Tetrahydroisoquinoline derivative and use thereof

Abstract

The present invention provides a tetrahydroisoquinoline derivative and a use thereof. Specifically, the present invention relates to a compound represented by formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising the compound, and an effect of the compound in prevention and treatment of diseases related to the central nervous system.

Description

Tetrahydroisoquinoline derivatives and uses thereof

[0001] This application claims priority to Chinese application No. 202311129751.9 filed on September 4, 2023, and Chinese application No. 202411195283.X filed on August 28, 2024, which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to tetrahydroisoquinoline derivatives and their uses, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, or pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical compositions comprising the tetrahydroisoquinoline derivatives, and the effects of the tetrahydroisoquinoline derivatives in preventing and treating central nervous system-related diseases such as pain, depression, and addiction. Background Art

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

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

[0005] Summary of the Invention

[0006] The present invention develops a series of active compounds based on the structure of corydalis, which have good analgesic effect.

[0007] In one aspect, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof:

[0008] wherein the variables are as defined herein.

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and a pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic agents.

[0010] In another aspect, the present invention provides use of the compound of the present invention in preparing a medicament for treating or preventing central nervous system-related diseases.

[0011] In another aspect, the present invention provides a method for treating or preventing a central nervous system-related disease in a subject, comprising administering to the subject a compound or pharmaceutical composition of the present invention.

[0012] In another aspect, the present invention provides a compound or a pharmaceutical composition of the present invention for use in treating or preventing central nervous system-related diseases.

[0013] In certain embodiments, the disorder is selected from the group consisting of pain, depression, and addiction.

[0014] In another specific embodiment, the pain is selected from neuralgia, perioperative pain (including pain before, during or after surgery, for example, somatic or visceral pain caused by postoperative trauma, postoperative incision, pain caused by visceral injury and other comprehensive pain) and cancer pain (such as pain caused by cancer).

[0015] In another specific embodiment, the pain is acute pain or chronic pain (including acute / chronic pain before, during or after surgery, acute neuropathic pain or chronic neuropathic pain).

[0016] In another embodiment, the neuropathic pain is central pain, such as spinal pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain.

[0017] In another specific embodiment, the postoperative pain is pain caused by surgery, such as pain caused by abdominal surgery, orthopedic surgery, cesarean section, or brain surgery.

[0018] In another specific embodiment, the compound or pharmaceutical composition is used for sedation or sleep assistance.

[0019] definition

[0020] Chemical definition

[0021] Definitions of specific functional groups and chemical terms are described in more detail below.

[0022] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0023] “C 1-18 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 18 carbon atoms. In some embodiments, C 1-10 Alkyl is preferred. In some embodiments, C 1-6 Alkyl is preferred. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), i-Bu(-CH2CH(CH3)2), or t-Bu(-C(CH3)3).

[0024] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] “C 1-10 "Alkylene" refers to the removal of C 1-10 In some embodiments, C 1-6 Alkylene is preferred. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene and C 1-2 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0027] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0028] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0029] “C 0-10 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-10 In some embodiments, "C 0-6 "Alkylene" is preferred. In some embodiments, C 0-4 Alkylene is preferred. In some embodiments, C 0-3 Alkylene is preferred. In some embodiments, C 0-2 Alkylene groups are preferred.

[0030] “C 1-10 "Deuterated alkyl" refers to the above-mentioned "C 1-10 Alkyl", which is substituted with one or more D groups. In some embodiments, C 1-6Deuterated alkyl is particularly preferred, more preferably C 1-4 Deuterated alkyl, more preferably C 1-3 Deuterated alkyl, more preferably C 1-2 Deuterated alkyl. Exemplary deuterated alkyl groups include, but are not limited to, -CD3, -CH2D, -CHD2, -CHDCH2D, -CH2CHD2, -CD2CD3, -CH2CH2CD3, -C(CH3)2CD3, and the like. The deuterated alkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0032] Therefore, “C 1-18 "Haloalkyl" refers to the above-mentioned "C 1-18 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-10 Halogenated alkyl is particularly preferred, more preferably C 1-6 Halogenated alkyl, more preferably C 1-4 Halogenated alkyl, more preferably C 1-3 Halogenated alkyl, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CH2CH2CF3, -C(CH3)2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] “C 3-14 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 3-10 Cycloalkyl, C 5-10 Cycloalkyl, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-7 Cycloalkyl, C 4-6 Cycloalkyl and C 5-6Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on any non-adjacent carbon atoms are connected to form a bridge ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycycloalkane sharing one carbon atom. Exemplary cycloalkyls include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0034] “C 3-7 "Cycloalkylene" refers to the removal of C 3-7 In some embodiments, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, preferably cyclopentylene, and especially preferably cyclopropylene.

[0035] "3-14 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon, and optionally containing 1, 2 or 3 double bonds or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. In some embodiments, a 3- to 10-membered heterocyclyl is preferred, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5- to 10-membered heterocyclyl is preferred, which is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3- to 7-membered heterocyclyl is preferred, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; and a 5- to 7-membered heterocyclyl is preferred. The term "heterocyclyl" refers to a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably, a 3- to 6-membered heterocyclyl is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably, a 4- to 6-membered heterocyclyl is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 5- to 6-membered heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 5- to 6-membered heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 5-membered heterocyclyl. Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. The heterocyclic group also includes the above-mentioned heterocyclic ring, wherein the substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. The heterocyclic group also includes the above-mentioned heterocyclic ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridine, oxirane, thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetane and thiidine. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolane, oxasulfuranyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thianyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include those in which the aforementioned heterocyclyl groups share one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group to form a bridged or spirocyclic ring. The shared atoms may be carbon or nitrogen atoms as long as valence permits. Heterocyclyl groups also include those in which the aforementioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 14 π electrons shared in a cyclic arrangement) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, C 6-10 Aryl is preferred. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-membered heteroaryls are particularly preferred. In other embodiments, 6-membered heteroaryls are particularly preferred. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. 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 include, but are not limited to, azacycloheptatrienyl, oxepatrienyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, 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.

[0038] “C 6-10"Arylene" refers to the removal of C 6-10 The divalent group is formed by the other hydrogen of the aryl group and may be substituted or unsubstituted. In some embodiments, phenylene is particularly preferred, preferably Preferred

[0039] "5-10 membered heteroarylene" refers to a divalent group formed by removing another hydrogen of a 5-10 membered heteroaryl, and may be substituted or unsubstituted. In some embodiments, a 9-10 membered heteroaryl is particularly preferred, preferably an indolylene, preferably In some embodiments, 5-6 membered heteroaryl groups are particularly preferred.

[0040] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0041] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc., as defined herein, are optionally substituted groups.

[0042] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NRbb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc)3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0043] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0044] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0045] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SRcc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0046] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0047] R dd Each of the is independently selected from: 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(=NRff )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, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0048] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0049] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0050] Rgg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 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 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 3-7 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0051] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0052] Other definitions

[0053] The term "anti-inflammatory drug" refers to drug molecules that have the activity to prevent or treat inflammation, inhibiting the production or release of inflammatory factors, and relieving inflammation and pain. Common anti-inflammatory drugs are divided into two major categories: one is steroidal anti-inflammatory drugs, which can be divided into sex hormones and corticosteroids. They can regulate sugar metabolism, water and salt metabolism, and provide anti-inflammatory, anti-allergic, and metabolic function improvements. Common steroidal anti-inflammatory drugs include dexamethasone and methylprednisolone. The other is non-steroidal anti-inflammatory drugs, such as loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetin, bromfenac, thiaprofen, indomethacin, sulindac, ketorolac, nimesulide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, naproxen, etodolac, rofecoxib, celecoxib, piroxicam, meloxicam, and hydroxyphenylbutazone.

[0054] The term "derivative" refers to a compound formed by replacing an atom or a group of atoms in a molecule with another atom or a group of atoms.

[0055] The term "central nervous system related disorders" includes, but is not limited to, pain, depression and addiction.

[0056] The term "pain" includes, but is not limited to, acute pain and chronic pain.

[0057] In one embodiment, the term "pain" includes, but is not limited to, the following pain: neuropathic pain, perioperative pain (including pain before, during or after surgery, for example, somatic or visceral pain caused by postoperative trauma, postoperative incision, pain caused by visceral injury or other comprehensive pain) and cancer pain (such as pain caused by cancer).

[0058] In one embodiment, the term "pain" refers to acute pain or chronic pain (including acute / chronic pain before, during or after surgery, acute neuropathic pain or chronic neuropathic pain).

[0059] In one embodiment, the term "neuralgia" refers to central pain, such as spinal pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain.

[0060] As used herein, the term "postoperative pain" refers to pain caused by surgery, such as pain caused by abdominal surgery, orthopedic surgery, cesarean section, brain surgery, or other surgery.

[0061] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0062] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0063] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0064] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0065] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are salts of amino acids, such as argininate, gluconate, galacturonate, and the like (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0066] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0067] "Disease," "disorder," and "condition" are used interchangeably herein.

[0068] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0069] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount. In some embodiments of the invention, the effective dose, calculated as the compound, is 0.1 mg / day to 1000 mg / day, preferably 3 mg / day to 300 mg / day, and more preferably 5 mg / day to 50 mg / day.

[0070] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0071] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0072] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 shows the DRG experimental results. Specific implementation plan

[0074] Herein, "compounds of the present invention" refers to the following compounds of formula (I), formula (II), formula (III), formula (III-1), etc., their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates, or pharmaceutically acceptable salts thereof.

[0075] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0076] In one embodiment, the present invention relates to a compound of formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof:

[0077] in,

[0078] R D Residues formed for drug molecules;

[0079] U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-;

[0080] W1, W2 and W3 are each independently selected from H, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0081] L is a chemical bond or Preferred

[0082] L1 is selected from a chemical bond, -C(O)-, -OC(O)-, -NR b C(O)-, -S(O)-, -S(O)2-, -OS(O) 1-2 -and-NR b S(O) 1-2 -;

[0083] L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene;

[0084] L3 is selected from O, S, NR', -C(O)-, -S(O)- and -S(O)2-;

[0085] n is selected from 0, 1, 2, 3, 4, 5 and 6;

[0086] The methylene group in is optionally substituted by 1, 2, 3, 4, 5 or 6 independent R;

[0087] R is independently selected from H, D, halogen, CN, ═O, —OR a 、-SR a 、-NR b R c 、-C 0-10 Alkylene-C(O)R a 、-C 0-10 Alkylene-OC(O)R a 、-C 0-10 Alkylene-C(O)OR a 、-C 0-10 Alkylene-NR b C(O)R a 、-C 0-10 Alkylene-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0088] R' is selected from H, C 1-18 Alkyl, C 1-18 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, or R' together with R and the atoms to which they are attached form a 3-10 membered heterocyclyl;

[0089] R a 、R b and R c Each independently selected from H, C 1-10 Alkyl and C 1-10 Haloalkyl, or R b With R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group;

[0090] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0091] In another embodiment, the compound of the present invention is further represented by formula (II), formula (III) or formula (III-1):

[0092] Wherein, each variable is as defined in the present invention.

[0093] In the compounds of the present invention, each group may be defined as follows.

[0094] R D

[0095] In one embodiment, R D The residues formed by the drug molecule.

[0096] In one embodiment, the drug molecule is an anti-inflammatory drug and its derivatives; in another embodiment, the drug molecule is an anti-inflammatory drug; in another embodiment, the drug molecule is a derivative of an anti-inflammatory drug.

[0097] In one embodiment, the anti-inflammatory drug is a nonsteroidal anti-inflammatory drug.

[0098] In one embodiment, the NSAID is loxoprofen; in another embodiment, the NSAID is flurbiprofen, such as S-flurbiprofen, such as R-flurbiprofen; in another embodiment, the NSAID is fenoprofen; in another embodiment, the NSAID is ketoprofen; in another embodiment, the NSAID is tolmetin; in another embodiment, the NSAID is bromfenac; in another embodiment, the NSAID is thiaprofen; in another embodiment, the NSAID is indomethacin; in another embodiment, the NSAID is sulindac; in another embodiment, the NSAID is ketorolac; in another embodiment, the NSAID is nimesulide; in another embodiment, the NSAID is In another embodiment, the nonsteroidal anti-inflammatory drug is mefenamic acid; in another embodiment, the nonsteroidal anti-inflammatory drug is clofenamic acid; in another embodiment, the nonsteroidal anti-inflammatory drug is diclofenac; in another embodiment, the nonsteroidal anti-inflammatory drug is aspirin; in another embodiment, the nonsteroidal anti-inflammatory drug is ibuprofen; in another embodiment, the nonsteroidal anti-inflammatory drug is naproxen; in another embodiment, the nonsteroidal anti-inflammatory drug is naproxen; in another embodiment, the nonsteroidal anti-inflammatory drug is etodolac; in another embodiment, the nonsteroidal anti-inflammatory drug is rofecoxib; in another embodiment, the nonsteroidal anti-inflammatory drug is celecoxib; in another embodiment, the nonsteroidal anti-inflammatory drug is piroxicam; in another embodiment, the nonsteroidal anti-inflammatory drug is meloxicam; in another embodiment, the nonsteroidal anti-inflammatory drug is oxyphenbutazone.

[0099] In a more specific embodiment, the drug molecule is selected from loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetin, bromfenac, thiaprofen, indomethacin, sulindac, ketorolac, nimesulide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, naproxen, etodolac, rofecoxib, celecoxib, piroxicam, meloxicam and oxyphenbutazone, and derivatives thereof; in another more specific embodiment, the drug molecule is selected from loxoprofen, flurbiprofen, indomethacin, mefenamic acid, clofenamic acid and aspirin, and derivatives thereof; in another more specific embodiment, the drug molecule is selected from flurbiprofen and clofenamic acid, and derivatives thereof; in another more specific embodiment, the drug molecule is selected from flurbiprofen and its derivatives; in another more specific embodiment, the drug molecule is selected from S-flurbiprofen and its derivatives; in another more specific embodiment, the drug molecule is selected from R-flurbiprofen and its derivatives.

[0100] In one embodiment, R D for In another embodiment, R D for

[0101] In one embodiment, for In another embodiment, for In another embodiment, for In another embodiment, for In another embodiment, for In another embodiment, for In another embodiment, for

[0102] In a more specific embodiment, Selected from the following structures: In another more specific embodiment, Selected from In another more specific embodiment, Selected from

[0103] Ring A

[0104] In one embodiment, Ring A is C6-10 Arylene, preferably phenylene, such as For example In another embodiment, ring A is a 5-10 membered heteroarylene group, preferably a 9-10 membered heteroarylene group (eg, an indolylene group, ), preferably a 5-6 membered heteroarylene group; in another embodiment, ring A is C 6-10 Aryl C 5-10 Cycloalkyl; In another embodiment, Ring A is C 6-10 In another embodiment, ring A is a 5-10 membered heteroaryl and C 5-10 In another embodiment, ring A is a 5-10 membered heteroaryl and a 5-10 membered heterocyclyl.

[0105] In a more specific embodiment, Ring A is selected from C 6-10 Arylene, 5-10 membered heteroarylene, C 6-10 Aryl C 5-10 Cycloalkyl, C 6-10 Aryl and 5-10 membered heterocyclic group, 5-10 membered heteroaryl and C 5-10 Cycloalkyl and 5-10 membered heteroaryl and 5-10 membered heterocyclyl; In another more specific embodiment, ring A is selected from C 6-10 arylene and 5-10 membered heteroarylene; in another more specific embodiment, ring A is selected from phenylene and 9-10 membered heteroarylene; preferably selected from phenylene and indolylene; in another more specific embodiment, ring A is phenylene; in another more specific embodiment, ring A is selected from In another more specific embodiment, Ring A is selected from In another more specific embodiment, Ring A is

[0106] Ring B

[0107] In one embodiment, Ring B is C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; In another embodiment, ring B is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; In another embodiment, ring B is C 6-10 Aryl, preferably phenyl; in another embodiment, Ring B is a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl; in another embodiment, L4-Ring B and R2 are absent.

[0108] In a more specific embodiment, Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl; In another more specific embodiment, ring B is selected from C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, ring B is selected from C 3-7 In another more specific embodiment, ring B is selected from phenyl and 5-6 membered heteroaryl.

[0109] R1

[0110] In one embodiment, R1 is H; in another embodiment, R1 is D; in another embodiment, R1 is halogen, preferably F; in another embodiment, R1 is CN; in another embodiment, R1 is -NO2; in another embodiment, R1 is -OR a , preferably -OMe; in another embodiment, R1 is -SR a In another embodiment, R1 is -NR b R c In another embodiment, R1 is -C(O)R a In another embodiment, R1 is -OC(O)R a , preferably -OC(O)CH3; in another embodiment, R1 is -C(O)OR a In another embodiment, R1 is -NR b C(O)R a In another embodiment, R1 is -C(O)NR b R c In another embodiment, R1 is -S(O)R a In another embodiment, R1 is -S(O)2R a In another embodiment, R1 is C 1-18 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably Me; in another embodiment, R1 is C 1-18 Halogenated alkyl, preferably C 1-10 Halogenated alkyl, preferably C 1-6 In another embodiment, R1 is C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 In another embodiment, R1 is a 3-14 membered heterocyclic group, preferably a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; In another embodiment, R1 is C 6-14 Aryl, preferably C6-10 Aryl, preferably phenyl; in another embodiment, R1 is 5-14 membered heteroaryl, preferably 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl; in another embodiment, R1 is optionally substituted by 1, 2 or 3 independent R 1s substituted; in another embodiment, R1 is unsubstituted.

[0111] In a more specific embodiment, R1 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a 、C 1-18 Alkyl, C 1-18 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)Ra 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl and C 1-6 In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, -OR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a 、C 1-6 Alkyl and C 1-6 In another more specific embodiment, R1 is independently selected from H, D, halogen, -OR a 、-OC(O)R a 、C 1-6 Alkyl and C 1-6Haloalkyl; in another more specific embodiment, R1 is independently selected from H, F, Me, -OMe and -OC(O)CH3.

[0112] In a more specific embodiment, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R1 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R1 is independently selected from H, D and halogen; in another more specific embodiment, R1 is independently H or F.

[0113] R2

[0114] In one embodiment, R2 is H; in another embodiment, R2 is D; in another embodiment, R2 is halogen, preferably Cl; in another embodiment, R2 is CN; in another embodiment, R2 is -NO2; in another embodiment, R2 is -OR a In another embodiment, R2 is -SR a In another embodiment, R2 is -NR b R c In another embodiment, R2 is -C(O)R a In another embodiment, R2 is -OC(O)R a In another embodiment, R2 is -C(O)OR a In another embodiment, R2 is -NR b C(O)R a In another embodiment, R2 is -C(O)NR b R c In another embodiment, R2 is -S(O)R a In another embodiment, R2 is -S(O)2R a In another embodiment, R2 is C 1-18 Alkyl, preferably C1-10 Alkyl, preferably C 1-6 Alkyl, preferably Me; in another embodiment, R2 is C 1-18 Halogenated alkyl, preferably C 1-10 Halogenated alkyl, preferably C 1-6 In another embodiment, R2 is C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 In another embodiment, R2 is a 3-14 membered heterocyclic group, preferably a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; In another embodiment, R2 is C 6-14 Aryl, preferably C 6-10 Aryl, preferably phenyl; in another embodiment, R2 is 5-14 membered heteroaryl, preferably 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl; in another embodiment, R2 is optionally replaced by 1, 2 or 3 independent R 2s substituted; in another embodiment, R2 is unsubstituted.

[0115] In a more specific embodiment, R2 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a 、C 1-18 Alkyl, C 1-18 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl; In another more specific embodiment, R2 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR bR c 、-S(O)R a 、-S(O)2R a 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; In another more specific embodiment, R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C1-6 Alkyl and C 1-6 In another more specific embodiment, R2 is independently selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R2 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R2 is independently selected from H, Cl and Me; in another more specific embodiment, R2 is independently selected from H and Cl.

[0116] In a more specific embodiment, R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, R2 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl; In another more specific embodiment, R2 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R2 is independently selected from H, D and halogen; in another more specific embodiment, R2 is independently H or D.

[0117] R 1s and R 2s

[0118] In one embodiment, R 1s is H; in another embodiment, R 1s is D; in another embodiment, R 1s is halogen; in another embodiment, R 1s is CN; in another embodiment, R 1s For-OR a In another embodiment, R 1s For-SR a In another embodiment, R 1s -NR b R c In another embodiment, R 1s -OC(O)Ra In another embodiment, R 1s -C(O)OR a In another embodiment, R 1s -NR b C(O)R a In another embodiment, R 1s -C(O)NR b R c In another embodiment, R 1s C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R 1s C 1-10 Halogenated alkyl, preferably C 1-6 haloalkyl; in another embodiment, R 1s C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R 1s It is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group.

[0119] In one embodiment, R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen; in another embodiment, R 2s is CN; in another embodiment, R 2s For-OR a In another embodiment, R 2s For-SR a In another embodiment, R 2s -NR b R c In another embodiment, R 2s -OC(O)R a In another embodiment, R 2s -C(O)OR a In another embodiment, R 2s -NR b C(O)R a In another embodiment, R 2s -C(O)NR b R c In another embodiment, R 2s C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R 2s C1-10 Halogenated alkyl, preferably C 1-6 haloalkyl; in another embodiment, R 2s C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R 2s It is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group.

[0120] In a more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl; in another more specific embodiment, R 1s Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0121] In a more specific embodiment, R 2s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl; in another more specific embodiment, R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl; in another more specific embodiment, R 2s Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0122] m

[0123] In one embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2; in another embodiment, m is 3; in another embodiment, m is 4; in another embodiment, m is 5.

[0124] In a more specific embodiment, m=0, 1, 2, 3, 4 or 5; in another more specific embodiment, m=0, 1, 2, 3 or 4; in another more specific embodiment, m=0, 1 or 2; in another more specific embodiment, m=0 or 1.

[0125] s

[0126] In one embodiment, s is 0; in another embodiment, s is 1; in another embodiment, s is 2; in another embodiment, s is 3; in another embodiment, s is 4; in another embodiment, s is 5.

[0127] In a more specific embodiment, s=0, 1, 2, 3, 4 or 5; in another more specific embodiment, s=0, 1 or 2.

[0128] L4

[0129] In one embodiment, L4 is a chemical bond; in another embodiment, L4 is -CR4R'4-, preferably -CH2-; in another embodiment, L4 is -NR b -, preferably -NH-; in another embodiment, L4 is O; in another embodiment, L4 is S; in another embodiment, L4 is -C(O)-; in another embodiment, L4 is -OC(O)-; in another embodiment, L4 is -C(O)O-; in another embodiment, L4 is -NR b C(O)-; In another embodiment, L4 is -C(O)NR b -; In another embodiment, L4 is -S(O)-; In another embodiment, L4 is -S(O)2-; In another embodiment, L4 and the carbon atom on ring A to which L4 is attached together form In another embodiment, L4 and the carbon atom on Ring A to which L4 is attached do not form

[0130] In a more specific embodiment, L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)-, -OC(O)-, -C(O)O-, -NR b C(O)-、-C(O)NR b -, -S(O)- and -S(O)2-; In another more specific embodiment, L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)- and -S(O)-; in another more specific embodiment, L4 is selected from a chemical bond, -CR4R'4-, -NRb -, O and -C(O)-; In another more specific embodiment, L4 is selected from a chemical bond, -NR b - and -C(O)-; in another more specific embodiment, L4 is selected from a chemical bond, -NH- and -C(O)-; in another more specific embodiment, L4 is selected from a chemical bond and -NH-.

[0131] L5

[0132] In one embodiment, L5 is a chemical bond; in another embodiment, L5 is O; in another embodiment, L5 is S; in another embodiment, L5 is NR'; in another embodiment, L5 is C 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene, preferably C 1-2 Alkylene, preferably methylene; in another embodiment, L5 is optionally substituted by one or more independent R3; in another embodiment, L5 is optionally substituted by 1, 2, 3, 4, 5 or 6 independent R3; in another embodiment, L5 is optionally substituted by 1, 2 or 3 independent R3; in another embodiment, L5 is optionally substituted by 1 R3; in another embodiment, L5 is unsubstituted.

[0133] In a more specific embodiment, L5 is selected from a chemical bond, O, S, NR' and C 1-10 In another more specific embodiment, L5 is a chemical bond or C 1-10 In another more specific embodiment, L5 is a chemical bond or C 1-6 In another more specific embodiment, L5 is a chemical bond or C 1-4 In another more specific embodiment, L5 is a chemical bond or C 1-2 Alkylene; in another more specific embodiment, L5 is a chemical bond or methylene; in another more specific embodiment, L5 is -CH(CH3)-.

[0134] R3

[0135] In one embodiment, R3 is H; in another embodiment, R3 is D; in another embodiment, R3 is halogen; in another embodiment, R3 is C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R3 is C 1-10 Halogenated alkyl, preferably C 1-6 Halogenated alkyl, preferably C1-4 Halogenated alkyl.

[0136] In a more specific embodiment, R3 is independently selected from H, D, halogen, C 1-10 Alkyl and C 1-10 In another more specific embodiment, R3 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R3 is independently selected from H, D, C 1-4 Alkyl and C 1-4 haloalkyl; in another more specific embodiment, R3 is independently selected from H and Me; in another more specific embodiment, R3 is Me.

[0137] R4 and R'4

[0138] In one embodiment, R4 is H; in another embodiment, R4 is D; in another embodiment, R4 is halogen; in another embodiment, R4 is C 1-6 Alkyl; in another embodiment, R4 is C 1-6 Halogenated alkyl.

[0139] In one embodiment, R'4 is H; in another embodiment, R'4 is D; in another embodiment, R'4 is halogen; in another embodiment, R'4 is C 1-6 Alkyl; in another embodiment, R'4 is C 1-6 Halogenated alkyl.

[0140] In a more specific embodiment, R4 and R'4 are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R4 and R'4 are independently selected from H, D, C 1-6 Alkyl and C 1-6 haloalkyl; in another more specific embodiment, R4 and R'4 are independently H or D.

[0141] X

[0142] In one embodiment, X is -C(O)-: In another embodiment, X is -S(O)-: In another embodiment, X is -S(O)2-.

[0143] In a more specific embodiment, X is selected from -C(O)-, -S(O)-, and -S(O)2-.

[0144] U1, U2, and U3

[0145] In one embodiment, U1 is O; in another embodiment, U1 is S; in another embodiment, U1 is -NH-; in another embodiment, U1 is -C(O)-; in another embodiment, U1 is -OC(O)-; in another embodiment, U1 is -NH-C(O)-; in one embodiment, U1 is -O-CH2-O-.

[0146] In one embodiment, U2 is O; in another embodiment, U2 is S; in one embodiment, U2 is -NH-; in another embodiment, U2 is -C(O)-; in another embodiment, U2 is -OC(O)-; in another embodiment, U2 is -NH-C(O)-; in one embodiment, U2 is -O-CH2-O-.

[0147] In one embodiment, U3 is O; in another embodiment, U3 is S; in one embodiment, U3 is -NH-; in another embodiment, U3 is -C(O)-; in another embodiment, U3 is -OC(O)-; in another embodiment, U3 is -NH-C(O)-; in one embodiment, U3 is O-CH2-O-.

[0148] In a more specific embodiment, U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-; in another more specific embodiment, U1, U2 and U3 are O.

[0149] W1, W2, and W3

[0150] In one embodiment, W1 is H; in another embodiment, W1 is C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably methyl; in another embodiment, W1 is C 1-10 Deuterated alkyl, preferably C 1-6 Deuterated alkyl, preferably CD3; in another embodiment, W1 is C 1-10 Halogenated alkyl, preferably C 1-6 In another embodiment, W1 is C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, W1 is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, W1 is C 6-10 Aryl, preferably phenyl; in another embodiment, W1 is a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl.

[0151] In one embodiment, W2 is H; in another embodiment, W2 is C1-10 Alkyl, preferably C 1-6 Alkyl, preferably methyl; in another embodiment, W2 is C 1-10 Deuterated alkyl, preferably C 1-6 Deuterated alkyl, preferably CD3; in another embodiment, W2 is C 1-10 Halogenated alkyl, preferably C 1-6 In another embodiment, W2 is C 3-10 Cycloalkyl, preferably C 3-7 In another embodiment, W2 is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; In another embodiment, W2 is C 6-10 Aryl, preferably phenyl; in another embodiment, W2 is a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl.

[0152] In one embodiment, W3 is H; in another embodiment, W3 is C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably methyl; in another embodiment, W3 is C 1-10 Deuterated alkyl, preferably C 1-6 Deuterated alkyl, preferably CD3; in another embodiment, W3 is C 1-10 Halogenated alkyl, preferably C 1-6 In another embodiment, W3 is C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, W3 is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; in another embodiment, W3 is C 6-10 Aryl, preferably phenyl; in another embodiment, W3 is a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl.

[0153] In a more specific embodiment, W1 is selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, W1 is selected from C 1-10 Alkyl, C 1- 10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl; In another more specific embodiment, W1 is selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C1-10 In another more specific embodiment, W1 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 In another more specific embodiment, W1 is C 1-6 Alkyl or C 1-6 Deuterated alkyl; in another more specific embodiment, W1 is methyl or CD3; in another more specific embodiment, W1 is C 1-6 Alkyl; in another more specific embodiment, W1, W2 and W3 are methyl.

[0154] In a more specific embodiment, W2 is selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, W2 is selected from C 1-10 Alkyl, C 1- 10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl; In another more specific embodiment, W2 is selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 In another more specific embodiment, W2 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 In another more specific embodiment, W2 is C 1-6 Alkyl or C 1-6 Deuterated alkyl; in another more specific embodiment, W2 is methyl or CD3; in another more specific embodiment, W2 is C 1-6 Alkyl; in another more specific embodiment, W2 is methyl.

[0155] In a more specific embodiment, W3 is selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; In another more specific embodiment, W3 is selected from C 1-10 Alkyl, C 1- 10 Deuterated alkyl, C 1-10Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl; In another more specific embodiment, W3 is selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 In another more specific embodiment, W3 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 In another more specific embodiment, W3 is C 1-6 Alkyl or C 1-6 Deuterated alkyl; in another more specific embodiment, W3 is methyl or CD3; in another more specific embodiment, W3 is C 1-6 Alkyl; in another more specific embodiment, W3 is methyl.

[0156] L

[0157] In one embodiment, L is a chemical bond; in another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is In another embodiment, L is

[0158] In one embodiment, The methylene group in is optionally substituted by 1, 2, 3, 4, 5 or 6 independent R; in another embodiment, The methylene group in is optionally substituted by 1, 2 or 3 R; in another embodiment, The methylene group in is optionally substituted by 1 R.

[0159] In a more specific embodiment, L is selected from: a chemical bond, In another more specific embodiment, L is selected from: a chemical bond, In another more specific embodiment, L is selected from: a chemical bond, In another more specific embodiment, L is selected from: a chemical bond, In another more specific embodiment, L is selected from: a chemical bond, In another more specific embodiment, L is selected from:

[0160] In a more specific embodiment, for

[0161] In a more specific embodiment, for

[0162] In a more specific embodiment, for

[0163] In a more specific embodiment, for

[0164] In a more specific embodiment, for

[0165] L1

[0166] In one embodiment, L1 is a chemical bond; in another embodiment, L1 is -C(O)-; in another embodiment, L1 is -OC(O)-; in another embodiment, L1 is -NR b C(O)-, for example, is -NHC(O)-; in another embodiment, L1 is -S(O)-; in another embodiment, L1 is -S(O)2-; in another embodiment, L1 is -OS(O) 1-2 -; In another embodiment, L1 is -NR b S(O) 1-2 -, for example -NHS(O) 1-2 -.

[0167] In a more specific embodiment, L1 is selected from a chemical bond, -C(O)-, -OC(O)-, and -NHC(O)-; in another more specific embodiment, L1 is selected from -C(O)- and -OC(O)-; in another more specific embodiment, L1 is -C(O)-.

[0168] In a more specific embodiment, L1 is selected from -C(O)-, -OC(O)-, and -NHC(O)-; in another more specific embodiment, L1 is selected from -OC(O)- and -NHC(O)-; in another more specific embodiment, L1 is selected from -OC(O)-.

[0169] L2

[0170] In one embodiment, L2 is a chemical bond; in another embodiment, L2 is C 3-7 In another embodiment, L2 is a 3-7 membered heterocyclyl group; In another embodiment, L2 is a phenylene group, for example For example In another embodiment, L2 is a 5-6 membered heteroarylene.

[0171] In a more specific embodiment, L2 is selected from a chemical bond, C 3-7 In another more specific embodiment, L2 is selected from a chemical bond, a phenylene group and a 5-6 membered heteroaryl group; In another more specific embodiment, L2 is selected from a chemical bond and a phenylene group; In another more specific embodiment, L2 is selected from a chemical bond, In another more specific embodiment, L2 is selected from a chemical bond and

[0172] L3

[0173] In one embodiment, L3 is O; in another embodiment, L3 is S; in another embodiment, L3 is NR', such as NH; in another embodiment, L3 is -C(O)-; in another embodiment, L3 is -S(O)-; in another embodiment, L3 is -S(O)2-.

[0174] In a more specific embodiment, L3 is selected from O, S and NR'; in another more specific embodiment, L2 is selected from O and NR'; in another more specific embodiment, L2 is selected from O and NH; in another more specific embodiment, L2 is selected from O and S.

[0175] n

[0176] In one embodiment, n is 0; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3; in another embodiment, n is 4; in another embodiment, n is 5; in another embodiment, n is 6.

[0177] In a more specific embodiment, n is selected from 0, 1, 2, and 3; in another more specific embodiment, n is selected from 1, 2, and 3; in another more specific embodiment, n is 1 or 2.

[0178] R

[0179] In one embodiment, R is H; in another embodiment, R is D; in another embodiment, R is halogen; in another embodiment, R is CN; in another embodiment, R is ═O; in another embodiment, R is -OR a In another embodiment, R is -SR a In another embodiment, R is -NR b R c In another embodiment, R is -C 0-10 Alkylene-C(O)R a , preferably -C 0-6 Alkylene-C(O)R a , preferably -C 0-3 Alkylene-C(O)R a In another embodiment, R is -C 0-10 Alkylene-OC(O)R a , preferably -C 0-6 Alkylene-OC(O)R a , preferably -C 0-3 Alkylene-OC(O)R a In another embodiment, R is -C 0-10 Alkylene-C(O)OR a , preferably -C 0-6 Alkylene-C(O)OR a , preferably -C 0-3 Alkylene-C(O)OR a , preferably C 0-3 Alkylene -C(O)OH, for example -C(O)OH, for example -(CH2)2C(O)OH; in another embodiment, R is -C 0-10 Alkylene-NR b C(O)R a , preferably -C 0-6 Alkylene-NR b C(O)R a , preferably -C0-3 Alkylene-NR b C(O)R a In another embodiment, R is -C 0-10 Alkylene-C(O)NR b R c , preferably -C 0-6 Alkylene-C(O)NR b R c , preferably -C 0-3 Alkylene-C(O)NR b R c In another embodiment, R is C 1-10 Alkyl, preferably C 1-6 Alkyl (e.g. isobutyl), preferably C 1-3 Alkyl (eg, methyl); in another embodiment, R is C 1-10 Halogenated alkyl, preferably C 1-6 Halogenated alkyl, preferably C 1-3 In another embodiment, R is C 3-6 In another embodiment, R is a 3-6 membered heterocyclyl.

[0180] In a more specific embodiment, R is independently selected from H, D, halogen, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a 、-C 0-6 Alkylene-OC(O)R a 、-C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a In another more specific embodiment, R is independently selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a In another more specific embodiment, R is independently selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a In another more specific embodiment, R is independently selected from H, D, =O, C 1-3 Alkyl, C1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a In another more specific embodiment, R is independently selected from H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a In another more specific embodiment, R is independently selected from H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a In another more specific embodiment, R is independently selected from H, D, =O and -C 0-3 Alkylene-C(O)OH.

[0181] In a more specific embodiment, R is independently selected from H, =O, methyl, isobutyl, -C(O)OH, and -(CH2)2C(O)OH; in another more specific embodiment, R is independently selected from H, =O, methyl, -C(O)OH, and -(CH2)2C(O)OH; in another more specific embodiment, R is independently selected from H, =O, methyl, and -(CH2)2C(O)OH; in another more specific embodiment, R is independently selected from H, =O, methyl, and -(CH2)2C(O)OH.

[0182] In a more specific embodiment, R is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R is independently selected from H, D, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R is independently selected from H, D, C 1-3 Alkyl and C 1-3 Haloalkyl; in another more specific embodiment, R is independently selected from H and Me.

[0183] R'

[0184] In one embodiment, R' is H; in another embodiment, R' is C 1-18 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' is C 1-18 Halogenated alkyl, preferably C 1-10 Halogenated alkyl, preferably C 1-6 In another embodiment, R' is C 3-10 Cycloalkyl, preferably C 3-7In another embodiment, R' is a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group; In another embodiment, R' together with R and the atoms to which they are attached form a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, preferably a Preferred Formation In another embodiment, R' and R and the atoms to which they are attached do not form a ring.

[0185] In a more specific embodiment, R' is selected from H, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl; In another more specific embodiment, R' is selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0186] R a 、R b and R c

[0187] In one embodiment, R a is H; in another embodiment, R a C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R a C 1-10 Halogenated alkyl, preferably C 1-6 haloalkyl; in another embodiment, R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group, preferably a 5-7 membered heterocyclic group; in another embodiment, R b 、R c and the atoms to which they are connected do not form a ring.

[0188] In a more specific embodiment, R a 、R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0189] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. D Any technical solution or any combination thereof can be combined with U1, U2, U3, W1, W2, W3, L, L1, L2, L3, n, R, R', ring A, ring B, R1, R2, R1s 、R 2s ,m,s,L4,L5,R3,R4,R'4,X,R a 、R b and R c The present invention is intended to include all of these technical solutions, which are not listed one by one due to space limitations.

[0190] In a more specific embodiment, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof:

[0191] in,

[0192] R D Residues formed for drug molecules;

[0193] U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-;

[0194] W1, W2 and W3 are each independently selected from H, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0195] L is a chemical bond or Preferred

[0196] L1 is selected from a chemical bond, -C(O)-, -OC(O)-, -NR b C(O)-, -S(O)-, -S(O)2-, -OS(O) 1-2 -and-NR b S(O) 1-2 -;

[0197] L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene;

[0198] L3 is selected from O, S, NR', -C(O)-, -S(O)- and -S(O)2-;

[0199] n is selected from 0, 1, 2, 3, 4, 5 and 6;

[0200] The methylene group in is optionally substituted by 1, 2, 3, 4, 5 or 6 independent R;

[0201] R is independently selected from H, D, halogen, CN, ═O, —OR a 、-SR a 、-NR b R c 、-C 0-10 Alkylene-C(O)R a 、-C 0-10 Alkylene-OC(O)R a 、-C 0-10 Alkylene-C(O)OR a 、-C 0-10 Alkylene-NR b C(O)R a 、-C 0-10 Alkylene-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0202] R' is selected from H, C 1-18 Alkyl, C 1-18 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, or R' together with R and the atoms to which they are attached form a 3-10 membered heterocyclyl;

[0203] R a 、R b and R c Each independently selected from H, C 1-10 Alkyl and C 1-10 Haloalkyl, or R b With R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group;

[0204] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0205] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R DThe drug molecule is an anti-inflammatory drug and its derivatives, preferably a non-steroidal anti-inflammatory drug and its derivatives, such as loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetin, bromfenac, thiaprofen, indomethacin, sulindac, ketorolac, nimesulide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, naproxen, etodolac, rofecoxib, celecoxib, piroxicam, meloxicam and oxyphenbutazone, and their derivatives.

[0206] In a more specific embodiment, the drug molecule is selected from loxoprofen, flurbiprofen, indomethacin, mefenamic acid, clofenamic acid and aspirin, and their derivatives; preferably selected from flurbiprofen and clofenamic acid, and their derivatives; preferably flurbiprofen and its derivatives; preferably, the flurbiprofen is S-flurbiprofen; preferably, the flurbiprofen is R-flurbiprofen.

[0207] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-, preferably O.

[0208] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 Halogenated alkyl, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Deuterated alkyl, preferably methyl or CD3, preferably C 1-6 Alkyl group, preferably methyl group.

[0209] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a chemical bond, -C(O)-, -OC(O)- and -NHC(O)-, preferably selected from a chemical bond, -C(O)- and -OC(O)-, preferably selected from -C(O)- and -OC(O)-, preferably -C(O)-.

[0210] In a more specific embodiment, L1 is selected from -C(O)-, -OC(O)-, and -NHC(O)-; preferably -OC(O)- and -NHC(O)-; preferably -OC(O)-.

[0211] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from a chemical bond, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene, preferably selected from chemical bonds, phenylene and 5-6 membered heteroarylene, preferably selected from chemical bonds and phenylene, preferably selected from chemical bonds, Preferably selected from chemical bonds and Chemical bonds are preferred.

[0212] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from O, S and NR'; preferably selected from O and NR'; preferably O and S; preferably O; preferably NR'.

[0213] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1, 2 and 3, preferably selected from 1, 2 and 3, preferably 1 or 2, preferably 1.

[0214] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: The methylene group in is optionally substituted by 1, 2 or 3 independent R groups, preferably is optionally substituted by 1 R group.

[0215] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from H, D, halogen, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a 、-C 0-6 Alkylene-OC(O)R a 、-C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a ; preferably selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a ; preferably selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a ; preferably selected from H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a ; preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a ; preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a ; preferably selected from H, D, =O and -C 0-3 Alkylene-C(O)OH.

[0216] In a more specific embodiment, R is independently selected from H, =O, methyl, isobutyl, -C(O)OH and -(CH2)2C(O)OH; preferably selected from H, =O, methyl, -C(O)OH and -(CH2)2C(O)OH; preferably selected from H, =O, methyl and -(CH2)2C(O)OH; preferably selected from H, =O and -(CH2)2C(O)OH.

[0217] In more specific embodiments, R is independently selected from H, D, halogen, C1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H, D, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably selected from H and Me.

[0218] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R' is selected from H, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably H.

[0219] In a more specific embodiment, R' together with R and the atoms to which they are attached form a 3-10 membered heterocyclyl, preferably a 3-7 membered heterocyclyl, preferably a 4-6 membered heterocyclyl, preferably Preferred Formation

[0220] In more specific embodiments, R' and R and the atoms to which they are attached do not form a ring.

[0221] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R a 、R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably H.

[0222] In a more specific embodiment, R b With R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group.

[0223] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R D for Preferably

[0224] in,

[0225] Ring A is selected from C 6-10 Arylene, 5-10 membered heteroarylene, C 6-10 Aryl C 5-10 Cycloalkyl, C 6-10 Aryl and 5-10 membered heterocyclic group, 5-10 membered heteroaryl and C 5-10 Cycloalkyl and 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0226] Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 6-10 Aryl and 5-10 membered heteroaryl, or -L4-ring B and R2 are absent;

[0227] R1 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a 、C 1-18 Alkyl, C 1-18 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 1s replace;

[0228] R 1s Independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0229] m = 0, 1, 2, 3, 4 or 5;

[0230] R2 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a 、C 1-18 Alkyl, C 1-18 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 2s replace;

[0231] R 2s Independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0232] s = 0, 1, 2, 3, 4, or 5;

[0233] L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)-, -OC(O)-, -C(O)O-, -NR b C(O)-、-C(O)NR b -, -S(O)- and -S(O)2-;

[0234] Or L4 and the carbon atom on ring A to which L4 is attached together form

[0235] L5 is selected from the group consisting of chemical bonds, O, S, NR' and C 1-10 Alkylene, optionally substituted by one or more independent R3;

[0236] R3 is independently selected from H, D, halogen, C 1-10 Alkyl and C 1-10 alkyl halide;

[0237] R4 and R'4 are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0238] X is selected from -C(O)-, -S(O)- and -S(O)2-, preferably -C(O)-.

[0239] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C 6-10 Arylene and 5-10 membered heteroarylene; preferably selected from phenylene and 9-10 membered heteroarylene; preferably selected from phenylene and indolylene; preferably phenylene; preferably selected from Preferably selected from Preferred

[0240] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably selected from phenyl and 5-6 membered heteroaryl; preferably C 6-10 Aryl, preferably phenyl.

[0241] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c、-S(O)R a 、-S(O)2R a 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, CN, -OR a 、-NRb R c 、-OC(O)R a 、-C(O)OR a 、C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, -OR a 、-OC(O)R a 、C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, F, Me, -OMe and -OC(O)CH3.

[0242] In more specific embodiments, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably H, D and halogen; preferably H or F; preferably halogen; preferably F.

[0243] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably selected from H, Cl and Me; preferably selected from H and Cl.

[0244] In more specific embodiments, R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably selected from H, D and halogen; more preferably H or D.

[0245] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 1s and R 2s Each independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0246] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein m = 0, 1, 2, 3 or 4; preferably m = 0, 1 or 2; preferably m = 0 or 1; preferably m = 1.

[0247] In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein s=0, 1 or 2; preferably s=0.

[0248] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)- and -S(O-); preferably selected from chemical bonds, -CR4R'4-, -NR b -, O and -C(O)-; preferably selected from chemical bonds, -NR b - and -C(O)-; preferably selected from a chemical bond, -NH- and -C(O)-; preferably selected from a chemical bond and -NH-; preferably a chemical bond.

[0249] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein L5 is a chemical bond or C 1-10 Alkylene, preferably a chemical bond or C 1-6 Alkylene, preferably a chemical bond or C 1-4 Alkylene, preferably a chemical bond or C 1-2 Alkylene, preferably a chemical bond or methylene, preferably -CH(CH3)-;

[0250] Preferably, L5 is optionally substituted with 1, 2, 3, 4, 5 or 6 independent R3, preferably optionally substituted with 1, 2 or 3 independent R3, preferably optionally substituted with 1 R3.

[0251] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-4 Alkyl and C 1-4 Haloalkyl; preferably selected from H and Me; preferably Me.

[0252] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and R'4 are independently selected from H, D, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably H or D.

[0253] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, having the following structure:

[0254] Wherein, each variable is as defined herein.

[0255] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof,

[0256] in,

[0257] Ring A is selected from C 6-10 Arylene and 5-10 membered heteroarylene;

[0258] Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, or -L4-ring B and R2 are absent;

[0259] R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR bR c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 independent R 1s replace;

[0260] R 1s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups;

[0261] m = 0, 1, 2, 3, 4 or 5;

[0262] R2 is selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 independent R 2s replace;

[0263] R2s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups;

[0264] s = 0, 1, 2, 3, 4, or 5;

[0265] L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)- and -S(O)-;

[0266] L5 is a chemical bond or C 1-6 Alkylene, optionally substituted with 1, 2, 3, 4, 5, or 6 independent R3;

[0267] R3 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0268] R4 and R'4 are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0269] U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-;

[0270] W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0271] L is a chemical bond or

[0272] L1 is selected from a chemical bond, -C(O)-, -OC(O)- and -NHC(O)-;

[0273] L2 is selected from chemical bonds, C 3-7Cycloalkylene, 3-7 membered heterocyclyl, phenylene and 5-6 membered heteroarylene;

[0274] L3 is selected from O, S and NR';

[0275] n is selected from 0, 1, 2, 3, 4, 5 and 6;

[0276] The methylene group in is optionally substituted by 1, 2 or 3 independent R;

[0277] R is independently selected from H, D, halogen, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a 、-C 0-6 Alkylene-OC(O)R a 、-C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a , preferably selected from H, D, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a ;

[0278] R' is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, or R' and R together with the atoms to which they are attached form a 3-7 membered heterocyclyl;

[0279] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R b With R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group;

[0280] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0281] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0282] Ring A is selected from C 6-10 Arylene and 5-10 membered heteroarylene, preferably selected from phenylene and 9-10 membered heteroarylene;

[0283] Ring B is selected from C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from phenyl and 5-6 membered heteroaryl; preferably C 6-10 Aryl, preferably phenyl, or -L4-ring B and R2 are absent;

[0284] R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, halogen, CN, -OR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a 、C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, halogen, -OR a 、-OC(O)R a 、C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, D and halogen, optionally substituted by 1, 2 or 3 independent R 1s replace;

[0285] R 1s Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0286] m=0, 1, 2, 3, 4 or 5, preferably m=0, 1 or 2;

[0287] R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)Ra 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, D and halogen, optionally substituted by 1, 2 or 3 independent R 2s replace;

[0288] R 2s Independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0289] s=0, 1, 2, 3, 4 or 5, preferably s=0, 1 or 2;

[0290] L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O and -C(O)-, preferably selected from chemical bonds, -NR b - and -C(O)-;

[0291] L5 is a chemical bond or C 1-4 Alkylene, preferably a chemical bond or C 1-2 Alkylene, optionally substituted by 1, 2 or 3 independent R3;

[0292] R3 is independently selected from H, D, C 1-4 Alkyl and C 1-4 alkyl halide;

[0293] R4 and R'4 are independently selected from H, D, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H and D;

[0294] U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-, preferably O;

[0295] W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 Halogenated alkyl, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl, preferably C1-6 Alkyl or C 1-6 Deuterated alkyl, preferably C 1-6 alkyl;

[0296] L is a chemical bond or

[0297] L1 is selected from a chemical bond, -C(O)- and -OC(O)-, preferably selected from -C(O)- and -OC(O)-, preferably -C(O)-;

[0298] L2 is selected from a chemical bond, a phenylene group and a 5-6 membered heteroarylene group, preferably selected from a chemical bond and a phenylene group;

[0299] L3 is selected from O and NR', preferably NR'; preferably O;

[0300] n is selected from 0, 1, 2 and 3, preferably selected from 1, 2 and 3, preferably 1 or 2, preferably 1;

[0301] The methylene group in is optionally substituted by 1, 2 or 3 independent R, preferably optionally substituted by 1 R;

[0302] R is independently selected from H, D, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, ═O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, ═O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, ═O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a , preferably selected from H, D, ═O and —C 0-3 Alkylene-C(O)OH;

[0303] R' is selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, or R' and R and the atoms to which they are attached together form a 4-6 membered heterocyclic group; preferably, R' and R do not form a ring;

[0304] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl and C1-6 Halogenated alkyl.

[0305] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0306] Ring A is selected from phenylene and indoleyl, preferably selected from Preferably phenylene, preferably selected from

[0307] Ring B is phenyl, or -L4-ring B and R2 are absent;

[0308] R1 is independently selected from H, F, Me, -OMe and -OC(O)CH3, preferably H or F;

[0309] m = 0, 1, or 2;

[0310] R2 is independently selected from H, Cl and Me, preferably selected from H and Cl;

[0311] s = 0, 1, or 2;

[0312] L4 is selected from a chemical bond, -NH- and -C(O)-; preferably selected from a chemical bond and -NH-; preferably a chemical bond;

[0313] L5 is a chemical bond or a methylene group, which is optionally substituted by one R3; preferably, L5 is -CH(CH3)-;

[0314] R3 is independently selected from H and Me; preferably Me;

[0315] U1, U2 and U3 are 0;

[0316] W1, W2 and W3 are methyl or CD3, preferably methyl;

[0317] L is a chemical bond or

[0318] L1 is selected from a chemical bond, -C(O)- and -OC(O)-;

[0319] L2 is selected from chemical bonds,

[0320] L3 is selected from O and NR';

[0321] n is 0, 1, 2, and 3;

[0322] The methylene group in is optionally substituted by 1 R;

[0323] R is independently selected from H, =O, methyl, isobutyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl and -(CH2)2C(O)OH, preferably selected from H, =O and -(CH2)2C(O)OH;

[0324] R' is H, or R' together with R and the atoms to which they are attached form Preferred Formation

[0325] In a more specific embodiment, Selected from the following structures:

[0326] Preferably selected from Preferably selected from

[0327] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof,

[0328] in,

[0329] R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 1s replace;

[0330] R 1s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0331] m = 0, 1, 2, 3, or 4;

[0332] R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、C 1-10Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 2s replace;

[0333] R 2s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0334] s = 0, 1, 2, 3, 4, or 5;

[0335] U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-;

[0336] W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Halogenated alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups;

[0337] L is a chemical bond or

[0338] L1 is selected from a chemical bond, -C(O)-, -OC(O)- and -NHC(O)-;

[0339] L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene;

[0340] L3 is selected from O, S and NR';

[0341] n is selected from 0, 1, 2, 3, 4, 5 and 6;

[0342] The methylene group in is optionally substituted by 1, 2 or 3 independent R;

[0343] R is independently selected from H, D, halogen, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6Alkylene-C(O)OR a 、-C 0-6 Alkylene-OC(O)R a 、-C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a , preferably selected from H, D, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a ;

[0344] R' is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, or R' and R together with the atoms to which they are attached form a 3-7 membered heterocyclyl;

[0345] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, or R b With R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group;

[0346] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0347] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0348] R1 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, D and halogen, optionally substituted by 1, 2 or 3 independent R 1s replace;

[0349] R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0350] m=0, 1, 2, 3 or 4, preferably m=0, 1 or 2;

[0351] R2 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D and halogen, more preferably H or D, optionally substituted by 1, 2 or 3 independent R 2s replace;

[0352] R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0353] s=0, 1, 2, 3, 4 or 5, preferably s=0, 1 or 2;

[0354] U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-, preferably O;

[0355] W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 Halogenated alkyl, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Deuterated alkyl, preferably C 1-6 alkyl;

[0356] L is a chemical bond or

[0357] L1 is selected from a chemical bond, -C(O)- and -OC(O)-, preferably selected from -C(O)- and -OC(O)-, preferably -C(O)-;

[0358] L2 is selected from a chemical bond, a phenylene group and a 5-6 membered heteroarylene group, preferably selected from a chemical bond and a phenylene group;

[0359] L3 is selected from O and NR', preferably NR'; preferably O;

[0360] n is selected from 0, 1, 2 and 3, preferably selected from 1, 2 and 3, preferably 1 or 2, preferably 1;

[0361] The methylene group in is optionally substituted by 1, 2 or 3 independent R, preferably optionally substituted by 1 R;

[0362] R is independently selected from H, D, ═O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, ═O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, ═O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, ═O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a , preferably selected from H, D, ═O and —C 0-3 Alkylene-C(O)OH;

[0363] R' is selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, or R' and R and the atoms to which they are attached together form a 4-6 membered heterocyclic group; preferably, R' and R do not form a ring;

[0364] R a Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0365] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0366] R1 is H or F; m=1;

[0367] R2 is H; s=0;

[0368] U1, U2 and U3 are 0;

[0369] W1, W2 and W3 are methyl or CD3, preferably methyl;

[0370] L is a chemical bond or

[0371] L1 is selected from a chemical bond, -C(O)- and -OC(O)-;

[0372] L2 is selected from chemical bonds,

[0373] L3 is selected from O and NR';

[0374] n is 0, 1, 2, and 3;

[0375] The methylene group in is optionally substituted by 1 R;

[0376] R is independently selected from H, =O, methyl, isobutyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl and -(CH2)2C(O)OH, preferably selected from H, =O and -(CH2)2C(O)OH;

[0377] R' is H, or R' together with R and the atoms to which they are attached form Preferred Formation

[0378] In more specific embodiments, L is selected from a chemical bond, Preferably selected from: chemical bonds, Preferably selected from: chemical bonds, Preferably selected from: chemical bonds, Preferably selected from: chemical bonds,

[0379] In a more specific embodiment, for

[0380] In a more specific embodiment, for

[0381] In a more specific embodiment, for

[0382] In a more specific embodiment, for

[0383] In a more specific embodiment, for

[0384] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof,

[0385] The definitions of the variables are as defined in this article.

[0386] In a more specific embodiment, for

[0387] In a more specific embodiment, for

[0388] In a more specific embodiment, the present invention provides a compound of formula (II), formula (III) or formula (III-1) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0389] L is

[0390] L1 is selected from -C(O)-, -OC(O)- and -NHC(O)-; preferably -OC(O)- and -NHC(O)-; preferably -OC(O)-;

[0391] L2 is a chemical bond;

[0392] L3 is selected from O, S and NR'; preferably O and S; preferably O;

[0393] n is selected from 1, 2 and 3, preferably 1 or 2, preferably 1;

[0394] The methylene group in is optionally substituted by 1, 2 or 3 (preferably 1) independent R;

[0395] R is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H, D, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-3Alkyl and C 1-3 Haloalkyl; preferably selected from H and Me;

[0396] The remaining groups are as defined in the present invention;

[0397] Preferably, L is

[0398] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

[0399] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0400] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0401] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0402] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0403] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0404] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0405] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0406] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0407] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0408] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0409] Pharmaceutical compositions and kits

[0410] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0411] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0412] Suitable formulations for administering the compounds of the present invention will be readily apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (particularly solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injection)), elixirs, syrups, cachets, emulsions, inhalants, or dispersible powders. The content of the one or more pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times a day.

[0413] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0414] Drug administration

[0415] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0416] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0417] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0418] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0419] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0420] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0421] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0422] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0423] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0424] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0425] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0426] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0427] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0428] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0429] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0430] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0431] Indications

[0432] The compounds of this invention can exert therapeutic effects through sedative or sleep-inducing effects, potentially benefiting a wide range of patients with central nervous system-related diseases. They also exhibit excellent analgesic, antidepressant, and anti-addiction properties and can be used to prepare analgesic, antidepressant, and anti-addiction drugs.

[0433] In one embodiment, the pain is selected from neuralgia, perioperative pain (including pain before, during or after surgery, for example, somatic or visceral pain caused by postoperative trauma, postoperative incision, pain caused by visceral injury and other comprehensive pain) and cancer pain (such as pain caused by cancer).

[0434] In one embodiment, the pain is acute pain or chronic pain (including acute / chronic pain before, during or after surgery, acute neuropathic pain or chronic neuropathic pain).

[0435] In one embodiment, the neuropathic pain is central pain, such as spinal pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain.

[0436] In one embodiment, the postoperative pain is pain caused by surgery, such as pain caused by abdominal surgery, orthopedic surgery, cesarean section, brain surgery or other surgery.

[0437] Example

[0438] The following will be combined with the accompanying drawings to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field based on the present invention are within the scope of protection of the present invention.

[0439] Abbreviations:

[0440] PE: petroleum ether;

[0441] EA: ethyl acetate;

[0442] DMAP: 4-dimethylaminopyridine;

[0443] DCM: dichloromethane;

[0444] DMF: N,N-dimethylformamide;

[0445] DCC: dicyclohexylcarbodiimide;

[0446] DBU: 1,8-diazobisspiro[5.4.0]undec-7-ene;

[0447] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide;

[0448] DIEA: N,N-diisopropylethylamine;

[0449] EtOH: ethanol;

[0450] Et3N: triethylamine;

[0451] HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate;

[0452] ACN: acetonitrile;

[0453] THF: tetrahydrofuran;

[0454] rt: room temperature;

[0455] LCMS: liquid chromatography-mass spectrometry;

[0456] TLC: thin layer chromatography.

[0457] The present invention is described in detail below with reference to specific examples. The synthesis method of the compound of the present invention is not particularly limited and can be synthesized by any method known to those skilled in the art.

[0458] Example 1

[0459] Synthesis of 1-1

[0460] To a 500ml reaction flask, 20.0g (1.0eq) of 1-SM and 200ml of dichloromethane were added. Under nitrogen, 8g of triethylamine was added dropwise. Under an ice bath, 18g of trifluoromethanesulfonic anhydride was added dropwise, and the mixture was warmed to room temperature and stirred overnight. LC / MS confirmed the completion of the reaction. 200ml of purified water was added to the reaction solution, stirred, and the layers separated. The aqueous phase was extracted with 100ml of dichloromethane. The combined dichloromethane phases were washed with 150ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The 330g sample residue was purified on a silica gel column to yield 1-1 (26.97g) in a 94.8% yield. MS: 474. 1 H NMR (400MHz, DMSO-d6) δ7.30(d,J=8.5Hz,1H),7.11(d,J=8.6Hz,1H),6.89(s,1H),6.70(s,1H),4.13(d,J=16.1Hz,1H),3.83(s,3H) ,3.74(d,J=9.4Hz,6H),3.53(dd,J=16.5,6.6Hz,3H),3.15(dd,J=11.1,3.7Hz,1H),2.99–2.86(m,1H),2.63(dd,J=15.6,9.6Hz,3H).

[0461] Example 2

[0462] Synthesis of 3-1

[0463] In a 1 L reaction flask, add 20.0 g (1.0 eq) of 1-1, tert-butyl carbamate, tripotassium phosphate, tris(dibenzylideneacetone)dipalladium(0), 2-(biphenyl)di-tert-butylphosphine, and 200 ml of 1,4-dioxane. Heat the temperature to 90°C under nitrogen and stir overnight. After LC / MS analysis of the reaction, filter the reaction mixture and rinse the filter cake with 50 ml of EA. Concentrate to dryness and purify the residue on a silica gel column to yield 22.0 g of 3-1 as a yellow solid, which is used directly in the next step.

[0464] Synthesis of Example 2

[0465] To a 50ml reaction flask, add 2.5g of 3-1 and 10ml of dichloromethane, add 10ml of hydrochloric acid dioxane solution dropwise, and stir at room temperature overnight. LC / MS detection shows that the reaction is complete, concentrate to dryness, add 20ml of DCM, and then add 20ml of saturated sodium carbonate solution to adjust the pH to alkaline. Separate the layers, wash the DCM phase with 20ml of saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate. The sample residue is purified on a silica gel column to obtain 1.05g of solid Example 2, with a yield of 54.4%. MS: 326, 1 H NMR (400MHz, DMSO-d6) δ6.85 (s, 1H), 6.67 (s, 1H), 6.65 (d, J = 8.0Hz, 1H), 6.55 (d,J=8.0Hz,1H),4.65(s,2H),4.05–4.01(m,1H),3.74(s,3H),3.72(s,3H),3. 63(s,3H),3.41–3.35(m,2H),3.27(dd,J=16.0Hz,4.0Hz,1H),3.10(dd,J=12. 0Hz, 4.0Hz, 1H), 2.97–2.89 (m, 1H), 2.60 (d, J = 16.0Hz, 1H), 2.48-2.42 (m, 2H).

[0466] Example 3

[0467] Synthesis of Example 3

[0468] Example 2 (400 mg, 1 eq) was added to 10 ml of DCM. DMAP (158 mg, 1.1 eq) and flurbiprofen (344 mg, 1.2 eq) were added at room temperature, followed by EDCI-HCl (451 mg, 2 eq). The mixture was stirred at room temperature overnight. LCMS analysis revealed no residual starting material. The product was quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and spin-dried. Purification by Prep-TLC afforded 220 mg of the product. MS: 567, 1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),7.64(d,J=8.3Hz,1H),7.50(dt,J=22.5,7.8Hz,5H),7 .42–7.34(m,3H),6.93–6.86(m,2H),6.68(s,1H),4.16(q,J=6.9Hz,1H),4.07(d,J=15.7Hz, 1H),3.74(s,3H),3.72(s,3H),3.53(s,3H),3.47–3.38(m,3H),3.16–3.08(m,1H),2.92(d,J =10.8Hz, 1H), 2.58 (dd, J = 25.3, 14.9Hz, 3H), 2.47 (d, J = 11.5Hz, 1H), 1.47 (d, J = 7.0Hz, 3H).

[0469] Example 4

[0470] The synthesis method is the same as in Example 3, MS: 567, 1 H NMR(400MHz,DMSO-d6)δ9.45(s,1H),7.64(d,J=8.3Hz,1H),7.50(dt,J=22.5,7.8Hz,5H),7 .42–7.34(m,3H),6.93–6.86(m,2H),6.68(s,1H),4.16(q,J=6.9Hz,1H),4.07(d,J=15.7Hz, 1H),3.74(s,3H),3.72(s,3H),3.53(s,3H),3.47–3.38(m,3H),3.16–3.08(m,1H),2.92(d,J =10.8Hz, 1H), 2.58 (dd, J = 25.3, 14.9Hz, 3H), 2.47 (d, J = 11.5Hz, 1H), 1.47 (d, J = 7.0Hz, 3H).

[0471] Example 5

[0472] The synthesis method is the same as in Example 3, MS: 567, 1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),7.64(d,J=8.3Hz,1H),7.50(dt,J=22.5,7.8Hz,5H),7 .42–7.34(m,3H),6.93–6.86(m,2H),6.68(s,1H),4.16(q,J=6.9Hz,1H),4.07(d,J=15.7Hz, 1H),3.74(s,3H),3.72(s,3H),3.53(s,3H),3.47–3.38(m,3H),3.16–3.08(m,1H),2.92(d,J =10.8Hz, 1H), 2.58 (dd, J = 25.3, 14.9Hz, 3H), 2.47 (d, J = 11.5Hz, 1H), 1.47 (d, J = 7.0Hz, 3H).

[0473] Example 6

[0474] Synthesis of Example 6

[0475] Example 2 (200 mg, 1 eq) was added to 5 ml of DMF. DIEA (759 mg, 10 eq) and indomethacin (252 mg, 1.2 eq) were added at room temperature, followed by a DMF solution of HATU (268 mg, 1.2 eq). LCMS analysis revealed no residual starting material. Purification by reverse-phase column chromatography afforded 282 mg of the product from Example 6. MS: 680, 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 8.36 (s, 1H), 7.67 (q, J = 8.6, 7.4Hz, 5H), 7.27 (d, J = 2.0 Hz,1H),6.94(d,J=9.0Hz,1H),6.89(d,J=11.1Hz,2H),6.73(dd,J=9.0,2.5Hz,1H),6.68(s,1 H),4.07(d,J=15.8Hz,1H),3.87(s,2H),3.77–3.72(m,9H),3.59(s,3H),3.46(s,1H),3.42( d,J=11.7Hz,2H),3.19–3.07(m,1H),2.93(t,J=11.2Hz,1H),2.66–2.55(m,2H),2.32(s,3H).

[0476] Example 7

[0477] Synthesis of Example 7

[0478] Dissolve 200 mg of Example 2 in 4 ml of dichloromethane, add 128 mg of 11-SM, and under nitrogen protection, add 195 mg of DMAP in an ice-water bath. Add a dichloromethane solution of 121 mg of DCC to the reaction mixture and stir overnight at room temperature. Wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and perform medium-pressure column chromatography. The eluate is concentrated and lyophilized to obtain 125.32 mg of Example 7. MS: 563, 1 HNMR(400MHz,DMSO-d6)δ9.94(s,1H),9.26(s,1H),7.89(d,J=7.8Hz,1H),7.47(d,J=8.2Hz,1H), 7.32(t,J=7.1Hz,1H),7.11–7.03(m,2H),7.01–6.81(m,5H),6.70(s,1H),4.10(d,J=15.4Hz,1H), 3.78–3.69(m,9H),3.48(d,J=13.4Hz,3H),2.68–2.56(m,2H),2.27(s,3H),2.09(s,3H),1.24(s,5H).

[0479] Example 8

[0480] Synthesis of Example 8

[0481] Example 2 (200 mg, 1 eq) was added to 5 ml of DCM. 12-2 (169 mg, 1.02 eq) and DMAP (215 mg, 3 eq) were added at room temperature, followed by the dropwise addition of a DCM solution of DCC (145.4 mg, 1.2 eq). The mixture was stirred at room temperature overnight. LCMS analysis indicated no residual starting material. The product was post-processed by quenching with water, extracting with DCM, drying over anhydrous sodium sulfate, concentrating, and then purified using a reverse-phase column to afford 170 mg of the product of Example 8. MS: 604. 1H NMR (400MHz, DMSO-d6) δ10.04(s,1H),9.72(s,1H),8.34(s,1H),7.95(d,J=7.7Hz,1H),7.49(t,J=7.6Hz,1H) ,7.43-7.38(m,3H),7.28(t,J=8.1Hz,1H),7.19(d,J=7.9Hz,1H),7.10(t,J=7.5Hz,1H),6.98(d,J=8.2Hz,1H ),6.91(s,1H),6.69(s,1H),5.60(d,J=8.0Hz,1H),4.10(d,J=15.7Hz,1H),3.76(s,3H),3.73(s,3H),3.69(s ,3H),3.51–3.44(m,3H),3.36–3.29(m,1H),3.14(d,J=6.5Hz,1H),2.95(t,J=11.2Hz,1H),2.65-2.59(m,2H).

[0482] Example 9

[0483] Synthesis of 14-1

[0484] Dissolve 96 mg of 14-SM in 4 ml of DCM, add 169 mg of oxalyl chloride, and stir under ice-water bath. After 5 minutes, remove the ice-water bath and stir at room temperature for 30 minutes. The reaction mixture is concentrated, and the concentrate of 14-1 is used directly in the next reaction.

[0485] Synthesis of Example 9

[0486] Dissolve 200 mg of Example 2 in 4 ml of DCM, add 593 mg of triethylamine, and stir at room temperature. Dissolve 14-1 obtained in the previous step in 2 ml of ultra-dry DCM and add dropwise to the above reaction solution. Stir at room temperature for 30 min, wash once with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column to obtain 158.21 mg of solid Example 9. MS: 502, mang 1H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 7.79 (d, J = 7.4Hz, 1H), 7.59 (t, J = 6.9H z,2H),7.41(t,J=7.6Hz,1H),7.26(d,J=8.0Hz,1H),6.98(d,J=8.2Hz,1H),6 .90(d,J=4.5Hz,1H),6.69(d,J=4.4Hz,1H),4.11(d,J=15.5Hz,1H),3.84–3 .71(m,12H),3.46(s,3H),2.64(d,J=13.8Hz,2H),2.25(s,3H),1.23(s,3H).

[0487] Example 10

[0488] Synthesis of 15-1

[0489] Dissolve 200 mg of Example 2 and 160 mg of isobenzofuranone in 5 ml of ultra-dry THF. Add 1.1 ml of n-butyllithium solution under nitrogen and stir in an ice-water bath. After 30 minutes, quench the reaction with water. Dilute with 50 ml of EA, wash twice with water, and once with saturated brine. Dry, filter, and concentrate. Purify by diluting with DCM and eluting on an 80 g prepacked silica gel column with 0-3% MeOH / DCM to yield 320 mg of compound 15-1.

[0490] Synthesis of Example 10

[0491] Dissolve 320 mg of 15-1 in 5 ml of ultra-dry DCM, add 165 mg of DMAP and 167 mg of DCC in an ice-water bath, and stir in an ice-water bath. After 30 min, add 165 mg of S-flurbiprofen and stir at room temperature overnight. The reaction solution was filtered, the filter cake was washed twice with DCM, the organic phase was washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification: dilute with DCM, elute with 45 g of pre-loaded silica gel column, 0-3% MeOH / DCM, collect and concentrate, and freeze-dry to obtain 138.1 mg of solid, which was purified by reverse phase column chromatography and freeze-dried to obtain 24.98 mg of Example 10. MS: [M+H] 701; 1H NMR(400MHz,DMSO-d6)δ9.742(s,1H),7.661-7.646(m,1H),7.533-7.375(m,10H),7.253-7.197(m,2H ),6.48(d,J=8.4Hz,1H),6.889(s,1H),6.696(s,1H),5.384(d,J=13.6Hz,1H),5.336(d,J=12.8Hz,1H ),4.092(d,J=15.6Hz,1H),3.939(q,J=7.6Hz,1H),3.764(s,3H),3.735(s,3H),3.722(s,3H),3.482- 3.426(m,3H),3.150-3.114(m,1H),2.971-2.913(m,1H),2.669-2.564(m,3H),1.440(d,J=7.2Hz,3H).

[0492] Example 11

[0493] Synthesis of 18-1

[0494] 18-SM (300 mg, 1 eq) was added to DMF and fully dissolved. HATU (762 mg, 1.1 eq) and DIEA (938 mg, 4 eq) were then added and stirred at 40°C for 1 hour. Benzyl alcohol (196 mg, 1 eq) was added to the reaction system and stirred for 2 hours to obtain the desired product. The reaction solution was washed with water and saturated brine, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 18-1 (330 mg).

[0495] Synthesis of 18-2

[0496] 18-1 (300 mg, 1.2 eq) and s-flurbiprofen (238 mg, 1 eq) were dissolved in ACN, and K2CO3 (404 mg, 3 eq) was added, followed by stirring for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 18-2 (420 mg).

[0497] Synthesis of 18-3

[0498] 18-2 (400 mg) was dissolved in methanol (3 ml), palladium hydroxide on carbon was added, H2 was replaced, and the mixture was stirred at room temperature for 3 h. Liquid chromatography-mass spectrometry was performed to obtain the desired product. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 18-3 (200 mg).

[0499] Synthesis of Example 11

[0500] 18-3 (200 mg, 1 eq) was dissolved in DCM, oxalyl chloride (152 mg, 2 eq) and one drop of DMF were added, and the mixture was stirred for 2 h. The mixture was concentrated to dryness under reduced pressure and then redissolved in DCM. The mixture was added to a solution of Example 2 (165 mg, 0.8 eq) in DCM. After the reaction was complete, the organic phase was washed with water and saturated sodium chloride, concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain Example 11 (33 mg). MS: 653, 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.54–7.38 (m, 6H ),7.23(dd,J=16.0,12.0Hz,2H),6.89(s,2H),6.69(s,1H),4.15–4.05(m,3H) ,3.88(d,J=8.0Hz,1H),3.75–3.73(m,8H),3.64(s,3H),3.45–3.41(m,4H),3. 15–3.10(m,1H),2.99–2.91(m,1H),1.91–1.87(m,2H),1.44(d,J=8.0Hz,3H).

[0501] Example 12

[0502] Synthesis of 19-1

[0503] 19-SM (300 mg, 1 eq) was added to ethanol, and thionyl chloride (448 mg, 2 eq) was added dropwise. The mixture was stirred for 1 hour and concentrated to dryness under reduced pressure to obtain 19-1 (160 mg). MS: 188.

[0504] Synthesis of 19-2

[0505] s-Flurbiprofen (200 mg, 1 eq) was dissolved in DCM, and 19-1 (153 mg, 1 eq), EDCI (187 mg, 1.2 eq), and DMAP (0 mg, 0.1 eq) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to dryness, and the residue was purified by column chromatography to give 19-2 (200 mg). MS: 414.

[0506] Synthesis of 19-3

[0507] Dissolve 19-2 (200 mg) in a 1:1:1 mixture of methanol, tetrahydrofuran, and water. Add lithium hydroxide monohydrate (101 mg, 5 eq) and stir for 1 hour. Adjust the pH of the reaction mixture to neutral with dilute hydrochloric acid, extract with ethyl acetate, and concentrate to dryness under reduced pressure to obtain 200 mg of crude 19-3. MS: 386.

[0508] Synthesis of Example 12

[0509] The crude product of 19-3 (150 mg) was dissolved in DCM, and Example 2 (130 mg, 1 eq), EDCI (87 mg, 1.2 eq), and DMAP (5 mg, 0.1 eq) were added. The mixture was stirred for 2 h. After the reaction was complete, the reaction solution was extracted with dichloromethane and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain Example 12 (139.7 mg). MS: 708, 1 H NMR(400MHz, DMSO-d6)δ9.28(d,J=8.0Hz,1H),8.05(s,1H),7.66(d,J=8.0Hz,1H),7.50–7.37 (m,6H),7.26–7.24(m,2H),6.90(d,J=8.0Hz,2H),6.69(s,1H),4.08(d,J=16.0Hz,1H),3.75– 3.65(m,10H),3.46–3.41(m,3H),3.14–2.91(m,4H),2.69–2.58(m,2H),2.54–2.46(m,1H),2. 29–2.28(m,2H),2.05–1.99(m,1H),1.66–1.61(m,1H),1.38–1.30(m,4H),0.85–0.74(m,7H).

[0510] Example 13

[0511] Synthesis of 20-1

[0512] 200mg of S-flurbiprofen was dissolved in 2ml of ultra-dry DCM under nitrogen protection, and 0.82ml of oxalyl chloride solution was added. The mixture was stirred in an ice-water bath for 30 minutes, and the reaction solution was concentrated. 85mg of γ-aminobutyric acid was dissolved in 2ml of THF, and 2ml of 2M NaOH solution was added under stirring. The previous concentrate was added to 2ml of THF and dissolved, and the mixture was added dropwise to the reaction solution. After 30 minutes, the reaction solution was concentrated. 50ml of EA was added for dilution, and the mixture was washed with water twice and saturated brine once. The mixture was dried, filtered, and concentrated. Medium-pressure preparation gave 20-1 (180mg).

[0513] Synthesis of Example 13

[0514] 116 mg of 20-1, 120 mg of Example 2, and 161 mg of HATU were dissolved in 2 ml of ultra-dry DMF, and DIEA was added with stirring. After 30 min, the reaction solution was diluted with 50 ml of water and extracted twice with DCM. The organic phases were combined, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, prepared under medium pressure, collected, concentrated, and lyophilized to obtain Example 13 (42.62 mg), MS: 651, 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.53–7.37(m,4H),7.25-7.22(m,2H),6 .90–6.85(m,2H),6.69-6.64(m,3H),6.56-6.54(d,J=8.0Hz,1H),4.66(s,2H) ,3.75-3.72(m,9H),3.66–3.63(m,5H),3.46-3.25(m,4H),3.12–3.09(m,3H) ,2.97-2.89(m,2H),2.63-2.58(m,2H),2.45-2.33(m,2H),1.38-1.34(m,2H).

[0515] Example 14

[0516] Synthesis of 21-1

[0517] s-Flurbiprofen (300mg, 1eq) is added to DCM, thionyl chloride (290mg, 2eq) is added dropwise after fully dissolving, stirred overnight, and spin-dried to obtain the acyl chloride of s-Flurbiprofen. The acyl chloride is dissolved in DCM, added to 21-SM (141mg, 1eq) and TEA (310mg, 2.5eq) and stirred at room temperature for 2 hours. The desired product is detected by liquid chromatography. The reaction solution is quenched with water and extracted three times with dichloromethane. The organic phase is washed with saturated common salt water, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure. Purification by column chromatography gives 21-1 (310mg). MS: 342.

[0518] Synthesis of Example 14

[0519] 21-1 (300 mg, 1 eq) was dissolved in DCM, and Example 2 (300 mg, 1 eq), EDCI (201 mg, 1.2 eq), and DMAP (10 mg, 0.1 eq) were added. The mixture was stirred at room temperature for 2 hours. Liquid chromatography-mass spectrometry indicated that the reaction was complete. The mixture was extracted three times with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The organic phase was purified by column chromatography using petroleum ether / ethyl acetate (1:5) to obtain the desired product Example 14 (120 mg). MS: [M+H] 664, 1 H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.71(d,J=8.0Hz,1H),7.56–7.38(m,6H) ,7.29–7.25(m,2H),6.93–6.88(m,2H),6.69(d,J=2.8Hz,1H),4.15–4.05(m,2 H),3.86–3.82(m,1H),3.75–3.73(m,9H),3.49–3.41(m,3H),3.16–3.10(m,1H ),2.98–2.91(m,1H),2.65–2.45(m,3H),2.01–1.82(m,4H),1.39–1.35(m,3H).

[0520] Example 15

[0521] Synthesis of 22-1

[0522] Dissolve 200 mg of 22-SM and 139 mg of 16-1 in 5 ml of DMF, add 178 mg of triethylamine with stirring, and stir overnight at room temperature. Dilute the reaction solution with water, adjust the pH to approximately 2 with hydrochloric acid, extract the aqueous phase twice with EA, combine the organic phases, wash twice with water and once with saturated brine, dry over anhydrous sodium sulfate, filter, and purify under medium pressure to yield 220 mg of 22-1.

[0523] Synthesis of 22-2

[0524] Dissolve 220 mg of 22-1 and 161 mg of Example 2 in 4 mL of DCM. Add anhydrous sodium carbonate with stirring, and stir overnight at room temperature. Dilute the reaction mixture with DCM, wash twice with water, once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate. Prepare 22-2 (162 mg) under medium pressure.

[0525] Synthesis of Example 15

[0526] 162 mg of 22-2 was dissolved in 4 ml of MeOH, 20 mg of palladium hydroxide was added, the mixture was purged with hydrogen three times, and the mixture was stirred at room temperature for 2 h. The reaction solution was filtered through a funnel with diatomaceous earth and concentrated. The mixture was prepared by reverse phase medium pressure, collected, concentrated, and lyophilized to obtain Example 15 (85.35 mg), MS: 696, 1 H NMR(400MHz,DMSO-d6)δ9.489(d,J=40.8Hz,1H),8.321(s,2H),7.972(s,1H),7.671(dd,J=14.4Hz, 4.8Hz,1H),7.532–7.387(m,6H),7.288–7.256(m,2H),6.903–6.853(m,2H),6.683(s,1H),4.094–4 .023(m,2H),3.851–3.841(m,1H),3.747–3.686(m,9H),3.606(s,2H),3.466–3.397(m,3H),3.136– 3.106(m,1H),2.969–2.902(m,1H),2.670–2.442(m,3H),2.008–1.828(m,2H),1.378–1.354(m,3H).

[0527] Example 16

[0528] Synthesis of 23-1

[0529] 23-SM (500 mg, 1.0 eq) was added to a single-necked vial. Under a nitrogen atmosphere and in an ice-water bath, oxalyl chloride (0.35 ml, 0.2 eq) was added dropwise. The system was stirred at room temperature for 3 h. LCMS monitoring indicated no residual starting material. The product was concentrated to dryness and used in the next step. The product content was determined using methanol.

[0530] Synthesis of 23-2

[0531] 23-1 was added to 1 ml of THF and 15 ml of aqueous ammonia was added dropwise under an ice-water bath. Stirred at room temperature overnight. LCMS showed no residual starting material. After post-treatment, the product was concentrated and dried, and then directly purified using a reverse column to obtain the product 23-2 (480 mg). MS: 244, 1 H NMR (400MHz, DMSO-d6) δ7.56–7.35(m,7H),7.23(d,J=9.3Hz,2H),6.92(s,1H),3.64(q,J=7.0Hz,1H),1.35(d,J=7.0Hz,3H).

[0532] Synthesis of 23-3

[0533] 23-2 (100 mg, 1 eq) was added to 2 mL of DCE. Oxalyl chloride (262.1 mg, 5 eq) was added dropwise under an ice-water bath and stirred at room temperature overnight. LCMS analysis indicated no residual starting material. The product was concentrated to dryness under a stream of nitrogen and used directly in the next step. MS: 316.

[0534] Synthesis of Example 16

[0535] 23-3 (crude product) was added to 1 mL of ultra-dry acetonitrile, and then added dropwise to a solution of Example 2 (153.9 mg, 1.1 eq, free form) in acetonitrile (1 mL). The system was heated at 50°C for 3 h. After post-treatment, the reaction solution was directly subjected to reverse-phase column chromatography, concentrated, and lyophilized to obtain Example 16 (67 mg). MS: 638, 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.56–7.45(m,6H),7.41–7.37(m,1H) ,7.34–7.30(m,2H),6.99–6.96(m,2H),6.73–6.70(m,1H),5.08(s,1H),4. 20–4.15(m,1H),3.76–3.74(m,6H),3.66–3.65(m,3H),3.55–3.46(m,3H), 3.21–3.16(m,1H),3.00(s,1H),2.72–2.67(m,3H),1.55(d,J=4.0Hz,3H).

[0536] Example 17

[0537] The synthetic reaction steps of Example 17 are the same as those of Example 16.

[0538] MS:638, 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.56–7.45(m,6H),7.41–7.37(m,1H) ,7.34–7.30(m,2H),6.99–6.96(m,2H),6.73–6.70(m,1H),5.08(s,1H),4. 20–4.15(m,1H),3.76–3.74(m,6H),3.66–3.65(m,3H),3.55–3.46(m,3H), 3.21–3.16(m,1H),3.00(s,1H),2.72–2.67(m,3H),1.55(d,J=4.0Hz,3H).

[0539] Example 18

[0540] Synthesis of 25-1

[0541] Dissolve 25-SM (1 g, 1.0 eq) in 17 ml of H2O and add NaHCO3 (1.06 g, 2.2 eq) at 0°C. Slowly add a solution of (Boc)2O (1.32 g, 1.06 eq) in dioxane (17 ml) dropwise at 0°C. Stir the system at room temperature overnight. LCMS monitoring revealed no residual starting material. Concentrate and adjust the pH to 3-4 with citric acid. Extract with a mixed solvent of DCM / MeOH (10:1), wash with a saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate, and spin-dry. The crude product of 25-1 was used directly in the next step. MS: 276.

[0542] Synthesis of 25-2

[0543] Example 2 (250 mg, 1.0 eq) was added to 7 ml of DCM, followed by the addition of 25-1 (243 mg, 1.2 eq) and DMAP (98.7 mg, 1.1 eq). After stirring, EDCI (282 mg, 2 eq) was added. The system was stirred at room temperature overnight. LCMS analysis showed no residual starting material. The reaction was quenched with water, extracted with DCM, washed with a saturated solution of ammonium chloride, dried over anhydrous sodium sulfate, concentrated, and spin-dried. Product 25-2 (350 mg) was purified by normal column chromatography. Yield: 79.7%, MS: 598.

[0544] Synthesis of 25-3

[0545] 25-2 (350 mg) was dissolved in 5 mL of DCM and 3 mL of 4 M HCl in 1,4-dioxane was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. LCMS analysis revealed no residual starting material. After post-treatment, the product was concentrated and spin-dried, then slurried with petroleum ether, filtered, and the filter cake was collected and dried to afford 295 mg of crude product 25-3, which was used directly in the next step. MS: 498.

[0546] Synthesis of 25-4

[0547] 25-3 (200 mg, 1 eq) was added to 6 ml of DCM. s-Flurbiprofen (118 mg, 1.2 eq) and DMAP (54 mg, 1.1 eq) were added at room temperature and stirred well. EDCI (154 mg, 2.0 eq) was then added. The mixture was stirred at room temperature for 4 h. LCMS analysis revealed no residual starting material. The reaction was quenched with water, extracted with DCM, washed with a saturated solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by prep-TLC to obtain product 25-4 (198 mg). Yield: 68.1%, MS: 724.

[0548] Synthesis of Example 18

[0549] Take 25-4 (198 mg, 1 eq) and add it to 3 ml of EtOH. Add an aqueous solution (3.2 ml) of lithium hydroxide monohydrate (16 mg, 1.5 eq). After stirring evenly, the system was heated at 60 ° C for 30 min. LCMS detection showed that no raw material remained. Concentrate, adjust the pH to 3-4 with dilute hydrochloric acid, extract with DCM, dry over anhydrous sodium sulfate, concentrate and dry. The residue was purified by reverse phase column. Concentrate and lyophilize to obtain Example 18 (123 mg). Yield: 63.7%, MS: 696, HNMR: 1H NMR(400MHz, DMSO-d6)δ9.18(s,1H),8.66(d,J=8.0Hz,1H),8.36(s,1H),7.66(d,J=8.0Hz,1H),7.54–7.36(m,6H),7 .30–7.24(m,2H),6.89–6.87(m,2H),6.69–6.68(m,1H),4.54(q,J=8.0Hz,1H),4.02(d,J=16.0Hz,1H),3.88–3.83(m ,1H),3.75–3.71(m,6H),3.54(s,3H),3.42–3.38(m,4H),3.11–3.07(m,1H),2.92-2.90(m,1H),2.63–2.59(m,1H),2 .46–2.43(m,1H),2.30–2.26(m,2H),2.05–1.99(m,1H),1.92–1.88(m,1H),1.95–1.81(m,1H),1.40(d,J=8.0Hz,3H).

[0550] Example 19

[0551] Synthesis of 26-1

[0552] Example 2 (500 mg, 1 eq) was dissolved in 10 ml of DCM, and triphosgene (217 mg, 0.5 eq) and triethylamine (444 mg, 3 eq) were added at 0°C, and the mixture was stirred at 0-10°C for 2 hours. Ethylene glycol (982 mg, 10 eq) was added to the system and stirred at room temperature for 1 hour. Liquid chromatography-mass spectrometry was performed, and the reaction solution was extracted twice with 50 ml of dichloromethane and washed once with 50 ml of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography with a 1:1 ratio of petroleum ether to ethyl acetate as the eluent to obtain 180 mg of the product in a yield of 29%.

[0553] Synthesis of Example 19

[0554] Dissolve 26-1 (180 mg, 1 eq) in 10 ml of dichloromethane, and add S-flurbiprofen (102 mg, 1 eq), EDCI (96 mg, 1.2 eq), and DMAP (5 mg, 0.1 eq). Stir at room temperature for 1 hour, and perform liquid chromatography-mass spectrometry. The organic phase is extracted twice with 10 ml of dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue is purified by column chromatography using a 1:1 ratio of oily ether to ethyl acetate as the eluent to obtain 72 mg of the product in a 26% yield. MS: [M+H] 655H NMR: 1H NMR(400MHz,DMSO–d6)δ8.750(s,1H),7.527–7.366(m,7H),7.272–7.16(m,2H),6.892–6 .878(m,2H),6.687(s,1H),4.348–4.263(m,4H),4.089(d,J=15.6Hz,1H),3.912(q,J=7.2 Hz,1H),3.751(s,3H),3.729(s,3H),3.640(s,3H),3.443–3.323(m,3H),3.114(dd,J1=1 0.4Hz,J2=4.4Hz,1H),2.975–2.907(m,1H),2.640–2.456(m,3H),1.448(d,J=7.2Hz,3H).

[0555] Example 20

[0556] Synthesis of 27-1

[0557] S-Flurbiprofen (500 mg, 1 eq) was dissolved in DCM, and EDCI (469 mg, 1.2 eq), DMAP (25 mg, 0.1 eq), NH4Cl (219 mg, 2 eq), and TEA (413 mg, 2 eq) were added. The mixture was stirred at room temperature for 2 hours. The reaction was complete after liquid chromatography-mass spectrometry (LC-MS / MS). The mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography with petroleum ether:ethyl acetate = 1:1 as eluent to give the product (397 mg) in an 80% yield.

[0558] Synthesis of 27-2

[0559] 27-1 (243 mg, 1 eq) was dissolved in 30 ml of a 37% formaldehyde aqueous solution, potassium hydroxide (5 mg, 0.1 eq) was added, and the mixture was stirred at 80°C for 5 minutes, then cooled to room temperature and stirred overnight. Liquid chromatography-mass spectrometry showed that the starting material disappeared, and TLC showed that new spots were generated. The reaction solution was extracted once with ethyl acetate (80 ml), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in 80 ml of dichloromethane, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent to obtain a crude product of 27-2 (411 mg).

[0560] Synthesis of 27-3

[0561] 27-2 (300 mg, 1 eq) was dissolved in 10 ml of ultra-dry DCM. After complete dissolution, thionyl chloride (259 mg, 2 eq) was added at 0 degrees Celsius and stirred at room temperature for 2 hours. 50 ml of n-hexane was added to the reaction solution, filtered, and the filter cake was rinsed with a small amount of n-hexane. The filtrate was concentrated to dryness under reduced pressure. The residue was redissolved in 10 ml of acetone, and triethylamine (440 mg, 4 eq) was added. The solution was concentrated to dryness under reduced pressure to obtain 208 mg of crude 27-3.

[0562] Synthesis of Example 20

[0563] 27-3 (200 mg, 1 eq) was dissolved in 2 ml of tetrahydrofuran, and Example 2 (191 mg, 1 eq) was added. The reaction was allowed to react at room temperature overnight. Liquid chromatography-mass spectrometry was performed, and the reaction solution was extracted with 20 ml of ethyl acetate, dried, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography with an eluent of ethyl acetate:petroleum ether = 1:1 to obtain a crude product. The crude product was separated by SFC to obtain 18 mg of the target product as an off-white solid with no odor. It was stored at room temperature.

[0564] MS: [M+H] 596.4, 1H NMR(400MHz,DMSO-d6)δ8.376(t,J=6.8Hz,1H),7.526-7.356(m,6H),7.200-7.123(m,2H),6.817(s, 1H),6.731-6.704(m,2H),6.601(d,J=11.2Hz,1H),5.457(t,J=8.8Hz,1H),4.553(t,J=8.4Hz,2H),4 .020(d,J=19.6Hz,1H),3.738(s,3H),3.726(s,3H),3.661(q,J=9.6Hz,1H),3.569(s,3H),3.400-3. 252(m,3H),3.113-3.057(m,1H),2.972-2.867(m,1H),2.635-2.397(m,3H),1.325(d,J=9.6Hz,3H).

[0565] Example 21

[0566] Synthesis of 28-1

[0567] To a 10ml vial, 140.0mg (1.5eq) of L-tyrosine ethyl ester, 2ml of DCM, and 295mg of DIEA (6.0eq) were added. The mixture was cooled in an ice bath under nitrogen. A solution of 100.0mg (1.0eq) of 23-1 in 1ml of DCM was added dropwise, and the mixture was allowed to react at room temperature for 2h. The reaction was monitored by LC / MS for completion. 20ml of purified water was added to the reaction solution, and the mixture was extracted with 2x20ml of DCM. The DCM phases were combined, washed with 20ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column to afford 150mg of 28-1 as a solid in a 90.4% yield. MS: 436. 1 H NMR(400MHz, DMSO-d6)δ9.218(s,1H),8.451(d,J=8.0Hz,1H),7.535–7.183(m,6H), 7.214–7.183(m,2H),6.981(d,J=8.4Hz,2H),6.651(d,J=8.4Hz,2H),4.393–4.336(m ,1H),3.989(q,J=7.2Hz,2H),3.730(q,J=6.8Hz,1H),2.914(dd,J=14.0Hz,6.0Hz,1 H), 2.807 (dd, J = 14.0Hz, 9.2Hz, 1H), 1.265 (d, J = 7.2Hz, 3H), 1.046 (t, J = 7.2Hz, 3H).

[0568] Synthesis of 28-2

[0569] To a 25ml reaction flask, add 250mg of 28-1 and dissolve it in 5ml of THF. Dissolve 121mg of lithium hydroxide in 2ml of water and add dropwise to the reaction mixture. After addition, warm to room temperature and stir for 1h. LC / MS monitoring of the reaction revealed completion. Adjust the pH to 3 with 1N hydrochloric acid and extract with 2x20ml of EA. Combine the EA phases, wash with 20ml of saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to yield 28-2 (220mg). Yield: 94.0%. MS: 408, 1 H NMR(400MHz,DMSO-d6)δ12.516(s,1H),9.198(s,1H), 8.315(d,J=8.0Hz,1H),7.537–7.371(m,6H),7.220–7.177(m,2H),6.993(d,J=8.4Hz,2H),6.651(d,J=8.4Hz,2H),4.379–4. 324 (m, 1H), 3.736 (q, J = 7.2Hz, 1H), 2.956 (dd, J = 13.6, 4.8Hz, 1H), 2.771 (dd, J = 14.0Hz, 5.6Hz, 1H), 1.245 (d, J = 7.2Hz, 3H).

[0570] Synthesis of 28-3

[0571] To a 10ml reaction flask, add 200mg of Example 2 (1.0eq) and 3ml of DCM. Cool the mixture to 0°C in an ice bath under nitrogen. Dissolve 160mg of triphosgene in 2ml of dichloromethane and add dropwise to the reaction mixture. Allow to react at low temperature for 2h. Dilute with 20ml of DCM, then wash with 20ml of saturated sodium chloride solution, dry over sodium sulfate, filter, and concentrate to yield 210mg of 28-3 as a solid, which was used directly in the next step.

[0572] Synthesis of Example 21

[0573] To a 10 ml reaction flask were added 28-2 (85 mg), DCM (2 ml), and triethylamine (100 ml). Under nitrogen, the mixture was cooled in an ice-water bath. 110 mg of 28-3 was dissolved in 1 ml of DCM and added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. The mixture was diluted with 20 ml of dichloromethane and 20 ml of purified water. The organic phase was washed with 20 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column to afford 48.4 mg of Example 21 as a solid, in a 31.3% yield. MS: 774, 1H NMR(400MHz,DMSO-d6)δ9.331(s,1H),7.961(s,1H),7.529–7.360(m,7H),7.241–7.189(m, 4H),7.055(d,J=8.0Hz,2H),6.938(d,J=8.4Hz,1H),6.891(s,1H),6.691(s,1H),4.241–4. 205(m,1H),4.096(d,J=16.0Hz,1H),3.757–3.752(m,6H),3.729(s,3H),3.528–3.389(m,4 H),3.167–3.105(m,2H),2.952–2.902(m,2H),2.676–2.611(m,3H),1.258(d,J=7.2Hz,3H).

[0574] Example 22

[0575] Synthesis of 29-1

[0576] 29-SM2 (1 g, 1.0 eq) and DIEA (2.08 g, 2.0 eq) were added to 10 ml of DCM. After complete dissolution, 29-SM1 (1.14 g, 1.1 eq) was slowly added dropwise. The mixture was stirred at room temperature overnight. TLC detection showed that there was almost no residual starting material. The reaction solution was concentrated to dryness under reduced pressure to obtain crude product 29-1 (2.5 g), which was used directly in the next step without purification.

[0577] Synthesis of 29-2

[0578] The crude product of 29-1 (1.2 g) and 23-SM (600 mg, 0.44 eq) were dissolved in ACN, and DBU (400 mg, 0.47 eq) was added. The mixture was stirred at 60°C overnight. The reaction solution was diluted with dichloromethane, extracted with water and dichloromethane, and the organic phase was washed with water and saturated sodium chloride solution, dried, and purified by column chromatography to obtain 29-2 (600 mg) in a yield of 57%. 1 H NMR (400MHz, DMSO-d6) δ7.558–7.407(m,6H),7.346–7.196(m,7H),5.847(d,J=6. 0Hz, 1H), 5.814 (d, J = 6.0Hz, 1H), 4.014 (q, J = 7.2Hz, 1H), 1.450 (d, J = 7.2Hz, 3H).

[0579] Synthesis of 29-3

[0580] 29-2 (300 mg) was dissolved in dichloromethane, and sulfonyl chloride was added dropwise at 0°C. The mixture was stirred at room temperature for 3 h, quenched with methanol, and the solvent was removed to obtain crude 29-3 (300 mg), which was directly used in the next reaction.

[0581] Synthesis of Example 22

[0582] Example 2 (200 mg, 1 eq) was dissolved in DCM, and DIEA (226 mg, 3 eq) was added. After complete dissolution, a 29-3% dichloromethane solution was added dropwise at 0°C. The mixture was allowed to react at room temperature for one hour. The reaction solution was purified by column chromatography using a prepacked column to obtain Example 22 (240 mg) in a 64% yield. MS: 641, 1 H NMR(400MHz,DMSO-d6)δ9.168(s,1H),7.480–7.446(m,5H),7.410–7.373(m,1H),7.273– 7.223(m,3H),6.896–6.882(m,2H),6.689(s,1H),5.805–5.749(m,2H),4.056–3.962(m,2 H),3.753(s,3H),3.729(s,3H),3.602(d,J=1.6Hz,3H),3.453–3.395(m,3H),3.109(dd, J=10.8Hz,3.6Hz,1H),2.974–2.893(m,1H),2.640–2.446(m,3H),1.456(d,J=6.8Hz,3H).

[0583] Example 23

[0584] Synthesis of 30-1

[0585] 30-SM2 (1 g, 1 eq) and DIEA (2.08 g, 2 eq) were added to DCM (8 ml). After full dissolution, 30-SM1 (1.26 g, 1.1 eq) was slowly added dropwise. The mixture was stirred at room temperature overnight and directly dried to obtain the crude product (2.5 g) of the desired product, which was used in the next step without purification.

[0586] Synthesis of 30-2

[0587] The crude product of 30-1 (1.29 g) and flurbiprofen (600 mg, 0.44 eq) were dissolved in ACN, and DBU (400 mg, 0.47 eq) was added and stirred overnight. The reaction solution was diluted with dichloromethane, extracted with water and dichloromethane, and the organic phase was washed with water and saturated sodium chloride solution, dried, and purified by column chromatography to obtain 30-2 (500 mg). MS: 438, 1 H NMR(400MHz,DMSO-d6)δ7.570–7.185(m,13H),6.938–6.875(m,1H),4.225–4.1 74(m,1H),4.086(d,J=1.6Hz,1H),3.963(q,J=7.2Hz,1H),1.474–1.418(m,6H).

[0588] Synthesis of 30-3

[0589] 30-2 (247 mg) was dissolved in dichloromethane (2 ml), and sulfonyl chloride was added dropwise at 0°C. The mixture was stirred at room temperature for 1 h, and the solvent was removed to obtain 280 mg of a crude product of 30-3.

[0590] Synthesis of Example 23

[0591] Example 2 (190 mg, 1 eq) was dissolved in DCM, and DIEA (300 mg, 4 eq) was added. After complete dissolution, a 30-3% solution of the crude product (280 mg) in dichloromethane was added dropwise at 0°C. The reaction solution was post-treated and purified by column chromatography to obtain a crude product, which was then purified by reverse phase column chromatography to obtain Example 23 (157 mg). MS: 655, 1 H NMR(400MHz,DMSO-d6)δ9.068(d,J=48.8Hz,1H),7.564–7.405(m,6H),7.299–7.2 03(m,3H),6.942–6.820(m,3H),6.709(s,1H),4.102–4.018(m,1H),3.964–3.934( m,1H),3.774(s,3H),3.750(s,3H),3.691–3.563(m,3H),3.480–3.412(m,3H),3.1 64–3.098(m,1H),3.000–2.912(m,1H),2.692–2.461(m,3H),1.510–1.434(m,6H).

[0592] Activity detection

[0593] Experimental Example 1

[0594] Animal mice (CD-1 mice, age: 6-8 weeks, sex: male, weight: 20-24 g, number: 120, animal provider: Beijing Sibeifu Biotechnology Co., Ltd.) were taken for a quarantine period of 7 days. Routine health examinations were completed by a veterinarian, and animals with abnormal performance were eliminated before the experiment.

[0595] Mice were housed in a clean room, with 5 mice per cage. The room temperature was 22±3°C, the humidity was 40-70%, and the lighting was alternating between light and dark for 12 hours. Cages were made of polycarbonate. Soft corn cob bedding was sterilized and cleaned under high pressure and changed twice a week. Feed and water: Clean-grade mouse feed was purchased from Beijing Keao Xieli Feed Co., Ltd. Drinking water was sterilized under high pressure, and food was irradiated with cobalt-60 radiation. Animals had free access to sterile food and water. All mice were weighed and their weights were recorded in detail before dosing.

[0596] Mice were fasted for 16 hours before administration. The drug was administered intravenously in a volume of 10 mL / kg at a dose of 10 mpk. Fifteen minutes after administration, 0.6% glacial acetic acid was injected into the peritoneal cavity of the mice. This acid deposited in the visceral and parietal peritoneum, causing deep, extensive, and prolonged pain. This resulted in a behavioral response, known as a writhing reaction, characterized by abdominal indentation, extension of the trunk and hind limbs, and elevation of the buttocks. The analgesic effect of the compound was evaluated by measuring the number of writhing reactions observed 20 minutes after the 0.6% glacial acetic acid injection and calculating the ratio of the number of writhing reactions observed in the untreated control group. This ratio was subtracted from 100% to obtain the inhibition rate.

[0597] Table 1 Note: s-FBS refers to S-flurbiprofen.

[0598] Experimental Example 2 DRG Experiment

[0599] Dorsal root ganglia (DRG) are primary neurons involved in sensory conduction, functioning to transmit and modulate bodily sensations, and to receive and transmit nociception. This study used a manual patch clamp technique to investigate the effects of test substances on the action potentials of isolated DRG neurons from SD rats.

[0600] Acute isolation of DRG: Anesthetize the rat with 20% (w / w) urethane and place it in a prone position. Disinfect the skin with 75% (v / v) alcohol. Use surgical scissors to cut the skin from the tail to fully expose the spine and remove the muscle tissue on both sides of the spine. Remove the spine from the tail vertebrae to the spine and place it in a 10cm culture dish filled with HBSS on an ice box. Cut off 1 / 3 of the cross-section of the spine with scissors. Find the L4-L6 part and remove the spinal cord. After the nerve fibers connecting the dorsal root ganglia can be seen, remove the DRG under a dissecting microscope and place it in a 35mm culture dish filled with HBSS. After removing all DRGs, cut off the nerve tissue connected to the DRG under a microscope, and then evenly chop the DRG with the nerves cut off and transfer it to a 15ml centrifuge tube. Centrifuge at 1000r for 5 minutes and remove the supernatant. Then, add 5 ml of digestion solution and incubate in a 37°C, 5% CO2 incubator for approximately 20 minutes. During this time, shake the tube to resuspend the tissue and pipette 2-3 times to filament the tissue until there are no more clumps. Once digestion is complete, add 5 ml of complete medium and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant. Finally, add an appropriate amount of complete medium, gently resuspend the cells, and apply the cell suspension to a cell slide in a culture dish. Allow the cells to adhere to the wall before performing patch clamp analysis.

[0601] Patch clamp recordings of neuronal action potentials were performed using the following voltage stimulation protocol: After whole-cell patch clamping, the recording mode was switched to current clamp mode. The membrane current was clamped at 0 pA. The clamp current was then increased in increments from -20 pA to approximately 360 pA for 0.8 seconds, then returned to 0 pA for 1 second. Changes in drug efficacy were also recorded under stimulation with 1.5-2x rheobase for 1 second. Data were acquired using an EPC10 amplifier (HEKA) and stored in PatchMaster (HEKA) software. The patch clamp procedure began with a recording electrode made from a capillary glass tube using a microelectrode puller. The electrode, filled with intracellular fluid, was then inserted into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator was used to immerse the electrode in extracellular fluid, and the electrode resistance (Rpip) was recorded. The electrode was then gently brought into contact with the cell surface, and negative pressure was applied to create a GΩ seal. At this time, fast capacitance compensation is performed, and negative pressure is continued to be applied to break the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation is performed and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is given. When the action potential of the whole-cell recording is stable, the drug is administered. The next concentration is detected after each drug concentration acts for about 5 minutes (or the action potential stabilizes). Multiple concentrations are detected for each test compound. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested use gravity perfusion to flow through the recording bath from low concentration to high concentration to act on the cells. A peristaltic pump is used for liquid exchange during recording. The current detected by each cell in the external solution without the compound serves as its own control group. At least 3 cells are used for each concentration and the test is repeated 3 times independently. All electrophysiological experiments were performed at room temperature.

[0602] As shown in Figure 1, 1μM S-FBS and 1μM Example 2 had no effect on inhibiting action potential conduction; 1μM Example 22 and 1μM Example 23 inhibited DRG neuron action potentials to varying degrees, demonstrating a nerve conduction blocking effect. This indicates that the analgesic mechanism of the compounds of the present invention is different from that of S-FBS and Example 2.

[0603] Each embodiment in this specification is described in a related manner. The same or similar parts between the embodiments can be referred to each other. Each embodiment focuses on the differences from other embodiments.

[0604] The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention are included in the scope of protection of the present invention.

Claims

1. A compound of formula (I), or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof: in, R D Residues formed for drug molecules; U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-; W1, W2 and W3 are each independently selected from H, C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; L is a chemical bond or Best L1 is selected from a chemical bond, -C(O)-, -OC(O)-, -NR b C(O)-, -S(O)-, -S(O)2-, -OS(O) 1-2 -and-NR b S(O) 1-2 -; L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene; L3 is selected from O, S, NR', -C(O)-, -S(O)- and -S(O)2-; n is selected from 0, 1, 2, 3, 4, 5 and 6; The methylene in is optionally substituted by 1, 2, 3, 4, 5 or 6 independent R; R is independently selected from H, D, halogen, CN, ═O, —OR a 、-SR a 、-NR b R c , -C 0-10 Alkylene-C(O)R a , -C 0-10 Alkylene-OC(O)R a , -C 0-10 Alkylene-C(O)OR a , -C 0-10 Alkylene-NR b C(O)R a , -C 0-10 Alkylene-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; R' is selected from H, C 1-18 Alkyl, C 1-18 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, or R' together with R and the atoms to which they are attached form a 3-10 membered heterocyclyl; R a , R b and R c Each independently selected from H, C 1-10 Alkyl and C 1-10 A haloalkyl group, or R b With R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

2. The compound of formula (I) according to claim 1, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R D is a residue formed by a drug molecule, wherein the drug molecule is an anti-inflammatory drug and its derivatives, preferably a non-steroidal anti-inflammatory drug and its derivatives, such as loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetin, bromfenac, thiaprofen, indomethacin, sulindac, ketorolac, nimesulide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, naproxenone, etodolac, rofecoxib, celecoxib, piroxicam, meloxicam and oxyphenbutazone, and their derivatives; Preferably, the drug molecule is selected from loxoprofen, flurbiprofen, indomethacin, mefenamic acid, clofenamic acid and aspirin, and their derivatives; preferably selected from flurbiprofen and clofenamic acid, and their derivatives; preferably flurbiprofen and its derivatives; preferably, the flurbiprofen is S-flurbiprofen; preferably, the flurbiprofen is R-flurbiprofen.

3. A compound of formula (I) according to claim 1 or 2, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-, preferably O.

4. A compound of formula (I) according to claim 1, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 Halogenated alkyl, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Deuterated alkyl, preferably methyl or CD3, preferably C 1-6 The alkyl group is preferably a methyl group.

5. A compound of formula (I) according to any one of claims 1 to 4, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from a chemical bond, -C(O)-, -OC(O)- and -NHC(O)-, preferably selected from a chemical bond, -C(O)- and -OC(O)-, preferably selected from -C(O)- and -OC(O)-, preferably -C(O)-; Preferably, L1 is selected from -C(O)-, -OC(O)- and -NHC(O)-; preferably -OC(O)- and -NHC(O)-; preferably -OC(O)-.

6. A compound of formula (I) according to any one of claims 1 to 5, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene, preferably selected from chemical bonds, phenylene and 5-6 membered heteroarylene, preferably selected from chemical bonds and phenylene, preferably selected from chemical bonds, Preferably selected from chemical bonds and Chemical bonds are preferred.

7. A compound of formula (I) according to any one of claims 1 to 6, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: L3 is selected from O, S and NR'; preferably selected from O and NR'; preferably O and S; preferably O; preferably NR'.

8. A compound of formula (I) according to any one of claims 1 to 7, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: n is selected from 0, 1, 2 and 3, preferably selected from 1, 2 and 3, preferably 1 or 2, preferably 1.

9. A compound of formula (I) according to any one of claims 1 to 8, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: The methylene in is optionally substituted by 1, 2 or 3 independent Rs, preferably optionally substituted by 1 R.

10. A compound of formula (I) according to any one of claims 1 to 9, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, D, halogen, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a , -C 0-6 Alkylene-OC(O)R a , -C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a ; preferably selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a ; preferably selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a ; preferably selected from H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a ; preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a ; preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a ; preferably selected from H, D, =O and -C 0- 3-alkylene-C(O)OH; Preferably, R is independently selected from H, =O, methyl, isobutyl, -C(O)OH and -(CH2)2C(O)OH; preferably selected from H, =O, methyl, -C(O)OH and -(CH2)2C(O)OH; preferably selected from H, =O, methyl and -(CH2)2C(O)OH; preferably selected from H, =O and -(CH2)2C(O)OH; Preferably, R is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H, D, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-3 Alkyl and C 1-3 Haloalkyl; preferably selected from H and Me.

11. A compound of formula (I) according to any one of claims 1 to 10, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R' is selected from H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; Preferably, R' together with R and the atoms to which they are attached form a 3-10 membered heterocyclic group, preferably a 3-7 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, preferably Preferred Formation Preferably, R' and R and the atoms to which they are attached do not form a ring.

12. A compound of formula (I) according to any one of claims 1 to 11, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R a , R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H; Preferably, R b With R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group.

13. A compound of formula (I) according to any one of claims 1 to 12, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R D for Preferably in, Ring A is selected from C 6-10 Arylene, 5-10 membered heteroarylene, C 6-10 Aryl C 5-10 Cycloalkyl, C 6-10 Aryl 5-10 membered heterocyclic group, 5-10 membered heteroaryl and C 5-10 Cycloalkyl and 5-10 membered heteroaryl and 5-10 membered heterocyclyl; Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 6-10 Aryl and 5-10 membered heteroaryl, or -L4-Ring B and R2 are absent; R1 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a , C 1-18 Alkyl, C 1-18 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 1s replace; R 1s Independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; m = 0, 1, 2, 3, 4 or 5; R2 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a , C 1-18 Alkyl, C 1-18 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 2s replace; R 2s Independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; s = 0, 1, 2, 3, 4 or 5; L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)-, -OC(O)-, -C(O)O-, -NR b C(O)-、-C(O)NR b -, -S(O)- and -S(O)2-; Or L4 and the carbon atom on ring A to which L4 is attached together form L5 is selected from the group consisting of chemical bonds, O, S, NR' and C 1-10 Alkylene, optionally substituted by one or more independent R3; R3 is independently selected from H, D, halogen, C 1-10 Alkyl and C 1-10 Haloalkyl; R4 and R'4 are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; X is selected from -C(O)-, -S(O)- and -S(O)2-, preferably -C(O)-.

14. A compound of formula (I) according to any one of claims 1 to 13, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from C 6-10 Arylene and 5-10 membered heteroarylene; preferably selected from phenylene and 9-10 membered heteroarylene; preferably selected from phenylene and indolylene; preferably phenylene; preferably selected from Preferably selected from Best 15. A compound of formula (I) according to any one of claims 1 to 14, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably selected from phenyl and 5-6 membered heteroaryl; preferably C 6-10 The aryl group is preferably a phenyl group.

16. A compound of formula (I) according to any one of claims 1 to 15, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、-S(O)2R a , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl and C 1-6 Haloalkyl; preferably selected from H, D, halogen, CN, -OR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a , C 1-6 Alkyl and C 1-6 haloalkyl; preferably selected from H, D, halogen, -OR a 、-OC(O)R a , C 1-6 Alkyl and C 1-6 Haloalkyl; preferably selected from H, F, Me, -OMe and -OC(O)CH3; Preferably, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably H, D and halogen; preferably H or F; preferably halogen; preferably F.

17. A compound of formula (I) according to any one of claims 1 to 16, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R2 is independently selected from H, D, halogen, CN, -NO2, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c 、-S(O)R a 、 -S(O)2R a , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl and C 1-6 haloalkyl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 haloalkyl; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; preferably selected from H, Cl and Me; preferably selected from H and Cl; Preferably, R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably selected from H, D and halogen; more preferably H or D.

18. A compound of formula (I) according to any one of claims 1 to 17, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1s and R 2s Each independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

19. A compound of formula (I) according to any one of claims 1 to 17, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: m=0, 1, 2, 3 or 4; preferably m=0, 1 or 2; preferably m=0 or 1; preferably m=1.

20. A compound of formula (I) according to any one of claims 1 to 19, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: s=0, 1 or 2; preferably s=0.

21. A compound of formula (I) according to any one of claims 1 to 20, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)- and -S(O)-; preferably selected from chemical bonds, -CR4R'4-, -NR b -, O and -C(O)-; preferably selected from chemical bonds, -NR b - and -C(O)-; preferably selected from a chemical bond, -NH- and -C(O)-; preferably selected from a chemical bond and -NH-; preferably a chemical bond.

22. A compound of formula (I) according to any one of claims 1 to 21, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: L5 is a chemical bond or C 1-10 Alkylene, preferably a chemical bond or C 1-6 Alkylene, preferably a chemical bond or C 1-4 Alkylene, preferably a chemical bond or C 1-2 Alkylene, preferably a chemical bond or methylene, preferably -CH(CH3)-; Preferably, L5 is optionally substituted with 1, 2, 3, 4, 5 or 6 independent R3, preferably optionally substituted with 1, 2 or 3 independent R3, preferably optionally substituted with 1 R3.

23. A compound of formula (I) according to any one of claims 1 to 21, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R3 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-4 Alkyl and C 1-4 Haloalkyl; preferably selected from H and Me; preferably Me.

24. A compound of formula (I) according to any one of claims 1 to 23, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R4 and R'4 are independently selected from H, D, C 1-6 Alkyl and C 1-6 The haloalkyl group is preferably H or D.

25. A compound of formula (I) according to any one of claims 1 to 24, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, having the following structure: in, The variables are defined in any one of claims 1-24.

26. A compound of formula (II) according to claim 25, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, in, Ring A is selected from C 6-10 Arylene and 5-10 membered heteroarylene; Ring B is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, or -L4-Ring B and R2 are absent; R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 independent R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; m = 0, 1, 2, 3, 4 or 5; R2 is selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, which are optionally substituted by 1, 2 or 3 independent R 2s replace; R 2s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic groups, preferably selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic group; s = 0, 1, 2, 3, 4 or 5; L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)- and -S(O)-; L5 is a chemical bond or C 1-6 Alkylene, optionally substituted with 1, 2, 3, 4, 5 or 6 independent R3; R3 is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R4 and R'4 are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-; W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; L is a chemical bond or L1 is selected from a chemical bond, -C(O)-, -OC(O)- and -NHC(O)-; L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclyl, phenylene and 5-6 membered heteroarylene; L3 is selected from O, S and NR'; n is selected from 0, 1, 2, 3, 4, 5 and 6; The methylene in is optionally substituted by 1, 2 or 3 independent R; R is independently selected from H, D, halogen, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a , -C 0-6 Alkylene-OC(O)R a , -C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a , preferably selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a ; R' is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, or R' and R together with the atoms to which they are attached form a 3-7 membered heterocyclyl; R a , R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 A haloalkyl group, or R b With R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

27. The compound of formula (II) according to claim 26, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from C 6-10 Arylene and 5-10 membered heteroarylene, preferably selected from phenylene and 9-10 membered heteroarylene; Ring B is selected from C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from phenyl and 5-6 membered heteroaryl; preferably C 6-10 Aryl, preferably phenyl, or -L4-Ring B and R2 are absent; R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, halogen, CN, -OR a 、-NR b R c 、-OC(O)R a 、-C(O)OR a , C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, halogen, -OR a 、-OC(O)R a , C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, D and halogen, optionally substituted by 1, 2 or 3 independent R 1s replace; R 1s are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m=0, 1, 2, 3, 4 or 5, preferably m=0, 1 or 2; R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c 、-C(O)R a 、-OC(O)R a 、-C(O)OR a 、-NR b C(O)R a 、-C(O)NR b R c , C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, halogen, CN, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, D and halogen, optionally substituted by 1, 2 or 3 independent R 2s replace; R 2s are independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; s=0, 1, 2, 3, 4 or 5, preferably s=0, 1 or 2; L4 is selected from a chemical bond, -CR4R'4-, -NR b -, O and -C(O)-, preferably selected from chemical bonds, -NR b - and -C(O)-; L5 is a chemical bond or C 1-4 Alkylene, preferably a chemical bond or C 1-2 Alkylene, optionally substituted by 1, 2 or 3 independent R3; R3 is independently selected from H, D, C 1-4 Alkyl and C 1-4 Haloalkyl; R4 and R'4 are independently selected from H, D, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H and D; U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-, preferably O; W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 Halogenated alkyl, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Deuterated alkyl, preferably C 1-6 alkyl; L is a chemical bond or L1 is selected from a chemical bond, -C(O)- and -OC(O)-, preferably selected from -C(O)- and -OC(O)-, preferably -C(O)-; L2 is selected from a chemical bond, a phenylene group and a 5-6 membered heteroarylene group, preferably selected from a chemical bond and a phenylene group; L3 is selected from O and NR', preferably NR'; preferably O; n is selected from 0, 1, 2 and 3, preferably selected from 1, 2 and 3, preferably 1 or 2, preferably 1; The methylene in is optionally substituted by 1, 2 or 3 independent R, preferably optionally substituted by 1 R; R is independently selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a , preferably selected from H, D, =O and -C 0-3 Alkylene-C(O)OH; R' is selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, or R' and R and the atoms to which they are attached together form a 4-6 membered heterocyclic group; preferably, R' and R do not form a ring; R a , R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

28. The compound of formula (II) of claim 27, or its isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenylene and indolylene, preferably selected from Preferably phenylene, preferably selected from Ring B is phenyl, or -L4-ring B and R2 are absent; R1 is independently selected from H, F, Me, -OMe and -OC(O)CH3, preferably H or F; m = 0, 1 or 2; R2 is independently selected from H, Cl and Me, preferably selected from H and Cl; s = 0, 1, or 2; L4 is selected from a chemical bond, -NH- and -C(O)-; preferably selected from a chemical bond and -NH-; preferably a chemical bond; L5 is a chemical bond or a methylene group, which is optionally substituted by 1 R3; preferably, L5 is -CH(CH3)-; R3 is independently selected from H and Me; preferably Me; U1, U2 and U3 are O; W1, W2 and W3 are methyl or CD3, preferably methyl; L is a chemical bond or L1 is selected from a chemical bond, -C(O)- and -OC(O)-; L2 is selected from a chemical bond, L3 is selected from O and NR'; n is 0, 1, 2, and 3; The methylene in is optionally substituted by 1 R; R is independently selected from H, =O, methyl, isobutyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl and -(CH2)2C(O)OH, preferably selected from H, =O and -(CH2)2C(O)OH; R' is H, or R' together with R and the atoms to which they are attached form Preferred Formation Preferably, Selected from the following structures: Preferably selected from Preferably selected from 29. A compound of formula (III) according to claim 25, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, in, R1 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; m = 0, 1, 2, 3 or 4; R2 is independently selected from H, D, halogen, CN, -OR a 、-SR a 、-NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, which are optionally substituted by 1, 2 or 3 independent R 2s replace; R 2s Independently selected from H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; s = 0, 1, 2, 3, 4 or 5; U1, U2 and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)- and -O-CH2-O-; W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, preferably selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclic group; L is a chemical bond or L1 is selected from a chemical bond, -C(O)-, -OC(O)- and -NHC(O)-; L2 is selected from chemical bonds, C 3-7 Cycloalkylene, 3-7 membered heterocyclylene, phenylene and 5-6 membered heteroarylene; L3 is selected from O, S and NR'; n is selected from 0, 1, 2, 3, 4, 5 and 6; The methylene in is optionally substituted by 1, 2 or 3 independent R; R is independently selected from H, D, halogen, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a , -C 0-6 Alkylene-OC(O)R a , -C 0-6 Alkylene-C(O)NR b R c and -C 0-6 Alkylene-NR b C(O)R a , preferably selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C(O)OR a and -C 0-6 Alkylene-OC(O)R a ; R' is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclyl, or R' and R together with the atoms to which they are attached form a 3-7 membered heterocyclyl; R a , R b and R c Each independently selected from H, C 1-6 Alkyl and C 1-6 A haloalkyl group, or R b With R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

30. The compound of formula (III) of claim 29, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, D and halogen, optionally substituted by 1, 2 or 3 independent R 1s replace; R 1s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m=0, 1, 2, 3 or 4, preferably m=0, 1 or 2; R2 is independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably selected from H, D and halogen, more preferably H or D, optionally substituted by 1, 2 or 3 independent R 2s replace; R 2s Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl and 3-7 membered heterocyclic groups, preferably selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; s=0, 1, 2, 3, 4 or 5, preferably s=0, 1 or 2; U1, U2 and U3 are each independently selected from O, S, -NH- and -C(O)-, preferably O; W1, W2 and W3 are each independently selected from C 1-10 Alkyl, C 1-10 Deuterated alkyl and C 1-10 Halogenated alkyl, preferably selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl and C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Deuterated alkyl, preferably C 1-6 alkyl; L is a chemical bond or L1 is selected from a chemical bond, -C(O)- and -OC(O)-, preferably selected from -C(O)- and -OC(O)-, preferably -C(O)-; L2 is selected from a chemical bond, a phenylene group and a 5-6 membered heteroarylene group, preferably selected from a chemical bond and a phenylene group; L3 is selected from O and NR', preferably NR'; preferably O; n is selected from 0, 1, 2 and 3, preferably selected from 1, 2 and 3, preferably 1 or 2, preferably 1; The methylene in is optionally substituted by 1, 2 or 3 independent R, preferably optionally substituted by 1 R; R is independently selected from H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a , preferably selected from H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a , preferably selected from H, D, =O and -C 0-3 Alkylene-C(O)OH; R' is selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl, preferably H, or R' and R and the atoms to which they are attached together form a 4-6 membered heterocyclic group; preferably, R' and R do not form a ring; R a Independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

31. The compound of formula (III) according to claim 30, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is H or F; m=1; R2 is H; s=0; U1, U2 and U3 are O; W1, W2 and W3 are methyl or CD3, preferably methyl; L is a chemical bond or L1 is selected from a chemical bond, -C(O)- and -OC(O)-; L2 is selected from a chemical bond, L3 is selected from O and NR'; n is 0, 1, 2, and 3; The methylene in is optionally substituted by 1 R; R is independently selected from H, =O, methyl, isobutyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl, -C(O)OH and -(CH2)2C(O)OH, preferably selected from H, =O, methyl and -(CH2)2C(O)OH, preferably selected from H, =O and -(CH2)2C(O)OH; R' is H, or R' together with R and the atoms to which they are attached form Preferred Formation Preferably, L is selected from: a chemical bond, Preferably selected from: chemical bonds, Preferably selected from: chemical bonds, Preferably selected from: chemical bonds, Preferably selected from: chemical bonds, Preferably, for Preferably, for Preferably, for Preferably, for Preferably, for 32. A compound of formula (III-1) according to claim 25, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, in, Each variable is defined as defined in any one of claims 1 to 31; Preferably, for Preferably, for 33. A compound of formula (II), formula (III) or formula (III-1) according to claim 25, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: L is L1 is selected from -C(O)-, -OC(O)- and -NHC(O)-; preferably -OC(O)- and -NHC(O)-; preferably -OC(O)-; L2 is a chemical bond; L3 is selected from O, S and NR'; preferably O and S; preferably O; n is selected from 1, 2 and 3, preferably 1 or 2, preferably 1; The methylene in is optionally substituted by 1, 2 or 3 (preferably 1) independent R; R is independently selected from H, D, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably H, D, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-3 Alkyl and C 1-3 Haloalkyl; preferably selected from H and Me; The remaining groups are defined as defined in any one of claims 1 to 32; Preferably, L is 34. A compound of formula (I) according to claim 1, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the following:

35. A pharmaceutical composition comprising a compound of any one of claims 1 to 34, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally with other therapeutic agents.

36. Use of a compound according to any one of claims 1 to 34, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 35 in the preparation of a medicament for treating or preventing a disease associated with the central nervous system.

37. A method for treating or preventing a central nervous system-related disease in a subject, comprising administering to the subject a compound of any one of claims 1-34, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 35.

38. A compound according to any one of claims 1 to 34, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 35, for use in treating or preventing a disease associated with the central nervous system.

39. The use of claim 36 or the method of claim 37 or the compound or pharmaceutical composition of claim 38, wherein The disease is selected from pain, depression and addiction.

40. The use or method or compound or pharmaceutical composition of claim 39, wherein: The pain is selected from neuralgia, perioperative pain (including pain before, during or after surgery, such as somatic or visceral pain caused by postoperative trauma and postoperative incision, pain caused by visceral injury and other comprehensive pain) and cancer pain (such as pain caused by cancer).

41. The use or method or compound or pharmaceutical composition of claim 40, wherein: The pain is acute pain or chronic pain (including acute / chronic pain before, during or after surgery, acute neuralgia or chronic neuralgia).

42. The use or method or compound or pharmaceutical composition of claim 40, wherein: The neuralgia is central pain, such as spinal cord pain, thalamic pain, pontine pain, medullary pain or cerebral cortex pain.

43. The use or method or compound or pharmaceutical composition of claim 40, wherein: The postoperative pain is pain caused after surgery, such as pain caused after abdominal surgery, orthopedic surgery, cesarean section or brain surgery.

44. The use of claim 36 or the method of claim 37 or the compound or pharmaceutical composition of claim 38, wherein The compound or pharmaceutical composition is used for sedation or sleep aid.

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