WO2024082629A1 - 哌嗪取代苯酚类衍生物及其用途 - Google Patents

哌嗪取代苯酚类衍生物及其用途 Download PDF

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WO2024082629A1
WO2024082629A1 PCT/CN2023/095079 CN2023095079W WO2024082629A1 WO 2024082629 A1 WO2024082629 A1 WO 2024082629A1 CN 2023095079 W CN2023095079 W CN 2023095079W WO 2024082629 A1 WO2024082629 A1 WO 2024082629A1
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alkyl
hydrogen
membered
membered saturated
alkynyl
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French (fr)
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张汉承
刘进
张文胜
陈光武
马海军
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成都麻沸散医药科技有限公司
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D213/68—One oxygen atom attached in position 4
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    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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.
  • 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.
  • propofol can cause severe adverse reactions such as circulatory depression, respiratory depression, injection pain, agitation, and polyphagia.
  • 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.
  • O/W oil-in-water
  • 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.
  • the onset time of fospropofol disodium is significantly slower, as long as 2.9 minutes, which cannot meet the requirement of rapid onset.
  • 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.
  • 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:
  • R is selected from hydrogen, COR a , COCH(NH 2 )R a , COOR h1 , CH 2 COOR h1 , a protecting group, PO(OR h1 )(OR h2 ) or CH 2 OPO(OR h1 )(OR h2 );
  • R a is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, aryl or heteroaryl;
  • R h1 and R h2 are each independently selected from hydrogen, C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, aryl or heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and 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 are not methyl at the same time;
  • R 7 and R 8 are each independently selected from hydrogen, halogen or C 1-4 alkyl
  • p is selected from an integer of 0 to 8, and each R 9 is independently selected from hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl; or p is selected from an integer of 2 to 8, wherein two R 9s are connected to form a ring, and the remaining R 9s are independently selected from hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl; or p is selected from an integer of 1 to 9, wherein one R 9 is connected to the nitrogen atom connected to R 10 to form a quaternary ammonium salt, and the remaining R 9s are independently selected from hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl;
  • R10 is selected from hydrogen , C1-4 alkyl , ( CRb1Rb2 ) mCOORc , ( CRb1Rb2 ) mCONRd1Rd2 , (CRb1Rb2 ) nORf , ( CRb1Rb2 ) nNRd1Rd2 , ( CRb1Rb2 ) nOCORe , ( CRb1Rb2 ) nNRd1CORe , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCOORc , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCONRd1Rd2 ;
  • R b1 , R b2 , R b3 and 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, 3-6 membered cycloalkyl, 3-6 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 they are attached form a 3-6 membered cyclic structure containing 0 or 1 heteroatom selected from N, O and S;
  • R c is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl;
  • R e is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl in the above R b1 , R b2 , R b3 , R b4 , R c and Re are unsubstituted or optionally substituted with 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, CN, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 and R d2 are each independently selected from hydrogen or C 1-4 alkyl
  • Rf is selected from hydrogen, C1-4 alkyl or halogenated C1-4 alkyl
  • R i is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;
  • n is selected from 0, 1, 2, 3, or 4;
  • n is selected from 2, 3, or 4;
  • t is selected from 1, 2, 3, or 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C 1-4 alkyl, or 3-6 membered saturated cycloalkyl;
  • p is selected from an integer of 0 to 8, and each R 9 is independently selected from hydrogen and C 1-4 alkyl; or p is selected from an integer of 2 to 8, wherein two R 9 are connected to form a ring, and the remaining R 9 are independently selected from hydrogen and C 1-4 alkyl; or p is selected from an integer of 1 to 9, wherein one R 9 is connected to the nitrogen atom connected to R 10 to form a quaternary ammonium salt, and the remaining R 9 are independently selected from hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl;
  • R10 is selected from hydrogen , C1-4 alkyl , ( CRb1Rb2 ) mCOORc , ( CRb1Rb2 ) mCONRd1Rd2 , (CRb1Rb2 ) nORf , ( CRb1Rb2 ) nNRd1Rd2 , ( CRb1Rb2 ) nOCORe , ( CRb1Rb2 ) nNRd1CORe , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCOORc , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCONRd1Rd2 ;
  • R b1 , R b2 , R b3 , and 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, 3-6-membered cycloalkyl, 3-6-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 they are attached form a 3-6-membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;
  • R c is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl;
  • R e is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl in the above R b1 , R b2 , R b3 , R b4 , R c and Re are unsubstituted or optionally substituted with 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, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, CN, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 and R d2 are each independently selected from hydrogen or C 1-4 alkyl
  • Rf is selected from hydrogen, C1-4 alkyl or halogenated C1-4 alkyl
  • R i is selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;
  • n is selected from 0, 1, 2, 3, or 4;
  • n is selected from 2, 3, or 4;
  • t is selected from 1, 2, 3, or 4.
  • R 11 and R 12 are each independently selected from methyl
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i are each independently selected from hydrogen and C 1-4 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to the same carbon atom are connected together to form a spirocycle, and the remaining groups are each independently selected from hydrogen and C 1-4 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are each independently selected from hydrogen and C 1-4 alkyl;
  • R10 is as described above in Formula II.
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; the spiro ring, bridged ring, or condensed ring contains 2, 3, or 4 heteroatom
  • R10 is selected from hydrogen , C1-4 alkyl , ( CRb1Rb2 ) mCOORc , ( CRb1Rb2 ) mCONRd1Rd2 , (CRb1Rb2 ) nORf , ( CRb1Rb2 ) nNRd1Rd2 , ( CRb1Rb2 ) nOCORe , ( CRb1Rb2 ) nNRd1CORe , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCOORc , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCONRd1Rd2 ;
  • R b1 , R b2 , R b3 , and 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, 3-6-membered saturated cycloalkyl, 3-6-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 they are connected form a 3-6-membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;
  • R c is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl;
  • R e is hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclyl, cycloalkyl, heterocyclyl, aryl and heteroaryl in the above R b1 , R b2 , R b3 , R b4 , R c and Re are 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 heterocyclyl, CN, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or
  • R d1 and R d2 are each independently selected from hydrogen or C 1-3 alkyl
  • Rf is selected from hydrogen, C1-3 alkyl or halogenated C1-3 alkyl
  • R i is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclic group;
  • n is selected from 0, 1, 2, 3, or 4;
  • n is selected from 2, 3, or 4;
  • t is selected from 1, 2, 3, or 4.
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; the spiro ring, bridged ring, or condensed ring contains 2, 3, or 4 heteroatom
  • R10 is selected from hydrogen , C1-4 alkyl , ( CRb1Rb2 ) mCOORc , ( CRb1Rb2 ) mCONRd1Rd2 , (CRb1Rb2 ) nORf , ( CRb1Rb2 ) nNRd1Rd2 , ( CRb1Rb2 ) nOCORe , ( CRb1Rb2 ) nNRd1CORe , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCOORc , ( CRb1Rb2 ) mCO ( CRb3Rb4 ) tCONRd1Rd2 ;
  • R b1 , R b2 , R b3 and R b4 are each independently selected from hydrogen, halogen, C 1-3 alkyl, Halogenated C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, 3-6-membered saturated cycloalkyl, 3-6-membered saturated heterocyclic group, aryl, heteroaryl, CN, ORf , SRf or NRd1Rd2 ; or Rb1 and Rb2 together with the carbon atom to which they are attached form a 3-6-membered ring structure containing 0 or 1 heteroatom selected from N, O and S;
  • R c is hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • R e is hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, aryl and heteroaryl in the above R b1 , R b2 , R b3 , R b4 , R c and Re are 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, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 and R d2 are each independently selected from hydrogen or C 1-3 alkyl
  • Rf is selected from hydrogen, C1-3 alkyl or halogenated C1-3 alkyl
  • R i is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclic group;
  • n is selected from 0, 1, 2, 3, or 4;
  • n is selected from 2, 3, or 4;
  • t is selected from 1, 2, 3, or 4.
  • R 10 is 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 COOR c , (CR b1 R b2 ) m CO(CR b3 R b4 ) t CONR d1 R d2 ;
  • R b1 , R b2 , R b3 , and 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, 3-6-membered saturated cycloalkyl, 3-6-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 they are connected form a 3-6-membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;
  • R c is hydrogen, C 1-2 alkyl, halogenated C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, phenyl or heteroaryl;
  • R e is hydrogen, C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, phenyl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, phenyl and heteroaryl in the above R b1 , R b2 , R b3 , R b4 , R c and Re are 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, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 and R d2 are each independently selected from hydrogen or C 1-2 alkyl
  • Rf is selected from hydrogen, C1-2 alkyl or halogenated C1-2 alkyl
  • R i is selected from hydrogen, C 1-2 alkyl, vinyl, ethynyl, 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclic group;
  • n is selected from 0, 1, 2, 3, or 4;
  • n is selected from 2, 3, or 4;
  • t is selected from 1, 2, 3, or 4.
  • 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; the halogen is selected from fluorine, chlorine and bromine.
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; the spiro ring, bridged ring, or condensed ring contains 2, 3, or 4 heteroatom
  • n is selected from 0, 1, 2, 3, or 4;
  • R b1 and 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, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or the carbon atom to which R b1 and R b2 are attached
  • the 3-6 membered ring structure contains 0 or 1 heteroatom selected from N, O and S;
  • R c is hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, aryl and heteroaryl in the above R b1 , R b2 and R c are 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, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 and R d2 are each independently selected from hydrogen or C 1-3 alkyl
  • Rf is selected from hydrogen, C1-3 alkyl or halogenated C1-3 alkyl
  • R i is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclic group.
  • R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to the same carbon atom are connected together to form a spiro ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; or in R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9h , and R 9i , two groups connected to different carbon atoms are connected together to form a bridged ring or a condensed ring, and the remaining groups are each independently selected from hydrogen and C 1-3 alkyl; the spiro ring, bridged ring, or condensed ring contains 2, 3, or 4 heteroatom
  • n is selected from 0, 1, 2, 3, or 4;
  • R b1 and 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, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl, heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or the carbon atom to which R b1 and R b2 are attached
  • the 3-6 membered ring structure contains 0 or 1 heteroatom selected from N, O and S;
  • R c is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • the alkyl, alkenyl, alkynyl, saturated cycloalkyl, saturated heterocyclic group, aryl and heteroaryl in the above R b1 , R b2 and R c are 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, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 and R d2 are each independently selected from hydrogen or C 1-3 alkyl
  • Rf is selected from hydrogen, C1-3 alkyl or halogenated C1-3 alkyl
  • R i is selected from hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclic group.
  • n is selected from 1, 2, or 3;
  • R b1 and 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 they are attached form a 3-4-membered ring structure, which contains 0 or 1 heteroatom selected from N, O, and S;
  • R c is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • the alkyl, saturated cycloalkyl, saturated heterocyclic group, aryl and heteroaryl in the above R b1 , R b2 and R c are 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, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 , R d2 , R f , and R i are as described above in Formula VI-1 or Formula VI-2.
  • n is selected from 1 or 2;
  • R b1 and 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;
  • R c is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, aryl or heteroaryl;
  • the alkyl, saturated cycloalkyl, saturated heterocyclic group, aryl and heteroaryl in the above R b1 , R b2 and R c are 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, NO 2 , OR f , SR f , NR d1 R d2 , COR i , COOR f , OCO i , CONR d1 R d2 , NR d1 COR i , NR d1 SO 2 R i or SO 2 R i ;
  • R d1 , R d2 , R f , and R i are as described above in Formula VI-1 or Formula VI-2.
  • n 1 or 2;
  • R b1 and R b2 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropane;
  • R c is methyl, ethyl, n-propyl, isopropyl, tert-butyl, CF 3 , cyclopropane,
  • the structure of the compound is selected from:
  • 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, succ
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the anesthesia is general anesthesia.
  • general anesthesia 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.
  • 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.
  • C a-b alkyl represents any alkyl group containing "a" to "b" carbon atoms.
  • C 1-6 alkyl refers to a straight or branched alkyl group containing 1 to 6 carbon atoms.
  • the ring in "p is selected from an integer of 2 to 8, wherein two R 9 are connected to form a ring" includes a spiro ring, a bridged ring, and a condensed ring.
  • 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.
  • Alkylene refers to the group remaining after the corresponding alkyl group loses a hydrogen atom.
  • C1-4 alkyl refers to a straight or branched alkylene group containing 1 to 4 carbon atoms;
  • C2 alkylene refers to
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or a polycyclic ring.
  • 3-6 membered saturated cycloalkyl refers to a saturated cycloalkyl having 3-6 ring carbon atoms.
  • 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).
  • ring heteroatom including but not limited to O, S or N.
  • 3-6 membered saturated heterocyclic group refers to a saturated heterocyclic group with 3-6 ring carbon atoms.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated ⁇ 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 ⁇ electron system.
  • Aryl groups may be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to here include oxygen, sulfur and nitrogen. Examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, tetrazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring.
  • the heteroaryl group may be optionally substituted or Not replaced.
  • “Bridged ring” refers to a polycyclic cycloalkyl group in which two rings share two non-adjacent carbon atoms.
  • Spiro refers to a polycyclic cycloalkyl group in which two rings share a common carbon atom.
  • fused ring refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • deuterated derivative refers to a compound in which one or more hydrogen atoms are replaced by deuterium.
  • “Pharmaceutically acceptable” means that a carrier, vehicle, diluent, excipient, and/or formed salt is generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor.
  • 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 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.
  • the pharmaceutically acceptable salts of the present invention may be acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates, carbonates, bisulfates, sulfates, borates, camphorsulfonates, citric acid salts, salt, 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, hydrogenphosphate, dihydrogenphosphate, pyroglutamate,
  • 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.
  • 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.
  • the administration modes of the compound or pharmaceutical composition of the present invention include (but are not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.
  • 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • 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, starch, 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) disintegrators, 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,
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • 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 thereof.
  • 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 cottons
  • 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 microcapsules with one or more of the above-mentioned excipients.
  • 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.
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • 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.
  • 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.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • 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.
  • the dosage form used clinically is mainly fat emulsion preparations, which are prone to cause a variety of adverse reactions in clinical practice.
  • 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.
  • 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.
  • 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.
  • the compound provided by the present invention has good salt-forming property, excellent water solubility and solubility that meets the requirements of preparations, and at the same time, has a low minimum effective dose of anesthesia, can take effect quickly and recover quickly, overcomes the shortcomings of propofol and its prodrug and fat emulsion preparations, and 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 clinical preparations for drugs with sedative, hypnotic and/or anesthetic effects and drugs that can control epilepsy. Drugs such as status epilepticus provide a new option.
  • 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.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a (Bruker Avance III 400) nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (d 6 -DMSO) or deuterated methanol (CD 3 OD) as the solvent and tetramethylsilane (TMS) as the internal standard.
  • d 6 -DMSO deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LCMS determination was performed using (Agilent LCMS 1260-6110) (ESI), column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 ⁇ m). Column temperature: 40°C; flow rate: 2.0 mL/min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH 3 CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH 3 CN + 0.05% TFA] within 3 minutes, maintained at this condition for 1 minute, then gradient to 95% [water + 0.05% TFA] and 5% [CH 3 CN + 0.05% TFA] within 0.05 minutes, and then maintained at this condition for 0.7 minutes.
  • 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.
  • Thin layer chromatography used products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2 ⁇ 0.03 mm.
  • TDGC2-1 contact voltage regulator (Zhejiang Tianzheng Electric Co., Ltd.);
  • WMNK-01 temperature controller (Shanghai Lulin Electric Co., Ltd.);
  • VRD-16 bipolar rotary vane vacuum pump (Zhejiang Feiyue Electromechanical Co., Ltd.);
  • 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 completed as monitored by TLC, H 2 O (100 mL) was added to the reaction system, and extracted with EtOAc (3 ⁇ 70 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product.
  • compound A1-2 (1.2 g, 2.73 mmol), Pd 2 (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 stirred at 50°C for 4 hours under nitrogen protection.
  • DIEA 349 mg, 2.70 mmol
  • methyl bromoacetate 303 mg, 1.98 mmol
  • A1-4 800 mg, 1.80 mmol
  • acetonitrile 8 mL
  • 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.
  • 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:
  • K 2 CO 3 (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.
  • 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 using a dry ice ethanol bath.
  • a solution of H 2 SO 4 (568.65 mg, 5.80 mmol, 2.0 eq) in Et 2 O (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.
  • Et 2 O (30 mL) was added to the crude product, stirred, filtered, and the solid was washed with Et 2 O (3 ⁇ 20 mL).
  • 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), Pd 2 (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 with nitrogen three times, and the nitrogen was protected and stirred at 70°C overnight.
  • the preparation method of compound A18 is similar to that of A11, using A11-2 (300 mg, 0.64 mmol) and tert-butyl bromoacetate 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%), and compound A18 is salified by H 2 SO 4 /Et 2 O to obtain white solid compound A18 sulfate (197.4 mg, yield 94.9%).
  • ESI [M+H] + 429.3.
  • 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), Pd 2 (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 with nitrogen three times, and the mixture was protected by nitrogen and stirred at 50 ° C for 24 hours.
  • the preparation method of A13-1 is the same as the first step of this example, which is obtained by reacting A1-4 (444.78 g, 1.0 mmol) with tert-butyl bromoacetate and then desilylation-protecting with TBAF.
  • TBAF 0.3 mL, 1 mol/L in THF, 0.3 mmol
  • A19S-2 132 mg, 0.23 mmol
  • 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.
  • Test Example 1 Screening and solubility test of the salt form of the compound A6S of the present invention
  • the compound A6S of the present invention can form hydrochloride, sulfate, methanesulfonate, phosphate, p-toluenesulfonate, benzenesulfonate, oxalate, maleate Moreover, each salt type has excellent water solubility, and the solubility in ultrapure water is greater than 8 mg/mL, which can meet the requirements of the preparation.
  • the amount of water used is less than 0.1 mL
  • the amount of water is greater than or equal to 0.1 mL and less than 1.0 mL;
  • the amount of water used is greater than or equal to 1.0 mL and less than 5.0 mL.
  • the salt form of the representative compound of the present invention has excellent water solubility and does not need to be prepared into a fat emulsion preparation, and can overcome various adverse reactions caused by the fat emulsion preparation.
  • Test Example 3 Determination of pharmacological data and safety data of the compounds of the present invention
  • 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 weighed 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 ⁇ 10 mg/kg; 10 mg/kg ⁇ C ⁇ 20 mg/kg; D>20 mg/kg.
  • the experiment selected SD rats, and the drug was administered through the tail vein (dosage rate 0.02ml/s, administration volume 0.6ml/rat).
  • the ED50 of the compound causing loss of righting reflex was determined by the sequential method.
  • the compound dose selection for each test started from 5mg/kg, and the actual administration dose was calculated according to the body weight of each animal before the test. The subsequent dose increase or decrease was determined according to the reaction of the experimental animal (whether the loss of righting reflex occurred).
  • the ED50 of the compound causing loss of righting reflex was calculated according to the formula. After the ED50 was measured, the compound's anesthesia onset time, anesthesia maintenance time, anesthesia recovery time, etc. were further tested under the 2ED50 dose condition.
  • the measured ED50 of the compound SD rats were still selected, and one side of the femoral artery was catheterized under basic anesthesia. While continuously monitoring the rats' arterial blood pressure, heart rate, respiratory rate and other indicators, the effects of the compound of the present invention on the rats' blood pressure, heart rate and respiratory rate at a dose of 2ED50 were observed when the rats were given a single injection through the tail vein (dosing rate 0.02 ml/s, dosing volume 0.6 ml/rat).
  • the experiment used SD rats, and the drug was administered through the tail vein (dosage rate 0.02ml/s, administration volume 0.5-1.0ml/100g body weight).
  • the dose of each test compound was selected starting from 4ED50 , and the actual dose was calculated according to the body weight of each animal before the test.
  • the sequential method was used to determine whether the compound caused death.
  • the increase or decrease of subsequent doses was determined based on the reaction of the experimental animals (whether death occurred).
  • the dose at which death occurred for the first time was determined as the minimum lethal dose.
  • the minimum lethal dose is defined as a multiple of the minimum anesthetic effective dose as an approximate therapeutic dose. Index.
  • the approximate therapeutic index in the present invention is further classified as follows: 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.
  • SD rats were selected for the test. After the tail vein catheter was placed, a single injection of 1.5ED 50 was given, followed by another injection of 1ED 50 one minute later. After the drug was administered, the tail vein catheter was connected to the syringe through an extension tube. The initial infusion rate for each rat was determined according to the specific compound. The infusion rate was halved after 5 minutes, and then adjusted every 5 minutes. The infusion rate was increased or decreased according to the rat's response. When the predetermined infusion time was reached, the infusion was stopped, and the time for the rat's righting reflex to recover, the time and type of adverse reactions in the experiment, etc. were observed and recorded.
  • the onset time and recovery time of anesthesia 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.
  • the effect of the compound on the circulation and respiration of the experimental animals can also be observed through the circulation effect experiment.
  • 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.
  • 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.
  • the present invention provides a piperazine-substituted phenol derivative as shown in formula I,
  • the derivatives not only have good salt-forming properties and excellent water solubility, which can meet the requirements of preparations, but also have a low minimum effective anesthetic dose, can take effect quickly and recover quickly, overcome the shortcomings of propofol fat emulsion preparations and propofol water-soluble prodrugs, and have better safety than propofol. They have broad application prospects in the preparation of drugs with sedative, hypnotic and/or anesthetic effects and drugs that can control status epilepticus, and provide a new choice for the clinical preparation of drugs with sedative, hypnotic and/or anesthetic effects and drugs that can control status epilepticus.

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Abstract

提供了一种结构如式(I)所示的哌嗪取代苯酚类衍生物。该化合物不仅成盐性好，水溶性优良，能满足制剂的要求，同时最小麻醉有效剂量低，能够快速起效和快速恢复，克服了丙泊酚和环泊酚的前药和脂肪乳制剂的缺点，在制备具有镇静、催眠和/或麻醉作用的药物以及能够控制癫痫持续状态的药物中具有广阔的应用前景。

Description

哌嗪取代苯酚类衍生物及其用途 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一类结构新颖的哌嗪取代苯酚类衍生物，其合成方法及其在制备具有镇静、催眠和/或麻醉作用的药物和制备能够控制癫痫持续状态的药物中的应用。
背景技术
丙泊酚是目前临床上普遍用于全身麻醉的诱导、全身麻醉的维持、ICU危重病人镇静的一种快速、短效静脉全身麻醉药。它具有麻醉诱导起效快、苏醒迅速且功能恢复完善，术后恶心呕吐发生率低等优点。
但是，临床应用实践中显示丙泊酚会导致严重的循环抑制、呼吸抑制、注射痛、躁动、多语等不良反应。为了提高丙泊酚的效价强度，研究者们在丙泊酚的基础上开发出的另一个结构类似的药物环泊酚，提高了效价，但仍未解决上述丙泊酚存在的问题。
由于丙泊酚和环泊酚既不溶于水也不能成盐，其临床上采用的剂型主要为脂肪乳制剂。该脂肪乳制剂是将丙泊酚或环泊酚溶解在植物油(主要成分为脂肪酸甘油三酯)中，以磷脂为乳化剂，加入等渗剂和注射用水制成的稳定的水包油型(O/W)乳剂，可供静脉注射。但是，近年来研究发现，脂肪乳制剂在临床上容易导致多种不良反应，包括：静脉炎症反应、急性肾衰、过敏反应、过敏性休克、心律失常、丙泊酚输注综合征等。为了克服脂肪乳制剂带来的不良反应，研究者们开发出了水溶性前药。磷丙泊酚二钠是一种水溶性丙泊酚前药，静脉注射后在体内被内皮细胞表面的碱性磷酸酶代谢产生活性药物丙泊酚，从而在大脑组织内迅速达到平衡，发挥剂量依赖性的催眠镇静作用。但是，与丙泊酚相比，磷丙泊酚二钠的起效时间明显减慢，长达2.9min，无法满足快速起效的要求。
为了解决上述问题，亟需开发出一种不仅具有优良的水溶性，同 时还能够快速起效的新型镇静、催眠和全身麻醉药物，克服或改进丙泊酚存在的上述问题。
发明内容
本发明的目的是提供一种结构新颖的式I所示哌嗪取代苯酚类衍生物，其合成方法及其在制备具有镇静、催眠和/或麻醉作用的药物和制备能够控制癫痫持续状态的药物中的应用。
本发明提供了式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物：
其中，R选自氢、CORa、COCH(NH2)Ra、COORh1、CH2COORh1、保护基团、PO(ORh1)(ORh2)或CH2OPO(ORh1)(ORh2)；Ra为氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；Rh1、Rh2各自独立地选自氢、C1-4烷基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
R1、R2、R3、R4、R5、R6各自独立地选自氢、卤素、C1～4烷基或3～6元环烷基；且R1、R2、R3、R4、R5和R6不同时为甲基；
R7、R8各自独立地选自氢、卤素或C1-4烷基；
p选自0～8的整数，各个R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；或者p选自2～8的整数，其中两个R9连接成环，其余R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；或者p选自1～9的整数，其中一个R9连接在与R10连接的氮原子上形成季铵盐，其余R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；
R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、 芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
Re为氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～4烷基、C1～4烷氧基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～4烷基；
Rf选自氢、C1～4烷基或卤代C1～4烷基；
Ri选自氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基或3～6元杂环基；
m选自0、1、2、3、或4；
n选自2、3、或4；
t选自1、2、3、或4。
进一步地，所述化合物的结构如式II所示：
其中，R1、R2、R3、R4、R5、R6各自独立地选自氢、卤素、C1～4烷基或3～6元饱和环烷基；
p选自0～8的整数，各个R9各自独立地选自氢、C1～4烷基；或者p选自2～8的整数，其中两个R9连接成环，其余R9各自独立地选自氢、C1～4烷基；或者p选自1～9的整数，其中一个R9连接在与R10连接的氮原子上形成季铵盐，其余R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；
R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
Re为氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～4烷基、C1～4烷氧基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～4烷基；
Rf选自氢、C1～4烷基或卤代C1～4烷基；
Ri选自氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基或3～6元杂环基；
m选自0、1、2、3、或4；
n选自2、3、或4；
t选自1、2、3、或4。
进一步地，所述化合物的结构如式III所示：
其中，R11、R12各自独立地选自甲基、
R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～4烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～4烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～4烷基；
R10如上述式II中所述。
进一步地，所述化合物的结构如式IV-1或式IV-2所示：
其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
Re为氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、环烷基、杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～3烷基；
Rf选自氢、C1～3烷基或卤代C1～3烷基；
Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基；
m选自0、1、2、3、或4；
n选自2、3、或4；
t选自1、2、3、或4。
进一步地，所述化合物的结构如式IV-1或式IV-2所示：
其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～3烷基、 卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
Re为氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～3烷基；
Rf选自氢、C1～3烷基或卤代C1～3烷基；
Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基；
m选自0、1、2、3、或4；
n选自2、3、或4；
t选自1、2、3、或4。
进一步地，所述结构片段为下述结构之一：

进一步地，所述化合物的结构如式V-1或式V-2所示：
其中，R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～2烷基、卤代C1～2烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、苯基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～2烷基、卤代C1～2烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、苯基或杂芳基；
Re为氢、C1～2烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、苯基或杂芳基；
上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、苯基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～2烷基、C1～2烷氧基、卤代C1～2烷基、乙烯基、乙炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～2烷基；
Rf选自氢、C1～2烷基或卤代C1～2烷基；
Ri选自氢、C1～2烷基、乙烯基、乙炔基、3～6元饱和环烷基或3～6元饱和杂环基；
m选自0、1、2、3、或4；
n选自2、3、或4；
t选自1、2、3、或4。
进一步地，所述3～6元饱和环烷基选自所述3～6元饱和杂环基选自 所述3-6元环状结构选自环丙烷基、环丁烷基、环戊烷基、环己烷基；所述卤素选自氟、氯、溴。
进一步地，所述化合物的结构如式VI-1或式VI-2所示：
其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
m选自0、1、2、3、或4；
Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原 子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rc中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～3烷基；
Rf选自氢、C1～3烷基或卤代C1～3烷基；
Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基。
进一步地，所述化合物的结构如式VI-1或式VI-2所示：
其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
m选自0、1、2、3、或4；
Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原 子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～4烷基、卤代C1～4烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rc中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2各自独立地选自氢或C1～3烷基；
Rf选自氢、C1～3烷基或卤代C1～3烷基；
Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基。
进一步地，所述结构片段为下述结构之一：
m选自1、2、或3；
Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、3～6元饱和环烷基、4～6元饱和杂环基；或Rb1和Rb2与其连接的碳原子一起形成3-4元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
Rc为氢、C1～4烷基、卤代C1～4烷基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rc中的烷基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2、Rf、Ri如上述式VI-1或式VI-2中所述。
进一步地，所述化合物的结构如式VII-1或式VII-2所示：
其中，m选自1或2；
Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、3～6元饱和环烷基、4～6元饱和杂环基；
Rc为氢、C1～4烷基、卤代C1～4烷基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
上述Rb1、Rb2、Rc中的烷基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
Rd1、Rd2、Rf、Ri如上述式VI-1或式VI-2中所述。
进一步地，式VI-1、式VI-2、式VII-1、或式VII-2中：
m选自1或2；
Rb1、Rb2各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙烷基；
Rc为甲基、乙基、正丙基、异丙基、叔丁基、CF3、环丙烷基、
进一步地，所述化合物的结构选自：




“*”表示手性中心。
进一步地，所述药学上可接受的盐为乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环已氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、茶磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟蔡酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐、昔萘酸盐、甲烷磺酸盐或对甲苯磺酸盐。
本发明还提供了一种药物，它是以上述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明还提供了上述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物在制备具有镇静、催眠和/或麻醉作用的药物和/或能够控制癫痫持续状态的药物中的用途。
本发明所述“具有镇静作用的药物”是指一种有效帮助睡眠和有效改善睡眠的药物。即能避免失眠对人体的严重危害，治疗失眠病，提高睡眠质量。
本发明所述“具有催眠作用的药物”是指一种能诱导睡意、促使睡眠的药物。即对中枢神经系统有抑制作用，小剂量引起镇静，过量导致全身麻醉。
本发明所述“具有麻醉作用的药物”是指由药物产生的一种中枢神经和(或)周围神经系统的可逆性功能抑制，这种抑制的特点主要是感觉特别是痛觉的丧失。
优选地，所述麻醉为全身麻醉。
本发明所述“全身麻醉”简称全麻，是指麻醉药进入体内后对中枢神经系统产生的暂时抑制，临床表现为神志消失、全身痛觉消失、遗忘、反射抑制和骨骼肌松弛。
本发明所述的“癫痫持续状态”是指癫痫连续发作之间意识未完全恢复又频繁再发，或发作持续30分钟以上不自行停止。长时间癫痫发作，若不及时治疗，可因高热、循环衰竭或神经元兴奋毒性损伤导致不可逆的脑损伤，致残率和病死率很高，因而癫痫状态是内科常见的急症。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表示任何含“a”至“b”个碳原子的烷基。例如，C1～6烷基是指包含1～6个碳原子的直链或支链的烷基。
本发明式I所示化合物中，“p选自2～8的整数，其中两个R9连接成环”中所述的环包括螺环、桥环、稠环。
本文“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换，包括该分子中同位原子或异位原子上的1个、2个或多个取代。
“亚烷基”指对应烷基失去一个氢原子后剩余的基团。例如，C1～4烷基是指包含1～4个碳原子的直链或支链的亚烷基；C2亚烷基指
表示结构片段之间的连接位点。
“环烷基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环。例如，“3～6元饱和环烷基”指环碳原子数为3～6的饱和的环烷基。
“杂环基”指饱和或不饱和的环状烃取代基；环状烃可以是单环也可以是多环，且携带至少一个环杂原子(包括但不限于O、S或N)。例如，“3～6元饱和杂环基”指环碳原子数为3～6的饱和的杂环基。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或 未取代的。
“桥环”指多环的环烷基，且该多环的环烷基中有两个环共用两个不相邻的碳原子。
“螺环”指多环的环烷基，且该多环的环烷基中有两个环共用一个碳原子。
“稠环”指多环的环烷基，且该多环的环烷基中有两个环共用两个相邻的碳原子。
本发明所述式III、式IV-1、式IV-2、式IV-1、式IV-2、式VI-1或式VI-2中，“R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环”是指R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起后，与作为一个整体，形成螺环；“R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环”是指R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起后，与作为一个整体，形成桥环或稠环。
“卤素”为氟、氯、溴或碘。
“氘代衍生物”指化合物中的一个或两个以上的氢原子被氘替换后得到的化合物。
“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
“盐”是将化合物或其立体异构体，与无机和/或有机酸和/或碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。
本发明中所述药学上可接受的盐可以是化合物的所述药学上可接受的盐为乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬 酸盐、环已氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、茶磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟蔡酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐、昔萘酸盐、甲烷磺酸盐、对甲苯磺酸盐或季铵盐。
本发明化合物或其组合物及使用方法：
本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于实施镇静、催眠和/或全身麻醉。本发明化合物也可用于控制癫痫持续状态等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。
本发明化合物或药物组合物的使用方式包括(但并不限于)：胃内、肠内、肠胃外(静脉内、肌肉内或皮下)、口服和各种局部给药。
用于肠胃外(静脉内、肌肉内、皮下)注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺 以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的安全和有效给药剂量。
与现有技术相比，本发明提供的化合物取得了以下有益效果：
1.本领域技术人员公知的，丙泊酚和环泊酚无法成盐，不溶于水，限制了其临床应用。但是本发明化合物能够成盐，且各盐型具有优良的水溶性并能满足制剂的要求。
2.本领域技术人员公知的，由于丙泊酚和环泊酚不溶于水，临床上采用的剂型主要为脂肪乳制剂，脂肪乳制剂在临床上容易导致多种不良反应。但是，本发明化合物的盐型具有优良的溶解性且溶解度满足制剂需求，能够有效克服脂肪乳剂引起的不良反应，提高安全性。
3.本领域技术人员公知的，丙泊酚和环泊酚的前药具有一定的水溶性，但是其效时间慢，无法满足快速起效和快速恢复的要求。但是，本发明化合物不是前药，而是活性成分，它起效时间短，能够快速产生全身麻醉作用。
综上，本发明提供的化合物不仅成盐性好，水溶性优良且溶解度满足制剂需求，同时最小麻醉有效剂量低，能够快速起效和快速恢复，克服了丙泊酚及其前药和脂肪乳制剂的缺点，在制备具有镇静、催眠和/或麻醉作用的药物以及能够控制癫痫持续状态的药物中具有广阔的应用前景，为临床上制备具有镇静、催眠和/或麻醉作用及控制癫 痫持续状态等的药物提供了一种新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400)核磁仪，测定溶剂为氘代二甲基亚砜(d6-DMSO)或者氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
LCMS的测定用(Agilent LCMS 1260-6110)(ESI)，柱子：Waters X-Bridge C18(50mm x 4.6mm x 3.5μm)。柱温：40℃；流速：2.0mL/min；流动相：在3分钟时间内从95％[water+0.05％TFA]和5％[CH3CN+0.05％TFA]梯度到0％[water+0.05％TFA]和100％[CH3CN+0.05％TFA]，在此条件下保持1分钟，再在0.05分钟内梯度到95％[water+0.05％TFA]和5％[CH3CN+0.05％TFA]，再保持此条件0.7分钟。
1)药材与试剂
薄层层析硅胶板使用烟台新诺化工有限公司HSGF254硅胶板，厚度为1mm。
薄层色谱法(TLC)使用烟台江友硅胶开发有限公司的产品，其规格为0.2±0.03mm。
柱层层析一般采用乳山市太阳干燥剂有限公司(山东威海)100～200目或者200～300目硅胶为载体。
2)主要仪器
Sartorius BSA124S电子天平(赛多利斯科学仪器北京有限公司)；
98-2磁力搅拌器(上海司乐仪器有限公司)；
MS-H-PRO+数控加热型磁力搅拌器(大龙兴创实验仪器北京股份公司)；
TDGC2-1型接触式调压器(浙江天正电器股份有限公司)；
WMNK-01型温控仪(上海禄霖电器有限公司)；
ZF-I三用紫外仪(上海安亭电子仪器厂)；
R-201旋转蒸发器(上海市申顺生物科技有限公司)；
W201D恒温水浴锅(上海市申顺生物科技有限公司)；
SHB-III循环水式真空泵(郑州汇成科工贸有限公司)；
SHB-B95移动水泵(郑州汇成科工贸有限公司)；
DLSB-5/20℃低温冷却循环泵(巩义市予华仪器有限公司)；
2XZ-2旋片式真空泵(临海市永昊真空设备有限公司)；
VRD-16双极旋片式真空泵(浙江飞越机电有限公司)；
DGJ-10C真空冷冻干燥机(上海博登生物科技有限公司)；
Biotage Isolera One快速制备液相色谱(Biotage Sweden AB公司)。
实施例1本发明化合物A1及盐酸盐的制备
1、化合物A1-1的制备
在0℃下，将NBS(6.71g,37.70mmol)加入到A-0(7.70g,37.69mmol)的乙腈(77mL)溶液中，0℃搅拌30分钟。经TLC监测反应完全后，向反应体系中加入H2O(100mL)，用EtOAc(3×70mL)萃取，合并有机相用饱和食盐水洗涤，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(二氯甲烷/石油醚(v/v)＝1/200～1/50)，TLC(二氯甲烷/石油醚(v/v)＝1/20)监测，收集Rf＝0.4～0.5部分，得到黄色油状化合物A1-1(4.21g，收率39.4％)。ESI[M+H]+＝283.1。
2、化合物A1-2的制备
在0℃下，将NaH(196mg,60％,4.90mmol)分批加入到A1-1(1.26g,4.45mmol)的干燥四氢呋喃(12mL)溶液中，搅拌30分钟后，加入TIPSCl(891mg,4.62mmol)。将反应体系升至室温，搅拌3小时。经TLC监测反应完全后，向反应体系中加入H2O(20mL)，用EtOAc (3×30mL)萃取，合并有机相用饱和食盐水洗涤，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(正庚烷为流动相)，TLC(乙酸乙酯/石油醚(v/v)＝1/50)监测，收集Rf＝0.5～0.6部分，得到白色固体化合物A1-2(1.93g，收率98.7％)。ESI[M+H]+＝439.3。
3、化合物A1-3的制备
在室温下，将化合物A1-2(1.2g,2.73mmol),Pd2(dba)3(125mg,0.14mmol),t-BuONa(394mg,4.10mmol)和JohnPhos(81mg,0.27mmol)溶解在1,4-二氧六环(15mL)溶液中，用氮气将反应体系置换三次，氮气保护，50℃搅拌4小时。经TLC监测反应完全后，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100～1/5)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.3～0.4部分，得到白色固体化合物A1-3(1.48g，收率99.5％)。ESI[M+H]+＝545.3。
4、化合物A1-4的制备
在0℃下，将TFA(2mL)加入到A1-3(1.48g,2.72mmol)的二氯甲烷(10mL)溶液中，0℃搅拌4小时。经TLC监测反应完全后，减压浓缩，饱和碳酸氢钠水溶液(20mL)碱化，用EtOAc(3×30mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝100/1～20/1)，TLC(二氯甲烷/甲醇(v/v)＝10/1)监测，收集Rf＝0.4～0.5部分，得到白色固体化合物A1-4(1.20g，收率99.2％)。ESI[M+H]+＝445.3。
5、化合物A1-5的制备
在0℃下，依次将DIEA(349mg,2.70mmol)和溴乙酸甲酯(303mg,1.98mmol)加入到A1-4(800mg,1.80mmol)的乙腈(8mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用EtOAc(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100～1/5)，TLC(乙酸乙酯/石油醚(v/v)＝1/2)监测，收集Rf＝0.5～0.6部分，得到白色固体化合物A1-5(692mg，收率74.4％)。ESI[M+H]+＝517.4。
6、化合物A1的制备
在0℃下，将TBAF(1.34mL,1mol/L in THF,1.34mmol)加入到A1-5(692mg,1.34mmol)的四氢呋喃(7mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用EtOAc(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100～1/2)，TLC(乙酸乙酯/石油醚(v/v)＝1/2)监测，收集Rf＝0.3～0.4部分， 得到白色固体化合物A1(200mg，收率41.4％)。ESI[M+H]+＝361.3。1H NMR(400MHz,CD3OD)δ6.84(d,J＝2.9Hz,1H),6.73(d,J＝2.9Hz,1H),3.76(s,3H),3.34(s,2H),3.33–3.27(m,1H),3.16–3.09(m,4H),2.83–2.74(m,4H),2.55–2.45(m,1H),1.29(d,J＝7.0Hz,3H),1.24(d,J＝6.9Hz,3H),1.23(d,J＝6.9Hz,3H),1.11–1.00(m,1H),0.62–0.52(m,1H),0.44–0.34(m,1H),0.26–0.17(m,1H),0.17–0.09(m,1H).
7、化合物A1盐酸盐的制备
在-20℃下，将HCl/Et2O(0.155mL,2mol/L in THF,0.31mmol)溶液缓慢加至A1(112mg,0.31mmol)的乙醚(5mL)溶液中，-20℃搅拌5分钟，经低温减压浓缩得到粗产品。粗产品经乙醚洗涤后得到白色固体化合物A1盐酸盐(71.7mg，收率58.3％)。ESI[M+H]+＝361.3。1H 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).
实施例2本发明化合物A2及盐酸盐、A5及盐酸盐、A6及盐酸盐的制备
化合物A2、A5、A6的制备方法类同于化合物A1，以A1-4为起始原料，与溴代化合物经取代，脱保护得到化合物A2、A5、A6。化合物A2、A5、A6相应的盐酸盐的制备方法也类同于化合物A1盐酸盐的制备方法。制备路线如下：
化合物A2盐酸盐：白色固体，71.2mg，ESI[M+H]+＝375.3。1H 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).
化合物A5盐酸盐：白色固体，132.9mg，ESI[M+H]+＝375.3。1H 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).
化合物A6盐酸盐：白色固体，114.7mg，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),1.14–1.03(m,1H),0.65–0.55(m,1H),0.45–0.36(m,1H),0.29–0.16(m,1H),0.13–0.04(m,1H).
实施例3本发明化合物A3及盐酸盐的制备
1、化合物A3-1的制备
在0℃下，依次将Et3N(205mg,2.0mmol)和3-氯-3-氧代丙酸甲酯(184mg,1.35mmol)加入到A1-4(300mg,0.67mmol)的二氯甲烷(5mL)溶液中，室温搅拌1小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用二氯甲烷(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/3)并收集Rf＝0.5～0.6部分得到白色固体化合物A3-1(350mg，收率95.2％)。ESI[M+H]+＝545.3。
2、化合物A3的制备
在0℃下，将TBAF(0.64mL,1mol/L in THF,0.64mmol)加入到A3-1(350mg,0.64mmol)的四氢呋喃(5mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用EtOAc(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/2)并收集Rf＝0.3～0.4部分得到白色固体化合物A3(224.5mg，收率89.9％)。ESI[M+H]+＝389.2。
3、化合物A3盐酸盐的制备
在-20℃下，将HCl/Et2O(0.29mL,2mol/L in THF,0.58mmol)溶液缓慢加至A3(224.5mg,0.58mmol)的乙醚(5mL)溶液中，-20℃搅拌5分钟，低温减压浓缩得到粗产品。粗产品经乙醚洗涤后得到白色固体化合物A3盐酸盐(224.6mg，收率91.5％)。ESI[M+H]+＝389.2。1H 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).
实施例4本发明化合物A4及盐酸盐的制备
化合物A4及盐酸盐的制备方法类同于化合物A1，以丙泊酚为起始原料制备得到。
化合物A4盐酸盐：白色固体，135.9mg，ESI[M+H]+＝335.3。1H 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).
实施例5本发明化合物A7及盐酸盐的制备
1、化合物A7-1的制备
在室温下，依次将K2CO3(93.2mg,0.67mmol)和2-溴乙醇(61.8mg,0.49mmol)加入到A1-4(200mg,0.45mmol)的乙腈(3mL)溶液中，80℃搅拌12小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用EtOAc(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(二氯甲烷/甲醇(v/v)＝10/1)并收集Rf＝0.5～0.6部分得到白色固体化合物A7-1(115mg，收率52.3％)。ESI[M+H]+＝489.3。
2、化合物A7的制备
在0℃下，将TBAF(0.24mL,1mol/L in THF,0.24mmol)加入到A7-1(115mg,0.24mmol)的四氢呋喃(3mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用EtOAc(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(二氯甲烷/甲醇(v/v)＝10/1)并收集Rf＝0.4～0.5部分得到白色固体化合物A7(70.6mg，收率90.3％)。ESI[M+H]+＝333.4。
3、化合物A7盐酸盐的制备
在-70℃下，将HCl/Et2O(0.16mL,2mol/L in THF,0.32mmol)溶液缓慢加至A7(70.6mg,0.21mmol)的乙醚(3mL)溶液中，-70℃搅拌 5分钟，低温减压浓缩得到粗产品。粗产品经乙醚洗涤后得到白色固体化合物A7盐酸盐(76.4mg，收率92.9％)。ESI[M+H]+＝333.4。
1H 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).
实施例6本发明化合物A8及盐酸盐的制备
1、化合物A8-1的制备
在0℃下，将LiOH.H2O(146mg,3.48mmol)加入到A1-5(900mg,1.74mmol)的THF/MeOH/H2O(9mL,v/v/v＝1/1/1)溶液中，室温搅拌1小时。经TLC监测反应完全后，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝100/1～10/1)，TLC(二氯甲烷/甲醇(v/v)＝10/1)监测，收集Rf＝0.4～0.5部分，得到白色固体化合物A8-1(730mg，收率82.4％)。ESI[M+H]+＝503.3。
2、化合物A8-2的制备
在室温下，将草酰氯(175mg,1.38mmol)加入到A8-1(233mg,0.46mmol)的二氯甲烷(5mL)中，室温搅拌1小时。经监测反应完全后，减压浓缩得到粗产品A8-2(260mg)，粗产品未经纯化直接用于下一步反应。
3、化合物A8-3的制备
在0℃下，将Et3N(93mg,0.92mmol)和氧杂环丁-3-醇(40.9mg,0.55mmol)加入到粗产品A8-2(260mg)的二氯甲烷(3mL)溶液中，室温搅拌2小时。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用二氯甲烷(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/2)并收集Rf＝0.3～0.4部分得到白色固体化合物A8-3(76.5mg，两步收率29.9％)。ESI[M+H]+＝559.3。
4、化合物A8的制备
在0℃下，将TBAF(0.14mL,1mol/L in THF,0.14mmol)加入到A8-3(76.5mg,0.14mmol)的四氢呋喃(2mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(5mL)加至反应体系，用EtOAc(3×15mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/1)并收集Rf＝0.3～0.4部分得到白色固体化合物A8(54mg，收率98.0％)。ESI[M+H]+＝403.3。
5、化合物A8盐酸盐的制备
在-20℃下，将HCl/Et2O(0.10mL,2mol/L in THF,0.20mmol)溶液缓慢加至A8(54mg,0.13mmol)的乙醚(3mL)溶液中，-20℃搅拌5分钟，低温减压浓缩得到粗产品。粗产品经乙醚洗涤后得到白色固体化合物A8盐酸盐(34.5mg，收率56.3％)。ESI[M+H]+＝403.3。
1H NMR(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),1.11–1.00(m,1H),0.63–0.53(m,1H),0.45–0.32(m,1H),0.25–0.17(m,1H),0.14–0.05(m,1H).
实施例7本发明化合物A6R及硫酸盐的制备
1、化合物A6R-1的制备
在室温下，依次将Et3N(910.7mg,9.0mmol,2.67eq),NaI(1.35g,9.0mmol,2.67eq)和(S)-2-氯丙酸甲酯(1.10g,9.0mmol,2.67eq)依次加入到A1-4(1.5g,3.37mmol,1eq)的干燥DMF(20mL)溶液中，60℃搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将体系降至室温，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～10％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.6部分，得到无色油状化合物A6R-1(1.685g，收率94.2％)。ESI[M+H]+＝531.4。
2、化合物A6R的制备
在冰浴0℃下，将TBAF(4.9mL,1mol/L in THF,4.9mmol,1.5eq) 加入到A6R-1(1.685g,3.17mmol,1eq)的干燥THF(20mL)溶液中，0℃搅拌2分钟。经TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测反应完全后，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～12％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状化合物A6R-2(1085.8mg，收率91.5％)。ESI[M+H]+＝375.2。
3、化合物A6R硫酸盐的制备
在室温下，将A6R(1085.8mg,2.90mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(568.65mg,5.80mmol,2.0eq)的Et2O(2mL)溶液缓慢加至A6R(112mg,0.31mmol)的乙醚(30mL)溶液中，-70℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(30mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×20mL)洗涤。将固体溶解在超纯水(30mL)中，经过冻干机冻干64小时得到白色固体化合物A6R硫酸盐(1526.42mg，收率100％)。ESI[M+H]+＝375.2。
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),1.11–1.03(m,1H),0.62–0.55(m,1H),0.44–0.36(m,1H),0.26–0.18(m,1H),0.11–0.03(m,1H).
实施例8本发明化合物A6S及硫酸盐的制备
1、化合物A6S-1的制备
在室温下，依次将Et3N(1.82g,18.0mmol,3eq)，NaI(2.70g,18.0mmol,3eq)和(S)-2-氯丙酸甲酯(2.21g,18.0mmol,3eq)依次加入到A1-4(2.67g,6.0mmol,1eq)的干燥DMF(25mL)溶液中，60℃搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将体系降至室温，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙 酸乙酯/石油醚(v/v)＝0～10％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.6部分，得到无色油状化合物A6S-1(2.833g,收率88.9％)。ESI[M+H]+＝531.4。
2、化合物A6S的制备
在冰浴0℃下，将TBAF(4.1mL,1mol/L in THF,4.1mmol,1.2eq)加入到A6S-1(1.805g,3.40mmol,1eq)的干燥THF(20mL)溶液中，0℃搅拌2分钟。经TLC(乙酸乙酯/石油醚(v/v)＝1/5，Rf＝0.5)监测反应完全后，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～12％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状化合物A6S(1.337g，收率100％)。ESI[M+H]+＝375.2。
3、化合物A6S硫酸盐的制备
在室温下，将A6S(1.337g,3.57mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(700.2mg,7.14mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(30mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×20mL)洗涤。将固体溶解在超纯水(30mL)中，经过冻干机冻干24小时得到白色固体化合物A6S硫酸盐(1856.5mg，收率100％)。ESI[M+H]+＝375.2。
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),1.12–1.04(m,1H),0.62–0.55(m,1H),0.44–0.35(m,1H),0.26–0.17(m,1H),0.12–0.03(m,1H).
实施例9本发明化合物A11及硫酸盐和A18及硫酸盐的制备
1、化合物A11-1的制备
在室温下，将化合物A1-2(6.0g,13.65mmol),4,7-二氮杂螺[2.5]辛烷-4-甲酸叔丁酯(5.0g,23.55mmol)，Pd2(dba)3(1.25g,1.37mmol),t-BuOK(3.06g,27.30mmol)和JohnPhos(814.7mg,2.73mmol)溶解在1,4-二氧六环(40mL)溶液中，用氮气将反应体系置换三次，氮气保护，70℃搅拌过夜。经TLC(正庚烷)监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状粗品化合物A11-1(5.7g)。ESI[M+H]+＝571.4。
2、化合物A11-2的制备
在冰盐浴0℃下，将TFA(5mL)加入到粗品化合物A11-1(5.7g,9.98mmol)的二氯甲烷(15mL)溶液中，0℃搅拌4小时。经TLC监测反应完全后，减压浓缩，饱和碳酸氢钠水溶液(20mL)碱化，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝1/1，然后甲醇/二氯甲烷(v/v)＝0～1/1)，TLC(甲醇/二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.5部分，得到无色油状化合物A11-2(3.617g，两步收率56.3％)。ESI[M+H]+＝471.4。
3、化合物A11-3的制备
在冰水浴0℃下，依次将DIEA(517.0mg,4.0mmol)和溴乙酸甲酯(458.9mg,3.0mmol)加入到A11-2(941.6mg,2.0mmol)的二氯甲烷(20mL)溶液中，室温搅拌过夜。经TLC(甲醇/二氯甲烷(v/v)＝1/10) 监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状化合物A11-3(920mg，收率77.0％)。ESI[M+H]+＝543.4。
4、化合物A11的制备
在冰盐浴0℃下，将TBAF(2.0mL,1mol/L in THF,2.0mmol)加入到A11-3(920mg,1.69mmol)的干燥THF(10mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～20％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状粗品化合物A11(660.2mg，收率100％)。ESI[M+H]+＝387.2。
5、化合物A11硫酸盐的制备
在室温下，将A11(537mg,1.39mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(276.7mg,2.82mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(20mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×20mL)洗涤。将固体溶解在超纯水(30mL)中，经过冻干机冻干24小时得到白色固体化合物A11硫酸盐(644.4mg，收率100％)。ESI[M+H]+＝387.2。
1H 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).
6、化合物A18硫酸盐的制备
化合物A18的制备方法类同于A11，使用A11-2(300mg,0.64mmol)和溴乙酸叔丁酯反应得到A18-1(346mg,0.59mmol，收率92.4％),A18-1经TBAF脱保护得到化合物A18(241.2mg,0.56mmol，收率94.9％),化合物A18经H2SO4/Et2O成盐得到白色固体化合物A18硫酸盐(197.4mg,收率94.9％)。ESI[M+H]+＝429.3。
1H 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).
实施例10本发明化合物A12及硫酸盐的制备
1、化合物A12-1的制备
在室温下，将化合物A1-2(2.0g,4.55mmol),tert-butyl(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(1.93g,9.10mmol),Pd2(dba)3(416.7mg,0.455mmol),t-BuOK(1.02g,9.09mmol)和JohnPhos(271.6mg,0.91mmol)溶解在1,4-二氧六环(30mL)溶液中，用氮气将反应体系置换三次，氮气保护，50℃搅拌24小时。经TLC(正庚烷)监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状粗品化合物A12-1(2.328g)。ESI[M+H]+＝571.4。
2、化合物A12-2的制备
在冰盐浴0℃下，将TFA(3mL)加入到粗品化合物A12-1(2.328g)的二氯甲烷(9mL)溶液中，0℃搅拌4小时。经TLC监测反应完全后，减压浓缩，饱和碳酸氢钠水溶液(20mL)碱化，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝1/1，然后甲醇/二氯甲烷(v/v)＝0～50％)，TLC(甲醇/二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.5部分，得到无色油状化合物A12-2(1.8g，两步收率84.0％)。ESI[M+H]+＝471.4。
3、化合物A12-3的制备
在冰水浴0℃下，依次将DIEA(544.0mg,4.2mmol)和溴乙酸甲酯(489.5mg,3.2mmol)加入到A12-2(1.0g,2.1mmol)的二氯甲烷(15mL)溶液中，室温搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10) 监测反应完全后，将H2O(20mL)加至反应体系，用二氯甲烷(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状粗品化合物A12-3(1.377g)。ESI[M+H]+＝543.4。
4、化合物A12的制备
在冰盐浴0℃下，将TBAF(3.1mL,1mol/L in THF,3.1mmol)加入到A12-3(1.377g,2.54mmol)的干燥THF(15mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～20％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状粗品化合物A12(840mg，两步收率100％)。ESI[M+H]+＝387.3。
5、化合物A12硫酸盐的制备
在室温下，将A12(773.3mg,2.0mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(394.2mg,4.0mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(20mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×20mL)洗涤。将固体溶解在超纯水(30mL)中，经过冻干机冻干24小时得到白色固体化合物A12硫酸盐(1060.6mg，收率100％)。ESI[M+H]+＝387.3。
1H 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).
实施例11本发明化合物A13及盐酸盐和A14及盐酸盐的制备
1、化合物A13-1的制备
在冰水浴0℃下，依次将DIEA(1.293g,10.0mmol)和溴乙酸叔丁酯(975.25mg,5.0mmol)加入到A1-4(444.78mg,1.0mmol)的二氯甲烷(20mL)溶液中，室温搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将H2O(20mL)加至反应体系，用二氯甲烷(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状化合物A13-1(512mg，收率91.6％)。ESI[M+H]+＝559.4。
2、化合物A13的制备
在冰盐浴0℃下，将TBAF(1.1mL,1mol/L in THF,1.1mmol)加入到A13-1(512mg,0.92mmol)的干燥THF(10mL)溶液中，0℃搅拌5分钟。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～20％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状化合物A13(360.0mg，收率97.2％)。ESI[M+H]+＝403.3。
3、化合物A13盐酸盐的制备
在室温下，将A13(360.0mg,0.89mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-60℃。将HCl/Et2O(0.67mL,2mol/L in Et2O,1.34mmol)溶液缓慢加至反应体系，-60℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(20mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×20mL)洗涤。将固体溶解在超纯水(30mL)中， 经过冻干机冻干24小时得到白色固体化合物A13盐酸盐(395mg，收率100％)。ESI[M+H]+＝403.3。
1H 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),0.62–0.54(m,1H),0.43–0.34(m,1H),0.25–0.18(m,1H),0.12–0.05(m,1H).
4、化合物A14-1的制备
A13-1的制备方法同本实施例的第一步反应，用A1-4(444.78g,1.0mmol)和溴乙酸叔丁酯反应经TBAF脱硅基保护后得到。
由于纯化A13-1的时候未将其中的溴乙酸叔丁酯去除干净，导致TBAF脱硅基保护后残余的溴乙酸叔丁酯继续和酚羟基反应得到A14(263.2mg，两步收率50.9％)
5、化合物A14盐酸盐的制备
在室温下，将A14(263.2mg,0.51mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-60℃。将HCl/Et2O(0.38mL,2mol/L in Et2O,0.76mmol)溶液缓慢加至反应体系，-60℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(20mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×20mL)洗涤。将固体溶解在超纯水(30mL)中，经过冻干机冻干24小时得到白色固体化合物A14盐酸盐(241.9mg，收率100％)。ESI[M+H]+＝517.4。
1H NMR(400MHz,CD3OD)δ6.88(d,J＝2.9Hz,1H),6.78(d,J＝2.9Hz,1H),4.23–4.12(m,4H),3.90–3.31(m,8H),3.35–3.18(m,1H),2.45–2.33(m,1H),1.55(s,9H),1.51(s,9H),1.27(d,J＝7.0Hz,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).
实施例12本发明化合物A15及硫酸盐的制备
1、化合物A15-1的制备
在冰水浴0℃下，依次将DIEA(360.54mg,2.81mmol)和溴乙酸(130.27mg,0.94mmol)加入到A1-4(417g,0.94mmol)的二氯甲烷(50mL)溶液中，室温搅拌48小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography(甲醇/二氯甲烷(v/v)＝0～30％)和Prep-TLC(甲醇/二 氯甲烷(v/v)＝1/10)纯化，TLC(甲醇/二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.5部分，得到无色油状化合物A15-1(209.9mg，收率44.4％)。ESI[M+H]+＝503.4。
2、化合物A15的制备
在冰盐浴0℃下，将TBAF(0.8mL,1mol/L in THF,0.8mmol)加入到A15-1(209.9mg,0.42mmol)的干燥THF(10mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography(甲醇/二氯甲烷(v/v)＝0～30％)和Prep-TLC(甲醇/二氯甲烷(v/v)＝1/10)纯化，TLC(甲醇/二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.4部分，得到无色油状化合物A15(121.7mg，收率83.6％)。ESI[M+H]+＝347.3。
3、化合物A15硫酸盐的制备
在室温下，将A15(121.7mg,0.35mmol,1.0eq)溶解在乙醚(10mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(68.9mg,0.7mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-60℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A15硫酸盐(138.1mg，收率100％)。ESI[M+H]+＝347.3。
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).
实施例13本发明化合物A16及硫酸盐的制备
1、化合物A16-1的制备
在室温下，依次将K2CO3(2.07g,15.0mmol)和2-溴-2-甲基丙酸甲酯(1.81g,10.0mmol)加入到A1-4(444.78g,1.0mmol)的MeCN(10mL)溶液中，封管70℃搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状化合物A16-1(253.0mg，收率46.4％)。ESI[M+ H]+＝545.4。
2、化合物A16的制备
在冰盐浴0℃下，将TBAF(0.6mL,1mol/L in THF,0.6mmol)加入到A15-1(253.0mg,0.46mmol)的干燥THF(10mL)溶液中，0℃搅拌1小时。经TLC监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography(乙酸乙酯/石油醚(v/v)＝0～20％)纯化，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状化合物A16(152.6mg，收率85.4％)。ESI[M+H]+＝389.2。
3、化合物A16硫酸盐的制备
在室温下，将A16(135.6mg,0.35mmol,1.0eq)溶解在乙醚(10mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(68.6mg,0.7mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(20mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A16硫酸盐(189.1mg，收率100％)。ESI[M+H]+＝389.2。
1H 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).
实施例14本发明化合物A17及盐酸盐的制备
1、化合物A17-1的制备
在冰水浴0℃下，依次将DIEA(932.7mg,7.2mmol)和溴乙酸叔丁酯(702.2mg,3.6mmol)加入到A4-4(300.0mg,0.72mmol)的二氯甲烷(20mL)溶液中，室温搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将H2O(20mL)加至反应体系，用二氯甲烷(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状粗品化合物A17-1(405.6mg)。ESI[M+H]+＝533.4。
2、化合物A17的制备
在冰盐浴0℃下，将TBAF(0.9mL,1mol/L in THF,0.9mmol)加 入到A17-1(405.6mg,0.76mmol)的干燥THF(10mL)溶液中，0℃搅拌10分钟。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～20％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状化合物A17(188.8mg，两步收率69.6％)。ESI[M+H]+＝377.3。
3、化合物A17盐酸盐的制备
在室温下，将A17(188.8mg,0.50mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-60℃。将HCl/Et2O(0.38mL,2mol/L in Et2O,0.76mmol)溶液缓慢加至反应体系，-60℃搅拌5分钟，经低温减压浓缩得到粗产品。将Et2O(20mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A17盐酸盐(211.6mg，收率100％)。ESI[M+H]+＝377.3。
1H 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).
实施例15本发明化合物A19及硫酸盐,A19S及硫酸盐和A19R及硫酸盐的制备
1、化合物A19S-1的制备
在室温下，将DIEA(122.3mg,0.944mmol)和(R)-2-溴丙酸(144.4mg,0.944mmol)加入到A1-4(420.0mg,0.944mmol)的二氯甲烷(15mL)溶液中，室温搅拌24小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(甲醇/二氯甲烷(v/v)＝1/100～1/10)，TLC(甲醇/ 二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.3部分，得到无色油状化合物A19S-1(227.3mg，收率44.2％)。ESI[M+H]+＝516.4。
2、化合物A19S-2的制备
在室温下，将DMAP(23.0mg,0.19mmol)和Boc2O(412mg,1.888mmol)加入到A19S-1(187mg,0.364mmol)的二氯甲烷(10mL)溶液中，室温搅拌24小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.7部分，得到无色油状化合物A19S-2(132mg，收率63.3％)。ESI[M+H]+＝573.4。
3、化合物A19S的制备
在室温下，将TBAF(0.3mL,1mol/L in THF,0.3mmol)加入到A19S-2(132mg,0.23mmol)的干燥THF(8mL)溶液中，0℃搅拌10分钟。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经Prep-TLC纯化(乙酸乙酯/石油醚(v/v)＝1/10)，收集Rf＝0.5部分，得到无色油状化合物A19S(77mg，收率92.4％)。ESI[M+H]+＝417.3。
4、化合物A19S硫酸盐的制备
在室温下，将A19S(77mg,0.185mmol,1.0eq)溶解在乙醚(10mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(36.3mg,0.37mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A19S硫酸盐(83.3mg，收率100％)。ESI[M+H]+＝417.3
1H 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＝6.9Hz,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).
化合物A19及硫酸盐和A19R及硫酸盐的制备方法类同于化合物A19S及硫酸盐。
实施例16本发明化合物A20及硫酸盐,A20S及硫酸盐和A20R及硫酸盐的制备
1、化合物A20S-1的制备
在室温下，依次将Et3N(218.4mg,2.158mmol,3eq)，NaI(323.5mg,2.158mmol,3eq)和(S)-2-氯丙酸甲酯(264.5mg,2.158mmol,3eq)依次加入到A4-4(300mg,0.716mmol,1eq)的干燥DMF(10mL)溶液中，60℃搅拌5小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将体系降至室温，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～20％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.6部分，得到无色油状化合物A20S-1(331.7mg,收率91.8％)。ESI[M+H]+＝505.4。
2、化合物A20S的制备
在冰浴0℃下，将TBAF(0.8mL,1mol/L in THF,0.8mmol,1.2eq)加入到A20S-1(331mg,0.656mmol,1eq)的干燥THF(20mL)溶液中，0℃搅拌10分钟。经TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～15％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.5部分，得到无色油状化合物A20S(214mg，收率93.6％)。 ESI[M+H]+＝349.2。
3、化合物A20S硫酸盐的制备
在室温下，将A20S(214mg,0.614mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(120.45mg,1.228mmol,2.0eq)的Et2O(2mL)溶液缓慢加至体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A20S硫酸盐(315.3mg，收率100％)。ESI[M+H]+＝349.2。
1H 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).
化合物A20及硫酸盐和A20R及硫酸盐的制备方法类同于目标化合物A20S及硫酸盐。
实施例17本发明化合物A21及盐酸盐,A21S及盐酸盐,A21R及盐酸盐和A27S及盐酸盐的制备
化合物A21,A21S和A21R的制备方法类同于化合物实施例15化合物A19,A19S和A19R。A21盐酸盐,A21S盐酸盐和A21R盐酸盐制备方法类同于实施例14化合物A17盐酸盐制备方法。使用化合物A4-4为起始原料。
化合物A21S-2在分离纯化的时候由于残留的Boc2O没有除干净，导致分离得到75.1mg无色油状化合物A27S，A27S盐酸盐制备方法类同于实施例14化合物A17盐酸盐制备方法。
A21S盐酸盐：白色固体，75.6mg。ESI[M+H]+＝391.3。
1H 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).
A27S盐酸盐：白色固体，64.9mg。ESI[M+H]+＝491.3。
1H 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).
实施例18本发明化合物A22及硫酸盐,A22S及硫酸盐和A22R及硫酸盐的制备
1、化合物A22S-1的制备
在室温下，依次将Et3N(204.76mg,2.024mmol,3eq)，NaI(303.30mg,2.024mmol,3eq)和(R)-2-溴丁酸甲酯(366.31mg,2.024mmol,3eq)依次加入到A1-4(300.0mg,0.675mmol,1eq)的干燥DMF(8mL)溶液中，60℃搅拌8小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将体系降至室温，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～8％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.6部分，得到无色油状化合物 A22S-1(296.0mg,收率80.5％)。ESI[M+H]+＝545.4。
2、化合物A22S的制备
在冰盐浴0℃下，将TBAF(0.7mL,1mol/L in THF,0.7mmol)加入到A22S-1(296mg,0.543mmol)的干燥THF(8mL)溶液中，0℃搅拌10分钟。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～7％)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.4部分，得到无色油状粗品化合物A22S(247.86mg)。ESI[M+H]+＝389.2。
3、化合物A22S硫酸盐的制备
在室温下，将A22S(247.86mg,0.638mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(125.12mg,1.276mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A22S硫酸盐(278.28mg，收率100％)。ESI[M+H]+＝389.2
1H 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).
化合物A22及硫酸盐和A22R及硫酸盐的制备方法类同于化合物A22S及硫酸盐。
实施例19本发明化合物A23及硫酸盐,A23S及硫酸盐和A23R及硫酸盐的制备
1、化合物A23-1的制备
在室温下，依次将Et3N(184.27mg,1.821mmol,3eq)，NaI(272.95mg,1.821mmol,3eq)和2-溴-3-甲基丁酸甲酯(355.20mg,1.821mmol,3eq)依次加入到A1-4(270.0mg,0.607mmol,1eq)的干燥DMF(10mL)溶液中，60℃搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10)监测反应完全后，将体系降至室温，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～8％)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.6部分，得到无色油状化合物A23-1(103.0mg,收率30.4％)。ESI[M+H]+＝559.4。
2、化合物A23的制备
在冰盐浴0℃下，将TBAF(0.25mL,1mol/L in THF,0.25mmol)加入到A23-1(103.0mg,0.184mmol)的干燥THF(5mL)溶液中，0℃搅拌10分钟。经TLC监测反应完全后，将H2O(20mL)加至反应体系，用乙酸乙酯(3×5mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～7％)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.3部分，得到无色油状化合物A23(46.1mg,收率62.2％)。ESI[M+H]+＝403.3。
3、化合物A23硫酸盐的制备
在室温下，将A23(46.1mg,0.115mmol,1.0eq)溶解在乙醚(20mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(22.46mg, 0.229mmol,2.0eq)的Et2O(2mL)溶液缓慢加至反应体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A23硫酸盐(54.18mg，收率100％)。ESI[M+H]+＝403.3
1H NMR(400MHz,CD3OD)δ7.38(d,J＝2.9Hz,1H),7.24(d,J＝2.9Hz,1H),3.79(s,3H),3.75–3.64(m,4H),3.36–3.31(m,1H),3.26–3.11(m,5H),2.53–2.42(m,1H),2.25–2.10(m,1H),1.29(d,J＝6.9Hz,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).
化合物A23及硫酸盐和A23R及硫酸盐的制备方法类同于化合物A23S及硫酸盐。
实施例20本发明化合物A24及硫酸盐,A24S及硫酸盐,A24R及硫酸盐和A26及硫酸盐的制备
1、化合物A24-1的制备
在室温下，依次将Et3N(341.6mg,3.376mmol,3eq)，NaI(337.0mg,2.248mmol,2eq)和2-溴-2-环丙基乙酸乙酯(465.5mg,2.248mmol,2eq)依次加入到A1-4(500.0mg,1.125mmol,1eq)的干燥DMF(10mL)溶液中，60℃搅拌4小时。经TLC(甲醇/二氯甲烷(v/v)＝1/10) 监测反应完全后，将体系降至室温，将H2O(30mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～5％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.5部分，得到无色油状化合物A24-1(512.7mg,收率79.9％)。ESI[M+H]+＝571.4。
2、化合物A24-2的制备
在冰盐浴0℃下，将NaOMe(0.25mL,0.25mmol)加入到A24-1(240.0mg,0.42mmol)的MeOH(5mL)溶液中，0℃搅拌10小时。经TLC监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～7％)，TLC(乙酸乙酯/石油醚(v/v)＝1/8)监测，收集Rf＝0.4部分，得到无色油状化合物A24-2(43.2mg,收率18.5％)。ESI[M+H]+＝557.4。
3、化合物A24的制备
在冰盐浴0℃下，将TBAF(0.1mL,1mol/L in THF,0.1mmol)加入到A24-2(43.2mg,0.078mmol)的干燥THF(5mL)溶液中，0℃搅拌10分钟。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用乙酸乙酯(3×5mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～7％)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.3部分，得到无色油状化合物A24(21.0mg,收率67.2％)。ESI[M+H]+＝401.3。
4、化合物A24硫酸盐的制备
在室温下，将A24(21.0mg,0.0524mmol,1.0eq)溶解在乙醚(10mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(10.30mg,0.105mmol,2.0eq)的Et2O(1mL)溶液缓慢加至反应体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A24硫酸盐(26.0mg，收率100％)。ESI[M+H]+＝401.3
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),0.86–0.77(m,1H),0.76–0.67(m,1H),0.67–0.53(m,2H),0.43–0.34(m,1H),0.25–0.18(m,1H),0.12–0.04(m,1H).
化合物A24S及硫酸盐和A24R及硫酸盐的制备方法类同于化合物A24及硫酸盐。
5、化合物A26及A26硫酸盐的制备
在冰盐浴0℃下，将TBAF(0.5mL,1mol/L in THF,0.5mmol)加入到A24-1(232.3mg,0.407mmol)的干燥THF(5mL)溶液中，0℃搅拌5分钟。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用乙酸乙酯(3×5mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经经flash column chromatography纯化(乙酸乙酯/石油醚(v/v)＝0～8％)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.3部分，得到无色油状化合物A26(160.0mg,收率94.8％)。ESI[M+H]+＝415.2。
在室温下，将A26(160.0mg,0.386mmol,1.0eq)溶解在乙醚(10mL)中，用干冰乙醇浴将反应体系降至-70℃。将H2SO4(75.70mg,0.772mmol,2.0eq)的Et2O(1mL)溶液缓慢加至反应体系，-70℃搅拌10分钟，经低温减压浓缩得到粗产品。将Et2O(10mL)加至粗产品，搅拌，抽滤，固体经Et2O(3×10mL)洗涤。将固体溶解在超纯水(20mL)中，经过冻干机冻干24小时得到白色固体化合物A26硫酸盐(220.59mg，收率100％)。ESI[M+H]+＝415.2
1H 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),1.28(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).
实施例21本发明化合物A25S的制备
在室温下，依次将A6S-1(200mg,0.377mmol),MeI(106.95mg,0.753mmol,2eq)和DIEA(146.4mg,1.133mmol)溶解在干燥DMF(10mL)溶液中，室温搅拌12小时。经TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测反应完全后，减压浓缩得到粗产品，粗产品经flash column chromatography纯化(甲醇/二氯甲烷(v/v)＝0～50％)，TLC(甲醇/二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.5部分，得到粗品化合物A25S-1 (301mg)。
在冰盐浴0℃下，将TBAF(0.1mL,1mol/L in THF,0.1mmol)加入到粗品化合物A25S-1(300mg)的干燥THF(5mL)溶液中，0℃搅拌10分钟。经TLC监测反应完全后，将H2O(10mL)加至反应体系，用乙酸乙酯(3×10mL)萃取，合并有机相用无水Na2SO4干燥，抽滤，减压浓缩得到粗产品，粗产品经经flash column chromatography纯化(甲醇/二氯甲烷(v/v)＝0～50％)，TLC(甲醇/二氯甲烷(v/v)＝1/10)监测，收集Rf＝0.5部分，得到无色油状化合物A25S(70.7mg,两步收率36.3％)。ESI[M-I]＝389.2。
1H 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).
以下通过试验例证明本发明的有益效果。
试验例1本发明化合物A6S盐型筛选及溶解度测试
1.实验方法
在室温下，将化合物A6S(1eq)溶解在Et2O(2mL)中，将对应酸(2eq)溶解在Et2O(序号1-4)或者MeOH(序号5-10)中，用注射器将酸溶液缓慢加至化合物A6S所在的反应体系，序号1-3室温搅拌1小时，序号5-10室温搅拌16小时。抽滤，固体用乙醚洗涤，干燥，得到化合物A6S相应盐型。然后测试各盐型在超纯水中的溶解度。
表1.本发明化合物A6S盐型筛选及溶解度
2.实验结果
从表1可以看出，本发明化合物A6S能够形成盐酸盐、硫酸盐、甲烷磺酸盐、磷酸盐、对甲苯磺酸盐、苯磺酸盐、草酸盐、马来酸盐 等各种类盐型。而且，各盐型均具有优良的水溶性，在超纯水中的溶解度均＞8mg/mL，均能满足制剂的要求。
试验例2本发明化合物盐型的溶解度测定
1.实验方法
称取10mg本发明化合物相应的盐，置于25℃±2℃，加入水，每隔5分钟强力振摇30秒钟，观察30分钟，上述试验体系中看不见溶质颗粒或液滴时，按照以下标准记录化合物成盐后的水溶性：
A:水的用量小于0.1mL；
B:水的用量大于等于0.1mL且小于1.0mL；
C:水的用量大于等于1.0mL且小于5.0mL。
2.实验结果
表2.本发明化合物盐型的溶解度
本领域技术人员公知的，丙泊酚和环泊酚无法成盐，不溶于水。 但是根据表2可以看出，本发明代表性化合物盐型具有优良的水溶性，不用制备成脂肪乳制剂，能够克服脂肪乳制剂带来的各种不良反应。
试验例3本发明化合物的药理数据和安全性数据测定
1.实验方法
(1)测试本发明代表性化合物在大鼠尾静脉注射后的麻醉效果(最小麻醉有效剂量的测定)：
试验选用SD大鼠，尾静脉给药(给药速度0.02ml/s，给药容积0.6ml/只)。以序贯法测定化合物是否导致翻正反射的消失。每次试验化合物剂量选择从1mg/kg开始，实际给药剂量按照每只动物试验前称量的体重计算。根据实验动物的反应(是否出现翻正反射消失)确定后续剂量的递增或递减。第一次出现翻正反射消失的剂量确定为最小麻醉有效剂量。本发明中最小麻醉有效剂量进一步归类为：A≤5mg/kg；5mg/kg<B≤10mg/kg；10mg/kg<C≤20mg/kg；D＞20mg/kg。
(2)测试本发明代表性化合物在大鼠尾静脉注射后的麻醉效果(半数有效剂量ED50的测定)及等效剂量的药理特点：
试验选用SD大鼠，尾静脉给药(给药速度0.02ml/s，给药容积0.6ml/只)。以序贯法测定化合物致翻正反射消失的ED50。每次试验化合物剂量选择从5mg/kg开始，实际给药剂量按照每只动物试验前称量的体重计算。根据实验动物的反应(是否出现翻正反射消失)确定后续剂量的递增或递减。当试验测试出五个同向变化的翻正反射消失与恢复后，根据公式计算出化合物致翻正反射消失的ED50。测得ED50后，在2ED50剂量条件下进一步测试化合物的麻醉起效时间、麻醉维持时间、麻醉恢复时间等。
(3)测试本发明代表性化合物在2ED50剂量条件下对大鼠血压、心率、呼吸频率的影响：
根据已测得的化合物的ED50，仍选用SD大鼠，在基础麻醉条件下选择一侧股动脉置管，在连续监测大鼠动脉血压、心率，以及呼吸频率等指标时，观察尾静脉单次注射给药(给药速度0.02ml/s，给药容积0.6ml/只)时本发明化合物在2ED50剂量条件下对大鼠血压、心率、呼吸频率的影响。
(4)测试本发明化合物在大鼠尾静脉注射后的最小致死剂量：
试验选用SD大鼠，尾静脉给药(给药速度0.02ml/s，给药容积为0.5-1.0ml/100克体重)。每次试验化合物剂量选择从4ED50开始，实际给药剂量按照每只动物试验前称量的体重计算。以序贯法测定化合物是否导致死亡。根据实验动物的反应(是否出现死亡)确定后续剂量的递增或递减。第一次出现死亡的剂量确定为最小致死剂量。本发明中将最小致死剂量为最小麻醉有效剂量的倍数定义为近似治疗 指数。本发明中近似治疗指数进一步归类为：近似治疗指数大于等于5时，归类为A；近似治疗指数小于5、大于等于3时，归类为B；近似治疗指数小于3时，归类为C。
(5)测试本发明化合物在大鼠持续输注不同时间后停药的恢复时间：
试验选用SD大鼠，尾静脉置管后单次注射给药1.5ED50、随后1分钟再注射1ED50剂量，给药后尾静脉置管上通过延长管连接注射器。根据具体化合物确定每只大鼠的起始输注速率，5分钟后将输注速率减半，之后每5分钟调整一次输注速率，根据大鼠的反应进行输注速度的调增或调减。当达到预定输注时间后停止输注，并观察记录大鼠翻正反射恢复的时间、试验中出现不良反应的时间和种类等。
在上述试验中，除了记录出现翻正反射消失的剂量，还可以记录麻醉的起效时间和恢复时间、翻正反射的持续时间和产生镇静作用的持续时间。在本发明化合物致翻正反射消失的剂量，还可以通过循环影响实验观察到化合物对实验动物循环和呼吸的影响。在持续输注实验中，还可以观察到本发明化合物在持续输注不同时间停药后至大鼠活动正常的苏醒时间。
2.实验结果
表3.本发明化合物盐型单次静脉注射的药理数据

从表3可以看出，本发明代表性化合物试验时所选盐型多数可以直接溶解在纯水或生理盐水中，最小麻醉有效剂量低，起效时间短，能够快速产生全身麻醉作用。
表4.本发明化合物的安全性数据
从表4可以看出，本发明代表性化合物除了能够快速产生全身麻醉作用和快速恢复之外，与丙泊酚相比还具有更好的安全性(包括更轻的循环抑制和呼吸抑制)；在持续输注时，麻醉恢复的时间更短，也具有更好的安全性。
结合表3和表4可以看出，本发明的代表性化合物具有优良的麻醉效果和/或具有优良的安全性，临床应用前景广阔。
综上，本发明提供了一种式I所示的哌嗪取代苯酚类衍生物，该 衍生物不仅成盐性好，水溶性优良，能满足制剂的要求，同时最小麻醉有效剂量低，能够快速起效和快速恢复，克服了丙泊酚脂肪乳制剂的缺点和丙泊酚水溶性前药的缺点，同时与丙泊酚相比具有更好的安全性，在制备具有镇静、催眠和/或麻醉作用的药物以及能够控制癫痫持续状态的药物中具有广阔的应用前景，为临床上制备具有镇静、催眠和/或麻醉作用及控制癫痫持续状态等的药物提供了一种新的选择。

Claims (17)

  1. 式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物：
    其中，R选自氢、CORa、COCH(NH2)Ra、COORh1、CH2COORh1、保护基团、PO(ORh1)(ORh2)或CH2OPO(ORh1)(ORh2)；Ra为氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；Rh1、Rh2各自独立地选自氢、C1-4烷基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
    R1、R2、R3、R4、R5、R6各自独立地选自氢、卤素、C1～4烷基或3～6元环烷基；且R1、R2、R3、R4、R5和R6不同时为甲基；
    R7、R8各自独立地选自氢、卤素或C1-4烷基；
    p选自0～8的整数，各个R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；或者p选自2～8的整数，其中两个R9连接成环，其余R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；或者p选自1～9的整数，其中一个R9连接在与R10连接的氮原子上形成季铵盐，其余R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；
    R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
    其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
    Re为氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元 杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～4烷基、C1～4烷氧基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～4烷基；
    Rf选自氢、C1～4烷基或卤代C1～4烷基；
    Ri选自氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基或3～6元杂环基；
    m选自0、1、2、3、或4；
    n选自2、3、或4；
    t选自1、2、3、或4。
  2. 根据权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式II所示：
    其中，R1、R2、R3、R4、R5、R6各自独立地选自氢、卤素、C1～4烷基或3～6元饱和环烷基；
    p选自0～8的整数，各个R9各自独立地选自氢、C1～4烷基；或者p选自2～8的整数，其中两个R9连接成环，其余R9各自独立地选自氢、C1～4烷基；或者p选自1～9的整数，其中一个R9连接在与R10连接的氮原子上形成季铵盐，其余R9各自独立地选自氢、C1～4烷基、卤代C1～4烷基；
    R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
    其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
    Re为氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～4烷基、C1～4烷氧基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～4烷基；
    Rf选自氢、C1～4烷基或卤代C1～4烷基；
    Ri选自氢、C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基或3～6元杂环基；
    m选自0、1、2、3、或4；
    n选自2、3、或4；
    t选自1、2、3、或4。
  3. 根据权利要求2所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式III所示：
    其中，R11、R12各自独立地选自甲基、
    R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～4 烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～4烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～4烷基；
    R10如权利要求2所述。
  4. 根据权利要求3所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式IV-1或式IV-2所示：
    其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
    R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
    其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～4烷基、卤代C1～4烷基、C2～4烯基、C2～4炔基、3～6元环烷基、3～6元杂环基、芳基或杂芳基；
    Re为氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、环烷基、杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～3烷基；
    Rf选自氢、C1～3烷基或卤代C1～3烷基；
    Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基；
    m选自0、1、2、3、或4；
    n选自2、3、或4；
    t选自1、2、3、或4。
  5. 根据权利要求4所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式IV-1或式IV-2所示：
    其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
    R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、 (CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
    其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    Re为氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～3烷基；
    Rf选自氢、C1～3烷基或卤代C1～3烷基；
    Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基；
    m选自0、1、2、3、或4；
    n选自2、3、或4；
    t选自1、2、3、或4。
  6. 根据权利要求3-5任一所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述结构片段为下述结构之一：
  7. 根据权利要求5所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式V-1或式V-2所示：
    其中，R10选自氢、C1～4烷基、(CRb1Rb2)mCOORc、(CRb1Rb2)mCONRd1Rd2、(CRb1Rb2)nORf、(CRb1Rb2)nNRd1Rd2、(CRb1Rb2)nOCORe、(CRb1Rb2)nNRd1CORe、(CRb1Rb2)mCO(CRb3Rb4)tCOORc、(CRb1Rb2)mCO(CRb3Rb4)tCONRd1Rd2；
    其中，Rb1、Rb2、Rb3、Rb4各自独立地选自氢、卤素、C1～2烷基、卤代C1～2烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、苯基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～2烷基、卤代C1～2烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、苯基或杂芳基；
    Re为氢、C1～2烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、苯基或杂芳基；
    上述Rb1、Rb2、Rb3、Rb4、Rc、Re中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、苯基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～2烷基、C1～2烷氧基、卤代C1～2烷基、乙烯基、乙炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～2烷基；
    Rf选自氢、C1～2烷基或卤代C1～2烷基；
    Ri选自氢、C1～2烷基、乙烯基、乙炔基、3～6元饱和环烷基或3～6元饱和杂环基；
    m选自0、1、2、3、或4；
    n选自2、3、或4；
    t选自1、2、3、或4。
  8. 根据权利要求7所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述3～6元饱和环烷基选自 所述3～6元饱和杂环基选自 所述3-6元环状结构选自环丙烷基、环丁烷基、环戊烷基、环己烷基；所述卤素选自氟、氯、溴。
  9. 根据权利要求5所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式VI-1或式VI-2所示：
    其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
    m选自0、1、2、3、或4；
    Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rc中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～3烷基；
    Rf选自氢、C1～3烷基或卤代C1～3烷基；
    Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或3～6元饱和杂环基。
  10. 根据权利要求1或4所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、 或其氘代衍生物，其特征在于：所述化合物的结构如式VI-1或式VI-2所示：
    其中，R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在同一个碳原子上的两个基团连接在一起，形成螺环，其余基团各自独立地选自氢、C1～3烷基；或者R9a、R9b、R9c、R9d、R9e、R9f、R9h、R9i中，连接在不同碳原子上的两个基团连接在一起，形成桥环或稠环，其余基团各自独立地选自氢、C1～3烷基；所述螺环、桥环或稠环中包含2、3或4个选自N、O、S的杂原子；
    m选自0、1、2、3、或4；
    Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基、杂芳基、CN、ORf、SRf或NRd1Rd2；或者Rb1和Rb2与其连接的碳原子一起形成3-6元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～4烷基、卤代C1～4烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rc中的烷基、烯基、炔基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2各自独立地选自氢或C1～3烷基；
    Rf选自氢、C1～3烷基或卤代C1～3烷基；
    Ri选自氢、C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基或 3～6元饱和杂环基。
  11. 根据权利要求10所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述结构片段为下述结构之一：
    m选自1、2、或3；
    Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、3～6元饱和环烷基、4～6元饱和杂环基；或Rb1和Rb2与其连接的碳原子一起形成3-4元环状结构，该环状结构中含有0或1个选自N、O、S的杂原子；
    Rc为氢、C1～4烷基、卤代C1～4烷基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rc中的烷基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2、Rf、Ri如权利要求10所述。
  12. 根据权利要求10所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构如式VII-1或式VII-2所示：
    其中，m选自1或2；
    Rb1、Rb2各自独立地选自氢、卤素、C1～3烷基、卤代C1～3烷基、3～6元饱和环烷基、4～6元饱和杂环基；
    Rc为氢、C1～4烷基、卤代C1～4烷基、3～6元饱和环烷基、3～6元饱和杂环基、芳基或杂芳基；
    上述Rb1、Rb2、Rc中的烷基、饱和环烷基、饱和杂环基、芳基、杂芳基未被取代或者任选地被一个或两个以上的下述基团取代：卤素、C1～3烷基、C1～3烷氧基、卤代C1～3烷基、C2～3烯基、C2～3炔基、3～6元饱和环烷基、3～6元饱和杂环基、CN、NO2、ORf、SRf、NRd1Rd2、CORi、COORf、OCORi、CONRd1Rd2、NRd1CORi、NRd1SO2Ri或SO2Ri；
    Rd1、Rd2、Rf、Ri如权利要求10所述。
  13. 根据权利要求10-12任一所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于，式VI-1、式VI-2、式VII-1、或式VII-2中：
    m选自1或2；
    Rb1、Rb2各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙烷基；
    Rc为甲基、乙基、正丙基、异丙基、叔丁基、CF3、环丙烷基、
  14. 根据权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述化合物的结构选自：




    “*”表示手性中心。
  15. 根据权利要求1～14任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物，其特征在于：所述药学上可接受的盐为乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环已氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、茶磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟蔡酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐、昔萘酸盐、甲烷磺酸盐或对甲苯磺酸盐。
  16. 一种药物，其特征在于：它是以权利要求1～15任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物为活性成分，加上药学上可接受的辅料制备而成的制剂。
  17. 权利要求1～15任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物在制备具有镇静、催眠和/或麻醉作用的药物和/或能够控制癫痫持续状态的药物中的用途。
PCT/CN2023/095079 2022-01-28 2023-05-18 哌嗪取代苯酚类衍生物及其用途 WO2024082629A1 (zh)

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