WO2023274258A1 - 一种杂原子取代的芳香类化合物及其制备方法和用途 - Google Patents

一种杂原子取代的芳香类化合物及其制备方法和用途 Download PDF

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WO2023274258A1
WO2023274258A1 PCT/CN2022/102054 CN2022102054W WO2023274258A1 WO 2023274258 A1 WO2023274258 A1 WO 2023274258A1 CN 2022102054 W CN2022102054 W CN 2022102054W WO 2023274258 A1 WO2023274258 A1 WO 2023274258A1
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hydrogen
alkyl
independently selected
heteroatom
hydroxyl
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French (fr)
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刘进
柯博文
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四川大学华西医院
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a heteroatom-substituted aromatic compound, a preparation method and application thereof.
  • Lidocaine a local anesthetic (local anesthetic) long-term clinically used in local nerve block and epidural anesthesia, has the advantages of strong penetrating power, strong and long-lasting drug effect, It can be used for local anesthesia by injection or surface anesthesia by infiltration.
  • lidocaine can not only be used for anesthesia of poultry animals, chickens, mammals, dogs, horses, pigs, alpacas, etc.
  • IVL intravenous injection
  • Assisting with general anesthesia can also significantly reduce the incidence of postoperative pain, reduce the consumption of opioids during operation, promote the recovery of bowel function in postoperative patients, and reduce the length of hospital stay and recovery time.
  • lidocaine while maintaining many clinical advantages of lidocaine, obtain anesthetic drugs with higher safety, faster metabolic rate, good recovery quality, and good analgesic effect, reduce the side effects of intravenous injection in the perioperative period, and improve its efficacy.
  • Safe use of dose ranges to improve postoperative delirium has significant clinical and economic value, thus making the application of this type of drug more extensive, with very important clinical significance and broad application prospects.
  • the present invention provides a heteroatom-substituted aromatic compound and its preparation method and application, which can satisfactorily achieve the above objectives.
  • the present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof:
  • X is selected from -NH- or -O-;
  • R 1 to R 7 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, substituted or Unsubstituted ester group, 3 to 6-membered cycloalkyl group, -OC(O)R 7 '; the substituent of the ester group is selected from -NR 8 'R 9 '; when X is selected from O, R 1 to At least 2 of R 5 are not simultaneously selected from hydrogen;
  • R 7 ' is selected from substituted C 1 to C 8 alkyl or -NR 8 'R 9 '; the substituent of the alkyl is selected from -NR 8 'R 9 ' or morpholinyl;
  • R 8 , R 8 ', R 9 , and R 9 ' are each independently selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; said alkyl, cycloalkane
  • the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, ester, -OC(O)OR 10 ' or hydrogen phosphate Sodium; and R 8 and R 9 are not unsubstituted C 1 -C 8 alkyl at the same time;
  • R 8 ' is connected to R 9 ', or R 8 is connected to R 9 to form an N atom
  • X 1 is selected from none, -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is selected from none, -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, halogen, amino, cyano, nitro, sulfonic acid, mercapto, ester, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 -alkyl, 3-6-membered cycloalkyl or 3-6-membered saturated heterocyclic group; the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said The heteroatoms of the saturated carbon heterocycle are O, S or N; the number of said heteroatoms is 1, 2 or 3.
  • R 1 to R 7 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, substituted or Unsubstituted ester group, 3 to 6-membered cycloalkyl group, -OC(O)R 7 '; the substituent of the ester group is selected from -NR 8 'R 9 '; when X is selected from O, R 1 to At least 2 of R 5 are not simultaneously selected from hydrogen;
  • R 7 ' is selected from substituted C 1 to C 8 alkyl or -NR 8 'R 9 '; the substituent of the alkyl is selected from -NR 8 'R 9 ' or morpholinyl;
  • R 8 ' is connected to R 9 ', or R 8 is connected to R 9 to form an N atom
  • R 10 ' is selected from hydrogen or C 1 -C 8 alkyl
  • X 1 is selected from none, -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is selected from none, -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, halogen, amino, cyano, nitro, sulfonic acid, mercapto, ester, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 -alkyl, 3-6-membered cycloalkyl or 3-6-membered saturated heterocyclic group; the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said The heteroatoms of the saturated carbon heterocycle are O, S or N; the number of said heteroatoms is 1, 2 or 3.
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano;
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, substituted or unsubstituted ester ;
  • the substituent of the ester group is selected from -NR 8 'R 9 ';
  • R 8 ' and R 9 ' are independently selected from C 1 -C 8 alkyl groups
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto
  • R 8 , R 9 are independently selected from substituted or unsubstituted C 2 -C 8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, the number of substituted substituents is any integer from 1 to 6, and the substituted
  • the groups are independently selected from C 1 ⁇ C 8 alkoxy, halogen, ester group, -OC(O)OR 10 ' or sodium hydrogen phosphate;
  • R 8 and R 9 are independently selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
  • the number of substituted substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, ester, -OC(O)OR 10 ' or phosphoric acid sodium hydrogen;
  • R 10 ' is selected from hydrogen or C 1 -C 8 alkyl.
  • R 7 ' is selected from substituted C 1 to C 8 alkyl or -NR 8 'R 9 '; the substituent of the alkyl is selected from -NR 8 'R 9 ' or morpholinyl;
  • R 8 ' and R 9 ' are independently selected from C 1 -C 8 alkyl groups
  • X 1 is selected from none, -O-, -CR 16 R 17 -;
  • Y 1 is selected from none, -CR 16 R 17 -;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, cyano, nitro, sulfonic acid, mercapto, ester; or In R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle; the heteroatom of the saturated carboheterocycle is O, S or N, the number of heteroatoms is 1, 2 or 3;
  • the compound is shown in formula II-B1:
  • X 1 is selected from none, -O-, -CR 16 R 17 -;
  • Y 1 is selected from none, -CR 16 R 17 -;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, cyano, nitro, sulfonic acid, mercapto, ester; or In R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle; the heteroatom of the saturated carboheterocycle is O, S or N, the number of heteroatoms is 1, 2 or 3.
  • R 1 to R 7 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester ;
  • X 1 is selected from none, -O-, -CR 16 R 17 -;
  • Y 1 is selected from none, -CR 16 R 17 -;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, cyano, nitro, sulfonic acid, mercapto, ester; or In R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle; the heteroatom of the saturated carboheterocycle is O, S or N, the number of heteroatoms is 1, 2 or 3;
  • Y 1 is selected from -CR 16 R 17 -, at least two of R 10 to R 17 are not selected from hydrogen; when R 6 or R 7 are both selected from hydrogen, or one of them are selected from methyl, when only two of R 10 to R 17 are not selected from hydrogen but are selected from methyl, R 12 and R 13 are not methyl at the same time, or R 16 and R 17 are not methyl at the same time, or Any one of R 10 and R 11 is different from any one of R 14 and R 15 ; or any one of R 12 and R 13 is different from any one of R 16 and R 17 ;
  • X 1 is selected from -O-
  • Y 1 is selected from -CR 16 R 17 -
  • R 6 and R 7 are both selected from hydrogen, and only two of R 10 to R 17 are not selected from hydrogen but selected from methyl
  • any one of R 10 and R 11 is different from any one of R 16 and R 17 , it is a methyl group; or any one of R 12 and R 13 is different from any one of R 14 and R 15. It is a methyl group;
  • R 1 and R 13 are selected from hydrogen, methyl or ethyl
  • R 5 are selected from alkyl groups
  • R 3 and R 6 are independently selected from hydrogen or methyl
  • R 12 and R 13 are not selected from methyl at the same time
  • one of R 12 and R 13 is selected from methyl, the other is not selected from hydroxyl or methyl;
  • the ring formed by the connection is not is a substituted or unsubstituted 4-membered saturated carbocyclic ring; or, the spiro ring formed by connection is not
  • R 1 to R 5 are independently selected from hydrogen, C 1 to C 4 alkyl, hydroxyl, and ester;
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 4 alkyl
  • X 1 is selected from none, -O-, -CR 16 R 17 -;
  • Y 1 is selected from none, -CR 16 R 17 -;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 4 alkyl; or in R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6-membered saturated carbocycle, 4-6 A saturated carboheterocycle; the heteroatom of the saturated carboheterocycle is O, S or N, and the number of the heteroatom is 1.
  • R 3 , R 6 , and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto , ester group;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 8 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, cyano, nitro, sulfonic acid, mercapto, ester; or In R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle; the heteroatoms of the saturated carboheterocycle are O, S, N, the number of heteroatoms is 1, 2 or 3;
  • R 3 is selected from hydrogen, C 1 -C 4 alkyl, hydroxyl, ester group
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 4 alkyl
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 4 alkyl; or in R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocycle;
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester;
  • R 10 to R 17 are independently selected from hydrogen, C 1 to C 4 alkyl; or in R 10 to R 17 , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocyclic ring.
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester;
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 8 alkyl
  • R 10 to R 15 are independently selected from hydrogen, C 1 to C 8 alkyl; or in R 10 to R 15 , two substituents on the same carbon atom are connected to form a 3-6-membered carbocycle, 3-6-membered Saturated carbon heterocyclic ring; the heteroatom of the saturated carbon heterocyclic ring is O, S or N, and the number of the heteroatoms is 1, 2 or 3;
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 4 alkyl
  • R 10 to R 15 are independently selected from hydrogen, C 1 to C 4 alkyl; or in R 10 to R 15 , two substituents on the same carbon atom are connected to form a 4-6 membered saturated carboheterocycle; the The heteroatom of the saturated carbon heterocyclic ring is O, S or N, and the number of said heteroatom is 1.
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester;
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 8 alkyl
  • R 10 to R 13 are independently selected from hydrogen, C 1 to C 8 alkyl; or in R 10 to R 13 , two substituents on the same carbon atom are connected to form a 3-6-membered carbocycle, 3-6-membered Saturated carbon heterocyclic ring; the heteroatom of the saturated carbon heterocyclic ring is O, S or N, and the number of the heteroatoms is 1, 2 or 3;
  • R 3 is selected from hydrogen, C 1 -C 4 alkyl, hydroxyl, ester group
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 4 alkyl
  • R 10 to R 13 are independently selected from hydrogen, C 1 to C 4 alkyl; or in R 10 to R 13 , two substituents on the same carbon atom are connected to form a 4-6 membered saturated carboheterocycle; the The heteroatom of the saturated carbon heterocyclic ring is O, S or N, and the number of said heteroatom is 1.
  • R 3 is selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester;
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 8 alkyl
  • R 10 ⁇ R 13 , R 16 ⁇ R 17 are independently selected from hydrogen, C 1 ⁇ C 8 alkyl; or R 10 ⁇ R 13 , R 16 ⁇ R 17 , two substituents on the same carbon atom are connected Forming a 3-6 membered saturated carbon heterocyclic ring; the heteroatoms of the saturated carbon heterocyclic ring are O, S, N, and the number of the heteroatoms is 1, 2 or 3;
  • R 6 to R 7 are independently selected from hydrogen, C 1 to C 4 alkyl
  • R 10 ⁇ R 13 , R 16 ⁇ R 17 are independently selected from hydrogen, C 1 ⁇ C 4 alkyl; or among R 10 ⁇ R 13 , R 16 ⁇ R 17 , two substituents on the same carbon atom are connected A 4- to 6-membered saturated carbon heterocycle is formed; the heteroatom of the saturated carbon heterocycle is O, S or N, and the number of the heteroatom is 1.
  • R 1 to R 5 are independently selected from hydrogen, C 1 to C 2 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester , 3-6 membered cycloalkyl, and at least 2 of R 1 to R 5 are not selected from hydrogen at the same time;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-6 membered cycloalkyl;
  • R 8 and R 9 are independently selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; the number of substituted substituents is any of 1-6 Integer, the substituents are independently selected from hydroxyl, C 1 ⁇ C 8 alkoxy, halogen, ester, -OC(O)OR 10 ' or sodium hydrogen phosphate; and R 8 and R 9 are not unsubstituted at the same time C 1 ⁇ C 8 alkyl;
  • R 10 ' is selected from C 1 -C 8 alkyl
  • X 1 is none, -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is none, -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle
  • the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate;
  • the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 10 to R 15 are not simultaneously selected from hydrogen; or, R 12 and R 13 are not selected from unsubstituted methyl;
  • R 10 to R 17 are not simultaneously selected from hydrogen
  • R 1 to R 5 are independently selected from hydrogen, C 1 to C 2 alkyl, C 1 to C 8 alkoxy, halogen, hydroxyl, amino, carboxyl, cyano, nitro, sulfonic acid, mercapto, ester , 3-6 membered cycloalkyl, and at least 2 of R 1 to R 5 are not selected from hydrogen at the same time;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-6 membered cycloalkyl;
  • R 8 and R 9 are independently selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; the number of substituted substituents is any of 1-6 Integer, the substituents are independently selected from hydroxyl, C 1 ⁇ C 8 alkoxy, halogen, ester, -OC(O)OR 10 ' or sodium hydrogen phosphate; and R 8 and R 9 are not unsubstituted at the same time C 1 ⁇ C 8 alkyl;
  • R 8 and R 9 are connected with N atom to form
  • R 10 ' is selected from C 1 -C 8 alkyl
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle
  • the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate;
  • the heteroatoms of the saturated heterocyclic group are O, S or N; the number of heteroatoms is 1, 2 or 3; when X 1 is -O-, Y 1 is -CR 16 R 17 -, R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when X 1 is -O-, Y 1 is -CR 16 R 17 -, and two of R 10 to R 17 are methyl, and the rest are hydrogen, R 12 or R 13 Any one of and any one of R 16 or R 17 cannot be selected from methyl at
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R' 10 to R' 11 , R' 14 to R' 15 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered ring Alkyl or 3-6 membered saturated heterocyclic group; the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, Carboxyl, ester or carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3; R' 12 to R' 13 are independently selected From hydrogen, hydroxyl, C 1 -C 8 alkoxy, substituted C 1 -C 8 alkyl, unsubstituted C 2 -C 8 alkyl, 3-6 membered cycloalkyl or 3-6 membered saturated heterocycle The number of substituents is any integer from 1 to 6, and the substituents are independently selected from
  • R' 10 to R' 15 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle,
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • X 2 is -O- or -CR 16 R 17 -;
  • R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are independently selected from hydrogen, hydroxyl, C 1 ⁇ C 8 alkoxy, substituted or unsubstituted C 1 ⁇ C 8 alkyl, 3 ⁇ 6 membered cycloalkyl Or a 3-6 membered saturated heterocyclic group; the number of the substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, carboxyl, ester group or methyl carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3; when X 2 is -CR 16 R 17 -, R" 10 ⁇ R" 15 , R 16 ⁇ R 17 are not selected from hydrogen at the same time;
  • R 10 ⁇ R” 15 , R 16 ⁇ R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 A saturated carbon heterocyclic ring, the heteroatom of the saturated carbon heterocyclic ring is O, S or N; the number of heteroatoms is 1, 2 or 3;
  • R 1 to R 5 are independently selected from hydrogen, C 1 to C 2 alkyl, hydroxyl, halogen or 3 to 6 membered cycloalkyl, and at least two of R 1 to R 5 are not selected from hydrogen at the same time;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 8 and R 9 are independently selected from substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-4 membered cycloalkyl; the number of the substituted substituent is 1, and the substituent are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen or ester; and R 8 and R 9 are not unsubstituted C 1 -C 3 alkyl at the same time;
  • R 8 and R 9 are connected with N atom to form
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 2 alkoxy, substituted or unsubstituted C 1 to C 4 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle group; the number of substituents is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or carboxylate; the saturated heterocyclic group
  • the heteroatom is O; the number of heteroatoms is 1; when X 1 is -O-, Y 1 is -CR 16 R 17 -, R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when X 1 is -O -, Y 1 is -CR 16 R 17 -, and two of R 10 to R 17 are methyl, and the rest are hydrogen, any one of R 12 or R 13 and any one of R 16 or R 17 cannot be at the same time selected from methyl;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocyclic ring is O, S or N; the number of the heteroatom is 1;
  • R' 10 to R' 15 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle,
  • the heteroatom of the saturated carbon heterocycle is O; the number of the heteroatom is 1;
  • X 2 is -O- or -CR 16 R 17 -;
  • R” 10 to R” 15 , R 16 to R 17 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, substituted or unsubstituted C 1 to C 3 alkyl, 3 to 6 membered cycloalkyl Or a 3-6 membered saturated heterocyclic group; the number of the substituents is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or carboxylate methyl ;
  • the heteroatom of the saturated heterocyclic group is O; the number of the heteroatom is 1; when X 2 is -CR 16 R 17 -, R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are not selected simultaneously from hydrogen;
  • R 10 ⁇ R” 15 , R 16 ⁇ R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 A saturated carbon heterocyclic ring, the heteroatom of the saturated carbon heterocyclic ring is O; the number of the heteroatoms is 1;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-4 membered cycloalkyl;
  • R 8 and R 9 are independently selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; the number of substituted substituents is any of 1-6 Integer, the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen or ester; and R 8 and R 9 are not unsubstituted C 1 -C 8 alkyl;
  • R 8 and R 9 are connected with N atom to form
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle
  • the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate;
  • the heteroatoms of the saturated heterocyclic group are O, S or N; the number of heteroatoms is 1, 2 or 3; when X 1 is -O-, Y 1 is -CR 16 R 17 -, R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when X 1 is -O-, Y 1 is -CR 16 R 17 -, and two of R 10 to R 17 are methyl, and the rest are hydrogen, R 12 or R 13 Any one of and any one of R 16 or R 17 cannot be selected from methyl at
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R' 10 to R' 11 , R' 14 to R' 15 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered ring Alkyl or 3-6 membered saturated heterocyclic group; the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, Carboxyl, ester or carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3; R' 12 to R' 13 are independently selected From hydrogen, hydroxyl, C 1 -C 8 alkoxy, substituted C 1 -C 8 alkyl, unsubstituted C 2 -C 8 alkyl, 3-6 membered cycloalkyl or 3-6 membered saturated heterocycle The number of substituents is any integer from 1 to 6, and the substituents are independently selected from
  • R' 10 to R' 15 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle,
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • X 2 is -O- or -CR 16 R 17 -;
  • R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are independently selected from hydrogen, hydroxyl, C 1 ⁇ C 8 alkoxy, substituted or unsubstituted C 1 ⁇ C 8 alkyl, 3 ⁇ 6 membered cycloalkyl Or a 3-6 membered saturated heterocyclic group; the number of the substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, carboxyl, ester group or methyl carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3; when X 2 is -CR 16 R 17 -, R" 10 ⁇ R" 15 , R 16 ⁇ R 17 are not selected from hydrogen at the same time;
  • R 10 ⁇ R” 15 , R 16 ⁇ R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 A saturated carbon heterocyclic ring, the heteroatom of the saturated carbon heterocyclic ring is O, S or N; the number of heteroatoms is 1, 2 or 3;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 8 and R 9 are independently selected from substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted 3-4 membered cycloalkyl; the number of the substituted substituent is 1, and the substituent are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen or ester; and R 8 and R 9 are not unsubstituted C 1 -C 3 alkyl at the same time;
  • R 8 and R 9 are connected with N atom to form
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 2 alkoxy, substituted or unsubstituted C 1 to C 4 alkyl, 3 to 6 membered cycloalkyl or 4 to 6 membered saturated heterocycle group; the number of substituents is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or carboxylate; the saturated heterocyclic group
  • the heteroatom is O, S or N; the number of said heteroatom is 1; when X 1 is -O-, Y 1 is -CR 16 R 17 -, R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when X 1 is -O-, Y 1 is -CR 16 R 17 -, and two of R 10 to R 17 are methyl and the rest are hydrogen, any one of R 12 or R 13 and R 16 or R 17 Any one cannot be selected from methyl at the same time;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocyclic ring is O, S or N; the number of the heteroatom is 1;
  • R' 10 to R' 11 , R' 14 to R' 15 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, substituted or unsubstituted C 1 to C 3 alkyl, 3 to 6 membered ring Alkyl or 3-6 membered saturated heterocyclic group; the number of substituents is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or methyl carboxylate Ester group; the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1; R' 12 to R' 13 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy group, substituted C 1 -C 3 alkyl group, unsubstituted C 2 -C 4 alkyl group, 3-6 membered cycloalkyl group or 3-6 membered saturated heterocyclic group; the number of the substituents is 1, and the The substituents are independently selected from
  • R' 10 to R' 15 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle,
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1;
  • X 2 is -O- or -CR 16 R 17 -;
  • R” 10 to R” 15 , R 16 to R 17 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, substituted or unsubstituted C 1 to C 3 alkyl, 3 to 6 membered cycloalkyl Or a 3-6 membered saturated heterocyclic group; the number of the substituents is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or carboxylate methyl ;
  • the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1; when X 2 is -CR 16 R 17 -, R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are not simultaneously selected from hydrogen;
  • R 10 ⁇ R” 15 , R 16 ⁇ R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 A saturated carbon heterocyclic ring, the heteroatom of the saturated carbon heterocyclic ring is O, S or N; the number of the heteroatom is 1;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-4 membered cycloalkyl;
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is -O- or -CR 16 R 17 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle group; the number of substituents to be substituted is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate ; the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1, 2 or 3; when X 1 is -O-, Y 1 is -CR 16 R 17 -, R 10 to R 17 cannot be selected from hydrogen at the same time; when X 1 is -O-, Y 1 is -CR 16 R 17 -, and two of R 10 to R 17 are methyl and the rest are hydrogen, R 12 or Any one of R 13 and any one of R 16 or R 17 cannot be selected from methyl at
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • Y 1 is -O- or -CR 16 R 17 -;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered carbocyclic ring or a 3-6 membered saturated carboheterocyclic ring, and the saturated
  • the heteroatom of the carboheterocycle is O, S or N; the number of the heteroatom is 1;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-4 membered cycloalkyl;
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle group; the number of substituents to be substituted is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate ;
  • the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1, 2 or 3; when X 1 is -O-, R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; When X 1 is -O-, and two of R 10 to R 17 are methyl and the rest are hydrogen, any one of R 12 or R 13 and any one of R 16 or R 17 cannot be selected from methyl at the same time ;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • X 1 is -O-, -S-, -SO-, -SO 2 -, -CR 16 R 17 - or -NR 18 -;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 2 alkoxy, substituted or unsubstituted C 1 to C 4 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle group; the number of substituents to be substituted is 1, and the substituents are independently selected from hydroxyl, C 1 to C 3 alkoxy, halogen, carboxyl, ester or methyl carboxylate; the saturated heterocycle
  • the heteroatom of the group is O, S or N; the number of said heteroatom is 1; when X 1 is -O-, R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when X 1 is -O-, and R When two of 10 to R 17 are methyl groups and the rest are hydrogen, any one of R 12 or R 13 and any one of R 16 or R 17 cannot be selected from methyl at the same time;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-4 membered cycloalkyl;
  • R 10 to R 17 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle group; the number of substituents to be substituted is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate ; the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1, 2 or 3; and R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when R 10 ⁇ R 17 has When two are methyl and the rest are hydrogen, any one of R 12 or R 13 and any one of R 16 or R 17 cannot be selected from methyl at the same time;
  • R 10 to R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 10 to R 17 are independently selected from hydrogen, hydroxyl, C 1 to C 2 alkoxy, substituted or unsubstituted C 1 to C 4 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle group; the number of substituents to be substituted is 1, and the substituents are independently selected from hydroxyl, C 1 to C 3 alkoxy, halogen, carboxyl, ester or methyl carboxylate; the saturated heterocycle
  • the heteroatom of the group is O, S or N; the number of said heteroatom is 1; and R 10 ⁇ R 17 cannot be selected from hydrogen at the same time; when two of R 10 ⁇ R 17 are methyl groups and the rest are hydrogen , any one of R 12 or R 13 and any one of R 16 or R 17 cannot be selected from methyl at the same time;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-6 membered cycloalkyl;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocycle
  • the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 to C 8 alkoxy, halogen, carboxyl, ester or methyl carboxylate;
  • the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 10 to R 18 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle, said
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 1 to R 5 are independently selected from C 1 to C 2 alkyl groups and 3 to 6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 10 to R 18 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, substituted or unsubstituted C 1 to C 4 alkyl or 3 to 4 membered cycloalkyl; the number of substituents is 1.
  • the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or methyl carboxylate.
  • R 1 to R 5 are independently selected from C 1 to C 2 alkyl groups and 3 to 6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 10 to R 17 are independently selected from hydrogen or unsubstituted C 1 to C 4 alkyl
  • R 1 to R 5 are independently selected from C 1 to C 2 alkyl groups and 3 to 6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 10 to R 17 are independently selected from hydrogen or unsubstituted C 1 to C 4 alkyl
  • R 1 to R 5 are independently selected from C 1 to C 2 alkyl groups and 3 to 6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 10 to R 17 are independently selected from hydrogen or unsubstituted C 1 to C 4 alkyl groups.
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R 10 to R 17 are independently selected from hydrogen or unsubstituted C 1 to C 3 alkyl groups.
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 -C 8 alkyl or 3-4 membered cycloalkyl;
  • R' 10 to R' 11 , R' 14 to R' 15 are independently selected from hydrogen, hydroxyl, C 1 to C 8 alkoxy, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 6 membered ring Alkyl or 3-6 membered saturated heterocyclic group; the number of substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, Carboxyl, ester or carboxylate; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3; R' 12 to R' 13 are independently selected From hydrogen, hydroxyl, C 1 -C 8 alkoxy, substituted C 1 -C 8 alkyl, unsubstituted C 2 -C 8 alkyl, 3-6 membered cycloalkyl or 3-6 membered saturated heterocycle group; the number of substituents to be substituted is any integer from 1 to 6, and the substitu
  • R' 10 to R' 15 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 membered saturated carboheterocycle,
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1, 2 or 3;
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen or C 1 -C 3 alkyl
  • R' 10 to R' 11 , R' 14 to R' 15 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, substituted or unsubstituted C 1 to C 3 alkyl, 3 to 6 membered ring Alkyl or 3-6 membered saturated heterocyclic group; the number of substituents to be substituted is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or carboxyl acid methyl ester group; the heteroatom of the saturated carbon heterocycle is O; the number of the heteroatom is 1; R' 12 to R' 13 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, Substituted C 1 -C 3 alkyl, unsubstituted C 2 -C 4 alkyl, 3-6 membered cycloalkyl or 3-6 membered saturated heterocyclic group; the number of substituted substituents is 1, and the The substituents are independently selected from
  • R' 10 to R' 15 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6-membered carbocycle or a 4-6-membered saturated carboheterocycle, so
  • the heteroatom of the saturated carbon heterocycle is O, S or N; the number of the heteroatom is 1.
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen or C 1 -C 8 alkyl
  • R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are independently selected from hydrogen, hydroxyl, C 1 ⁇ C 8 alkoxy, substituted or unsubstituted C 1 ⁇ C 8 alkyl, 3 ⁇ 6 membered cycloalkyl Or a 3-6 membered saturated heterocyclic group; the number of the substituted substituents is any integer from 1 to 6, and the substituents are independently selected from hydroxyl, C 1 -C 8 alkoxy, halogen, carboxyl, Ester group or methyl carboxylate group; the heteroatom of the saturated heterocyclic group is O, S or N; the number of heteroatoms is 1, 2 or 3; R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are not simultaneously selected from hydrogen;
  • R 10 ⁇ R” 15 , R 16 ⁇ R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6 One-membered saturated carbon heterocyclic ring, the heteroatoms of the saturated carbon heterocyclic ring are O, S or N; the number of the heteroatoms is 1, 2 or 3.
  • R 1 and R 5 are independently selected from C 1 -C 2 alkyl groups and 3-6 membered cycloalkyl groups;
  • R 6 and R 7 are independently selected from hydrogen, C 1 to C 3 alkyl or 3 to 4 membered cycloalkyl;
  • R” 10 to R” 15 , R 16 to R 17 are independently selected from hydrogen, hydroxyl, C 1 to C 3 alkoxy, substituted or unsubstituted C 1 to C 3 alkyl, 3 to 6 membered cycloalkyl Or a 3-6 membered saturated heterocyclic group; the number of the substituted substituents is 1, and the substituents are independently selected from hydroxyl, C 1 -C 3 alkoxy, halogen, carboxyl, ester or methyl carboxylate Ester group; the heteroatom of the saturated heterocyclic group is O, S or N; the number of the heteroatom is 1; R” 10 ⁇ R” 15 , R 16 ⁇ R 17 are not selected from hydrogen at the same time;
  • R 10 ⁇ R” 15 , R 16 ⁇ R 17 the groups on the same carbon atom or on two adjacent carbon atoms are respectively connected to form a 3-6 membered saturated carbocycle or a 3-6
  • the compound is one of the following compounds:
  • the present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its prodrug in the preparation of analgesic medicine;
  • the analgesic drug is a drug that produces analgesic effect on animals or humans through intravenous injection.
  • the present invention also provides the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its prodrug in the preparation of general anesthesia drug;
  • the anesthetic drug is a drug that produces general anesthesia on animals or humans through intravenous injection.
  • the present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its prodrug in the preparation of other clinical anesthetic drugs;
  • the anesthetic drug is a drug that produces other clinically used anesthetic effects on animals or humans through intravenous injection.
  • the present invention also provides a drug, which is composed of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its prodrug as the active ingredient, plus pharmaceutically acceptable auxiliary materials or preparations prepared from auxiliary ingredients.
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its prodrug and other drugs.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • the structure of the compound refers to a structure that can exist stably.
  • substitution means that the hydrogen atoms in the molecule are replaced by other different atoms or molecules.
  • alkyl refers to an aliphatic hydrocarbon group and refers to a saturated hydrocarbon group.
  • the alkyl moiety may be straight-chain or branched-chain.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
  • the minimum and maximum values of carbon atom content in hydrocarbon groups are indicated by prefixes, for example, the prefix (C a ⁇ C b ) alkyl means any alkyl group containing "a" to "b" carbon atoms .
  • C 1 -C 8 alkyl refers to straight or branched chain alkyl groups containing 1 to 8 carbon atoms.
  • C 1 -C 8 alkoxy refers to an alkoxy group containing 1 to 8 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • the ester group is selected from methyl formate, methyl acetate, ethyl acetate and the like.
  • a saturated carbocycle is a cycloalkyl group
  • a saturated carboheterocycle is a saturated heterocyclic group
  • linking to form a 3-6 membered saturated carbocycle refers to Among them, two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbocyclic ring. If R 10 and R 11 are connected to form a 3-membered saturated carbocycle:
  • linking to form a 3-6 membered saturated carbon heterocycle refers to In , two substituents on the same carbon atom are connected to form a 3-6 membered saturated carbon heterocyclic ring. There is at least one heteroatom in the saturated carbon heterocyclic ring, and the heteroatom is O, S or N, and the remaining ring atoms are carbon .
  • the saturated carbon heterocycle is If X1 and Y1 are None, R10 and R11 are connected to form or R10 and R11 are joined to form
  • Opioids provide a good choice for clinical anesthesia and analgesia in the perioperative period, but while providing analgesic effects, opioids also have related adverse reactions (constipation, nausea, lethargy, excessive sedation, respiratory depression, central nervous Opioid-free anesthesia (OFA) refers to the anesthesia and analgesia that do not apply any opioid drugs to patients during and after surgery, and are opioid drugs.
  • Opioidsparing is an anesthesia strategy that goes a step further. During the operation, other types of anesthesia, such as combined nerve block and regional block, will be used to achieve the anesthesia effect.
  • the heteroatom-substituted aromatic compound of the present invention is a kind of lidocaine derivative, and while improving its analgesic effect, it also exhibits higher safety and general anesthesia effect.
  • Such compounds are not only suitable for single intravenous injection for low-dose (0.5ED 50 ) analgesia, but also for preoperative anesthesia induction, preoperative intubation, and general anesthesia for minor operations. Time for major surgery compound intravenous anesthesia.
  • the compound of the present invention can provide better safety guarantee for intravenous analgesia, general anesthesia, anesthesia induction, auxiliary anesthesia and other anesthesia drugs.
  • the compound of the present invention can reduce the use of morphine drugs in the perioperative period, and reduce postoperative complications such as postoperative pain, nausea and vomiting, intestinal paralysis, constipation, cognitive dysfunction, and even sleep disorders, and promote the recovery of surgical patients. It can reduce the length of hospital stay and promote the enhanced postoperative rehabilitation plan, which can be routinely included in the perioperative enhanced recovery program, and has a good application prospect.
  • the intravenous injection of the compound of the present invention can exert a quick-acting analgesic effect and take into account the effect of general anesthesia.
  • the compound of the present invention has high safety, good analgesic effect (low dose is used for analgesia), good quality of recovery (high dose is used for general anesthesia), and its LD50 is increased to 2-10 times compared with lidocaine at the same time. Applications in intravenous analgesia, general anesthesia and other anesthesia fields have great development value and clinical application prospects.
  • the compound of the present invention can be prepared as an analgesic and general anesthesia drug for animals or humans via intravenous route.
  • the compound of the present invention has good analgesic effect, general anesthesia and other anesthesia effects. Compared with traditional lidocaine, it has higher safety, better analgesic effect, shorter recovery time after anesthesia, and better recovery quality , Higher safety index.
  • the compound of the present invention is especially suitable as a drug for producing analgesia and/or general anesthesia and/or other anesthesia effects on animals or humans through intravenous injection, reducing the use of opioid anesthesia (ORA) or opioid-free anesthesia (OFA).
  • ORA opioid anesthesia
  • OFA opioid-free anesthesia
  • the compound of the present invention can reduce common postoperative complications such as postoperative pain, nausea and vomiting, intestinal paralysis, constipation, cognitive dysfunction, and even sleep disorders, promote the recovery of surgical patients, reduce hospitalization time, and promote the enhancement of postoperative rehabilitation programs. It can be routinely included in the enhanced recovery program during the perioperative period, and has a good application prospect.
  • Fig. 1 is the equal-dose drug effect evaluation of the compound of the present invention on rats in a chronic compression pain (CCI) model; A: von Frey mechanical stimulation pain threshold changes, B: infrared heat stimulation pain threshold changes.
  • CCI chronic compression pain
  • Fig. 2 is the recovery time t1 and t2 of LORR recovery to rat sedation score of 0 for rat LORR after 60 min combined infusion of the compound of the present invention and propofol; A is the recovery time t1; B is the recovery time t2.
  • Figure 3 shows the effect of continuous infusion of propofol combined with other anesthetic drugs on blood pressure.
  • Figure 4 shows the effect of continuous infusion of propofol combined with other anesthetic drugs on the heart.
  • the raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.
  • TLC thin-layer silica gel plate is used for fluorescence color development; column chromatography silica gel adopts 200-300 mesh silica gel; rotary evaporator is EYELA N-1100; nuclear magnetic resonance spectrum is determined by Bruker BioSpin GmbH 400MHz, with TMS as internal standard and deuterated water , deuterated chloroform as solvent.
  • reaction solution was directly washed with 1M hydrochloric acid solution, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 31 g of a white solid (Intermediate 2I), with a yield of 78%.
  • Embodiment 2 the preparation of compound LD-1
  • Embodiment 3 the preparation of compound LD-2 ⁇ LD-16, LD-33 ⁇ LD-41, LD-43
  • Embodiment 4 the preparation of compound LD-18
  • Embodiment 5 the preparation of compound LD-17, LD-19 ⁇ LD-32, LD-42
  • Embodiment 6 the preparation of compound LD-45, LD-46
  • Embodiment 8 the preparation of compound LD-44
  • reaction solution was directly washed with 1M hydrochloric acid solution, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain brown yellow solid M-2, 1.03 g, with a yield of 69.7%. Purity: 96.6%, melting point: 243.8-244.2°C.
  • Embodiment 9 the preparation of compound LD-48, LD-52, LD-55, LD-57
  • Embodiment 10 the preparation of compound LD-49, LD-53
  • step 1
  • step 1
  • step 1
  • step 1
  • Embodiment 14 the preparation of compound LDO-12
  • step 1
  • Embodiment 16 the preparation of compound LDO-46
  • step 1
  • step 1
  • step 1
  • Sichuan Dashuo Company provides SPF grade healthy SD rats (200-300g each), KM mice (25-35g each), ICR mice (25-35g each), half male and half male.
  • the temperature of the feeding environment is 25 ⁇ 1 degrees Celsius, the humidity is 40%-60%, 12h alternating light and dark, light (8:00-20:00) and darkness (20:00-8:00), in sawdust bedding cages; animals Raise in separate cages, with no more than 5 animals in each cage; free intake of water and food, fasting for 8-10 hours before the test, and unlimited drinking water.
  • the present invention uses the sequential method to measure the median lethal dose (LD 50 ) of the compound without using the Bliss method, because the sequential method saves about 1/3 of the animals compared with the Bliss method, and the results measured by the two have no significant difference .
  • the dosage formula ratio between the groups of the mouse sequential method in this test is based on the literature (document Garfield, JM&Bukusoglu, C. Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse. Anesthesia and analgesia.83, 156-161 (1996).
  • mice When the test results of two adjacent mice appear (+) to (-) or (-) to (+), it is recorded as a crossing point, and the test is repeated until 5 crossings appear in the same direction for each test drug, and the test ends. After administration, mice were transferred to observation cages and observed for at least 1 h. During the whole experiment, the mice inhaled oxygen (2L/min) with open masks, and used a temperature-changing plate to prevent the mice from lowering their body temperature.
  • 2L/min 2L/min
  • mice tail vein bolus administration lidocaine Lidocaine, Lid
  • the present invention includes but not limited to the compound in the above-mentioned examples, or its salt, or its stereoisomer, or its solvate, or its prodrug. Control the administration volume at 0.1-0.2mL, and control the administration time at 10 seconds. The state of the mice was observed after administration.
  • the present invention includes but is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, and their general anesthesia effects on mice are shown in Table 11.
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, compared with lidocaine, It has improved the safety of this class of drugs as analgesic and general anesthetic drugs for intravenous injection (LD 50 increased by about 3-10 times), and made up for the previous shortcomings of lidocaine as too low in safety.
  • Test example 2 the present invention includes but is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs on mouse glacial acetic acid-induced writhing models, etc.
  • the experimental scheme is: according to the experimental grouping, inject 0.05mmol/kg lidocaine (Lidocaine, Lid) and the compound, or its salt, or its compound included in the present invention but not limited to the above-mentioned examples in the right side of the mouse 10 minutes in advance.
  • Stereoisomers, or their solvates, or their prodrugs, and the matrix control group were administered an equal volume of normal saline, and the time point at this time was recorded as "0".
  • inhibition rate [(average latency period of drug administration group-average latency period value of model group)/average latency period value of model group] ⁇ 100%.
  • Analgesic rate [(average number of writhing times in model group-average number of writhing times in treatment group)/average number of writhing times in model group] ⁇ 100%.
  • the compound of the present invention is to the equivalent dose pharmacodynamic evaluation result of the writhing model induced by glacial acetic acid in mice
  • the inhibition rate of the mice in the lidocaine group to the writhing model induced by glacial acetic acid was 31.19%, and the analgesic rate was 47.99%, showing a certain degree of analgesic effect.
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs all perform better at equal doses (0.05mmol/kg)
  • the analgesic effect that is, the inhibition rate is 53.38-95.5%, which is increased by 0.7-2 times; the analgesic rate is 59.74-89.97%, which is increased by 24%-87%.
  • Test Example 3 the present invention includes and is not limited to the compounds in the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs on rat sciatic nerve chronic compression pain (CCI) model Isodose Pharmacodynamic Evaluation
  • Rats were anesthetized with 2% pentobarbital sodium at a dose of 3ml/kg, and the hair on the left hind limb was uniformly shaved. Predict the approximate position of the rat sciatic nerve in vitro, cut the skin 2-3cm transversely after povidone iodine disinfection, bluntly separate the muscles to expose the sciatic nerve, gently pick up the glass minute needle, and use leather sheep catgut (soaked in saline in advance to make it softening) to ligate the four knots equidistantly, and the strength should be as uniform as possible so that the mice tremble slightly.
  • Lidocaine can inhibit the occurrence and development of pain within 1-7 days of CCI neuropathic model formation, and the pain sensitization occurs again after drug withdrawal (i.e. 8-14 days), returned to the same level as the matrix control group.
  • the present invention includes and is not limited to the occurrence and development of neuropathic pain by the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs (1-7 days) Has better relief than lidocaine.
  • Test Example 4 Determination of the general anesthesia of mice by a compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof including but not limited to the compounds in the above-mentioned examples by a sequential method Effect
  • Whether the righting reflex disappears is used as the standard for whether the compound of the present invention has general anesthesia effect.
  • the onset time refers to placing the mouse in the supine position after the injection, and the mouse can not turn its front paws to the prone position, and the maintenance time is ⁇ 10 seconds is the standard for the disappearance of the righting reflex of the front paw of the mouse, which is used as an effective index of the compound.
  • the present invention uses the sequential method to measure the half effective dose (ED 50 ) and the half lethal dose (LD 50 ) of the compound.
  • the Bliss method is not used because the sequential method saves about 1/3 of animals than the Bliss method, and both The measured results were not significantly different.
  • the dosage formula ratio between the groups of the mouse sequential method in this test is based on the literature (document Garfield, JM&Bukusoglu, C. Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse. Anesthesia and analgesia.83, 156-161 (1996).
  • mice were transferred to observation cages and observed for at least 1 h. During the whole experiment, the mice inhaled oxygen (2L/min) with open masks, and used a temperature-changing plate to prevent the mice from lowering their body temperature.
  • mice tail vein bolus administration lidocaine Lidocaine, Lid
  • the present invention includes but not limited to the compound in the above-mentioned examples, or its salt, or its stereoisomer, or its solvate, or its prodrug.
  • Control the administration volume at 0.1-0.2mL, and control the administration time at 10 seconds.
  • Table 13 shows the general anesthesia effects of the compounds, salts, stereoisomers, solvates, or prodrugs included in the above examples, but not limited to, by the present invention on mice.
  • TI in Table 13 is the therapeutic index, which is the ratio of LD 50 to ED 50 .
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, compared with lidocaine, not only can achieve general anesthesia effect, And all have greater therapeutic index (TI).
  • TI therapeutic index
  • An ideal intravenous general anesthetic needs to meet the characteristics of short onset time, large safety value range, and fast recovery from anesthesia.
  • the compound of the present invention or its salt, or its stereoisomer, or its solvate, or its precursor
  • the therapeutic index (TI) of the drug is 1.8-3.0 times the TI value of lidocaine, which improves the safety of this type of drug as a general anesthetic drug and makes up for the low safety of lidocaine as a general anesthetic drug. .
  • Test Example 5 the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs in SD rats with medium dose intravenous infusion for 60min to reduce Dosage of Propofol
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrug groups, whose recovery time in rats is less than that of propofol (Propofol, Pro) Therefore, it is speculated that the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, whose half-life of metabolism in vivo is shorter than that of propofol .
  • the ED 50 of Pro is 11.29mg/kg, and the infusion rate is 1.0mg/kg/min pump injection; the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvents Refer to Table 13 for the ED 50 of the compound or its prodrug, and the infusion rate is 5% ED 50 mg/kg/min. Adjust the infusion rate of propofol according to the tail pinch reaction, and adjust the speed according to the reaction of the animal, mostly increasing or decreasing the initial dose by 10%. If the tail pinching reaction is (+), increase the pumping rate of propofol by 10%; if the tailing reaction is (-), then decrease the pumping rate of propofol by 10%.
  • each subsequent group will receive propofol (concentration is 10%) or the compound included in the present invention and not limited to the above-mentioned examples, or its corresponding single dose in an increment of 20%. Adjustment of the infusion dose of the salt, or its stereoisomer, or its solvate, or its prodrug.
  • the drug pump was stopped, and the time of each reaction of the rat and the total amount of propofol used were recorded: the time from the stop of drug administration to the recovery of the righting reflex of the rat was recorded as the recovery time t1 (Fig. 2A); The time for the righting reflex of rats to recover to a sedation score of 0 (measured once every 5 minutes) was defined as the recovery time t2 (Fig. 2B).
  • the sedation score has 6 grades: 0 points for normal limb muscle tone, ability to maintain voluntary activities and responsiveness; 1 point for obvious tactile movements (rats tend to stay close to the edge of the cage); 2 points for backward balance disorder points; forelimb upright less than 60 degrees, ataxia is 3 points; prone, can not stand, can only rely on abdominal support for 4 points; righting reflex loss is 5 points.
  • the righting reflex does not disappear, record the administration time, sedation score immediately after administration, sedation onset time, and sedation reaction complete disappearance time (sedation onset time: the time from administration to the occurrence of obvious tactile movements in experimental animals) time; sedation reaction completely disappeared time: the experimental animal from the obvious tactile movement to autonomous activity and sensitive response time). If the righting reflex of the rat disappears, it is also necessary to record in detail the time of administration, the starting time of the disappearance of the righting reflex, and the recovery time of the righting reflex of the rat.
  • the present invention includes and is not limited to the compounds in the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrug groups from the end of drug infusion to the rats of the prodrug group.
  • LORR recovery time t1 is significantly lower than the recovery time t1 (Fig. 2A) of Pro group rats; LORR recovers to the recovery time t2 that the sedation score of rats is 0, that is, the time mean value of rats fully recovering to normal state, the present invention includes and does not The group of compounds limited to the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs was significantly higher than the Pro group ( FIG. 2B ).
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs and Pro, in continuous intravenous infusion for 60 min alone, and the present invention includes And not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrug groups, the recovery time and recovery quality of rats are significantly better.
  • the present invention includes and is not limited to compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs have great The application value and extremely high application advantages, such as outpatient gastroenteroscopy, artificial abortion, etc.;
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates Drugs, or their prodrugs, have a greater range of safe values than lidocaine, and may be more suitable for long-term intravenous infusion in combination with other anesthetics than lidocaine.
  • Propofol as a commonly used clinical general anesthesia drug, is usually accompanied by strong injection pain (28% to 85% in children, 28% to 90% in adults, and large doses and long-term infusion of propofol Propofol may cause severe complications such as metabolic acidosis, multiple organ failure, hyperlipidemia, liver fat infiltration, rhabdomyolysis, etc., and has a significant hypotensive effect, and severe cases can lead to death, that is, "propofol infusion Syndrome" (PIS). Therefore, continuous infusion of propofol and other anesthetic drugs is often used clinically to reduce the clinical adverse reactions of propofol.
  • PIS personalofol infusion Syndrome
  • the present invention includes and is not limited to the compounds in the above examples, or their salts , or its stereoisomers, or its solvates, or its prodrugs compared with the traditional lidocaine and propofol were used in combination, and the rats were continuously infused according to the above calculation speed.
  • Test Example 6 Determination of the general anesthesia of mice by the compounds included in the present invention without limitation, or their salts, or their stereoisomers, or their solvates, or their prodrugs, using a sequential method Effect
  • Whether the righting reflex disappears is used as the standard for whether the compound of the present invention has general anesthesia effect.
  • the onset time refers to placing the mouse in the supine position after the injection, and the mouse can not turn its front paws to the prone position, and the maintenance time is ⁇ 10 seconds is the standard for the disappearance of the righting reflex of the front paw of the mouse, which is used as an effective index of the compound.
  • the present invention uses the sequential method to measure the half effective dose (ED 50 ) and the half lethal dose (LD 50 ) of the compound.
  • the Bliss method is not used because the sequential method saves about 1/3 of animals than the Bliss method, and both The measured results were not significantly different.
  • the dosage formula ratio between the groups of the mouse sequential method in this test is based on the literature (document Garfield, JM&Bukusoglu, C. Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse. Anesthesia and analgesia.83, 156-161 (1996).
  • mice were transferred to observation cages and observed for at least 1 h. During the whole experiment, the mice inhaled oxygen (2L/min) with open masks, and used a temperature-changing plate to prevent the mice from lowering their body temperature.
  • the present invention includes and is not limited to the general anesthesia effect of compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs on mice
  • TI in Table 14 is the therapeutic index, which is the ratio of LD 50 to ED 50 .
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, compared with lidocaine, Not only can achieve a similar effect of general anesthesia, but also have a greater therapeutic index (TI).
  • TI therapeutic index
  • An ideal intravenous general anesthetic needs to meet the characteristics of short onset time, large safety value range, and fast recovery from anesthesia.
  • the compound of the present invention or its salt, or its stereoisomer, or its solvate, or its precursor
  • the therapeutic index (TI) of the drug is 1-2.5 times the TI value of lidocaine, which improves the safety of this type of drug as a general anesthetic drug and makes up for the low safety of lidocaine as a general anesthetic drug. .
  • Test Example 7 The present invention includes but is not limited to the compound in the above-mentioned examples, or its salt, or its stereoisomer, or its solvate, or its prodrug on the equivalent dose pharmacodynamic evaluation of mice
  • ICR mice were divided into half male and half male, and divided into random groups after weighing, with 8 mice in each group.
  • each group of experimental mice was injected into the tail vein of Lidocaine (Lidocaine, Lid) and the present invention includes and is not limited to the compound in the above-mentioned examples, or its salt, or its steric compound.
  • the injection dose of each group was 2 ⁇ ED 50 (twice the amount of ED 50 ).
  • the definition of the onset time is the same as in Test Example 6; the time of action refers to the disappearance of the righting reflex (LORR) of the mice, and the time until the front paws of the mice turn over to the prone position automatically; the recovery time refers to the time when the LORR of the mice returns to fully awake, Muscle tone is normal for this period of time.
  • LORR righting reflex
  • the present invention includes and is not limited to the compounds in the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs to the equivalent dose pharmacodynamic evaluation results of mice
  • LORR (+) represents the number of positive righting reflexes (disappearance of righting reflex) in each drug group; poor quality of awakening represents the number of poor mental states of experimental animals after waking up, and most of them show sluggishness in a long period of time, listlessness, etc.
  • Scoring criteria 1 point: waking up for more than 2 minutes and unable to walk normally within 3 minutes; 2 points: waking up for more than 1 minute and returning to normal walking within 3 minutes; 3 points: waking up for less than 1 minute and returning to normal walking within 2 minutes; 4 points: waking up time Less than 1 minute and return to normal walking within 1 minute; 5 points: wake up time is less than 1 minute and return to normal walking within 30 seconds.
  • the present invention's research finds: under the dose of 2 * ED50 tail vein bolus administration, the positive rate of tail pinch reaction of lidocaine group mouse is 25%, and mortality rate is high (25%), and recovery quality score is low ( 2 points), indicating that lidocaine at this dose as a general anesthesia drug has poor anesthesia effect, low safety, and poor postoperative delirium effect; the positive tail pinching reaction of the mice in the propofol group was 0, and the mortality rate was 0, However, the recovery quality score was only 1 point, indicating that the postoperative delirium was extremely poor.
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, all exhibit good general anesthesia effects at equal doses.
  • Test Example 8 Determination of the general anesthesia of rats by the compounds included in the present invention without limitation, or their salts, or their stereoisomers, or their solvates, or their prodrugs, using a sequential method Effect
  • the sequential method for measuring ED 50 and LD 50 is the same as that in Test Example 6.
  • the definitions and test methods are the same as in Test Example 6, except that ICR mice are replaced by SD rats.
  • the injection medicine is Propofol (Propofol, Pro) and the present invention includes and is not limited to the compound in the above-mentioned examples, or its salt, or its stereoisomer Construct, or its solvate, or its prodrug, flush the tube with 0.2ml of normal saline after injection to reduce drug residue in the indwelling needle.
  • the administration speed is 10-15 seconds, and the total volume of the injected liquid does not exceed 1.5ml.
  • the state of the rats was observed after administration.
  • the present invention includes but is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs.
  • the general anesthesia effects on rats are shown in Table 16.
  • the present invention includes and is not limited to the general anesthesia effect of compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs on rats
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs.
  • the TI value for general anesthesia of rats is 2-3.7 times that of phenol, reflecting higher safety and better recovery quality.
  • the present invention includes and is not limited to the compounds in the foregoing examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, whose action time is shorter than that of lidocaine. Conducive to the recovery quality of rats after anesthesia.
  • Test Example 9 Propofol combined with but not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs or lidocaine in SD Intravenous infusion in rats for 60 min
  • Propofol as a commonly used clinical general anesthesia drug, is usually accompanied by strong injection pain (28% to 85% in children, 28% to 90% in adults, and large doses and long-term infusion of propofol Propofol may cause severe complications such as metabolic acidosis, multiple organ failure, hyperlipidemia, liver fat infiltration, rhabdomyolysis, etc., and has a significant hypotensive effect, and severe cases can lead to death, that is, "propofol infusion Syndrome" (PIS). Therefore, continuous infusion of propofol and other anesthetic drugs is often used clinically to reduce the clinical adverse reactions of propofol.
  • PIS personalofol infusion Syndrome
  • the present invention includes and is not limited to the compounds in the above examples, or their salts , or its stereoisomers, or its solvates, or its prodrugs compared with traditional lidocaine and propofol are combined, and the rats are continuously infused according to the calculated speed.
  • the literature (document Tao, T. et al.Protective effects of propofol against whole cerebral ischemia/reperfusion injury in rats through the inhibition of the apoptosis-inducing factor pathway. Brain research 1644,9-14(2016). Yue,ZYet al.Propofol prevents neuronal mtDNA deletion and cerebral damage due to ischemia/reperfusion injury in rats.
  • the ED 50 of Pro is 11.29 mg/kg, and the infusion rate is 1.0 mg/kg/min pump injection; the present invention includes but is not limited to the compounds in the above examples,
  • the ED 50 of its salt, or its stereoisomer, or its solvate, or its prodrug refers to Test Example 8 (Table 16), and the infusion rate is 1% ED 50 mg/kg/min pump injection ( ED 50 with reference to the table 16 of test example 8).
  • Example 8 Test Example 8
  • Example 8 Example 16
  • the infusion rate is 1% ED 50 mg/kg/min pump injection ( ED 50 with reference to the table 16 of test example 8).
  • Experimental random grouping 1. carry out continuous infusion (Pro group) with normal saline by the above-mentioned propofol dose of calculation, 2.
  • propofol dose of calculation in conjunction with the present invention comprises And not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs
  • the 1% dose of propofol was continuously infused at the same time (Pro+LDO-X group), 3The dose of propofol calculated above combined with 1% ED 50 of the dose of lidocaine was continuously infused (Pro+Lid group).
  • lidocaine assisted propofol in general anesthesia, it could reduce the recovery time of rats after continuous infusion and the dosage of propofol to a certain extent (-24.6%), and partially relieved the pain as shown in Figure 3. It is shown that due to the adverse reaction of high dose and long-term infusion of propofol, the blood pressure drops, but also because the safety of lidocaine itself is too low, the mortality rate of rats is increased (-25%).
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs when assisting propofol in general anesthesia, not only can significantly reduce The wake-up time after the continuous infusion of rats reduces the dosage of propofol (-49.1%), and can also significantly eliminate the adverse reactions caused by large doses and long-term infusions of propofol with a large range of blood pressure changes ( Fig.
  • the present invention includes and is not limited to the compounds in the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs have an ester structure that is easily catabolized in vivo, Therefore, it has higher safety than lidocaine and improves the survival rate of rats (+25%).
  • echocardiographic results showed that the use of LDO-X in the Pro+LDO-X group exerted a significant cardioprotective effect, while lidocaine in the Pro+Lid group does not have this effect.
  • Test Example 10 the present invention includes but is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs on mouse glacial acetic acid-induced writhing models, etc.
  • the experimental scheme is: according to the experimental grouping, inject 0.05mmol/kg lidocaine (Lidocaine, Lid) and the compound, or its salt, or its compound included in the present invention but not limited to the above-mentioned examples in the right side of the mouse 10 minutes in advance.
  • Stereoisomers, or their solvates, or their prodrugs, and the matrix control group were administered an equal volume of normal saline, and the time point at this time was recorded as "0".
  • inhibition rate [(average latency period of drug administration group-average latency period value of model group)/average latency period value of model group] ⁇ 100%.
  • Analgesic rate [(average number of writhing times in model group-average number of writhing times in drug administration group)/average number of writhing times in model group] ⁇ 100%.
  • the present invention includes and is not limited to the compounds in the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs to the equivalent dosage of the writhing model induced by glacial acetic acid in mice Pharmacodynamic evaluation results
  • the compounds of the present invention have good analgesic and/or anesthetic effects for intravenous injection.
  • intravenous administration it not only improves the traditional lidocaine's good analgesic effect on various pains, but also has higher safety; and as a general anesthesia drug, the recovery time after anesthesia is shorter, the recovery quality is better, and the safety index is higher. high.
  • the present invention includes and is not limited to the compounds in the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, which are more effective than lidocaine in the continuous infusion anesthesia regimen.
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, which are especially suitable for producing analgesia in animals or humans by intravenous injection. and/or anesthesia and other clinical anesthesia.
  • the present invention includes and is not limited to the compounds in the above examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs, which can be the analgesic and global medicines of lidocaine drugs in intravenous administration.
  • anesthesia and other clinical anesthesia fields provides better safety assurance and reduces the use of opioid anesthesia (ORA) or opioid-free anesthesia (OFA).
  • ORA opioid anesthesia
  • OFA opioid-free anesthesia
  • the compound of the present invention can reduce common postoperative complications such as postoperative pain, nausea and vomiting, intestinal paralysis, constipation, cognitive dysfunction, and even sleep disorders, promote the recovery of surgical patients, reduce hospitalization time, and promote the enhancement of postoperative rehabilitation programs. It can be routinely included in the enhanced recovery program during the perioperative period, and has a good application prospect.

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Abstract

提供一种杂原子取代的芳香类化合物及其制备方法和用途，属于医药化学领域。所述化合物为式I 所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物。所述化合物可用于制备经静脉途径对动物或人产生全身麻醉作用的中枢抑制性药物和/或镇痛药物，其静脉注射能够发挥速效、短效的全身麻醉和/或镇痛作用。所述化合物治疗指数高、安全性高，且具有更快的苏醒时间、更好的苏醒质量、更好的镇痛效果，为静脉注射镇痛、全身麻醉以及其他麻醉临床用途领域提供巨大的开发价值和临床应用前景。

Description

一种杂原子取代的芳香类化合物及其制备方法和用途 技术领域
本发明属于医药化学领域，具体涉及一种杂原子取代的芳香类化合物及其制备方法和用途。
背景技术
利多卡因(Lidocaine)，一种临床上长期应用于局部神经阻滞、硬膜外麻醉的局部***(局麻药)，该药物兼具表明穿透力强、药效强而持久的优点，既可以用于注射作局部麻醉，也可浸润作表面麻醉。同时多项研究表明，利多卡因不仅可用于禽类动物鸡和哺乳动物狗、马、猪、羊驼等的麻醉，并且在临床围术期进行利多卡因静脉注射(IVL)，不但能够高效地进行全身麻醉辅助，而且还可以显著减少术后疼痛发生率、减少术中阿片类药物消耗、促进术后患者肠功能恢复以及减少住院时间和康复时间。
Figure PCTCN2022102054-appb-000001
IVL在腹部手术中的显著镇痛收益已得到证实，但其在其他类型的手术中的镇痛效果以及其治疗窗(TI)窄等问题仍存在许多争议，研究表明IVL的临床阵痛收益具有广泛的不确定性。目前，对于日益增加的临床上其他适应症，如预防异丙酚引起的注射疼痛、预防痛觉过敏、减少手术中气管插/拔管反应，以及辅助全身麻醉深度等，利多卡因的治疗指数(TI)很低。此外，利多卡因安全记录范围比较窄，具有潜在的心脏毒性和神经毒性，因此在临床应用中受到很大程度的限制。
因此，在保持利多卡因诸多临床优点的同时，获得具有更高安全性、更快代谢速率、良好苏醒质量、良好镇痛效果的***物，降低在围术期静脉注射用药的副作用、提高其安全使用剂量范围，改善术后谵妄具有重大的临床和经济价值，从而使这类药物的应用范围更加广泛，具有非常重要的临床意义和广阔的应用前景。
发明内容
鉴于上述情况，本发明提供了一种杂原子取代的芳香类化合物及其制备方法和用途，可以满意地实现上述目的。
本发明提供了式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物：
Figure PCTCN2022102054-appb-000002
其中，
X选自-NH-或-O-；
R 1～R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、取代或未取代的酯基、3～6元环烷基、-OC(O)R 7’；所述酯基的取代基选自-NR 8’R 9’；当X选自O时，R 1～R 5中至少有2个不同时选自氢；
R 7’选自取代的C 1～C 8烷基或-NR 8’R 9’；所述烷基的取代基选自-NR 8’R 9’或吗啉基；
R 8、R 8’、R 9、R 9’分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述烷基、环烷基的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
或者R 8’与R 9’连接、或R 8与R 9连接与N原子形成
Figure PCTCN2022102054-appb-000003
R 10’选自C 1～C 8烷基；
X 1选自无、-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1选自无、-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、卤素、氨基、氰基、硝基、磺酸基、巯基、酯基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原 子为O、S或N；所述杂原子个数为1、2或3。
进一步地，所述化合物如式II所示：
Figure PCTCN2022102054-appb-000004
其中，
R 1～R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、取代或未取代的酯基、3～6元环烷基、-OC(O)R 7’；所述酯基的取代基选自-NR 8’R 9’；当X选自O时，R 1～R 5中至少有2个不同时选自氢；
R 7’选自取代的C 1～C 8烷基或-NR 8’R 9’；所述烷基的取代基选自-NR 8’R 9’或吗啉基；
R 8、R 8’、R 9、R 9’分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述烷基、环烷基的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
或者R 8’与R 9’连接、或R 8与R 9连接与N原子形成
Figure PCTCN2022102054-appb-000005
R 10’选自氢或C 1～C 8烷基；
X 1选自无、-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1选自无、-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、卤素、氨基、氰基、硝基、磺酸基、巯基、酯基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3。
进一步地，所述化合物如式II-A所示：
Figure PCTCN2022102054-appb-000006
其中，
R 6、R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基；
R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、取代或未取代的酯基；所述酯基的取代基选自-NR 8’R 9’；
R 8’、R 9’分别独立选自C 1～C 8烷基；
当R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基时，R 8、R 9分别独立选自取代或未取代的C 2～C 8烷基、取代或未取代的3～6元环烷基，所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；
当R 3选自取代或未取代的酯基时，R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；
R 10’选自氢或C 1～C 8烷基。
进一步地，所述化合物如式II-B所示：
Figure PCTCN2022102054-appb-000007
其中，
R 7’选自取代的C 1～C 8烷基或-NR 8’R 9’；所述烷基的取代基选自-NR 8’R 9’或吗啉基；
R 8’、R 9’分别独立选自C 1～C 8烷基；
X 1选自无、-O-、-CR 16R 17-；
Y 1选自无、-CR 16R 17-；
R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
优选地，所述化合物如式II-B1所示：
Figure PCTCN2022102054-appb-000008
其中，
X 1选自无、-O-、-CR 16R 17-；
Y 1选自无、-CR 16R 17-；
R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3。
进一步地，所述化合物如式II-C所示：
Figure PCTCN2022102054-appb-000009
其中，
R 1～R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
X 1选自无、-O-、-CR 16R 17-；
Y 1选自无、-CR 16R 17-；
R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
当X 1选自-O-，Y 1选自-CR 16R 17-时，R 10～R 17中至少有两个不选自氢；当 R 6或R 7均选自氢，或者其中一个选自甲基，R 10～R 17中仅有两个不选自氢而选自甲基时，R 12和R 13不同时为甲基，或者R 16和R 17不同时为甲基，或者R 10和R 11中任意一个与R 14和R 15任意一个不同时为甲基；或者R 12和R 13中任意一个与R 16和R 17任意一个不同时为甲基；
或者，当X 1选自-O-，Y 1选自-CR 16R 17-，R 6和R 7均选自氢，R 10～R 17中仅有两个不选自氢而选自甲基时，R 10和R 11中任意一个与R 16和R 17任意一个不同时为甲基；或者R 12和R 13中任意一个与R 14和R 15任意一个不同时为甲基；
或者，当X 1和Y 1选自无，R 2、R 4、R 7、R 10、R 11、R 14、R 15选自氢，R 1选自氢、甲基或乙基，R 5选自烷基，R 3、R 6分别独立选自氢或甲基，R 12、R 13中有一个选自氢时，另一个不选自羟基、氨基；R 12和R 13均不选自氢时，R 12和R 13不同时选自甲基；R 12、R 13中有一个选自甲基时，另一个不选自羟基、甲烷基；
或者，当X 1和Y 1一个选自无、一个选自-CR 16R 17-，R 10～R 17是同一个碳原子上的两个取代基连接形成环时，所连接形成的环不为取代或未取代的4元饱和碳环；或者，所连接形成的螺环不为
Figure PCTCN2022102054-appb-000010
优选地，
R 1～R 5分别独立选自氢、C 1～C 4烷基、羟基、酯基；
R 6～R 7分别独立选自氢、C 1～C 4烷基；
X 1选自无、-O-、-CR 16R 17-；
Y 1选自无、-CR 16R 17-；
R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
进一步地，所述化合物如式II-C1所示：
Figure PCTCN2022102054-appb-000011
其中，
R 3、R 6、R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S、N，所述杂原子个数为1、2或3；
优选地，
R 3选自氢、C 1～C 4烷基、羟基、酯基；
R 6～R 7分别独立选自氢、C 1～C 4烷基；
R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环。
进一步地，所述化合物如式II-D1所示：
Figure PCTCN2022102054-appb-000012
其中，
R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环；
或者，所述化合物如式II-D2所示：
Figure PCTCN2022102054-appb-000013
其中，
R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环。
进一步地，所述化合物如式II-C2所示：
Figure PCTCN2022102054-appb-000014
其中，
R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
R 6～R 7分别独立选自氢、C 1～C 8烷基；
R 10～R 15分别独立选自氢、C 1～C 8烷基；或者R 10～R 15中，同一个碳原子上的两个取代基连接形成3～6元碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
优选地，
R 3选自氢、C 1～C 4烷基、羟基、酯基；
R 6～R 7分别独立选自氢、C 1～C 4烷基；
R 10～R 15分别独立选自氢、C 1～C 4烷基；或者R 10～R 15中，同一个碳原子上的两个取代基连接形成4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
进一步地，所述化合物如式II-C3所示：
Figure PCTCN2022102054-appb-000015
其中，
R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
R 6～R 7分别独立选自氢、C 1～C 8烷基；
R 10～R 13分别独立选自氢、C 1～C 8烷基；或者R 10～R 13中，同一个碳原子上的两个取代基连接形成3～6元碳环、3～6元饱和碳杂环；所述饱和碳杂环 的杂原子为O、S或N，所述杂原子个数为1、2或3；
优选地，
R 3选自氢、C 1～C 4烷基、羟基、酯基；
R 6～R 7分别独立选自氢、C 1～C 4烷基；
R 10～R 13分别独立选自氢、C 1～C 4烷基；或者R 10～R 13中，同一个碳原子上的两个取代基连接形成4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
进一步地，所述化合物如式II-C4所示：
Figure PCTCN2022102054-appb-000016
其中，
R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
R 6～R 7分别独立选自氢、C 1～C 8烷基；
R 10～R 13、R 16～R 17分别独立选自氢、C 1～C 8烷基；或者R 10～R 13、R 16～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S、N，所述杂原子个数为1、2或3；
优选地，
R 3选自氢、C 1～C 4烷基、羟基、酯基；
R 6～R 7分别独立选自氢、C 1～C 4烷基；
R 10～R 13、R 16～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 13、R 16～R 17中，同一个碳原子上的两个取代基连接形成4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
进一步地，所述化合物如式III所示：
Figure PCTCN2022102054-appb-000017
其中，
R 1～R 5分别独立选自氢、C 1～C 2烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基、3～6元环烷基，且R 1～R 5中至少有2个不同时选自氢；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～6元环烷基；
R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
或者R 8、R 9连接与N原子形成
Figure PCTCN2022102054-appb-000018
R 10’选自C 1～C 8烷基；
X 1为无、-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为无、-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
当X 1和Y 1同时为无时，R 10～R 15不同时选自氢；或者，R 12、R 13不选自未取代的甲基；
当X 1为-CR 16R 17-，Y 1为无时，R 10～R 17不同时选自氢；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000019
进一步地，
R 1～R 5分别独立选自氢、C 1～C 2烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基、3～6元环烷基，且R 1～R 5中至少有2个不同时选自氢；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～6元环烷基；
R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
或者R 8、R 9连接与N原子形成
Figure PCTCN2022102054-appb-000020
Figure PCTCN2022102054-appb-000021
R 10’选自C 1～C 8烷基；
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所 述杂原子个数为1、2或3；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 8烷氧基、取代的C 1～C 8烷基、未取代的C 2～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 10～R’ 15不同时选自氢；
或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
X 2为-O-或-CR 16R 17-；
R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000022
优选地，
R 1～R 5分别独立选自氢、C 1～C 2烷基、羟基、卤素或3～6元环烷基，且R 1～R 5中至少有2个不同时选自氢；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 8、R 9分别独立选自取代或未取代的C 1～C 3烷基、取代或未取代的3～4元环烷基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素或酯基；且R 8、R 9不同时为未取代的C 1～C 3烷基；
或者R 8、R 9连接与N原子形成
Figure PCTCN2022102054-appb-000023
Figure PCTCN2022102054-appb-000024
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 3烷氧基、取代的C 1～C 3烷基、未取代的C 2～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；R’ 10～R’ 15不同时选自氢；
或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O；所述杂原子个数为1；
X 2为-O-或-CR 16R 17-；
R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子 上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O；所述杂原子个数为1；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000025
进一步地，所述化合物具有如式III-A所示结构：
Figure PCTCN2022102054-appb-000026
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素或酯基；且R 8、R 9不同时为未取代的C 1～C 8烷基；
或者R 8、R 9连接与N原子形成
Figure PCTCN2022102054-appb-000027
Figure PCTCN2022102054-appb-000028
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、 2或3；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 8烷氧基、取代的C 1～C 8烷基、未取代的C 2～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 10～R’ 15不同时选自氢；
或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
X 2为-O-或-CR 16R 17-；
R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000029
优选地，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 8、R 9分别独立选自取代或未取代的C 1～C 3烷基、取代或未取代的3～4元环烷基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3 烷氧基、卤素或酯基；且R 8、R 9不同时为未取代的C 1～C 3烷基；
或者R 8、R 9连接与N原子形成
Figure PCTCN2022102054-appb-000030
Figure PCTCN2022102054-appb-000031
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或4～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 3烷氧基、取代的C 1～C 3烷基、未取代的C 2～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R’ 10～R’ 15不同时选自氢；
或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
X 2为-O-或-CR 16R 17-；
R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000032
进一步地，所述化合物具有如式III-B所示结构：
Figure PCTCN2022102054-appb-000033
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000034
优选地，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
Y 1为-O-或-CR 16R 17-；
R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000035
进一步地，所述化合物具有如式III-C所示结构：
Figure PCTCN2022102054-appb-000036
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8 烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-时，R 10～R 17不能同时选自氢；当X 1为-O-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000037
优选地，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 1为-O-时，R 10～R 17不能同时选自氢；当X 1为-O-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000038
进一步地，所述化合物具有如式III-D所示结构：
Figure PCTCN2022102054-appb-000039
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
R 10～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；且R 10～R 17不能同时选自氢；当R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
优选地，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 10～R 17分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；且R 10～R 17不能同时选自氢；当R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
或者，R 10～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1。
进一步地，所述化合物具有如式III-E所示结构：
Figure PCTCN2022102054-appb-000040
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～6元环烷基；
R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
Figure PCTCN2022102054-appb-000041
优选地，
R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 10～R 18分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 4烷基或3～4元环烷基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基。
进一步地，所述化合物如式III-F-1所示：
Figure PCTCN2022102054-appb-000042
其中，
R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 10～R 17分别独立选自氢或未取代的C 1～C 4烷基；
或，所述化合物如式III-F-2所示：
Figure PCTCN2022102054-appb-000043
R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 10～R 17分别独立选自氢或未取代的C 1～C 4烷基；
或，所述化合物如式III-F-3所示：
Figure PCTCN2022102054-appb-000044
R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 10～R 17分别独立选自氢或未取代的C 1～C 4烷基。
进一步地，所述化合物如式IV所示：
Figure PCTCN2022102054-appb-000045
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R 10～R 17分别独立选自氢或未取代的C 1～C 3烷基。
进一步地，所述化合物如式V所示：
Figure PCTCN2022102054-appb-000046
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 8烷氧基、取代的C 1～C 8烷基、未取代的C 2～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 10～R’ 15不同时选自氢；
或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
优选地，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢或C 1～C 3烷基；
R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和碳杂环的杂原子为O；所述杂原子个数为1；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 3烷氧基、取代的C 1～C 3烷基、未取代的C 2～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R’ 10～R’ 15不同时选自氢；
或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或4～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1。
进一步地，所述化合物如式VI所示：
Figure PCTCN2022102054-appb-000047
其中，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢或C 1～C 8烷基；
R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R” 10～R” 15、R 16～R 17不同时选自氢；
或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3。
优选地，
R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取 代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R” 10～R” 15、R 16～R 17不同时选自氢；
或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2022102054-appb-000048
Figure PCTCN2022102054-appb-000049
Figure PCTCN2022102054-appb-000050
Figure PCTCN2022102054-appb-000051
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在制备镇痛药物中的用途；
优选地，所述镇痛药物为经静脉注射对动物或者人产生镇痛作用的药物。
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在制备全身***物中的用途的药物；
优选地，所述***物为经静脉注射对动物或者人产生全身麻醉作用的药物。
本发明还提供了前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在制备其他临床***物中的用途；
优选地，所述***物为经静脉注射对动物或者人产生临床上使用的其他麻醉作用的药物。
本发明还提供了一种药物，它是由前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
本发明还提供了一种药物组合物，它包括前述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物以及其他药物。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名***命名。
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。
本发明中，所述化合物的结构均是指能够稳定存在的结构。
本发明中，所述“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
本发明中，“烷基”，是指脂肪族烃基团，指饱和烃基。烷基部分可以是直链烷基，亦可以是支链烷基。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等等。
本发明中，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(C a～C b)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C 1～C 8烷基是指包含1～8个碳原子的直链或支链烷基。C 1～C 8烷氧基是指包含1～8个碳原子的烷氧基。
本发明中，卤素是指氟、氯、溴、碘。
本发明中，酯基选自甲酸甲酯基、乙酸甲酯基、乙酸乙酯基等等。
本发明中，饱和碳环就是环烷基，饱和碳杂环就是饱和杂环基。
本发明中，连接形成3～6元饱和碳环是指
Figure PCTCN2022102054-appb-000052
中，同一个碳原子上两个取代基连接，形成的3～6元饱和碳环。如R 10和R 11连接形成3元饱和碳环：
Figure PCTCN2022102054-appb-000053
本发明中，连接形成3～6元饱和碳杂环是指
Figure PCTCN2022102054-appb-000054
中，同一个碳原子上两个取代基连接，形成的3～6元饱和碳杂环，该饱和碳杂环中至少有一个杂原子，杂原子为O、S或N，其余环原子为碳。优选地，饱和碳杂环为
Figure PCTCN2022102054-appb-000055
如X 1和Y 1为无，R 10和R 11连接形成
Figure PCTCN2022102054-appb-000056
Figure PCTCN2022102054-appb-000057
或R 10和R 11连接形成
Figure PCTCN2022102054-appb-000058
本发明中，“CR 14R 15”的结构式为
Figure PCTCN2022102054-appb-000059
阿片类药物为围术期临床麻醉与镇痛提供了良好的选择，但是阿片类药物在提供镇痛作用的同时，也存在相关不良反应(便秘、恶心、嗜睡、过度镇静、呼吸抑制、中枢神经毒性反应、成瘾性)；无阿片麻醉(Opioid-free anesthesia，OFA)是指在手术中及手术后，不通过任何途径、给患者应用任何阿片类药物的麻醉和镇痛，是阿片类药物节约(Opioidsparing)向前更进一步的麻醉策略。手术中将复合神经阻滞、区域阻滞等其他类型的麻醉方式，来达到麻醉效果。但具有以下缺点：“抗伤害作用”效果不明，OFA缺乏普适性；适用范围局限且需多药组合替代；使用阿片类替代药物可能对原本疾病的并发症无用。多项研究明确指出，围术期静脉注射利多卡因具有减少疼痛、恶心、肠麻痹时间以及减少阿片类药的需求和缩短住院时间等临床功效，可能是加快康复的有效手段之一。但是由于治疗指数低、安全性差等原因，在作为静脉注射药物的临床应用方面难以得到发展。
本发明杂原子取代的芳香类化合物是一类利多卡因衍生物，在提高其镇痛作用的同时，还表现出更高的安全性，以及全身麻醉作用。该类化合物既适合单次静脉注射用于低剂量(0.5ED 50)镇痛，也适用于术前麻醉诱导、术前辅助插管、短小手术静脉全身麻醉，亦可持续输注，用于长时间大手术复合静脉麻醉。本发明化合物作为镇痛和***物可为静脉注射镇痛、全身麻醉、麻醉诱导、辅助麻醉及其他麻醉用药提供更好的安全性保障。同时，本发明化合物可降低围术期***类药物的使用，并减少术后疼痛、恶心呕吐、 肠麻痹、便秘、认知功能障碍、甚至睡眠障碍等手术后常见并发症，促进手术患者康复，减少住院时间，促进增强术后康复计划，可以将其常规纳入围术期增强恢复方案中，具有良好的应用前景。
本发明化合物静脉注射能够发挥速效镇痛作用，且兼顾全身麻醉作用。本发明化合物安全性高、镇痛效果好(低剂量作镇痛用)，苏醒质量佳(高剂量作全麻用)，同时与利多卡因相比其LD 50提高至2-10倍，在静脉注射镇痛、全身麻醉领域以及其他麻醉领域的应用有巨大的开发价值和临床应用前景。本发明化合物可制备作为经静脉途径对动物或人产生镇痛和全身麻醉作用药物。
综上，本发明化合物兼具良好的镇痛效果、全身麻醉以及其他麻醉效果，与传统利多卡因相比安全性更高，镇痛效果更好，麻醉后恢复时间更短、苏醒质量更好、安全指数更高。本发明化合物尤其适合于作为经静脉注射对动物或者人产生镇痛和/或全身麻醉和/或其他麻醉作用的药物，减少阿片麻醉(ORA)或者无阿片麻醉(OFA)的使用。并且，本发明化合物可减少术后疼痛、恶心呕吐、肠麻痹、便秘、认知功能障碍、甚至睡眠障碍等手术后常见并发症，促进手术患者康复，减少住院时间，促进增强术后康复计划，可以将其常规纳入围术期增强恢复方案中，具有良好的应用前景。
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。
附图说明
图1为本发明化合物对大鼠做个神经慢性压迫痛(CCI)模型等剂量药效评价；A：von Frey机械刺激痛阈变化，B：红外热刺激痛阈变化。
图2为本发明化合物与丙泊酚联合输注60min对大鼠LORR恢复时间t1和LORR恢复到大鼠镇静评分为0的恢复时间t2；A为恢复时间t1；B为恢复时间t2。
图3为丙泊酚联合其他***物进行持续输注对血压的影响。
图4为丙泊酚联合其他***物进行持续输注对心脏的影响。
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。
本实验所用溶剂均为分析纯。TLC薄层硅胶板用荧光显色；柱层析硅胶 采用200-300目硅胶；旋转蒸发仪为EYELA N-1100；核磁共振图谱采用Bruker BioSpin GmbH 400MHz测定，以TMS为内标，采用氘代水、氘代氯仿作为溶剂。
实施例1、中间体2I的制备
Figure PCTCN2022102054-appb-000060
将20g 2,6-二甲基苯胺(1)和54mL N,N-二异丙基乙胺(DIPEA)溶解在200mL二氯甲烷(DCM)中，置于冰浴条件下，滴加1～2倍摩尔量(33.1～66.2g)溴乙酰溴(M-Br)的二氯甲烷稀释液(40mL)，稀释液中溴乙酰溴的浓度为35％(v/v)。滴加完后转至室温反应10min，硅胶薄层层析板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到白色固体(中间体2I)31g，产率78％。
中间体2I： 1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.17–7.06(m,3H),4.07(s,2H),2.24(s,6H).
按照上述方法，将不同原料1与不同原料M-Br合成不同中间体2，具体结构如下表1：
表1.不同中间体2的合成原料和表征信息
Figure PCTCN2022102054-appb-000061
实施例2、化合物LD-1的制备
Figure PCTCN2022102054-appb-000062
将1g中间体2I、0.54g 2,3,6-三甲基吗啉、1.14g碳酸钾加入10mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经 柱层析得到白色固体LD-1
Figure PCTCN2022102054-appb-000063
1.05g，产率88.2％。纯度：98.7％，熔点：191.0-191.4℃。
化合物LD-1： 1H NMR(400MHz,CDCl 3)δ(ppm):9.66(s,1H),7.31(dt,J＝11.2,5.6Hz,3H),4.02(s,2H),3.88(m,2H),3.72(m,1H),3.35(m,2H),2.28(s,6H),1.54(m,9H).HRMS:[C 17H 26N 2O 2] +,290.1994.
实施例3、化合物LD-2～LD-16、LD-33～LD-41、LD-43的制备
下列表2中的化合物均按实施例1首先合成中间体2I，然后与不同含氮原料按照实施例2的方法合成对应终产物：
表2.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000064
Figure PCTCN2022102054-appb-000065
Figure PCTCN2022102054-appb-000066
Figure PCTCN2022102054-appb-000067
实施例4、化合物LD-18的制备
Figure PCTCN2022102054-appb-000068
将1g中间体2II、0.56g 2,3,5,6-四甲基吗啉、1.08g碳酸钾加入10mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体LD-18
Figure PCTCN2022102054-appb-000069
1.14g，产率92.0％。纯度：99.2％，熔点：168.2-168.7℃。
化合物LD-18： 1H NMR(400MHz,CDCl 3)δ(ppm):9.29(s,1H),7.14(dt,J＝9.2,4.8Hz,3H),3.82(s,2H),3.29(m,2H),2.10(s,6H),1.52(d,J＝11.2Hz,6H),0.92-0.86(m,8H).HRMS:[C 19H 30N 2O 2] +,318.2307.
实施例5、化合物LD-17、LD-19～LD-32、LD-42的制备
下列表3中的化合物均按实施例1首先合成中间体2II，然后与不同含氮原料按照实施例4的方法合成对应终产物：
表3.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000070
Figure PCTCN2022102054-appb-000071
Figure PCTCN2022102054-appb-000072
实施例6、化合物LD-45、LD-46的制备
Figure PCTCN2022102054-appb-000073
将1g原料LD-OH、287.86mg乙酸、989.05mg DCC和48.80mg DMAP加入10mL二氯甲烷中，室温反应8h，硅胶薄层层析板显示反应完全。减压蒸馏后溶解于50mL二氯甲烷中，水洗3遍后经硅胶柱层析纯化，得白色固体LD-45
Figure PCTCN2022102054-appb-000074
1.04g，产率89.4％。纯度：99.0％，熔点：189.1-189.8℃。
化合物LD-45： 1H NMR(400MHz,CDCl 3)δ(ppm):8.83(s,1H),7.09(d,J＝1.1Hz,3H),4.23(t,J＝5.5Hz,2H),3.34(s,2H),2.91(t,J＝5.5Hz,2H),2.75(q,J＝7.1Hz,2H),2.23(s,6H).HRMS:[C 16H 24N 2O 3] +,292.1787.
下列表4中的化合物制备按实施例8步骤1，首先合成中间体2III，然后与含氮原料按照实施例2合成中间体
Figure PCTCN2022102054-appb-000075
然后按照本实施例上述方法加入2倍摩尔量的乙酸、DCC和DMAP到20mL二氯甲烷中，合成终产物LD-46：
表4.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000076
实施例7、化合物LD-47的制备
Figure PCTCN2022102054-appb-000077
将1g原料LD-OH、473.96mg吡啶加入10mL二氯甲烷中，冰浴下滴加734.28mg氯甲酸异丙酯，室温反应3h，硅胶薄层层析板显示反应完全。减压蒸馏后的粗品经硅胶柱层析纯化，得黄色油状物LD-47
Figure PCTCN2022102054-appb-000078
1.61g，产率86.84％。纯度：99.1％。
化合物LD-47： 1H NMR(400MHz,CDCl 3)δ(ppm):8.80(s,1H),7.08(d,J＝1.3Hz,3H),4.77(hept,J＝6.3Hz,1H),4.26(t,J＝5.4Hz,2H),3.33(s,2H),2.93(t,J＝5.5Hz,2H),2.75(q,J＝7.1Hz,2H),2.23(s,6H),1.15(t,J＝6.9Hz,9H).HRMS:[C 18H 28N 2O 4] +,336.2049.
实施例8、化合物LD-44的制备
Figure PCTCN2022102054-appb-000079
步骤1：
将0.49g N-羟基丁二酰亚胺和9.22g三乙胺溶解在200mL干燥四氢呋喃(THF)中，并置于冰浴条件下滴加溴乙酰溴的二氯甲烷稀释液(50mL)，稀释液中溴乙酰溴的浓度为35％(v/v)，低温下搅拌1h，随后转至室温反应4h。将上述反应液于冰浴下滴加至10g 3,5-二甲基-4-氨基苯酚的THF溶液中，反应2h。硅胶薄层层析板显示原料反应完全。减压浓缩后经硅胶柱层析纯化得到棕色油状物(中间体2III)11.2g，产率59.53％。
步骤2：
将450mg中间体2III、191.27mg二乙胺、361.42mg碳酸钾加入5mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经柱层析得到棕色固体M-1
Figure PCTCN2022102054-appb-000080
300mg，产率68.74％。纯度：98.8％，熔点：201.0-201.9℃。
步骤3：
将1g中间体M-1和0.59mL N,N-二异丙基乙胺(DIPEA)溶解在10mL二氯甲烷(DCM)中，置于冰浴条件下，滴加溴乙酰溴的二氯甲烷稀释液(1mL)，稀释液中溴乙酰溴的浓度为35％(v/v)。滴加完后转至室温反应10min，硅胶薄层层析板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到棕黄色固体M-2，1.03g，产率69.7％。纯度：96.6％，熔点：243.8-244.2℃。
步骤4：
将1g中间体M-2、393.99mg二乙胺、557.54mg碳酸钾加入10mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经柱层析得到棕色固体LD-44
Figure PCTCN2022102054-appb-000081
756mg，产率77.25％。纯度： 96.9％，熔点：218.5-219.3℃。
1H NMR(400MHz,CDCl 3)δ(ppm):9.89(s,1H),7.24(s,2H),3.85(s,2H),3.52(s,2H),2.72-2.56(m,8H),2.14(s,6H),12.28(m,12H).HRMS:[C 20H 33N 3O 3] +,363.2522.
实施例9、化合物LD-48、LD-52、LD-55、LD-57的制备
Figure PCTCN2022102054-appb-000082
将1g中间体2III、506.30mg吗啉、803.16mg碳酸钾加入10mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体LD-48
Figure PCTCN2022102054-appb-000083
768mg，产率75.0％。纯度：98.4％，熔点：226.2.0-226.9℃。
1H NMR(400MHz,CDCl 3)δ(ppm):9.08(s,1H),7.42(s,1H),6.51(s,2H),3.60(td,J＝4.8,2.4Hz,4H),3.21(s,2H),2.60(dt,J＝4.8,2.4Hz,4H),2.21(s,6H).HRMS:[C14H20N2O 3] +,264.1474.
下列表5中的化合物制备均按实施例8步骤1，首先合成中间体2III，然后与不同含氮原料按照实施例9上述方法合成对应终产物：
表5.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000084
Figure PCTCN2022102054-appb-000085
实施例10、化合物LD-49、LD-53的制备
Figure PCTCN2022102054-appb-000086
步骤1：
将1g中间体2III、669.33mg 2,6-二甲基吗啉、803.16mg碳酸钾加入10mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体M-3
Figure PCTCN2022102054-appb-000087
850mg，产率75.04％。纯度：97.2％，熔点：221.0-221.9℃。
步骤2：
将1g中间体M-3和0.57mL N,N-二异丙基乙胺(DIPEA)溶解在10mL二氯甲烷(DCM)中，置于冰浴条件下，滴加乙酰氯的二氯甲烷稀释液(1mL)，稀释液中乙酰氯的浓度为35％(v/v)。滴加完后转至室温反应10min，硅胶薄层层析板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到棕黄色固体LD-49
Figure PCTCN2022102054-appb-000088
0.81g，产率70.99％。纯度：95.8％，熔点：235.5-236.2℃。 1H NMR(400MHz,CDCl 3)δ(ppm):6.89(s,2H),3.86(qt,J＝5.2,2.8Hz,2H),3.40–3.27(m,4H),2.90(dd,J＝12.0,2.8Hz,1H),2.68(dd,J＝12.0,2.8Hz,1H),2.20(s,3H),2.10(s,6H),1.20(d,J＝5.6Hz,6H).HRMS:[C 18H 26N 2O 4] +,334.1893.
下列表6中的化合物制备均按实施例8步骤1，首先合成中间体2III，然后与不同含氮原料按照实施例10上述方法合成对应终产物LD-53：
表6.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000089
Figure PCTCN2022102054-appb-000090
实施例11、化合物LD-50、LD-51、LD-54、LD-56、LD-58的制备
Figure PCTCN2022102054-appb-000091
步骤1：
将1g化合物LD-48和0.63mL N,N-二异丙基乙胺(DIPEA)溶解在10mL二氯甲烷(DCM)中，置于冰浴条件下，滴加溴乙酰溴的二氯甲烷稀释液(1mL)，稀释液中溴乙酰溴的浓度为35％(v/v)。滴加完后转至室温反应10min，硅胶薄层层析板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到棕黄色固体M-4
Figure PCTCN2022102054-appb-000092
0.90g，产率61.75％。纯度：96.4％，熔点：217.7-218.5℃。
步骤2：
将1g中间体M-4、339.21mg 2,6-二甲基吗啉、538.10mg碳酸钾加入10mL乙腈中，室温反应2h，硅胶薄层层析板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体LD-50
Figure PCTCN2022102054-appb-000093
660mg，产率64.95％。纯度：98.0％，熔点：228.8-229.6℃。 1H NMR(400MHz,CDCl 3)δ(ppm):8.92(s,1H),6.82(s,2H),3.69–3.61(m,8H),3.40(s,2H),3.20(s,2H),2.54–2.32(m,8H),2.26(s,6H).HRMS:[C 20H 29N 3O 5] +,391.4680.
下列表7中的化合物制备均按实施例8步骤1，首先合成中间体2III，然后与不同含氮原料按照实施例11上述方法合成对应终产物：
表7.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000094
Figure PCTCN2022102054-appb-000095
实施例12、化合物LDO-1～10、LDO-13～37、LDO-39～63、LDO-65～76的制备
Figure PCTCN2022102054-appb-000096
Figure PCTCN2022102054-appb-000097
步骤1：
将20g 2,6-二甲基苯酚和54mL DIPEA溶解在200mL二氯甲烷中，置于冰浴条件下，滴加溴乙酰溴(2eq.)的二氯甲烷稀释液(50mL)，滴加完转室温反应10min，点硅胶板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到白色固体(中间体化合物2A)32g，产率81.0％。纯度：99.5％，熔点：97.4-97.8℃。
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.17–7.06(m,3H),4.07(s,2H)，2.24(s,6H)。
步骤2：
将1g中间体化合物2A、0.86g N,N-二乙醇胺、1.14g碳酸钾加入10mL乙腈中，室温反应2h，点硅胶板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体(化合物LDO-1)780mg，产率70.9％。纯度：98.1％，熔点：148.9-149.4℃。HRMS:[C 14H 21NO 4] +,267.1471.
1H NMR(400MHz,CDCl 3)δ7.12–7.04(m,3H),4.42(s,2H),4.08(s,2H),3.96–3.82(m,4H),3.54–3.41(m,4H),2.11(s,6H).
下列表8中的化合物制备均按本实施例步骤1用不同的原料1合成对应中间体2A-n，然后与不同含氮原料合成对应终产物：
表8.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000098
Figure PCTCN2022102054-appb-000099
Figure PCTCN2022102054-appb-000100
Figure PCTCN2022102054-appb-000101
Figure PCTCN2022102054-appb-000102
Figure PCTCN2022102054-appb-000103
Figure PCTCN2022102054-appb-000104
Figure PCTCN2022102054-appb-000105
Figure PCTCN2022102054-appb-000106
Figure PCTCN2022102054-appb-000107
Figure PCTCN2022102054-appb-000108
Figure PCTCN2022102054-appb-000109
Figure PCTCN2022102054-appb-000110
Figure PCTCN2022102054-appb-000111
Figure PCTCN2022102054-appb-000112
Figure PCTCN2022102054-appb-000113
实施例13、化合物LDO-11的制备
Figure PCTCN2022102054-appb-000114
步骤1：
将20g 2,6-二甲基苯酚和54mL DIPEA溶解在200mL二氯甲烷中，置于冰浴条件下，滴加2-溴丙酰溴(2eq.)的二氯甲烷稀释液(50mL)，滴加完转室温反应10min，点硅胶板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到白色固体(中间体化合物2B)33.8g，产率80.4％。纯度：97.8％，熔点：104.7-105.1℃。
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.37(t,J＝6.0Hz,1H),7.16(d,J＝4.8Hz,2H),4.67(m,1H)，2.18(s,6H),2.02(d,J＝5.6Hz,3H)。
步骤2：
将1g中间体化合物2B、0.48g 2,5-二甲基吗啉、1.14g碳酸钾加入10mL乙腈中，室温反应2h，点硅胶板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体(化合物LDO-11)1048mg，产率87.5％。纯度：97.7％，熔点：107.1-107.6℃。HRMS:[C 17H 25NO 3] +,291.1834.
1H NMR(400MHz,CDCl 3)δ7.38(t,J＝6.4Hz,1H),7.08(d,J＝4.4Hz,2H),3.64-3.48(m,5H),2.58(t,J＝7.2Hz,2H),2.46–2.12(m,2H),2.11(s,6H),1.18(d,J＝4.8Hz,3H).
实施例14、化合物LDO-12的制备
Figure PCTCN2022102054-appb-000115
步骤1：
将20g 2,6-二甲基苯酚和54mL DIPEA溶解在200mL二氯甲烷中，置于冰浴条件下，滴加2-溴代异丁酰溴(2eq.)的二氯甲烷稀释液(50mL)，滴加完转室温反应10min，点硅胶板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到白色固体(中间体化合物2C)34.1g，产率76.8％。纯度：98.1％，熔点：116.5-116.9℃。
1H NMR(400MHz,CDCl 3)δ7.41-7.26(m,3H),2.18(s,6H),2.06(s,6H)。
步骤2：
将1g中间体化合物2C、0.43g 2,6-二甲基吗啉、1.14g碳酸钾加入10mL乙腈中，室温反应2h，点硅胶板显示反应完全。过滤，减压浓缩后，经柱层析得到白色固体(化合物LDO-12)975mg，产率86.6％。纯度：96.9％，熔点：118.2-118.8℃。HRMS:[C 18H 27NO 3] +,305.1991.
1H NMR(400MHz,CDCl 3)δ7.32(m,3H),4.12-3.94(m,2H),2.64(m,2H),2.58(m,2H),2.10(s,6H),1.16(d,J＝3.6Hz,6H).
实施例15、化合物LDO-44～45的制备
Figure PCTCN2022102054-appb-000116
将1g化合物LDO-41
Figure PCTCN2022102054-appb-000117
溶于10mL二氯甲烷中，冰浴下分批次加入0.65g间氯过氧苯甲酸，反应过夜，点硅胶板显示反应完全。减压浓缩后，经柱层析得到713mg白色固体(化合物LDO-44)，产率67.2％。纯度：96.9％，熔点：165.4-165.9℃。
1H NMR(400MHz,CDCl 3)δ7.19–6.99(m,3H),4.23(s,2H),3.91–3.21(m,4H),3.20–2.52(m,4H),2.10(d,J＝22.4Hz,6H).HRMS:[C 14H 19NO 3S] +,281.1086.
下列表9中的化合物以实施例12中步骤1、2合成所得对应中间体
Figure PCTCN2022102054-appb-000118
然后按照本实施例方法合成对应终产物LDO-45：
表9.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000119
Figure PCTCN2022102054-appb-000120
实施例16、化合物LDO-46的制备
Figure PCTCN2022102054-appb-000121
将1g化合物LDO-41
Figure PCTCN2022102054-appb-000122
溶于10mL二氯甲烷中，冰浴下分批次加入0.65g间氯过氧苯甲酸，反应过夜，点硅胶板显示反应完全。减压浓缩后，经柱层析得到750mg白色固体(化合物LDO-46)，产率66.9％。纯度：97.7％，熔点：181.4-182.0℃。
1H NMR(400MHz,CDCl 3)δ7.18–7.04(m,3H),4.79(s,2H),4.49(dd,J＝19.2,7.2Hz,2H),4.13(d,J＝13.6Hz,2H),3.67–3.39(m,2H),3.19(d,J＝14.0Hz,2H),2.10(s,6H).HRMS:[C 14H 19NO 4S] +,297.1035.
实施例17、化合物LDO-77、LOD-78的制备
Figure PCTCN2022102054-appb-000123
步骤1：
将1g 2,6-二甲基-3-硝基苯酚和2.4mL DIPEA溶解在10mL二氯甲烷中，置于冰浴条件下，滴加溴乙酰溴(2eq.，2.4g)的二氯甲烷稀释液(10mL)，滴加完转室温反应10min，点硅胶板显示原料反应完全。直接用1M的盐酸溶液洗反应液，有机层用无水硫酸钠干燥后，减压浓缩得到淡黄色固体2D，0.69g，产率41.5％。纯度：96.3％，熔点：85.7-86.6℃。
1H NMR(400MHz,CDCl 3)δ8.06(d,J＝8.2Hz,1H),7.62(d,J＝8.0Hz,1H),4.50(s,2H),2.56(s,3H),2.13(s,3H)。
步骤2：
将1g中间体化合物2D、0.26g二乙胺、0.95g碳酸钾加入10mL乙腈中，室温反应2h，点硅胶板显示反应完全。过滤，减压浓缩后，经柱层析得 到白色固体(化合物LDO-77)703mg，产率72.3％。纯度：96.4％，熔点：168.4-168.9℃。HRMS:[C 14H 20N 2O 4] +,280.1424.
1H NMR(400MHz,CDCl 3)δ7.76(d,J＝8.2Hz,1H),7.31(d,J＝8.2Hz,1H),4.12(s,2H),2.74(s,4H),2.22(s,3H),1.06(t,J＝6.9Hz,6H).
下列表10中的化合物制备均按本实施例步骤1用不同的原料1
Figure PCTCN2022102054-appb-000124
合成对应中间体
Figure PCTCN2022102054-appb-000125
然后与二乙胺合成对应终产物LOD-78：
表10.本发明其他化合物的合成信息
Figure PCTCN2022102054-appb-000126
实施例18、化合物LDO-79的制备
Figure PCTCN2022102054-appb-000127
步骤1：
将1g中间体化合物2A、0.37g二乙醇胺、1.14g碳酸钾加入10mL乙腈中，室温反应2h，点硅胶板显示反应完全。过滤，减压浓缩后，经柱层析得到白色中间体698mg，产率67.7％。纯度：97.1％，熔点：96.7-97.5℃。HRMS:[C 14H 21NO 3] +,251.1520.
1H NMR(400MHz,CDCl 3)δ7.09–6.89(m,3H),3.64(dt,J＝6.3,5.4Hz,2H),3.55(s,2H),2.76–2.62(m,5H),2.20(s,6H),1.11–1.05(m,3H).
步骤2：
将1g上述白色中间体
Figure PCTCN2022102054-appb-000128
242mg乙酸、821mg DCC和48.9mg DMAP加入10mL二氯甲烷中，室温反应8h，硅胶薄层层析板显示反应完全。减压蒸馏后溶解于50mL二氯甲烷中，水洗3遍后经硅胶柱层析 纯化，得白色固体LDO-79
Figure PCTCN2022102054-appb-000129
0.78g，产率66.3％。纯度：98.2％，熔点：112.1-112.6℃。
化合物LDO-78： 1H NMR(400MHz,CDCl 3)δ(ppm):7.18–7.02(m,3H),4.20(t,J＝5.7Hz,2H),3.50(s,2H),2.88(t,J＝5.7Hz,2H),2.68(q,J＝7.2Hz,2H),2.21(s,6H),2.04(s,2H),1.08(t,J＝7.2Hz,3H).HRMS:[C 16H 23NO 4] +,293.1627.
实施例19、化合物LDO-80的制备
Figure PCTCN2022102054-appb-000130
将1g实施例18所得中间体
Figure PCTCN2022102054-appb-000131
474mg吡啶加入10mL二氯甲烷中，冰浴下滴加651mg氯甲酸乙酯，室温反应3h，硅胶薄层层析板显示反应完全。减压蒸馏后的粗品经硅胶柱层析纯化，得微黄色固体LDO-80
Figure PCTCN2022102054-appb-000132
1.02g，产率79.2％。纯度：98.6％，熔点：101.2-101.8℃。
化合物LDO-80： 1H NMR(400MHz,CDCl 3)δ(ppm):δ7.12–6.84(m,3H),4.26–4.18(m,4H),3.54(s,2H),2.97(t,J＝5.7Hz,2H),2.71(q,J＝7.2Hz,2H),2.20(s,6H),1.33(t,J＝6.4Hz,3H),1.11–1.05(m,3H).HRMS:[C 17H 25NO 5] +,323.1735.
实施例20、化合物LDO-81的制备
Figure PCTCN2022102054-appb-000133
Figure PCTCN2022102054-appb-000134
步骤1：
将1g实施例18所得中间体
Figure PCTCN2022102054-appb-000135
678mg叔丁醇钾加入10mL二氯甲烷中，冰浴下滴加925mg磷酸二乙酯(溶解在10mL二氯甲烷中)，室温反应12h，硅胶薄层层析板显示反应完全。加入40mL水淬灭反应，用乙酸乙酯萃取(30mL*2)，合并干燥后的有机相经减压蒸馏后的粗品经硅胶柱层析纯化，得黄色中间体
Figure PCTCN2022102054-appb-000136
1.52g，产率98.0％。纯度：98.8％。
步骤2：
将0.1g上述中间体溶解于1mL无水氯仿溶剂中，在氮气保护环境中缓慢滴加734mg TMSBr，室温搅拌8h后加入0.2ml水和2ml甲醇淬灭反应，室温继续搅拌0.5h。随即加入42.5mg无水碳酸钠，继续室温搅拌1h。经减压浓缩除去所有溶剂后得黄色固体LDO-81，148mg，产率98.7％。纯度：98.2％，熔点：167.1-167.7℃。
化合物LDO-81： 1H NMR(400MHz,CDCl 3)δ(ppm):δ7.14–6.80(m,3H),4.08(dt,J＝8.4,5.0Hz,2H),3.54(s,2H),2.88(t,J＝5.0Hz,2H),2.71(q,J＝7.2Hz,2H),2.20(s,6H),1.11–1.05(m,3H).HRMS:[C 14H 20NNa 2O 6P] +,375.2684.
以下通过具体试验例来证明本发明的有益效果。
试验动物
四川省达硕公司提供SPF级健康SD大鼠(每只200-300g)、KM小鼠(每 只25-35g)、ICR小鼠(每只25-35g)，雌雄各半。单位资质许可证：SYXK(川)2015-030。本研究经过四川大学华西临床学院动物伦理委员会批准，所有动物饲养方式、设施环境按照国家研究委员会生命科学委员会实验室动物资源研究所(华盛顿特区国家科学院出版社)指南进行(2010年)。饲养环境温度25±1摄氏度，湿度在40％-60％，12h明暗交替，光照(8:00-20:00)和黑暗(20:00-8:00)，锯木屑垫料笼中；动物分笼饲养，每笼喂养只数不超过5只；自由摄取水喝食物，试验前禁食8-10h，不限饮水。
试验例1、采用序贯法测定本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的半数致死量(LD 50)
本发明用序贯法来测定化合物的半数致死量(LD 50)，没有采用Bliss法，是因为序贯法比Bliss法节约约1/3的动物，而两者测得的结果并没有显著差异。本试验小鼠序贯法的组间剂量公式比根据文献(文献Garfield,J.M.&Bukusoglu,C.Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse.Anesthesia and analgesia.83,156-161(1996).和文献Nelson,K.E.,Rauch,T.,Terebuh,V.&D'Angelo,R.A comparison of intrathecal fentanyl and sufentanil for labor analgesia.Anesthesiology.96,1070-1073(2002).)得出，剂量安排最好在4-5个剂量组间上下移动，给药从中间剂量组开始，给药后立即观察小鼠的生存情况，LD 50的测试组间剂量组设置同上，如第一只小鼠死亡记作(+)，下一只小鼠用低一级剂量；反之，小鼠存活记作(-)，下一只小鼠用高一级剂量。相邻两只小鼠试验结局出现(+)转(-)或者(-)转(+)记为一个交叉点，试验反复进行，直至每种受试药物相同向出现5个交叉，试验结束。给药后将小鼠转移至观察笼，观察至少1h。整个试验过程中，小鼠开放面罩吸氧(2L/min)，使用变温板，防止小鼠体温降低。
固定器将小鼠固定，露出尾巴，用75％的酒精棉球轻轻擦拭，扩张小鼠尾静脉。KM小鼠尾静脉推注给药利多卡因(Lidocaine,Lid)和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物。控制给药体积在0.1-0.2mL，给药时间控制在10秒。给药后观察小鼠状态。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的全身麻醉效果如表11所示。
表11.本发明化合物对小鼠的的半数致死量(LD 50)
Figure PCTCN2022102054-appb-000137
Figure PCTCN2022102054-appb-000138
注：表11中LD 50值越大说明导致死亡的药物剂量越大，和/或治疗有效的药物剂量越小，药物越安全。
由表11的结果可知：本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，与利多卡因相比，提升了这一类药物作为静脉注射用的镇痛、全身***物的安全性(LD 50提高约3-10倍)，弥补了之前利多卡因作为安全性太低的缺点。
试验例2、本发明包含且不限于上述实施例中的化合物、或其盐、或其 立体异构体、或其溶剂合物、或其前体药物对小鼠冰醋酸诱导的扭体模型等剂量药效学评价
实验选取成年ICR小鼠，称重后雌雄各半，按不同药物处理随机分组，每组8只。本实验采用的是经典的冰醋酸诱导的小鼠扭体模型，模型建立采用腹腔注射0.6％的冰醋酸溶液(Singh PP,Junnarkar AY,Rao CS,Varma RK,Shridhar DR.Acetic acid and phenylquinone writhing test:a critical study in mice.Methods Find Exp Clin Pharmacol.1983Nov；5(9):601-6.)。实验方案为：按照实验分组，提前10min于小鼠右侧腹腔注射0.05mmol/kg的利多卡因(Lidocaine,Lid)和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，基质对照组则给药等体积的生理盐水，并记此时的时间点为“0”。然后于小鼠左侧腹腔按照0.1mL/10g的量注射0.6％的冰醋酸溶液，并记录此时的时间点为“10”，即可开始记录小鼠开始出现扭体的潜伏时间，并记录此后第5min(此刻时间点记录为“15”)后15min内(终点时间点记为“30”)的扭体次数。即从时间点“10”开始记录潜伏时间，从时间点“15”–“30”记录扭体次数。并计算抑制率和镇痛率：抑制率＝[(给药组潜伏期均值－模型组潜伏期均值)/模型组潜伏期均值]×100％。镇痛率＝[(模型组扭体次数均值－给药组扭体次数均值)/模型组扭体次数均值]×100％。结果如表12所示。
表12.本发明化合物对小鼠冰醋酸诱导的扭体模型等剂量药效学评价结果
Figure PCTCN2022102054-appb-000139
Figure PCTCN2022102054-appb-000140
根据表12可知，利多卡因组小鼠对于冰醋酸诱导的扭体模型抑制率为31.19％，镇痛率为47.99％，具有一定程度的镇痛作用。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在等剂量(0.05mmol/kg)下均表现更优的镇痛效果，即抑制率在53.38-95.5％，提高了0.7-2倍；镇痛率在59.74-89.97％，提高了24％-87％。
试验例3、本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对大鼠坐骨神经慢性压迫痛(CCI)模型等剂量药效学评价
实验选取成年SD小鼠，称重后雌雄各半。造模方法：2％戊巴比妥钠按3ml/kg剂量进行大鼠麻醉，统一对左后肢剃毛。体外预判大鼠坐骨神经大致位置，碘伏消毒后横向剪开皮肤2-3cm，钝性分离肌肉使坐骨神经暴露，玻璃分针轻轻挑起后用革制羊肠线(事先用生理盐水浸泡使其软化)对其进行等距离结扎四个结，力度尽量统一致老鼠轻轻颤抖为准。结扎结束后，用羊肠线连续缝合肌肉和筋膜，用4-0#缝合线打单结缝合皮肤。机械刺激用von Frey测得，取第一次连续出现三次的值为疼痛阈值，红外热刺激用60℃条件进行测量，取三次平均值，每次至少测量间隔3min。
结果如图1所示，利多卡因能够在CCI神经病理性模型形成的1-7天内对疼痛的发生和发展具有抑制作用，并且在停药后(即8-14天)痛觉敏化再 次发生，恢复到与基质对照组同等水平。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对神经病理性疼痛的发生、发展(第1-7天)具有比利多卡因更好的缓解作用。
试验例4、采用序贯法测定本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的全身麻醉效果
以翻正反射是否消失作为本发明化合物是否有全身麻醉作用的标准，起效时间是指注射完毕后将小鼠放置为仰卧位，以小鼠前爪不能自行翻转为俯卧位、且维持时间≥10秒为小鼠前爪翻正反射消失的标准，作为化合物有效的指标。
本发明用序贯法来测定化合物的半数有效量(ED 50)和半数致死量(LD 50)，没有采用Bliss法，是因为序贯法比Bliss法节约约1/3的动物，而两者测得的结果并没有显著差异。本试验小鼠序贯法的组间剂量公式比根据文献(文献Garfield,J.M.&Bukusoglu,C.Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse.Anesthesia and analgesia.83,156-161(1996).和文献Nelson,K.E.,Rauch,T.,Terebuh,V.&D'Angelo,R.A comparison of intrathecal fentanyl and sufentanil for labor analgesia.Anesthesiology.96,1070-1073(2002).)得出，剂量安排最好在4-5个剂量组间上下移动，给药从中间剂量组开始，给药后立即观察小鼠翻正反射的情况，如第一只小鼠给药后翻正消失10s小鼠死亡记作(+)，下一只小鼠用低一级剂量；反之，未出现翻正反射或翻正反射小于10s记作(-)，下一只小鼠用高一级剂量，以此类推，记录起效时间。LD 50的测试组间剂量组设置同上，如第一只小鼠死亡记作(+)，下一只小鼠用低一级剂量；反之，小鼠存活记作(-)，下一只小鼠用高一级剂量。相邻两只小鼠试验结局出现(+)转(-)或者(-)转(+)记为一个交叉点，试验反复进行，直至每种受试药物相同向出现5个交叉，试验结束。给药后将小鼠转移至观察笼，观察至少1h。整个试验过程中，小鼠开放面罩吸氧(2L/min)，使用变温板，防止小鼠体温降低。
固定器将小鼠固定，露出尾巴，用75％的酒精棉球轻轻擦拭，扩张小鼠尾静脉。KM小鼠尾静脉推注给药利多卡因(Lidocaine,Lid)和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物。控制给药体积在0.1-0.2mL，给药时间控制在10秒。给药后观察小鼠状态。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的全身麻醉效果如表13所示。
表13.本发明化合物对小鼠的全身麻醉效果
Figure PCTCN2022102054-appb-000141
Figure PCTCN2022102054-appb-000142
注：表13中TI为治疗指数，是LD 50与ED 50的比值TI值越大说明导致死亡的药物剂量越大，和/或治疗有效的药物剂量越小，药物越安全。
本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，与利多卡因相比，不仅能够达到全身麻醉效果，并且均具有更大的治疗指数(TI)。理想的静脉全身***需要符合起效时间短、安全值范围大、麻醉恢复快的特点，本发明的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的治疗指数(TI)均为利多卡因TI值的1.8-3.0倍，提升了这一类药物作为全身***物的安全性，弥补了之前利多卡因作为全身***安全性太低的缺点。
试验例5、本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在SD大鼠中等剂量静脉输注60min减少丙泊酚用量
1、输注速率和时间的设定
本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、 或其溶剂合物、或其前体药物组的大鼠恢复时间小于丙泊酚(Propofol,Pro)组，故推测本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在体内代谢的半衰期比丙泊酚更短。根据对药物持续输注5个半衰期的实验结果分析，以及联合药物血药浓度浓度稳态这一药理学原理，得出丙泊酚的分布半衰期为2-8min，因此本发明设计的泵药时间为60min。
结合文献(文献Tao,T.et al.Protective effects of propofol against whole cerebral ischemia/reperfusion injury in rats through the inhibition of the apoptosis-inducing factor pathway.Brain research 1644,9-14(2016).和文献Yue,Z.Y.et al.Propofol prevents neuronal mtDNA deletion and cerebral damage due to ischemia/reperfusion injury in rats.Brain research 1594,108-114(2015).)查阅确定丙泊酚组的常用最小输注速率1.0mg/kg/min，这个最小输注速率的数值约为大鼠ED数值的10％，故输注速率数值参考本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的10％ED 50。Pro的ED 50为11.29mg/kg，输注速度为1.0mg/kg/min泵注；本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的ED 50参照表13，输注速度为5％ED 50mg/kg/min泵注。根据夹尾反应对丙泊酚的输注速度进行调节，根据动物反应调节速度多数为增加或减少初始剂量的10％。如夹尾反应为(+)，则将丙泊酚的泵注速度上调10％；如夹尾反应为(－)，则将丙泊酚的泵注速度下降10％。如在试验中途，出现大鼠体动，则后续各组相应单次以20％的增量进行丙泊酚(浓度为10％)或者本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物输注剂量的调节。输注60min后，停止泵药，并纪录大鼠各反应的时间和丙泊酚使用总量：从停止给药到大鼠翻正反射恢复的时间记录为恢复时间t1(图2A)；纪录大鼠大鼠翻正反射恢复到镇静评分为0的时间(5min测一次)为恢复时间t2(图2B)。
2、试验方法
取雌雄各半的SD大鼠，称重后随机分组，每组8只，大鼠尾静脉单次注射1.3×ED 50剂量的Propofol和本发明包含且不限于上述实施例的药物。将propofol和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物用微泵注射器按照上述计结果进行持续输注，根据夹尾反应调节泵注速度。
3、镇静评分观察
镇静评分共6级：四肢肌张力正常，能保持自主活动且反应灵敏为0分；明显的趋触性运动(大鼠趋向于停留在靠近笼子边缘的位置)为1分；后退 平衡失调为2分；前肢直立不到60度，共济失调为3分；俯卧，不能站立，只能靠腹部支撑为4分；翻正反射消失为5分。
如翻正反射未消失，分别记录给药时间、给药后即刻镇静评分，镇静起始时间和镇静反应完全消失时间(镇静起始时间：实验动物从给药到出现明显的趋触性运动的时间；镇静反应完全消失时间：实验动物从出现明显的趋触性运动到自主活动且反应灵敏的时间)。若大鼠翻正反射消失，那么还需要详细记录给药时间、翻正反射消失起始时间，大鼠翻正反射恢复时间。
4、结果
由图2可知：本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物组的大鼠从结束药物输注到LORR恢复时间t1显著低于Pro组大鼠的恢复时间t1(图2A)；LORR恢复到大鼠镇静评分为0的恢复时间t2，即大鼠完全恢复正常状态的时间均值，本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物组显著高于Pro组(图2B)。该结果显示单独持续静脉输注60min本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物和Pro，本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物组的大鼠苏醒时间和苏醒质量显著更优。因此，本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在短时间(<60min)的手术中具有极大的应用价值和极高的应用优势，如门诊胃肠镜检查、人流等；另外，本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物比利多卡因具有更大的安全值范围，可能比利多卡因更适合复合其他***品进行长时间的静脉输注。
丙泊酚作为临床上常用的全身筋脉***物，通常伴有强烈的注射痛(儿童发生率28％～85％，成人发生率28％～90％，并且大剂量、长时间输注丙泊酚之后可能引起代谢性酸中毒已、多器官衰竭、高脂血症肝脏脂肪浸润、横纹肌溶解等严重并发症，并且具有显著的降血压作用，严重者可导致死亡，即“丙泊酚输注综合征”(PIS)。所以临床多采用联合丙泊酚与其他***物进行持续输注，以降低丙泊酚的临床不良反应。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对比传统利多卡因与丙泊酚进行联合用药，按上述计算速度进行大鼠持续输注。实验随机分组：①按表13计算的丙泊酚剂量与生理盐水进行持续输注(Pro组)、②按表13计算的丙泊酚剂量联合本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的 10％的剂量进行同时持续输注(Pro+LD-X组)、③按表13计算的丙泊酚剂量联合利多卡因剂量的10％进行持续输注(Pro+Lid组)。实验结果：按上述方法进行混合输注最后，计算出丙泊酚给药量分别为①Pro组：35.0±7.2mg、②Pro+LD-X组：16.8±3.3mg、③Pro+Lid组：27.3±4.8mg。
试验例6、采用序贯法测定本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的全身麻醉效果
以翻正反射是否消失作为本发明化合物是否有全身麻醉作用的标准，起效时间是指注射完毕后将小鼠放置为仰卧位，以小鼠前爪不能自行翻转为俯卧位、且维持时间≥10秒为小鼠前爪翻正反射消失的标准，作为化合物有效的指标。
本发明用序贯法来测定化合物的半数有效量(ED 50)和半数致死量(LD 50)，没有采用Bliss法，是因为序贯法比Bliss法节约约1/3的动物，而两者测得的结果并没有显著差异。本试验小鼠序贯法的组间剂量公式比根据文献(文献Garfield,J.M.&Bukusoglu,C.Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse.Anesthesia and analgesia.83,156-161(1996).和文献Nelson,K.E.,Rauch,T.,Terebuh,V.&D'Angelo,R.A comparison of intrathecal fentanyl and sufentanil for labor analgesia.Anesthesiology.96,1070-1073(2002).)得出，剂量安排最好在4-5个剂量组间上下移动，给药从中间剂量组开始，给药后立即观察小鼠翻正反射的情况，如第一只小鼠给药后翻正消失10s小鼠死亡记作(+)，下一只小鼠用低一级剂量；反之，未出现翻正反射或翻正反射小于10s记作(-)，下一只小鼠用高一级剂量，以此类推，记录起效时间。LD 50的测试组间剂量组设置同上，如第一只小鼠死亡记作(+)，下一只小鼠用低一级剂量；反之，小鼠存活记作(-)，下一只小鼠用高一级剂量。相邻两只小鼠试验结局出现(+)转(-)或者(-)转(+)记为一个交叉点，试验反复进行，直至每种受试药物相同向出现5个交叉，试验结束。给药后将小鼠转移至观察笼，观察至少1h。整个试验过程中，小鼠开放面罩吸氧(2L/min)，使用变温板，防止小鼠体温降低。
固定器将小鼠固定，露出尾巴，用75％的酒精棉球轻轻擦拭，扩张小鼠尾静脉。ICR小鼠尾静脉推注给药利多卡因(Lidocaine,Lid)和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物。控制给药体积在0.1-0.2mL，给药时间控制在10秒。给药后观察小鼠状态。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的全身麻醉效果如表14所示。
表14.本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的全身麻醉效果
Figure PCTCN2022102054-appb-000143
Figure PCTCN2022102054-appb-000144
Figure PCTCN2022102054-appb-000145
注：表14中TI为治疗指数，是LD 50与ED 50的比值，TI值越大说明导致死亡的药物剂量越大，和/或治疗有效的药物剂量越小，药物越安全。
由表14的结果可知：本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，与利多卡因相比，不仅能够达到类似的全身麻醉效果，并且均具有更大的治疗指数(TI)。理想的静脉全身***需要符合起效时间短、安全值范围大、麻醉恢复快的特点，本发明的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的治疗指数(TI)均为利多卡因TI值的1-2.5倍，提升了这一类药物作为全身***物的安全性，弥补了之前利多卡因作为全身***安全性太低的缺点。
试验例7、本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠的等剂量药效学评价
取ICR小鼠雌雄各半，称重后随机分组，每组8只。按照试验例6所述的方法分别对各组实验小鼠尾静脉推注给药利多卡因(Lidocaine,Lid)和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，各组注射剂量均为2×ED 50(ED 50的两倍量)。起效时间的定义与试验例6相同；作用时间是指小鼠翻正反射(LORR)消失，到小鼠前爪自行翻转为俯卧位的时间；恢复时间是指小鼠LORR恢复至完全清醒、肌张力正常这一段时间。
文献(Garfield J M,Bukusoglu C.Propofol and Ethanol Produce Additive Hypnotic and Anesthetic Effects in the Mouse[J].Anesthesia&Analgesia,1996,83(1):156-161.)曾用夹尾刺激研究了其他全麻药Propofol、ethanal、硫喷妥钠和芬太尼对小鼠和大鼠的麻醉作用，实验表明用夹尾刺激作为静脉***麻醉效果的判定是比较可行的。夹尾反应越剧烈(夹尾反应阳性越高)，说明全麻效果越差。本发明同样使用夹尾刺激判断化合物的麻醉效果。试验结果如表15所示。
表15.本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、 或其溶剂合物、或其前体药物对小鼠的等剂量药效学评价结果
Figure PCTCN2022102054-appb-000146
Figure PCTCN2022102054-appb-000147
Figure PCTCN2022102054-appb-000148
注：LORR(+)表示各药物组呈现翻正反射阳性(翻正反射消失)的数量；苏醒质量差表示实验动物苏醒后精神状态差的数量，多表现出较长时间内行动迟缓，萎靡等评分标准：1分：苏醒时间大于2min且3min内无法正常行走；2分：苏醒时间大于1min且3min内恢复正常行走；3分：苏醒时间小于1min且2min内恢复正常行走；4分：苏醒时间小于1min且1min内恢复正常行走；5分：苏醒时间小于1min且30s内恢复正常行走。
本发明研究发现：在2×ED 50尾静脉推注给药的剂量下，利多卡因组小鼠的夹尾反应阳性率为25％、且死亡率高(25％)、苏醒质量评分低(2分)，说明利多卡因在该剂量下作为全身***物麻醉效果差、安全性均低、术后谵妄效果差；丙泊酚组小鼠的夹尾反应阳性为0，死亡率为0，但是苏醒质量评分仅1分，说明其术后谵妄极差。而本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在等剂量下均表现出良好的全身麻醉效果良好且稳定，安全性高(死亡率为0)、苏醒质量评分高，意味着有着良好的术后谵妄。
试验例8、采用序贯法测定本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对大鼠的全身麻醉效果
序贯法测定ED 50和LD 50方法同试验例6。其中，定义和试验方法均同试验例6，只是将ICR小鼠替换为SD大鼠。
将SD大鼠放于固定器中，露出尾巴固定，用75％酒精棉球轻轻擦拭，或者45℃温水浸泡1-2min，软化大鼠尾巴角质层，扩张尾静脉，用24G静脉留置针行大鼠尾静脉穿刺置管，用胶布妥善固定留置针。注射药物前回抽，以回抽见血作为置管成功的标准，注射药物为丙泊酚(Propofol，Pro)和本发 明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，注射完毕用0.2ml生理盐水冲管，减少药物残留在留置针中，给药速度10-15秒，注射液体总体积不超过1.5ml。给药后观察大鼠状态。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对大鼠的全身麻醉效果如表16所示。
表16.本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对大鼠的全身麻醉效果
Figure PCTCN2022102054-appb-000149
试验结果说明：本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对大鼠全身麻醉的TI值是丙泊酚的2-3.7倍，体现出更高的安全性和更好的苏醒质量。并且本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的作用时间较利多卡因的作用时间更短，有利于麻醉后大鼠的苏醒质量。
试验例9、丙泊酚联合本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物或者利多卡因在SD大鼠中静脉输注60min
丙泊酚作为临床上常用的全身筋脉***物，通常伴有强烈的注射痛(儿童发生率28％～85％，成人发生率28％～90％，并且大剂量、长时间输注丙泊酚之后可能引起代谢性酸中毒已、多器官衰竭、高脂血症肝脏脂肪浸润、横纹肌溶解等严重并发症，并且具有显著的降血压作用，严重者可导致死亡，即“丙泊酚输注综合征”(PIS)。所以临床多采用联合丙泊酚与其他***物进行持续输注，以降低丙泊酚的临床不良反应。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对比传统利多卡因与丙泊酚进行联合用药，按计算速度进行大鼠持续输注。结合文献(文献Tao,T.et al.Protective effects of propofol against whole cerebral ischemia/reperfusion injury in rats through the inhibition of the apoptosis-inducing factor pathway.Brain research 1644,9-14(2016).和文献Yue,Z.Y.et al.Propofol prevents neuronal mtDNA deletion and cerebral damage due to ischemia/reperfusion injury in rats.Brain research 1594,108-114(2015).)查阅确定丙泊酚组的常用最小输注速率1.0mg/kg/min，这个最小输注速率的数值约为试验例8中测得的大鼠ED数值的10％，联合输注速率数值参考本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的1％ED 50。Pro的ED 50为11.29mg/kg，输注速度为1.0mg/kg/min泵注；本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的ED 50参照试验例8(表16)，输注速度为1％ED 50mg/kg/min泵注(ED 50参照试验例8的表16)。实验随机分组：①按试上述计算的丙泊酚剂量进行与生理盐水持续输注(Pro组)、②按上述计算的丙泊酚剂量联合本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物的1％剂量进行同时持续输注(Pro+LDO-X组)、③按上述计算的丙泊酚剂量联合利多卡因剂量的1％ED 50进行持续输注(Pro+Lid组)。实验结果：①Pro组中SD大鼠的存活率为75％，死亡率为25％，夹尾反应消失率为100％，不良反应中呼吸困难1只(12.5％)；②Pro+LDO-X组SD大鼠存活率均为100％，不良反应中呼吸困难均少于等于1只(≤12.5％)；③Pro+Lid组SD大鼠的存活率为75％，死亡率为25％，不良反应中呼吸困难4只(50％)。按上述方法进行混合输注最后，计算出丙泊酚给药量分别为①Pro组：35.0±7.2mg、②Pro+LD-X组：17.8±3.3mg、③Pro+Lid组26.4±3.7mg。
综上所述，利多卡因辅助丙泊酚进行全身麻醉时，能够一定程度上降低大鼠持续输注之后的苏醒时间和丙泊酚的用药量(-24.6％)，部分缓解了如图3所示由于大剂量和长时间输注丙泊酚带来的血压下降的不良反应，但是也由于利多卡因自身的安全性过低，导致大鼠死亡率反而增加(-25％)。而本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物辅助丙泊酚进行全身麻醉时，不仅能够显著降低大鼠持续输注之后的苏醒时间，降低了丙泊酚的用药量(-49.1％)，还能显著消除了由于大剂量和长时间输注丙泊酚带来的血压变化幅度大的不良反应(图 3)，并且由于本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物具有易于体内分解代谢的酯结构，因此具有比利多卡因具有更高的安全性，提高了大鼠的生存率(+25％)。最为重要的是，在麻醉过程中，如图4所示，心脏超声结果显示Pro+LDO-X组中LDO-X的使用发挥了显著的心脏保护作用，而Pro+Lid组中的利多卡因则不具有这一作用。
试验例10、本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠冰醋酸诱导的扭体模型等剂量药效学评价
实验选取成年ICR小鼠，称重后雌雄各半，按不同药物处理随机分组，每组8只。本实验采用的是经典的冰醋酸诱导的小鼠扭体模型，模型建立采用腹腔注射0.6％的冰醋酸溶液(Singh PP,Junnarkar AY,Rao CS,Varma RK,Shridhar DR.Acetic acid and phenylquinone writhing test:a critical study in mice.Methods Find Exp Clin Pharmacol.1983 Nov；5(9):601-6.)。实验方案为：按照实验分组，提前10min于小鼠右侧腹腔注射0.05mmol/kg的利多卡因(Lidocaine,Lid)和本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，基质对照组则给药等体积的生理盐水，并记此时的时间点为“0”。然后于小鼠左侧腹腔按照0.1mL/10g的量注射0.6％的冰醋酸溶液，并记录此时的时间点为“10”，即可开始记录小鼠开始出现扭体的潜伏时间，并记录此后第5min(此刻时间点记录为“15”)后15min内(终点时间点记为“30”)的扭体次数。即从时间点“10”开始记录潜伏时间，从时间点“15”–“30”记录扭体次数。并计算抑制率和镇痛率：抑制率＝[(给药组潜伏期均值－模型组潜伏期均值)/模型组潜伏期均值]×100％。镇痛率＝[(模型组扭体次数均值－给药组扭体次数均值)/模型组扭体次数均值]×100％，结果如表17所示。
表17.本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物对小鼠冰醋酸诱导的扭体模型等剂量药效学评价结果
Figure PCTCN2022102054-appb-000150
Figure PCTCN2022102054-appb-000151
本发明研究发现：利多卡因组小鼠对于冰醋酸诱导的扭体模型抑制率为31.19％，镇痛率为47.99％，具有一定程度的镇痛作用。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在等剂量(0.05mmol/kg)下均表现更优的镇痛效果，即抑制率在53.40-96.80％，提高了0.7-2倍；镇痛率在61.13-78.85％，提高了24.5％-64.3％。
综上所述，本发明化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物具有良好的静脉注射用镇痛或/和麻醉效果。通过静脉用药，不但提高了传统利多卡因对多种疼痛具有良好镇痛作用，并且具有更高的安全性；并且作为全身***物，麻醉后恢复时间更短、苏醒质量更好、安全指数更高。并且本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在持续输注麻醉方案中还具有比利多卡因更加显著的减少丙泊酚用量和减少阿片类药物用量的效果，可同时作为理想的静脉注射用镇痛药物和***物。因此，本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物尤其适合于经静脉注射对动物或者人产生镇痛和/或麻醉作用以及临床其他麻醉作用。本发明包含且不限于上述实施例中的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物可为利多卡因类药物在静脉用药的镇痛和全麻以及临床其他麻醉领域的使用提供更好的安全性保障，减少阿片麻醉(ORA)或者无阿片麻醉(OFA)的使用。进而，本发明化合物可减少术后疼痛、恶心呕吐、肠麻痹、便秘、认知功能障碍、甚至睡眠障碍等手术后常见并发症，促进手术患者康复，减少住院时间，促进增强术后康复计划，可以将其常规纳入围术期增强恢复方案中，具有良好的应用前景。

Claims (27)

  1. 式I所示的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物：
    Figure PCTCN2022102054-appb-100001
    其中，
    X选自-NH-或-O-；
    R 1～R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、取代或未取代的酯基、3～6元环烷基、-OC(O)R 7’；所述酯基的取代基选自-NR 8’R 9’；当X选自O时，R 1～R 5中至少有2个不同时选自氢；
    R 7’选自取代的C 1～C 8烷基或-NR 8’R 9’；所述烷基的取代基选自-NR 8’R 9’或吗啉基；
    R 8、R 8’、R 9、R 9’分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述烷基、环烷基的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
    或者R 8’与R 9’连接、或R 8与R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100002
    R 10’选自C 1～C 8烷基；
    X 1选自无、-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1选自无、-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、卤素、氨基、氰基、硝基、磺酸基、巯基、酯基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3。
  2. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II所示：
    Figure PCTCN2022102054-appb-100003
    其中，
    R 1～R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、取代或未取代的酯基、3～6元环烷基、-OC(O)R 7’；所述酯基的取代基选自-NR 8’R 9’；当X选自O时，R 1～R 5中至少有2个不同时选自氢；
    R 7’选自取代的C 1～C 8烷基或-NR 8’R 9’；所述烷基的取代基选自-NR 8’R 9’或吗啉基；
    R 8、R 8’、R 9、R 9’分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述烷基、环烷基的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
    或者R 8’与R 9’连接、或R 8与R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100004
    R 10’选自氢或C 1～C 8烷基；
    X 1选自无、-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1选自无、-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、卤素、氨基、氰基、硝基、磺酸基、巯基、酯基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3。
  3. 根据权利要求2所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-A所示：
    Figure PCTCN2022102054-appb-100005
    其中，
    R 6、R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基；
    R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、取代或未取代的酯基；所述酯基的取代基选自-NR 8’R 9’；
    R 8’、R 9’分别独立选自C 1～C 8烷基；
    当R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基时，R 8、R 9分别独立选自取代或未取代的C 2～C 8烷基、取代或未取代的3～6元环烷基，所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；
    当R 3选自取代或未取代的酯基时，R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；
    R 10’选自氢或C 1～C 8烷基。
  4. 根据权利要求2所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-B所示：
    Figure PCTCN2022102054-appb-100006
    其中，
    R 7’选自取代的C 1～C 8烷基或-NR 8’R 9’；所述烷基的取代基选自-NR 8’R 9’或吗啉基；
    R 8’、R 9’分别独立选自C 1～C 8烷基；
    X 1选自无、-O-、-CR 16R 17-；
    Y 1选自无、-CR 16R 17-；
    R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
    优选地，所述化合物如式II-B1所示：
    Figure PCTCN2022102054-appb-100007
    其中，
    X 1选自无、-O-、-CR 16R 17-；
    Y 1选自无、-CR 16R 17-；
    R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3。
  5. 根据权利要求2所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-C所示：
    Figure PCTCN2022102054-appb-100008
    其中，
    R 1～R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    X 1选自无、-O-、-CR 16R 17-；
    Y 1选自无、-CR 16R 17-；
    R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
    当X 1选自-O-，Y 1选自-CR 16R 17-时，R 10～R 17中至少有两个不选自氢；当R 6或R 7均选自氢，或者其中一个选自甲基，R 10～R 17中仅有两个不选自氢而选自甲基时，R 12和R 13不同时为甲基，或者R 16和R 17不同时为甲基，或者R 10和R 11中任意一个与R 14和R 15任意一个不同时为甲基；或者R 12和R 13中任意一个与R 16和R 17任意一个不同时为甲基；
    或者，当X 1选自-O-，Y 1选自-CR 16R 17-，R 6和R 7均选自氢，R 10～R 17中仅有两个不选自氢而选自甲基时，R 10和R 11中任意一个与R 16和R 17任意一个不同时为甲基；或者R 12和R 13中任意一个与R 14和R 15任意一个不同时为甲基；
    或者，当X 1和Y 1选自无，R 2、R 4、R 7、R 10、R 11、R 14、R 15选自氢，R 1选自氢、甲基或乙基，R 5选自烷基，R 3、R 6分别独立选自氢或甲基，R 12、R 13中有一个选自氢时，另一个不选自羟基、氨基；R 12和R 13均不选自氢时，R 12和R 13不同时选自甲基；R 12、R 13中有一个选自甲基时，另一个不选自羟基、甲烷基；
    或者，当X 1和Y 1一个选自无、一个选自-CR 16R 17-，R 10～R 17是同一个碳原子上的两个取代基连接形成环时，所连接形成的环不为取代或未取代的4元饱和碳环；或者，所连接形成的螺环不为
    Figure PCTCN2022102054-appb-100009
    优选地，
    R 1～R 5分别独立选自氢、C 1～C 4烷基、羟基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 4烷基；
    X 1选自无、-O-、-CR 16R 17-；
    Y 1选自无、-CR 16R 17-；
    R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
  6. 根据权利要求5所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-C1所示：
    Figure PCTCN2022102054-appb-100010
    其中，
    R 3、R 6、R 7分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    R 10～R 17分别独立选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、氰基、硝基、磺酸基、巯基、酯基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S、N，所述杂原子个数为1、2或3；
    优选地，
    R 3选自氢、C 1～C 4烷基、羟基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 4烷基；
    R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环。
  7. 根据权利要求6所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-D1所示：
    Figure PCTCN2022102054-appb-100011
    其中，
    R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环；
    或者，所述化合物如式II-D2所示：
    Figure PCTCN2022102054-appb-100012
    其中，
    R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    R 10～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳环。
  8. 根据权利要求5所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-C2所示：
    Figure PCTCN2022102054-appb-100013
    其中，
    R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 8烷基；
    R 10～R 15分别独立选自氢、C 1～C 8烷基；或者R 10～R 15中，同一个碳原子上的两个取代基连接形成3～6元碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
    优选地，
    R 3选自氢、C 1～C 4烷基、羟基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 4烷基；
    R 10～R 15分别独立选自氢、C 1～C 4烷基；或者R 10～R 15中，同一个碳原子上的两个取代基连接形成4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
  9. 根据权利要求5所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-C3所示：
    Figure PCTCN2022102054-appb-100014
    其中，
    R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 8烷基；
    R 10～R 13分别独立选自氢、C 1～C 8烷基；或者R 10～R 13中，同一个碳原子上的两个取代基连接形成3～6元碳环、3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1、2或3；
    优选地，
    R 3选自氢、C 1～C 4烷基、羟基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 4烷基；
    R 10～R 13分别独立选自氢、C 1～C 4烷基；或者R 10～R 13中，同一个碳原子上的两个取代基连接形成4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
  10. 根据权利要5所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式II-C4所示：
    Figure PCTCN2022102054-appb-100015
    其中，
    R 3选自氢、C 1～C 8烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 8烷基；
    R 10～R 13、R 16～R 17分别独立选自氢、C 1～C 8烷基；或者R 10～R 13、R 16～R 17中，同一个碳原子上的两个取代基连接形成3～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S、N，所述杂原子个数为1、2或3；
    优选地，
    R 3选自氢、C 1～C 4烷基、羟基、酯基；
    R 6～R 7分别独立选自氢、C 1～C 4烷基；
    R 10～R 13、R 16～R 17分别独立选自氢、C 1～C 4烷基；或者R 10～R 13、R 16～R 17中，同一个碳原子上的两个取代基连接形成4～6元饱和碳杂环；所述饱和碳杂环的杂原子为O、S或N，所述杂原子个数为1。
  11. 根据权利要求1所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式III所示：
    Figure PCTCN2022102054-appb-100016
    其中，
    R 1～R 5分别独立选自氢、C 1～C 2烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基、3～6元环烷基，且R 1～R 5中至少有2个不同时选自氢；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～6元环烷基；
    R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
    或者R 8、R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100017
    R 10’选自C 1～C 8烷基；
    X 1为无、-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为无、-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、 2或3；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    当X 1和Y 1同时为无时，R 10～R 15不同时选自氢；或者，R 12、R 13不选自未取代的甲基；
    当X 1为-CR 16R 17-，Y 1为无时，R 10～R 17不同时选自氢；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100018
  12. 根据权利要求11所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：
    R 1～R 5分别独立选自氢、C 1～C 2烷基、C 1～C 8烷氧基、卤素、羟基、氨基、羧基、氰基、硝基、磺酸基、巯基、酯基、3～6元环烷基，且R 1～R 5中至少有2个不同时选自氢；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～6元环烷基；
    R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、酯基、-OC(O)OR 10’或磷酸氢钠；且R 8、R 9不同时为未取代的C 1～C 8烷基；
    或者R 8、R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100019
    Figure PCTCN2022102054-appb-100020
    R 10’选自C 1～C 8烷基；
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 8烷氧基、取代的C 1～C 8烷基、未取代的C 2～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 10～R’ 15不同时选自氢；
    或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    X 2为-O-或-CR 16R 17-；
    R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
    或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100021
    优选地，
    R 1～R 5分别独立选自氢、C 1～C 2烷基、羟基、卤素或3～6元环烷基，且R 1～R 5中至少有2个不同时选自氢；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 8、R 9分别独立选自取代或未取代的C 1～C 3烷基、取代或未取代的3～4元环烷基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素或酯基；且R 8、R 9不同时为未取代的C 1～C 3烷基；
    或者R 8、R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100022
    Figure PCTCN2022102054-appb-100023
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
    R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 3烷氧基、取代的C 1～C 3烷基、未取代的C 2～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基 分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；R’ 10～R’ 15不同时选自氢；
    或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O；所述杂原子个数为1；
    X 2为-O-或-CR 16R 17-；
    R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O；所述杂原子个数为1；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
    或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O；所述杂原子个数为1；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100024
  13. 根据权利要求11所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物具有如式III-A所示结构：
    Figure PCTCN2022102054-appb-100025
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
    R 8、R 9分别独立选自取代或未取代的C 1～C 8烷基、取代或未取代的3～6元环烷基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素或酯基；且R 8、R 9不同时为未取代的C 1～C 8烷基；
    或者R 8、R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100026
    Figure PCTCN2022102054-appb-100027
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 8烷氧基、取代的C 1～C 8烷基、未取代的C 2～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 10～R’ 15不同时选自氢；
    或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    X 2为-O-或-CR 16R 17-；
    R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
    或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100028
    优选地，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 8、R 9分别独立选自取代或未取代的C 1～C 3烷基、取代或未取代的3～4元环烷基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素或酯基；且R 8、R 9不同时为未取代的C 1～C 3烷基；
    或者R 8、R 9连接与N原子形成
    Figure PCTCN2022102054-appb-100029
    Figure PCTCN2022102054-appb-100030
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或4～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中 任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
    R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 3烷氧基、取代的C 1～C 3烷基、未取代的C 2～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R’ 10～R’ 15不同时选自氢；
    或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
    X 2为-O-或-CR 16R 17-；
    R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 2为-CR 16R 17-时，R” 10～R” 15、R 16～R 17不同时选自氢；
    或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100031
  14. 根据权利要求11所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物具有如式III-B所示结构：
    Figure PCTCN2022102054-appb-100032
    Figure PCTCN2022102054-appb-100033
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100034
    优选地，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    Y 1为-O-或-CR 16R 17-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 1为-O-，Y 1为-CR 16R 17-时，R 10～R 17不能同时选自氢；当X 1为-O-，Y 1为-CR 16R 17-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100035
  15. 根据权利要求14所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物具有如式III-C所示结构：
    Figure PCTCN2022102054-appb-100036
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；当X 1为-O-时，R 10～R 17不能同时选自氢；当X 1为-O-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100037
    优选地，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    X 1为-O-、-S-、-SO-、-SO 2-、-CR 16R 17-或-NR 18-；
    R 10～R 18分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4 烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；当X 1为-O-时，R 10～R 17不能同时选自氢；当X 1为-O-，且R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100038
  16. 根据权利要求15所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物具有如式III-D所示结构：
    Figure PCTCN2022102054-appb-100039
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
    R 10～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；且R 10～R 17不能同时选自氢；当R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    优选地，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 10～R 17分别独立选自氢、羟基、C 1～C 2烷氧基、取代或未取代的C 1～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；且R 10～R 17不能同时选自氢；当R 10～R 17中有两个为甲基，其余为氢时，R 12或R 13中任意一个与R 16或R 17中任意一个不可同时选自甲基；
    或者，R 10～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1。
  17. 根据权利要求15所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物具有如式III-E所示结构：
    Figure PCTCN2022102054-appb-100040
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～6元环烷基；
    R 10～R 18分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；
    或者，R 10～R 18中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    当R 1与R 5同时选自相同取代基时，R 8与R 9不可连接形成
    Figure PCTCN2022102054-appb-100041
    优选地，
    R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 10～R 18分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 4烷基或3～4元环烷基；所述取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基。
  18. 根据权利要求15所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式III-F-1所示：
    Figure PCTCN2022102054-appb-100042
    其中，
    R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 10～R 17分别独立选自氢或未取代的C 1～C 4烷基；
    或，所述化合物如式III-F-2所示：
    Figure PCTCN2022102054-appb-100043
    R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 10～R 17分别独立选自氢或未取代的C 1～C 4烷基；
    或，所述化合物如式III-F-3所示：
    Figure PCTCN2022102054-appb-100044
    R 1～R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 10～R 17分别独立选自氢或未取代的C 1～C 4烷基。
  19. 根据权利要求14所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式IV所示：
    Figure PCTCN2022102054-appb-100045
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R 10～R 17分别独立选自氢或未取代的C 1～C 3烷基。
  20. 根据权利要求13所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式V所示：
    Figure PCTCN2022102054-appb-100046
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 8烷基或3～4元环烷基；
    R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤 素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 8烷氧基、取代的C 1～C 8烷基、未取代的C 2～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R’ 10～R’ 15不同时选自氢；
    或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    优选地，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢或C 1～C 3烷基；
    R’ 10～R’ 11、R’ 14～R’ 15分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和碳杂环的杂原子为O；所述杂原子个数为1；R’ 12～R’ 13分别独立选自氢、羟基、C 1～C 3烷氧基、取代的C 1～C 3烷基、未取代的C 2～C 4烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R’ 10～R’ 15不同时选自氢；
    或者，R’ 10～R’ 15中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元碳环或4～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1。
  21. 根据权利要求13所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物如式VI所示：
    Figure PCTCN2022102054-appb-100047
    其中，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢或C 1～C 8烷基；
    R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 8烷氧基、取代或未取代的C 1～C 8烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1～6中的任意整数，所述取代基分别独立选自羟基、C 1～C 8烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1、2或3；R” 10～R” 15、R 16～R 17不同时选自氢；
    或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1、2或3；
    优选地，
    R 1、R 5分别独立选自C 1～C 2烷基、3～6元环烷基；
    R 6、R 7分别独立选自氢、C 1～C 3烷基或3～4元环烷基；
    R” 10～R” 15、R 16～R 17分别独立选自氢、羟基、C 1～C 3烷氧基、取代或未取代的C 1～C 3烷基、3～6元环烷基或3～6元饱和杂环基；所述取代的取代基个数为1，所述取代基分别独立选自羟基、C 1～C 3烷氧基、卤素、羧基、酯基或羧酸甲酯基；所述饱和杂环基的杂原子为O、S或N；所述杂原子个数为1；R” 10～R” 15、R 16～R 17不同时选自氢；
    或者，R” 10～R” 15、R 16～R 17中，在同一个碳原子上或者在相邻两个碳原子上的基团分别相连接形成3～6元饱和碳环或3～6元饱和碳杂环，所述饱和碳杂环的杂原子为O、S或N；所述杂原子个数为1。
  22. 根据权利要求1～21任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物，其特征在于：所述化合物为如下化合物之一：
    Figure PCTCN2022102054-appb-100048
    Figure PCTCN2022102054-appb-100049
    Figure PCTCN2022102054-appb-100050
    Figure PCTCN2022102054-appb-100051
    Figure PCTCN2022102054-appb-100052
  23. 权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在制备镇痛药物中的用途；
    优选地，所述镇痛药物为经静脉注射对动物或者人产生镇痛作用的药物。
  24. 权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在制备全身***物中的用途的药物；
    优选地，所述***物为经静脉注射对动物或者人产生全身麻醉作用的药物。
  25. 权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物在制备其他临床***物中的用途；
    优选地，所述***物为经静脉注射对动物或者人产生临床上使用的其他麻醉作用的药物。
  26. 一种药物，其特征在于：它是由权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
  27. 一种药物组合物，其特征在于：它包括权利要求1～22任一项所述的化合物、或其盐、或其立体异构体、或其溶剂合物、或其前体药物以及其他药物。
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