～１８ Heteroaryl, more alternatively C ３～１２ heteroaryl), wherein each Rg is independently selected from hydroxyl and C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ alkoxy), Above Y ５ is a single bond, unsubstituted or amino-substituted C １～１８ Alkylene (alternatively, C １～１２ alkylene, more alternatively C ３～６ alkylene), Above Y ６ represents a single bond, —NH—C(NH)—, —(O—CH ２ -CH ２ ) ｍ - or -CH ２ -(O-CH ２ -CH ２ ) ｎ -, wherein m and n are each independently selected from any natural number from 2 to 20 (alternatively, any natural number from 2 to 10); Above Y ７ is amino, C １～３０ Alkoxy (alternatively, C １～２０ Alkoxy, more alternatively C １～１２ Alkoxy, and alternatively, C １～３ alkoxy) or hydroxyl; The above L １ and the above L ２ When both of R １ is not hydroxyl, U １ , U ２ and U ３ are each independently —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O- and -O-, or U ２ Available ring atoms and U on ３ the available ring atoms above are connected via Q groups to form a 4- to 8-membered ring, alternatively a 5- or 6-membered ring; Q is a single bond; NR ３ ; 1 or 2 CH ２ is O, S and NR ３ C optionally independently substituted with a group selected from １～３ alkylene; and C═C in which any CH to form a C═C double bond is optionally replaced with N. ２～３ alkenylene; W １ , W ２ and W ３ are each independently C １～１８ Alkyl (alternatively, C １～１２ alkyl, more alternatively C １～６ alkyl) or -(O-C ２～６ alkylene) ｐ (Alternatively, —(O—C ２～４ alkylene) ｐ , or more alternatively, —(O—CH ２ -CH ２ ) ｐ wherein p is selected from any natural number from 1 to 18, alternatively any natural number from 1 to 10; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl, and aralkyl, when present in each occurrence, may each be present in one, two, three, or more R ３ wherein the R ３ is independently, at each occurrence, halogen, cyano, nitro, C １～６ Alkyl, C ３～１０ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, C ６～１２ aralkyl, and the substituent R ３ The alkyl, alkylene, cyclic hydrocarbon group, heterocyclyl, aryl, heteroaryl and aralkyl related to the above may independently be halogen, OH, oxo, amino, cyano, nitro, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cyclic hydrocarbon group, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl and C ６～１２ optionally further substituted with 1, 2, 3 or more substituents selected from aralkyl; The compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

3. The heteroaryl, the heteroarylene, and 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, alternatively N; Alternatively, the heteroaryl, the heteroarylene, and the C containing at least one heteroatom may be １２～１７ the number of heteroatoms in the fused ring group is 1 to 3, alternatively 1 to 2; Alternatively, the C １２～１７ Tetracondensed ring group 【Chemistry 3】 That is, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

4. The compound has the formula II: 【Chemistry 4】 is a compound of The above L ２ represents 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 -X １ -PRa(O)-X ２ -, wherein each Ra is independently selected from hydrogen, hydroxyl, halogen, C ６～３０ Aryl, C ３～３０ Heteroaryl, C １～３０ Hydrocarbon group, 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-, -O-C ６～３０ Aryl-C １～１８ Alkylene- or -O-C ３～３０ Heteroaryl-C １～１８ alkylene-, and the Ra and X ２ may be connected to form a ring, Above X １ is a single bond or -C １～１８ alkylene-O-; Above X ２ represents a single bond, —O—, or —NR ＊ - (e.g., -NH-), The above R １ is hydrogen, hydroxyl, amino, C １～３０ Hydrocarbon group, C １～３０ Alkoxy, unsubstituted or Rb-substituted C １２～３０ A fused ring group, unsubstituted or alkyl group in which a hydrogen atom is replaced by Rc １～１８ Alkyl-C ６～３０ Arylene-C １～１８ Alkylene-, C １～１２ Alkyl-O—C(O)—C １～１２ Alkylene-imino-, C ６～３０ Aryl-C １～１８ Alkylene-, —O—C(O)—Y １ , -C １～１２ Alkylene—C(O)—O—Y ２ , —O—C １～１２ Alkylene-O-C(O)-Y ３ , -C=CH-Y ４ or -Y ５ -Y ６ -Y ７ , -CHR ＃ R ＃＃ is selected from Here, R ＃ and R ＃＃ are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C １２～３０ a fused ring group, or —NHC(NH)NH—; Each Rb is independently unsubstituted or substituted with halogen. １～３０ Alkoxy, C ６～３０ Aryl, C ３～３０ Heteroaryl or C １～３０ alkyl, Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. ３～１０ cycloalkyl; Above Y １ is unsubstituted or substituted with Re, C １～３０ Alkyl, C ３～１０ Cycloalkyl, C ６～３０ Aryl or C ３～３０ heteroaryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C ６～３０ aryl; Above Y ２ is unsubstituted or Rf-substituted C １２～３０ fused ring groups, wherein each Rf is independently selected from C １～３０ alkoxy; Above Y ３ is C １～１８ Alkyl or —O—C １～１８ alkyl, Above Y ４ is unsubstituted or substituted with Rg, C ６～３０ Aryl or C ３～３０ heteroaryl, wherein each Rg is independently hydroxyl or C １～３０ alkoxy; Above Y ５ is a single bond, unsubstituted or amino-substituted C １～１８ alkylene; Above Y ６ represents a single bond, —NH—C(NH)—, —(O—CH ２ -CH ２ ) ｍ - or -CH ２ -(O-CH ２ -CH ２ ) ｎ wherein m and n are each independently selected from any natural number from 2 to 20; Above Y ７ is amino, C １～３０ selected from alkoxy or hydroxyl, A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

5. The compound has the formula I-1: 【Chemistry 5】 is a compound of In the ceremony, L １ is selected from a single bond, —O—, —NH—, —S— or —P(O)OH—, alternatively a single bond, —O— and —NH—; The above L ２ represents a single bond, —C(O)—, —C(O)—O—, —C １～１８ Alkylene-, -C １～１８ Alkylene-O- (e.g., -(CH ２ ) １～５ -O-), -C(O)-C １～１８ Alkyl-, C １～３０ Alkoxy (e.g., -(OCH ２ CH ２ ) ２～８ -) or -X １ -PRa(O)-X ２ - is selected from, Each of the Ra's independently represents hydrogen, hydroxyl, halogen, C ６～３０ Aryl, C ３～３０ Heteroaryl, C １～３０ Hydrocarbon group, 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-, -O-C ６～３０ Aryl-C １～１８ Alkylene- or -O-C ３～３０ Heteroaryl-C １～１８ alkylene-, and the available ring atoms on Ra are selected from X ２ may be directly connected to form a 4- to 7-membered ring, alternatively a 5- or 6-membered ring, Above X １ represents a single bond, —O— or —C １～１８ Alkylene-O-, alternatively a single bond, -O- or -(CH ２ ) １～３ O—(e.g., —CH ２ O-), Above X ２ represents a single bond, —O—, or —NR ＊ -, where R ＊ is H or C １～６ alkyl (e.g., methyl, ethyl, isopropyl); The above R １ is absent or is selected from hydrogen, hydroxyl, amino, C １～３０ Hydrocarbon group (C １～３０ The hydrocarbon group has 0 to 10 double or triple bonds, alternatively 0 to 6 double or triple bonds), C １～３０ Alkoxy, unsubstituted or Rb-substituted C １２～３０ A fused ring group, unsubstituted or alkyl group in which a hydrogen atom is replaced by Rc １～１８ Alkyl-C ６～３０ Arylene-C １～１８ Alkylene-, C １～１２ Alkyl-O—C(O)—C １～１２ Alkylene-imino-, C ６～３０ Aryl-C １～１８ Alkylene-, —O—C(O)—Y １ , -C １～１２ Alkylene—C(O)—O—Y ２ , —O—C １～１２ Alkylene-O-C(O)-Y ３ , -CH=CH-Y ４ or -Y ５ -Y ６ -Y ７ , -CHR ＃ R ＃＃ is selected from Here, R ＃ and R ＃＃ are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C １２～３０ a fused ring group, or —NHC(NH)NH—; Each Rb is independently unsubstituted or substituted with halogen. １～３０ Alkoxy, C ６～３０ Aryl, C ３～３０ Heteroaryl or C １～３０ alkyl, Each Rc is independently unsubstituted or C substituted with hydroxyl, oxo, or thioxo. ３～１０ cycloalkyl; Above Y １ is unsubstituted or substituted with Re, C １～３０ Alkyl, C ３～１０ Cycloalkyl, C ６～３０ Aryl or C ３～３０ heteroaryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C ６～３０ aryl; Above Y ２ is unsubstituted or Rf-substituted C １２～３０ fused ring groups, wherein each Rf is independently selected from C １～３０ alkoxy; Above Y ３ is C １～１８ Alkyl or —O—C １～１８ alkyl, Above Y ４ is unsubstituted or substituted with Rg, C ６～３０ Aryl or C ３～３０ heteroaryl, wherein each Rg is independently hydroxyl or C １～３０ alkoxy; Above Y ５ is a single bond, unsubstituted or amino-substituted C １～１８ alkylene; Above Y ６ represents a single bond, —NH—C(NH)—, —(O—CH ２ -CH ２ ) ｍ - or -CH ２ -(O-CH ２ -CH ２ ) ｎ wherein m and n are each independently selected from any natural number from 2 to 20; Above Y ７ is amino, C １～３０ selected from alkoxy or hydroxyl, A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

6. The above L ２ represents a single bond, —C(O)—, —C(O)—O—, C １～６ Alkylene, -C １～６ Alkylene -O- or -X １ -PRa(O)-X ２ -, wherein each Ra is independently selected from hydrogen, hydroxyl, C ６～１２ Aryl-O— or C ６～１２ Aryl-C １～６ Alkylene-O-, -O-C ６～３０ Aryl-C １～１８ Alkylene- or -O-C ３～３０ Heteroaryl-C １～１８ alkylene-, and the Ra and X ２ may be connected to form a ring, Above X １ is a single bond or -C １～６ alkylene-O-; Above X ２ is selected from a single bond, —O—, and —NH—; The above R １ is absent, hydrogen, hydroxyl, amino, C １～３０ Alkyl, C １～３０ Alkoxy, unsubstituted or methoxy-substituted C containing at least one heteroatom １２～１７ Tetra-fused ring group, oxocyclopentyl-C １～６ Alkylene-C ６～１２ Arylene-C １～６ Alkylene-, hydroxycyclopentyl-C １～６ Alkylene-C ６～１２ Arylene-C １～６ Alkylene-, C １～６ Alkyl-O—C(O)—C １～６ Alkylene-imino-, C ６～１２ Aryl-C １～６ Alkylene-, —O—C(O)—Y １ , -C １～１２ Alkylene—C(O)—O—Y ２ , —O—C １～１２ Alkylene-O-C(O)-Y ３ , -C=CH-Y ４ or -Y ５ -Y ６ -Y ７ , -CHR ＃ R ＃＃ is selected from Here, R ＃ and R ＃＃ are each independently 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 H, hydroxyl, amino, halogen, alkyl, cycloalkyl, aryl, heteroaryl, unsubstituted or Rb-substituted C １２～３０ a fused ring group, or —NHC(NH)NH—; Above Y １ is unsubstituted or substituted with Re, C １～６ Alkyl, C ３～６ Cycloalkyl or C ６～１２ aryl, wherein each Re is independently selected from unsubstituted or halogen-substituted C ６～１２ aryl; Above Y ３ is C １～６ Alkyl or —O—C １～６ alkyl, Above Y ４ is unsubstituted or Rg-substituted C ６～１２ aryl, wherein each Rg is independently selected from hydroxyl or methoxy; Above Y ５ is a single bond, unsubstituted or amino-substituted C １～６ alkylene; Above Y ６ represents a single bond, —NH—C(NH)—, —(O—CH ２ -CH ２ ) ｍ - or -CH ２ -(O-CH ２ -CH ２ ) ｎ wherein m and n are each independently selected from any natural number from 2 to 10; Above Y ７ is amino, C １～６ selected from alkoxy or hydroxyl, A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

7. The above R １ is absent, hydrogen, hydroxyl, amino, aryl (e.g., phenyl), C １～３０ Alkyl, C １～３０ Alkoxy (e.g., —OCH ３ ), unsubstituted or substituted with 1, 2, 3, 4 or 5 Rb １２～３０ Fused cyclic group, -(CH ２ ) １～１０ —C(O)—OC １２～３０ Fused cyclic group, -O-C(O)-Y １ , -C １～１２ Alkylene—C(O)—O—Y ２ , —O—C １～１２ Alkylene-O-C(O)-Y ３ , -C=CH-Y ４ or -Y ５ -Y ６ -Y ７ , -CHR ＃ R ＃＃ Alternatively, absent, hydrogen, hydroxyl, amino, aryl (e.g., phenyl), C １～３０ Alkyl, C １～３０ Alkoxy (e.g., —OCH ３ ), unsubstituted or Rb-substituted C １２～３０ Fused cyclic group, -(CH ２ ) １～１０ —C(O)—OC １２～３０ Fused cyclic group, -O-C(O)-Y １ , -C １～１２ Alkylene—C(O)—O—Y ２ , —O—C １～１２ Alkylene-O-C(O)-Y ３ , -C=CH-Y ４ or -Y ５ -Y ６ -Y ７ , -CHR ＃ R ＃＃ , Alternatively, H, —OH, —NH ２ , -OCH ３ , methyl, ethyl, isopropyl, cyclopropyl, -(CH ２ ) ｐ CH ３ , -(CH ２ ) ｐ OCH ３ , -(CH ２ ) ｐ NH ２ , -(CH ２ ) ｐ OH, -(OCH ２ CH ２ ) qCH ３ , -(OCH ２ CH ２ ) qOCH ３ , -(OCH ２ CH ２ )qOH, -(OCH ２ CH ２ ) qNH ２ , phenyl, 【Chemistry 6-1】 【Chemistry 6-2】 The structure of Alternatively, H, —OH, —NH ２ , -OCH ３ , methyl, ethyl, isopropyl, cyclopropyl, -(CH ２ ) ｐ CH ３ , -(CH ２ ) ｐ OCH ３ , -(CH ２ ) ｐ NH ２ , -(CH ２ ) ｐ OH, -(OCH ２ CH ２ ) qCH ３ , -(OCH ２ CH ２ ) qOCH ３ , -(OCH ２ CH ２ )qOH, -(OCH ２ CH ２ ) qNH ２ , phenyl, 【Chemistry 7】 is selected from the structure 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; A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

8. The compound has the formula III: 【Chemistry 8】 is a compound of A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

9. Each of the Ra's independently represents hydroxyl, C ６～１２ Aryl-O—,C ６～１２ Aryl-C １～６ Alkylene —O— or —O—C ６～１２ Aryl-C １～６ alkylene-, and the Ra and X ２ may be connected to form a ring, Above X １ is a single bond or -C １～６ alkylene-O-; Above X ２ is selected from a single bond, —O—, and —NH—; The above R １ is absent, hydrogen, hydroxyl, C １～６ Alkyl-O—C(O)—C １～６ Alkylene-imino-, C ６～１２ Aryl-C １～６ Alkylene- or -O-C １～１２ Alkylene-O-C(O)-Y ３ and the above Y ３ But -O-C １～６ selected from alkyl, 9. The compound of claim 8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

10. The compound is represented by formula IVa, IVb or IVc: 【Chemistry 9】 is a compound of wherein ring G in formula IVc is C ６～１２ is an aryl ring, 10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

11. The compound has the formula V: 【Chemistry 10】 is a compound of A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

12. The compound has formula VIa or VIb: 【Chemistry 11】 is a compound of 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 (alternatively, any natural number from 1 to 6), and r, s, and t are not simultaneously 0.

12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

13. The compound has the formula VII: 【Chemistry 12】 is a compound of wherein n is selected from any natural number from 2 to 20, alternatively from any natural number from 2 to 10; 12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

14. The compound has the formula VIII: 【Chemistry 13】 is a compound of In the formula, Z is C １～３０ Alkylene, C ３～１０ Cycloalkylene, C ６～３０ Arylene, C ３～３０ selected from heteroarylene or -C=CH-; A is hydroxyl, halogen, C ６～３０ C substituted with aryl or Rc １～１８ alkyl, wherein each Rc is independently unsubstituted or substituted with hydroxyl, oxo, or thioxo. ３～１０ cycloalkyl; B is hydroxyl, 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 0; 12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

15. The compound has the formula IX: 【Chemistry 14】 is a compound of A is C substituted with Rc １～１８ alkyl, wherein each Rc is independently selected from C substituted with oxo. ３～１０ cycloalkyl; B is a halogen or C ６～３０ aryl; x is selected from 1 and y is selected from 0 or 1; 15. The compound of claim 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

16. The compound has the formula X: 【Chemistry 15】 is a compound of In the formula, M １ are each independently selected from a single bond or —C(O)—; L ３ is C １～１２ alkylene, 10. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and mixtures thereof.

17. The compound has the formula XI: 【Chemistry 16】 is a compound of In the ceremony, L ３ is C １～１２ alkylene; Alternatively, U １ , U ２ and U ３ are each independently selected from —O—; １ , W ２ and W ３ are each independently selected from methyl; 17. The compound of claim 16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

18. The compound has the formula XII: 【Chemistry 17】 is a compound of 10. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and mixtures thereof.

19. The above L ２ is selected from a single bond or —O—; The above R １ is hydrogen, amino or -Y ５ -Y ６ -Y ７ is selected from Above Y ５ is a single bond, unsubstituted or amino-substituted C ３～１２ alkylene, 17. The compound of claim 16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

20. The compound has the formula XIII: 【Chemistry 18】 is a compound of Alternatively, the above Y ５ is unsubstituted or amino-substituted C ３～１２ alkylene, alternatively unsubstituted or amino-substituted C ３～６ alkylene, 17. The compound of claim 16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

21. The compound has the formula XIV: 【Chemistry 19】 is a compound of 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

22. The above L １ is selected from —O— or —NH—; The above L ２ is —C(O)— or C １～１８ alkylene; Above Y ７ But Amino, C １～３０ Alkyl, C １～３０ selected from alkoxy or hydroxyl, 20. 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.

23. The compound has the formula XVa or XVb: 【Chemistry 20】 is a compound of Alternatively, the above Y ７ is selected from methoxy or hydroxyl; 20. 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.

24. U １ , U ２ and U ３ are each independently selected from —O—; W １ , W ２ and W ３ However, each independently, C １～１８ alkyl, alternatively C １～１２ alkyl, more alternatively C １～６ alkyl, and alternatively, methyl; 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

25. The compound has the formula Ia: 【Chemical 21】 , alternatively, 【Chemical 22】 wherein L １ , L ２ , W １ , R １ and R ＊ is as defined in claim 1 or 2, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

26. The compound is represented by formula XVI, XVI-1, XVI-2, XVI-3 or XVI-4: 【Chemical 23】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１８ alkyl, M ４ represents a chemical bond, —O—, —NH—, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)O—, —OC(O)NH—, or —C １～１０ alkylene-, Alternatively, U １ , U ２ and U ３ is independently selected from —O—C(O)— or —O—; W １ , W ２ and W ３ are independently １～１２ alkyl, alternatively C １～６ alkyl, M ４ is selected from a chemical bond, —NH—, —C(O)O—, —OC(O)—, —NHC(O)O—, or —OC(O)NH—; Alternatively, U １ , U ２ and U ３ is —O—, W １ , W ２ and W ３ are independently １～６ alkyl, alternatively C １～４ alkyl, and more alternatively, methyl; M ４ is selected from —NHC(O)O— or —OC(O)NH—; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

27. The compound has the formula VIII, VIII-1 or VIII-2: 【Chemistry 24】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—C(O)—, —NH—C(O)—, —O—CH ２ -O- or -O; W １ , W ２ and W ３ are independently １～１２ alkyl, Z is a chemical bond, —O—, —NH—, —C １～１２ Alkylene-, -C １～１２ Alkylene -O-C 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)O-C １～１０ Alkylene-, -C １～１０ Alkylene-NHC(O)-C １～１０ Alkylene-, -C １～１０ Alkylene-NHC(O)O-C 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-, alternatively a chemical bond or -C １～６ Alkylene-NHC(O)-C １～６ alkylene-, The above Z is a halogen, —C(O)OH, —C(O)O—C １～６ Alkyl, —C(O)—C １～６ Alkyl, —O—C １～６ Alkyl, C １～６ Alkyl or C １～６ optionally substituted with 1, 2, 3, 4, or 5 substituents selected from haloalkyl; A and B are independently H, halogen, OH, -L Ａ -C ３～１０ cycloalkyl, -L Ａ -3 to 10-membered heterocyclyl, -L Ａ -C ６～１２ Aryl or -L Ａ - 5 to 12 membered heteroaryl, alternatively 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 above A and B are halogen, C １～６ Alkyl or C １～６ optionally further substituted with haloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; Alternatively, U １ , U ２ and U ３ is independently selected from —O—C(O)— or —O—; W １ , W ２ and W ３ are independently １～６ alkyl, Z is a chemical bond, —O—, —NH—, —C １～６ Alkylene-, -C １～６ Alkylene-C(O)-C １～６ Alkylene-, -C １～６ Alkylene-C(O)O-C １～６ Alkylene-, -C １～６ Alkylene-NHC(O)-C １～６ Alkylene-, -C １～６ Alkylene-C(O)NH-C １～６ Alkylene-, alternatively 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 above Z is halogen, C(O)OH, C(O)O—C １～６ Alkyl, C １～６ Alkyl or C １～６ optionally substituted with 1, 2 or 3 substituents selected from haloalkyl; A and B are independently H, halogen, C ６～１０ Aryl, —NH—C ６～１０ Aryl, —O—C ６～１０ Aryl, —C(O)—C ６～１０ Aryl and —C(O)O—C ６～１０ aryl, alternatively halogen, C ６～１０ Aryl or —NH—C ６～１０ aryl; The above A and B are halogen, C １～６ Alkyl or C １～６ optionally further substituted with haloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; More alternatively, U １ , U ２ and U ３ is —O—, W １ , W ２ and W ３ are independently １～４ alkyl, alternatively methyl; Z is a chemical bond, -C １～４ Alkylene-NHC(O)-C １～４ Alkylene- or -C １～４ Alkylene-C(O)NH-C １～４ Alkylene-, alternatively a chemical bond or -C １～４ Alkylene-NHC(O)-C １～４ alkylene-, The above Z is halogen, C(O)OH, C(O)O—C １～４ Alkyl or C １～４ optionally substituted with 1, 2 or 3 substituents selected from alkyl; A and B are independently selected from H, halogen, phenyl, or —NH-phenyl, alternatively F, phenyl, or NH-phenyl; wherein A and B are optionally further substituted with halogen; x and y are 0, 1 or 2; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

28. The compound has formula II, II-1, II-2, I-1, I-2, or I-3: 【Chemistry 25】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, L １ is selected from a single bond, —O—, or —NH—; L ２ Ha-C １～１２ alkylene-, wherein the alkylene is C １～６ may be further substituted with alkyl, R １ is -OC(O)-Y １ is selected from Y １ is C １～１２ Alkyl, C ３～１０ Cycloalkyl, C ６～１８ Aryl or C ３～１８ heteroaryl; １ is C １～６ may be further substituted with alkyl, Y １ Alternatively, C １～６ Alkyl, more alternatively CH ３ and Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, L １ is selected from —O— or —NH—; L ２ Ha-C １～６ alkylene-, wherein the alkylene is C １～６ may be further substituted with alkyl, R １ is -OC(O)-Y １ is selected from Y １ is C １～６ Alkyl, C ３～６ Cycloalkyl or C ６～１２ aryl; １ is C １～６ may be further substituted with alkyl, Y １ Alternatively, CH ３ and More alternatively, U １ , U ２ and U ３ is —O—, W １ , W ２ and W ３ is CH ３ and L １ is -O-, L ２ は、-CH ２ -、-CH(CH ３ )-、 【Chemical Formula 26】 and R １ teeth, 【Chemical 27】 Selected from:

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

29. The compound has the formula III, III-1 or III-2: 【Chemical 28】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, X １ is a chemical bond or -C １～６ alkylene-O-; X ２ is a chemical bond, —O— or —C(O)—, R １ is absent or H, —NH—C １～１２ Alkylene-C(O)-O-C １～１２ Alkyl, —C １～１２ Alkylene-C ６～１８ Aryl, —O—C １～１２ Alkylene-O-C(O)-Y ３ where R １ a hydrogen atom in the alkylene is optionally substituted with Rd; Y ３ Ha-O-C １～６ alkyl, and １～６ Alkyl is C １～６ may be further substituted with alkyl, Ra is OH, -OC ６～１８ Aryl, —O—C １～１２ Alkylene-C ６～１８ Aryl or —O—C ６～１８ Aryl-C １～１２ alkyl; Or Ra and X ２ are connected to form a ring, Rd is C １～１２ Alkyl or C １～１２ alkoxy; Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, X １ is a chemical bond or -C １～６ alkylene-O-; X ２ is a chemical bond, —O— or —C(O)—, R １ is absent or H, —NH—C １～６ Alkylene-C(O)-O-C １～６ Alkyl, —C １～６ Alkylene-C ６～１０ Aryl, —O—C １～６ Alkylene-O-C(O)-Y ３ where R １ a hydrogen atom in the alkylene is optionally substituted with Rd; Y ３ Ha-O-C １～６ alkyl, and １～６ Alkyl is C １～６ may be further substituted with alkyl, Ra is OH, -OC ６～１２ Aryl, —O—C １～６ Alkylene-C ６～１２ Aryl or —O—C ６～１２ Aryl-C １～６ alkyl; Or Ra and X ２ are connected to form a ring, Rd is C １～６ is alkyl, More alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and X １ is a chemical bond or -CH ２ -O-; X ２ is a chemical bond or —O—, R １ is absent or H, 【Chemical 29】 , -CH ２ -phenyl or 【Chemistry 30】 is selected from Ra is OH, —O-phenyl or —O—CH ２ -phenyl or -O-phenyl-CH ３ Selected from or Or Ra and X ２ are connected to form a ring, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

30. The compound is represented by formula IVa, IVa-1, IVa-2, IVb, IVb-1, IVb-2, IVc, IVc-1 or IVc-2: 【Chemical 31】 is a compound of wherein ring G is C ６～１２ aryl, alternatively C ６～１０ aryl, more alternatively phenyl; Various other variables are as defined in claim 29.

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.

31. The compound has formula V, V-1, or V-2: 【Chemical 32】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, R １ is C １～３０ Alkyl, C ２～３０ Alkenyl, C １～２０ Alkoxy, and unsubstituted —O—C in which a hydrogen atom in the alkylene is replaced by Rd １～１２ Alkylene-O-C(O)-Y ３ is selected from Rd is C １～１２ alkyl, R １ Alternatively, C ６～１０ Alkyl or C １０～３０ is alkenyl, Y ３ is C １～１２ Alkyl or O-C １～１２ alkyl, Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, R １ is C １～３０ Alkyl, C ２～３０ Alkenyl, C １～６ Alkoxy, and unsubstituted —O—C in which a hydrogen atom in the alkylene is replaced by Rd １～６ Alkylene-O-C(O)-Y ３ is selected from Rd is C １～６ alkyl, R １ Alternatively, C ６～１０ Alkyl or C １０～３０ is alkenyl, Y ３ is C １～６ is alkyl, More alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and R １ is CH ３ , 【Chemical 33】 , C ７ Alkyl, C ８ Alkyl, C ９ 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, 【Chemical 34】 Selected from:

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

32. The above compound has the formula VIa, VIa-1, VIa-2, VIb, VIb-1, VIb-2, VIc, VIc-1 or VIc-2: 【Chemical 35】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, r and 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; Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, r and 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 alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and 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; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

33. The compound has the formula VII, VII-1, VII-2, XIV, XIV-1 or XIV-2: 【Chemical 36】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, m and n are selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, alternatively 6, 7, 8, 9 or 10, more alternatively 7, 8 or 9; L １ is a chemical bond, —O— or —NH—, L ２ is -C(O)-, -C(O)O-, -C(O)-C １～１８ Alkylene- or -O-C １～１８ alkylene-, Y ７ is C １～１２ is an alkoxy, Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, m and n are selected from 2, 3, 4, 5, 6, 7, 8, 9 or 10, alternatively 7, 8 or 9; L １ is —O— or —NH—, alternatively —O—; L ２ is -C(O)- or -C(O)-C １～６ alkylene-, Y ７ is C １～３ is an alkoxy, More alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and m and n are 3, 4, 5, 6, 7, 8, alternatively 3 or 8; L １ is O, L ２ is -C(O)- or -C(O)-C １～４ alkylene-, alternatively —C(O)—; Y ７ is C １～３ Alkoxy, alternatively OCH ３ That is, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

34. The compound has the formula VIII, VIII-1 or VIII-2: 【Chemical 37】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, Z is C １～３０ Alkylene or C ２～３０ alkenylene, wherein Z is selected from 1, 2 or 3 R ３ is optionally replaced by R ３ is C １～６ is alkyl, A is optionally substituted with halogen, OH, or Rc; １～１８ Alkyl or C ６～３０ aryl, optionally substituted with OH, Rc, C １～１８ Alkyl or C ６～３０ aryl, more alternatively C ６～３０ aryl; B is halogen, OH or C ６～３０ aryl, alternatively halogen or OH, more alternatively halogen; Rc is C optionally substituted with OH, oxo or thioxo. ３～１０ Cycloalkyl, alternatively C substituted with oxo ３～１０ cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, Z is C １～６ Alkylene or C ２～６ alkenylene, alternatively C １～３ alkylene, wherein Z is selected from 1, 2 or 3 R ３ is optionally replaced by R ３ is C １～６ is alkyl, A is optionally substituted with halogen, OH, or Rc; １～６ Alkyl or C ６～１２ aryl, optionally substituted with OH, Rc, C １～６ Alkyl or C ６～１２ aryl, more alternatively C ６～１２ aryl; B is halogen, OH or C ６～１２ aryl, alternatively halogen or OH, more alternatively halogen; Rc is C optionally substituted with OH or oxo. ３～１０ cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; More alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and Z is -CH(CH ３ )-, -CH=CH- or -CH ２ -CH ２ - is selected from, A is F, OH, phenyl, 【Chemical Formula 38】 , alternatively OH, phenyl or 【Chemical 39】 and more alternatively selected from phenyl; B is selected from F, OH or phenyl, alternatively F or OH, more alternatively F; x and y are 0, 1 or 2; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

35. The compound is represented by formula IX, IX-1, or IX-2: 【Chemistry 40】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, A is H or C substituted with Rc １～１８ alkyl, B is a halogen or C ６～３０ aryl, alternatively halogen or C ６～１２ aryl; Rc is C optionally substituted with OH, oxo or thioxo. ３～１０ Cycloalkyl, alternatively C substituted with oxo ３～１０ cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, A is H or C substituted with Rc １～６ alkyl, alternatively H; B is a halogen or C ６～１０ aryl, alternatively selected from F or phenyl; Rc is a C substituted with oxo or OH. ３～１０ Cycloalkyl, alternatively C substituted with oxo ３～１０ cycloalkyl; x is 0, 1 or 2; y is 0, 1, 2 or 3; More alternatively, U １ , U ２ and U ３ is —O—, W １ , W ２ and W ３ is CH ３ and A is, 【Chemistry 41】 is selected from B is selected from F or phenyl; x is 0 or 1; y is 0 or 1; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

36. The compound has the formula X, X-1, X-2, X-3 or X-4: 【Chemistry 42】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, M １ are each independently a chemical bond or —C(O)—; alternatively, two M １ are not chemical bonds, L ３ is a chemical bond or -C １～１８ -alkylene-, or alternatively a chemical bond; Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, M １ are each independently a chemical bond or —C(O)—; alternatively, two M １ are not chemical bonds, L ３ is a chemical bond or -C １～１２ -alkylene-, or alternatively a chemical bond; More alternatively, U １ , U ２ and U ３ is —O—, W １ , W ２ and W ３ is CH ３ and M １ are each independently a chemical bond or —C(O)—; alternatively, two M １ are not chemical bonds, L ３ is a chemical bond or -C １～６ -Alkylene-, e.g., a chemical bond, -CH ２ -, -CH ２ CH ２ CH ２ - or -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ -, alternatively selected from a chemical bond; 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

37. The compound has formula XI, XI-1, XI-2, XI-3, or XI-4: 【Chemistry 43】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ are independently １～１２ alkyl, L ３ Ha-C １～１８ -alkylene-, Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ are independently １～６ alkyl, L ３ Ha-C １～１２ -alkylene-, More alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and L ３ Ha-C １～６ -Alkylene-, for example, -CH ２ CH ２ CH ２ - or -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ -is, 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

38. The compound has formula XII, XII-1, or XII-2: 【Chemical 44】 is a compound of During the ceremony, U １ , U ２ and U ３ are independently —O—, —O—C(O)—, —NH—C(O)—, or —O—CH ２ -O-; W １ , W ２ and W ３ is C １～１２ is alkyl, L ２ is a chemical bond, —C(O)— or —C(O)O—, R １ is H, OH or -Y ５ -Y ６ -Y ７ is selected from Y ５ is unsubstituted or NH ２ C substituted with １～１２ is alkylene, Y ６ is a single bond or —NH—C(NH)—, Y ７ is NH ２ , OH or C １～１２ is an alkoxy, Alternatively, U １ , U ２ and U ３ is selected from —O— or —OC(O)—; W １ , W ２ and W ３ is C １～６ is alkyl, L ２ is a chemical bond or —C(O)—, R １ is H, OH or -Y ５ -Y ６ -Y ７ is selected from Y ５ is unsubstituted or NH ２ C substituted with ３～６ is alkylene, Y ６ is a single bond or —NH—C(NH)—, Y ７ is NH ２ or OH, More alternatively, U １ , U ２ and U ３ is O, W １ , W ２ and W ３ is CH ３ and L ２ is a chemical bond or —C(O)—, R １ H, 【Chemistry 45】 Selected from:

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

39. The compound has the formula XIII, XIII-1 or XIII-2: 【Chemistry 46】 is a compound of During the ceremony, The various variables are as defined in claim 38.

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.

40. The compound is 【Chemistry 47-1】 【Chemistry 47-2】 【Chemistry 47-3】 【Chemistry 47-4】 【Chemistry 47-5】 Selected from:

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and mixtures thereof.

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 to 40.

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

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

44. Use of a compound according to any one of claims 1 to 40, a stereoisomer, a pharmaceutically acceptable salt, an ester, an optical isomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, a chelate, a complex, a clathrate or a prodrug according to claim 41, or a composition according to claim 42, in the manufacture of a medicament for the prevention and / or treatment of a central nervous system related disease.

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

46. 45. The use of claim 44, wherein the medicament is used for pain caused by post-operative trauma, post-operative incision, or organ metastasis of cancer.

47. 42. A method for analgesia, antidepressant or anti-drug addiction, comprising administering to a subject in need thereof an effective dose of a compound according to any one of claims 1 to 40, a stereoisomer, a pharmaceutically acceptable salt, an ester, an optical isomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, a chelate, a complex, a clathrate or a prodrug of claim 41, or a composition according to claim 42, wherein said administration is by oral, rectal, nasal, topical or parenteral administration.

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

Images