Tetrahydroisoquinoline derivatives and their use

Abstract

The present invention provides tetrahydroisoquinoline derivatives and their uses. Specifically, the present invention relates to the compound represented by formula (I), or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions comprising the above compound, as well as the effects of the above compound in the prevention and treatment of central nervous system-related diseases. [C1] TIFF2026530092000299.tif35156

Description

[Technical Field]

[0001] This application claims priority to Chinese application 202311129751.9 filed on 4 September 2023 and Chinese application 202411195283.X filed on 28 August 2024, both of which are incorporated herein by reference.

[0002] <Technical field> This disclosure relates to tetrahydroisoquinoline derivatives, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof, and their uses. This disclosure also relates to pharmaceutical compositions comprising the tetrahydroisoquinoline derivatives, and to the use of the tetrahydroisoquinoline derivatives in the prevention and treatment of central nervous system-related disorders such as pain, depression, and addiction. [Background technology]

[0003] l-Coridalmin (l-DL) is an isoquinoline alkaloid with a tetracyclic structure and possesses analgesic, detoxifying, and antidrug-dependent effects. Its chemical name is (S)-2,3,9-trimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline-10-ol, and it has the following structure. [ka]

[0004] Corydalmin is one of the effective bioalkaloid components found in Corydalis yanhusuo, a traditional Chinese medicine. However, its natural content is extremely low, limiting its application in the pharmaceutical field. Therefore, research into other active compounds based on the structure of corydalmin is urgently needed. [Overview of the project] [Means for solving the problem]

[0005] Based on the structure of coridarumin, this disclosure has developed a series of active compounds that exhibit excellent analgesic effects.

[0006] In one embodiment, the disclosure provides a compound of formula (I), or an isotopic variant thereof, a tautomer, a stereoisomer, a prodrug, a polymorph, a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0007] In the formula, each variable is as defined herein.

[0008] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure, a pharmaceutically acceptable carrier, adjuvant, or vehicle, and optionally other therapeutic agents.

[0009] In another embodiment, the Disclosure provides the use of the compounds of the Disclosure in the manufacture of pharmaceuticals for the treatment or prevention of central nervous system-related disorders.

[0010] In another embodiment, the Disclosure provides a method for treating or preventing a central nervous system-related disorder in which the subject is administered a compound or a pharmaceutical composition of the Disclosure in which the subject is located.

[0011] In another embodiment, the Disclosure provides compounds or pharmaceutical compositions of the Disclosure for use in the treatment or prevention of central nervous system-related disorders.

[0012] In one specific embodiment, the above-mentioned disease is selected from the group consisting of pain, depression, and addiction.

[0013] In another specific embodiment, said pain is selected from the group consisting of neuralgia, perioperative pain (including pre-operative, intra-operative, or post-operative pain, such as somatic pain or visceral pain caused by post-operative trauma or post-operative incision, pain caused by visceral injury, and other general pain), and cancer pain (such as pain caused by cancer).

[0014] In another specific embodiment, said pain is acute pain or chronic pain (including pre-operative, intra-operative, or post-operative acute / chronic pain, acute neuralgia, or chronic neuralgia).

[0015] In another specific embodiment, said neuralgia is central pain such as spinal cord pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain.

[0016] In another specific embodiment, said post-operative pain is pain caused by surgery, such as pain resulting from abdominal surgery, orthopedic surgery, cesarean section, or brain surgery.

[0017] In another specific embodiment, said compound or pharmaceutical composition is used to assist sedation or sleep.

[0018] Definitions

[0019] Chemical Definitions

[0020] Definitions of specific functional groups and chemical terms are described in detail below.

[0021] When a range of values is given, it is intended to encompass each value and all subranges within that range. For example, "C 1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C4-6 , C 4-5 , C 5-6 It includes alkyl groups.

[0022] "C 1-18 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 18 carbon atoms. In some embodiments, C 1-10 Alkyl is an option. In some embodiments, C 1-6 Alkyl is an option. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl, and C 1-2 Alkyl is an option. C 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). 1-6 The term "alkyl" also includes heteroalkyls in which one or more carbon atoms (1, 2, 3, or 4, etc.) are substituted with heteroatoms (such as oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). Alkyl alkyls may optionally be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2), or t-Bu(-C(CH3)3).

[0023] "C 2-6 An "alkenyl" refers to a linear or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C2-4 alkenyls are optional. 2-6Examples of alkenyls include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), and hexenyl (C6). 2-6 The term "alkenyl" also includes heteroalkenyls in which one or more carbon atoms (1, 2, 3, or 4, etc.) are substituted with heteroatoms (oxygen, sulfur, nitrogen, boron, silicon, or phosphorus, etc.). The alkenyl group may optionally be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0024] "C 2-6 "Alkynyl" refers to a linear or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C2-4 alkynyls are optional. 2-6 Examples of alkynyls are not particularly limited, but include ethinyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), and hexynyl (C6). 2-6 The term "alkynyl" also includes heteroalkynyls in which one or more carbon atoms (1, 2, 3, or 4, etc.) are substituted with heteroatoms (oxygen, sulfur, nitrogen, boron, silicon, or phosphorus, etc.). The alkynyl group may optionally be substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] "C 1-10 "Alkylene" refers to C 1-10 This refers to a divalent group obtained by removing another hydrogen atom from an alkyl group, which may be substituted or unsubstituted. In some embodiments, C 1-6 Alkylene is an option. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene and C 1-2Alkylenes are an option. Unsubstituted alkylenes are not particularly limited, but examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Substituted alkylenes, such as alkylenes substituted with one or more alkyl(methyl) groups, are not particularly limited, but include substituted methylene (-CH(CH3)- and -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, and -CH2C(CH3)2-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2C(CH3)2-).

[0026] "C 2-6 "Alkenylene" refers to C 2-6 This refers to a divalent group obtained by removing another hydrogen from an alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 Alkenylenes are a particular option. Unsubstituted alkenylenes are not particularly limited, but include vinylene (-CH=CH-) and propenylene (-CH=CHCH2- and -CH2CH=CH-, etc.). Substituted alkenylenes, such as alkenylenes substituted with one or more alkyl (methyl) groups, are not particularly limited, but include substituted vinylene (-C(CH3)=CH- and -CH=C(CH3)-) and 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-, and -CH2-CH=C(CH3)-).

[0027] "C 2-6 "Alkynylene" is C 2-6This refers to a divalent group obtained by removing another hydrogen from an alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 Alkynylenes are a particular option. Examples of alkynylenes, though not limited to them, include ethynylene (-C≡C-) and substituted or unsubstituted propynylenes (-C≡CCH2-).

[0028] "C 0-10 "Alkylene" refers to a chemical bond and the aforementioned "C 1-10 This refers to "alkylene". In some embodiments, "C 0-6 Alkylene is an option. In some embodiments, C 0-4 Alkylene is an option. In some embodiments, C 0-3 Alkylene is an option. In some embodiments, C 0-2 Alkylene is an option.

[0029] "C 1-10 "Deuterated alkyl" refers to the aforementioned "C" which is substituted with one or more D (deuterium) groups. 1-10 Refers to an alkyl group. In some embodiments, C 1-6 Alkyl deuterated compounds are a particular option, and even more alternatively, C 1-4 It is an alkyl deuterated, and even alternatively, C 1-3 It is an alkyl deuterated, and the most alternative is C 1-2 This is a deuterated alkyl group. Examples of this deuterated alkyl group include -CD3, -CH2D, -CHD2, -CHDCH2D, -CH2CHD2, -CD2CD3, -CH2CH2CD3, and -C(CH3)2CD3. The deuterated alkyl group may be substituted with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent at any available bond position.

[0030] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0031] Therefore, "C1-18 "Haloalkyl" refers to the aforementioned "C 1-18 This refers to a molecule in which the "alkyl" group is substituted with one or more halogen groups. In some embodiments, C 1-10 Haloalkyl groups are a particular option, and even more alternatively, C 1-6 It is a haloalkyl, and even alternatively, C 1-4 It is a haloalkyl, and even alternatively, C 1-3 It is a haloalkyl, and even alternatively, C 1-2 It is a haloalkyl group. Examples of haloalkyl groups, though not particularly limited, include -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CH2CH2CF3, -C(CH3)2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethylethyl. The haloalkyl group may be substituted with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent at any available bond position.

[0032] "C 3-14 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms, containing no heteroatoms, and 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 a particular option, C 5-7 Cycloalkyl, C 4-6 Cycloalkyl, and C 5-6Cycloalkyls are another option. Cycloalkyls also include ring systems in which the aforementioned cycloalkyl ring is condensed with one or more aryl or heteroaryl groups, with the bond position located on the cycloalkyl ring, in which case the carbon number also indicates the carbon number in the cycloalkyl system. Cycloalkyls also include those in which substituents on any non-adjacent carbon atoms of the aforementioned cycloalkyl ring bond to form a bridging ring, together forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyls also include those in which substituents on the same carbon atom of the aforementioned cycloalkyl ring bond to form a ring, together forming a polycyclic alkane sharing one carbon atom. Examples of cycloalkyls are not particularly limited, but include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), [ka] Examples include (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), and cycloheptatrienyl (C7). The cycloalkyl group may be substituted with one or more substituents as needed, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] "C 3-7 "Cycloalkylene" refers to C 3-7 This refers to a divalent group obtained by removing another hydrogen atom from a cycloalkyl group, which may be substituted or unsubstituted. In some embodiments, C 3-6 Cycloalkylene, C 3-5 Cycloalkylenes, and C 3-4 Cycloalkylene is a particular option, cyclopentylene is an alternative, and cyclopropylene is an even more alternative.

[0034] A "3-14 membered heterocyclil" refers to a saturated or unsaturated group of a 3-14 membered non-aromatic ring system having a ring carbon atom and 1-5 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and the group optionally contains 1, 2, or 3 double or triple bonds. In heterocyclils containing one or more nitrogen atoms, the bond position may be a carbon atom or a nitrogen atom, as long as the valence allows. In some embodiments, a 3-10 membered heterocyclil is an option, which is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1-5 ring heteroatoms. In some embodiments, a 5-10 membered heterocyclil is an option, which is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-5 ring heteroatoms. In some embodiments, a 3-7 membered heterocyclil is an option, which is a 3-7 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms. The options are 5-7 membered heterocyclyls, which are 5-7 membered non-aromatic ring systems having a ring carbon atom and 1-3 ring heteroatoms. The options are 3-6 membered heterocyclyls, which are 3-6 membered non-aromatic ring systems having a ring carbon atom and 1-3 ring heteroatoms. The options are 4-6 membered heterocyclyls, which are 4-6 membered non-aromatic ring systems having a ring carbon atom and 1-3 ring heteroatoms. Further options are 5-6 membered heterocyclyls, which are 5-6 membered non-aromatic ring systems having a ring carbon atom and 1-3 ring heteroatoms. Further options are 5-membered heterocyclyls. Heterocyclyls also include ring systems in which the aforementioned heterocyclyl ring is fused with one or more cycloalkyl groups and the bond site is on the heterocyclyl ring, or ring systems in which the aforementioned heterocyclyl ring is fused with one or more aryl or heteroaryl groups and the bond site is on the heterocyclyl ring. In this case as well, the number of ring members indicates the number of ring members of the heterocyclyl ring system. Heterocyclines also include those in which substituents on any non-adjacent carbon or nitrogen atom of the heterocyclyl ring bond to form a bridging ring, forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclines also include those in which substituents on the same carbon atom of the heterocyclyl ring bond to form a ring, forming a polycyclic heteroalkane sharing one carbon atom.Examples of three-membered heterocyclils containing one heteroatom include, but are not limited to, azilidinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclils containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclils containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclils containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclils containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclils containing one heteroatom include, but are not limited to, piperidinyl, dihydropyranil, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclils containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclils containing three heteroatoms include, but are not limited to, triazinanil. Examples of seven-membered heterocyclils containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of five-membered heterocyclils fused with a C6 aryl ring (hereinafter also referred to as 5,6-bicyclic heterocyclils) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranil, dihydrobenzothienyl, and benzoxazolinonil. The six-membered heterocyclyl condensed with a C6 aryl ring (hereinafter also referred to as a 6,6-bicyclic heterocyclyl) is not particularly limited, but examples include tetrahydroquinolinyl and tetrahydroisoquinolinyl.Heterocyclils also include those in which the aforementioned heterocyclils share one or two atoms with a cycloalkyl, heterocyclil, aryl, or heteroaryl group to form a bridging ring or spiro ring, where the shared atom may be a carbon or nitrogen atom, as long as its valence allows. Heterocyclils also include those described above, where the heterocyclil group may be substituted with one or more substituents as needed, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] "C 6-14 "Aryl" refers to a monocyclic or polycyclic (tricyclic, etc.) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and not containing heteroatoms (for example, a system having 6 or 14 π electrons shared in a cyclic configuration). In some embodiments, C 6-10 Aryls are an option. In some embodiments, the aryl has six ring carbon atoms ("C6 aryl"; phenyl, etc.). In some embodiments, the aryl has ten ring carbon atoms ("C6 aryl"). 10 "Aryl" (e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aforementioned aryl ring is condensed with one or more cycloalkyl or heterocyclyl groups, with the bond position located on the aryl ring, in which case the carbon number also indicates the carbon number of the aryl ring system. The aryl group may be substituted with one or more substituents as needed, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] A "5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (e.g., a system with 6, 10, or 14 π electrons shared in a cyclic configuration), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the bond site may be carbon or nitrogen, as long as the valence allows. Bicyclic heteroaryl systems may contain one or more heteroatoms in one or both rings. Heteroaryls also encompass ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl groups, with the bond site located on the heteroaryl ring, in which case again, the carbon number indicates the carbon number of the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryls, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms, are optional. In some embodiments, 5-6 membered heteroaryls, which are monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms, are particularly preferred. In some other embodiments, 5-membered heteroaryls are particularly preferred. In some other embodiments, 6-membered heteroaryls are particularly preferred. Examples of 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Examples of 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (1,2,4-oxadiazolyl, etc.), and thiadiazolyl. Examples of 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl or pyridonyl. Examples of six-membered heteroaryl compounds containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl, although these are not particularly limited.Examples of six-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl. Examples of seven-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryls include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be substituted with one or more substituents as needed, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] "C 6-10 "Arirene" is C 6-10 This refers to a divalent group obtained by removing another hydrogen atom from an aryl group, which may be substituted or unsubstituted. In some embodiments, phenylene is a particular choice, and alternatively, [ka] And alternatively, [ka] That is the case.

[0038] "5-10 membered heteroarylene" refers to a divalent group obtained by removing another hydrogen atom from a 5-10 membered heteroaryl group, which may be substituted or unsubstituted. In some embodiments, 9-10 membered heteroarylene is a particular choice, with indolylene as an alternative, and alternatively, [ka] it is. In some embodiments, 5- to 6-membered heteroarylene is a particularly preferred option.

[0039] Divalent groups obtained by removing an additional hydrogen from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined above are collectively referred to as "-ylene". Cyclic groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl are collectively referred to as "cyclyl".

[0040] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl as defined herein are groups that may be optionally substituted.

[0041] Substituents on carbon atoms are not particularly limited, and include 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(=NR bb )OR aa、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(Rcc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc Examples include alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, each independently containing 0, 1, 2, 3, 4, or 5 R dd It is substituted with the base, or

[0042] Two geminal hydrogen atoms on a carbon atom are =O, =S, =NN(R) bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb , or =NOR cc It has been replaced with,

[0043] Each R aa These are independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups are bonded to form a heterocyclyl or heteroaryl ring, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base,

[0044] Each R bb These are independently hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR 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, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb The groups are bonded to form a heterocyclyl or heteroaryl ring, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base,

[0045] Each R cc R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups are bonded to form a heterocyclyl or heteroaryl ring, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with the base,

[0046] Each R dd These are independently 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 )Rff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee)2, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which independently has 0, 1, 2, 3, 4, or 5 R gg It is substituted with a base, or two geminal R's dd Substituents may be bonded to form =O or =S.

[0047] Each R ee R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg It is substituted with the base,

[0048] Each R ff R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups are bonded to form a heterocyclyl or heteroaryl ring, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. gg It is substituted with the base,

[0049] Each R gg These are 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 1-6Alkyl) + 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 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6Alkyl, -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 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 It can be an aryl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, or two geminal Rs. gg Substituents may be bonded to form =O or =S, X - It is a counterion.

[0050] The substituents on the nitrogen atom are not particularly limited, but include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa, -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bonded to a nitrogen atom cc The groups are bonded to form a heterocyclyl or heteroaryl ring, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R groups. dd It is substituted with R aa , R bb , R cc , and R dd This is as stated above.

[0051] Other definitions

[0052] "Anti-inflammatory agents" refer to pharmaceutical molecules that are active in preventing or treating inflammation, and can reduce inflammation and pain by inhibiting the production or release of inflammatory factors. General anti-inflammatory agents are mainly classified into two categories. One is steroidal anti-inflammatory agents, which can be further divided into sex hormones and corticosteroids, and they regulate glucose metabolism as well as water and salt metabolism, exhibiting anti-inflammatory and anti-allergic effects and improving metabolic function. Common steroidal anti-inflammatory agents include dexamethasone and methylprednisolone. The other category is nonsteroidal anti-inflammatory drugs (NSAIDs), which include loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetin, bromfenac, tiaprofenic acid, indomethacin, sulindac, ketorolac, nimeslide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, nabumetone, etodolac, lofecoxib, celecoxib, piroxicam, meloxicam, and oxyfenbutazone.

[0053] A "derivative" refers to a compound obtained by substituting one atom or group of atoms in a molecule with another atom or group of atoms.

[0054] "Central nervous system-related disorders" include, but are not limited to, pain, depression, and addiction.

[0055] "Pain" is not particularly limited, but includes acute pain and chronic pain.

[0056] In one embodiment, "pain" is not particularly limited, but includes neuralgia, perioperative pain (including preoperative, intraoperative, or postoperative pain, such as somatic or visceral pain due to postoperative trauma or incision, pain due to visceral injury, and other generalized pain), and cancer pain (such as pain due to cancer).

[0057] In one embodiment, “pain” is acute pain or chronic pain (including preoperative, intraoperative, or postoperative acute / chronic pain, acute neuralgia, or chronic neuralgia).

[0058] In one embodiment, "neuralgia" refers to central pain such as spinal pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain.

[0059] "Postoperative pain" refers to pain resulting from surgery, such as abdominal surgery, orthopedic surgery, cesarean section, or brain surgery.

[0060] In this specification, “to treat” or “treatment” refers to reversing, reducing, or inhibiting the progression of a disorder or condition, or one or more symptoms of such disorder or condition, or preventing such disorder or condition. In this specification, the noun “treatment” refers to the action of the verb “to treat” as defined above.

[0061] In this specification, “pharmaceutically acceptable salts” means carboxylate salts and amino acid addition salts of the compounds disclosed herein that are suitable for use in contact with patient tissue without causing excessive toxicity, irritation, or allergic reactions, within the bounds of sound medical judgment, that are balanced by a reasonable benefit-risk ratio, and that are effective for the intended use, and include zwitterionic forms (where possible) of the compounds disclosed herein.

[0062] pharmaceutically acceptable base addition salts are those formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0063] Base addition salts of acidic compounds can be prepared by conventional methods by contacting the free acid form with a sufficient amount of the desired base to form a salt. Free acids can be regenerated by conventional methods by contacting the salt form with an acid and separating the free acid. While the free acid form differs somewhat from its salt form in some physical properties, such as solubility in polar solvents, for the purposes of this disclosure, the salt is equivalent to its free acid.

[0064] The salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydrobromic acid, and phosphoric acid. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate. Salts may also be prepared from aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and organic acids such as aliphatic and aromatic sulfonic acids. Typical salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, and mesylate. Pharmaceutically acceptable salts include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as cations of non-toxic ammonium, quaternary ammonium, and amines, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Furthermore, amino acid salts such as arginates, glucons, and galacturons are also included (see, for example, Berge SMet al., “Pharmaceutical Salts”, J.Pharm.Sci., 1977;66:1-19 (as incorporated herein by reference)).

[0065] The “subjects” to whom the compounds are administered are not particularly limited, but include humans (i.e., males or females of any age group, e.g., pediatric subjects (infants, children, or adolescents, etc.) or adult subjects (young adults, middle-aged adults, or elderly adults, etc.)), and / or non-human animals, e.g., mammals such as primates (crab-eating macaques or rhesus macaques, etc.), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0066] In this specification, the terms "disease," "disorder," and "condition" are used interchangeably.

[0067] Unless otherwise indicated, the term “to treat” in this specification includes, but also includes, an action that reduces the severity of a particular disease, disorder, or condition, or delays or slows the progression of such disease, disorder, or condition, if the subject is suffering from such disease, disorder, or condition (“therapeutic treatment”), and an action that occurs before the subject begins to suffer from a particular disease, disorder, or condition (“preventive treatment”).

[0068] Generally, the “effective dose” of a compound refers to an amount sufficient to induce the desired biological response. Those skilled in the art will understand that the effective dose of the compounds in this disclosure may vary depending on the biological purpose, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, health status, and symptoms of the subject. Effective doses include therapeutic and prophylactic doses. In some embodiments of this disclosure, effective doses calculated based on the compound range from 0.1 mg / day to 1000 mg / day, alternatively from 3 mg / day to 300 mg / day, and further alternatively from 5 mg / day to 50 mg / day.

[0069] Unless otherwise indicated herein, “therapeutic dose” of a compound means an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or an amount that delays or minimizes one or more symptoms associated with the disease, disorder, or condition. The therapeutic dose of a compound means an amount that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. “Therapeutic dose” may include an amount that improves the overall treatment, an amount that reduces or avoids the symptoms or causes of the disease or condition, or an amount that enhances the therapeutic effect of other therapeutic agents.

[0070] Unless otherwise indicated herein, the “preventive dose” of a compound means an amount sufficient to prevent a disease, disorder, or condition, an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount that prevents the recurrence of a disease, disorder, or condition. The preventive dose of a compound means the amount that, when used alone or in combination with other agents, provides a preventive benefit in the prevention of a disease, disorder, or condition. The “preventive dose” may include an amount that improves overall prevention or enhances the preventive effect of other preventive agents.

[0071] "Concomitant use" and related terms refer to the simultaneous or sequential administration of the compounds of this disclosure with an additional therapeutic agent. For example, the compounds of this disclosure may be administered simultaneously or sequentially with the additional therapeutic agent in separate unit dosage forms, or simultaneously with the additional therapeutic agent in a single unit dosage form. [Brief explanation of the drawing]

[0072] [Figure 1] The results of the DRG trial are shown. [Modes for carrying out the invention]

[0073] In this specification, “compounds of the disclosure” means compounds such as those of formula (I), formula (II), formula (III), and formula (III-1), or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or their pharmaceutically acceptable salts.

[0074] In this specification, compounds are named using standard nomenclature. For compounds having a chiral center, it will be understood that all optical isomers and mixtures thereof are included unless otherwise specified. Furthermore, all isomer compounds and carbon-carbon double bonds included in this disclosure may exist in either the Z-form or the E-form unless otherwise specified. Compounds existing in different tautomer forms are not limited to specific tautomers, but are intended to encompass all tautomer forms.

[0075] In one embodiment, the disclosure relates to a compound of formula (I), or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof. [ka]

[0076] During the ceremony,

[0077] R D These are residues formed by drug molecules;

[0078] U1, U2, and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)-, and -O-CH2-O-;

[0079] W1, W2, and W3 are independent of H and C respectively. 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10Selected from aryls and 5-10 member heteroaryls;

[0080] L is a chemical bond or [ka] And alternatively, [ka] and;

[0081] L1 is 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 - Selected from;

[0082] L2 is a chemical bond, C 3-7 Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes;

[0083] L3 is selected from O, S, NR', -C(O)-, -S(O)-, and -S(O)2-;

[0084] n is selected from 0, 1, 2, 3, 4, 5, and 6;

[0085] [ka] The methylene group in may be substituted with 1, 2, 3, 4, 5, or 6 independent R groups;

[0086] R is independent of 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 0-10Alkylene-C(O)OR a , -C 0-10 Alkilen-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 Selected from cycloalkyl and 3- to 6-membered heterocyclines;

[0087] R' is H, C 1-18 Alkyl, C 1-18 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, or R' and R together with the atoms to which they are bonded form a 3- to 10-membered heterocycline;

[0088] R a , R b , and R c H and C are independent of each other. 1-10 Alkyl, and C 1-10 Selected from haloalkyls, or R b and R c However, together with the atoms they bond to, they form 3- to 10-membered heterocyclines;

[0089] Each of the above groups may be deuterated to the maximum extent of complete deuteration.

[0090] In another embodiment, the compounds of the present disclosure are further represented by formula (II), formula (III), or formula (III-1). [ka]

[0091] In the formula, each variable is as defined in this disclosure.

[0092] In the compounds of this disclosure, each group may be defined as follows:

[0093] R D

[0094] In one embodiment, R D These are residues formed by drug molecules.

[0095] In one embodiment, the drug molecule is an anti-inflammatory agent and its derivatives. In another embodiment, the drug molecule is an anti-inflammatory agent. In yet another embodiment, the drug molecule is a derivative of an anti-inflammatory agent.

[0096] In one embodiment, the anti-inflammatory agent is a nonsteroidal anti-inflammatory drug.

[0097] In one embodiment, the nonsteroidal anti-inflammatory agent is loxoprofen. In another embodiment, the nonsteroidal anti-inflammatory agent is flurbiprofen, for example S-flurbiprofen, for example R-flurbiprofen. In yet another embodiment, the nonsteroidal anti-inflammatory agent is fenoprofen. In yet another embodiment, the nonsteroidal anti-inflammatory agent is ketoprofen. In yet another embodiment, the nonsteroidal anti-inflammatory agent is tolmetin. In yet another embodiment, the nonsteroidal anti-inflammatory agent is bromfenac. In yet another embodiment, the nonsteroidal anti-inflammatory agent is tiaprofenic acid. In yet another embodiment, the nonsteroidal anti-inflammatory agent is indomethacin. In yet another embodiment, the nonsteroidal anti-inflammatory agent is sulindac. In yet another embodiment, the nonsteroidal anti-inflammatory agent is ketorolac. In yet another embodiment, the nonsteroidal anti-inflammatory agent is nimeslide. In yet another embodiment, the nonsteroidal anti-inflammatory agent is mefenamic acid. In yet another embodiment, the nonsteroidal anti-inflammatory agent is clofenamic acid. In yet another embodiment, the nonsteroidal anti-inflammatory agent is diclofenac. In another embodiment, the nonsteroidal anti-inflammatory agent is aspirin. In another embodiment, the nonsteroidal anti-inflammatory agent is ibuprofen. In another embodiment, the nonsteroidal anti-inflammatory agent is naproxen. In another embodiment, the nonsteroidal anti-inflammatory agent is nabumetone. In another embodiment, the nonsteroidal anti-inflammatory agent is etodolac. In another embodiment, the nonsteroidal anti-inflammatory agent is rofecoxib. In another embodiment, the nonsteroidal anti-inflammatory agent is celecoxib. In another embodiment, the nonsteroidal anti-inflammatory agent is piroxicam. In another embodiment, the nonsteroidal anti-inflammatory agent is meloxicam. In another embodiment, the nonsteroidal anti-inflammatory agent is oxyfenbutazone.

[0098] In one more specific embodiment, the drug molecule is selected from loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetine, bromfenac, tiaprofenic acid, indomethacin, sulindac, ketorolac, nimeslide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, nabumetone, etodolac, lofecoxib, celecoxib, piroxicam, meloxicam, and oxyfenbutazone, as well as their derivatives. In another more specific embodiment, the drug molecule is selected from loxoprofen, flurbiprofen, indomethacin, mefenamic acid, clofenamic acid, and aspirin, as well as their derivatives. In yet another more specific embodiment, the drug molecule is selected from flurbiprofen and clofenamic acid, as well as their derivatives. In yet 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 yet another, more specific embodiment, the drug molecule is selected from R-flurbiprofen and its derivatives.

[0099] In one embodiment, R D teeth [ka] In another embodiment, R D teeth [ka] That is the case.

[0100] In one embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] That is the case.

[0101] In a more specific embodiment, [ka] The following structure: [ka] Selected from. In another, more specific embodiment, [ka] teeth [ka] Selected from. In another, more specific embodiment, [ka] teeth [ka] Selected from.

[0102] Ring A

[0103] In one embodiment, ring A is C 6-10 It is allirene, and alternatively phenylene, for example. [ka] For example, [ka] In another embodiment, ring A is a 5-10 member heteroarylene, and alternatively a 9-10 member heteroarylene (e.g., indolylene, e.g., [ka] ) and alternatively a 5-6 member heteroarylene. In another embodiment, ring A is C 6-10 Aryl condensation C 5-10 It is a cycloalkyl. In another embodiment, ring A is C 6-10 It is an aryl condensed 5-10 member heterocyclyl. In another embodiment, ring A is a 5-10 member heteroaryl condensed C 5-10It is a cycloalkyl group. In another embodiment, ring A is a 5-10 member heteroaryl condensed 5-10 member heterocyclyl group.

[0104] In a more specific embodiment, ring A is C 6-10 Arirene, 5-10 member heteroarirene, C 6-10 Aryl condensation C 5-10 Cycloalkyl, C 6-10 Aryl condensed 5-10 member heterocyclyl, 5-10 member heteroaryl condensed C 5-10 Selected from cycloalkyls and 5-10 member heteroaryl condensations and 5-10 member heterocyclyls. In another, more specific embodiment, ring A is C 6-10 It is selected from arylenes and 5-10 membered heteroarylenes. In another, more specific embodiment, ring A is selected from phenylenes and 9-10 membered heteroarylenes, and alternatively from phenylenes and indolylenes. In another, more specific embodiment, ring A is phenylene. In another, more specific embodiment, ring A is [ka] Selected from. In another, more specific embodiment, ring A is [ka] Selected from. In another, more specific embodiment, ring A is [ka] That is the case.

[0105] Ring B

[0106] In one embodiment, ring B is C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is a cycloalkyl. In another embodiment, ring B is a 3- to 10-membered heterocyclyl, and alternatively, a 3- to 7-membered heterocyclyl. In another embodiment, ring B is C 6-10It is aryl, and alternatively phenyl. In another embodiment, ring B is a 5- to 10-membered heteroaryl, and alternatively 5- to 6-membered heteroaryl. In yet another embodiment, L4-ring B and R2 are absent.

[0107] In a more specific embodiment, ring B is C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In another, more specific embodiment, ring B is C 6-10 Selected from aryls and 5-10 membered heteroaryls. In another, more specific embodiment, ring B is C 3-7 The ring B is selected from cycloalkyls, 3- to 7-membered heterocyclines, phenyls, and 5- to 6-membered heteroaryls. In another, more specific embodiment, ring B is selected from phenyls and 5- to 6-membered heteroaryls.

[0108] R1

[0109] In one embodiment, R1 is H. In another embodiment, R1 is D. In yet another embodiment, R1 is a halogen, and alternatively F. In yet another embodiment, R1 is CN. In yet another embodiment, R1 is -NO2. In yet another embodiment, R1 is -OR a 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 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 cIn 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 It is alkyl, and alternatively C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl, and alternatively Me. In another embodiment, R1 is C 1-18 It is a haloalkyl, and alternatively C 1-10 It is a haloalkyl, and alternatively C 1-6 It is a haloalkyl. In another embodiment, R1 is C 3-14 It is a cycloalkyl, and alternatively C 3-10 It is a cycloalkyl, and alternatively C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is a cycloalkyl. In another embodiment, R1 is a 3- to 14-membered heterocycline, alternatively a 3- to 10-membered heterocycline, and alternatively a 3- to 7-membered heterocycline. In another embodiment, R1 is C 6-14 It is aryl, and alternatively C 6-10 It is an aryl, and alternatively a phenyl. In another embodiment, R1 is a 5-14 member heteroaryl, alternatively a 5-10 member heteroaryl, and alternatively a 5-6 member heteroaryl. In another embodiment, R1 is one, two, or three independent R 1s It may be substituted with . In another embodiment, R1 is unsubstituted.

[0110] In a more specific embodiment, R1 is independently 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)Ra -S(O)2R a , C 1-18 Alkyl, C 1-18 Haloalkyl, C 3-14 Cycloalkyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls. In another, more specific embodiment, R1 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, R1 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, R1 is independently 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines. In another, more specific embodiment, R1 is independently 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 Selected from haloalkyls. In another, more specific embodiment, R1 is independently 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 Selected from haloalkyls. In another, more specific embodiment, R1 is independently H, D, halogen, -OR a -OC(O)R a , C 1-6 Alkyl, and C 1-6 It is selected from haloalkyl groups. In another, more specific embodiment, R1 is independently selected from H, F, Me, -OMe, and -OC(O)CH3.

[0111] In a more specific embodiment, R1 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In another, more specific embodiment, R1 is independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 It is selected from haloalkyls. In another, more specific embodiment, R1 is independently selected from H, D, and halogens. In yet another, more specific embodiment, R1 is independently H or F.

[0112] R2

[0113] In one embodiment, R2 is H. In another embodiment, R2 is D. In yet another embodiment, R2 is a halogen, and alternatively, Cl. In yet another embodiment, R2 is CN. In yet another embodiment, R2 is -NO2. In yet 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 aIn another embodiment, R2 is C 1-18 It is alkyl, and alternatively C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl, and alternatively Me. In another embodiment, R2 is C 1-18 It is a haloalkyl, and alternatively C 1-10 It is a haloalkyl, and alternatively C 1-6 It is a haloalkyl. In another embodiment, R2 is C 3-14 It is a cycloalkyl, and alternatively C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is a cycloalkyl. In another embodiment, R2 is a 3- to 14-membered heterocycline, alternatively a 3- to 10-membered heterocycline, and alternatively a 3- to 7-membered heterocycline. In another embodiment, R2 is C 6-14 It is aryl, and alternatively C 6-10 It is an aryl, and alternatively a phenyl. In another embodiment, R2 is a 5-14 member heteroaryl, alternatively a 5-10 member heteroaryl, and alternatively a 5-6 member heteroaryl. In another embodiment, R2 is one, two, or three independent R 2s It may be substituted with. In another embodiment, R2 is unsubstituted.

[0114] In a more specific embodiment, R2 is independently 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 member heterocyclyl, C6-14 Selected from aryls and 5-14 member heteroaryls. In another, more specific embodiment, R2 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, R2 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, R2 is independently 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)NRb R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 The following are selected from cycloalkyls, 3- to 7-membered heterocyclines, phenyls, and 5- to 6-membered heteroaryls. In another, more specific embodiment, R2 is independently H, D, halogens, 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 Selected from haloalkyls. In another, more specific embodiment, R2 is independently H, D, halogen, CN, C 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, R2 is independently H, D, halogen, C 1-6 Alkyl, and C 1-6 It is selected from a haloalkyl group. In another, more specific embodiment, R2 is independently selected from H, Cl, and Me. In yet another, more specific embodiment, R2 is independently selected from H and Cl.

[0115] In a more specific embodiment, R2 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls. In another, more specific embodiment, R2 is independently H, D, halogens, CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines. In another, more specific embodiment, R2 is independently H, D, halogen, C 1-6 Alkyl, and C 1-6 It is selected from haloalkyls. In another, more specific embodiment, R2 is independently selected from H, D, and halogens. In yet another, more specific embodiment, R2 is independently H or D.

[0116] R 1s and R 2s

[0117] In one embodiment, R 1s In another embodiment, R 1s In another embodiment, R 1s is a halogen. In another embodiment, R 1s is CN. In another embodiment, R 1s は-OR a In another embodiment, R 1s Ha-SR a In another embodiment, R 1s -NR b R c In another embodiment, R 1s -OC(O)R a In another embodiment, R 1s is -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 is C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl. In another embodiment, R 1s is C 1-10 It is a haloalkyl, and alternatively C 1-6In another embodiment, R 1s is C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is cycloalkyl. In another embodiment, R 1s These are 3-10 member heterocyclines, and alternatively, 3-7 member heterocyclines.

[0118] In one embodiment, R 2s In another embodiment, R 2s In another embodiment, R 2s is a halogen. In another embodiment, R 2s is CN. In another embodiment, R 2s は-OR a In another embodiment, R 2s Ha-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 is -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 is C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl. In another embodiment, R 2s is C 1-10 It is a haloalkyl, and alternatively C 1-6 In another embodiment, R 2s is C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is cycloalkyl. In another embodiment, R 2sThese are 3-10 member heterocyclines, and alternatively, 3-7 member heterocyclines.

[0119] In a more specific embodiment, R 1s These are independently H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3-10 membered heterocyclines. In another, more specific embodiment, R 1s These are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines. In another, more specific embodiment, R 1s These are independently H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups.

[0120] In a more specific embodiment, R 2s These are independently H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3-10 membered heterocyclines. In another, more specific embodiment, R 2s These are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines. In another, more specific embodiment, R 2s These are independently H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups.

[0121] m

[0122] In one embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2. In yet another embodiment, m is 3. In yet another embodiment, m is 4. In yet another embodiment, m is 5.

[0123] 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 yet another more specific embodiment, m = 0, 1, or 2. In yet another more specific embodiment, m = 0 or 1.

[0124] s

[0125] In one embodiment, s is 0. In another embodiment, s is 1. In yet another embodiment, s is 2. In yet another embodiment, s is 3. In yet another embodiment, s is 4. In yet another embodiment, s is 5.

[0126] In a more specific embodiment, s = 0, 1, 2, 3, 4, or 5. In another more specific embodiment, s = 0, 1, or 2.

[0127] L4

[0128] In one embodiment, L4 is a chemical bond. In another embodiment, L4 is -CR4R'4-, and alternatively -CH2-. In yet another embodiment, L4 is -NR b - and alternatively -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 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 bonded are both [ka] In another embodiment, L4 and the carbon atoms on ring A to which L4 is bonded are [ka] It does not form.

[0129] In a more specific embodiment, L4 is 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- are selected. In another, more specific embodiment, L4 is a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)-, and -S(O)- are selected. In another, more specific embodiment, L4 is a chemical bond, -CR4R'4-, -NR b -, O, and -C(O)- are selected. In another, more specific embodiment, L4 is a chemical bond, -NR b -, and -C(O)- are selected. In another, more specific embodiment, L4 is selected from a chemical bond, -NH-, and -C(O)-. In yet another, more specific embodiment, L4 is selected from a chemical bond and -NH-.

[0130] L5

[0131] In one embodiment, L5 is a chemical bond. In another embodiment, L5 is O. In yet another embodiment, L5 is S. In yet another embodiment, L5 is NR'. In yet another embodiment, L5 is C 1-10 It is an alkylene, and alternatively C 1-6 It is an alkylene, and alternatively C1-4 It is an alkylene, and alternatively C 1-2 It is an alkylene, and alternatively, a methylene. In another embodiment, L5 may be substituted with one or more independent R3s. In another embodiment, L5 may be substituted with 1, 2, 3, 4, 5, or 6 independent R3s. In another embodiment, L5 may be substituted with 1, 2, or 3 independent R3s. In another embodiment, L5 may be substituted with 1 R3. In another embodiment, L5 is unsubstituted.

[0132] In a more specific embodiment, L5 is a chemical bond, O, S, NR', and C 1-10 Selected from alkylenes. In another, more specific embodiment, L5 is a chemical bond or C 1-10 It is alkylene. In another, more specific embodiment, L5 is a chemical bond or C 1-6 It is alkylene. In another, more specific embodiment, L5 is a chemical bond or C 1-4 It is alkylene. In another, more specific embodiment, L5 is a chemical bond or C 1-2 It is alkylene. In another, more specific embodiment, L5 is a chemical bond or methylene. In yet another, more specific embodiment, L5 is -CH(CH3)-.

[0133] R3

[0134] In one embodiment, R3 is H. In another embodiment, R3 is D. In yet another embodiment, R3 is halogen. In yet another embodiment, R3 is C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl, and alternatively C 1-4 It is alkyl. In another embodiment, R3 is C 1-10 It is a haloalkyl, and alternatively C 1-6 It is a haloalkyl, and alternatively C 1-4 It is a haloalkyl group.

[0135] In a more specific embodiment, R3 is independently H, D, halogen, C 1-10 Alkyl, and C 1-10 Selected from haloalkyls. In another, more specific embodiment, R3 is independently H, D, halogen, C 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, R3 is independently H, D, C 1-4 Alkyl, and C 1-4 It is selected from a haloalkyl group. In another, more specific embodiment, R3 is independently selected from H and Me. In yet another, more specific embodiment, R3 is Me.

[0136] R4 and R'4

[0137] In one embodiment, R4 is H. In another embodiment, R4 is D. In yet another embodiment, R4 is halogen. In yet another embodiment, R4 is C 1-6 It is alkyl. In another embodiment, R4 is C 1-6 It is a haloalkyl group.

[0138] In one embodiment, R'4 is H. In another embodiment, R'4 is D. In yet another embodiment, R'4 is halogen. In yet another embodiment, R'4 is C 1-6 It is alkyl. In another embodiment, R'4 is C 1-6 It is a haloalkyl group.

[0139] In a more specific embodiment, R4 and R'4 are independently H, D, halogen, C 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, R4 and R'4 are independently H, D, C 1-6 Alkyl, and C 1-6 Selected from a haloalkyl group. In another, more specific embodiment, R4 and R'4 are independently H or D.

[0140] X

[0141] In one embodiment, X is -C(O)-. In another embodiment, X is -S(O)-. In yet another embodiment, X is -S(O)2-.

[0142] In a more specific embodiment, X is selected from -C(O)-, -S(O)-, and -S(O)2-.

[0143] U1, U2, and U3

[0144] In one embodiment, U1 is O. In another embodiment, U1 is S. In yet another embodiment, U1 is -NH-. In yet another embodiment, U1 is -C(O)-. In yet another embodiment, U1 is -OC(O)-. In yet another embodiment, U1 is -NH-C(O)-. In one embodiment, U1 is -O-CH2-O-.

[0145] 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-.

[0146] 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-.

[0147] 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.

[0148] W1, W2, and W3

[0149] In one embodiment, W1 is H. In another embodiment, W1 is C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl, and alternatively methyl. In another embodiment, W1 is C 1-10 It is an alkyl deuterated, and alternatively C 1-6 It is an alkyl deuterated, and alternatively CD3. In another embodiment, W1 is C 1-10 It is a haloalkyl, and alternatively C 1-6 It is a haloalkyl. In another embodiment, W1 is C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is a cycloalkyl. In another embodiment, W1 is a 3- to 10-membered heterocycline, and alternatively, a 3- to 7-membered heterocycline. In another embodiment, W1 is C 6-10 It is an aryl, and alternatively a phenyl. In another embodiment, W1 is a 5- to 10-membered heteroaryl, and alternatively a 5- to 6-membered heteroaryl.

[0150] In one embodiment, W2 is H. In another embodiment, W2 is C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl, and alternatively methyl. In another embodiment, W2 is C 1-10 It is an alkyl deuterated, and alternatively C 1-6 It is an alkyl deuterated, and alternatively, CD3. In another embodiment, W2 is C 1-10 It is a haloalkyl, and alternatively C 1-6 It is a haloalkyl. In another embodiment, W2 is C 3-10 It is a cycloalkyl, and alternatively C 3-7It is a cycloalkyl. In another embodiment, W2 is a 3- to 10-membered heterocycline, and alternatively, a 3- to 7-membered heterocycline. In another embodiment, W2 is C 6-10 It is an aryl, and alternatively a phenyl. In another embodiment, W2 is a 5- to 10-membered heteroaryl, and alternatively a 5- to 6-membered heteroaryl.

[0151] In one embodiment, W3 is H. In another embodiment, W3 is C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl, and alternatively methyl. In another embodiment, W3 is C 1-10 It is an alkyl deuterated, and alternatively C 1-6 It is an alkyl deuterated, and alternatively, CD3. In another embodiment, W3 is C 1-10 It is a haloalkyl, and alternatively C 1-6 In another embodiment, W3 is C 3-10 It is a cycloalkyl, and alternatively C 3-7 It is a cycloalkyl. In another embodiment, W3 is a 3- to 10-membered heterocycline, and alternatively, a 3- to 7-membered heterocycline. In another embodiment, W3 is C 6-10 It is an aryl, and alternatively a phenyl. In another embodiment, W3 is a 5- to 10-membered heteroaryl, and alternatively a 5- to 6-membered heteroaryl.

[0152] In a more specific embodiment, W1 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, W1 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10Selected from cycloalkyls and 3- to 10-membered heterocyclines. In another, more specific embodiment, W1 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, and C 1-10 Selected from haloalkyls. In another, more specific embodiment, W1 is C 1-6 Alkyl, C 1-6 Alkyl deuterated, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, W1 is C 1-6 Alkyl or C 1-6 It is a deuterated alkyl. In another, more specific embodiment, W1 is methyl or CD3. In yet another, more specific embodiment, W1 is C 1-6 It is alkyl. In another, more specific embodiment, W1, W2, and W3 are methyl.

[0153] In a more specific embodiment, W2 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, W2 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines. In another, more specific embodiment, W2 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, and C 1-10 Selected from haloalkyls. In another, more specific embodiment, W2 is C 1-6 Alkyl, C 1-6 Alkyl deuterated, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, W2 is C 1-6 Alkyl or C 1-6It is a deuterated alkyl. In another, more specific embodiment, W2 is methyl or CD3. In yet another, more specific embodiment, W2 is C 1-6 It is alkyl. In another, more specific embodiment, W2 is methyl.

[0154] In a more specific embodiment, W3 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. In another, more specific embodiment, W3 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines. In another, more specific embodiment, W3 is C 1-10 Alkyl, C 1-10 Alkyl deuterated, and C 1-10 Selected from haloalkyls. In another, more specific embodiment, W3 is C 1-6 Alkyl, C 1-6 Alkyl deuterated, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, W3 is C 1-6 Alkyl or C 1-6 It is a deuterated alkyl. In another, more specific embodiment, W3 is methyl or CD3. In yet another, more specific embodiment, W3 is C 1-6 It is alkyl. In another, more specific embodiment, W3 is methyl.

[0155] L

[0156] In one embodiment, L is a chemical bond. In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] In another embodiment, L is [ka] That is the case.

[0157] In one embodiment, [ka] The methylene group in may be substituted with 1, 2, 3, 4, 5, or 6 independent R groups. In another embodiment, [ka] The methylene group in may be substituted with 1, 2, or 3 R groups. In another embodiment, [ka] The methylene group in this compound may be substituted with a single R.

[0158] In a more specific embodiment, L is a chemical bond, [ka] Selected from. In another, more specific embodiment, L is a chemical bond, [ka] Selected from. In another, more specific embodiment, L is a chemical bond, [ka] Selected from. In another, more specific embodiment, L is a chemical bond, [ka] Selected from. In another, more specific embodiment, L is a chemical bond, [ka] Selected from. In another, more specific embodiment, L is [ka] Selected from.

[0159] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0160] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0161] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0162] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0163] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0164] L1

[0165] In one embodiment, L1 is a chemical bond. In another embodiment, L1 is -C(O)-. In yet another embodiment, L1 is -OC(O)-. In yet another embodiment, L1 is -NR b It is C(O)-, for example, -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 - and for example, -NHS(O) 1-2 - is

[0166] In one more specific embodiment, L1 is selected from chemical bonds, -C(O)-, -OC(O)-, and -NHC(O)-. In another more specific embodiment, L1 is selected from -C(O)- and -OC(O)-. In yet another more specific embodiment, L1 is -C(O)-.

[0167] In one 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 yet another more specific embodiment, L1 is selected from -OC(O)-.

[0168] L2

[0169] In one embodiment, L2 is a chemical bond. In another embodiment, L2 is C 3-7 It is a cycloalkylene. In another embodiment, L2 is a 3- to 7-membered heterocyclene. In yet another embodiment, L2 is phenylene, for example [ka] For example, [ka] In another embodiment, L2 is a 5-6 member heteroarylene.

[0170] In a more specific embodiment, L2 is a chemical bond, C 3-7 The L2 is selected from cycloalkylene, 3- to 7-membered heterocyclene, phenylene, and 5- to 6-membered heteroarylene. In another more specific embodiment, L2 is selected from a chemical bond, phenylene, and 5- to 6-membered heteroarylene. In another more specific embodiment, L2 is selected from a chemical bond and phenylene. In another more specific embodiment, L2 is a chemical bond, [ka] Selected from. In another, more specific embodiment, L2 is a chemical bond and [ka] Selected from.

[0171] L3

[0172] In one embodiment, L3 is O. In another embodiment, L3 is S. In yet another embodiment, L3 is NR', for example, NH. In yet another embodiment, L3 is -C(O)-. In yet another embodiment, L3 is -S(O)-. In yet another embodiment, L3 is -S(O)2-.

[0173] 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 yet another more specific embodiment, L2 is selected from O and NH. In yet another more specific embodiment, L2 is selected from O and S.

[0174] n

[0175] In one embodiment, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2. In yet another embodiment, n is 3. In yet another embodiment, n is 4. In yet another embodiment, n is 5. In yet another embodiment, n is 6.

[0176] In one 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 yet another more specific embodiment, n is 1 or 2.

[0177] R

[0178] In one embodiment, R is H. In another embodiment, R is D. In yet another embodiment, R is halogen. In yet another embodiment, R is CN. In yet another embodiment, R is =O. In yet 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 Therefore, alternatively, -C 0-6 Alkylene-C(O)R a Therefore, alternatively, -C 0-3 Alkylene-C(O)R a In another embodiment, R is -C 0-10 Alkylene-OC(O)Ra and, alternatively, -C 0-6 alkylene-OC(O)R a and, alternatively, -C 0-3 alkylene-OC(O)R a . In another embodiment, R is -C 0-10 alkylene-C(O)OR a and, alternatively, -C 0-6 alkylene-C(O)OR a and, alternatively, -C 0-3 alkylene-C(O)OR a and, alternatively, 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 and, alternatively, -C 0-6 alkylene-NR b C(O)R a and, alternatively, -C 0-3 alkylene-NR b C(O)R a . In another embodiment, R is -C 0-10 alkylene-C(O)NR b R c and, alternatively, -C 0-6 alkylene-C(O)NR b R c and, alternatively, -C 0-3 alkylene-C(O)NR b R c . In another embodiment, R is C 1-10 alkyl, alternatively C 1-6 alkyl (such as isobutyl), alternatively C 1-3 alkyl (such as methyl). In another embodiment, R is C 1-10 haloalkyl, alternatively C 1-6 haloalkyl, alternatively C 1-3 haloalkyl. In another embodiment, R is C 3-6 cycloalkyl. In another embodiment, R is 3- to 6-membered heterocyclyl.

[0179] In a more specific embodiment, R is independently 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 Alkilen-NR b C(O)R a Selected from. In another, more specific embodiment, R is independently 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 Selected from. In another, more specific embodiment, R is independently H, D, = O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from. In another, more specific embodiment, R is independently H, D, = O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from. In another, more specific embodiment, R is independently H, D, = O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a Selected from. In another, more specific embodiment, R is independently H, D, = O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a Selected from. In another, more specific embodiment, R is independently H, D, =O, and -C 0-3 Selected from alkylene-C(O)OH.

[0180] In one 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 yet another more specific embodiment, R is independently selected from H, =O, methyl, and -(CH2)2C(O)OH. In yet another more specific embodiment, R is independently selected from H, =O, and -(CH2)2C(O)OH.

[0181] In a more specific embodiment, R is independently H, D, halogen, C 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, R is independently H, D, C 1-6 Alkyl, and C 1-6 Selected from haloalkyls. In another, more specific embodiment, R is independently H, D, C 1-3 Alkyl, and C 1-3 It is selected from a haloalkyl group. In another, more specific embodiment, R is independently selected from H and Me.

[0182] R'

[0183] In one embodiment, R' is H. In another embodiment, R' is C 1-18 It is alkyl, and alternatively C 1-10 It is alkyl, and alternatively C 1-6 It is alkyl. In another embodiment, R' is C 1-18 It is a haloalkyl, and alternatively C 1-10 It is a haloalkyl, and alternatively C 1-6 It is a haloalkyl. In another embodiment, R' is C 3-10 It is a cycloalkyl, and alternatively C 3-7is cycloalkyl. In another embodiment, R' is 3- to 10-membered heterocyclyl, alternatively 3- to 7-membered heterocyclyl. In another embodiment, R' and R together with the atom to which they are attached form a 3- to 10-membered heterocyclyl, alternatively form a 3- to 7-membered heterocyclyl, alternatively form a 4- to 6-membered heterocyclyl, alternatively

Chemical Structure

Chemical Structure

[0184] In a more specific embodiment, R' is selected from H, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclyl. In another more specific embodiment, R' is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0185] R a , R b , and R c

[0186] In one embodiment, R a is H. In another embodiment, R a is C 1-10 alkyl, alternatively C 1-6 alkyl. In another embodiment, R a is C 1-10 haloalkyl, alternatively C 1-6 haloalkyl. In another embodiment, R b and R c together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl, alternatively form a 5- to 7-membered heterocyclyl. In another embodiment, Rb and R c They do not form a ring with the atoms to which they bond.

[0187] In a more specific embodiment, R a , R b , and R c H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups.

[0188] Any one technical solution or any combination thereof in any one specific embodiment can be combined with any one technical solution or any combination thereof in any other specific embodiment. For example, R D Any one technical solution or any combination thereof for U1, U2, U3, W1, W2, W3, L, L1, L2, L3, n, R, R', ring A, ring B, R1, R2, R 1s , R 2s , m, s, L4, L5, R3, R4, R'4, X, R a , R b , and R c This disclosure can be combined with any one of the following technical solutions or any combination thereof. While this disclosure is intended to encompass all combinations of these technical solutions, not all of them are described herein due to space limitations.

[0189] In a more specific embodiment, the present disclosure provides a compound of formula (I), or an isotopic variant thereof, a tautomer, a stereoisomer, a prodrug, a polymorph, a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0190] During the ceremony,

[0191] R DThese are residues formed by drug molecules;

[0192] U1, U2, and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)-, and -O-CH2-O-;

[0193] W1, W2, and W3 are independent of H and C respectively. 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls;

[0194] L is a chemical bond or [ka] And alternatively, [ka] and;

[0195] L1 is 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 - Selected from;

[0196] L2 is a chemical bond, C 3-7 Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes;

[0197] L3 is selected from O, S, NR', -C(O)-, -S(O)-, and -S(O)2-;

[0198] n is selected from 0, 1, 2, 3, 4, 5, and 6;

[0199] [ka] The methylene group in may be substituted with 1, 2, 3, 4, 5, or 6 independent R groups;

[0200] R is independent of 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 Alkilen-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 Selected from cycloalkyl and 3- to 6-membered heterocyclines;

[0201] R' is H, C 1-18 Alkyl, C 1-18 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, or R' and R together with the atoms to which they are bonded form a 3- to 10-membered heterocycline;

[0202] R a , R b , and R c H and C are independent of each other. 1-10 Alkyl, and C 1-10 Selected from haloalkyls, or R b and R c However, together with the atoms they bond to, they form 3- to 10-membered heterocyclines;

[0203] Each of the above groups may be deuterated to the maximum extent of complete deuteration.

[0204] In a more specific embodiment, this disclosure is R D The present invention provides compounds of formula (I) described above, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof, wherein the residue is formed by a drug molecule, and the drug molecule is an anti-inflammatory agent and its derivatives, or alternatively, a nonsteroidal anti-inflammatory agent such as loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetine, bromfenac, tiaprofenic acid, indomethacin, sulindac, ketorolac, nimeslide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, nabumetone, etodolac, lofecoxib, celecoxib, piroxicam, meloxicam, and oxyfenbutazone, or a pharmaceutically acceptable salt thereof.

[0205] In a more specific embodiment, the drug molecule is selected from loxoprofen, flurbiprofen, indomethacin, mefenamic acid, clofenamic acid, and aspirin, as well as their derivatives, alternatively from flurbiprofen and clofenamic acid, as well as their derivatives, alternatively from flurbiprofen and its derivatives, alternatively from flurbiprofen, where flurbiprofen is S-flurbiprofen, and alternatively from flurbiprofen, where flurbiprofen is R-flurbiprofen.

[0206] In a more specific embodiment, the present disclosure provides a compound of formula (I) described above, 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)-, and alternatively O.

[0207] In a more specific embodiment, the present disclosure describes how W1, W2, and W3 are each independently C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively C 1-10 Alkyl, C 1-10 Alkyl deuterated, and C 1-10 Selected from haloalkyls, alternatively C 1-6 Alkyl, C 1-6 Alkyl deuterated, and C 1-6 Selected from haloalkyls, alternatively C 1-6 Alkyl or C 1-6 Alkyl deuterated, alternatively methyl or CD3, or alternatively C 1-6 The present invention provides compounds of formula (I) described above, which are alkyl, or alternatively methyl, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

[0208] In a more specific embodiment, the present disclosure 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 L1 is selected from a chemical bond, -C(O)-, -OC(O)-, and -NHC(O)-, alternatively selected from a chemical bond, -C(O)-, and -OC(O)-, alternatively selected from -C(O)- and -OC(O)-, and alternatively -C(O)-.

[0209] In a more specific embodiment, L1 is selected from -C(O)-, -OC(O)-, and -NHC(O)-, alternatively selected from -OC(O)- and -NHC(O)-, and alternatively -OC(O)-.

[0210] In a more specific embodiment, the disclosure describes a chemical bond where L2 is C 3-7Selected from cycloalkylenes, 3-7 membered heterocyclenes, phenylenes, and 5-6 membered heteroarylenes, alternatively chemically bonded, selected from phenylenes and 5-6 membered heteroarylenes, alternatively chemically bonded, and selected from phenylenes, alternatively chemically bonded, [ka] Selected from, alternatively, chemical bonds and [ka] The present invention provides compounds of formula (I) above, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof, selected from and alternatively characterized by a chemical bond.

[0211] In a more specific embodiment, the present disclosure 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 L3 is selected from O, S, and NR', alternatively selected from O and NR', alternatively selected from O and S, alternatively O, or alternatively NR'.

[0212] In a more specific embodiment, the present disclosure provides a compound of formula (I) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, where n is selected from 0, 1, 2, and 3, alternatively selected from 1, 2, and 3, alternatively 1 or 2, or alternatively 1.

[0213] In a more specific embodiment, this disclosure refers to, [ka] The present invention provides the compound of formula (I) described above, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof, wherein the methylene group in may be substituted with one, two, or three independent R groups, or alternatively, with one R group.

[0214] In a more specific embodiment, the present disclosure provides that R is independently 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 Alkilen-NR b C(O)R a Selected from, alternatively 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 Selected from, alternatively H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, and -C 0-3The present invention provides compounds of formula (I) above, selected from alkylene-C(O)OH, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

[0215] In a more specific embodiment, R is independently selected from H, =O, methyl, isobutyl, -C(O)OH, and -(CH2)2C(O)OH, alternatively selected from H, =O, methyl, -C(O)OH, and -(CH2)2C(O)OH, alternatively selected from H, =O, methyl, and -(CH2)2C(O)OH, and alternatively selected from H, =O, and -(CH2)2C(O)OH.

[0216] In a more specific embodiment, R is independently H, D, halogen, C 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, and C. 1-3 Alkyl, and C 1-3 Selected from haloalkyl groups, and alternatively selected from H and Me.

[0217] In a more specific embodiment, the present disclosure is provided that R' is H, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, substituted with H, C 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I) above, selected from haloalkyls, substituted with H, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, or pharmaceutically acceptable salts thereof.

[0218] In a more specific embodiment, R' and R, together with the atom they bond to, form a 3- to 10-membered heterocycline, alternatively a 3- to 7-membered heterocycline, alternatively a 4- to 6-membered heterocycline, alternatively [ka] Forms, and alternatively [ka] It forms.

[0219] In a more specific embodiment, R' and R do not form a ring with the atom to which they are bonded.

[0220] In a more specific embodiment, this disclosure is R a , R b , and R c H and C are independent of each other. 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I) above, selected from haloalkyls, substituted with H, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, or pharmaceutically acceptable salts thereof.

[0221] In a more specific embodiment, R b and R c These, along with the atoms they bond to, form 3- to 7-membered heterocyclines.

[0222] In a more specific embodiment, this disclosure is R D but [ka] Alternatively, [ka] The present invention provides the compound of formula (I) described above, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

[0223] During the ceremony,

[0224] Ring A is C 6-10 Arirene, 5-10 member heteroarirene, C 6-10 Aryl condensation C 5-10 Cycloalkyl, C 6-10 Aryl condensed 5-10 member heterocyclyl, 5-10 member heteroaryl condensed C 5-10 Selected from cycloalkyls and 5-10 member heteroaryl condensations of 5-10 member heterocyclyls;

[0225] Ring B is C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively C 6-10 Selected from aryls and 5- to 10-membered heteroaryls, or lacking the -L4- rings B and R2;

[0226] R1 is independently 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 member heterocyclyl, C 6-14 Selected from aryls and 5- to 14-membered heteroaryls, with 1, 2, or 3 independent R 1s It may also be replaced with;

[0227] R 1s These are independently 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 Selected from cycloalkyl and 3- to 10-membered heterocyclines;

[0228] m = 0, 1, 2, 3, 4, or 5;

[0229] R2 is independently 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 member heterocyclyl, C 6-14 Selected from aryls and 5- to 14-membered heteroaryls, with 1, 2, or 3 independent R 2s It may also be replaced with;

[0230] R 2s These are independently 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 Selected from cycloalkyl and 3- to 10-membered heterocyclines;

[0231] s = 0, 1, 2, 3, 4, or 5;

[0232] L4 is 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- are selected,

[0233] Alternatively, L4 and the carbon atom on ring A to which L4 is bonded together [ka] form;

[0234] L5 is a chemical bond consisting of O, S, NR', and C 1-10 Selected from alkylenes, which may be substituted with one or more independent R3 groups;

[0235] R3 is independent of H, D, halogen, and C 1-10 Alkyl, and C 1-10 Selected from haloalkyl;

[0236] R4 and R'4 are independent of H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl;

[0237] X is selected from -C(O)-, -S(O)-, and -S(O)2-, with the alternative being -C(O)-.

[0238] In a more specific embodiment, the present disclosure relates to a ring A being C 6-10 Selected from arylene and 5-10 member heteroarylene, alternatively selected from phenylene and 9-10 member heteroarylene, alternatively selected from phenylene and indolylene, alternatively phenylene, alternatively [ka] Selected from, alternatively [ka] Selected from, alternatively [ka] The present invention provides the compound of formula (I) described above, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

[0239] In a more specific embodiment, the present disclosure relates to a ring B being C 3-7 Selected from cycloalkyls, 3-7 member heterocyclyls, phenyls, and 5-6 member heteroaryls, alternatively selected from phenyls and 5-6 member heteroaryls, alternatively C 6-10 The present invention provides compounds of formula (I) described above, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, with aryl, or phenyl, as alternatively, with phenyl, or pharmaceutically acceptable salts thereof.

[0240] In a more specific embodiment, the disclosure provides that R1 is independently 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 Rc ,-S(O)R a -S(O)2R a , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively H, D, halogens, 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, 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 Rc , C 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively 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 Selected from haloalkyls, alternatively H, D, halogens, -OR a -OC(O)R a , C 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I) described above, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, selected from haloalkyl groups, and alternatively selected from H, F, Me, -OMe, and -OC(O)CH3, or pharmaceutically acceptable salts thereof.

[0241] In a more specific embodiment, R1 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alternatively H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively selected from H, D, and halogens, alternatively H or F, alternatively halogens, and alternatively F.

[0242] In a more specific embodiment, the disclosure provides that R2 is independently H, D, halogen, CN, -NO2, -ORa , -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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively H, D, halogens, 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively H, D, halogens, 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 3-7Selected from cycloalkyls, 3-7 membered heterocyclyls, phenyls, and 5-6 membered heteroaryls, alternatively H, D, halogens, 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 Selected from haloalkyls, alternatively H, D, halogens, CN, and C 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I) above, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, selected from haloalkyls, and alternatively selected from H, Cl, and Me, and alternatively selected from H and Cl, or pharmaceutically acceptable salts thereof.

[0243] In a more specific embodiment, R2 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls, alternatively H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6Selected from haloalkyls, alternatively selected from H, D, and halogens, and further alternatively H or D.

[0244] In a more specific embodiment, this disclosure is R 1s and R 2s Each of these is independent of H, D, halogen, CN, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I) above, selected from haloalkyls, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

[0245] In a more specific embodiment, the present disclosure provides a compound of formula (I) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, where m=0, 1, 2, 3, or 4, alternatively m=0, 1, or 2, alternatively m=0 or 1, or alternatively m=1.

[0246] In a more specific embodiment, the present disclosure 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 s=0, 1, or 2, or alternatively s=0.

[0247] In a more specific embodiment, the disclosure shows that L4 is a chemical bond, -CR4R'4-, -NR b -, selected from O, S, -C(O)-, and -S(O)-, alternatively chemical bonds, -CR4R'4-, -NRb -, O, and -C(O)- are selected, and alternatively, chemical bonds, -NR b The present invention provides compounds of formula (I) above, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, selected from - and -C(O)-, substituted with a chemical bond, selected from -NH- and -C(O)-, substituted with a chemical bond, and selected from -NH-, substituted with a chemical bond, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, which are pharmaceutically acceptable.

[0248] In a more specific embodiment, the disclosure describes a case where L5 is a chemical bond or C 1-10 Alkylene, alternatively chemical bond or C 1-6 Alkylene, alternatively chemical bond or C 1-4 Alkylene, alternatively chemical bond or C 1-2 Alkylene, alternatively a chemical bond or methylene, alternatively -CH(CH3)-;

[0249] The present invention provides the compound of formula (I) described above, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof, in which case L5 may be substituted with 1, 2, 3, 4, 5, or 6 independent R3 molecules, or alternatively, with L5 substituted with 1, 2, or 3 independent R3 molecules, or alternatively, with L5 substituted with 1 R3 molecule.

[0250] In a more specific embodiment, the present disclosure provides that R3 independently comprises H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, and C. 1-4 Alkyl, and C 1-4 The present invention provides compounds of formula (I) above, or isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof, selected from haloalkyls, and alternatively selected from H and Me, and alternatively Me, or pharmaceutically acceptable salts thereof.

[0251] In a more specific embodiment, the present disclosure describes how R4 and R'4 independently correspond to H, D, and C. 1-6 Alkyl, and C 1-6 The present invention provides compounds of formula (I) above, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof, selected from haloalkyls, substituted with H or D.

[0252] In a more specific embodiment, the present disclosure provides a compound of formula (I) having the following structure, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0253] In the formula, the variables are as defined herein.

[0254] In a more specific embodiment, the present disclosure provides a compound of formula (II) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0255] During the ceremony,

[0256] Ring A is C 6-10 Selected from arylenes and 5-10 membered heteroarylenes;

[0257] Ring B is C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively C 3-7Selected from cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, or lacking the -L4- rings B and R2;

[0258] R1 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines, with 1, 2, or 3 independent R groups. 1s It may also be replaced with;

[0259] R 1s These are independently H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively H, D, halogens, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C3-7 Selected from cycloalkyl and 3- to 7-membered heterocyclyl;

[0260] m = 0, 1, 2, 3, 4, or 5;

[0261] R2 can be H, D, halogen, CN, or -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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines, with 1, 2, or 3 independent R groups. 2s It may also be replaced with;

[0262] R 2s These are independently H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively H, D, halogens, CN, and C. 1-6 Alkyl, C1-6 Haloalkyl, C 3-7 Selected from cycloalkyl and 3- to 7-membered heterocyclyl;

[0263] s = 0, 1, 2, 3, 4, or 5;

[0264] L4 is a chemical bond, -CR4R'4-, -NR b -, O, S, -C(O)-, and -S(O)- are selected;

[0265] L5 is a chemical bond or C 1-6 It is an alkylene, and may be substituted with 1, 2, 3, 4, 5, or 6 independent R3 groups;

[0266] R3 is independent of H, D, halogen, and C 1-6 Alkyl, and C 1-6 Selected from haloalkyl;

[0267] R4 and R'4 are independent of H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl;

[0268] U1, U2, and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)-, and -O-CH2-O-;

[0269] W1, W2, and W3 are each independent of C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyl and 3- to 10-membered heterocyclines;

[0270] L is a chemical bond or [ka] and;

[0271] L1 is selected from the chemical bonds -C(O)-, -OC(O)-, and -NHC(O)-;

[0272] L2 is a chemical bond, C 3-7 Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes;

[0273] L3 is selected from O, S, and NR';

[0274] n is selected from 0, 1, 2, 3, 4, 5, and 6;

[0275] [ka] The methylene group in this compound may be substituted with one, two, or three independent R groups;

[0276] R is independent of 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 Alkilen-NR b C(O)R a Selected from, alternatively 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 Selected from;

[0277] R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, or R' and R together with the atoms to which they are bonded form a 3- to 7-membered heterocycline;

[0278] R a , R b , and R c H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, or R b and R c However, together with the atoms they bond to, they form 3-7 membered heterocyclines;

[0279] Each of the above groups may be deuterated to the maximum extent of complete deuteration.

[0280] In a more specific embodiment, the present disclosure provides a compound of formula (II) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is defined as follows:

[0281] Ring A is C 6-10 Selected from arylenes and 5-10 member heteroarylenes, and alternatively selected from phenylenes and 9-10 member heteroarylenes;

[0282] Ring B is C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively selected from phenyls and 5-6 member heteroaryls, alternatively C 6-10 Either an aryl group, or alternatively a phenyl group, or the absence of the -L4- rings B and R2;

[0283] R1 is independently H, D, halogen, CN, -OR a , -SR a , -NR b Rc , -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 Selected from haloalkyls, alternatively 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 Selected from haloalkyls, alternatively H, D, halogens, -OR a -OC(O)R a , C 1-6 Alkyl, and C 1-6 Selected from haloalkyls, and alternatively selected from H, D, and halogens, with 1, 2, or 3 independent Rs 1s It may also be replaced with;

[0284] R 1s These are independently H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl;

[0285] m = 0, 1, 2, 3, 4, or 5, alternatively m = 0, 1, or 2;

[0286] R2 is independently 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 1-6Selected from haloalkyls, alternatively H, D, halogens, CN, and C 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, and alternatively selected from H, D, and halogens, with 1, 2, or 3 independent Rs 2s It may also be replaced with;

[0287] R 2s These are independently H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl;

[0288] s = 0, 1, 2, 3, 4, or 5, or alternatively s = 0, 1, or 2;

[0289] L4 is a chemical bond, -CR4R'4-, -NR b -, O, and -C(O)- are selected, and alternatively, chemical bonds, -NR b -, and -C(O)- are selected;

[0290] L5 is a chemical bond or C 1-4 Alkylene, alternatively chemical bond or C 1-2 It is an alkylene, and may be substituted with 1, 2, or 3 independent R3 groups;

[0291] R3 is independent of H, D, and C 1-4 Alkyl, and C 1-4 Selected from haloalkyl;

[0292] R4 and R'4 are independently H, D, C 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups, and alternatively selected from H and D;

[0293] U1, U2, and U3 are each independently selected from O, S, -NH-, and -C(O)-, with O as an alternative;

[0294] W1, W2, and W3 are each independent of C 1-10 Alkyl, C 1-10 Alkyl deuterated, and C 1-10 Selected from haloalkyls, alternatively C 1-6 Alkyl, C 1-6 Alkyl deuterated, and C 1-6 Selected from haloalkyls, alternatively C 1-6 Alkyl or C 1-6 Alkyl deuterated, alternatively C 1-6 It is alkyl;

[0295] L is a chemical bond or [ka] and;

[0296] L1 is selected from chemical bonds, -C(O)-, and -OC(O)-, alternatively selected from -C(O)- and -OC(O)-, and alternatively -C(O)-;

[0297] L2 is selected from a chemical bond, phenylene, and 5-6 member heteroarylene, and alternatively from a chemical bond and phenylene;

[0298] L3 is selected from O and NR', with NR' being the alternative and O being the alternative;

[0299] n is selected from 0, 1, 2, and 3, alternatively selected from 1, 2, and 3, alternatively 1 or 2, and alternatively 1;

[0300] [ka] The methylene group in may be substituted with one, two, or three independent R groups, or alternatively, with one R group;

[0301] R is independent of H, D, =O, C 1-6Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, and -C 0-3 Selected from alkylene-C(O)OH;

[0302] R' is H, C 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups, alternatively H, or R' and R form a 4- to 6-membered heterocycline with the atom to which they are bonded; alternatively, R' and R do not form a ring;

[0303] R a , R b , and R c H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups.

[0304] In a more specific embodiment, the present disclosure provides a compound of formula (II) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is defined as follows:

[0305] Ring A is selected from phenylene and indolylene, and alternatively [ka] Selected from, alternatively phenylene, alternatively [ka] Selected from;

[0306] Ring B is phenyl, or -L4-ring B and R2 are absent;

[0307] R1 is independently selected from H, F, Me, -OMe, and -OC(O)CH3, and is alternatively H or F;

[0308] m = 0, 1, or 2;

[0309] R2 is independently selected from H, Cl, and Me, and alternatively selected from H and Cl;

[0310] s = 0, 1, or 2;

[0311] L4 is selected from a chemical bond, -NH-, and -C(O)-, and alternatively selected from a chemical bond and -NH-, and alternatively a chemical bond;

[0312] L5 is a chemical bond or methylene group, which may be substituted with one R3, or alternatively, L5 is -CH(CH3)-;

[0313] R3 is independently selected from H and Me, with Me being an alternative;

[0314] U1, U2, and U3 are O;

[0315] W1, W2, and W3 are methyl or CD3, substituted with methyl;

[0316] L is a chemical bond or [ka] and;

[0317] L1 is selected from the chemical bonds, -C(O)- and -OC(O)-;

[0318] L2 is a chemical bond. [ka] Selected from;

[0319] L3 is selected from O and NR';

[0320] n is 0, 1, 2, and 3;

[0321] [ka] The methylene group in this compound may be substituted with one R;

[0322] R is independently selected from H, =O, methyl, isobutyl, -C(O)OH, and -(CH2)2C(O)OH, alternatively selected from H, =O, methyl, -C(O)OH, and -(CH2)2C(O)OH, alternatively selected from H, =O, methyl, and -(CH2)2C(O)OH, alternatively selected from H, =O, and -(CH2)2C(O)OH;

[0323] R' is H, or R' and R are together with the atom they bond to. [ka] Forms, and alternatively [ka] It forms.

[0324] In a more specific embodiment, [ka] The following structure: [ka] Selected from, alternatively [ka] Selected from, alternatively [ka] Selected from.

[0325] In a more specific embodiment, the present disclosure provides a compound of formula (III) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0326] During the ceremony,

[0327] R1 is independently 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 heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, with 1, 2, or 3 independent R 1s It may also be replaced with;

[0328] R 1s These are independently H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyl and 3- to 10-membered heterocyclines;

[0329] m = 0, 1, 2, 3, or 4;

[0330] R2 is independently H, D, halogen, CN, -ORa , -SR a , -NR b R c , C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, with 1, 2, or 3 independent R 2s It may also be replaced with;

[0331] R 2s These are independently H, D, halogen, CN, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyl and 3- to 10-membered heterocyclines;

[0332] s = 0, 1, 2, 3, 4, or 5;

[0333] U1, U2, and U3 are each independently selected from O, S, -NH-, -C(O)-, -OC(O)-, -NH-C(O)-, and -O-CH2-O-;

[0334] W1, W2, and W3 are each independent of C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, alternatively C 1-10 Alkyl, C 1-10 Alkyl deuterated, C 1-10 Haloalkyl, C 3-10 Selected from cycloalkyl and 3- to 10-membered heterocyclines;

[0335] L is a chemical bond or [ka] and;

[0336] L1 is selected from the chemical bonds -C(O)-, -OC(O)-, and -NHC(O)-;

[0337] L2 is a chemical bond, C 3-7 Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes;

[0338] L3 is selected from O, S, and NR';

[0339] n is selected from 0, 1, 2, 3, 4, 5, and 6;

[0340] [ka] The methylene group in this compound may be substituted with one, two, or three independent R groups;

[0341] R is independent of 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 Alkilen-NR b C(O)R a Selected from, alternatively 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 Selected from;

[0342] R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7Selected from cycloalkyls and 3- to 7-membered heterocyclines, or R' and R together with the atoms to which they are bonded form a 3- to 7-membered heterocycline;

[0343] R a , R b , and R c These are H and C, which are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, or R b and R c However, together with the atoms they bond to, they form 3-7 membered heterocyclines;

[0344] Each of the above groups may be deuterated to the maximum extent of complete deuteration.

[0345] In a more specific embodiment, the present disclosure provides a compound of formula (III) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is as follows:

[0346] R1 is independent of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, and alternatively selected from H, D, and halogens, with 1, 2, or 3 independent Rs 1s It may also be replaced with;

[0347] R 1s These are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups;

[0348] m = 0, 1, 2, 3, or 4, alternatively m = 0, 1, or 2;

[0349] R2 is independent of H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively selected from H, D, and halogens, and further alternatively H or D, with 1, 2, or 3 independent R 2s It may also be replaced with;

[0350] R 2s These are independently H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyl;

[0351] s = 0, 1, 2, 3, 4, or 5, or alternatively s = 0, 1, or 2;

[0352] U1, U2, and U3 are each independently selected from O, S, -NH-, and -C(O)-, with O as an alternative;

[0353] W1, W2, and W3 are each independent of C 1-10 Alkyl, C 1-10 Alkyl deuterated, and C 1-10 Selected from haloalkyls, alternatively C 1-6 Alkyl, C 1-6 Alkyl deuterated, and C 1-6 Selected from haloalkyls, alternatively C 1-6 Alkyl or C 1-6Alkyl deuterated, alternatively C 1-6 It is alkyl;

[0354] L is a chemical bond or [ka] and;

[0355] L1 is selected from chemical bonds, -C(O)-, and -OC(O)-, alternatively selected from -C(O)- and -OC(O)-, and alternatively -C(O)-;

[0356] L2 is selected from a chemical bond, phenylene, and 5-6 member heteroarylene, and alternatively from a chemical bond and phenylene;

[0357] L3 is selected from O and NR', with NR' being the alternative and O being the alternative;

[0358] n is selected from 0, 1, 2, and 3, alternatively selected from 1, 2, and 3, alternatively 1 or 2, and alternatively 1;

[0359] [ka] The methylene group in may be substituted with one, two, or three independent R groups, or alternatively, with one R group;

[0360] R is independent of H, D, =O, C 1-6 Alkyl, C 1-6 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl, C 1-3 Haloalkyl and -C 0-6 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, C 1-3 Alkyl and -C 0-6 Alkylene-C(O)ORa Selected from, alternatively H, D, =O, C 1-3 Alkyl and -C 0-3 Alkylene-C(O)OR a Selected from, alternatively H, D, =O, and -C 0-3 Selected from alkylene-C(O)OH;

[0361] R' is H, C 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups, alternatively H, or R' and R form a 4- to 6-membered heterocycline with the atom to which they are bonded; alternatively, R' and R do not form a ring;

[0362] R a H and C are independent of each other. 1-6 Alkyl, and C 1-6 Selected from haloalkyl groups.

[0363] In a more specific embodiment, the present disclosure provides a compound of formula (III) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein the compound is as follows:

[0364] R1 is either H or F; m=1;

[0365] R2 is H; s=0;

[0366] U1, U2, and U3 are O;

[0367] W1, W2, and W3 are methyl or CD3, substituted with methyl;

[0368] L is a chemical bond or [ka] and;

[0369] L1 is selected from the chemical bonds, -C(O)- and -OC(O)-;

[0370] L2 is a chemical bond. [ka] Selected from;

[0371] L3 is selected from O and NR';

[0372] n is 0, 1, 2, and 3;

[0373] [ka] The methylene group in this compound may be substituted with one R;

[0374] R is independently selected from H, =O, methyl, isobutyl, -C(O)OH, and -(CH2)2C(O)OH, alternatively selected from H, =O, methyl, -C(O)OH, and -(CH2)2C(O)OH, alternatively selected from H, =O, methyl, and -(CH2)2C(O)OH, alternatively selected from H, =O, and -(CH2)2C(O)OH;

[0375] R' is H, or R' and R are together with the atom they bond to. [ka] Forms, and alternatively [ka] It forms.

[0376] In a more specific embodiment, L is a chemical bond, [ka] Selected from, alternatively chemical bonds, [ka] and Selected from, alternatively chemical bonds, [ka] Selected from, alternatively chemical bonds, [ka] Selected from, alternatively chemical bonds, [ka] Selected from.

[0377] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0378] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0379] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0380] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0381] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0382] In a more specific embodiment, the present disclosure provides a compound of formula (III-1) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0383] In the formula, the variables are as defined herein.

[0384] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0385] In a more specific embodiment, [ka] teeth [ka] That is the case.

[0386] In a more specific embodiment, the present disclosure provides a compound of formula (II), formula (III), or formula (III-1) described above, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is defined as follows:

[0387] L is [ka] and;

[0388] L1 is selected from -C(O)-, -OC(O)-, and -NHC(O)-, alternatively selected from -OC(O)- and -NHC(O)-, and alternatively -OC(O)-;

[0389] L2 is a chemical bond;

[0390] L3 is selected from O, S, and NR', alternatively selected from O and S, and alternatively O;

[0391] n is selected from 1, 2, and 3, and is alternatively 1 or 2, or alternatively 1;

[0392] [ka] The methylene group in this can be substituted with one, two, or three (or alternatively, one) independent R groups;

[0393] R is independent of H, D, halogen, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, and C. 1-6 Alkyl, and C 1-6 Selected from haloalkyls, alternatively H, D, and C. 1-3 Alkyl, and C 1-3 Selected from haloalkyl groups, and alternatively selected from H and Me;

[0394] The remaining elements are as defined herein;

[0395] Alternatively, L is [ka] That is the case.

[0396] In a more specific embodiment, this disclosure refers to, [ka] [ka] [ka] [ka] The present invention provides compounds of formula (I) described above, selected from the group consisting of the above, or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

[0397] The compounds of this disclosure may contain one or more chiral centers and may therefore exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this disclosure may be individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or in the form of a mixture of stereoisomers, such as a racemic mixture or a mixture enriched with one or more stereoisomers. The isomers may be separated from the mixture by methods known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or alternative isomers may be prepared by asymmetric synthesis.

[0398] The compounds of this disclosure may exist in the form of tautomers. Tautomers are functional isomers resulting from the rapid movement of atoms between two positions within a molecule. Tautomers are special functional isomers. A pair of tautomers can be interconverted, but usually one isomer, which is relatively stable, is the primary form of existence. The most representative examples are enol and keto tautomers.

[0399] Those skilled in the art will understand that organic compounds can form complexes with the solvent in which they react or precipitate or crystallize. These complexes are called “solvates.” If the solvent is water, the complex is called a “hydrate.” This disclosure encompasses all solvates of the compounds of this disclosure.

[0400] A “solvate” refers to a compound or its salt in a form bonded to a solvent, usually formed by solvolysis. Such physical bonds may include hydrogen bonds. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether. The compounds described herein can be prepared, for example, in crystalline form and solvated. Preferred solvates include pharmaceutically acceptable solvates, as well as stoichiometric and non-stoichiometric solvates. Solvates can sometimes be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvates” include both solution-phase solvates and isolated solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0401] A "hydrate" refers to a compound that has bonded with water. Typically, the ratio of the number of water molecules in the compound hydrate to the number of compound molecules in the hydrate is determined. Therefore, the hydrate of a compound can be represented by, for example, the general formula R·xH2O (where R is the compound and x is a number greater than 0). A given compound can form more than one type of hydrate, such as a monohydrate (x is 1), a hypohydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0402] The compounds of this disclosure may exist in amorphous or crystalline (polymorphic) forms. Furthermore, the compounds of this disclosure may exist in one or more crystalline forms. Therefore, this disclosure encompasses both amorphous and crystalline forms of the compounds of this disclosure. "Polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) with a specific crystal-packed arrangement. All polymorphs have the same elemental composition. Typically, different crystalline forms have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, photoelectronic properties, stability, and solubility. One crystalline form may become dominant depending on factors such as the recrystallization solvent, crystallization rate, and storage temperature. Various polymorphs of a compound can be prepared by crystallizing under different conditions.

[0403] This disclosure further encompasses isotope-labeled compounds (isotope variants), which are equivalent to those described in formula (I), except that one or more atoms are substituted with atoms having atomic masses or mass numbers different from those commonly found in nature. The isotopes that can be introduced into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35S, 18 F, and 36 Examples include Cl. Compounds of the Disclosure, their prodrugs, and pharmaceutically acceptable salts of such compounds or prodrugs, including the above isotopes and / or other isotopes of other atoms, are all included within the scope of the Disclosure. Radioactive isotopes ( 3 H and 14 Certain isotope-labeled compounds of this disclosure, such as those incorporating tritium (i.e., C), are useful for tissue distribution studies of drugs and / or substrates. 3 H) and carbon-14 (i.e.) 14 C) Isotopes are particularly desirable in terms of ease of preparation and detectability. Furthermore, deuterium (i.e.) 2 Substitution with heavier isotopes such as H) may improve metabolic stability and be therapeutically beneficial (e.g., prolongation of in vivo half-life or reduction of dose), and may therefore be an option in some situations. The isotope-labeled compounds of formula (I) and their prodrugs of this disclosure can generally be prepared by substituting the non-isotope labeling reagent with a readily available isotope labeling reagent in the following procedures and / or processes disclosed in the Examples and Preparations.

[0404] Furthermore, prodrugs are also included in the context of this disclosure. Herein, “prodrug” refers to a compound that is converted in vivo to an active form with therapeutic effects by hydrolysis in the blood or elsewhere. Pharmaceutically acceptable prodrugs are listed in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and D. Fleisher, S. Ramon and H. Barbra, “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2) 115-130, all of which are incorporated herein by reference.

[0405] A prodrug is a covalent compound of the present disclosure that releases the parent compound in vivo when administered to a patient. Prodrugs are generally prepared by modifying a functional group, such modification is carried out so that the parent compound is produced by conventional procedures or by cleavage in vivo. Examples of prodrugs include compounds of the present disclosure in which a hydroxyl group, an amino group, or a sulfhydryl group is bonded to any group, which cleaves upon administration to a patient to form a hydroxyl group, an amino group, or a sulfhydryl group. Therefore, typical examples of prodrugs, though not limited to those mentioned above, include acetic acid / amide, formic acid / amide, and benzoic acid / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of the compound of formula (I). In the case of carboxylic acids (-COOH), esters such as methyl esters and ethyl esters can be used. The ester itself may be active and / or hydrolyzable under human biological conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release a hydrophilic acid or a salt thereof.

[0406] The disclosure further provides pharmaceutical formulations 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. Any of these forms are included in the disclosure.

[0407] Pharmaceutical compositions and kits

[0408] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure (also referred to as the “Active Ingredient”) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the Disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the Disclosure. In some embodiments, the pharmaceutical composition comprises a preventively effective amount of the compound of the Disclosure.

[0409] As used in this disclosure, pharmaceutically acceptable excipients refer to non-toxic carriers, adjuvants, or vehicles that do not impair the pharmacological activity of the compounds formulated together. Examples of pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (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, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0410] Suitable formulations for administering the compounds of this disclosure will be apparent to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, solutions (especially solutions for injection (subcutaneous, intravenous, and intramuscular) and solutions for infusion (injectable)), elixirs, syrups, cachets, emulsions, inhalants, or dispersible powders. The content of the pharmaceutically active compound should be in the range of 0.1 to 90% by weight, or alternatively 0.5 to 50% by weight, of the total composition, i.e., an amount sufficient to provide the dosage range defined below. If necessary, the prescribed dose may be administered multiple times a day.

[0411] The Disclosure further includes a kit (such as a pharmaceutical package). The kit provided may include the compound of the Disclosure, an additional therapeutic agent, and first and second containers (such as vials, ampoules, bottles, syringes, and / or divisible packaging, or other suitable containers) for containing the compound of the Disclosure and the additional therapeutic agent. In some embodiments, the kit provided may further include, as necessary, a third container for containing pharmaceutical excipients for diluting or suspending the compound of the Disclosure and / or the additional therapeutic agent. In some embodiments, the compound of the Disclosure and the additional therapeutic agent provided in the first and second containers are combined to form a unit dosage form.

[0412] Administration

[0413] The pharmaceutical compositions provided herein can be administered by many routes, including, but are not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, or implantation. For example, as used herein, parenteral administration includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-arterial administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intra-mental administration, intrafocal administration, and intracranial injection or infusion techniques.

[0414] Typically, the compounds provided herein are administered in effective doses. The actual dosage of the compound may be determined by a physician based on the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight, and response, the severity of the patient's symptoms, and other relevant factors.

[0415] When used to prevent a condition of this disclosure, the compounds provided herein are typically administered to subjects at risk of developing such condition at the dosage levels described above, under the supervision and based on the advice of a physician. Subjects at risk of developing a particular condition generally include individuals with a family history of the condition or individuals identified as particularly susceptible to the condition through genetic testing or screening.

[0416] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration refers to administering the compound or its pharmaceutical composition over a long period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, and 5 years, and may continue indefinitely, for example, for the remainder of the subject's life. In some embodiments, chronic administration is intended to maintain a constant blood concentration of the compound over a long period, such as within a therapeutic window.

[0417] The pharmaceutical compositions of this disclosure may be further delivered using various administration methods. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus to raise the blood concentration of the compound to an effective level. The bolus dose depends on the target systemic level of the active ingredient in the body. For example, an intramuscular or subcutaneous bolus dose allows for slow release of the active ingredient, while a bolus administered directly intravenously (e.g., intravenous (IV) infusion) allows for more rapid delivery, resulting in a rapid increase in the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion via intravenous (IV) infusion or the like to bring the concentration of the active ingredient in the target body to a steady state. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

[0418] Oral compositions may be in the form of a bulk liquid solution or suspension, or a bulk powder. However, more typically, for ease of precise administration, compositions are provided in unit dosage forms. A "unit dosage form" refers to a physically independent unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of the active substance suitable to produce the desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes for liquid compositions, and pills, tablets, and capsules for solid compositions. In such compositions, the compound typically constitutes a small amount of the component (about 0.1 to about 50% by weight, or alternatively about 1 to about 40% by weight), with the remainder consisting of various carriers or excipients and processing aids useful for forming the desired dosage form.

[0419] For oral administration, typical dosing regimens involve 1 to 5 oral doses per day, particularly 2 to 4 oral doses, and typically 3 oral doses per day. When using these dosing regimens, each dose provides approximately 0.01 to 20 mg / kg of the compound disclosed herein, and alternatively, each dose provides approximately 0.1 to 10 mg / kg, particularly 1 to 5 mg / kg.

[0420] To achieve blood concentrations similar to, or lower than, those obtained by injection, transdermal doses are typically selected in amounts of approximately 0.01 to 20% by weight, alternatively approximately 0.1 to 20% by weight, alternatively approximately 0.1 to 10% by weight, and even more alternatively approximately 0.5 to 15% by weight.

[0421] The injection dose level ranges from approximately 1 hour to approximately 120 hours, particularly from 24 hours to 96 hours, and from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve a sufficient steady-state level, a preload bolus administration of approximately 0.1 mg / kg to approximately 10 mg / kg or more may be performed. For human patients weighing 40-80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0422] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier, as well as buffers, suspending agents and dispersants, colorants, and flavoring agents. Solid forms may include, for example, any of the following components or compounds having similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow promoters such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0423] Injectable compositions are typically based on sterile saline or phosphate-buffered saline for injection, or other injectable excipients known in the art. As described above, in such compositions, the active compound typically constitutes a small amount, usually about 0.05 to 10% by weight, with the remainder consisting of injectable excipients and the like.

[0424] Transdermal compositions are typically formulated as topical ointments or creams containing an 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 may be formulated as a cream using an oil-in-water cream base, etc. Such transdermal formulations are well known in the art and generally include the active ingredient or other components to improve the stable skin penetration of the formulation. Any such known transdermal formulations and components are included within the scope provided in this disclosure.

[0425] The compounds of this disclosure may also be administered via a transdermal device. Therefore, transdermal administration may be performed using reservoir-type, porous membrane-type, or various solid matrix patches.

[0426] The above-mentioned components of compositions for oral, injectable, or topical administration are representative examples only. Additional materials and processing techniques are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which are incorporated herein by reference.

[0427] The compounds of this disclosure may also be administered in a sustained-release form or via a sustained-release drug delivery system. A typical description of sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0428] This disclosure further relates to pharmaceutically acceptable formulations of the compounds of this disclosure. 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, each consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, and the linked sugar portion may contain one or more substituents, but are not particularly limited, such as methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0429] Indications

[0430] The compounds disclosed herein exert therapeutic effects through sedation or sleep adjunct, providing therapeutic benefits to a large number of patients with central nervous system-related disorders. The compounds disclosed herein also possess excellent analgesic, antidepressant, and anti-dependent properties and can be used in the manufacture of analgesics, antidepressants, and anti-dependent drugs.

[0431] In one embodiment, pain is selected from the group consisting of neuralgia, perioperative pain (including preoperative, intraoperative, or postoperative pain, such as somatic or visceral pain due to postoperative trauma or incision, pain due to visceral injury, and other generalized pain), and cancer pain (such as pain due to cancer).

[0432] In one embodiment, the pain is acute pain or chronic pain (including preoperative, intraoperative, or postoperative acute / chronic pain, acute neuralgia, or chronic neuralgia).

[0433] In one embodiment, neuralgia is central pain such as spinal pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain.

[0434] In one embodiment, postoperative pain is pain resulting from surgery, such as pain resulting from abdominal surgery, orthopedic surgery, cesarean section, or brain surgery. [Examples]

[0435] The technical solutions of this disclosure will be clearly and completely described below with reference to the attached drawings. It will be clear that the embodiments described are not all but a selection of the embodiments of this disclosure. All other embodiments that can be obtained by those skilled in the art based on the embodiments of this disclosure are all covered within the scope of this disclosure.

[0436] Abbreviation:

[0437] PE: Petroleum ether

[0438] EA: Ethyl acetate

[0439] DMAP: 4-dimethylaminopyridine

[0440] DCM: Dichloromethane

[0441] DMF: N,N-dimethylformamide

[0442] DCC: Dicyclohexylcarbodiimide

[0443] DBU:1,8-Diazabicyclo[5.4.0]Undeca-7-En

[0444] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide

[0445] DIEA: N,N-diisopropylethylamine

[0446] EtOH: Ethanol

[0447] Et3N: Triethylamine

[0448] HATU: N,N,N',N'-Tetramethyl-O-(7-Azabenzotriazol-1-yl)uronium hexafluorophosphate

[0449] ACN: Acetonitrile

[0450] THF: Tetrahydrofuran

[0451] rt: room temperature

[0452] LCMS: Liquid Chromatography Mass Spectrometry

[0453] TLC: Thin-layer chromatography

[0454] The present disclosure will be described in detail below with reference to specific examples, but the method of synthesizing the compounds of this disclosure is not particularly limited and can be synthesized by any method known to those skilled in the art.

[0455] Example 1 [ka]

[0456] 1-1 synthesis [ka]

[0457] 20.0 g (1.0 equivalent) of 1-SM and 200 mL of dichloromethane were added to a 500 mL reaction flask. 8 g of triethylamine was added under a nitrogen atmosphere. 18 g of anhydrous trifluoromethanesulfonic acid was added dropwise under an ice bath, and the mixture was heated to room temperature and stirred overnight. The completion of the reaction was confirmed by LC / MS. 200 mL of purified water was added to the reaction solution. The mixture was stirred and separated into layers. The aqueous phase was extracted with 100 mL of dichloromethane. The dichloromethane layers were combined, washed with 150 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated by filtration. 330 g of the residue was purified by silica gel column chromatography to obtain 1-1 (26.97 g) in 94.8% yield. MS:474. 1 H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.89 (s, 1H), 6.70 (s, 1H), 4.13 (d, J = 16.1 Hz, 1H), 3.83 (s, 3H), 3.74 (d, J = 9.4 Hz, 6H), 3.53 (dd, J = 16.5, 6.6 Hz, 3H), 3.15 (dd, J = 11.1, 3.7 Hz, 1H), 2.99‐2.86 (m, 1H), 2.63 (dd, J = 15.6, 9.6 Hz, 3H).

[0458] Example 2 [ka]

[0459] 3-1 synthesis [ka]

[0460] 1-1 (20.0 g, 1.0 equivalent), tert-butyl carbamate, tripotassium phosphate, tris(dibenzylideneacetone)dipalladium(0), 2-(biphenyl)di-tert-butylphosphine, and 200 mL of 1,4-dioxane were added to a 1 L reaction flask. The mixture was heated to 90°C under a nitrogen atmosphere and stirred overnight. The completion of the reaction was confirmed by LC / MS. The reaction mixture was filtered, and the filter cake was rinsed with 50 mL of EA. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to obtain 22.0 g of 3-1 as a yellow solid. This was used directly in the next step without further purification.

[0461] Synthesis of Example 2 [ka]

[0462] 2.5 g of 3-1 and 10 mL of dichloromethane were added to a 50 mL reaction flask. 10 mL of dioxane solution in hydrochloric acid was added dropwise, and the mixture was stirred overnight at room temperature. The completion of the reaction was confirmed by LC / MS. The mixture was concentrated to dryness. Then, 20 mL of DCM was added, followed by 20 mL of saturated sodium carbonate solution to adjust the pH to alkaline. The layers were separated, the DCM layer was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain 1.05 g of Example 2 as a solid in 54.4% yield. MS: 326, 1H NMR (400 MHz, DMSO-d6) δ 6.85 (s, 1H), 6.67(s, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 4.05 - 4.01 (m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.63 (s, 3H), 3.41 - 3.35 (m, 2H), 3.27 (dd, J = 16.0 Hz, 4.0 Hz, 1H), 3.10 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 2.97 - 2.89 (m, 1H), 2.60 (d, J = 16.0 Hz, 1H), 2.48-2.42 (m, 2H).

[0463] Example 3 [ka]

[0464] Synthesis of Example 3 [ka]

[0465] 400 mg (1 equivalent) of Example 2 was added to 10 mL of DCM. DMAP (158 mg, 1.1 equivalents) and flurbiprofen (344 mg, 1.2 equivalents) were added at room temperature, followed by EDCI·HCl (451 mg, 2 equivalents). The mixture was stirred overnight at room temperature. LC-MS confirmed that no starting materials remained. As a work-up, the reaction was quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated, and dried using a rotary evaporator. The residue was purified by Prep-TLC to obtain 220 mg of product. MS: 567, 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.50 (dt, J = 22.5, 7.8 Hz, 5H), 7.42 ‐ 7.34 (m, 3H), 6.93 ‐ 6.86 (m, 2H), 6.68 (s, 1H), 4.16 (q, J = 6.9 Hz, 1H), 4.07 (d, J = 15.7 Hz, 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 = 10.8 Hz, 1H), 2.58 (dd, J = 25.3, 14.9 Hz, 3H), 2.47 (d, J = 11.5 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H).

[0466] Example 4

change

[0467] Example 3 was synthesized by the same method. MS: 567, 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.50 (dt, J = 22.5, 7.8 Hz, 5H), 7.42 ‐ 7.34 (m, 3H), 6.93 ‐ 6.86 (m, 2H), 6.68 (s, 1H), 4.16 (q, J = 6.9 Hz, 1H), 4.07 (d, J = 15.7 Hz, 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 = 10.8 Hz, 1H), 2.58 (dd, J = 25.3, 14.9 Hz, 3H), 2.47 (d, J = 11.5 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H).

[0468] Example 5

change

[0469] Example 3 was synthesized by the same method. MS: 567, 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.50 (dt, J = 22.5, 7.8 Hz, 5H), 7.42 ‐ 7.34 (m, 3H), 6.93 ‐ 6.86 (m, 2H), 6.68 (s, 1H), 4.16 (q, J = 6.9 Hz, 1H), 4.07 (d, J = 15.7 Hz, 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 = 10.8 Hz, 1H), 2.58 (dd, J = 25.3, 14.9 Hz, 3H), 2.47 (d, J = 11.5 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H).

[0470] Example 6

change

[0471] Synthesis of Example 6

change

[0472] 200 mg (1 equivalent) of Example 2 was added to 5 mL of DMF. DIEA (759 mg, 10 equivalents) and indomethacin (252 mg, 1.2 equivalents) were added at room temperature, followed by the dropwise addition of a DMF solution of HATU (268 mg, 1.2 equivalents). LC-MS confirmed that no starting material remained. The residue was purified by reverse-phase column chromatography to obtain 282 mg of the product of Example 6. MS: 680, 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.36 (s, 1H), 7.67 (q, J = 8.6, 7.4 Hz, 5H), 7.27 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 11.1 Hz, 2H), 6.73 (dd, J = 9.0, 2.5 Hz, 1H), 6.68 (s, 1H), 4.07 (d, J = 15.8 Hz, 1H), 3.87 (s, 2H), 3.77 - 3.72 (m, 9H), 3.59 (s, 3H), 3.46 (s, 1H), 3.42 (d, J = 11.7 Hz, 2H), 3.19 - 3.07 (m, 1H), 2.93 (t, J = 11.2 Hz, 1H), 2.66 - 2.55 (m, 2H), 2.32 (s, 3H).

[0473] Example 7 [ka]

[0474] Synthesis of Example 7 [ka]

[0475] 200 mg of Example 2 was dissolved in 4 mL of dichloromethane. Then, 128 mg of 11-SM was added, followed by 195 mg of DMAP under ice bath cooling and a nitrogen atmosphere. A solution of 121 mg of DCC in dichloromethane was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by medium-pressure column chromatography, and the eluate was subsequently concentrated and freeze-dried to obtain 125.32 mg of the product of Example 7. MS:563, 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.26 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 7.1 Hz, 1H), 7.11 - 7.03 (m, 2H), 7.01 - 6.81 (m, 5H), 6.70 (s, 1H), 4.10 (d, J = 15.4 Hz, 1H), 3.78 - 3.69 (m, 9H), 3.48 (d, J = 13.4 Hz, 3H), 2.68 - 2.56 (m, 2H), 2.27 (s, 3H), 2.09 (s, 3H), 1.24 (s, 5H).

[0476] Example 8 [ka]

[0477] Synthesis of Example 8 [ka]

[0478] 200 mg (1 equivalent) of Example 2 was added to 5 mL of DCM. Then, 169 mg (1.02 equivalents) of 12-2 and DMAP (215 mg, 3 equivalents) were added at room temperature, followed by the dropwise addition of a DCM solution of DCC (145.4 mg, 1.2 equivalents). The mixture was stirred overnight at room temperature. LC-MS confirmed that no starting materials remained. For workup, the reaction was quenched with water, extracted with DCM, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography to obtain 170 mg of the product of Example 8. MS: 604. 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.72 (s, 1H), 8.34 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.43-7.38 (m, 3H), 7.28 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 6.69 (s, 1H), 5.60 (d, J = 8.0 Hz, 1H), 4.10 (d, J = 15.7 Hz, 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 = 6.5 Hz, 1H), 2.95 (t, J = 11.2 Hz, 1H), 2.65-2.59 (m, 2H).

[0479] Example 9 [ka]

[0480] 14-1 synthesis [ka]

[0481] 14-SM96 mg was dissolved in 4 mL of DCM, and 169 mg of oxalyl chloride was added. The mixture was stirred under ice water cooling. After 5 minutes, the ice water bath was removed, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the concentrate of 14-1 was used directly in the next reaction.

[0482] Synthesis of Example 9 [ka]

[0483] 200 mg of Example 2 was dissolved in 4 mL of DCM, and 593 mg of triethylamine was added. The mixture was stirred at room temperature. 14-1 obtained in the previous step was dissolved in 2 mL of super-anhydrous DCM and added dropwise to the reaction mixture above. The mixture was stirred at room temperature for 30 minutes, then washed once each with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain 158.21 mg of the product of Example 9 as a solid. MS: 502, mang 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.59 (t, J = 6.9 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 4.5 Hz, 1H), 6.69 (d, J = 4.4 Hz, 1H), 4.11 (d, J = 15.5 Hz, 1H), 3.84 - 3.71 (m, 12H), 3.46 (s, 3H), 2.64 (d, J = 13.8 Hz, 2H), 2.25 (s, 3H), 1.23 (s, 3H).

[0484] Example 10 [ka]

[0485] 15-1 synthesis [ka]

[0486] 200 mg of Example 2 and 160 mg of isobenzofuranone were dissolved in 5 mL of ultra-dehydrated THF. 1.1 mL of n-butyllithium solution was added under a nitrogen atmosphere with ice bath cooling, and the mixture was stirred under ice bath cooling. After 30 minutes, the reaction was quenched with water. The mixture was diluted with 50 mL of EA and washed twice with water and once with saturated saline. The mixture was then dried, filtered, and concentrated. Purification: The mixture was diluted with DCM, eluted and purified using 0-3% MeOH / DCM on an 80 g pre-packed silica gel column to obtain 320 mg of compound 15-1.

[0487] Synthesis of Example 10 [ka]

[0488] 15-1 320 mg was dissolved in 5 mL of ultra-dehydrated DCM. Under ice bath cooling, 165 mg of DMAP and 167 mg of DCC were added, and the mixture was stirred under ice bath cooling. After 30 minutes, 165 mg of S-flurbiprofen was added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed twice with DCM. The organic layer was washed twice with water and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification: The mixture was diluted with DCM, eluted and purified using 0-3% MeOH / DCM on a 45 g pre-packed silica gel column. The fraction was collected, concentrated, and lyophilized to obtain 138.1 mg of solid. This solid was further purified by reverse-phase column chromatography and lyophilized to obtain 24.98 mg of Example 10. MS: [M+H] 701; 1H NMR (400 MHz, DMSO-d6) δ 9.742 (s, 1H), 7.661-7.646 (m, 1H), 7.533-7.375 (m, 10H), 7.253-7.197 (m, 2H), 6.48 (d, J = 8.4 Hz, 1H), 6.889 (s, 1H), 6.696 (s, 1H), 5.384 (d, J = 13.6 Hz, 1H), 5.336 (d, J = 12.8 Hz, 1H), 4.092 (d, J = 15.6 Hz, 1H), 3.939 (q, J = 7.6 Hz, 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 = 7.2 Hz, 3H).

[0489] Example 11 [ka]

[0490] 18-1 synthesis [ka]

[0491] 18-SM (300 mg, 1 equivalent) was added to DMF. After complete dissolution, HATU (762 mg, 1.1 equivalents) and DIEA (938 mg, 4 equivalents) were added. The mixture was stirred at 40°C for 1 hour. Then, benzyl alcohol (196 mg, 1 equivalent) was added to the reaction system, and stirring was continued for 2 hours to obtain the desired product. The reaction mixture was washed with water and saturated brine, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain 18-1 (330 mg).

[0492] 18-2 synthesis [ka]

[0493] 18-1 (300 mg, 1.2 equivalents) and S-flurbiprofen (238 mg, 1 equivalent) were dissolved in ACN. K2CO3 (404 mg, 3 equivalents) was added, and the mixture was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, and then concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain 18-2 (420 mg).

[0494] 18-3 synthesis [ka]

[0495] 18-2 (400 mg) was dissolved in 3 mL of methanol. Carbon-supported palladium hydroxide was added, and the atmosphere was replaced with H2. The mixture was stirred at room temperature for 3 hours. The acquisition of the target product was confirmed by LC-MS. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain 18-3 (200 mg).

[0496] Synthesis of Example 11 [ka]

[0497] 18-3 (200 mg, 1 equivalent) was dissolved in DCM. Oxalyl chloride (152 mg, 2 equivalents) and 1 drop of DMF were added, and the mixture was stirred for 2 hours. Then, it was concentrated to dryness under reduced pressure and redissolved in DCM. This solution was added to the DCM solution of Example 2 (165 mg, 0.8 equivalents). After the reaction was complete, the organic phase was washed with water and saturated sodium chloride solution, and then concentrated to dryness under reduced pressure. The residue was purified by column chromatography to obtain Example 11 (33 mg). MS: 653, 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.54 - 7.38 (m, 6H), 7.23 (dd, J = 16.0, 12.0 Hz, 2H), 6.89 (s, 2H), 6.69 (s, 1H), 4.15 - 4.05 (m, 3H), 3.88 (d, J = 8.0 Hz, 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 = 8.0 Hz, 3H).

[0498] Example 12 [ka]

[0499] 19-1 synthesis [ka]

[0500] 19-SM (300 mg, 1 equivalent) was added to ethanol. Thionyl chloride (448 mg, 2 equivalents) was added dropwise, and the mixture was stirred for 1 hour. The mixture was then concentrated to dryness under reduced pressure to obtain 19-1 (160 mg). MS: 188.

[0501] 19-2 synthesis [ka]

[0502] S-flurbiprofen (200 mg, 1 equivalent) was dissolved in DCM. Then, 19-1 (153 mg, 1 equivalent), EDCI (187 mg, 1.2 equivalents), and DMAP (0 mg, 0.1 equivalents) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to dryness. The residue was purified by column chromatography to obtain 19-2 (200 mg). MS: 414.

[0503] 19-3 synthesis [ka]

[0504] 19-2 (200 mg) was dissolved in a mixed solvent of methanol:tetrahydrofuran:water = 1:1:1. Lithium hydroxide monohydrate (101 mg, 5 equivalents) was added, and the mixture was stirred for 1 hour. The reaction mixture was adjusted to a neutral pH with dilute hydrochloric acid, extracted with ethyl acetate, and concentrated to dryness under reduced pressure to obtain crude product 19-3 200 mg. MS: 386.

[0505] Synthesis of Example 12 [ka]

[0506] Crude product 19-3 (150 mg) was dissolved in DCM. Example 2 (130 mg, 1 equivalent), EDCI (87 mg, 1.2 equivalents), and DMAP (5 mg, 0.1 equivalents) were added, and the mixture was stirred for 2 hours. After the reaction was complete, the reaction mixture 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, 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J = 8.0 Hz, 1H), 8.05 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.50 - 7.37 (m, 6H), 7.26 - 7.24 (m, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 4.08 (d, J = 16.0 Hz, 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).

[0507] Example 13 [ka]

[0508] 20-1 synthesis [ka]

[0509] Under a nitrogen atmosphere, 200 mg of S-flurbiprofen was dissolved in 2 mL of ultra-anhydrous DCM. 0.82 mL of oxalyl chloride solution was added, and the mixture was stirred under ice bath cooling. After 30 minutes, the reaction mixture was concentrated. 85 mg of γ-aminobutyric acid was dissolved in 2 mL of THF, and 2 mL of 2 M NaOH solution was added while stirring. The concentrate was dissolved in 2 mL of THF and added dropwise to the reaction mixture. After 30 minutes, the reaction mixture was concentrated. The mixture was diluted in 50 mL of EA and washed twice with water and once with saturated saline. The mixture was then dried, filtered, and concentrated. The residue was purified by medium-pressure chromatography to obtain 20-1 (180 mg).

[0510] Synthesis of Example 13 [ka]

[0511] 20-1 (116 mg), Example 2 (120 mg), and HATU (161 mg) were dissolved in 2 mL of ultra-dehydrated DMF. DIEA was added while stirring. After 30 minutes, the reaction mixture 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, and dried over anhydrous sodium sulfate. The mixture was purified by medium-pressure chromatography, and the recovered fraction was subsequently concentrated and freeze-dried to obtain Example 13 (42.62 mg). MS: 651, 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (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 = 8.0 Hz, 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).

[0512] Example 14 [ka]

[0513] 21-1 synthesis [ka]

[0514] S-flurbiprofen (300 mg, 1 equivalent) was added to DCM. After complete dissolution, thionyl chloride (290 mg, 2 equivalents) was added dropwise, and the mixture was stirred overnight. The mixture was then concentrated to dryness using a rotary evaporator to obtain the acid chloride of S-flurbiprofen. The acid chloride was dissolved in DCM and added to a mixture of 21-SM (141 mg, 1 equivalent) and TEA (310 mg, 2.5 equivalents). The mixture was stirred at room temperature for 2 hours. The desired product was confirmed by LC-MS. The reaction was quenched with water and extracted three times with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to obtain 21-1 (310 mg). MS: 342.

[0515] Synthesis of Example 14 [ka]

[0516] 21-1 (300 mg, 1 equivalent) was dissolved in DCM. Example 2 (300 mg, 1 equivalent), EDCI (201 mg, 1.2 equivalents), and DMAP (10 mg, 0.1 equivalents) were added. The mixture was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS. The mixture was extracted three times with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried using a rotary evaporator. The residue 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, 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56 - 7.38 (m, 6H), 7.29 - 7.25 (m, 2H), 6.93 - 6.88 (m, 2H), 6.69 (d, J = 2.8 Hz, 1H), 4.15 - 4.05 (m, 2H), 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).

[0517] Example 15 [ka]

[0518] 22-1 synthesis [ka]

[0519] 200 mg of 22-SM and 139 mg of 16-1 were dissolved in 5 mL of DMF. 178 mg of triethylamine was added while stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the pH of the solution was adjusted to approximately 2 with hydrochloric acid. The aqueous phase was extracted twice with EA. The organic phases were combined, washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue was purified by medium-pressure preparative chromatography to obtain 220 mg of 22-1.

[0520] 22-2 synthesis [ka]

[0521] 220 mg of 22-1 and 161 mg of Example 2 were dissolved in 4 mL of DCM. Anhydrous sodium carbonate was added while stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed twice with water and once with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative chromatography at medium pressure to obtain 22-2 (162 mg).

[0522] Synthesis of Example 15 [ka]

[0523] 22-2 162 mg was dissolved in 4 mL of MeOH. 20 mg of palladium hydroxide was added, the mixture was purged three times with hydrogen, and stirred at room temperature for 2 hours. The reaction mixture was filtered through a funnel containing diatomaceous earth, and the filtrate was concentrated. The residue was purified by reverse-phase medium-pressure preparative chromatography, and the recovered fraction was concentrated and freeze-dried to obtain Example 15 (85.35 mg). MS: 696, 1 H NMR (400 MHz, DMSO-d6) δ 9.489 (d, J = 40.8 Hz, 1H), 8.321(s, 2H), 7.972(s, 1H), 7.671(dd, J = 14.4 Hz, 4.8 Hz, 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).

[0524] Example 16 [ka]

[0525] 23-1 synthesis [ka]

[0526] 23-SM (500 mg, 1.0 equivalent) was placed in a necked flask. Oxalyl chloride (0.35 mL, 0.2 equivalent) was added dropwise under a nitrogen atmosphere with ice bath cooling. The mixture was stirred at room temperature for 3 hours. LC-MS monitoring confirmed that no starting material remained. The mixture was concentrated to dryness by rotary evaporation and used in the next step. The product content was measured using methanol.

[0527] 23-2 synthesis [ka]

[0528] Product 23-1 was incorporated into 1 mL of THF, and 15 mL of ammonia solution was added dropwise under ice bath cooling. The mixture was stirred overnight at room temperature. LC-MS detection confirmed that no starting material remained. As a work-up, the mixture was concentrated to dryness by rotary evaporation and then purified by reverse-phase column chromatography to obtain product 23-2 (480 mg). MS: 244, 1 H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.35 (m, 7H), 7.23 (d, J = 9.3 Hz, 2H), 6.92 (s, 1H), 3.64 (q, J = 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H).

[0529] 23-3 synthesis [ka]

[0530] 23-2 (100 mg, 1 equivalent) was incorporated into 2 mL of DCE. Oxalyl chloride (262.1 mg, 5 equivalents) was added dropwise under ice bath cooling. The mixture was stirred overnight at room temperature. LC-MS detection confirmed that no starting material remained. The mixture was concentrated to dryness by rotary evaporation under a nitrogen stream and used directly in the next step. MS: 316

[0531] Synthesis of Example 16 [ka]

[0532] 23-3 (crude product) was taken into 1 mL of super-dehydrated acetonitrile, and then added dropwise to a 1 mL solution of acetonitrile containing Example 2 (153.9 mg, 1.1 equivalents, free form). The system was heated at 50°C for 3 hours. As a work-up, the reaction mixture was subjected to reverse-phase column chromatography, concentrated, and freeze-dried to obtain Example 16 (67 mg). MS: 638, 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (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 = 4.0 Hz, 3H).

[0533] Example 17 [ka]

[0534] Example 17 was synthesized using the same procedure as described in Example 16.

[0535] MS: 638, 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (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 = 4.0 Hz, 3H).

[0536] Example 18 [ka]

[0537] 25-1 synthesis [ka]

[0538] 25-SM (1 g, 1.0 equivalent) was dissolved in 17 mL of H2O. NaHCO3 (1.06 g, 2.2 equivalents) was added at 0°C. (Boc)2O (1.32 g, 1.06 equivalents) in a 17 mL solution of dioxane was slowly added dropwise at 0°C. The mixture was stirred overnight at room temperature. LC-MS monitoring confirmed that no starting material remained. The mixture was concentrated, and the pH was adjusted to 3-4 with citric acid. The mixture was extracted with a DCM / MeOH (10:1) mixed solvent, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation. Crude product 25-1 was used directly in the next step. MS: 276.

[0539] 25-2 synthesis [ka]

[0540] Example 2 (250 mg, 1.0 equivalent) was added to 7 mL of DCM, followed by 25-1 (243 mg, 1.2 equivalents) and DMAP (98.7 mg, 1.1 equivalents). After homogeneous stirring, EDCI (282 mg, 2 equivalents) was added. The mixture was stirred overnight at room temperature. LC-MS detection confirmed that no starting material remained. Water was added to quench the reaction, extracted with DCM, washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation. The residue was purified by positive-phase column chromatography to obtain product 25-2 (350 mg). Yield: 79.7%. MS: 598.

[0541] 25-3 synthesis [ka]

[0542] 25-2 (350 mg) was dissolved in 5 mL of DCM. A 3 mL solution of 1,4-dioxane in 4 M HCl was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. LC-MS detection confirmed that no starting material remained. As a work-up, the mixture was concentrated to dryness by rotary evaporation. The mixture was slurryed with petroleum ether and subsequently filtered. The filtered cake was collected and dried to obtain 295 mg of crude product 25-3. This was used directly in the next step. MS: 498.

[0543] 25-4 synthesis [ka]

[0544] Product 25-3 (200 mg, 1 equivalent) was added to 6 mL of DCM. S-flurbiprofen (118 mg, 1.2 equivalents) and DMAP (54 mg, 1.1 equivalents) were added at room temperature. After homogeneous stirring, EDCI (154 mg, 2.0 equivalents) was added. The mixture was stirred at room temperature for 4 hours. LC-MS detection confirmed that no starting material remained. Water was added to quench the reaction, extracted with DCM, washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation. The residue was purified by Prep-TLC to obtain product 25-4 (198 mg). Yield: 68.1%. MS: 724.

[0545] Synthesis of Example 18 [ka]

[0546] 25-4 (198 mg, 1 equivalent) was added to 3 mL of EtOH. An aqueous solution of lithium hydroxide monohydrate (16 mg, 1.5 equivalents) (3.2 mL) was added. After homogeneous stirring, the mixture was heated at 60°C for 30 minutes. LC-MS detection confirmed that no starting material remained. The mixture was concentrated, the pH was adjusted to 3-4 with dilute hydrochloric acid, extracted by DCM, dried over anhydrous sodium sulfate, and concentrated to dryness by rotary evaporation. The residue was purified by reverse-phase column chromatography, followed by concentration and freeze-drying to obtain Example 18 (123 mg). Yield: 63.7%. MS: 696, HNMR: 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.66 (d, J = 8.0 Hz, 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 = 8.0 Hz, 1H), 4.02 (d, J = 16.0 Hz, 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 = 8.0 Hz, 3H).

[0547] Example 19 [ka]

[0548] 26-1 synthesis [ka]

[0549] Example 2 (500 mg, 1 equivalent) was dissolved in 10 mL of DCM. Triphosgene (217 mg, 0.5 equivalents) and triethylamine (444 mg, 3 equivalents) were added at 0°C. The mixture was stirred at 0-10°C for 2 hours. Then, ethylene glycol (982 mg, 10 equivalents) was added to the system, and the mixture was stirred at room temperature for 1 hour. LC-MS analysis was performed. The reaction mixture was extracted twice with 50 mL of dichloromethane and washed once with 50 mL of saturated saline. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was eluted and purified by column chromatography with petroleum ether:ethyl acetate = 1:1 to obtain 180 mg of product. Yield: 29%.

[0550] Synthesis of Example 19 [ka]

[0551] 26-1 (180 mg, 1 equivalent) was dissolved in 10 mL of dichloromethane. S-flurbiprofen (102 mg, 1 equivalent), EDCI (96 mg, 1.2 equivalents), and DMAP (5 mg, 0.1 equivalents) were added. The mixture was stirred at room temperature for 1 hour, and LC-MS analysis was performed. The organic phase was extracted twice with 10 mL of dichloromethane, washed once with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was eluted and purified by column chromatography with petroleum ether:ethyl acetate = 1:1 to obtain 72 mg of product. Yield: 26%. MS: [M+H] 655 HNMR: 1H NMR (400 MHz, DMSO-d6) δ 8.750 (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 = 15.6 Hz, 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 = 10.4 Hz, J2 = 4.4 Hz, 1H), 2.975‐2.907(m, 1H), 2.640‐2.456(m, 3H), 1.448(d, J = 7.2 Hz, 3H).

[0552] Example 20 [ka]

[0553] 27-1 synthesis [ka]

[0554] S-flurbiprofen (500 mg, 1 equivalent) was dissolved in DCM. EDCI (469 mg, 1.2 equivalents), DMAP (25 mg, 0.1 equivalent), NH4Cl (219 mg, 2 equivalents), and TEA (413 mg, 2 equivalents) were added. The mixture was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS analysis. The mixture was concentrated to dryness under reduced pressure, and the residue was eluted and purified by column chromatography using petroleum ether:ethyl acetate = 1:1 to obtain the product (397 mg). Yield: 80%.

[0555] 27-2 synthesis [ka]

[0556] 27-1 (243 mg, 1 equivalent) was dissolved in 30 mL of 37% formaldehyde aqueous solution. Potassium hydroxide (5 mg, 0.1 equivalent) was added, and the mixture was stirred at 80°C for 5 minutes. The mixture was then cooled to room temperature and stirred overnight. Disappearance of the starting material was confirmed by LC-MS analysis, and the formation of new spots was confirmed by TLC analysis. The reaction mixture was extracted once with 80 mL of ethyl acetate. 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 and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was eluted and purified by column chromatography with petroleum ether:ethyl acetate = 1:1 to obtain crude product 27-2 (411 mg).

[0557] 27-3 synthesis [ka]

[0558] 27-2 (300 mg, 1 equivalent) was dissolved in 10 mL of super-anhydrous DCM. After complete dissolution, thionyl chloride (259 mg, 2 equivalents) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. 50 mL of n-hexane was added to the reaction mixture, followed by filtration. The filtrate was rinsed with a small amount of n-hexane. The filtrate was concentrated under reduced pressure. The residue was redissolved in 10 mL of acetone, and triethylamine (440 mg, 4 equivalents) was added. The mixture was concentrated under reduced pressure to dryness to obtain crude product 27-3 208 mg.

[0559] Synthesis of Example 20 [ka]

[0560] 27-3 (200 mg, 1 equivalent) was dissolved in 2 mL of tetrahydrofuran. Example 2 (191 mg, 1 equivalent) was added, and the mixture was stirred overnight at room temperature. LC-MS analysis was performed. The reaction mixture was extracted with 20 mL of ethyl acetate, dried, filtered, and concentrated to dryness under reduced pressure. The residue was eluted by column chromatography with ethyl acetate:petroleum ether = 1:1 and purified to obtain the crude product. The crude product was separated by preparative SFC to obtain 18 mg of the target product as an off-white solid. This product was odorless and stored at room temperature.

[0561] MS: [M+H] 596.4, 1H NMR (400 MHz, DMSO-d6) δ 8.376(t, J = 6.8 Hz, 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 = 11.2 Hz, 1H), 5.457(t, J = 8.8 Hz, 1H), 4.553(t, J = 8.4 Hz, 2H), 4.020(d, J = 19.6 Hz, 1H), 3.738(s, 3H), 3.726(s, 3H), 3.661(q, J = 9.6 Hz, 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 = 9.6 Hz, 3H).

[0562] Example 21 [ka]

[0563] Synthesis of 28-1 [ka]

[0564] In a 10 mL flask, 140.0 mg (1.5 equivalents) of L-tyrosine ethyl ester, 2 mL of DCM, and 295 mg (6.0 equivalents) of DIEA were added. The mixture was cooled in an ice bath under a nitrogen atmosphere, and 1 mL of 100.0 mg (1.0 equivalent) of 23-1 solution of DCM was added dropwise. The mixture was warmed to room temperature and reacted for 2 hours. The reaction was observed by LC / MS to confirm completion. Next, 20 mL of purified water was added to the reaction mixture, and the mixture was extracted with 20 mL of DCM twice. The DCM layers were combined, washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain 150 mg of product 28-1 as a solid. Yield 90.4%. MS:436. 1H NMR (400 MHz, DMSO-d6) δ 9.218 (s, 1H), 8.451 (d, J = 8.0 Hz, 1H), 7.535 - 7.183 (m, 6H), 7.214 - 7.183 (m, 2H), 6.981 (d, J = 8.4 Hz, 2H), 6.651 (d, J = 8.4 Hz, 2H), 4.393 - 4.336 (m, 1H), 3.989 (q, J = 7.2 Hz, 2H), 3.730 (q, J = 6.8 Hz, 1H), 2.914 (dd, J = 14.0Hz, 6.0 Hz, 1H), 2.807 (dd, J = 14.0 Hz, 9.2 Hz, 1H), 1.265 (d, J = 7.2 Hz, 3H), 1.046 (t, J = 7.2 Hz, 3H).

[0565] 28-2 synthesis [ka]

[0566] 250 mg of 28-1 was added to a 25 mL reaction flask, followed by 5 mL of THF, and dissolved. 121 mg of lithium hydroxide was dissolved in 2 mL of water and added dropwise to the reaction mixture. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. The reaction was observed by LC / MS to confirm completion. The reaction mixture was adjusted to pH 3 using 1 N hydrochloric acid and extracted with 20 mL of EA x 2. The EA layers were combined, washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 28-2 (220 mg). Yield 94.0%. MS: 408. 1H NMR (400 MHz, DMSO-d6) δ 12.516(s, 1H), 9.198 (s, 1H), 8.315 (d, J = 8.0 Hz, 1H), 7.537 - 7.371(m, 6H), 7.220 - 7.177 (m, 2H), 6.993 (d, J = 8.4 Hz, 2H), 6.651 (d, J = 8.4 Hz, 2H), 4.379 - 4.324 (m, 1H), 3.736 (q, J = 7.2 Hz, 1H), 2.956 (dd, J = 13.6, 4.8 Hz, 1H), 2.771 (dd, J = 14.0 Hz, 5.6 Hz, 1H), 1.245 (d, J = 7.2 Hz, 3H).

[0567] 28-3 synthesis [ka]

[0568] 200 mg (1.0 equivalent) of Example 2 and 3 mL of DCM were added to a 10 mL reaction flask. The mixture was cooled to 0°C in an ice bath under a nitrogen atmosphere. 160 mg of triphosgene was dissolved in 2 mL of dichloromethane and added dropwise to the reaction mixture. The mixture was reacted at low temperature for 2 hours. The mixture was diluted with 20 mL of DCM, washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 210 mg of 28-3 as a solid. This was used directly in the next step.

[0569] Synthesis of Example 21 [ka]

[0570] 28-2 (85 mg), DCM (2 mL), and triethylamine (100 mL) were added to a 10 mL reaction flask. The mixture was cooled in an ice bath under a nitrogen atmosphere. 1 mL of DCM solution containing 28-3 (110 mg) was added dropwise to the reaction mixture. After addition, 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 solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column chromatography to obtain 48.4 mg as solid in a yield of 31.3%. MS: 774, 1 H NMR (400 MHz, DMSO-d6) δ 9.331(s, 1H), 7.961(s, 1H), 7.529 - 7.360(m, 7H), 7.241 - 7.189 (m, 4H), 7.055 (d, J = 8.0 Hz, 2H), 6.938(d, J = 8.4 Hz, 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, 4H), 3.167 - 3.105 (m, 2H), 2.952 - 2.902 (m, 2H), 2.676 - 2.611 (m, 3H), 1.258 (d, J = 7.2 Hz, 3H).

[0571] Example 22 [ka]

[0572] 29-1 synthesis [ka]

[0573] 29-SM2 (1 g, 1.0 equivalent) and DIEA (2.08 g, 2.0 equivalent) were added to 10 mL of DCM. After complete dissolution, 29-SM1 (1.14 g, 1.1 equivalent) was slowly added dropwise. The mixture was stirred overnight at room temperature. TLC analysis confirmed that almost no starting material remained. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude product 29-1 (2.5 g). This was used directly in the next step without purification.

[0574] 29-2 synthesis [ka]

[0575] Crude product 29-1 (1.2 g) and 23-SM (600 mg, 0.44 equivalents) were dissolved in ACN. DBU (400 mg, 0.47 equivalents) was added, and the mixture was stirred overnight at 60°C. The reaction mixture was diluted with dichloromethane and extracted with water and dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, and then concentrated to dryness by rotary evaporation. The residue was purified by column chromatography to obtain 29-2 (600 mg). Yield: 57%. 1 H NMR (400 MHz, DMSO-d6) δ 7.558 - 7.407(m, 6H), 7.346 - 7.196 (m, 7H), 5.847 (d, J = 6.0 Hz, 1H), 5.814 (d, J = 6.0 Hz, 1H), 4.014 (q, J = 7.2 Hz, 1H), 1.450 (d, J = 7.2 Hz, 3H).

[0576] 29-3 synthesis [ka]

[0577] 29-2 (300 mg) was dissolved in dichloromethane. Sulfonyl chloride was added dropwise at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with methanol, and the solvent was removed to obtain crude product 29-3 (300 mg). This was used directly in the next step.

[0578] Synthesis of Example 22 [ka]

[0579] Example 2 (200 mg, 1 equivalent) was dissolved in DCM. DIEA (226 mg, 3 equivalents) was added. After complete dissolution, dichloromethane solution 29-3 was added dropwise at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction mixture was purified by pre-packed column chromatography to obtain Example 22 (240 mg). Yield: 64%. MS: 641. 1 H NMR (400 MHz, DMSO-d6) δ 9.168 (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, 2H), 3.753 (s, 3H), 3.729 (s, 3H), 3.602 (d, J = 1.6 Hz, 3H), 3.453 - 3.395 (m, 3H), 3.109 (dd, J = 10.8 Hz, 3.6 Hz, 1H), 2.974 - 2.893 (m, 1H), 2.640 - 2.446 (m, 3H), 1.456 (d, J = 6.8 Hz, 3H).

[0580] Example 23 [ka]

[0581] 30-1 synthesis [ka]

[0582] 30-SM2 (1 g, 1 equivalent) and DIEA (2.08 g, 2 equivalents) were added to 8 mL of DCM. After complete dissolution, 30-SM1 (1.26 g, 1.1 equivalents) was slowly added dropwise. The mixture was stirred overnight at room temperature, and then concentrated to dryness by rotary evaporation to obtain the desired crude product (2.5 g). This was used directly in the next step without purification.

[0583] 30-2 synthesis [ka]

[0584] Crude product 30-1 (1.29 g) and flurbiprofen (600 mg, 0.44 equivalents) were dissolved in ACN. DBU (400 mg, 0.47 equivalents) was added, and the mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with water and dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, concentrated to dryness by rotary evaporation, and purified by column chromatography to obtain 30-2 (500 mg). MS: 438, 1 H NMR (400 MHz, DMSO-d6) δ 7.570 - 7.185 (m, 13H), 6.938 - 6.875 (m, 1H), 4.225 - 4.174 (m,1H), 4.086 (d, J = 1.6 Hz, 1H), 3.963 (q, J = 7.2 Hz, 1H), 1.474 - 1.418 (m, 6H).

[0585] 30-3 synthesis [ka]

[0586] 30-2 (247 mg) was dissolved in dichloromethane (2 mL). Sulfonyl chloride was added dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The solvent was removed to obtain crude product 30-3 280 mg.

[0587] Synthesis of Example 23 [ka]

[0588] Example 2 (190 mg, 1 equivalent) was dissolved in DCM, and DIEA (300 mg, 4 equivalents) was added. After complete dissolution, a dichloromethane solution of crude product 30-3 (280 mg) was added dropwise at 0°C. The reaction mixture was post-processed and then purified by column chromatography to obtain the crude product. This was further purified by reverse-phase column chromatography to obtain Example 23 (157 mg). MS: 655, 1 H NMR (400 MHz, DMSO-d6) δ 9.068 (d, J = 48.8 Hz, 1H), 7.564 - 7.405 (m, 6H), 7.299 - 7.203 (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), 3.164 - 3.098 (m, 1H), 3.000 - 2.912 (m, 1H), 2.692 - 2.461 (m, 3H), 1.510 - 1.434 (m, 6H).

[0589] Activity evaluation Test Example 1

[0590] Animals: Mice (CD-1 mice, age: 6-8 weeks, sex: male, weight: 20-24g, number: 120, supplier: Beijing Spefu Biotechnology Co.,Ltd.). A 7-day isolation period was established. Routine health checks were performed by a veterinarian, and animals found to be abnormal before the test were excluded.

[0591] Mice were housed in a cleanroom, with 5 mice per cage. The room temperature was 22±3°C, humidity 40-70%, and the light-dark cycle was 12 hours. The cages were made of polycarbonate. Soft corn cob-derived bedding, sterilized by high-pressure steam, was used and replaced twice a week. Clean-grade rodent feed and water were purchased from Beijing Keao Xieli Feed Co., Ltd. Drinking water was autoclaved, and feed was sterilized by cobalt-60 irradiation. The animals were given free access to sterilized feed and water. All mice were weighed before administration, and the data was recorded in detail.

[0592] Mice were fasted for 16 hours prior to drug administration. Administration was performed intravenously, with a volume of 10 mL / kg and a dose of 10 mg / kg. Fifteen minutes after administration, 0.6% acetic acid was injected into the peritoneal cavity of the mice. Acetic acid accumulated in the visceral and parietal peritoneum, causing deep, widespread, and persistent pain, inducing a behavioral response in mice characterized by abdominal depression, extension of the trunk and hind limbs, and elevation of the buttocks. This response is called the "squirming response." The number of struggling responses exhibited by the mice was used as an indicator of the pain response to evaluate the analgesic effect of the compound. The number of struggling responses occurring 20 minutes after 0.6% acetic acid injection was observed, and the ratio to the number of struggling responses in the control group (which did not receive the test compound) was calculated. This ratio was subtracted from 100% to obtain the inhibition rate, which was recorded. [Table 1]

[0593] Test Example 2: DRG Test

[0594] The dorsal root ganglia (DRGs) are primary neurons of sensory transmission, responsible for transmitting and regulating bodily sensations and receiving and conducting nociceptive signals. In this study, the effects of test substances on the action potentials of DRG neurons isolated from SD rats were investigated using the manual patch-clamp method.

[0595] Acute isolation of DRG: Rats were anesthetized with 20% w / w urethane and placed in a prone position. The skin was disinfected with 75% v / v alcohol. The spine was exposed by incision from the tail with scissors, and muscle tissue on both sides of the spine was removed. The spine was resected from the caudal vertebrae and placed in a 10 cm diameter culture dish containing HBSS on ice. The upper 1 / 3 of the spinal column cross-section was resected with scissors. The L4-L6 region was identified, and after removal of the spinal cord, nerve fibers connected to the dorsal root ganglia were visualized. The DRG was carefully excised under a dissecting microscope and transferred to a 35 mm culture dish containing HBSS. After all DRG was collected, nerve tissue attached to the DRG was excised under a microscope. The excised DRG was uniformly shredded and transferred to a 15 mL centrifuge tube and centrifuged at 1000 rpm for 5 minutes. The supernatant was removed. Then, 5 mL of digestion solution was added, and the mixture was digested in a 37°C, 5% CO2 incubator for approximately 20 minutes. During digestion, the centrifuge tube was gently shaken to resuspend the tissue, and the tissue was tritulated 2-3 times with a pipette until the tissue became thread-like and the tissue clumps disappeared, at which point digestion was considered complete. After digestion, 5 mL of complete medium was added, and the mixture was centrifuged at 1000 rpm for 5 minutes. The supernatant was removed. Finally, an appropriate amount of complete medium was added to gently resuspend the cells. The cell suspension was seeded onto a glass coverslip placed in a culture dish. After the neurons had adhered, the coverslip was used for patch-clamp detection.

[0596] Patch clamp detection: The following voltage stimulation protocol was used to record neuronal action potentials in whole-cell patch-clamp mode. After whole-cell seal formation, the recording mode was switched to CurrentClamp mode. The cell membrane current was clamped at 0 pA. The clamp current was gradually increased in 20 pA increments from -20 pA to approximately +360 pA, with a duration of 0.8 seconds at each step, and then returned to 0 pA and held for 1 second. Furthermore, changes in drug effect under stimulation 1.5 to 2 times that of Rheobase stimulation were recorded for a stimulation time of 1 second. Experimental data were acquired using an EPC10 amplifier (HEKA) and saved in PatchMaster (HEKA) software. For the patch-clamp procedure, first, a borosilicate glass capillary was stretched using a microelectrode puller to create the recording electrode. Next, the electrode filled with intracellular fluid was mounted in the electrode holder. Under an inverted microscope, the tip of the electrode was inserted into the extracellular fluid using a micromanipulator, and the electrode resistance (Rpip) was recorded. Next, electrodes were gently brought into contact with the cell surface, and negative pressure was applied to form a GΩ seal. At this point, high-speed capacitance compensation was performed. The negative pressure was continued to break the cell membrane, and the whole cell was recorded. Finally, low-speed capacitance compensation was performed, and experimental parameters such as series resistance (Rs) were recorded. Leakage compensation was not performed. Once the action potential recorded in whole-cell mode stabilized, drug administration was started. Each drug concentration was applied for approximately 5 minutes (or until the action potential stabilized) before testing the next concentration. Multiple concentrations were investigated for each compound. A coverslip containing cells was placed in the recording chamber mounted on an inverted microscope. Blank control solution and working solutions of the test compounds were sequentially flowed into the recording chamber from low to high concentrations by gravity perfusion to act on the cells, and fluid exchange was promoted with a peristaltic pump during recording. For each cell, the current detected in the compound-free solution was used as a self-control. For each concentration, independent repeated measurements (n=3) were performed using at least 3 cells. All electrophysiological tests were performed at room temperature.

[0597] As shown in Figure 1, 1 μM S-FBS and 1 μM Example 2 did not inhibit action potential conduction. However, 1 μM Examples 22 and 23 suppressed action potentials in DRG neurons to varying degrees, exhibiting nerve conduction blocking effects. This indicates that the analgesic mechanism of the compounds disclosed herein is different from that of S-FBS and Example 2.

[0598] The various embodiments described herein are described in relation to each other, and identical or similar parts among the embodiments can be referenced to one another. Each embodiment focuses on the differences from the other embodiments.

[0599] The above description illustrates only preferred embodiments of the present invention and does not limit the scope of the invention. Any modifications, equivalent substitutions, improvements, etc., implemented within the spirit and principles of the invention are all included within the scope of the invention.

Claims

1. Compounds of formula (I), or their isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 (In the formula, R Ｄ These are residues formed by drug molecules; U １ , U ２ , and U ３ These are independently O, S, -NH-, -C(O)-, -O-C(O)-, -NH-C(O)-, and -O-CH ２ Selected from -O-; W １ , W ２ , and W ３ are each independently selected from H, C １－１０ alkyl, C １－１０ deuterated alkyl, C １－１０ haloalkyl, C ３－１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; L is a chemical bond or 【Chemistry 2】 And alternatively, 【Transformation 3】 And; L １ These are chemical bonds, -C(O)-, -OC(O)-, -NR ｂ C(O)-, -S(O)-, -S(O) ２ -, -OS(O) １－２ -, and -NR ｂ S(O) １－２ - Selected from; L ２ C is a chemical bond. ３－７ Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes; L ３ are O, S, NR', -C(O)-, -S(O)-, and -S(O) ２ - Selected from; n is selected from 0, 1, 2, 3, 4, 5, and 6; 【Chemistry 4】 The methylene group in may be substituted with 1, 2, 3, 4, 5, or 6 independent R groups; R is independent of 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 Selected from cycloalkyl and 3- to 6-membered heterocyclines; R' is H, C １－１８ Alkyl, C １－１８ Haloalkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines, or R' and R together with the atoms to which they are bonded form 3- to 10-membered heterocyclines; R ａ , R ｂ , and R ｃ These are H and C, which are independent of each other. １－１０ Alkyl and C １－１０ Selected from haloalkyls, or R ｂ and R ｃ However, together with the atoms they bond to, they form 3- to 10-membered heterocyclines; Each of the above groups may be deuterated to the maximum extent of complete deuteration.

2. R Ｄ This is a residue formed by a drug molecule, and the drug molecule is an anti-inflammatory agent and its derivatives, or alternatively, a nonsteroidal anti-inflammatory agent and its derivatives such as loxoprofen, flurbiprofen, fenoprofen, ketoprofen, tolmetin, bromfenac, tiaprofenic acid, indomethacin, sulindac, ketorolac, nimeslide, mefenamic acid, clofenamic acid, diclofenac, aspirin, ibuprofen, naproxen, nabumetone, etodolac, lofecoxib, celecoxib, piroxicam, meloxicam, and oxyfenbutazone. Alternatively, the drug molecule may be selected from loxoprofen, flurbiprofen, indomethacin, mefenamic acid, clofenamic acid, and aspirin, and their derivatives; alternatively, flurbiprofen and clofenamic acid, and their derivatives; alternatively, flurbiprofen and its derivatives; alternatively, the flurbiprofen may be S-flurbiprofen; alternatively, the flurbiprofen may be R-flurbiprofen. A compound of formula (I) as described in claim 1, or an isotopic variant thereof, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.

3. U １ , U ２ , and U ３ Each is independently selected from O, S, -NH-, and -C(O)-, and alternatively O. A compound of formula (I) as described in claim 1 or 2, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.

4. W １ , W ２ , and W ３ Each is independent of C １－１０ Alkyl, C １－１０ Alkyl deuterated, C １－１０ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively C １－１０ Alkyl, C １－１０ Alkyl deuterated, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively C １－１０ Alkyl, C １－１０ Alkyl deuterated, and C １－１０ Selected from haloalkyls, alternatively C １－６ Alkyl, C １－６ Alkyl deuterated, and C １－６ Selected from haloalkyls, alternatively C １－６ Alkyl or C １－６ Alkyl deuterated, or alternatively methyl or CD ３ Alternatively, C １－６ Alkyl, or alternatively methyl, A compound of formula (I) as described in any one of claims 1 to 3, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.

5. L １ is selected from chemical bonds, -C(O)-, -OC(O)-, and -NHC(O)-, alternatively selected from chemical bonds, -C(O)-, and -OC(O)-, alternatively selected from -C(O)- and -OC(O)-, and alternatively -C(O)-, Alternatively, L １ is selected from -C(O)-, -OC(O)-, and -NHC(O)-, alternatively selected from -OC(O)- and -NHC(O)-, alternatively -OC(O), A compound of formula (I) as described in 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.

6. L ２ C is a chemical bond. ３－７ Selected from cycloalkylene, 3-7 membered heterocyclene, phenylene, and 5-6 membered heteroarylene, alternatively a chemical bond, selected from phenylene and 5-6 membered heteroarylene, alternatively a chemical bond, and selected from phenylene, alternatively a chemical bond, 【Transformation 5】 Selected from, alternatively, chemical bonds and 【Transformation 6】 Selected from, alternatively a chemical bond, A compound of formula (I) as described in 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.

7. L ３ is selected from O, S, and NR', alternatively selected from O and NR', alternatively selected from O and S, alternatively O, alternatively NR', A compound of formula (I) as described in 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.

8. n is selected from 0, 1, 2, and 3, alternatively selected from 1, 2, and 3, alternatively 1 or 2, alternatively 1. A compound of formula (I) as described in 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. 【Request Item 9】 【Chemistry 7】 The methylene group in may be substituted with one, two, or three independent R groups, or alternatively, with one R group. A compound of formula (I) as described in 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.

10. R is each independently 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 is selected from; alternatively, 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 is selected from; alternatively, selected from H, D, =O, C １－６ alkyl, C １－６ haloalkyl, and -C ０－６ alkylene-C(O)OR ａ is selected from; alternatively, selected from H, D, =O, C １－３ alkyl, C １－３ haloalkyl, and -C ０－６ alkylene-C(O)OR ａ is selected from; alternatively, selected from H, D, =O, C １－３ alkyl, and -C ０－６ alkylene-C(O)OR ａ is selected from; alternatively, selected from H, D, =O, C １－３ alkyl, and -C ０－３ alkylene-C(O)OR ａ is selected from; alternatively, selected from H, D, =O, and -C ０－３ alkylene-C(O)OH, Alternatively, R can be independently H, =O, methyl, isobutyl, -C(O)OH, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, methyl, -C(O)OH, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, methyl, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, and -(CH ２ ) ２ Selected from C(O)OH, Alternatively, R can be independently H, D, halogen, C １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, and C. １－３ Alkyl and C １－３ Selected from haloalkyls, and alternatively selected from H and Me, A compound of formula (I) as described in 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.

11. R' is H, C １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines, substituted with H, C １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, Alternatively, R' and R, together with the atom they bond to, form a 3- to 10-membered heterocycline; alternatively, they form a 3- to 7-membered heterocycline; alternatively, they form a 4- to 6-membered heterocycline; alternatively, 【Transformation 8】 Forms, and alternatively 【Chemistry 9】 Forming, Alternatively, R' and R do not form a ring with the atom to which they are bonded. A compound of formula (I) as described in 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.

12. R ａ , R ｂ , and R ｃ These are H and C, which are independent of each other. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, Alternatively, R ｂ and R ｃ However, together with the atoms they bond to, they form 3- to 7-membered heterocyclines. A compound of formula (I) as described in 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.

13. R Ｄ teeth 【Chemistry 10】 Alternatively, 【Chemistry 11】 And in the formula, Ring A is C ６－１０ Arirene, 5-10 member heteroarirene, C ６－１０ Aryl condensation C ５－１０ Cycloalkyl, C ６－１０ Aryl condensed 5-10 member heterocyclyl, 5-10 member heteroaryl condensed C ５－１０ Selected from cycloalkyls and 5-10 member heteroaryl condensations of 5-10 member heterocyclyls; Ring B is C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, or -L ４ - Rings B and R ２ It does not exist; R １ These are independently H, D, halogen, CN, -NO ２ , -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) ２ R ａ , C １－１８ Alkyl, C １－１８ Haloalkyl, C ３－１４ Cycloalkyl, 3-14 member heterocyclyl, C ６－１４ Selected from aryls and 5- to 14-membered heteroaryls, with 1, 2, or 3 independent R １ｓ It is also fine if it is replaced with; R １ｓ These are independently 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 Selected from cycloalkyl and 3- to 10-membered heterocyclyl; m = 0, 1, 2, 3, 4, or 5; R ２ These are independently H, D, halogen, CN, -NO ２ , -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) ２ R ａ , C １－１８ Alkyl, C １－１８ Haloalkyl, C ３－１４ Cycloalkyl, 3-14 member heterocyclyl, C ６－１４ Selected from aryls and 5- to 14-membered heteroaryls, with 1, 2, or 3 independent R ２ｓ It is also fine if it is replaced with; R ２ｓ These are independently 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 Selected from cycloalkyl and 3- to 10-membered heterocyclyl; s = 0, 1, 2, 3, 4, or 5; L ４ is a chemical bond, -CR ４ R' 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 - to be selected from, Or L ４ And, L ４ The carbon atom on ring A to which it is bonded together 【Chemistry 12】 Forming; L ５ These are chemical bonds, O, S, NR', and C １－１０ Selected from alkylenes, one or more independent R ３ It is also fine if it is replaced with; R ３ These are independently H, D, halogen, and C. １－１０ Alkyl and C １－１０ Selected from haloalkyls; R ４ and R' ４ These are independently H, D, halogen, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; X is -C(O)-, -S(O)-, and -S(O) ２ - is selected from, and alternatively -C(O)-, A compound of formula (I) as described in 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.

14. Ring A is C ６－１０ Selected from arylene and 5-10 member heteroarylene, alternatively selected from phenylene and 9-10 member heteroarylene, alternatively selected from phenylene and indolylene, alternatively phenylene, alternatively 【Chemistry 13】 Selected from, alternatively 【Chemistry 14】 Selected from, alternatively 【Chemistry 15】 That is, A compound of formula (I) as described in 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.

15. Ring B is C ３－７ Selected from cycloalkyl, 3-7 member heterocyclyl, phenyl, and 5-6 member heteroaryl, alternatively selected from phenyl and 5-6 member heteroaryl, alternatively C ６－１０ Aryl, or alternatively, phenyl. A compound of formula (I) as described in 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.

16. R １ These are independently H, D, halogen, CN, -NO ２ , -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) ２ R ａ , C １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, 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 Selected from haloalkyls, alternatively H, D, halogens, CN, -OR ａ , -NR ｂ R ｃ , -OC(O)R ａ , -C(O)OR ａ , C １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, halogen, -OR ａ , -OC(O)R ａ , C １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, F, Me, -OMe, and -OC(O)CH ３ Selected from, Alternatively, R １ These are independently 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively selected from H, D, and halogens, alternatively H or F, alternatively halogen, alternatively F. A compound of formula (I) as described in 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.

17. R ２ These are independently H, D, halogen, CN, -NO ２ , -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) ２ R ａ , C １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls, 3- to 7-membered heterocyclines, phenyls, and 5- to 6-membered heteroaryls, alternatively H, D, halogens, 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 Selected from haloalkyls, alternatively H, D, halogens, CN, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively selected from H, Cl, and Me, alternatively selected from H and Cl, Alternatively, R ２ These are independently 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively selected from H, D, and halogens, and further alternatively H or D. A compound of formula (I) as described in 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.

18. R １ｓ and R ２ｓ These are H, D, halogen, CN, and C, respectively, independently. １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively H, D, halogens, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyl groups, A compound of formula (I) as described in 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.

19. m = 0, 1, 2, 3, or 4, alternatively m = 0, 1, or 2, alternatively m = 0 or 1, alternatively m = 1. A compound of formula (I) as described in 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.

20. s = 0, 1, or 2; alternatively, s = 0. A compound of formula (I) as described in 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.

21. L ４ is a chemical bond, -CR ４ R' ４ -, -NR ｂ -, O, S, -C(O)-, and -S(O)- are selected, and alternatively, chemical bonds, -CR ４ R' ４ -, -NR ｂ -, O, and -C(O)- are selected, and alternatively chemical bonds, -NR ｂ - and -C(O)- are selected, and alternatively a chemical bond; -NH- and -C(O)- are selected, and alternatively a chemical bond; and -NH- are selected, and alternatively a chemical bond. A compound of formula (I) as described in 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.

22. L ５ is a chemical bond or C １－１０ Alkylene, alternatively chemical bond or C １－６ Alkylene, alternatively chemical bond or C １－４ Alkylene, alternatively chemical bond or C １－２ Alkylene, alternatively a chemical bond or methylene, alternatively -CH(CH) ３ ) - and Alternatively, L ５ This consists of 1, 2, 3, 4, 5, or 6 independent R ３ It may be substituted with, or alternatively, one, two, or three independent R ３ It may be substituted with one R, or alternatively, one R ３ It may be replaced with A compound of formula (I) as described in 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.

23. R ３ These are independently H, D, halogen, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, and C. １－４ Alkyl and C １－４ Selected from haloalkyls, alternatively selected from H and Me, alternatively Me. A compound of formula (I) as described in 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.

24. R ４ and R' ４ These are H, D, and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyl groups, substituted with H or D. A compound of formula (I) as described in 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.

25. The following structure: 【Chemistry 16】 (wherein each variable is defined as in any one of claims 1 to 24) A compound of formula (I) as described in 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.

26. A compound of formula (II) as described in claim 25, or an isotopic variant thereof, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 17】 (In the formula, Ring A is C ６－１０ Selected from arylenes and 5- to 10-membered heteroarylenes; Ring B is C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively C ３－７ Selected from cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, or -L ４ - Rings B and R ２ It does not exist; R １ These are independently 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines, with 1, 2, or 3 independent R groups. １ｓ It is also fine if it is replaced with; R １ｓ These are independently H, D, halogen, CN, and C. １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively H, D, halogens, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyl and 3- to 7-membered heterocyclyl; m = 0, 1, 2, 3, 4, or 5; R ２ 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively H, D, halogens, 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 Selected from cycloalkyls and 3- to 7-membered heterocyclines, with 1, 2, or 3 independent R groups. ２ｓ It is also fine if it is replaced with; R ２ｓ These are independently H, D, halogen, CN, and C. １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines, alternatively H, D, halogens, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyl and 3- to 7-membered heterocyclyl; s = 0, 1, 2, 3, 4, or 5; L ４ is a chemical bond, -CR ４ R' ４ -, -NR ｂ Selected from -, O, S, -C(O)-, and -S(O)-; L ５ is a chemical bond or C １－６ It is an alkylene with 1, 2, 3, 4, 5, or 6 independent R ３ It is also fine if it is replaced with; R ３ These are independently H, D, halogen, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; R ４ and R' ４ These are independently H, D, halogen, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; U １ , U ２ , and U ３ These are independently O, S, -NH-, -C(O)-, -O-C(O)-, -NH-C(O)-, and -O-CH ２ Selected from -O-; W １ , W ２ , and W ３ Each is independent of C １－１０ Alkyl, C １－１０ Alkyl deuterated, C １－１０ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively C １－１０ Alkyl, C １－１０ Alkyl deuterated, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyl and 3- to 10-membered heterocyclyl; L is a chemical bond or 【Chemistry 18】 And; L １ The chemical bond is selected from -C(O)-, -OC(O)-, and -NHC(O)-; L ２ C is a chemical bond. ３－７ Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes; L ３ is selected from O, S, and NR'; n is selected from 0, 1, 2, 3, 4, 5, and 6; 【Chemistry 19】 The methylene group in may be substituted with one, two, or three independent R groups; R is independent of 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 Selected from, alternatively 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 Selected from; R' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, or R' and R together with the atoms to which they are bonded form 3- to 7-membered heterocyclines; R ａ , R ｂ , and R ｃ These are H and C, which are independent of each other. １－６ Alkyl and C １－６ Selected from haloalkyls, or R ｂ and R ｃ However, together with the atoms they bond to, they form 3- to 7-membered heterocyclines; Each of the above groups may be deuterated to the maximum extent of complete deuteration.

27. Ring A is C ６－１０ Selected from arylenes and 5- to 10-membered heteroarylenes, and alternatively selected from phenylenes and 9- to 10-membered heteroarylenes; Ring B is C ６－１０ Selected from aryls and 5-10 member heteroaryls, alternatively selected from phenyls and 5-6 member heteroaryls, alternatively C ６－１０ Aryl, or alternatively phenyl, or -L ４ - Rings B and R ２ It does not exist; R １ These are independently 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 Selected from haloalkyls, alternatively H, D, halogens, CN, -OR ａ , -NR ｂ R ｃ , -OC(O)R ａ , -C(O)OR ａ , C １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, halogen, -OR ａ , -OC(O)R ａ , C １－６ Alkyl and C １－６ Selected from haloalkyls, and alternatively selected from H, D, and halogens, with 1, 2, or 3 independent Rs. １ｓ It is also fine if it is replaced with; R １ｓ These are independently H, D, halogen, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; m = 0, 1, 2, 3, 4, or 5, or alternatively m = 0, 1, or 2; R ２ These are independently 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 Selected from haloalkyls, alternatively H, D, halogens, CN, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, and alternatively selected from H, D, and halogens, with 1, 2, or 3 independent Rs. ２ｓ It is also fine if it is replaced with; R ２ｓ These are independently H, D, halogen, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; s = 0, 1, 2, 3, 4, or 5, or alternatively s = 0, 1, or 2; L ４ is a chemical bond, -CR ４ R' ４ -, -NR ｂ -, O, and -C(O)- are selected, and alternatively chemical bonds, -NR ｂ - and -C(O)- are selected; L ５ is a chemical bond or C １－４ Alkylene, alternatively chemical bond or C １－２ It is an alkylene and has 1, 2, or 3 independent R ３ It is also fine if it is replaced with; R ３ These are H, D, and C, independently. １－４ Alkyl and C １－４ Selected from haloalkyls; R ４ and R' ４ These are H, D, and C, independently. １－６ Alkyl and C １－６ Selected from haloalkyls, and alternatively selected from H and D; U １ , U ２ , and U ３ Each is independently selected from O, S, -NH-, and -C(O)-, and is alternatively O; W １ , W ２ , and W ３ Each is independent of C １－１０ Alkyl, C １－１０ Alkyl deuterated, and C １－１０ Selected from haloalkyls, alternatively C １－６ Alkyl, C １－６ Alkyl deuterated, and C １－６ Selected from haloalkyls, alternatively C １－６ Alkyl or C １－６ Alkyl deuterated, alternatively C １－６ It is alkyl; L is a chemical bond or 【Chemistry 20】 And; L １ is selected from chemical bonds, -C(O)-, and -OC(O)-, alternatively selected from -C(O)- and -OC(O)-, and alternatively -C(O)-; L ２ It is selected from chemical bonds, phenylene, and 5-6 membered heteroarylenes, and alternatively selected from chemical bonds and phenylene; L ３ is selected from O and NR', substituted for NR', and substituted for O; n is selected from 0, 1, 2, and 3, alternatively selected from 1, 2, and 3, alternatively 1 or 2, alternatively 1; 【Chemistry 21】 The methylene group in may be substituted with one, two, or three independent R groups, or alternatively, with one R group; R is independent of H, D, =O, C １－６ Alkyl, C １－６ Haloalkyl and -C ０－６ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, C １－３ Alkyl, C １－３ Haloalkyl and -C ０－６ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, C １－３ Alkyl and -C ０－６ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, C １－３ Alkyl and -C ０－３ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, and -C ０－３ Selected from alkylene-C(O)OH; R' is H, C １－６ Alkyl and C １－６ Selected from haloalkyl groups, alternatively H, or R' and R form a 4- to 6-membered heterocycline with the atom to which they are bonded; alternatively, R' and R do not form a ring; R ａ , R ｂ , and R ｃ These are H and C, which are independent of each other. １－６ Alkyl and C １－６ Selected from haloalkyl groups, The compound of formula (II) as described in claim 26, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

28. Ring A is selected from phenylene and indolylene, and alternatively 【Chemistry 22】 Selected from, alternatively phenylene, alternatively 【Chemistry 23】 Selected from; Ring B is either phenyl or -L ４ - Rings B and R ２ It does not exist; R １ These are independently H, F, Me, -OMe, and -OC(O)CH ３ Selected from, alternatively H or F; m = 0, 1, or 2; R ２ These are independently selected from H, Cl, and Me, and alternatively selected from H and Cl; s = 0, 1, or 2; L ４ is selected from a chemical bond, -NH-, and -C(O)-, and alternatively selected from a chemical bond and -NH-, and alternatively a chemical bond; L ５ is a chemical bond or methylene, and one R ３ It may be replaced with L ５ is -CH(CH ３ ) - and; R ３ It is independently selected from H and Me, and alternatively Me; U １ , U ２ , and U ３ is O; W １ , W ２ , and W ３ is methyl or CD ３ Alternatively, methyl is used; L is a chemical bond or 【Chemistry 24】 And; L １ The chemical bond is selected from -C(O)- and -OC(O)-; L ２ is a chemical bond, 【Chemistry 25】 Selected from; L ３ is selected from O and NR'; n is 0, 1, 2, and 3; 【Chemistry 26】 The methylene group in this may be substituted with one R; R is independently H, =O, methyl, isobutyl, -C(O)OH, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, methyl, -C(O)OH, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, methyl, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, and -(CH ２ ) ２ Selected from C(O)OH; R' is H, or R' and R are together with the atom to which they are bonded. 【Chemistry 27】 Forms, and alternatively 【Chemistry 28】 Forming; Alternatively, 【Chemistry 29】 The structure is as follows: 【Transformation 30】 Selected from, alternatively 【Chemistry 31】 Selected from, alternatively 【Chemistry 32】 Selected from, The compound of formula (II) as described in claim 27, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

29. A compound of formula (III) as described in claim 25, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof: 【Transformation 33】 (In the formula, R １ These are independently 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, with 1, 2, or 3 independent R １ｓ It is also fine if it is replaced with; R １ｓ These are independently H, D, halogen, CN, and C. １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyl and 3- to 10-membered heterocyclyl; m = 0, 1, 2, 3, or 4; R ２ These are independently 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 heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, with 1, 2, or 3 independent R ２ｓ It is also fine if it is replaced with; R ２ｓ These are independently H, D, halogen, CN, and C. １－１０ Alkyl, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyl and 3- to 10-membered heterocyclyl; s = 0, 1, 2, 3, 4, or 5; U １ , U ２ , and U ３ These are independently O, S, -NH-, -C(O)-, -O-C(O)-, -NH-C(O)-, and -O-CH ２ Selected from -O-; W １ , W ２ , and W ３ Each is independent of C １－１０ Alkyl, C １－１０ Alkyl deuterated, C １－１０ Haloalkyl, C ３－１０ Cycloalkyl, 3-10 membered heterocyclyl, C ６－１０ Selected from aryls and 5- to 10-membered heteroaryls, alternatively C １－１０ Alkyl, C １－１０ Alkyl deuterated, C １－１０ Haloalkyl, C ３－１０ Selected from cycloalkyl and 3- to 10-membered heterocyclyl; L is a chemical bond or 【Transformation 34】 And; L １ The chemical bond is selected from -C(O)-, -OC(O)-, and -NHC(O)-; L ２ C is a chemical bond. ３－７ Selected from cycloalkylenes, 3- to 7-membered heterocyclylenes, phenylenes, and 5- to 6-membered heteroarylenes; L ３ is selected from O, S, and NR'; n is selected from 0, 1, 2, 3, 4, 5, and 6; 【Chemistry 35】 The methylene group in may be substituted with one, two, or three independent R groups; R is independent of 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 Selected from, alternatively 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 Selected from; R' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, or R' and R together with the atoms to which they are bonded form 3- to 7-membered heterocyclines; R ａ , R ｂ , and R ｃ These are H and C, which are independent of each other. １－６ Alkyl and C １－６ Selected from haloalkyls, or R ｂ and R ｃ However, together with the atoms they bond to, they form 3- to 7-membered heterocyclines; Each of the above groups may be deuterated to the maximum extent of complete deuteration.

30. R １ These are independently H, D, halogen, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, and alternatively selected from H, D, and halogens, with 1, 2, or 3 independent Rs. １ｓ It is also fine if it is replaced with; R １ｓ These are independently H, D, halogen, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; m = 0, 1, 2, 3, or 4, or alternatively, m = 0, 1, or 2; R ２ These are independently H, D, halogen, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls, alternatively selected from H, D, and halogens, and further alternatively H or D, with 1, 2, or 3 independent R ２ｓ It is also fine if it is replaced with; R ２ｓ These are independently H, D, halogen, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ３－７ Selected from cycloalkyls and 3- to 7-membered heterocyclines, alternatively H, D, halogens, and C. １－６ Alkyl and C １－６ Selected from haloalkyls; s = 0, 1, 2, 3, 4, or 5, or alternatively s = 0, 1, or 2; U １ , U ２ , and U ３ Each is independently selected from O, S, -NH-, and -C(O)-, and is alternatively O; W １ , W ２ , and W ３ Each is independent of C １－１０ Alkyl, C １－１０ Alkyl deuterated, and C １－１０ Selected from haloalkyls, alternatively C １－６ Alkyl, C １－６ Alkyl deuterated, and C １－６ Selected from haloalkyls, alternatively C １－６ Alkyl or C １－６ Alkyl deuterated, alternatively C １－６ It is alkyl; L is a chemical bond or 【Transformation 36】 And; L １ is selected from chemical bonds, -C(O)-, and -OC(O)-, alternatively selected from -C(O)- and -OC(O)-, and alternatively -C(O)-; L ２ It is selected from chemical bonds, phenylene, and 5-6 membered heteroarylenes, and alternatively selected from chemical bonds and phenylene; L ３ is selected from O and NR', substituted for NR', and substituted for O; n is selected from 0, 1, 2, and 3, alternatively selected from 1, 2, and 3, alternatively 1 or 2, alternatively 1; 【Chemistry 37】 The methylene group in may be substituted with one, two, or three independent R groups, or alternatively, with one R group; R is independent of H, D, =O, C １－６ Alkyl, C １－６ Haloalkyl and -C ０－６ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, C １－３ Alkyl, C １－３ Haloalkyl and -C ０－６ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, C １－３ Alkyl and -C ０－６ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, C １－３ Alkyl and -C ０－３ Alkylene-C(O)OR ａ Selected from, alternatively H, D, =O, and -C ０－３ Selected from alkylene-C(O)OH; R' is H, C １－６ Alkyl and C １－６ Selected from haloalkyl groups, alternatively H, or R' and R form a 4- to 6-membered heterocycline with the atom to which they are bonded; alternatively, R' and R do not form a ring; R ａ H and C are independent of each other. １－６ Alkyl and C １－６ Selected from haloalkyl groups, The compound of formula (III) as described in claim 29, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

31. R １ is H or F; m = 1; R ２ H is; s = 0; U １ , U ２ , and U ３ is O; W １ , W ２ , and W ３ is methyl or CD ３ Alternatively, methyl is used; L is a chemical bond or 【Chemistry 38】 And; L １ The chemical bond is selected from -C(O)- and -OC(O)-; L ２ is a chemical bond, 【Chemistry 39】 Selected from; L ３ is selected from O and NR'; n is 0, 1, 2, and 3; 【Chemistry 40】 The methylene group in this may be substituted with one R; R is independently H, =O, methyl, isobutyl, -C(O)OH, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, methyl, -C(O)OH, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, methyl, and -(CH ２ ) ２ Selected from C(O)OH, alternatively H, =O, and -(CH ２ ) ２ Selected from C(O)OH; R' is H, or R' and R are together with the atom to which they are bonded. 【Chemistry 41】 Forms, and alternatively 【Chemistry 42】 Forming; Alternatively, L is a chemical bond. 【Chemistry 43】 Selected from, alternatively chemical bonds, 【Chemistry 44】 Selected from, alternatively chemical bonds, 【Chemistry 45】 Selected from, alternatively chemical bonds, 【Chemistry 46】 Selected from, alternatively chemical bonds, 【Chemistry 47】 Selected from; Alternatively, 【Chemistry 48】 teeth 【Chemistry 49】 And; Alternatively, [Transformation 50] teeth 【Chemistry 51】 And; Alternatively, 【Chemistry 52】 teeth 【Chemistry 53】 And; Alternatively, 【Chemistry 54】 teeth 【Transformation 55】 And; Alternatively, 【Transformation 56】 teeth 【Chemistry 57】 That is, The compound of formula (III) as described in claim 30, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof.

32. A compound of formula (III-1) as described in claim 25, or its isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates, or pharmaceutically acceptable salts thereof: 【Chemistry 58】 (In the formula, each variable is defined as in any one of claims 1 to 31; Alternatively, 【Chemistry 59】 teeth 【Transformation 60】 And; Alternatively, 【Chemistry 61】 teeth 【Transformation 62】 (That is the case.)

33. L is 【Transformation 63】 And; L １ is selected from -C(O)-, -OC(O)-, and -NHC(O)-, alternatively selected from -OC(O)- and -NHC(O)-, and alternatively -OC(O)-; L ２ is a chemical bond; L ３ is selected from O, S, and NR', alternatively selected from O and S, and alternatively O; n is selected from 1, 2, and 3, and alternatively 1 or 2, and alternatively 1; 【Chemistry 64】 The methylene group in may be substituted with one, two, or three (or alternatively, one) independent R groups; R is each independently selected from H, D, halogen, C １－６ alkyl, and C １－６ haloalkyl; alternatively, it is selected from H, D, C １－６ alkyl, and C １－６ haloalkyl; alternatively, it is selected from H, D, C １－３ alkyl, and C １－３ haloalkyl; alternatively, it is selected from H and Me; The remaining groups are defined as in any one of claims 1 to 32; Alternatively, L is 【Transformation 65】 That is, A compound of formula (II), formula (III), or formula (III-1) as described in claim 25, or an isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.

34. The following compounds: 【Chemistry 66-1】 【Chemistry 66-2】 【Chemistry 66-3】 【Chemistry 66-4】 【Chemistry 66-5】 Selected from, A compound of formula (I) as described in claim 1, or an isotopic variant thereof, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising 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, a pharmaceutically acceptable carrier, adjuvant, or vehicle, and optionally 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 manufacture of a pharmaceutical for the treatment or prevention of central nervous system disorders.

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

39. The above-mentioned disease is selected from pain, depression, and addiction, and the use according to claim 36, the method according to claim 37, or the compound or pharmaceutical composition according to claim 38.

40. The use, method, compound, or pharmaceutical composition according to claim 39, wherein the above-mentioned pain is selected from the group consisting of neuralgia, perioperative pain (including preoperative, intraoperative, or postoperative pain such as somatic or visceral pain due to postoperative trauma or postoperative incision, pain due to visceral injury, and other generalized pain), and cancer pain (pain due to cancer, etc.).

41. The use, method, compound, or pharmaceutical composition according to claim 40, wherein the pain is acute pain or chronic pain (including preoperative, intraoperative, or postoperative acute / chronic pain, acute neuralgia, or chronic neuralgia).

42. The above-mentioned neuralgia is central pain such as spinal pain, thalamic pain, pontine pain, medullary pain, or cerebral cortical pain, as per claim 40, the use, method, compound, or pharmaceutical composition.

43. The postoperative pain described above is pain resulting from surgery, such as pain resulting from abdominal surgery, orthopedic surgery, cesarean section, or brain surgery, as described in claim 40.

44. The compound or pharmaceutical composition described above is used for sedation or as an aid to sleep, as described in claim 36, as described in claim 37, or as described in claim 38.

Images