Piperazine-substituted phenol derivatives and uses thereof

Abstract

Abstract: A piperazine-substituted phenol derivative having the structure represented by formula (I) is provided. This compound not only has good salt-forming properties and excellent water solubility to meet pharmaceutical requirements, but also has a low minimum effective dose of anesthetics, rapid onset of action, and rapid recovery. This overcomes the drawbacks of prodrugs and lipid emulsion formulations of propofol and ciprofol, and is expected to be used in the preparation of drugs with sedative, hypnotic, and / or anesthetic effects and drugs for controlling status epilepticus. TIFF2025535407000076.tif41170

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and specifically, the present invention relates to piperazine-substituted phenol derivatives having unique structures, methods for their synthesis, and their application in the preparation of drugs with sedative, hypnotic and / or anesthetic effects, and drugs capable of controlling status epilepticus. [Background technology]

[0002] Propofol is a fast-acting, short-acting intravenous general anesthetic that is often used for the induction and maintenance of general anesthesia, and for sedation of critically ill patients in the ICU. It has the advantages of rapid induction of anesthesia, rapid recovery, complete functional recovery, and a low incidence of postoperative nausea and vomiting. TIFF2025535407000002.tif24170

[0003] However, clinical practice has revealed that propofol can cause serious side effects such as circulatory depression, respiratory depression, injection pain, agitation, and talkativeness. In order to enhance the efficacy of propofol, researchers have developed a structurally similar drug, ciprofol, which can enhance the efficacy of propofol, but this has not solved the above problems of propofol. TIFF2025535407000003.tif30170

[0004] Because propofol and cipropofol are insoluble in water and do not form salts, their clinical use is primarily in the form of lipid emulsions. Lipid emulsions are stable oil-in-water (O / W) emulsions prepared by dissolving propofol or ciprofol in vegetable oil (mainly fatty acid triglycerides), using phospholipids as an emulsifier, adding an isotonic agent and water for injection, allowing for intravenous injection. However, recent studies have revealed that lipid emulsions are prone to various side effects in clinical settings, including venous inflammatory reactions, acute renal failure, allergic reactions, anaphylactic shock, arrhythmias, and propofol infusion syndrome. To overcome these side effects, researchers have developed water-soluble prodrugs. Fospropofol disodium is a water-soluble prodrug of propofol that, after intravenous injection, is metabolized by alkaline phosphatase on the surface of endothelial cells in the body to produce the active drug propofol. This propofol rapidly equilibrates in brain tissue and exerts a dose-dependent hypnotic and sedative effect. However, compared with propofol, the onset of action of fospropofol disodium is significantly slower at 2.9 minutes, and it does not meet the requirement of rapid action.

[0005] In order to solve the above problems, there is an urgent need to develop a new type of sedative, hypnotic, and general anesthetic agent that not only has excellent water solubility but also a rapid onset of action, in order to overcome or improve the above problems of propofol. Summary of the Invention

[0006] The object of the present invention is to provide piperazine-substituted phenolic derivatives having novel structures, processes for their synthesis, and their use in the preparation of drugs having sedative, hypnotic and / or anesthetic effects, and drugs capable of suppressing status epilepticus.

[0007] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof. TIFF2025535407000004.tif63170

[0008] (where R is hydrogen, COR a , COCH(NH2)R a , COOR h1 , CH2COOR h1 , protecting group, PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 ) and R a is hydrogen, C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group; R h1 , R h2 are each independently hydrogen, C 1-4 It is selected from an alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0009] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen, or C 1~4 selected from alkyl groups or 3- to 6-membered cycloalkyl groups, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 and cannot simultaneously be methyl groups.

[0010] R 7 , R 8 are each independently hydrogen, halogen or C 1-4 It is selected from alkyl groups.

[0011] p is selected from integers of 0 to 8, and each R 9 are each independently hydrogen, C 1~4Alkyl group, halogen-substituted C 1~4 alkyl groups, or p is selected from integers of 2 to 8, of which two R 9 are linked to form a ring, and the remaining R 9 are each independently hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 alkyl groups, or p is selected from integers of 1 to 9, of which one R 9 is R 10 and the remaining R 9 are each independently hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 It is selected from alkyl groups.

[0012] R 10 is hydrogen, C 1~4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CRb3 R b4 ) t CONR d1 R d2 Selected from.

[0013] where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1~4 Alkyl group, halogen-substituted C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3- to 6-membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0014] R c is hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0015] R e is hydrogen, C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0016] R b1 , R b2 , R b3 , R b4 , R c , R eThe alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in 1~4 Alkyl group, C 1~4 Alkoxy group, halogen-substituted C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0017] R d1 , R d2 are each independently hydrogen or C 1~4 It is selected from alkyl groups.

[0018] R f is hydrogen, C 1~4 Alkyl or halogen substituted C 1~4 It is selected from alkyl groups.

[0019] R i is hydrogen, C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 It is selected from an alkynyl group, a 3- to 6-membered cycloalkyl group, or a 3- to 6-membered heterocyclic group.

[0020] m is selected from 0, 1, 2, 3, or 4.

[0021] n is selected from 2, 3, or 4.

[0022] t is selected from 1, 2, 3, or 4.

[0023] Furthermore, the structure of the compound is as shown in Formula II. TIFF2025535407000005.tif70170

[0024] (However, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen, or C 1~4 It is selected from alkyl groups and 3- to 6-membered saturated cycloalkyl groups.

[0025] p is selected from integers of 0 to 8, and each R 9 are each independently hydrogen, C 1~4 alkyl groups, or p is selected from integers of 2 to 8, of which two R 9 are linked to form a ring, and the remaining R 9 are each independently hydrogen, C 1~4 alkyl groups, or p is selected from integers of 1 to 9, of which one R 9 is R 10 and the remaining R 9 are each independently hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 It is selected from alkyl groups.

[0026] R 10 is hydrogen, C 1~4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n ORf , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from.

[0027] where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1~4 Alkyl group, halogen-substituted C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0028] R c is hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 Alkyl group, C2~4 Alkenyl group, C 2~4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0029] R e is hydrogen, C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0030] R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in 1~4 Alkyl group, C 1~4 Alkoxy group, halogen-substituted C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0031] R d1 , R d2 are each independently hydrogen or C 1~4 It is selected from alkyl groups.

[0032] Rf is hydrogen, C 1~4 Alkyl or halogen substituted C 1~4 It is selected from alkyl groups.

[0033] R i is hydrogen, C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 It is selected from an alkynyl group, a 3- to 6-membered cycloalkyl group, or a 3- to 6-membered heterocyclic group.

[0034] m is selected from 0, 1, 2, 3, or 4.

[0035] n is selected from 2, 3, or 4.

[0036] t is selected from 1, 2, 3, or 4.

[0037] Furthermore, the structure of the compound is as shown in Formula III. TIFF2025535407000006.tif69170

[0038] (However, R 11 , R 12 are each independently a methyl group, Selected from TIFF2025535407000007.tif12170.

[0039] R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1~4 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9iAmong these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1~4 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1~4 It is selected from alkyl groups.

[0040] R 10 is as described above in Formula II.

[0041] Furthermore, the structure of the compound is as represented by formula IV-1 or formula IV-2. TIFF2025535407000008.tif65170

[0042] (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0043] R 10 is hydrogen, C 1~4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from.

[0044] where R b1 , R b2 , R b3 , R b4are each independently hydrogen, halogen, or C 1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0045] R c is hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 Alkyl group, C 2~4 Alkenyl group, C 2~4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group.

[0046] R e is hydrogen, C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0047] R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in 1~3 Alkyl group, C 1~3 Alkoxy group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0048] R d1 , R d2 are each independently hydrogen or C 1~3 It is selected from alkyl groups.

[0049] R f is hydrogen, C 1~3 Alkyl or halogen substituted C 1~3 R is selected from alkyl groups. i is hydrogen, C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is selected from an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group.

[0050] m is selected from 0, 1, 2, 3, or 4.

[0051] n is selected from 2, 3, or 4.

[0052] t is selected from 1, 2, 3, or 4.

[0053] Furthermore, the structure of the compound is as represented by formula IV-1 or formula IV-2. TIFF2025535407000009.tif65170

[0054] (However, R 9a, R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0055] R 10 is hydrogen, C 1~4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 )n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from.

[0056] where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0057] R c is hydrogen, C 1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0058] R e is hydrogen, C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0059] R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, aryl, and heteroaryl groups in 1~3 Alkyl group, C 1~3 Alkoxy group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0060] R d1 , R d2 are each independently hydrogen or C 1~3 It is selected from alkyl groups.

[0061] R f is hydrogen, C 1~3 Alkyl or halogen substituted C 1~3 It is selected from alkyl groups.

[0062] R i is hydrogen, C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is selected from an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group.

[0063] m is selected from 0, 1, 2, 3, or 4.

[0064] n is selected from 2, 3, or 4.

[0065] t is selected from 1, 2, 3, or 4.

[0066] Furthermore, the structural fragment TIFF2025535407000010.tif34170 has one of the following structures: TIFF2025535407000011.tif78170

[0067] Furthermore, the structure of the compound is as represented by Formula V-1 or Formula V-2. TIFF2025535407000012.tif65170

[0068] (However, R 10 is hydrogen, C 1~4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 Rb2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from.

[0069] where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1~2 Alkyl group, halogen-substituted C 1~2 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, phenyl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0070] R c is hydrogen, C 1~2 Alkyl group, halogen-substituted C 1~2 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, a phenyl group, or a heteroaryl group.

[0071] R e is hydrogen, C 1~2 Alkyl group, C2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, a phenyl group, or a heteroaryl group.

[0072] R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, phenyl, and heteroaryl groups in 1~2 Alkyl group, C 1~2 Alkoxy group, halogen-substituted C 1~2 Alkyl group, vinyl group, ethynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0073] R d1 , R d2 are each independently hydrogen or C 1~2 It is selected from alkyl groups.

[0074] R f is hydrogen, C 1~2 Alkyl or halogen substituted C 1~2 It is selected from alkyl groups.

[0075] R i is hydrogen, C 1~2It is selected from an alkyl group, a vinyl group, an ethynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group.

[0076] m is selected from 0, 1, 2, 3, or 4.

[0077] n is selected from 2, 3, or 4.

[0078] t is selected from 1, 2, 3, or 4.

[0079] Furthermore, the 3- to 6-membered saturated cycloalkyl group is TIFF2025535407000013.tif15170, and the 3- to 6-membered saturated heterocyclic group is selected from TIFF2025535407000014.tif19170, wherein the 3- to 6-membered cyclic structure is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and the halogen is selected from fluorine, chlorine, and bromine.

[0080] Furthermore, the structure of the compound is as represented by formula VI-1 or formula VI-2. TIFF2025535407000015.tif69170

[0081] (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1~3alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0082] m is selected from 0, 1, 2, 3, or 4.

[0083] R b1 , R b2 are each independently hydrogen, halogen, or C 1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0084] R c is hydrogen, C 1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0085] R b1 , R b2 , Rc The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, aryl, and heteroaryl groups in 1~3 Alkyl group, C 1~3 Alkoxy group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0086] R d1 , R d2 are each independently hydrogen or C 1~3 It is selected from alkyl groups.

[0087] R f is hydrogen, C 1~3 Alkyl or halogen substituted C 1~3 It is selected from alkyl groups.

[0088] R i is hydrogen, C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 is selected from an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group.

[0089] Furthermore, the structure of the compound is as represented by formula VI-1 or formula VI-2. TIFF2025535407000016.tif69170

[0090] (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1~3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0091] m is selected from 0, 1, 2, 3, or 4.

[0092] R b1 , R b2 are each independently hydrogen, halogen, or C 1~3 Alkyl group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 Rd2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0093] R c is hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 Alkyl group, C 2~3 Alkenyl group, C 2~3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0094] R b1 , R b2 , R c The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, aryl, and heteroaryl groups in 1~3 Alkyl group, C 1~3 Alkoxy group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0095] R d1 , R d2 are each independently hydrogen or C 1~3 It is selected from alkyl groups.

[0096] R f is hydrogen, C 1~3 Alkyl or halogen substituted C 1~3 It is selected from alkyl groups.

[0097] R i is hydrogen, C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 is selected from an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group.

[0098] Furthermore, the structural fragment TIFF2025535407000017.tif29170 has one of the following structures: TIFF2025535407000018.tif110170 (m is selected from 1, 2, or 3.

[0099] R b1 , R b2 are each independently hydrogen, halogen, or C 1~3 Alkyl group, halogen-substituted C 1~3 alkyl group, a 3- to 6-membered saturated cycloalkyl group, a 4- to 6-membered saturated heterocyclic group, or R b1 and R b2 form a 3- or 4-membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S.

[0100] R c is hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4 It is an alkyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0101] R b1 , R b2 , R cThe alkyl, saturated cycloalkyl, saturated heterocyclic, aryl and heteroaryl groups in 1~3 Alkyl group, C 1~3 Alkoxy group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0102] R d1 , R d2 , R f , R i is as described in Formula VI-1 or Formula VI-2 above.

[0103] Furthermore, the structure of the compound is as represented by Formula VII-1 or Formula VII-2. TIFF2025535407000019.tif69170 (where m is selected from 1 or 2.

[0104] R b1 , R b2 are each independently hydrogen, halogen, or C 1~3 Alkyl group, halogen-substituted C 1~3 It is selected from an alkyl group, a 3- to 6-membered saturated cycloalkyl group, and a 4- to 6-membered saturated heterocyclic group.

[0105] R c is hydrogen, C 1~4 Alkyl group, halogen-substituted C 1~4It is an alkyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group.

[0106] R b1 , R b2 , R c The alkyl, saturated cycloalkyl, saturated heterocyclic, aryl and heteroaryl groups in 1~3 Alkyl group, C 1~3 Alkoxy group, halogen-substituted C 1~3 Alkyl group, C 2~3 Alkenyl group, C 2~3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO2, OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO2R i or SO2R i and is substituted with one or more groups selected from:

[0107] R d1 , R d2 , R f , R i is as described in Formula VI-1 or Formula VI-2 above.

[0108] Furthermore, in Formula VI-1, Formula VI-2, Formula VII-1, or Formula VII-2, m is selected from 1 or 2; R b1 , R b2 are each independently selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group; R cis a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a CF3 group, a cyclopropyl group, TIFF2025535407000020.tif30170

[0109] is.

[0110] Furthermore, the structure of the compound is selected from the following: TIFF2025535407000021.tif192170TIFF2025535407000022.tif233170TIFF2025535407000023.tif251170TIFF2025535407000024.tif80170("*" indicates a chiral center.)

[0111] Further, the pharmaceutically acceptable salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, hydrogensulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfamate, ethanedisulfonate, ethylsulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, and lactate. , malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalenecarboxylate, theaflavicate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, aldarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate or p-toluenesulfonate.

[0112] The present invention also provides a drug formulation comprising the above-mentioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof as an active ingredient, in addition to a pharmaceutically acceptable adjuvant.

[0113] The present invention also provides use of the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, in the preparation of a drug having sedative, hypnotic and / or anesthetic effects and / or a drug capable of suppressing status epilepticus.

[0114] The term "drugs with sedative effects" as used herein refers to drugs that have the effect of helping sleep and improving sleep, that is, they can prevent the serious harm caused to the human body by insomnia, treat insomnia, and improve the quality of sleep.

[0115] The term "drugs with hypnotic effects" as used herein refers to drugs that can induce drowsiness and promote sleep, i.e., drugs that have a depressant effect on the central nervous system, causing sedation in small doses and general anesthesia in excessive doses.

[0116] In the present invention, the term "drugs with anesthetic effects" refers to reversible drug-induced suppression of central and / or peripheral nervous system functions, the main characteristic of which is loss of sensation, particularly pain sensation.

[0117] Preferably, the anesthesia is general anesthesia.

[0118] "General anesthesia" as used herein is also abbreviated as "total anesthesia," and is a temporary suppression of the central nervous system after an anesthetic agent has entered the body. Clinical symptoms include loss of consciousness, generalized analgesia, memory loss, reflex inhibition, and skeletal muscle relaxation.

[0119] The term "status epilepticus" as used herein refers to a series of epileptic seizures that frequently recur before full recovery of consciousness, or that last for more than 30 minutes and do not terminate spontaneously. If prolonged epileptic seizures are not treated promptly, they can cause irreversible brain damage due to high fever, circulatory failure, or excitotoxic neuronal damage, resulting in high disability and mortality rates. Status epilepticus is therefore a common emergency condition in internal medicine.

[0120] Regarding the definition of terms used in the present invention: unless otherwise stated, the first definition provided for a group or term in this specification applies to that group or term throughout the specification. For terms not specifically defined in this specification, those skilled in the art can provide their definitions from the disclosure and context.

[0121] The minimum and maximum carbon atom content in the hydrocarbon group is indicated by a prefix, e.g., the prefix C a~b The alkyl group represents an alkyl group containing any number of carbon atoms, from "a" to "b". For example, C 1~6 Alkyl group refers to straight or branched chain alkyl groups containing from 1 to 6 carbon atoms.

[0122] In the compound represented by formula I of the present invention, "p" is selected from integers of 2 to 8, and two R 9 are linked to form a ring" includes spiro rings, bridged rings, and fused rings.

[0123] As used herein, the term "substitution" refers to the replacement of one, two, or more hydrogen atoms in a molecule with other, different atoms or molecules, including the replacement of one, two, or more atoms at the same position or atoms at different positions in the molecule.

[0124] An "alkylene group" refers to a group in which the corresponding alkyl group has lost one hydrogen atom. For example, C 1~4 An alkyl group refers to a straight or branched chain alkylene group containing 1 to 4 carbon atoms, and a C2 alkylene group refers to Points to TIFF2025535407000025.tif13170.

[0125] TIFF2025535407000026.tif6170 shows the linkage sites between the structural fragments.

[0126] A "cycloalkyl group" is a saturated or unsaturated cyclic hydrocarbon substituent, and the cyclic hydrocarbon may be monocyclic or polycyclic. For example, a "3- to 6-membered saturated cycloalkyl group" refers to a saturated cycloalkyl group having 3 to 6 carbon atoms in the ring.

[0127] A "heterocyclic group" is a saturated or unsaturated cyclic hydrocarbon substituent, which may be monocyclic or polycyclic and has at least one ring heteroatom, including, but not limited to, O, S, or N. For example, a "3- to 6-membered saturated heterocyclic group" refers to a saturated heterocyclic group having 3 to 6 ring carbon atoms.

[0128] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π-electron system, such as phenyl or naphthyl. The rings of the aryl group may be fused to other cyclic groups (including saturated and unsaturated rings), but they must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent ring must be a carbon atom in the ring that has a conjugated π-electron system. Aryl groups can be substituted or unsubstituted.

[0129] A "heteroaryl group" refers to a heteroaromatic group containing one or more heteroatoms. Heteroatoms include oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, and tetrazolyl groups. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring integrally connected to the parent structure is the heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.

[0130] A "bridged ring" refers to a polycyclic cycloalkyl group in which two rings share two non-adjacent carbon atoms.

[0131] A "spirocycle" refers to a polycyclic cycloalkyl group in which two rings share one carbon atom.

[0132] The term "fused ring" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.

[0133] In the formula III, formula IV-1, formula IV-2, formula IV-1, formula IV-2, formula VI-1 or formula VI-2 according to the present invention, "R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i "Two groups linked to the same carbon atom are linked together to form a spiro ring" means that R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i After two groups linked to the same carbon atom are linked together, TIFF2025535407000027.tif23170 refers to the formation of a spiro ring as a whole, and "R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i "Two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring" means that R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i After two groups linked to the same carbon atom are linked together, TIFF2025535407000028.tif23170 and the whole refer to the formation of a bridged ring or fused ring.

[0134] "Halogen" is fluorine, chlorine, bromine or iodine.

[0135] "Deuterium-substituted derivative" refers to a compound obtained by substituting one or more hydrogen atoms in the compound with deuterium.

[0136] "Pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and / or formed salt is chemically or physically compatible with the other ingredients that normally make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0137] "Salts" refer to acidic and / or basic salts formed by a compound or its stereoisomer with inorganic and / or organic acids and / or bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, e.g., alkylammonium salts. These salts may be obtained directly from the final isolation and purification of the compound. They may also be obtained by mixing the compound or its stereoisomer with an appropriate amount of acid or base (e.g., in equal amounts). These salts may be obtained by forming a precipitate in a solution and recovering it by filtration, or by recovering it after evaporating the solvent, or by reacting it in an aqueous medium and then lyophilizing it.

[0138] The pharmaceutically acceptable salt according to the present invention may be any of the pharmaceutically acceptable salts of the compound, including acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, hydrogensulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfamate, ethanedisulfonate, ethylsulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, and the like. salts, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalenecarboxylate, theaflavate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, aldarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate or quaternary ammonium salts.

[0139] Compounds of the Invention or Compositions Thereof and Methods of Use: The compounds of the present invention, their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to induce sedation, hypnosis, and / or general anesthesia. The compounds of the present invention are also useful for suppressing status epilepticus and the like.

[0140] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount, and a pharmacologically acceptable excipient or carrier.

[0141] Modes of use of the compounds or pharmaceutical compositions of the present invention include, but are not limited to, intragastric, intraenteral, parenteral (intravenous, intramuscular or subcutaneous), oral administration and various topical administrations.

[0142] Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions and emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar, calcium carbonate, or the like. They are mixed with ingredients such as cereals, potato starch, tapioca starch, alginic acid, some complex silicates and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption promoters such as quaternary ammonium compounds, (g) wetting agents such as cetanol and glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0144] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents, compatibilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0145] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings or shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the active compound or compounds may be delayed in a certain part of the digestive tract. Examples of encapsulating materials that can be used include polymeric materials and wax-based materials. If necessary, the active compound may be microencapsulated with one or more of the above-mentioned excipients.

[0146] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants, as required.

[0147] Besides these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes.

[0148] In addition to the active compound, suspensions may contain a suspending agent such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxy, agar, or mixtures of these substances.

[0149] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0150] When using pharmaceutical compositions, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, at a dosage that is considered pharmaceutically safe and effective.

[0151] Compared with existing technologies, the compounds provided by the present invention have achieved the following beneficial effects: 1. As known to those skilled in the art, propofol and ciprofol cannot form salts and are insoluble in water, limiting their clinical applications. However, the compounds of the present invention can form salts, and each salt form has excellent water solubility and can meet the requirements of pharmaceutical formulations.

[0152] 2. As known to those skilled in the art, propofol and ciprofol are insoluble in water, so the dosage forms used in clinical practice are mainly fat emulsions, which are prone to various adverse reactions in clinical practice. However, the salt forms of the compounds of the present invention have excellent solubility and can meet the requirements of formulations, so they can effectively overcome the adverse reactions caused by fat emulsions and improve safety.

[0153] 3. As known to those skilled in the art, although the prodrugs of propofol and ciprofol have a certain degree of water solubility, they have a slow onset of action and cannot meet the requirements for rapid onset and rapid recovery. However, the compound of the present invention is not a prodrug but an active ingredient, which has a fast onset of action and can quickly achieve general anesthetic effect.

[0154] As described above, the compound provided by the present invention has good salt formation properties and excellent water solubility, and its solubility meets the requirements of formulations. At the same time, it has a low minimum effective dose of anesthetics, allowing for rapid onset of effect and rapid recovery. This overcomes the shortcomings of propofol, its prodrugs, and lipid emulsions, and has the potential for wide use in the preparation of drugs with sedative, hypnotic, and / or anesthetic effects and drugs capable of suppressing status epilepticus. It also provides a new option for the preparation of drugs with sedative, hypnotic, and / or anesthetic effects and drugs capable of suppressing status epilepticus in clinical practice.

[0155] Of course, various other modifications, substitutions or changes may be made based on the above content of the present invention using ordinary technical knowledge and ordinary means in this field, provided that they do not deviate from the above basic technical idea of ​​the present invention.

[0156] The above content of the present invention will be explained in more detail below by specific embodiments in the form of examples. However, it should be understood that the scope of the above gist of the present invention is not limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

[0157] Specific Embodiments All materials and equipment used in specific embodiments of the present invention are known products and were purchased commercially.

[0158] The structure of the compound was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) was 10 -6 The NMR data are shown in ppm. A Bruker Avance III 400 nuclear magnetic resonance spectrometer was used for the NMR measurements, and the solvent used was deuterated dimethyl sulfoxide (d6-DMSO) or deuterated methanol (CD3OD). The internal standard solution was tetramethylsilane (TMS).

[0159] LCMS measurements were performed using an Agilent LCMS 1260-6110 (ESI) column with a Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm) column. Column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 3 min, maintained under these conditions for 1 min, and then gradient to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 min, maintained under these conditions for an additional 0.7 min.

[0160] 1) Medicines and reagents The thin-layer chromatography silica gel plate used was HSGF254 silica gel plate from Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm.

[0161] Thin layer chromatography (TLC) was performed using products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2±0.03 mm.

[0162] For column chromatography, 100–200 mesh or 200–300 mesh silica gel from Rushan City Sun Desiccant Co., Ltd. (Weihai, Shandong) was generally used as the carrier.

[0163] 2) Main Instruments Sartorius BSA124S electronic balance scale (Sartorius Scientific Instruments Beijing Co., Ltd.); 98-2 Magnetic Stirrer (Shanghai Sile Instrument Co., Ltd.); MS-H-PRO + Digitally controlled heating magnetic stirrer (Dalong Xingchuang Experimental Instruments Beijing Co., Ltd.); TDGC2-1 type contact voltage regulator (Zhejiang Tianzheng Electric Co., Ltd.); WMNK-01 type temperature controller (Shanghai Lulin Electrical Co., Ltd.); ZF-I three-function ultraviolet meter (Shanghai Anting Electronic Instruments Factory); R-201 rotary evaporator (Shanghai Shenshun Biotechnology Co., Ltd.); W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.); SHB-III circulating water vacuum pump (Zhengzhou Huicheng Technology Co., Ltd.); SHB-B95 portable water pump (Zhengzhou Huichengke Industry and Trade Co., Ltd.); DLSB-5 / 20℃ low temperature cooling circulation pump (Guiyi Yuhua Yi Equipment Co., Ltd.); 2XZ-2 rotary vacuum pump (Linhai City Yonghao Vacuum Equipment Co., Ltd.); VRD-16 bipolar rotary vane vacuum pump (Zhejiang Feiyue Mechanical & Electrical Co., Ltd.); DGJ-10C vacuum freeze dryer (Shanghai Bodeng Biological Technology Co., Ltd.); Biotage Isolera One preparative high-performance liquid chromatography (Biotage Sweden AB).

[0164] Example 1 Preparation of Compound A1 and its Hydrochloride Salt of the Present Invention TIFF2025535407000029.tif128170

[0165] 1. Preparation of Compound A1-1 NBS (6.71 g, 37.70 mmol) was added to a solution of A-0 (7.70 g, 37.69 mmol) in acetonitrile (77 mL) at 0 °C and stirred for 30 min at 0 °C. After monitoring the reaction completion by TLC, the reaction mixture was added with HO (100 mL) and extracted with EtOAc (3 × 70 mL). The combined organic phases were washed with saturated brine, dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 1 / 200 to 1 / 50). TLC (dichloromethane / petroleum ether (v / v) = 1 / 20) monitored the Rf = 0.4–0.5 fractions, and the yellow oily compound A1-1 (4.21 g, 39.4% yield) was obtained. ES1 [M + H] + = 283.1.

[0166] 2. Preparation of Compound A1-2 NaH (196 mg, 60%, 4.90 mmol) was added in portions to a solution of A1-1 (1.26 g, 4.45 mmol) in dry tetrahydrofuran (12 mL) at 0 °C. After stirring for 30 min, TIPSCl (891 mg, 4.62 mmol) was added. The reaction mixture was heated to room temperature and stirred for 3 h. After monitoring the reaction for completeness by TLC, HO (20 mL) was added to the reaction mixture and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (n-heptane mobile phase) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 50). The fraction with Rf = 0.5–0.6 was collected to give compound A1-2 (1.93 g, 98.7% yield) as a white solid. ESI [M + H] + = 439.3.

[0167] 3. Preparation of Compounds A1-3 Compound A1-2 (1.2 g, 2.73 mmol), Pd2(dba)3 (125 mg, 0.14 mmol), t-BuONa (394 mg, 4.10 mmol), and JohnPhos (81 mg, 0.27 mmol) were added to a solution of 1,4-dioxane (15 mL) at room temperature. The reaction mixture was purged with nitrogen gas three times and then stirred under nitrogen gas protection at 50 °C for 4 h. After monitoring the reaction for completeness by TLC, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with Rf = 0.3–0.4 was collected to give compound A1-3 (1.48 g, 99.5% yield) as a white solid. ES1 [M + H] + = 545.3.

[0168] 4. Preparation of Compounds A1-4 TFA (2 mL) was added to a solution of A1-3 (1.48 g, 2.72 mmol) in dichloromethane (10 mL) at 0 °C and stirred for 4 h at 0 °C. After monitoring the complete reaction by TLC, the mixture was concentrated under reduced pressure, alkalized with saturated aqueous sodium bicarbonate (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1 to 20 / 1) and monitored by TLC (dichloromethane / methanol (v / v) = 10 / 1). The fraction with Rf = 0.4–0.5 was collected to give compound A1-4 (1.20 g, 99.2% yield) as a white solid. ESI [M + H] + = 445.3.

[0169] 5. Preparation of Compounds A1-5 DIEA (349 mg, 2.70 mmol) and methyl bromoacetate (303 mg, 1.98 mmol) were added sequentially to a solution of A1-4 (800 mg, 1.80 mmol) in acetonitrile (8 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After monitoring the reaction completion by TLC, HO (10 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.5–0.6 was collected to give compound A1-5 (692 mg, 74.4% yield) as a white solid. ESI [M + H] + = 517.4.

[0170] 6. Preparation of Compound A1 TBAF (1.34 mL, 1 mol / L in THF, 1.34 mmol) was added to a solution of A1-5 (692 mg, 1.34 mmol) in tetrahydrofuran (7 mL) at 0 °C and stirred for 1 h at 0 °C. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture and extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.3–0.4 was collected to give compound A1 (200 mg, 41.4% yield) as a white solid. ESI [M + H] + = 361.3. 1H NMR (400MHz, CD3OD) δ 6.84 (d, J = 2.9 Hz, 1H), 6.73 (d, J = 2.9 Hz, 1H), 3.76 (s, 3H), 3.34 (s, 2H), 3.33 - 3.27 (m, 1H), 3.16 - 3.09 (m, 4H), 2.83 - 2.74 (m, 4H), 2.55 - 2.45 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz,3H), 1.11 - 1.00 (m, 1H), 0.62 - 0.52 (m, 1H), 0.44 - 0.34 (m, 1H), 0.26 - 0.17 (m, 1H), 0.17 - 0.09 (m, 1H).

[0171] 7. Preparation of Compound A1 Hydrochloride A solution of HCl / EtO (0.155 mL, 2 mol / L in THF, 0.31 mmol) was slowly added to a solution of A1 (112 mg, 0.31 mmol) in diethyl ether (5 mL) at -20 °C, stirred for 5 min at -20 °C, and concentrated under reduced pressure at low temperature to give the crude product. After washing the crude product with diethyl ether, a white solid, compound A1 hydrochloride (71.7 mg, 58.3% yield), was obtained. ESI [M + H] + = 361.3. 1 H NMR (400MHz, CD3OD) δ 7.01 (s, 1H), 6.89 (s, 1H), 4.06 (s, 2H), 3.84 (s, 3H), 3.54 - 3.36 (m, 8H), 3.35 - 3.25 (m, 1H), 2.52 - 2.41 (m, 1H), 1.26 (d, J = 6.9 Hz, 3H), 1.21 (d, J = 6.9 Hz, 6H), 1.09 - 0.99 (m, 1H), 0.61 - 0.52 (m, 1H), 0.40 - 0.32 (m, 1H), 0.25 - 0.16 (m, 1H), 0.12 - 0.03 (m, 1H).

[0172] Example 2 Preparation of Compounds A2 and Hydrochloride, A5 and Hydrochloride, and A6 and Hydrochloride of the Present Invention The preparation method of compounds A2, A5, and A6 is the same as that of compound A1. Using A1-4 as the starting material, compounds A2, A5, and A6 are obtained by substituting with a bromine compound and deprotecting. The preparation method of the corresponding hydrochlorides of compounds A2, A5, and A6 is also the same as that of compound A1 hydrochloride. The preparation route is as follows: TIFF2025535407000030.tif132170

[0173] Compound A2 hydrochloride: white solid, 71.2 mg, ESI[M + H] + = 375.3. 1 H NMR (400MHz, d6-DMSO) 10.61 (s, 1H), 6.75 (s, 1H), 6.63 (s, 1H), 3.67 (s, 3H), 3.65 - 3.51 (m, 4H), 3.46 - 3.35 (m, 2H), 3.31 - 3.22 (m, 1H), 3.22 - 3.10 (m, 2H), 3.07 - 2.91 (m, 4H), 2.48 - 2.40 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.8 Hz, 6H), 1.07 - 0.98 (m, 1H), 0.52 - 0.44 (m, 1H), 0.34 - 0.24 (m, 1H), 0.18 - 0.11 (m, 1H), 0.09 - 0.01 (m, 1H).

[0174] Compound A5 hydrochloride: white solid, 132.9 mg, ESI [M + H] + = 375.3. 1H NMR (400 MHz, CD3OD) δ 7.16 (d, J = 2.9 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.18 (s, 2H), 3.68 - 3.58 (m, 8H), 3.35 - 3.27 (m, 1H), 2.54 - 2.42 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 6H), 1.11 - 1.01 (m, 1H), 0.63 - 0.53 (m, 1H), 0.43 - 0.32 (m, 1H), 0.27 - 0.18 (m, 1H), 0.13 - 0.04 (m, 1H).

[0175] Compound A6 acid acid: white solid, 114.7 mg, ESI [M + H] + = 375.3. 1 H NMR (400 MHz, CD3OD) δ 7.30 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 2.9 Hz, 1H), 4.28 (q, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.81 - 3.76 (m, 4H), 3.72 - 3.60 (m, 4H), 3.36 - 3.31 (m, 1H), 2.55 - 2.45 (m, 1H), 1.64 (d, J = 7.2 Hz, 3H), 1.28 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H), 1.14 - 1.03 (m, 1H), 0.65 - 0.55 (m, 1H), 0.45 - 0.36 (m, 1H), 0.29 - 0.16 (m, 1H), 0.13 - 0.04 (m, 1H).

[0176] Example 3: Preparation of Compound A3 and Acetyl Acid of the present invention TIFF2025535407000031.tif40170

[0177] 1. Preparation of Compound A3-1 EtN (205 mg, 2.0 mmol) and methyl 3-chloro-3-oxopropionate (184 mg, 1.35 mmol) were added to a solution of A1-4 (300 mg, 0.67 mmol) in dichloromethane (5 mL) at 0 °C and stirred at room temperature for 1 h. After monitoring the reaction for completeness by TLC, HO (10 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) to obtain a white solid compound A3-1 (350 mg, 95.2% yield) with a Rf = 0.5–0.6 fraction. ES1 [M + H] + = 545.3.

[0178] 2. Preparation of Compound A3 TBAF (0.64 mL, 1 mol / L in THF, 0.64 mmol) was added to a solution of A3-1 (350 mg, 0.64 mmol) in tetrahydrofuran (5 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) to obtain compound A3 (224.5 mg, 89.9% yield) as a white solid. ESI [M + H] + = 389.2.

[0179] 3. Preparation of Compound A3 Hydrochloride At -20°C, a solution of HCl / EtO (0.29 mL, 2 mol / L in THF, 0.58 mmol) was slowly added to a solution of A3 (224.5 mg, 0.58 mmol) in diethyl ether (5 mL). The mixture was stirred at -20°C for 5 minutes and then concentrated under reduced pressure at low temperature to give the crude product. After washing the crude product with diethyl ether, a white solid, compound A3 hydrochloride (224.6 mg, 91.5% yield), was obtained. ESI [M + H] + = 389.2. 1 H NMR (400MHz, d6-DMSO) δ 7.44 (s, 1H), 6.70 (d, J = 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 3.63 (s, 3H), 3.62 - 3.56 (m, 4H), 3.55 - 3.49 (m, 2H), 3.31 - 3.21 (m, 1H), 3.01 - 2.95 (m, 2H), 2.96 - 2.89 (m, 2H), 2.48 - 2.40 (m, 1H), 1.17 (dd, J = 7.0, 3.2 Hz, 3H), 1.13 (d, J= 6.8 Hz, 6H), 1.06 - 0.95 (m, 1H), 0.52 - 0.44 (m, 1H), 0.34 - 0.24 (m, 1H), 0.18 - 0.10 (m, 1H), 0.09 - 0.02 (m, 1H).

[0180] Example 4 Preparation of Compound A4 and its Hydrochloride Salt of the Present Invention TIFF2025535407000032.tif75170

[0181] Compound A4 and its hydrochloride were prepared in the same manner as Compound A1, and were obtained by purifying propofol as the starting material.

[0182] Compound A4 hydrochloride: white solid, 135.9 mg, ESI [M + H] + = 335.3. 1H NMR (400MHz, CD3OD) δ 6.98 (s, 2H), 4.14 (s, 2H), 3.85 (s, 3H), 3.61 - 3.50 (m, 8H), 3.36 - 3.31 (m, 2H), 1.22 (d, J = 6.9 Hz, 12H).

[0183] Example 5 Preparation of Compound A7 and its Hydrochloride Salt of the Invention TIFF2025535407000033.tif38170

[0184] 1. Preparation of Compound A7-1 K2CO3 (93.2 mg, 0.67 mmol) and 2-bromoethanol (61.8 mg, 0.49 mmol) were added to a solution of A1-4 (200 mg, 0.45 mmol) in acetonitrile (3 mL) at room temperature, and the mixture was stirred at 80 °C for 12 h. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol (v / v) = 10 / 1) to obtain a white solid compound A7-1 (115 mg, 52.3% yield) with a Rf = 0.5–0.6 fraction. ES1 [M + H] + = 489.3.

[0185] 2. Preparation of Compound A7 TBAF (0.24 mL, 1 mol / L in THF, 0.24 mmol) was added to a solution of A7-1 (115 mg, 0.24 mmol) in tetrahydrofuran (3 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol (v / v) = 10 / 1) to obtain compound A7 (70.6 mg, 90.3% yield) as a white solid. ESI [M + H] + = 333.4.

[0186] 3. Preparation of Compound A7 Hydrochloride A solution of A7 (70.6 mg, 0.21 mmol) in HCl / EtO (0.16 mL, 2 mol / L in THF, 0.32 mmol) was slowly added to a solution of A7 (70.6 mg, 0.21 mmol) in diethyl ether (3 mL) at -70 °C, stirred for 5 minutes at -70 °C, and concentrated under reduced pressure at low temperature to give the crude product. After washing the crude product with diethyl ether, a white solid, compound A7 hydrochloride (76.4 mg, 92.9% yield), was obtained. ESI [M + H] + = 333.4. 1 H NMR (400 MHz, CD3OD) δ 7.19 (d, J = 2.9 Hz, 1H), 7.06 (d, J = 2.9 Hz, 1H), 3.97 - 3.93 (m, 2H), 3.88 - 3.52 (m, 8H), 3.46 - 3.40 (m, 2H), 3.35 - 3.31 (m, 1H), 2.52 - 2.42 (m, 1H), 1.27 (d, J= 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H), 1.12 - 1.00 (m, 1H), 0.63 - 0.53 (m, 1H), 0.44 - 0.33 (m, 1H), 0.27 - 0.15 (m, 1H), 0.13 - 0.05 (m, 1H).

[0187] Example 6 Preparation of Compound A8 and its Hydrochloride Salt of the Invention TIFF2025535407000034.tif88170

[0188] 1. Preparation of Compound A8-1 LiOH.HO (146 mg, 3.48 mmol) was added to a solution of A1-5 (900 mg, 1.74 mmol) in THF / MeOH / HO (9 mL, v / v / v = 1 / 1 / 1) at 0 °C and stirred at room temperature for 1 h. After monitoring the reaction completion by TLC, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1 to 10 / 1) and monitored by TLC (dichloromethane / methanol (v / v) = 10 / 1). The fraction with Rf = 0.4–0.5 was collected to give white solid compound A8-1 (730 mg, 82.4% yield). ESI [M + H] + = 503.3.

[0189] 2. Preparation of Compound A8-2 Oxalyl chloride (175 mg, 1.38 mmol) was added to A8-1 (233 mg, 0.46 mmol) in dichloromethane (5 mL) at room temperature, and the mixture was stirred for 1 h at room temperature. After monitoring for complete reaction, the mixture was concentrated under reduced pressure to give crude product A8-2 (260 mg), which was used directly in the next reaction without further purification.

[0190] 3. Preparation of compound A8-3 EtN (93 mg, 0.92 mmol) and oxetan-3-ol (40.9 mg, 0.55 mmol) were added to a solution of crude product A8-2 (260 mg) in dichloromethane (3 mL) at 0 °C and stirred at room temperature for 2 h. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) to obtain a white solid compound A8-3 (76.5 mg, 29.9% yield for two steps) with a Rf = 0.3–0.4. ES1 [M + H] + = 559.3.

[0191] 4. Preparation of Compound A8 TBAF (0.14 mL, 1 mol / L in THF, 0.14 mmol) was added to a solution of A8-3 (76.5 mg, 0.14 mmol) in tetrahydrofuran (2 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After monitoring the complete reaction by TLC, HO (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound A8 (54 mg, 98.0% yield) as a white solid with an Rf of 0.3–0.4. ES1 [M + H] + = 403.3.

[0192] 5. Preparation of Compound A8 Hydrochloride A solution of HCl / EtO (0.10 mL, 2 mol / L in THF, 0.20 mmol) was slowly added to a solution of A8 (54 mg, 0.13 mmol) in diethyl ether (3 mL) at -20 °C, stirred for 5 minutes at -20 °C, and concentrated under reduced pressure at low temperature to give the crude product. After washing the crude product with diethyl ether, a white solid compound A8 hydrochloride (34.5 mg, 56.3% yield) was obtained. ESI [M + H] + = 403.3. 1 H NMR (400 MHz, CD3OD) δ 7.15 (s, 1H), 7.02 (s, 1H), 5.64 - 5.57 (m, 1H), 4.95 - 4.90 (m, 2H), 4.70 - 4.64 (m, 2H), 4.13 - 4.04 (m, 2H), 3.62 - 3.54 (m, 4H), 3.51 - 3.41 (m, 4H), 3.35 - 3.31 (m, 1H), 2.55 - 2.41 (m, 1H), 1.27 (d, J= 6.9 Hz, 3H), 1.22 (d, J = 6.8 Hz, 6H), 1.11 - 1.00 (m, 1H), 0.63 - 0.53 (m, 1H), 0.45 - 0.32 (m, 1H), 0.25 - 0.17 (m, 1H), 0.14 - 0.05 (m, 1H).

[0193] Example 7 Preparation of Compound A6R and Sulfate of the Invention TIFF2025535407000035.tif44170

[0194] 1. Preparation of compound A6R-1 EtN (910.7 mg, 9.0 mmol, 2.67 eq), NaI (1.35 g, 9.0 mmol, 2.67 eq), and (S)-methyl 2-chloropropionate (1.10 g, 9.0 mmol, 2.67 eq) were added sequentially to a solution of A1-4 (1.5 g, 3.37 mmol, 1 eq) in dry DMF (20 mL) at room temperature, and the mixture was stirred at 60 °C for 4 h. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), the reaction mixture was cooled to room temperature, HO (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.6 was collected to obtain colorless oily compound A6R-1 (1.685 g, 94.2% yield). ESI [M + H] + = 531.4.

[0195] 2. Preparation of compound A6R TBAF (4.9 mL, 1 mol / L in THF, 4.9 mmol, 1.5 eq) was added to a solution of A6R-1 (1.685 g, 3.17 mmol, 1 eq) in dry THF (20 mL) in an ice bath at 0°C, and the mixture was stirred at 0°C for 2 minutes. After monitoring the complete reaction by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), HO (30 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–12%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.5 was collected to obtain colorless oily compound A6R-2 (1085.8 mg, 91.5% yield). ESI [M + H] + = 375.2.

[0196] 3. Preparation of compound A6R sulfate A6R (1085.8 mg, 2.90 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (568.65 mg, 5.80 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to a solution of A6R (112 mg, 0.31 mmol) in diethyl ether (30 mL). The mixture was stirred at -70 °C for 5 min and then concentrated under reduced pressure to give the crude product. Et2O (30 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 20 mL). The solid was dissolved in ultrapure water (30 mL) and lyophilized for 64 h in a lyophilizer to give the white solid compound A6R sulfate (1526.42 mg, 100% yield). ESI [M + H] + = 375.2. 1H NMR (400 MHz, CD3OD) δ 7.27 (d, J= 2.9 Hz, 1H), 7.14 (d, J= 2.9 Hz, 1H), 4.25 (q, J= 7.2 Hz, 1H), 3.87 (s, 3H), 3.79 - 3.72 (m, 4H), 3.69 - 3.57 (m, 4H), 3.35 - 3.31 (m, 1H), 2.54 - 2.41 (m, 1H), 1.63 (d, J= 7.2 Hz, 3H), 1.28 (d, J= 6.9 Hz, 3H), 1.23 (d, J= 6.9 Hz, 6H), 1.11 - 1.03 (m, 1H), 0.62 - 0.55 (m, 1H), 0.44 - 0.36 (m, 1H), 0.26 - 0.18 (m, 1H), 0.11 - 0.03 (m, 1H).

[0197] Example 8: Preparation of compound A6S and dioxosulfate TIFF2025535407000036.tif43170

[0198] 1. Preparation of compound A6S-1 EtN (1.82 g, 18.0 mmol, 3 eq), NaI (2.70 g, 18.0 mmol, 3 eq), and (S)-methyl 2-chloropropionate (2.21 g, 18.0 mmol, 3 eq) were added sequentially to a solution of A1-4 (2.67 g, 6.0 mmol, 1 eq) in dry DMF (25 mL) at room temperature, and the mixture was stirred at 60 °C for 4 h. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), the reaction mixture was cooled to room temperature, HO (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–10%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.6 was collected to obtain colorless oily compound A6S-1 (2.833 g, 88.9% yield). ESI [M + H] + = 531.4.

[0199] 2. Preparation of compound A6S TBAF (4.1 mL, 1 mol / L in THF, 4.1 mmol, 1.2 eq) was added to a solution of A6S-1 (1.805 g, 3.40 mmol, 1 eq) in dry THF (20 mL) in an ice bath at 0°C, and the mixture was stirred at 0°C for 2 minutes. After monitoring the complete reaction by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5, Rf = 0.5), HO (30 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–12%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The Rf = 0.5 fraction was collected to obtain colorless oily compound A6S (1.337 g, 100% yield). ESI [M + H] + = 375.2.

[0200] 3. Preparation of compound A6S sulfate A6S (1.337 g, 3.57 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (700.2 mg, 7.14 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 5 min, and concentrated under reduced pressure to give the crude product. Et2O (30 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 20 mL). The solid was dissolved in ultrapure water (30 mL) and lyophilized for 24 h in a lyophilizer to give the white solid compound A6S sulfate (1856.5 mg, 100% yield). ESI [M + H] + = 375.2. 1H NMR (400 MHz, CD3OD) δ 7.27 (d, J= 2.9 Hz, 1H), 7.14 (d, J= 2.9 Hz, 1H), 4.25 (q, J= 7.2 Hz, 1H), 3.87 (s, 3H), 3.80 - 3.71 (m, 4H), 3.69 - 3.57 (m, 4H), 3.36 - 3.30 (m, 1H), 2.52 - 2.43 (m, 1H), 1.63 (d, J= 7.2 Hz, 3H), 1.28 (d, J= 6.9 Hz, 3H), 1.23 (d, J= 6.9 Hz, 6H), 1.12 - 1.04 (m, 1H), 0.62 - 0.55 (m, 1H), 0.44 - 0.35 (m, 1H), 0.26 - 0.17 (m, 1H), 0.12 - 0.03 (m, 1H).

[0201] Example 9 Preparation of Compounds A11 and Sulfate and A18 and Sulfate of the Invention TIFF2025535407000037.tif121170

[0202] 1. Preparation of Compound A11-1 Compound A1-2 (6.0 g, 13.65 mmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (5.0 g, 23.55 mmol), Pd2(dba)3 (1.25 g, 1.37 mmol), t-BuOK (3.06 g, 27.30 mmol), and JohnPhos (814.7 mg, 2.73 mmol) were dissolved in 1,4-dioxane (40 mL) at room temperature. The reaction system was purged with nitrogen gas three times, and then the mixture was stirred overnight at 70 °C under nitrogen gas protection. After monitoring the reaction completion by TLC (n-heptane), the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with Rf = 0.5 was collected to obtain the colorless oily crude product Compound A11-1 (5.7 g). ESI [M + H] + = 571.4.

[0203] 2. Preparation of Compound A11-2 In an ice-salt bath at 0 °C, TFA (5 mL) was added to a solution of crude compound A11-1 (5.7 g, 9.98 mmol) in dichloromethane (15 mL) and stirred at 0 °C for 4 h. After monitoring the reaction for completeness by TLC, the mixture was concentrated under reduced pressure, alkalized with saturated aqueous sodium bicarbonate (20 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1, followed by methanol / dichloromethane (v / v) = 0 to 1 / 1). The fraction with an Rf = 0.5 was collected and used to obtain colorless oily compound A11-2 (3.617 g, 56.3% yield for two steps). ESI [M + H] + = 471.4.

[0204] 3. Preparation of compound A11-3 DIEA (517.0 mg, 4.0 mmol) and methyl bromoacetate (458.9 mg, 3.0 mmol) were added successively to a solution of A11-2 (941.6 mg, 2.0 mmol) in dichloromethane (20 mL) in an ice-water bath at 0° C., and the mixture was stirred at room temperature overnight. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.5 was collected to obtain colorless oily compound A11-3 (920 mg, 77.0% yield). ESI [M + H] + = 543.4.

[0205] 4. Preparation of Compound A11 In an ice-salt bath at 0 °C, TBAF (2.0 mL, 1 mol / L in THF, 2.0 mmol) was added to a solution of A11-3 (920 mg, 1.69 mmol) in dry THF (10 mL) and stirred at 0 °C for 1 h. After monitoring the complete reaction by TLC, HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.5 was collected to give the crude product, compound A11 (660.2 mg, 100% yield), as a colorless oil. ESI [M + H] + = 387.2.

[0206] 5. Preparation of Compound A11 Sulfate A11 (537 mg, 1.39 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (276.7 mg, 2.82 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 5 min, and concentrated under reduced pressure to give the crude product. Et2O (20 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 20 mL). The solid was dissolved in ultrapure water (30 mL) and lyophilized for 24 h in a lyophilizer to give compound A11 sulfate (644.4 mg, 100% yield) as a white solid. ESI [M + H] + = 387.2. 1 H NMR (400 MHz, CD3OD) δ 7.44 (d, J= 2.9 Hz, 1H), 7.31 (d, J= 3.0 Hz, 1H), 3.89 (s, 2H), 3.75 (s, 3H), 3.73 - 3.63 (m, 2H), 3.54 - 3.45 (m, 2H), 3.37 - 3.31 (m, 3H), 2.55 - 2.42 (m, 1H), 1.30 (d, J= 6.9 Hz, 3H), 1.25 (d, J= 6.9 Hz, 6H), 1.14 - 1.05 (m, 3H), 0.94 - 0.86 (m, 2H), 0.64 - 0.56 (m, 1H), 0.45 - 0.36 (m, 1H), 0.31 - 0.17 (m, 1H), 0.14 - 0.03 (m, 1H).

[0207] 6. Preparation of Compound A18 Sulfate Compound A18 was prepared in the same manner as A11. A11-2 (300 mg, 0.64 mmol) was reacted with tert-butyl bromoacetate to give A18-1 (346 mg, 0.59 mmol, 92.4% yield). A18-1 was deprotected with TBAF to give compound A18 (241.2 mg, 0.56 mmol, 94.9% yield). Compound A18 was salted with HSO / EtO to give compound A18 sulfate (197.4 mg, 94.9% yield) as a white solid. ESI [M + H] + = 429.3. 1 H NMR (400MHz, CD3OD) δ 7.44 (t, J= 2.7 Hz, 1H), 7.30 (t, J= 2.6 Hz, 1H), 3.89 (s, 2H), 3.80 - 3.43 (m, 6H), 3.37 - 3.32 (m, 1H), 2.55 - 2.42 (m, 1H), 1.50 (s, 5H), 1.30 (d, J= 6.9 Hz, 3H), 1.25 (d, J= 6.8 Hz, 6H), 1.21 (s, 4H), 1.16 - 1.04 (m, 3H), 0.98 - 0.87 (m, 2H), 0.64 - 0.54 (m, 1H), 0.45 - 0.36 (m, 1H), 0.28 - 0.18 (m, 1H), 0.14 - 0.03 (m, 1H).

[0208] Example 10 Preparation of Compound A12 and Sulfate of the Invention TIFF2025535407000038.tif98170

[0209] 1. Preparation of compound A12-1 Compound A1-2 (2.0 g, 4.55 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.93 g, 9.10 mmol), Pd2(dba)3 (416.7 mg, 0.455 mmol), t-BuOK (1.02 g, 9.09 mmol), and JohnPhos (271.6 mg, 0.91 mmol) were dissolved in 1,4-dioxane (30 mL) at room temperature. The reaction system was purged with nitrogen gas three times, and then stirred under nitrogen gas protection at 50 °C for 24 hours. After monitoring the reaction completion by TLC (n-heptane), the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with Rf = 0.5 was collected to obtain the colorless oily crude product Compound A12-1 (2.328 g). ESI [M + H] + = 571.4.

[0210] 2. Preparation of Compound A12-2 In an ice-salt bath at 0°C, TFA (3 mL) was added to a solution of crude compound A12-1 (2.328 g) in dichloromethane (9 mL) and stirred at 0°C for 4 hours. After monitoring the reaction for completeness by TLC, the mixture was concentrated under reduced pressure, alkalized with saturated aqueous sodium bicarbonate (20 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1, then methanol / dichloromethane (v / v) = 0 to 50%). The fraction with an Rf = 0.5 was collected and used to obtain colorless oily compound A12-2 (1.8 g, 84.0% yield for two steps). ES1 [M + H] + = 471.4.

[0211] 3. Preparation of compound A12-3 DIEA (544.0 mg, 4.2 mmol) and methyl bromoacetate (489.5 mg, 3.2 mmol) were added successively to a solution of A12-2 (1.0 g, 2.1 mmol) in dichloromethane (15 mL) in an ice-water bath at 0°C, and the mixture was stirred at room temperature for 4 hours. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), HO (20 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.5 was collected to obtain the colorless oily crude product, compound A12-3 (1.377 g). ESI [M + H] + = 543.4.

[0212] 4. Preparation of compound A12 In an ice-salt bath at 0 °C, TBAF (3.1 mL, 1 mol / L in THF, 3.1 mmol) was added to a solution of A12-3 (1.377 g, 2.54 mmol) in dry THF (15 mL) and stirred at 0 °C for 1 h. After monitoring the reaction completion by TLC, HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.5 was collected to give the crude product, compound A12 (840 mg, 100% yield for two steps), as a colorless oil. ESI [M + H] + = 387.3.

[0213] 5. Preparation of compound A12 sulfate A12 (773.3 mg, 2.0 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (394.2 mg, 4.0 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 5 min, and concentrated under reduced pressure to give the crude product. Et2O (20 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 20 mL). The solid was dissolved in ultrapure water (30 mL) and lyophilized for 24 h in a lyophilizer to give compound A12 sulfate (1060.6 mg, 100% yield) as a white solid. ESI [M + H] + = 387.3. 1 H NMR (400 MHz, CD3OD) δ 7.13 (d, J= 2.5 Hz, 1H), 7.00 (d, J= 2.6 Hz, 1H), 4.59 (s, 2H), 3.77 (s, 2H), 3.76 (s, 3H), 3.36 - 3.32 (m, 5H), 2.52 - 2.42 (m, 1H), 2.27 - 2.10 (m, 4H), 1.28 (d, J= 6.9 Hz, 3H), 1.23 (d, J= 6.9 Hz, 6H), 1.13 - 1.03 (m, 1H), 0.63 - 0.54 (m, 1H), 0.43 - 0.34 (m, 1H), 0.28 - 0.18 (m, 1H), 0.13 - 0.03 (m, 1H).

[0214] Example 11 Preparation of Compounds A13 and Hydrochloride and A14 and Hydrochloride of the Invention TIFF2025535407000039.tif103170

[0215] 1. Preparation of Compound A13-1 DIEA (1.293 g, 10.0 mmol) and tert-butyl bromoacetate (975.25 mg, 5.0 mmol) were added sequentially to a solution of A1-4 (444.78 mg, 1.0 mmol) in dichloromethane (20 mL) in an ice-water bath at 0°C, and the mixture was stirred at room temperature for 4 hours. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), HO (20 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.5 was collected to obtain colorless oily compound A13-1 (512 mg, 91.6% yield). ESI [M + H] + = 559.4.

[0216] 2. Preparation of compound A13 In an ice-salt bath at 0 °C, TBAF (1.1 mL, 1 mol / L in THF, 1.1 mmol) was added to a solution of A13-1 (512 mg, 0.92 mmol) in dry THF (10 mL) and stirred at 0 °C for 5 min. After monitoring the complete reaction by TLC, HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.5 was collected to give compound A13 (360.0 mg, 97.2% yield) as a colorless oil. ESI [M + H] + = 403.3.

[0217] 3. Preparation of Compound A13 Hydrochloride A13 (360.0 mg, 0.89 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -60 °C in a dry ice ethanol bath. HCl / EtO (0.67 mL, 2 mol / L in EtO, 1.34 mmol) solution was slowly added to the reaction mixture, stirred at -60 °C for 5 min, and concentrated under reduced pressure to give the crude product. EtO (20 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with EtO (3 × 20 mL). The solid was dissolved in ultrapure water (30 mL) and lyophilized for 24 h in a lyophilizer to give compound A13 hydrochloride (395 mg, 100% yield) as a white solid. ESI [M + H] + = 403.3. 1 H NMR (400 MHz, CD3OD) δ 7.19 (d, J= 2.8 Hz, 1H), 7.06 (d, J= 2.8 Hz, 1H), 4.17 (s, 2H), 3.75 - 3.58 (m, 8H), 3.35 - 3.32 (m, 1H), 2.54 - 2.41 (m, 1H), 1.55 (s, 9H), 1.27 (d, J= 6.9 Hz, 3H), 1.22 (d, J= 6.9 Hz, 6H), 1.11 - 1.01 (m, 1H), 0.62 - 0.54 (m, 1H), 0.43 - 0.34 (m, 1H), 0.25 - 0.18 (m, 1H), 0.12 - 0.05 (m, 1H).

[0218] 4. Preparation of Compound A14-1 The preparation method of A13-1 was the same as that of Step 1 in this example, in which A1-4 (444.78 g, 1.0 mmol) was reacted with tert-butyl bromoacetate, followed by desilylation protection with TBAF to obtain A13-1. During the production of A13-1, the tert-butyl bromoacetate was not completely removed. Therefore, the remaining tert-butyl bromoacetate after desilylation with TBAF continued to react with the phenolic hydroxyl group to give A14 (263.2 mg, two-step yield 50.9%).

[0219] 5. Preparation of Compound A14 Hydrochloride A14 (263.2 mg, 0.51 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -60 °C in a dry ice ethanol bath. HCl / EtO (0.38 mL, 2 mol / L in EtO, 0.76 mmol) solution was slowly added to the reaction mixture, stirred at -60 °C for 5 min, and concentrated under reduced pressure to obtain the crude product. EtO (20 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with EtO (3 × 20 mL). The solid was dissolved in ultrapure water (30 mL) and lyophilized for 24 h in a lyophilizer to obtain compound A14 hydrochloride (241.9 mg, 100% yield) as a white solid. ESI [M + H] + = 517.4. 1 H NMR (400 MHz, CD3OD) δ 6.88 (d, J= 2.9 Hz, 1H), 6.78 (d, J= 2.9 Hz, 1H), 4.23 - 4.12 (m, 4H), 3.90 - 3.31 (m, 8H), 3.35 - 3.18 (m, 1H), 2.45 - 2.33 (m, 1H), 1.55 (s, 9H), 1.51 (s, 9H), 1.27 (d, J= 7.0 Hz, 3H), 1.22 (d, J= 6.9 Hz, 3H), 1.21 (d, J= 6.9 Hz, 3H), 1.05 - 0.93 (m, 1H), 0.61 - 0.51 (m, 1H), 0.38 - 0.29 (m, 1H), 0.26 - 0.17 (m, 1H), 0.17 - 0.08 (m, 1H).

[0220] Example 12 Preparation of Compound A15 and Sulfate of the Invention TIFF2025535407000040.tif48170

[0221] 1. Preparation of compound A15-1 DIEA (360.54 mg, 2.81 mmol) and bromoacetic acid (130.27 mg, 0.94 mmol) were added sequentially to a solution of A1-4 (417 g, 0.94 mmol) in dichloromethane (50 mL) in an ice-water bath at 0 °C, and the mixture was stirred at room temperature for 48 h. After monitoring the reaction completion by TLC (methanol / dichloromethane (v / v) = 1 / 10), the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0 to 30%) and prep-TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with an Rf = 0.5 was collected and used to give colorless oily compound A15-1 (209.9 mg, 44.4% yield). ESI [M + H] + = 503.4.

[0222] 2. Preparation of Compound A15 In an ice-salt bath at 0°C, TBAF (0.8 mL, 1 mol / L in THF, 0.8 mmol) was added to a solution of A15-1 (209.9 mg, 0.42 mmol) in dry THF (10 mL), and the mixture was stirred at 0°C for 1 h. After monitoring the complete reaction by TLC, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0 to 30% ethanol / dichloromethane (v / v) = 1 / 10) and prep-TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with an Rf = 0.4 was collected and used to give colorless oily compound A15 (121.7 mg, 83.6% yield). ESI [M + H] + = 347.3.

[0223] 3. Preparation of compound A15 sulfate A15 (121.7 mg, 0.35 mmol, 1.0 eq) was dissolved in diethyl ether (10 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (68.9 mg, 0.7 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -60 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give compound A15 sulfate (138.1 mg, 100% yield) as a white solid. ESI [M + H] + = 347.3. 1H NMR (400 MHz, CD3OD) δ 7.08 (d, J= 2.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 4.18 (s, 2H), 3.67 - 3.53 (m, 8H), 3.35 - 3.31 (m, 1H), 2.51 - 2.42 (m, 1H), 1.27 (d, J= 6.9 Hz, 3H), 1.22 (d, J= 6.8 Hz, 6H), 1.11 - 1.01 (m, 1H), 0.61 - 0.52 (m, 1H), 0.43 - 0.33 (m, 1H), 0.24 - 0.16 (m, 1H), 0.12 - 0.04 (m, 1H).

[0224] Example 13 Preparation of Compound A16 and Sulfate of the Invention TIFF2025535407000041.tif45170

[0225] 1. Preparation of compound A16-1 K2CO3 (2.07 g, 15.0 mmol) and methyl 2-bromo-2-methylpropionate (1.81 g, 10.0 mmol) were added to a solution of A1-4 (444.78 g, 1.0 mmol) in MeCN (10 mL) at room temperature, and the mixture was sealed and stirred at 70 °C for 4 hours. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.5 was collected to obtain colorless oily compound A16-1 (253.0 mg, 46.4% yield). ESI [M + H] + = 545.4.

[0226] 2. Preparation of compound A16 In an ice-salt bath at 0°C, TBAF (0.6 mL, 1 mol / L in THF, 0.6 mmol) was added to a solution of A15-1 (253.0 mg, 0.46 mmol) in dry THF (10 mL), and the mixture was stirred at 0°C for 1 h. After monitoring the complete reaction by TLC, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with Rf = 0.5 was collected to give colorless oily compound A16 (152.6 mg, 85.4% yield). ESI [M + H] + = 389.2.

[0227] 3. Preparation of compound A16 sulfate A16 (135.6 mg, 0.35 mmol, 1.0 eq) was dissolved in diethyl ether (10 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (68.6 mg, 0.7 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (20 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give compound A15 sulfate (189.1 mg, 100% yield) as a white solid. ESI [M + H] + = 389.2. 1 H NMR (400MHz, CD3OD) δ 7.23 (d, J= 2.9 Hz, 1H), 7.09 (d, J= 2.9 Hz, 1H), 3.88 (s, 3H), 3.78 - 3.67 (m, 4H), 3.64 - 3.51 (m, 4H), 3.37 - 3.32 (m, 1H), 2.54 - 2.39 (m, 1H), 1.66 (s, 6H), 1.28 (d, J= 6.9 Hz, 3H), 1.23 (d, J= 6.8 Hz, 6H), 1.12 - 1.02 (m, 1H), 0.64 - 0.54 (m, 1H), 0.43 - 0.34 (m, 1H), 0.26 - 0.18 (m, 1H), 0.12 - 0.03 (m, 1H).

[0228] Example 14 Preparation of Compound A17 and its Hydrochloride Salt of the Present Invention TIFF2025535407000042.tif47170

[0229] 1. Preparation of compound A17-1 DIEA (932.7 mg, 7.2 mmol) and tert-butyl bromoacetate (702.2 mg, 3.6 mmol) were added sequentially to a solution of A4-4 (300.0 mg, 0.72 mmol) in dichloromethane (20 mL) in an ice-water bath at 0°C, and the mixture was stirred at room temperature for 4 hours. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), HO (20 mL) was added to the reaction mixture and extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.5 was collected to obtain the colorless oily crude product, Compound A17-1 (405.6 mg). ESI [M + H] + = 533.4.

[0230] 2. Preparation of compound A17 In an ice-salt bath at 0 °C, TBAF (0.9 mL, 1 mol / L in THF, 0.9 mmol) was added to a solution of A17-1 (405.6 mg, 0.76 mmol) in dry THF (10 mL) and stirred at 0 °C for 10 min. After monitoring the complete reaction by TLC, HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.5 was collected and used to give compound A17 (188.8 mg, 69.6% yield for the two steps) as a colorless oil. ESI [M + H] + = 377.3.

[0231] 3. Preparation of Compound A17 Hydrochloride A17 (188.8 mg, 0.50 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -60 °C in a dry ice ethanol bath. HCl / EtO (0.38 mL, 2 mol / L in EtO, 0.76 mmol) solution was slowly added to the reaction mixture, stirred at -60 °C for 5 min, and concentrated under reduced pressure to obtain the crude product. EtO (20 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with EtO (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to obtain compound A14 hydrochloride (211.6 mg, 100% yield) as a white solid. ESI [M + H] + = 377.3. 1 H NMR (400MHz, CD3OD) δ 6.94 (s, 2H), 4.12 (s, 2H), 3.62 - 3.52 (m, 8H), 3.36 - 3.32 (m, 2H), 1.55 (s,95H), 1.21 (d, J= 6.9 Hz, 12H).

[0232] Example 15 Preparation of Compounds A19 and Sulfate, A19S and Sulfate, and A19R and Sulfate of the Present Invention TIFF2025535407000043.tif119170

[0233] 1. Preparation of compound A19S-1 DIEA (122.3 mg, 0.944 mmol) and (R)-2-bromopropionic acid (144.4 mg, 0.944 mmol) were added to a solution of A1-4 (420.0 mg, 0.944 mmol) in dichloromethane (15 mL) at room temperature, and the mixture was stirred for 24 h at room temperature. After monitoring the reaction completion by TLC (methanol / dichloromethane (v / v) = 1 / 10), the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with an Rf = 0.3 was collected to obtain colorless oily compound A19S-1 (227.3 mg, 44.2% yield). ESI [M + H] + = 516.4.

[0234] 2. Preparation of compound A19S-2 DMAP (23.0 mg, 0.19 mmol) and BocO (412 mg, 1.888 mmol) were added to a solution of A19S-1 (187 mg, 0.364 mmol) in dichloromethane (10 mL) at room temperature, and the mixture was stirred at room temperature for 24 hours. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), HO (30 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with an Rf = 0.7 was collected to obtain colorless oily compound A19S-2 (132 mg, 63.3% yield). ESI [M + H] + = 573.4.

[0235] 3. Preparation of compound A19S TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of A19S-2 (132 mg, 0.23 mmol) in dry THF (8 mL) at room temperature, and the mixture was stirred at 0 °C for 10 min. After monitoring the complete reaction by TLC, HO (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The Rf = 0.5 fraction was recovered to give compound A19S (77 mg, 92.4% yield) as a colorless oil. ESI [M + H] + = 417.3.

[0236] 4. Preparation of compound A19S sulfate A19S (77 mg, 0.185 mmol, 1.0 eq) was dissolved in diethyl ether (10 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (36.3 mg, 0.37 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give compound A15 sulfate (83.3 mg, 100% yield) as a white solid. ESI [M + H] + =417.3 1H NMR (400MHz, CD3OD) δ 7.16 (d, J = 2.9 Hz, 1H), 7.03 (d, J = 2.9 Hz, 1H), 4.13 (q, J = 7.2 Hz, 1H), 3.73 - 3.55 (m, 8H), 3.36 - 3.32 (m, 1H), 2.52 - 2.42 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.55 (s, 9H), 1.27 (d, J = 6.9 Hz, 3H), 1.25 - 1.18 (m, 6H), 1.10 - 1.02 (m, 1H), 0.61 - 0.54 (m, 1H), 0.43 - 0.35 (m, 1H), 0.25 - 0.17 (m, 1H), 0.12 - 0.03 (m, 1H). The methods for preparing Compound A19 and sulfate and Compound A19R and sulfate are similar to those for Compound A19S and sulfate.

[0237] Example 16 Preparation of Compounds A20 and Sulfate, A20S and Sulfate, and A20R and Sulfate of the Present Invention TIFF2025535407000044.tif158170

[0238] 1. Preparation of compound A20S-1 EtN (218.4 mg, 2.158 mmol, 3 eq), NaI (323.5 mg, 2.158 mmol, 3 eq), and (S)-methyl 2-chloropropionate (264.5 mg, 2.158 mmol, 3 eq) were added sequentially to a solution of A4-4 (300 mg, 0.716 mmol, 1 eq) in dry DMF (10 mL) at room temperature, and the mixture was stirred at 60 °C for 5 h. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), the reaction mixture was cooled to room temperature, HO (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.6 was collected to obtain colorless oily compound A20S-1 (331.7 mg, 91.8% yield). ESI [M + H] + = 505.4.

[0239] 2. Preparation of compound A20S TBAF (0.8 mL, 1 mol / L in THF, 0.8 mmol, 1.2 eq) was added to a solution of A20S-1 (331 mg, 0.656 mmol, 1 eq) in dry THF (20 mL) in an ice bath at 0°C, and the mixture was stirred at 0°C for 10 minutes. After monitoring the reaction completion by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–15%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.5 was collected to obtain colorless oily compound A20S (214 mg, 93.6% yield). ESI [M + H] + = 349.2.

[0240] 3. Preparation of compound A20S sulfate A20S (214 mg, 0.614 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (120.45 mg, 1.228 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to obtain the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to obtain the white solid compound A20S sulfate (315.3 mg, 100% yield). ESI [M + H] + = 349.2. 1H NMR (400MHz, CD3OD) δ 7.09 (s, 2H), 4.21 (q, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.74 - 3.66 (m, 4H), 3.65 - 3.49 (m, 4H), 3.38 - 3.32 (m, 2H), 1.61 (d, J= 7.2 Hz, 3H), 1.23 (d, J = 6.9 Hz, 12H). The preparation methods of compounds A20 and sulfate and A20R and sulfate are similar to those of the target compounds A20S and sulfate.

[0241] Example 17 Preparation of Compounds A21 and Hydrochloride, A21S and Hydrochloride, A21R and Hydrochloride, and A27S and Hydrochloride of the Present Invention TIFF2025535407000045.tif162170

[0242] The preparation methods of compounds A21, A21S, and A21R were the same as those of compounds A19, A19S, and A19R in Example 15. The preparation methods of A21 hydrochloride, A21S hydrochloride, and A21R hydrochloride were the same as those of compound A17 hydrochloride in Example 14. Compound A4-4 was used as the starting material.

[0243] During the isolation and purification of compound A21S-2, the remaining BocO was not completely removed, so 75.1 mg of colorless oily compound A27S was obtained by isolation. The method for preparing A27S hydrochloride was the same as that for compound A17 hydrochloride in Example 14.

[0244] A21S hydrochloride: white solid, 75.6 mg. ESI [M + H] + = 391.3. 1H NMR (400MHz, CD3OD) δ 7.03 (s, 2H), 4.14 (q, J = 7.2 Hz, 1H), 3.70 - 3.52 (m, 8H), 3.39 - 3.32 (m, 2H), 1.61 (d, J= 7.2 Hz, 3H), 1.55 (s, 9H), 1.22 (d, J= 6.9 Hz, 12H).

[0245] A27S hydrochloride: white solid, 64.9 mg. ESI [M + H] + = 491.3. 1 H NMR (400MHz, CD3OD) δ 6.79 (s, 2H), 4.29 - 3.94 (m, 1H), 3.93 - 3.03 (m, 8H), 3.01 - 2.92 (m, 2H), 1.64 - 1.56 (m, 3H), 1.55 (s, 9H), 1.52 (s, 9H), 1.19 (d, J = 6.9 Hz, 12H).

[0246] Example 18 Preparation of Compounds A22 and Sulfate, A22S and Sulfate, and A22R and Sulfate of the Present Invention TIFF2025535407000046.tif138170

[0247] 1. Preparation of compound A22S-1 EtN (204.76 mg, 2.024 mmol, 3 eq), NaI (303.30 mg, 2.024 mmol, 3 eq), and (R)-2-bromobutyric acid methyl ester (366.31 mg, 2.024 mmol, 3 eq) were added sequentially to a solution of A1-4 (300.0 mg, 0.675 mmol, 1 eq) in dry DMF (8 mL) at room temperature, and the mixture was stirred at 60 °C for 8 h. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), the reaction mixture was cooled to room temperature, HO (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–8%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.6 was collected to obtain colorless oily compound A22S-1 (296.0 mg, 80.5% yield). ESI [M + H] + = 545.4.

[0248] 2. Preparation of compound A22S In an ice-salt bath at 0 °C, TBAF (0.7 mL, 1 mol / L in THF, 0.7 mmol) was added to a solution of A22S-1 (296 mg, 0.543 mmol) in dry THF (8 mL) and stirred at 0 °C for 10 min. After monitoring the complete reaction by TLC, HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 7%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with an Rf = 0.4 was collected to obtain the crude product compound A22S (247.86 mg) as a colorless oil. ESI [M + H] += 389.2.

[0249] 3. Preparation of compound A22S sulfate A22S (247.86 mg, 0.638 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (125.12 mg, 1.276 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give the white solid compound A20S sulfate (278.28 mg, 100% yield). ESI [M + H] + =389.2 1 H NMR (400MHz, CD3OD) δ 7.30 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 2.9 Hz, 1H), 3.84 (s, 3H), 3.73 - 3.68 (m, 4H), 3.65 - 3.60 (m, 1H), 3.49 - 3.42 (m, 4H), 3.36 - 3.32 (m, 1H), 2.54 - 2.43 (m, 1H), 2.02 - 1.93 (m, 2H), 1.28 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H), 1.09 (dd, J = 7.8, 2.9 Hz, 1H), 1.04 (t, J = 7.4 Hz, 3H), 0.64 - 0.56 (m, 1H), 0.44 - 0.36 (m, 1H), 0.27 - 0.19 (m, 1H), 0.12 - 0.03 (m, 1H). The preparation methods of compound A22 and sulfate and A22R and sulfate are similar to those of compound A22S and sulfate.

[0250] Example 19 Preparation of Compounds A23 and Sulfate, A23S and Sulfate, and A23R and Sulfate of the Present Invention TIFF2025535407000047.tif146170

[0251] 1. Preparation of compound A23-1 EtN (184.27 mg, 1.821 mmol, 3 eq), NaI (272.95 mg, 1.821 mmol, 3 eq), and methyl 2-bromo-3-methylbutyrate (355.20 mg, 1.821 mmol, 3 eq) were added to a solution of A1-4 (270.0 mg, 0.607 mmol, 1 eq) in dry DMF (10 mL) at room temperature, and the mixture was stirred at 60 °C for 4 h. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), the reaction mixture was cooled to room temperature, HO (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 8%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with an Rf = 0.6 was collected to obtain colorless oily compound A23-1 (103.0 mg, 30.4% yield). ESI [M + H] + = 559.4.

[0252] 2. Preparation of Compound A23 In an ice-salt bath at 0 °C, TBAF (0.25 mL, 1 mol / L in THF, 0.25 mmol) was added to a solution of A23-1 (103.0 mg, 0.184 mmol) in dry THF (5 mL) and stirred at 0 °C for 10 min. After monitoring the complete reaction by TLC, HO (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 7%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with an Rf = 0.3 was collected to give compound A23 (46.1 mg, 62.2% yield) as a colorless oil. ESI [M + H] + = 403.3.

[0253] 3. Preparation of compound A23 sulfate A23 (46.1 mg, 0.115 mmol, 1.0 eq) was dissolved in diethyl ether (20 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (22.46 mg, 0.229 mmol, 2.0 eq) in Et2O (2 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give compound A20S sulfate (54.18 mg, 100% yield). ESI [M + H] + =403.3 1H NMR (400MHz, CD3OD) δ 7.38 (d, J = 2.9 Hz, 1H), 7.24 (d, J = 2.9 Hz, 1H), 3.79 (s, 3H), 3.75 - 3.64 (m, 4H), 3.36 - 3.31 (m, 1H), 3.26 - 3.11 (m, 5H), 2.53 - 2.42 (m, 1H), 2.25 - 2.10 (m, 1H), 1.29 (d, J = 6.9 Hz, 3H), 1.24 (d, J= 6.9 Hz, 6H), 1.11 (d, J = 6.6 Hz, 3H), 1.09 - 1.03 (m, 1H), 0.95 (d, J= 6.6 Hz, 3H), 0.64 - 0.55 (m, 1H), 0.45 - 0.36 (m, 1H), 0.27 - 0.18 (m, 1H), 0.12 - 0.03 (m, 1H). The methods for preparing Compound A23 and sulfate and Compound A23R and sulfate are similar to those for Compound A23S and sulfate.

[0254] Example 20 Preparation of Compounds A24 and Sulfate, A24S and Sulfate, A24R and Sulfate, and A26 and Sulfate of the Present Invention TIFF2025535407000048.tif153170

[0255] 1. Preparation of Compound A24-1 EtN (341.6 mg, 3.376 mmol, 3 eq), NaI (337.0 mg, 2.248 mmol, 2 eq), and ethyl 2-bromo-2-cyclopropylacetate (465.5 mg, 2.248 mmol, 2 eq) were added sequentially to a solution of A1-4 (500.0 mg, 1.125 mmol, 1 eq) in dry DMF (10 mL) at room temperature, and the mixture was stirred at 60 °C for 4 h. After monitoring the complete reaction by TLC (methanol / dichloromethane (v / v) = 1 / 10), the reaction mixture was cooled to room temperature, HO (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 5%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with an Rf = 0.5 was collected to obtain colorless oily compound A24-1 (512.7 mg, 79.9% yield). ESI [M + H] + = 571.4.

[0256] 2. Preparation of Compound A24-2 In an ice-salt bath at 0°C, NaOMe (0.25 mL, 0.25 mmol) was added to a solution of A24-1 (240.0 mg, 0.42 mmol) in MeOH (5 mL), and the mixture was stirred at 0°C for 10 h. After monitoring the complete reaction by TLC, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 7%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with Rf = 0.4 was collected to give colorless oily compound A24-2 (43.2 mg, 18.5% yield). ESI [M + H] + = 557.4.

[0257] 3. Preparation of compound A24 In an ice-salt bath at 0 °C, TBAF (0.1 mL, 1 mol / L in THF, 0.1 mmol) was added to a solution of A24-2 (43.2 mg, 0.078 mmol) in dry THF (5 mL) and stirred at 0 °C for 10 min. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 5 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–7%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with an Rf = 0.3 was collected to give compound A24 (21.0 mg, 67.2% yield) as a colorless oil. ESI [M + H] + = 401.3.

[0258] 4. Preparation of compound A24 sulfate A24 (21.0 mg, 0.0524 mmol, 1.0 eq) was dissolved in diethyl ether (10 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (10.30 mg, 0.105 mmol, 2.0 eq) in Et2O (1 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give compound A20S sulfate (26.0 mg, 100% yield). ESI [M + H] + =401.3 1H NMR (400MHz, CD3OD) δ 7.17 (d, J = 2.9 Hz, 1H), 7.04 (d, J = 2.9 Hz, 1H), 3.88 (s, 3H), 3.75 - 3.62 (m, 6H), 3.57 - 3.49 (m, 2H), 3.40 (d, J = 10.2 Hz, 1H), 3.35 - 3.32 (m, 1H), 2.52 - 2.43 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.21 - 1.17 (m, 1H), 1.12 - 1.01 (m, 1H), 1.01 - 0.91 (m, 1H), 0.86 - 0.77 (m, 1H), 0.76 - 0.67 (m, 1H), 0.67 - 0.53 (m, 2H), 0.43 - 0.34 (m,1H), 0.25 - 0.18 (m, 1H), 0.12 - 0.04 (m, 1H). The methods for preparing Compound A24S and sulfate and Compound A24R and sulfate are similar to those for Compound A24 and sulfate.

[0259] 5. Preparation of Compound A26 and A26 Sulfate In an ice-salt bath at 0 °C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of A24-1 (232.3 mg, 0.407 mmol) in dry THF (5 mL) and stirred at 0 °C for 5 min. After monitoring the complete reaction by TLC, HO (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0–8%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with an Rf = 0.3 was collected to give compound A26 (160.0 mg, 94.8% yield) as a colorless oil. ESI [M + H] + = 415.2.

[0260] A26 (160.0 mg, 0.386 mmol, 1.0 eq) was dissolved in diethyl ether (10 mL) at room temperature and cooled to -70 °C in a dry ice ethanol bath. A solution of H2SO4 (75.70 mg, 0.772 mmol, 2.0 eq) in Et2O (1 mL) was slowly added to the reaction mixture, stirred at -70 °C for 10 min, and concentrated under reduced pressure to give the crude product. Et2O (10 mL) was added to the crude product, stirred, and suction filtered. The solid was washed with Et2O (3 × 10 mL). The solid was dissolved in ultrapure water (20 mL) and lyophilized for 24 h in a lyophilizer to give compound A20S sulfate (220.59 mg, 100% yield). ESI [M + H] + =415.2 1 H NMR (400MHz, CD3OD) δ 7.23 (d, J = 2.9 Hz, 1H), 7.09 (d, J = 2.9 Hz, 1H), 4.44 - 4.26 (m, 2H), 3.88 - 3.76 (m, 2H), 3.76 - 3.69 (m, 4H), 3.66 - 3.57 (m, 2H), 3.47 (d, J = 10.2 Hz, 1H), 3.37 - 3.31 (m, 1H), 2.53 - 2.42 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.28 (d, J= 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 6H), 1.22 - 1.19 (m, 1H), 1.14 - 1.03 (m, 1H), 1.02 - 0.93 (m, 1H), 0.89 - 0.80 (m, 1H), 0.81 - 0.72 (m, 1H), 0.71 - 0.63 (m, 1H), 0.63 - 0.53 (m, 1H), 0.43 - 0.34 (m, 1H), 0.26 - 0.17 (m, 1H), 0.12 - 0.03 (m, 1H).

[0261] Example 21 Preparation of Compound A25S of the Invention TIFF2025535407000049.tif53170

[0262] A solution of A6S-1 (200 mg, 0.377 mmol), MeI (106.95 mg, 0.753 mmol, 2 eq), and DIEA (146.4 mg, 1.133 mmol) in dry DMF (10 mL) was stirred at room temperature for 12 h. After monitoring the reaction completion by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0 to 50%) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with an Rf = 0.5 was collected to give the crude product compound A25S-1 (301 mg).

[0263] In an ice-salt bath at 0 °C, TBAF (0.1 mL, 1 mol / L in THF, 0.1 mmol) was added to a solution of crude compound A25S-1 (300 mg) in dry THF (5 mL) and stirred at 0 °C for 10 min. After monitoring the reaction for completeness by TLC, HO (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous NaSO, suction filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0 to 50%). The fraction with an Rf = 0.5 was collected and used to give compound A25S (70.7 mg, 36.3% yield for two steps) as a colorless oil. ESI [M - I] = 389.2. 1H NMR (400MHz, CD3OD) δ 7.48 (d, J = 3.3 Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 4.46 - 4.32 (m, 2H), 3.97 - 3.85 (m, 2H), 3.60 (s, 3H), 3.52 - 3.47 (m, 1H), 3.45 (s, 3H), 3.37 (m, 1H), 3.12 (m, 2H), 3.04 - 2.82 (m, 2H), 2.58 - 2.39 (m, 1H), 1.31 (m, 6H), 1.27 - 1.24 (m, 6H), 1.12 (m, 1H), 0.66 - 0.57 (m, 1H), 0.42 (m, 1H), 0.25 (m, 1H), 0.07 (m, 1H). The following test examples demonstrate the beneficial effects of the present invention.

[0264] Test Example 1 Screening of the A6S salt form of the compound of the present invention and measurement of solubility 1. Experimental Method Compound A6S (1 eq) was dissolved in EtO (2 mL) at room temperature, and the corresponding acid (2 eq) was dissolved in EtO (Nos. 1-4) or MeOH (Nos. 5-10). The acid solution was slowly added to the reaction system containing compound A6S via syringe. Nos. 1-3 were stirred at room temperature for 1 hour, and Nos. 5-10 were stirred at room temperature for 16 hours. The solid was filtered under suction, washed with diethyl ether, and dried to obtain the corresponding salt form of compound A6S. The solubility of each salt form in ultrapure water was then measured. TIFF2025535407000050.tif96170

[0265] 2. Experimental Results As can be seen from Table 1, compound A6S of the present invention can form various salt forms, such as hydrochloride, sulfate, methanesulfonate, phosphate, p-toluenesulfonate, benzenesulfonate, oxalate, maleate, etc. Furthermore, each salt form has excellent water solubility, with a solubility in ultrapure water exceeding 8 mg / mL, which can meet the requirements of formulations.

[0266] Test Example 2: Measurement of solubility of salt forms of the compound of the present invention 1. Experimental Method 10 mg of the corresponding salt of the compound of the present invention was weighed, and water was added at 25°C ± 2°C. The mixture was vigorously shaken for 30 seconds every 5 minutes and observed for 30 minutes. When no particles or droplets of the solute were observed in the test system, the water solubility of the compound after salt formation was recorded according to the following criteria. A: water dose <0.1 mL; B: water dose ≥ 0.1 mL and < 1.0 mL; C: Water dose ≥ 1.0 mL and < 5.0 mL.

[0267] 2. Experimental Results Those skilled in the art are well aware that propofol and cipropofol cannot form salts and are insoluble in water. However, as can be seen from Table 2, the salt forms of the representative compounds of the present invention have excellent water solubility, eliminating the need for lipid emulsions and overcoming various side effects associated with lipid emulsions.

[0268] Test Example 3: Measurement of pharmacological and safety data of the compound of the present invention 1. Experimental Method (1) Anesthetic effect test of representative compounds of the present invention after tail vein injection in rats (measurement of minimum effective dose of anesthetic): SD rats were used in the test, and the drug was administered via the tail vein (administration rate 0.02 ml / s, dose 0.6 ml / dose). A sequential method was used to determine whether the compound caused the loss of righting reflex. The dose of each test compound was selected starting from 1 mg / kg, and the actual dose was calculated based on the body weight of each animal measured before the test. Subsequent increases or decreases in the dose were determined based on the animal's response (presence or absence of loss of righting reflex). The dose at which the initial loss of righting reflex occurred was determined as the minimum effective dose of anesthesia. The minimum effective dose of anesthesia in the present invention is further defined as A≦5 mg / kg; 5 mg / kg <B≦10 mg / kg;10 mg / kg<C≦20 mg / kg;D> It was classified as 20 mg / kg.

[0269] (2) Anesthetic effect (50% effective dose ED) of the representative compounds of the present invention after tail vein injection in rats 50 Measurement of pharmacological properties of equivalent doses: The test was conducted using SD rats, and the drug was administered into the tail vein (administration rate 0.02 ml / s, dose 0.6 ml / dose). 50 The dose of each test compound was selected starting from 5 mg / kg, and the actual dose was calculated based on the body weight of each animal measured before the test. Subsequent increases or decreases in the dose were determined based on the animal's response (presence or absence of loss of righting reflex). In the test, the loss and recovery of five isotropic changes in the righting reflex were measured, and then the ED of the compound that caused the loss of righting reflex was calculated. 50 was calculated according to the formula: ED 50 After measuring, 2 ED 50 Under the dosage conditions, the time to onset of anesthetic action of the compound, the time to maintain anesthetic action, the time to recover from anesthetic action, etc. were also measured.

[0270] (3) 2ED 50 Measurement of the effects of representative compounds of the present invention on blood pressure, heart rate, and respiratory rate in rats under various dose conditions: Compound ED 50 According to the measurements, SD rats were still used under basic anesthesia, and one femoral artery was intubated. Under the condition that the rat's arterial blood pressure, heart rate, and respiratory rate were continuously monitored, 2ED was administered by a single injection into the tail vein (administration rate 0.02 ml / s, administration volume 0.6 ml / rat). 50 The effects of the compounds of the present invention on the blood pressure, heart rate and respiratory rate of rats under the administration conditions were observed.

[0271] (4) Measurement of the minimum lethal dose of the compounds of the present invention after tail vein injection in rats: SD rats were used and administered via the tail vein (administration rate: 0.02 ml / s, dose: 0.5-1.0 ml / 100 g body weight). The dose of the compound selected for each test was 4ED 50The dose started from 0.01 mg / kg, and the actual dose was calculated according to the body weight of each animal, which was measured before the test. Whether the compound caused death was determined in a sequential manner. Subsequent increases or decreases in the dose were determined based on the reaction of the experimental animals (presence or absence of death). The dose at which the first death occurred was defined as the minimum lethal dose. In the present invention, the minimum lethal dose was defined as a multiple of the minimum effective dose of anesthetic, which is the approximate therapeutic index. In the present invention, the approximate therapeutic index is further classified as follows: if the approximate therapeutic index is 5 or more, it is classified as A; if the approximate therapeutic index is less than 5 but 3 or more, it is classified as B; and if the approximate therapeutic index is less than 3, it is classified as C.

[0272] (5) Measurement of recovery time of the compound of the present invention after discontinuation after continuous infusion administration for different time periods using rats: SD rats were used in the test, and 1.5ED 50 given as a single injection, followed 1 minute later by an additional 1ED 50 After administration, the syringe was attached to the tail vein cannula via an extension tube. The infusion rate for each rat was determined based on the specific compound. After 5 minutes, the infusion rate was halved, and then adjusted every 5 minutes, increasing or decreasing the infusion rate depending on the rat's response. When the prescribed infusion time was reached, the infusion was stopped, and the recovery time of the righting reflex and the onset and type of side effects during the test were observed and recorded.

[0273] In the above test, the dosage at which the loss of righting reflex occurs is recorded, and the onset and recovery time of anesthesia, the duration of righting reflex, and the duration of sedative effect can also be recorded.For the dose at which the compound of the present invention causes the loss of righting reflex, the effect of the compound on the circulation and respiration of experimental animals can also be observed by a circulatory effect test.In a continuous infusion experiment, the continuous infusion of the compound of the present invention is administered for different times, and the recovery time from the time of discontinuation until the rats begin to behave normally can be observed.

[0274] 2. Experimental Results TIFF2025535407000052.tif247170TIFF2025535407000053.tif121170As can be seen from Table 3, most of the salt forms selected for testing of the representative compounds of the present invention can be directly dissolved in pure water or saline, have a low minimum effective dose of anesthetic, a short onset of action, and can rapidly produce a general anesthetic effect.

[0275] As can be seen from Table 4, the representative compounds of the present invention can produce rapid general anesthetic effects and rapid recovery, and in addition, have a superior safety profile (including milder circulatory depression and respiratory depression) compared to propofol, and when administered by continuous infusion, have a shorter anesthetic recovery time and superior safety profile.

[0276] Combining Tables 3 and 4, the representative compounds of the present invention have excellent anesthetic effects and / or excellent safety, and are expected to have a wide range of clinical applications.

[0277] As described above, the present invention provides a piperazine-substituted phenol derivative represented by Formula I, which has good salt-forming properties and excellent water solubility, such that the solubility meets the requirements of pharmaceutical formulations, a low minimum effective dose of anesthetics, and rapid onset and recovery. This overcomes the drawbacks of propofol and ciprofol prodrugs and lipid emulsion formulations, and has superior safety compared to propofol. It is expected to be useful in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs for controlling status epilepticus, providing a new clinical option for the preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs for controlling status epilepticus.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof. (where R is hydrogen, COR a , COCH(NH 2 )R a , COOR h1 , C.H. 2 COOR h1 , protecting group, PO(OR h1 )(OR h2 ) or CH 2 OPO(OR h1 )(OR h2 ) and R a is hydrogen, C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group; R h1 , R h2 are each independently hydrogen, C 1-4 It is selected from an alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen, or C 1～4 selected from alkyl groups or 3- to 6-membered cycloalkyl groups, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 and cannot simultaneously be methyl groups. R 7 , R 8 are each independently hydrogen, halogen or C 1-4 It is selected from alkyl groups. p is selected from an integer from 0 to 8, and each R 9 are each independently hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 alkyl groups, or p is selected from an integer of 2 to 8, of which two R 9 are linked to form a ring, and the remaining R 9 are each independently hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 alkyl groups, or p is an integer from 1 to 9, of which one R 9 is R 10 and the remaining R 9 are each independently hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 It is selected from alkyl groups. R 10 is hydrogen, C 1～4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from. where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1～4 Alkyl group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group. R e is hydrogen, C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in 1～4 Alkyl group, C 1～4 Alkoxy group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～4 It is selected from alkyl groups. R f is hydrogen, C 1～4 Alkyl or halogen substituted C 1～4 It is selected from alkyl groups. R i is hydrogen, C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is selected from an alkynyl group, a 3- to 6-membered cycloalkyl group, or a 3- to 6-membered heterocyclic group. m is selected from 0, 1, 2, 3, or 4. n is selected from 2, 3, or 4. t is selected from 1, 2, 3, or 4.)

2. 2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula II: (However, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halogen, or C 1～4 It is selected from an alkyl group or a 3- to 6-membered saturated cycloalkyl group. p is selected from an integer from 0 to 8, and each R 9 are each independently hydrogen, C 1～4 alkyl groups, or p is selected from an integer of 2 to 8, of which two R 9 are linked to form a ring, and the remaining R 9 are each independently hydrogen, C 1～4 alkyl groups, or p is an integer from 1 to 9, of which one R 9 is R 10 and the remaining R 9 are each independently hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 It is selected from alkyl groups. R 10 is hydrogen, C 1～4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from. where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1～4 Alkyl group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group. R e is hydrogen, C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in 1～4 Alkyl group, C 1～4 Alkoxy group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 Alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～4 It is selected from alkyl groups. R f is hydrogen, C 1～4 Alkyl or halogen substituted C 1～4 It is selected from alkyl groups. vR i is hydrogen, C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is selected from an alkynyl group, a 3- to 6-membered cycloalkyl group, or a 3- to 6-membered heterocyclic group. m is selected from 0, 1, 2, 3, or 4. n is selected from 2, 3, or 4. t is selected from 1, 2, 3, or 4.)

3. 3. The compound of claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula III: (However, R 11 , R 12 are each independently a methyl group, Selected from. R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1～4 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1～4 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1～4 It is selected from alkyl groups. R 10 is as described in claim 2.)

4. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula IV-1 or Formula IV-2. (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S; R 10 is hydrogen, C 1～4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from. where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1～3 Alkyl group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 Alkyl group, C 2～4 Alkenyl group, C 2～4 It is an alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclic group, an aryl group, or a heteroaryl group. R e is hydrogen, C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, cycloalkyl, heterocyclic, aryl, and heteroaryl groups in 1～3 Alkyl group, C 1～3 Alkoxy group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～3 It is selected from alkyl groups. R f is hydrogen, C 1～3 Alkyl or halogen substituted C 1～3 It is selected from alkyl groups. R i is hydrogen, C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is selected from an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group. m is selected from 0, 1, 2, 3, or 4. n is selected from 2, 3, or 4. t is selected from 1, 2, 3, or 4.)

5. The compound according to claim 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula IV-1 or Formula IV-2. (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S; R 10 is hydrogen, C 1～4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from. where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1～3 Alkyl group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～3 Alkyl group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R e is hydrogen, C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, aryl, and heteroaryl groups in 1～3 Alkyl group, C 1～3 Alkoxy group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～3 It is selected from alkyl groups. R f is hydrogen, C 1～3 Alkyl or halogen substituted C 1～3 It is selected from alkyl groups. R i is hydrogen, C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is selected from an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group. m is selected from 0, 1, 2, 3, or 4. n is selected from 2, 3, or 4. t is selected from 1, 2, 3, or 4.)

6. The structural fragment teeth, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, according to any one of claims 3 to 5, characterized in that it has any one of the following structures:

7. The compound according to claim 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula V-1 or Formula V-2. (However, R 10 is hydrogen, C 1～4 Alkyl groups, (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CONR d1 R d2 , (CR b1 R b2 ) n OR f , (CR b1 R b2 ) n NR d1 R d2 , (CR b1 R b2 ) n OCOR e , (CR b1 R b2 ) n NR d1 COR e , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 Selected from. where R b1 , R b2 , R b3 , R b4 are each independently hydrogen, halogen, or C 1～2 Alkyl group, halogen-substituted C 1～2 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, phenyl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～2 Alkyl group, halogen-substituted C 1～2 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, a phenyl group, or a heteroaryl group. R e is hydrogen, C 1～2 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, a phenyl group, or a heteroaryl group. R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, phenyl, and heteroaryl groups in 1～2 Alkyl group, C 1～2 Alkoxy group, halogen-substituted C 1～2 Alkyl group, vinyl group, ethynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～2 It is selected from alkyl groups. R f is hydrogen, C 1～2 Alkyl or halogen substituted C 1～2 It is selected from alkyl groups. R i is hydrogen, C 1～2 It is selected from an alkyl group, a vinyl group, an ethynyl group, a 3- to 6-membered saturated cycloalkyl group, or a 3- to 6-membered saturated heterocyclic group. m is selected from 0, 1, 2, 3, or 4. n is selected from 2, 3, or 4. t is selected from 1, 2, 3, or 4.)

8. The 3- to 6-membered saturated cycloalkyl group wherein the 3- to 6-membered saturated heterocyclic group is selected from wherein the 3- to 6-membered ring structure is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; and the halogen is selected from fluorine, chlorine, and bromine.

9. The compound according to claim 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula VI-1 or Formula VI-2. (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S; m is selected from 0, 1, 2, 3, or 4. R b1 , R b2 are each independently hydrogen, halogen, or C 1～3 Alkyl group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～3 Alkyl group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R c The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, aryl, and heteroaryl groups in 1～3 Alkyl group, C 1～3 Alkoxy group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～3 It is selected from alkyl groups. R f is hydrogen, C 1～3 Alkyl or halogen substituted C 1～3 It is selected from alkyl groups. R i is hydrogen, C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 alkynyl group, 3- to 6-membered saturated cycloalkyl group, or 3- to 6-membered saturated heterocyclic group.

10. The compound according to claim 1 or 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula VI-1 or Formula VI-2. (However, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to the same carbon atom are linked together to form a spiro ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i Among these, two groups linked to different carbon atoms are linked together to form a bridged ring or a fused ring, and the remaining groups are each independently hydrogen, C 1～3 alkyl groups, wherein the spiro, bridged or fused ring contains 2, 3 or 4 heteroatoms selected from N, O and S; m is selected from 0, 1, 2, 3, or 4. R b1 , R b2 are each independently hydrogen, halogen, or C 1～3 Alkyl group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, aryl group, heteroaryl group, CN, OR f , S.R. f or NR d1 R d2 or R b1 and R b2 form a 3-6 membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 Alkyl group, C 2～3 Alkenyl group, C 2～3 It is an alkynyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R c The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, aryl, and heteroaryl groups in 1～3 Alkyl group, C 1～3 Alkoxy group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 are each independently hydrogen or C 1～3 It is selected from alkyl groups. R f is hydrogen, C 1～3 Alkyl or halogen substituted C 1～3 It is selected from alkyl groups. R i is hydrogen, C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 alkynyl group, 3- to 6-membered saturated cycloalkyl group, or 3- to 6-membered saturated heterocyclic group.

11. The structural fragment 11. The compound of claim 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that: (m is selected from 1, 2, or 3. R b1 , R b2 are each independently hydrogen, halogen, or C 1～3 Alkyl group, halogen-substituted C 1～3 alkyl group, a 3- to 6-membered saturated cycloalkyl group, a 4- to 6-membered saturated heterocyclic group, or R b1 and R b2 form a 3- or 4-membered ring structure together with the carbon atoms connected thereto, and the ring structure contains 0 or 1 heteroatom selected from N, O, and S. R c is hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 It is an alkyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R c The alkyl, saturated cycloalkyl, saturated heterocyclic, aryl and heteroaryl groups in 1～3 Alkyl group, C 1～3 Alkoxy group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 , R f , R i is as described in claim 10.)

12. The compound according to claim 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, characterized in that the structure of the compound is represented by Formula VII-1 or Formula VII-2. (where m is selected from 1 or 2. R b1 , R b2 are each independently hydrogen, halogen, or C 1～3 Alkyl group, halogen-substituted C 1～3 It is selected from an alkyl group, a 3- to 6-membered saturated cycloalkyl group, and a 4- to 6-membered saturated heterocyclic group. R c is hydrogen, C 1～4 Alkyl group, halogen-substituted C 1～4 It is an alkyl group, a 3- to 6-membered saturated cycloalkyl group, a 3- to 6-membered saturated heterocyclic group, an aryl group, or a heteroaryl group. R b1 , R b2 , R c The alkyl, saturated cycloalkyl, saturated heterocyclic, aryl and heteroaryl groups in 1～3 Alkyl group, C 1～3 Alkoxy group, halogen-substituted C 1～3 Alkyl group, C 2～3 Alkenyl group, C 2～3 Alkynyl group, 3- to 6-membered saturated cycloalkyl group, 3- to 6-membered saturated heterocyclic group, CN, NO 2 , OR f , S.R. f , N.R. d1 R d2 , C.O.R. i , COOR f ,OCOR i ,CONR d1 R d2 , N.R. d1 COR i , N.R. d1 SO 2 R i or SO 2 R i and is substituted with one or more groups selected from: R d1 , R d2 , R f , R i is as described in claim 10.)

13. In Formula VI-1, Formula VI-2, Formula VII-1, or Formula VII-2, m is selected from 1 or 2; R b1 , R b2 are each independently selected from hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group; R c represents a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, and CF 3 , a cyclopropyl group, 13. The compound according to any one of claims 10 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, wherein

14. The structure of the compound is ("*" indicates a chiral center.) 2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, selected from the group consisting of:

15. The pharmaceutically acceptable salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, hydrogensulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfamate, ethanedisulfonate, ethylsulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalenecarboxylate, theaphthalenecarboxylate, tetrahydrofuran ...

15. The compound according to any one of claims 1 to 14, characterized in that it is a vinate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, aldarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate or p-toluenesulfonate salt, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof.

16. A drug characterized in that it is a formulation comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof as an active ingredient, in addition to a pharmaceutically acceptable auxiliary agent.

17. Use of a compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterium-substituted derivative thereof, in the preparation of a drug having sedative, hypnotic and / or anesthetic effects and a drug capable of suppressing status epilepticus.

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