Piperazine substituted phenol derivatives and uses thereof

Abstract

The invention discloses a piperazine substituted phenol derivative and its use, belonging to the field of pharmaceutical chemistry. The structure of the piperazine substituted phenol derivative is shown in Formula I. The compound provided by the invention not only has good salt-forming property and excellent water solubility, can meet the requirements of the preparation, but also has a low minimum effective dose of anesthesia, can take effect quickly and recover quickly, overcomes the shortcomings of the prodrug and fat emulsion preparation of propofol and propofol, and has broad application prospects in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs capable of controlling status epilepticus.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry; in particular, the present invention relates to a class of piperazine-substituted phenol derivatives with novel structures, a synthesis method thereof and an application thereof in preparing drugs with sedative, hypnotic and / or anesthetic effects and in preparing drugs capable of controlling status epilepticus. Background Art

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

[0003]

[0004] However, clinical practice shows that propofol can cause severe adverse reactions such as circulatory depression, respiratory depression, injection pain, agitation, and polyphagia. In order to improve the potency of propofol, researchers developed another structurally similar drug, propofol, based on propofol, which improved the potency but still did not solve the above problems of propofol.

[0005]

[0006] Since propofol and propofol are neither soluble in water nor can they form salts, the dosage forms used clinically are mainly fat emulsion preparations. The fat emulsion preparation is a stable oil-in-water (O / W) emulsion made by dissolving propofol or propofol in vegetable oil (the main component is fatty acid triglycerides), using phospholipids as emulsifiers, adding isotonic agents and water for injection, and can be used for intravenous injection. However, studies in recent years have found that fat emulsion preparations are prone to cause a variety of adverse reactions in clinical practice, including: venous inflammatory reactions, acute renal failure, allergic reactions, anaphylactic shock, arrhythmias, propofol infusion syndrome, etc. In order to overcome the adverse reactions caused by fat emulsion preparations, researchers have developed water-soluble prodrugs. Fospropofol disodium is a water-soluble propofol prodrug. After intravenous injection, it is metabolized by alkaline phosphatase on the surface of endothelial cells in the body to produce active drug propofol, thereby quickly reaching equilibrium in brain tissue and exerting a dose-dependent hypnotic and sedative effect. However, compared with propofol, the onset time of fospropofol disodium is significantly slower, as long as 2.9 minutes, which cannot meet the requirement of rapid onset.

[0007] In order to solve the above problems, it is urgent to develop a new type of sedative, hypnotic and general anesthetic drug that not only has excellent water solubility but also can take effect quickly, so as to overcome or improve the above problems of propofol. Summary of the invention

[0008] The purpose of the present invention is to provide a novel piperazine-substituted phenol derivative of formula I, a synthesis method thereof and its use in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and in the preparation of drugs capable of controlling status epilepticus.

[0009] 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 deuterated derivative thereof:

[0010]

[0011] Wherein R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、CH2COOR h1 , protecting groups, PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a For hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R h1 , R h2 are each independently selected from hydrogen, C 1-4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0012] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, halogen, C 1～4 Alkyl or 3-6 membered cycloalkyl; and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Not methyl at the same time;

[0013] R 7 , R 8 are each independently selected from hydrogen, halogen or C 1-4 alkyl;

[0014] p is an integer selected from 0 to 8, each R 9 are each independently selected from hydrogen, C 1～4 Alkyl, halogenated C 1～4Alkyl; or p is an integer selected from 2 to 8, wherein two R 9 Connect into a ring, the rest R 9 are each independently selected from hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl; or p is an integer selected from 1 to 9, wherein one R 9 Connect with R 10 The nitrogen atom connected forms a quaternary ammonium salt, and the remaining R 9 are each independently selected from hydrogen, C 1～4 Alkyl, halogenated C 1～4 alkyl;

[0015] R 10 Selected from hydrogen, C 1～4 Alkyl, (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 ;

[0016] Among them, R b1 , R b2 , R b3 , Rb4 are each independently selected from hydrogen, halogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0017] R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0018] R e For hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0019] The above R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R ior SO2R i ;

[0020] R d1 , R d2 are each independently selected from hydrogen or C 1～4 alkyl;

[0021] R f Selected from hydrogen, C 1～4 Alkyl or halogenated C 1～4 alkyl;

[0022] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group;

[0023] m is selected from 0, 1, 2, 3, or 4;

[0024] n is selected from 2, 3, or 4;

[0025] t is selected from 1, 2, 3, or 4.

[0026] Furthermore, the structure of the compound is shown in Formula II:

[0027]

[0028] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, halogen, C 1～4 Alkyl or 3-6 membered saturated cycloalkyl;

[0029] p is an integer selected from 0 to 8, each R 9 are each independently selected from hydrogen, C 1～4 Alkyl; or p is an integer selected from 2 to 8, wherein two R 9 Connect into a ring, the rest R 9 are each independently selected from hydrogen, C 1～4 Alkyl; or p is an integer selected from 1 to 9, wherein one R 9 Connect with R 10 The nitrogen atom connected forms a quaternary ammonium salt, and the remaining R 9 are each independently selected from hydrogen, C 1～4 Alkyl, halogenated C 1～4 alkyl;

[0030] R 10 Selected from hydrogen, C 1～4 Alkyl, (CR b1R 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 ;

[0031] Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0032] R cFor hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0033] R e For hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0034] The above R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0035] R d1 , R d2 are each independently selected from hydrogen or C 1～4 alkyl;

[0036] R f Selected from hydrogen, C 1～4 Alkyl or halogenated C 1～4 alkyl;

[0037] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group;

[0038] m is selected from 0, 1, 2, 3, or 4;

[0039] n is selected from 2, 3, or 4;

[0040] t is selected from 1, 2, 3, or 4.

[0041] Furthermore, the structure of the compound is shown in Formula III:

[0042]

[0043] Among them, R 11 , R 12 Each independently selected from methyl,

[0044] R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are independently selected from hydrogen, C 1～4 alkyl;

[0045] R 10 As described above in Formula II.

[0046] Furthermore, the structure of the compound is shown in Formula IV-1 or Formula IV-2:

[0047]

[0048] Among them, R 9a , R9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; the spiro ring, bridged ring or condensed ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0049] R 10 Selected from hydrogen, C 1～4 Alkyl, (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 , (CRb1 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 ;

[0050] Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0051] R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0052] R e For hydrogen, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl or heteroaryl;

[0053] The above R b1 , R b2 , R b3 , R b4 , R c , R eThe alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic, cycloalkyl, heterocyclic, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～3 Alkyl, C 1～3 Alkoxy, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0054] R d1 , R d2 are each independently selected from hydrogen or C 1～3 alkyl;

[0055] R f Selected from hydrogen, C 1～3 Alkyl or halogenated C 1～3 alkyl;

[0056] R i Selected from hydrogen, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl or 3- to 6-membered saturated heterocyclic group;

[0057] m is selected from 0, 1, 2, 3, or 4;

[0058] n is selected from 2, 3, or 4;

[0059] t is selected from 1, 2, 3, or 4.

[0060] Furthermore, the structure of the compound is shown in Formula IV-1 or Formula IV-2:

[0061]

[0062] Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R9f , R 9h , R 9i are each independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; the spiro ring, bridged ring or condensed ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0063] R 10 Selected from hydrogen, C 1～4 Alkyl, (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 Rb4 ) t COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 ;

[0064] Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0065] R c For hydrogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl or heteroaryl;

[0066] R e For hydrogen, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl or heteroaryl;

[0067] The above R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～3 Alkyl, C 1～3 Alkoxy, halogenated C 1～3 Alkyl, C2～3 Alkenyl, C 2～3 Alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0068] R d1 , R d2 are each independently selected from hydrogen or C 1～3 alkyl;

[0069] R f Selected from hydrogen, C 1～3 Alkyl or halogenated C 1～3 alkyl;

[0070] R i Selected from hydrogen, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl or 3- to 6-membered saturated heterocyclic group;

[0071] m is selected from 0, 1, 2, 3, or 4;

[0072] n is selected from 2, 3, or 4;

[0073] t is selected from 1, 2, 3, or 4.

[0074] Furthermore, the structural fragment One of the following structures:

[0075]

[0076] Furthermore, the structure of the compound is shown in Formula V-1 or Formula V-2:

[0077]

[0078] Among them, R 10 Selected from hydrogen, C 1～4 Alkyl, (CR b1 R b2 ) m COORc , (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 ;

[0079] Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～2 Alkyl, halogenated C 1～2 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, phenyl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0080] R c For hydrogen, C 1～2 Alkyl, halogenated C1～2 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, phenyl or heteroaryl;

[0081] R e For hydrogen, C 1～2 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, phenyl or heteroaryl;

[0082] The above R b1 , R b2 , R b3 , R b4 , R c , R e The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, phenyl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～2 Alkyl, C 1～2 Alkoxy, halogenated C 1～2 Alkyl, vinyl, ethynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0083] R d1 , R d2 are each independently selected from hydrogen or C 1～2 alkyl;

[0084] R f Selected from hydrogen, C 1～2 Alkyl or halogenated C 1～2 alkyl;

[0085] R i Selected from hydrogen, C 1～2 Alkyl, vinyl, ethynyl, 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclic group;

[0086] m is selected from 0, 1, 2, 3, or 4;

[0087] n is selected from 2, 3, or 4;

[0088] t is selected from 1, 2, 3, or 4.

[0089] Furthermore, the 3-6 membered saturated cycloalkyl group is selected from The 3- to 6-membered saturated heterocyclic group is selected from The 3-6 membered ring structure is selected from cyclopropane, cyclobutane, cyclopentane and cyclohexane; and the halogen is selected from fluorine, chlorine and bromine.

[0090] Furthermore, the structure of the compound is shown in Formula VI-1 or Formula VI-2:

[0091]

[0092] Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; the spiro ring, bridged ring or condensed ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0093] m is selected from 0, 1, 2, 3, or 4;

[0094] R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, C2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0095] R c For hydrogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl or heteroaryl;

[0096] The above R b1 , R b2 , R c The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～3 Alkyl, C 1～3 Alkoxy, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0097] R d1 , R d2 are each independently selected from hydrogen or C 1～3 alkyl;

[0098] R f Selected from hydrogen, C 1～3 Alkyl or halogenated C 1～3 alkyl;

[0099] Ri Selected from hydrogen, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl or 3- to 6-membered saturated heterocyclic group.

[0100] Furthermore, the structure of the compound is shown in Formula VI-1 or Formula VI-2:

[0101]

[0102] Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are independently selected from hydrogen, C 1～3 Alkyl; the spiro ring, bridged ring or condensed ring contains 2, 3 or 4 heteroatoms selected from N, O and S;

[0103] m is selected from 0, 1, 2, 3, or 4;

[0104] R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 Rd2 ; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0105] R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, aryl or heteroaryl;

[0106] The above R b1 , R b2 , R c The alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～3 Alkyl, C 1～3 Alkoxy, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0107] R d1 , R d2 are each independently selected from hydrogen or C 1～3 alkyl;

[0108] R f Selected from hydrogen, C 1～3 Alkyl or halogenated C 1～3 alkyl;

[0109] R i Selected from hydrogen, C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3- to 6-membered saturated cycloalkyl or 3- to 6-membered saturated heterocyclic group.

[0110] Furthermore, the structural fragment One of the following structures:

[0111]

[0112] m is selected from 1, 2, or 3;

[0113] R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-6 membered saturated cycloalkyl, 4-6 membered saturated heterocyclic group; or R b1 and R b2 Together with the carbon atom to which it is attached, it forms a 3-4-membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S;

[0114] R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;

[0115] The above R b1 , R b2 , R c The alkyl, saturated cycloalkyl, saturated heterocyclic group, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～3 Alkyl, C 1～3 Alkoxy, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0116] R d1 , R d2 , R f , R i As described in the above formula VI-1 or formula VI-2.

[0117] Furthermore, the structure of the compound is shown in Formula VII-1 or Formula VII-2:

[0118]

[0119] wherein m is selected from 1 or 2;

[0120] R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3- to 6-membered saturated cycloalkyl, 4- to 6-membered saturated heterocyclic group;

[0121] R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;

[0122] The above R b1 , R b2 , R c The alkyl, saturated cycloalkyl, saturated heterocyclic group, aryl, heteroaryl in the group is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～3 Alkyl, C 1～3 Alkoxy, halogenated C 1～3 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ;

[0123] R d1 , R d2 , R f , R i As described in the above formula VI-1 or formula VI-2.

[0124] Further, in Formula VI-1, Formula VI-2, VII-1, or Formula VII-2:

[0125] m is selected from 1 or 2;

[0126] R b1 , R b2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropane;

[0127] R c Methyl, ethyl, n-propyl, isopropyl, tert-butyl, CF3, cyclopropane,

[0128] Furthermore, the structure of the compound is selected from:

[0129]

[0130]

[0131]

[0132]

[0133] “*” indicates a chiral center.

[0134] Further, the pharmaceutically acceptable salt is acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate or p-toluenesulfonate.

[0135] The present invention also provides a drug, which is a preparation prepared with the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative as an active ingredient and pharmaceutically acceptable excipients.

[0136] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug with sedative, hypnotic and / or anesthetic effects and / or a drug capable of controlling status epilepticus.

[0137] The "drug with sedative effect" mentioned in the present invention refers to a drug that effectively helps sleep and effectively improves sleep, that is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0138] The "drug with hypnotic effect" mentioned in the present invention refers to a drug that can induce drowsiness and promote sleep, that is, it has an inhibitory effect on the central nervous system, causes sedation in a small dose, and causes general anesthesia in an overdose.

[0139] The "drug with anesthetic effect" mentioned in the present invention refers to a reversible functional inhibition of the central nervous system and (or) peripheral nervous system produced by the drug, and the main characteristic of this inhibition is the loss of sensation, especially pain sensation.

[0140] Preferably, the anesthesia is general anesthesia.

[0141] The "general anesthesia" mentioned in the present invention is referred to as general anesthesia, which refers to the temporary inhibition of the central nervous system after the anesthetic enters the body. The clinical manifestations are loss of consciousness, loss of general pain, amnesia, reflex inhibition and skeletal muscle relaxation.

[0142] The "status epilepticus" described in the present invention refers to the frequent recurrence of epileptic seizures without complete recovery of consciousness between consecutive seizures, or seizures that last for more than 30 minutes without stopping on their own. If prolonged epileptic seizures are not treated in time, they may cause irreversible brain damage due to high fever, circulatory failure or neuronal excitotoxic damage, with high disability and mortality rates, so epileptic status is a common emergency in internal medicine.

[0143] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0144] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1～6 The alkyl group refers to a straight chain or branched chain alkyl group containing 1 to 6 carbon atoms.

[0145] In the compound represented by formula I of the present invention, "p" is selected from an integer of 2 to 8, wherein two R 9 The ring described in "connected to form a ring" includes a spiro ring, a bridged ring, and a condensed ring.

[0146] The term "substituted" herein refers to the replacement of one, two or more hydrogen atoms in a molecule by other different atoms or molecules, including one, two or more substitutions on the isotopic or ectopic atoms in the molecule.

[0147] "Alkylene" refers to the group remaining after the corresponding alkyl group loses a hydrogen atom. 1～4 Alkyl refers to a straight or branched chain alkylene group containing 1 to 4 carbon atoms; C2 alkylene refers to

[0148] Indicates the connection site between structural fragments.

[0149] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or a polycyclic ring. For example, "3-6 membered saturated cycloalkyl" refers to a saturated cycloalkyl having 3-6 ring carbon atoms.

[0150] "Heterocyclic group" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carry at least one ring heteroatom (including but not limited to O, S or N). For example, "3-6 membered saturated heterocyclic group" refers to a saturated heterocyclic group with 3-6 ring carbon atoms.

[0151] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups may be substituted or unsubstituted.

[0152] "Heteroaryl" refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0153] "Bridged ring" refers to a polycyclic cycloalkyl group in which two rings share two non-adjacent carbon atoms.

[0154] "Spirocycle" refers to a polycyclic cycloalkyl group in which two rings share a common carbon atom.

[0155] "Fused ring" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.

[0156] In the formula III, formula IV-1, formula IV-2, formula IV-1, formula IV-2, formula VI-1 or formula VI-2 of the present invention, “R 9a , R 9b , R9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to the same carbon atom are connected together to form a spiro ring. 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the case of two groups attached to the same carbon atom, As a whole, it forms a spiral ring; "R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula, two groups connected to different carbon atoms are connected together to form a bridged ring or a fused ring. 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the case of two groups attached to the same carbon atom, As a whole, a bridged ring or a condensed ring is formed.

[0157] "Halogen" is fluorine, chlorine, bromine or iodine.

[0158] The term "deuterated derivative" refers to a compound in which one or more hydrogen atoms are replaced by deuterium.

[0159] "Pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0160] "Salt" refers to acidic and / or basic salts formed by a compound or its stereoisomers with inorganic and / or organic acids and / or bases, including zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. They can also be obtained by mixing the compound, or its stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0161] The pharmaceutically acceptable salt of the present invention can be acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate or quaternary ammonium salt.

[0162] The compounds or compositions of the present invention and methods of use thereof:

[0163] The compounds of the present invention and their various crystal 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 implement sedation, hypnosis and / or general anesthesia. The compounds of the present invention can also be used to control status epilepticus, etc.

[0164] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0165] The administration of the compound or pharmaceutical composition of the present invention includes (but is not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.

[0166] Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0167] 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 the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0168] 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 conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0169] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0170] Dosage forms for topical administration of the compounds of the invention 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 that may be required.

[0171] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0172] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0173] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0174] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically safe and effective dosage.

[0175] Compared with the prior art, the compounds provided by the present invention have achieved the following beneficial effects:

[0176] 1. It is well known to those skilled in the art that propofol and picopropofol cannot form salts and are insoluble in water, which limits their clinical application. However, the compounds of the present invention can form salts, and each salt form has excellent water solubility and can meet the requirements of the preparation.

[0177] 2. As is well known to those skilled in the art, since propofol and propofol are insoluble in water, the dosage form used clinically is mainly fat emulsion preparations, which are prone to cause a variety of adverse reactions in clinical practice. However, the salt form of the compound of the present invention has excellent solubility and the solubility meets the requirements of the preparation, which can effectively overcome the adverse reactions caused by fat emulsions and improve safety.

[0178] 3. As is well known to those skilled in the art, the prodrugs of propofol and clonidine have certain water solubility, but their effect time is slow and cannot meet the requirements of rapid onset and rapid recovery. However, the compound of the present invention is not a prodrug, but an active ingredient, which has a short onset time and can quickly produce a general anesthetic effect.

[0179] In summary, the compound provided by the present invention not only has good salt-forming property, excellent water solubility and solubility that meets the preparation requirements, but also has a low minimum effective anesthetic dose, can take effect quickly and recover quickly, overcomes the shortcomings of propofol and its prodrug and fat emulsion preparations, has broad application prospects in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs that can control status epilepticus, and provides a new choice for the clinical preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs that can control status epilepticus.

[0180] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0181] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0182] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0183] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 nuclear magnetic spectrometer, the measurement solvent was deuterated dimethyl sulfoxide (d6-DMSO) or deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0184] LCMS determination was performed using (Agilent LCMS 1260-6110) (ESI), column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm). 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] within 3 minutes, maintained under this condition for 1 minute, then gradient to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] within 0.05 minutes, and then maintained under this condition for 0.7 minutes.

[0185] 1) Medicinal materials and reagents

[0186] The thin layer chromatography silica gel plate used was HSGF254 silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm.

[0187] Thin layer chromatography (TLC) used products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2±0.03 mm.

[0188] Column chromatography generally uses 100-200 mesh or 200-300 mesh silica gel produced by Rushan Sun Desiccant Co., Ltd. (Weihai, Shandong) as a carrier.

[0189] 2) Main instruments

[0190] Sartorius BSA124S electronic balance (Sartorius Scientific Instruments Beijing Co., Ltd.);

[0191] 98-2 magnetic stirrer (Shanghai Silu Instrument Co., Ltd.);

[0192] MS-H-PRO + CNC heating magnetic stirrer (Dalong Xingchuang Experimental Instrument Beijing Co., Ltd.);

[0193] TDGC2-1 contact voltage regulator (Zhejiang Tianzheng Electric Co., Ltd.);

[0194] WMNK-01 temperature controller (Shanghai Lulin Electric Co., Ltd.);

[0195] ZF-I three-purpose UV instrument (Shanghai Anting Electronic Instrument Factory);

[0196] R-201 rotary evaporator (Shanghai Shenshun Biotechnology Co., Ltd.);

[0197] W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.);

[0198] SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0199] SHB-B95 mobile water pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0200] DLSB-5 / 20℃ low temperature cooling circulation pump (Gongyi Yuhua Instrument Co., Ltd.);

[0201] 2XZ-2 rotary vane vacuum pump (Linhai Yonghao Vacuum Equipment Co., Ltd.);

[0202] VRD-16 bipolar rotary vane vacuum pump (Zhejiang Feiyue Electromechanical Co., Ltd.);

[0203] DGJ-10C vacuum freeze dryer (Shanghai Boden Biotechnology Co., Ltd.);

[0204] Biotage Isolera One fast preparative liquid chromatography (Biotage Sweden AB).

[0205] Example 1 Preparation of Compound A1 and Hydrochloride of the Present Invention

[0206]

[0207] 1. Preparation of Compound A1-1

[0208] At 0°C, 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) and stirred at 0°C for 30 minutes. After the reaction was complete as monitored by TLC, H2O (100 mL) was added to the reaction system, extracted with EtOAc (3×70 mL), the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 1 / 200 to 1 / 50), monitored by TLC (dichloromethane / petroleum ether (v / v) = 1 / 20), and the Rf = 0.4 to 0.5 portion was collected to obtain a yellow oily compound A1-1 (4.21 g, yield 39.4%). ESI[M+H] + =283.1.

[0209] 2. Preparation of Compound A1-2

[0210] At 0°C, NaH (196 mg, 60%, 4.90 mmol) was added in batches to a solution of A1-1 (1.26 g, 4.45 mmol) in dry tetrahydrofuran (12 mL). After stirring for 30 minutes, TIPSCl (891 mg, 4.62 mmol) was added. The reaction system was warmed to room temperature and stirred for 3 hours. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with EtOAc (3×30 mL), the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (n-heptane as mobile phase), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 50), and Rf = 0.5-0.6 was collected to obtain a white solid compound A1-2 (1.93 g, yield 98.7%). ESI [M+H] + =439.3.

[0211] 3. Preparation of Compound A1-3

[0212] At room temperature, 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 dissolved in 1,4-dioxane (15 mL) solution, and the reaction system was replaced with nitrogen three times, and the mixture was protected by nitrogen and stirred at 50°C for 4 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product, which 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 Rf = 0.3 to 0.4 portion was collected to obtain a white solid compound A1-3 (1.48 g, yield 99.5%). ESI [M+H] + =545.3.

[0213] 4. Preparation of Compound A1-4

[0214] At 0°C, TFA (2 mL) was added to a solution of A1-3 (1.48 g, 2.72 mmol) in dichloromethane (10 mL), and stirred at 0°C for 4 hours. After the reaction was completed as monitored by TLC, it was concentrated under reduced pressure, alkalized with saturated sodium bicarbonate aqueous solution (20 mL), extracted with EtOAc (3×30 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100 / 1 to 20 / 1), monitored by TLC (dichloromethane / methanol (v / v) = 10 / 1), and Rf = 0.4 to 0.5 was collected to obtain a white solid compound A1-4 (1.20 g, yield 99.2%). ESI [M+H] + =445.3.

[0215] 5. Preparation of Compound A1-5

[0216] At 0°C, DIEA (349 mg, 2.70 mmol) and methyl bromoacetate (303 mg, 1.98 mmol) were added to a solution of A1-4 (800 mg, 1.80 mmol) in acetonitrile (8 mL) in sequence and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 5), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2), and the Rf = 0.5 to 0.6 portion was collected to obtain a white solid compound A1-5 (692 mg, yield 74.4%). ESI[M+H]+ =517.4.

[0217] 6. Preparation of Compound A1

[0218] At 0°C, TBAF (1.34 mL, 1 mol / L in THF, 1.34 mmol) was added to a tetrahydrofuran (7 mL) solution of A1-5 (692 mg, 1.34 mmol) and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100-1 / 2), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2), and the Rf = 0.3-0.4 portion was collected to obtain a white solid compound A1 (200 mg, yield 41.4%). ESI [M+H] + =361.3.

[0219] 7. Preparation of Compound A1 Hydrochloride

[0220] At -20°C, slowly add HCl / Et2O (0.155mL, 2mol / L in THF, 0.31mmol) solution to a solution of A1 (112mg, 0.31mmol) in ether (5mL), stir at -20°C for 5 minutes, and concentrate under reduced pressure at low temperature to obtain a crude product. The crude product was washed with ether to obtain a white solid compound A1 hydrochloride (71.7mg, yield 58.3%). ESI[M+H] + =361.3. 1 H NMR(400MHz,CD3OD)δ7.01(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=6.9Hz,3H),1.21(d,J=6.9Hz,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).

[0221] Example 2 Preparation of Compound A2 and Hydrochloride, A5 and Hydrochloride, A6 and Hydrochloride of the Present Invention

[0222] The preparation method of compound A2, A5, A6 is similar to that of compound A1, using A1-4 as the starting material, and then replacing with a bromine compound and deprotecting to obtain compound A2, A5, A6. The preparation method of the corresponding hydrochloride of compound A2, A5, A6 is also similar to that of the hydrochloride of compound A1. The preparation route is as follows:

[0223]

[0224] 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=6.9Hz,3H),1.14(d,J=6.8Hz,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).

[0225] Compound A5 hydrochloride: white solid, 132.9 mg, ESI [M+H] + =375.3. 1 H NMR (400MHz, CD3OD) δ7.16(d,J=2.9Hz,1H),7.03(d,J=2.8Hz,1H),4.32(q,J=7. 1Hz,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=7.1Hz,3H),1.27(d,J=6.9Hz,3H),1.22(d,J=6.9Hz,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).

[0226] Compound A6 hydrochloride: white solid, 114.7 mg, ESI [M+H] + =375.3. 1H NMR (400MHz, CD3OD) δ7.30(d,J=2.9Hz,1H),7.16(d,J=2.9Hz,1H),4.28(q,J=7.2Hz, 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=7.2Hz,3H),1.28(d,J=6.9Hz,3H),1.23(d,J=6.9Hz,6H),1.14–1.0 3(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).

[0227] Example 3 Preparation of Compound A3 and Hydrochloride of the Invention

[0228]

[0229] 1. Preparation of Compound A3-1

[0230] At 0°C, Et3N (205 mg, 2.0 mmol) and methyl 3-chloro-3-oxopropanoate (184 mg, 1.35 mmol) were added to a dichloromethane (5 mL) solution of A1-4 (300 mg, 0.67 mmol) in sequence and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with dichloromethane (3×15 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) and the Rf = 0.5-0.6 portion was collected to obtain a white solid compound A3-1 (350 mg, yield 95.2%). ESI[M+H] + =545.3.

[0231] 2. Preparation of Compound A3

[0232] At 0°C, TBAF (0.64 mL, 1 mol / L in THF, 0.64 mmol) was added to a tetrahydrofuran (5 mL) solution of A3-1 (350 mg, 0.64 mmol) and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) and the Rf = 0.3-0.4 portion was collected to obtain a white solid compound A3 (224.5 mg, yield 89.9%). ESI [M+H] + =389.2.

[0233] 3. Preparation of Compound A3 Hydrochloride

[0234] At -20°C, slowly add HCl / Et2O (0.29 mL, 2 mol / L in THF, 0.58 mmol) solution to a solution of A3 (224.5 mg, 0.58 mmol) in ether (5 mL), stir at -20°C for 5 minutes, and concentrate under reduced pressure at low temperature to obtain a crude product. The crude product was washed with ether to obtain a white solid compound A3 hydrochloride (224.6 mg, yield 91.5%). ESI [M+H] + =389.2. 1 H NMR (400MHz, d6-DMSO) δ7.44(s,1H),6.70(d,J=2.8Hz,1H),6.59(d,J=2.8Hz,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=7.0,3.2Hz,3H),1.13(d,J=6.8Hz,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).

[0235] Example 4 Preparation of Compound A4 and Hydrochloride of the Present Invention

[0236]

[0237] The preparation method of compound A4 and its hydrochloride is similar to that of compound A1, and they are prepared using propofol as the starting material.

[0238] Compound A4 hydrochloride: white solid, 135.9 mg, ESI [M+H] + =335.3. 1 H NMR (400MHz, CD3OD) δ6.98 (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 = 6.9Hz, 12H).

[0239] Example 5 Preparation of Compound A7 and Hydrochloride of the Invention

[0240]

[0241] 1. Preparation of Compound A7-1

[0242] At room temperature, 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) in sequence, and stirred at 80°C for 12 hours. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (dichloromethane / methanol (v / v) = 10 / 1) and the Rf = 0.5-0.6 portion was collected to obtain a white solid compound A7-1 (115 mg, yield 52.3%). ESI[M+H] + =489.3.

[0243] 2. Preparation of Compound A7

[0244] At 0°C, TBAF (0.24 mL, 1 mol / L in THF, 0.24 mmol) was added to a tetrahydrofuran (3 mL) solution of A7-1 (115 mg, 0.24 mmol) and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (dichloromethane / methanol (v / v) = 10 / 1) and the Rf = 0.4-0.5 portion was collected to obtain a white solid compound A7 (70.6 mg, yield 90.3%). ESI [M+H] + =333.4.

[0245] 3. Preparation of Compound A7 Hydrochloride

[0246] At -70°C, slowly add HCl / Et2O (0.16mL, 2mol / L in THF, 0.32mmol) solution to a solution of A7 (70.6mg, 0.21mmol) in ether (3mL), stir at -70°C for 5 minutes, and concentrate under reduced pressure at low temperature to obtain a crude product. The crude product was washed with ether to obtain a white solid compound A7 hydrochloride (76.4mg, yield 92.9%). ESI[M+H] + =333.4. 1 H NMR (400MHz, CD3OD) δ7.19(d,J=2.9Hz,1H),7.06(d,J=2.9Hz,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=6.9Hz,3H),1.23(d,J=6.9Hz,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).

[0247] Example 6 Preparation of Compound A8 and Hydrochloride of the Invention

[0248]

[0249] 1. Preparation of Compound A8-1

[0250] At 0°C, LiOH.H2O (146 mg, 3.48 mmol) was added to a solution of A1-5 (900 mg, 1.74 mmol) in THF / MeOH / H2O (9 mL, v / v / v = 1 / 1 / 1) and stirred at room temperature for 1 hour. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product, which 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 Rf = 0.4 to 0.5 portion was collected to obtain a white solid compound A8-1 (730 mg, yield 82.4%). ESI [M+H] + =503.3.

[0251] 2. Preparation of Compound A8-2

[0252] At room temperature, oxalyl chloride (175 mg, 1.38 mmol) was added to A8-1 (233 mg, 0.46 mmol) in dichloromethane (5 mL), and stirred at room temperature for 1 hour. After monitoring the completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product A8-2 (260 mg), which was used directly in the next step without purification.

[0253] 3. Preparation of Compound A8-3

[0254] At 0°C, Et3N (93 mg, 0.92 mmol) and oxetane-3-ol (40.9 mg, 0.55 mmol) were added to a solution of crude product A8-2 (260 mg) in dichloromethane (3 mL) and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with dichloromethane (3×15 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) and the Rf = 0.3-0.4 portion was collected to obtain a white solid compound A8-3 (76.5 mg, two-step yield 29.9%). ESI[M+H] + =559.3.

[0255] 4. Preparation of Compound A8

[0256] At 0°C, TBAF (0.14 mL, 1 mol / L in THF, 0.14 mmol) was added to a tetrahydrofuran (2 mL) solution of A8-3 (76.5 mg, 0.14 mmol) and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (5 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the Rf = 0.3-0.4 portion was collected to obtain a white solid compound A8 (54 mg, yield 98.0%). ESI [M+H] + =403.3.

[0257] 5. Preparation of Compound A8 Hydrochloride

[0258] At -20°C, slowly add HCl / Et2O (0.10mL, 2mol / L in THF, 0.20mmol) solution to a solution of A8 (54mg, 0.13mmol) in ether (3mL), stir at -20°C for 5 minutes, and concentrate under reduced pressure at low temperature to obtain a crude product. The crude product was washed with ether to obtain a white solid compound A8 hydrochloride (34.5mg, yield 56.3%). ESI[M+H] +=403.3. 1 HNMR(400MHz,CD3OD)δ7.15(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=6.9Hz,3H),1.22(d,J=6.8Hz,6H),1.11–1.0 0(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).

[0259] Example 7 Preparation of Compound A6R and Sulfate of the Present Invention

[0260]

[0261] 1. Preparation of compound A6R-1

[0262] At room temperature, Et3N (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 in sequence to a solution of A1-4 (1.5 g, 3.37 mmol, 1 eq) in dry DMF (20 mL), and stirred at 60 °C for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the system was cooled to room temperature, H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf=0.6 portion was collected to obtain a colorless oily compound A6R-1 (1.685 g, yield 94.2%). ESI[M+H] + =531.4.

[0263] 2. Preparation of compound A6R

[0264] In an ice bath at 0°C, TBAF (4.9 mL, 1 mol / L in THF, 4.9 mmol, 1.5 eq) was added to a dry THF (20 mL) solution of A6R-1 (1.685 g, 3.17 mmol, 1 eq) and stirred at 0°C for 2 minutes. After the reaction was complete as monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-12%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A6R-2 (1085.8 mg, yield 91.5%). ESI [M+H] + =375.2.

[0265] 3. Preparation of Compound A6R Sulfate

[0266] At room temperature, A6R (1085.8 mg, 2.90 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 ether (30 mL), stirred at -70 °C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (30 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×20 mL). The solid was dissolved in ultrapure water (30 mL) and freeze-dried in a freeze dryer for 64 hours to obtain a white solid compound A6R sulfate (1526.42 mg, yield 100%). ESI [M+H] + =375.2.

[0267] 1H NMR (400MHz, CD3OD) δ7.27(d,J=2.9Hz,1H),7.14(d,J=2.9Hz,1H),4.25(q,J=7.2Hz, 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=7.2Hz,3H),1.28(d,J=6.9Hz,3H),1.23(d,J=6.9Hz,6H),1.11–1.0 3(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).

[0268] Example 8 Preparation of Compound A6S and Sulfate of the Present Invention

[0269]

[0270] 1. Preparation of compound A6S-1

[0271] At room temperature, Et3N (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) and stirred at 60 °C for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the system was cooled to room temperature, H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf=0.6 portion was collected to obtain a colorless oily compound A6S-1 (2.833 g, yield 88.9%). ESI[M+H] + =531.4.

[0272] 2. Preparation of Compound A6S

[0273] 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 stirred at 0°C for 2 minutes. After the reaction was complete as monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5, Rf = 0.5), H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-12%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A6S (1.337 g, yield 100%). ESI[M+H] + =375.2.

[0274] 3. Preparation of Compound A6S Sulfate

[0275] At room temperature, A6S (1.337 g, 3.57 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (30 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×20 mL). The solid was dissolved in ultrapure water (30 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A6S sulfate (1856.5 mg, yield 100%). ESI [M+H] + =375.2.

[0276] 1H NMR (400MHz, CD3OD) δ7.27(d,J=2.9Hz,1H),7.14(d,J=2.9Hz,1H),4.25(q,J=7.2Hz, 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=7.2Hz,3H),1.28(d,J=6.9Hz,3H),1.23(d,J=6.9Hz,6H),1.12–1.0 4(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).

[0277] Example 9 Preparation of Compounds A11 and Sulfate and A18 and Sulfate of the Present Invention

[0278]

[0279] 1. Preparation of Compound A11-1

[0280] At room temperature, 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) solution, and the reaction system was replaced three times with nitrogen, protected by nitrogen, and stirred at 70 °C overnight. After the reaction was completed as monitored by TLC (n-heptane), the crude product was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily crude compound A11-1 (5.7 g). ESI [M+H] + =571.4.

[0281] 2. Preparation of Compound A11-2

[0282] TFA (5 mL) was added to a solution of crude compound A11-1 (5.7 g, 9.98 mmol) in dichloromethane (15 mL) in an ice-salt bath at 0°C and stirred at 0°C for 4 hours. After the reaction was completed as monitored by TLC, it was concentrated under reduced pressure, alkalized with saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1, then methanol / dichloromethane (v / v) = 0-1 / 1), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), and the Rf = 0.5 portion was collected to obtain a colorless oil compound A11-2 (3.617 g, two-step yield 56.3%). ESI [M+H] + =471.4.

[0283] 3. Preparation of Compound A11-3

[0284] In an ice-water bath at 0°C, DIEA (517.0 mg, 4.0 mmol) and methyl bromoacetate (458.9 mg, 3.0 mmol) were added to a dichloromethane (20 mL) solution of A11-2 (941.6 mg, 2.0 mmol) in sequence and stirred at room temperature overnight. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oil compound A11-3 (920 mg, yield 77.0%). ESI [M+H] + =543.4.

[0285] 4. Preparation of Compound A11

[0286] In an ice-salt bath at 0°C, TBAF (2.0 mL, 1 mol / L in THF, 2.0 mmol) was added to a dry THF (10 mL) solution of A11-3 (920 mg, 1.69 mmol) and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily crude compound A11 (660.2 mg, yield 100%). ESI [M+H] + =387.2.

[0287] 5. Preparation of Compound A11 Sulfate

[0288] At room temperature, A11 (537 mg, 1.39 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (20 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×20 mL). The solid was dissolved in ultrapure water (30 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A11 sulfate (644.4 mg, yield 100%). ESI [M+H] + =387.2.

[0289] 1 H NMR (400MHz, CD3OD) δ7.44(d,J=2.9Hz,1H),7.31(d,J=3.0Hz,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=6.9Hz,3H),1.25(d,J=6.9Hz,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).

[0290] 6. Preparation of Compound A18 Sulfate

[0291] The preparation method of compound A18 is similar to that of A11. A11-2 (300 mg, 0.64 mmol) and tert-butyl bromoacetate are used to react to obtain A18-1 (346 mg, 0.59 mmol, yield 92.4%). A18-1 is deprotected by TBAF to obtain compound A18 (241.2 mg, 0.56 mmol, yield 94.9%). Compound A18 is salified by H2SO4 / Et2O to obtain white solid compound A18 sulfate (197.4 mg, yield 94.9%). ESI[M+H] + =429.3.

[0292] 1 H NMR (400MHz, CD3OD) δ7.44(t,J=2.7Hz,1H),7.30(t,J=2.6Hz,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= 6.9Hz,3H),1.25(d,J=6.8Hz,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).

[0293] Example 10 Preparation of Compound A12 and Sulfate of the Present Invention

[0294]

[0295] 1. Preparation of Compound A12-1

[0296] At room temperature, 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) solution, and the reaction system was replaced three times with nitrogen, protected by nitrogen, and stirred at 50 ° C for 24 hours. After the reaction was completed as monitored by TLC (n-heptane), the crude product was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oily crude compound A12-1 (2.328 g). ESI [M + H] + =571.4.

[0297] 2. Preparation of Compound A12-2

[0298] TFA (3 mL) was added to a solution of crude compound A12-1 (2.328 g) in dichloromethane (9 mL) in an ice-salt bath at 0°C, and stirred at 0°C for 4 hours. After the reaction was completed as monitored by TLC, it was concentrated under reduced pressure, alkalized with saturated sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1, then methanol / dichloromethane (v / v) = 0-50%), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A12-2 (1.8 g, two-step yield 84.0%). ESI [M+H] + =471.4.

[0299] 3. Preparation of Compound A12-3

[0300] In an ice-water bath at 0°C, DIEA (544.0 mg, 4.2 mmol) and methyl bromoacetate (489.5 mg, 3.2 mmol) were added to a dichloromethane (15 mL) solution of A12-2 (1.0 g, 2.1 mmol) in sequence and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), H2O (20 mL) was added to the reaction system, extracted with dichloromethane (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oily crude compound A12-3 (1.377 g). ESI [M+H] + =543.4.

[0301] 4. Preparation of Compound A12

[0302] In an ice-salt bath at 0°C, TBAF (3.1 mL, 1 mol / L in THF, 3.1 mmol) was added to a dry THF (15 mL) solution of A12-3 (1.377 g, 2.54 mmol) and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily crude compound A12 (840 mg, two-step yield 100%). ESI [M+H] + =387.3.

[0303] 5. Preparation of Compound A12 Sulfate

[0304] At room temperature, A12 (773.3 mg, 2.0 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (20 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×20 mL). The solid was dissolved in ultrapure water (30 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A12 sulfate (1060.6 mg, yield 100%). ESI [M+H] + =387.3.

[0305] 1 H NMR (400MHz, CD3OD) δ7.13(d,J=2.5Hz,1H),7.00(d,J=2.6Hz,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=6.9Hz,3H),1.23(d,J=6.9Hz,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).

[0306] Example 11 Preparation of Compound A13 and its hydrochloride and Compound A14 and its hydrochloride

[0307]

[0308] 1. Preparation of Compound A13-1

[0309] In an ice-water bath at 0°C, DIEA (1.293 g, 10.0 mmol) and tert-butyl bromoacetate (975.25 mg, 5.0 mmol) were added to a dichloromethane (20 mL) solution of A1-4 (444.78 mg, 1.0 mmol) in sequence and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), H2O (20 mL) was added to the reaction system, extracted with dichloromethane (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oil compound A13-1 (512 mg, yield 91.6%). ESI[M+H] + =559.4.

[0310] 2. Preparation of Compound A13

[0311] In an ice-salt bath at 0°C, TBAF (1.1 mL, 1 mol / L in THF, 1.1 mmol) was added to a dry THF (10 mL) solution of A13-1 (512 mg, 0.92 mmol) and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A13 (360.0 mg, yield 97.2%). ESI [M+H] + =403.3.

[0312] 3. Preparation of Compound A13 Hydrochloride

[0313] At room temperature, A13 (360.0 mg, 0.89 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -60 ° C with a dry ice ethanol bath. HCl / Et2O (0.67 mL, 2 mol / L in Et2O, 1.34 mmol) solution was slowly added to the reaction system, stirred at -60 ° C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (20 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×20 mL). The solid was dissolved in ultrapure water (30 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A13 hydrochloride (395 mg, yield 100%). ESI [M+H] + =403.3.

[0314] 1 H NMR (400MHz, CD3OD) δ7.19(d,J=2.8Hz,1H),7.06(d,J=2.8Hz,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=6.9Hz,3H),1.22(d,J=6.9Hz,6H),1.11–1.01(m,1H),0.6 2–0.54(m,1H),0.43–0.34(m,1H),0.25–0.18(m,1H),0.12–0.05(m,1H).

[0315] 4. Preparation of Compound A14-1

[0316] The preparation method of A13-1 is the same as the first step of this example, wherein A1-4 (444.78 g, 1.0 mmol) and tert-butyl bromoacetate are reacted and then desilylated with TBAF to obtain the product.

[0317] Since the tert-butyl bromoacetate was not completely removed during the purification of A13-1, the residual tert-butyl bromoacetate after TBAF desilylation continued to react with the phenolic hydroxyl group to obtain A14 (263.2 mg, two-step yield 50.9%)

[0318] 5. Preparation of Compound A14 Hydrochloride

[0319] At room temperature, A14 (263.2 mg, 0.51 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -60 °C with a dry ice ethanol bath. HCl / Et2O (0.38 mL, 2 mol / L in Et2O, 0.76 mmol) solution was slowly added to the reaction system, stirred at -60 °C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (20 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×20 mL). The solid was dissolved in ultrapure water (30 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A14 hydrochloride (241.9 mg, yield 100%). ESI[M+H] + =517.4.

[0320] 1 H NMR (400MHz, CD3OD) δ6.88(d,J=2.9Hz,1H),6.78(d,J=2.9Hz,1H),4.23–4.12(m,4 H),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,9 H),1.27(d,J=7.0Hz,3H),1.22(d,J=6.9Hz,3H),1.21(d,J=6.9Hz,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).

[0321] Example 12 Preparation of Compound A15 and Sulfate of the Present Invention

[0322]

[0323] 1. Preparation of Compound A15-1

[0324] In an ice-water bath at 0°C, DIEA (360.54 mg, 2.81 mmol) and bromoacetic acid (130.27 mg, 0.94 mmol) were added to a dichloromethane (50 mL) solution of A1-4 (417 g, 0.94 mmol) in sequence and stirred at room temperature for 48 hours. After the reaction was completed as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0-30%) and Prep-TLC (methanol / dichloromethane (v / v) = 1 / 10), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), and the Rf = 0.5 portion was collected to obtain a colorless oil compound A15-1 (209.9 mg, yield 44.4%). ESI [M+H] + =503.4.

[0325] 2. Preparation of Compound A15

[0326] In an ice-salt bath at 0°C, TBAF (0.8 mL, 1 mol / L in THF, 0.8 mmol) was added to a dry THF (10 mL) solution of A15-1 (209.9 mg, 0.42 mmol) and stirred at 0°C for 1 hour. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0-30%) and Prep-TLC (methanol / dichloromethane (v / v) = 1 / 10), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), and the Rf = 0.4 portion was collected to obtain a colorless oily compound A15 (121.7 mg, yield 83.6%). ESI [M+H] + =347.3.

[0327] 3. Preparation of Compound A15 Sulfate

[0328] At room temperature, A15 (121.7 mg, 0.35 mmol, 1.0 eq) was dissolved in ether (10 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -60 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A15 sulfate (138.1 mg, yield 100%). ESI [M+H] +=347.3.

[0329] 1H NMR (400MHz, CD3OD) δ7.08(d,J=2.8Hz,1H),6.95(d,J=2.8Hz,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=6.9Hz,3H),1.22(d,J=6.8Hz,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).

[0330] Example 13 Preparation of Compound A16 and Sulfate of the Present Invention

[0331]

[0332] 1. Preparation of Compound A16-1

[0333] At room temperature, K2CO3 (2.07 g, 15.0 mmol) and methyl 2-bromo-2-methylpropionate (1.81 g, 10.0 mmol) were added to a MeCN (10 mL) solution of A1-4 (444.78 g, 1.0 mmol) in sequence, and the mixture was sealed and stirred at 70°C for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), and the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oil compound A16-1 (253.0 mg, yield 46.4%). ESI[M+H] + =545.4.

[0334] 2. Preparation of Compound A16

[0335] In an ice-salt bath at 0°C, TBAF (0.6 mL, 1 mol / L in THF, 0.6 mmol) was added to a dry THF (10 mL) solution of A15-1 (253.0 mg, 0.46 mmol) and stirred at 0°C for 1 hour. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product, which 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 / 8). The Rf = 0.5 portion was collected to obtain a colorless oily compound A16 (152.6 mg, yield 85.4%). ESI [M+H] + =389.2.

[0336] 3. Preparation of Compound A16 Sulfate

[0337] At room temperature, A16 (135.6 mg, 0.35 mmol, 1.0 eq) was dissolved in ether (10 mL), and the reaction system was cooled to -70 °C using 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (20 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A16 sulfate (189.1 mg, yield 100%). ESI[M+H] + =389.2.

[0338] 1 H NMR (400MHz, CD3OD) δ7.23(d,J=2.9Hz,1H),7.09(d,J=2.9Hz,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=6.9Hz,3H),1.23(d,J=6.8Hz,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).

[0339] Example 14 Preparation of Compound A17 and its Hydrochloride

[0340]

[0341] 1. Preparation of Compound A17-1

[0342] In an ice-water bath at 0°C, DIEA (932.7 mg, 7.2 mmol) and tert-butyl bromoacetate (702.2 mg, 3.6 mmol) were added to a dichloromethane (20 mL) solution of A4-4 (300.0 mg, 0.72 mmol) in sequence and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), H2O (20 mL) was added to the reaction system, extracted with dichloromethane (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oily crude compound A17-1 (405.6 mg). ESI[M+H] + =533.4.

[0343] 2. Preparation of Compound A17

[0344] In an ice-salt bath at 0°C, TBAF (0.9 mL, 1 mol / L in THF, 0.9 mmol) was added to a dry THF (10 mL) solution of A17-1 (405.6 mg, 0.76 mmol) and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A17 (188.8 mg, two-step yield 69.6%). ESI [M+H] + =377.3.

[0345] 3. Preparation of Compound A17 Hydrochloride

[0346] At room temperature, A17 (188.8 mg, 0.50 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -60 °C with a dry ice ethanol bath. HCl / Et2O (0.38 mL, 2 mol / L in Et2O, 0.76 mmol) solution was slowly added to the reaction system, stirred at -60 °C for 5 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (20 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A17 hydrochloride (211.6 mg, yield 100%). ESI [M+H] + =377.3.

[0347] 1 H NMR (400MHz, CD3OD) δ6.94 (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 = 6.9Hz, 12H).

[0348] Example 15 Preparation of Compounds A19 and Sulfate, A19S and Sulfate, and A19R and Sulfate of the Present Invention

[0349]

[0350] 1. Preparation of compound A19S-1

[0351] At room temperature, 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) and stirred at room temperature for 24 hours. After the reaction was completed as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the mixture was concentrated under reduced pressure to obtain a crude product, which 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 Rf = 0.3 portion was collected to obtain a colorless oil compound A19S-1 (227.3 mg, yield 44.2%). ESI [M+H] + =516.4.

[0352] 2. Preparation of compound A19S-2

[0353] At room temperature, DMAP (23.0 mg, 0.19 mmol) and Boc2O (412 mg, 1.888 mmol) were added to a dichloromethane (10 mL) solution of A19S-1 (187 mg, 0.364 mmol) and stirred at room temperature for 24 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.7 portion was collected to obtain a colorless oil compound A19S-2 (132 mg, yield 63.3%). ESI [M+H] + =573.4.

[0354] 3. Preparation of compound A19S

[0355] At room temperature, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a dry THF (8 mL) solution of A19S-2 (132 mg, 0.23 mmol) and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by Prep-TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A19S (77 mg, yield 92.4%). ESI [M+H] + =417.3.

[0356] 4. Preparation of Compound A19S Sulfate

[0357] At room temperature, A19S (77 mg, 0.185 mmol, 1.0 eq) was dissolved in ether (10 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A19S sulfate (83.3 mg, yield 100%). ESI [M+H] +=417.3

[0358] 1 H NMR (400MHz, CD3OD) δ7.16(d,J=2.9Hz,1H),7.03(d,J=2.9Hz,1H),4.13(q,J=7.2Hz,1H),3 .73–3.55(m,8H),3.36–3.32(m,1H),2.52–2.42(m,1H),1.61(d,J=7.2Hz,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 preparation methods of compound A19 and its sulfate and A19R and its sulfate are similar to those of compound A19S and its sulfate.

[0359] Example 16 Preparation of Compounds A20 and Sulfate, A20S and Sulfate, and A20R and Sulfate of the Present Invention

[0360]

[0361] 1. Preparation of compound A20S-1

[0362] At room temperature, Et3N (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 in sequence to a solution of A4-4 (300 mg, 0.716 mmol, 1 eq) in dry DMF (10 mL), and stirred at 60 °C for 5 hours. After the reaction was completed as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the system was cooled to room temperature, H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.6 portion was collected to obtain a colorless oily compound A20S-1 (331.7 mg, yield 91.8%). ESI [M+H] + =505.4.

[0363] 2. Preparation of compound A20S

[0364] 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 stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A20S (214 mg, yield 93.6%). ESI [M+H] + =349.2.

[0365] 3. Preparation of Compound A20S Sulfate

[0366] At room temperature, A20S (214 mg, 0.614 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A20S sulfate (315.3 mg, yield 100%). ESI [M+H] + =349.2.

[0367] 1 H NMR(400MHz,CD3OD)δ7.09(s,2H),4.21(q,J=7.2Hz,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=7.2Hz,3H),1.23(d,J=6.9Hz,12H).

[0368] The preparation methods of compound A20 and its sulfate and A20R and its sulfate are similar to the target compound A20S and its sulfate.

[0369] Example 17 Preparation of the compounds A21 and hydrochloride, A21S and hydrochloride, A21R and hydrochloride, and A27S and hydrochloride of the present invention

[0370]

[0371] The preparation methods of compounds A21, A21S and A21R are similar to those of compounds A19, A19S and A19R in Example 15. The preparation methods of A21 hydrochloride, A21S hydrochloride and A21R hydrochloride are similar to those of compound A17 hydrochloride in Example 14. Compound A4-4 is used as the starting material.

[0372] Since the residual Boc2O was not completely removed during the separation and purification of compound A21S-2, 75.1 mg of colorless oily compound A27S was isolated. The preparation method of A27S hydrochloride was similar to the preparation method of compound A17 hydrochloride in Example 14.

[0373] A21S hydrochloride: white solid, 75.6 mg. ESI [M+H] + =391.3.

[0374] 1 H NMR(400MHz,CD3OD)δ7.03(s,2H),4.14(q,J=7.2Hz,1H),3.70–3.52(m,8H),3 .39–3.32(m,2H),1.61(d,J=7.2Hz,3H),1.55(s,9H),1.22(d,J=6.9Hz,12H).

[0375] A27S hydrochloride: white solid, 64.9 mg. ESI [M+H] + =491.3.

[0376] 1 H NMR(400MHz,CD3OD)δ6.79(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=6.9Hz,12H).

[0377] Example 18 Preparation of Compounds A22 and Sulfate, A22S and Sulfate, and A22R and Sulfate of the Present Invention

[0378]

[0379] 1. Preparation of compound A22S-1

[0380] At room temperature, Et3N (204.76 mg, 2.024 mmol, 3 eq), NaI (303.30 mg, 2.024 mmol, 3 eq) and (R)-methyl 2-bromobutyrate (366.31 mg, 2.024 mmol, 3 eq) were added to a solution of A1-4 (300.0 mg, 0.675 mmol, 1 eq) in dry DMF (8 mL) and stirred at 60 °C for 8 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the system was cooled to room temperature, H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-8%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.6 portion was collected to obtain a colorless oily compound A22S-1 (296.0 mg, yield 80.5%). ESI [M+H] + =545.4.

[0381] 2. Preparation of Compound A22S

[0382] In an ice-salt bath at 0°C, TBAF (0.7 mL, 1 mol / L in THF, 0.7 mmol) was added to a dry THF (8 mL) solution of A22S-1 (296 mg, 0.543 mmol) and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.4 portion was collected to obtain a colorless oily crude compound A22S (247.86 mg). ESI [M+H] + =389.2.

[0383] 3. Preparation of Compound A22S Sulfate

[0384] At room temperature, A22S (247.86 mg, 0.638 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A22S sulfate (278.28 mg, yield 100%). ESI [M+H] + =389.2

[0385] 1 H NMR (400MHz, CD3OD) δ7.30(d,J=2.9Hz,1H),7.16(d,J=2.9Hz,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=6.9Hz,3H),1.24(d,J=6.8Hz,6H),1.09(dd,J=7.8,2.9Hz,1H),1.04(t ,J=7.4Hz,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).

[0386] The preparation methods of compound A22 and its sulfate and A22R and its sulfate are similar to those of compound A22S and its sulfate.

[0387] Example 19 Preparation of Compounds A23 and Sulfate, A23S and Sulfate, and A23R and Sulfate of the Present Invention

[0388]

[0389] 1. Preparation of Compound A23-1

[0390] At room temperature, Et3N (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) and stirred at 60°C for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the system was cooled to room temperature, H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-8%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.6 portion was collected to obtain a colorless oily compound A23-1 (103.0 mg, yield 30.4%). ESI [M+H] + =559.4.

[0391] 2. Preparation of Compound A23

[0392] In an ice-salt bath at 0°C, TBAF (0.25 mL, 1 mol / L in THF, 0.25 mmol) was added to a dry THF (5 mL) solution of A23-1 (103.0 mg, 0.184 mmol) and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system, extracted with ethyl acetate (3×5 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.3 portion was collected to obtain a colorless oil compound A23 (46.1 mg, yield 62.2%). ESI [M+H] + =403.3.

[0393] 3. Preparation of Compound A23 Sulfate

[0394] At room temperature, A23 (46.1 mg, 0.115 mmol, 1.0 eq) was dissolved in ether (20 mL), and the reaction system was cooled to -70 °C with 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A23 sulfate (54.18 mg, yield 100%). ESI [M+H] + =403.3

[0395] 1 H NMR(400MHz,CD3OD)δ7.38(d,J=2.9Hz,1H),7.24(d,J=2.9Hz,1H),3.79(s,3H),3.75–3.6 4(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=6.9Hz,3H),1.24(d,J=6.9Hz,6H),1.11(d,J=6.6Hz,3H),1.09–1.03(m,1H),0.95(d, J=6.6Hz,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).

[0396] The preparation methods of compound A23 and its sulfate and A23R and its sulfate are similar to those of compound A23S and its sulfate.

[0397] Example 20 Preparation of Compounds A24 and Sulfate, A24S and Sulfate, A24R and Sulfate, and A26 and Sulfate

[0398]

[0399] 1. Preparation of Compound A24-1

[0400] At room temperature, Et3N (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), and stirred at 60°C for 4 hours. After the reaction was complete as monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the system was cooled to room temperature, H2O (30 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-5%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A24-1 (512.7 mg, yield 79.9%). ESI [M+H] + =571.4.

[0401] 2. Preparation of Compound A24-2

[0402] In an ice-salt bath at 0°C, NaOMe (0.25 mL, 0.25 mmol) was added to a MeOH (5 mL) solution of A24-1 (240.0 mg, 0.42 mmol) and stirred at 0°C for 10 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product, which 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 / 8). The Rf = 0.4 portion was collected to obtain a colorless oily compound A24-2 (43.2 mg, yield 18.5%). ESI [M+H] + =557.4.

[0403] 3. Preparation of Compound A24

[0404] In an ice-salt bath at 0°C, TBAF (0.1 mL, 1 mol / L in THF, 0.1 mmol) was added to a dry THF (5 mL) solution of A24-2 (43.2 mg, 0.078 mmol) and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with ethyl acetate (3×5 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.3 portion was collected to obtain a colorless oil compound A24 (21.0 mg, yield 67.2%). ESI [M+H] + =401.3.

[0405] 4. Preparation of Compound A24 Sulfate

[0406] At room temperature, A24 (21.0 mg, 0.0524 mmol, 1.0 eq) was dissolved in ether (10 mL), and the reaction system was cooled to -70 °C using 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A24 sulfate (26.0 mg, yield 100%). ESI[M+H] + =401.3

[0407] 1H NMR (400MHz, CD3OD) δ7.17(d,J=2.9Hz,1H),7.04(d,J=2.9Hz,1H),3.88(s,3H),3.75–3.62(m,6H),3.57– 3.49(m,2H),3.40(d,J=10.2Hz,1H),3.35–3.32(m,1H),2.52–2.43(m,1H),1.27(d,J=7.0Hz,3H),1.23(d ,J=6.9Hz,3H),1.22(d,J=6.9Hz,3H),1.21–1.17(m,1H),1.12–1.01(m,1H),1.01–0.91(m,1H),0.86–0.7 7(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).

[0408] The preparation methods of compound A24S and its sulfate and A24R and its sulfate are similar to those of compound A24 and its sulfate.

[0409] 5. Preparation of Compound A26 and A26 Sulfate

[0410] In an ice-salt bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a dry THF (5 mL) solution of A24-1 (232.3 mg, 0.407 mmol) and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with ethyl acetate (3×5 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether (v / v) = 0-8%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.3 portion was collected to obtain a colorless oil compound A26 (160.0 mg, yield 94.8%). ESI [M+H] + =415.2.

[0411] At room temperature, A26 (160.0 mg, 0.386 mmol, 1.0 eq) was dissolved in ether (10 mL), and the reaction system was cooled to -70 °C using 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 system, stirred at -70 °C for 10 minutes, and concentrated under reduced pressure at low temperature to obtain a crude product. Et2O (10 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et2O (3×10 mL). The solid was dissolved in ultrapure water (20 mL) and freeze-dried in a freeze dryer for 24 hours to obtain a white solid compound A26 sulfate (220.59 mg, yield 100%). ESI [M+H] + =415.2

[0412] 1 H NMR (400MHz, CD3OD) δ7.23(d,J=2.9Hz,1H),7.09(d,J=2.9Hz,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=10.2Hz,1H),3.37–3.31(m,1H),2.53–2.42(m,1H),1.35(t,J=7.1Hz,3H),1.2 8(d,J=6.9Hz,3H),1.23(d,J=6.9Hz,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).

[0413] Example 21 Preparation of Compound A25S of the Present Invention

[0414]

[0415] At room temperature, A6S-1 (200 mg, 0.377 mmol), MeI (106.95 mg, 0.753 mmol, 2 eq) and DIEA (146.4 mg, 1.133 mmol) were dissolved in dry DMF (10 mL) solution in turn and stirred at room temperature for 12 hours. After the reaction was completed as monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), the crude product was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0-50%), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), and the Rf = 0.5 portion was collected to obtain crude compound A25S-1 (301 mg).

[0416] 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) in an ice-salt bath at 0°C and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the organic phases were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (methanol / dichloromethane (v / v) = 0-50%), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), and the Rf = 0.5 portion was collected to obtain a colorless oily compound A25S (70.7 mg, two-step yield 36.3%). ESI [MI] = 389.2.

[0417] 1 H NMR (400MHz, CD3OD) δ7.48(d,J=3.3Hz,1H),7.34(d,J=3.3Hz,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).

[0418] The beneficial effects of the present invention are demonstrated by test examples below.

[0419] Test Example 1 Screening and solubility test of the salt form of the compound A6S of the present invention

[0420] 1. Experimental Methods

[0421] At room temperature, compound A6S (1 eq) was dissolved in Et2O (2 mL), and the corresponding acid (2 eq) was dissolved in Et2O (serial number 1-4) or MeOH (serial number 5-10). The acid solution was slowly added to the reaction system where compound A6S was located using a syringe. Serial number 1-3 was stirred at room temperature for 1 hour, and serial number 5-10 was stirred at room temperature for 16 hours. The solid was filtered, washed with ether, and dried to obtain the corresponding salt form of compound A6S. The solubility of each salt form in ultrapure water was then tested.

[0422] Table 1. Screening and solubility of salt forms of compound A6S of the present invention

[0423]

[0424] 2. Experimental results

[0425] As can be seen from Table 1, the compound A6S of the present invention can form various salt forms such as hydrochloride, sulfate, methanesulfonate, phosphate, p-toluenesulfonate, benzenesulfonate, oxalate, maleate, etc. Moreover, each salt form has excellent water solubility, and the solubility in ultrapure water is all greater than 8 mg / mL, which can meet the requirements of the preparation.

[0426] Test Example 2 Solubility Determination of Salt Forms of Compounds of the Present Invention

[0427] 1. Experimental Methods

[0428] Weigh 10 mg of the corresponding salt of the compound of the present invention, place at 25°C ± 2°C, add water, shake vigorously for 30 seconds every 5 minutes, and observe for 30 minutes. When no solute particles or droplets are seen in the above test system, record the water solubility of the compound after salt formation according to the following standards:

[0429] A: The amount of water used is less than 0.1 mL;

[0430] B: The amount of water is greater than or equal to 0.1 mL and less than 1.0 mL;

[0431] C: The amount of water used is greater than or equal to 1.0 mL and less than 5.0 mL.

[0432] 2. Experimental results

[0433] Table 2. Solubility of salt forms of compounds of the present invention

[0434] Compound No. Test compound salt Solubility of salt-forming compound A1 Hydrochloride A A2 Hydrochloride A A3 Hydrochloride C A4 Hydrochloride A A5 Hydrochloride A A6 Hydrochloride A A6R Sulfate A A6S Sulfate A A7 Hydrochloride B A8 Hydrochloride B A11 Sulfate A A12 Sulfate A A13 Hydrochloride A A14 Hydrochloride C A15 Sulfate A A16 Sulfate A A17 Hydrochloride C A18 Sulfate A A19S Sulfate A A20S Sulfate A A21S Hydrochloride C A22S Sulfate A A23 Sulfate C A24 Sulfate C A26 Sulfate A A27S Hydrochloride C

[0435] It is well known to those skilled in the art that propofol and picopropofol cannot form salts and are insoluble in water. However, according to Table 2, it can be seen that the salt forms of the representative compounds of the present invention have excellent water solubility and do not need to be prepared into fat emulsion preparations, which can overcome various adverse reactions caused by fat emulsion preparations.

[0436] Test Example 3 Determination of pharmacological data and safety data of the compounds of the present invention

[0437] 1. Experimental Methods

[0438] (1) Testing the anesthetic effect of representative compounds of the present invention after tail vein injection in rats (determination of the minimum effective anesthetic dose):

[0439] SD rats were selected for the test, and the drug was administered through the tail vein (dosage rate 0.02 ml / s, administration volume 0.6 ml / rat). The sequential method was used to determine whether the compound caused the disappearance of the righting reflex. The dose of the compound for each test started from 1 mg / kg, and the actual dose was calculated according to the body weight of each animal before the test. The increase or decrease of subsequent doses was determined based on the reaction of the experimental animals (whether the righting reflex disappeared). The dose at which the righting reflex disappeared for the first time was determined as the minimum anesthetic effective dose. The minimum anesthetic effective dose in the present invention is further classified as: A≤5 mg / kg; 5 mg / kg <B≤10mg / kg;10mg / kg<C≤20mg / kg;D>20mg / kg。

[0440] (2) Testing the anesthetic effect of the representative compounds of the present invention after tail vein injection in rats (median effective dose ED 50 Determination of) and pharmacological characteristics of equivalent doses:

[0441] SD rats were selected for the experiment and the drug was administered through the tail vein (dosage rate 0.02 ml / s, administration volume 0.6 ml / rat). The ED of the compound-induced loss of righting reflex was determined by the sequential method. 50 The compound dose selection for each test starts at 5 mg / kg, and the actual dose is calculated based on the weight of each animal before the test. The subsequent dose increase or decrease is determined based on the experimental animal's response (whether the righting reflex disappears or not). When the test tests the disappearance and recovery of the righting reflex in five directions, the ED value of the compound causing the righting reflex disappearance is calculated according to the formula 50 . ED was measured 50 Later, in 2ED 50 The anesthetic onset time, anesthetic maintenance time, anesthetic recovery time, etc. of the compound were further tested under the dosage conditions.

[0442] (3) Testing the representative compounds of the present invention in 2ED 50 Effects on blood pressure, heart rate and respiratory rate of rats under different dosage conditions:

[0443] According to the ED of the compound 50 SD rats were selected again, and one side of the femoral artery was cannulated under basic anesthesia. The rats' arterial blood pressure, heart rate, respiratory rate and other indicators were continuously monitored. The effect of single tail vein injection (administration rate 0.02 ml / s, administration volume 0.6 ml / rat) of the compound of the present invention at 2ED 50 Effects of dosage conditions on blood pressure, heart rate and respiratory rate of rats.

[0444] (4) Testing the minimum lethal dose of the compound of the present invention after tail vein injection in rats:

[0445] SD rats were selected for the experiment, and the drug was administered through the tail vein (dosage rate 0.02 ml / s, administration volume 0.5-1.0 ml / 100 grams of body weight). The dose of each test compound was selected from 4ED 50 Initially, the actual dosage is calculated according to the weight of each animal weighed before the test. The sequential method is used to determine whether the compound causes death. The increase or decrease of subsequent doses is determined based on the reaction of the experimental animals (whether death occurs). The dose at which death occurs for the first time is determined as the minimum lethal dose. In the present invention, the minimum lethal dose is defined as a multiple of the minimum anesthetic effective dose as the approximate therapeutic index. The approximate therapeutic index in the present invention is further classified as: when the approximate therapeutic index is greater than or equal to 5, it is classified as A; when the approximate therapeutic index is less than 5 and greater than or equal to 3, it is classified as B; when the approximate therapeutic index is less than 3, it is classified as C.

[0446] (5) Testing the recovery time of the compound of the present invention after continuous infusion of different time periods in rats:

[0447] The experiment used SD rats, and a single injection of 1.5ED 50 , then inject 1ED again 1 minute later 50 Dosage, after administration, the tail vein catheter is connected to the syringe through an extension tube. The initial infusion rate of each rat is determined according to the specific compound, and the infusion rate is halved after 5 minutes. The infusion rate is adjusted every 5 minutes thereafter, and the infusion rate is increased or decreased according to the rat's response. When the predetermined infusion time is reached, the infusion is stopped, and the time for the righting reflex of the rat to recover, the time and type of adverse reactions in the test, etc. are observed and recorded.

[0448] In the above test, in addition to recording the dose at which the righting reflex is lost, the onset time and recovery time of anesthesia, the duration of the righting reflex and the duration of the sedative effect can also be recorded. At the dose of the compound of the present invention that causes the righting reflex to be lost, the effect of the compound on the circulation and respiration of the experimental animals can also be observed through the circulation effect experiment. In the continuous infusion experiment, the awakening time of the rats to normal activities after the compound of the present invention is stopped at different times of continuous infusion can also be observed.

[0449] 2. Experimental results

[0450] Table 3. Pharmacological data of single intravenous injection of salt form of the compound of the present invention

[0451]

[0452]

[0453] It can be seen from Table 3 that most of the salt forms selected in the test of representative compounds of the present invention can be directly dissolved in pure water or physiological saline, have a low minimum effective anesthetic dose, a short onset time, and can quickly produce a general anesthetic effect.

[0454] Table 4. Safety data of the compounds of the present invention

[0455]

[0456] As can be seen from Table 4, the representative compounds of the present invention, in addition to being able to quickly produce general anesthesia and rapid recovery, also have better safety (including milder circulatory depression and respiratory depression) compared with propofol; when continuously infused, the anesthesia recovery time is shorter and also has better safety.

[0457] It can be seen from Table 3 and Table 4 that the representative compounds of the present invention have excellent anesthetic effects and / or excellent safety and have broad prospects for clinical application.

[0458] In summary, the present invention provides a piperazine substituted phenol derivative as shown in formula I, which not only has good salt-forming property and excellent water solubility, and can meet the requirements of the preparation, but also has a low minimum effective anesthetic dose, can quickly take effect and quickly recover, overcomes the shortcomings of propofol fat emulsion preparations and the shortcomings of propofol water-soluble prodrugs, and has better safety than propofol. It has broad application prospects in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs that can control status epilepticus, and provides a new choice for the clinical preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs that can control status epilepticus.

Claims

1. A compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof: in, R is selected from hydrogen, CH2COOR h1 ; R h1 Selected from C 1-4 alkyl; R 2 is hydrogen, R 5 is hydrogen, R 3 Selected from C 1～4 Alkyl, R 6 Selected from C 1～4 Alkyl, R 1 Selected from C 1～4 Alkyl, R 4 Selected from C 1～4 Alkyl or 3-membered cycloalkyl; R 7 is hydrogen, R 8 is hydrogen; p is selected from an integer of 0 to 2, and each R 9 are each independently selected from hydrogen, C 1～4 Alkyl; or p is 2, where two R 9 Connected into spiral ring or bridge ring; R 10 Selected from (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c ; Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered cycloalkyl; R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered cycloalkyl; R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～4 Alkyl, C 1～4 Alkoxy, 3-membered cycloalkyl; m is selected from 0, 1, 2, 3, or 4; t is selected from 1, 2, 3, or 4.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula II: Among them, R 2 is hydrogen, R 5 is hydrogen, R 3 Selected from C 1～4 Alkyl, R 6 Selected from C 1～4 Alkyl, R 1 Selected from C 1～4 Alkyl, R 4 Selected from C 1～4 Alkyl or 3-membered cycloalkyl; p is selected from an integer of 0 to 2, and each R 9 are each independently selected from hydrogen, C 1～4 Alkyl; or p is 2, where two R 9 Connected into spiral ring or bridge ring; R 10 Selected from (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c ; Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered cycloalkyl; R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～4 Alkyl, C 1～4 Alkoxy, 3-membered cycloalkyl; m is selected from 0, 1, 2, 3, or 4; t is selected from 1, 2, 3, or 4.

3. The compound according to claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula III: Among them, R 11 is methyl, R 12 Selected from methyl, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula (a), two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula (a), two groups attached to different carbon atoms are connected together to form a bridged ring, and the remaining groups are independently selected from hydrogen; R 10 As described in claim 2.

4. The compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IV-1 or Formula IV-2: Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula (a), two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the embodiment, two groups connected to different carbon atoms are connected together to form a bridge ring, and the remaining groups are independently selected from hydrogen; the spiro ring or bridge ring contains 2, 3 or 4 N heteroatoms; R 10 Selected from (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c ; Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～3 Alkyl, C 1～3 Alkoxy, 3-membered saturated cycloalkyl; m is selected from 0, 1, 2, 3, or 4; t is selected from 1, 2, 3, or 4.

5. The compound according to claim 4, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IV-1 or Formula IV-2: Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula (a), two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the embodiment, two groups connected to different carbon atoms are connected together to form a bridge ring, and the remaining groups are independently selected from hydrogen; the spiro ring or bridge ring contains 2, 3 or 4 N heteroatoms; R 10 Selected from (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c ; Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～3 Alkyl, C 1～3 Alkoxy, 3-membered saturated cycloalkyl; m is selected from 0, 1, 2, 3, or 4; t is selected from 1, 2, 3, or 4.

6. The compound according to any one of claims 3 to 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structural fragment One of the following structures: 。 7. The compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula V-1 or Formula V-2: Among them, R 10 Selected from (CR b1 R b2 ) m COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t COOR c ; Among them, R b1 , R b2 , R b3 , R b4 are each independently selected from hydrogen, halogen, C 1～2 Alkyl, halogenated C 1～2 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～2 Alkyl, halogenated C 1～2 Alkyl, 3-membered saturated cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～2 Alkyl, C 1～2 Alkoxy, 3-membered saturated cycloalkyl; m is selected from 0, 1, 2, 3, or 4; t is selected from 1, 2, 3, or 4.

8. The compound according to claim 5, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VI-1 or Formula VI-2: Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula (a), two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the embodiment, two groups connected to different carbon atoms are connected together to form a bridge ring, and the remaining groups are independently selected from hydrogen; the spiro ring or bridge ring contains 2, 3 or 4 N heteroatoms; m is selected from 0, 1, 2, 3, or 4; R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～3 Alkyl, C 1～3 Alkoxy, 3-membered saturated cycloalkyl.

9. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VI-1 or Formula VI-2: Among them, R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i are each independently selected from hydrogen, C 1～4 Alkyl; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the formula (a), two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are independently selected from hydrogen; or R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , R 9i In the embodiment, two groups connected to different carbon atoms are connected together to form a bridge ring, and the remaining groups are independently selected from hydrogen; the spiro ring or bridge ring contains 2, 3 or 4 N heteroatoms; m is selected from 0, 1, 2, 3, or 4; R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered saturated cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～3 Alkyl, C 1～3 Alkoxy, 3-membered saturated cycloalkyl.

10. The compound according to claim 9, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structural fragment One of the following structures: m is selected from 1, 2, or 3; R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered saturated cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～3 Alkyl, C 1～3 Alkoxy, 3-membered saturated cycloalkyl.

11. The compound according to claim 9, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VII-1 or Formula VII-2: wherein m is selected from 1 or 2; R b1 , R b2 are each independently selected from hydrogen, halogen, C 1～3 Alkyl, halogenated C 1～3 Alkyl, 3-membered saturated cycloalkyl; R c For hydrogen, C 1～4 Alkyl, halogenated C 1～4 Alkyl, 3-membered saturated cycloalkyl; The above R c The alkyl group in the group is unsubstituted or optionally substituted by one or two or more of the following groups: 1～3 Alkyl, C 1～3 Alkoxy, 3-membered saturated cycloalkyl.

12. The compound according to any one of claims 9 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: In Formula VI-1, Formula VI-2, VII-1, or Formula VII-2: m is selected from 1 or 2; R b1 , R b2 Each is independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropane; R c Methyl, ethyl, n-propyl, isopropyl, tert-butyl, CF3, cyclopropane, 13. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that: The structure of the compound is selected from: "*" indicates a chiral center.

14. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The pharmaceutically acceptable salt is acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, sulphosulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate or xinafoate.

15. The compound according to claim 14, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative, characterized in that: The toluenesulfonate is p-toluenesulfonate.

16. A drug, characterized in that: The invention relates to a preparation prepared by taking the compound described in any one of claims 1 to 15, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative as an active ingredient and adding pharmaceutically acceptable excipients.

17. Use of the compound according to any one of claims 1 to 15, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated derivative in the preparation of a drug having sedative, hypnotic and / or anesthetic effects and / or a drug capable of controlling status epilepticus.

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