WO2023274258A1

WO2023274258A1 - Heteroatom-substituted aromatic compound, and preparation method therefor and use thereof

Info

Publication number: WO2023274258A1
Application number: PCT/CN2022/102054
Authority: WO
Inventors: 刘进; 柯博文
Original assignee: 四川大学华西医院
Priority date: 2021-06-29
Filing date: 2022-06-28
Publication date: 2023-01-05
Also published as: CN115536607A

Abstract

Provided are a heteroatom-substituted aromatic compound, and a preparation method therefor and the use thereof, which belong to the field of medicinal chemistry. The compound is a compound as represented by formula I, or a salt, a stereoisomer, a solvate, or a prodrug thereof. The compound can be used for preparing a central inhibitory drug and/or an analgesic drug that exerts a systemic anesthetic effect on an animal or a human being via an intravenous route, wherein the intravenous injection can exert quick-acting and short-acting systemic anesthetic and/or analgesic effects. The compound has a high therapeutic index, high safety, shorter wake-up time, better wake-up quality and better analgesic effect, and provides a great development value and clinical application prospects for the fields of intravenous injection analgesia, systemic anesthesia and other clinical applications of anesthesia.

Description

A heteroatom-substituted aromatic compound and its preparation method and use

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a heteroatom-substituted aromatic compound, a preparation method and application thereof.

Background technique

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. At the same time, a number of studies have shown that lidocaine can not only be used for anesthesia of poultry animals, chickens, mammals, dogs, horses, pigs, alpacas, etc., and intravenous injection (IVL) of lidocaine during the clinical perioperative period can not only effectively 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.

The significant analgesic benefit of IVL in abdominal surgery has been confirmed, but there are still many controversies about its analgesic effect in other types of surgery and its narrow therapeutic window (TI). Studies have shown that the clinical pain benefit of IVL has a wide range uncertainty. At present, the therapeutic index of lidocaine ( TI) is very low. In addition, lidocaine has a relatively narrow safety record and potential cardiotoxicity and neurotoxicity, so its clinical application is largely limited.

Therefore, 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.

Contents of the invention

In view of the above situation, 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:

in,

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;

Or 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 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;

Alternatively, in 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.

Further, the compound is shown in formula II:

in,

R ₁₀ ' is selected from hydrogen or C ₁ -C ₈ alkyl;

Y ₁ is selected from none, -O- or -CR ₁₆ R ₁₇ -;

Further, the compound is shown in formula II-A:

in,

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;

When 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;

When R ₃ is selected from substituted or unsubstituted ester groups, 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.

Further, the compound is shown in formula II-B:

in,

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;

Preferably, the compound is shown in formula II-B1:

in,

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.

Further, the compound is shown in formula II-C:

in,

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 -;

When X ₁ is selected from -O-, 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 ;

Alternatively, when 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 When 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;

Alternatively, when X ₁ and Y ₁ are selected from none, R ₂ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , R ₁₄ , R ₁₅ are selected from hydrogen, R ₁ is 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, and when one of R ₁₂ and R ₁₃ is selected from hydrogen, the other is not selected from hydroxyl or amino; neither R ₁₂ nor R ₁₃ is selected from For hydrogen, R ₁₂ and R ₁₃ are not selected from methyl at the same time; when one of R ₁₂ and R ₁₃ is selected from methyl, the other is not selected from hydroxyl or methyl;

Alternatively, when one of X ₁ and Y ₁ is selected from none, and one is selected from -CR ₁₆ R ₁₇ -, and R ₁₀ to R ₁₇ are two substituents on the same carbon atom connected to form a ring, 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

Preferably,

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.

Further, the compound is shown in formula II-C1:

in,

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;

Preferably,

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 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.

Further, the compound is shown in formula II-D1:

in,

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;

Alternatively, the compound is shown in formula II-D2:

in,

Further, the compound is shown in formula II-C2:

in,

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;

Preferably,

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 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.

Further, the compound is shown in formula II-C3:

in,

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;

Preferably,

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.

Further, the compound is shown in formula II-C4:

in,

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;

Preferably,

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 ～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.

Further, the compound is shown in formula III:

in,

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;

Or 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 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;

Alternatively, in 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;

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 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;

When X ₁ and Y ₁ are both absent, R ₁₀ to R ₁₅ are not simultaneously selected from hydrogen; or, R ₁₂ and R ₁₃ are not selected from unsubstituted methyl;

When X ₁ is -CR ₁₆ R ₁₇ - and Y ₁ is none, R ₁₀ to R ₁₇ are not simultaneously selected from hydrogen;

When R ₁ and R ₅ are selected from the same substituent at the same time, R ₈ and R ₉ cannot be connected to form

further,

Or 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 the same time;

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 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; R' ₁₀ to R' ₁₅ are not simultaneously selected from hydrogen;

Or, in 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;

Or, in 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;

Preferably,

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;

Or 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;

Alternatively, in 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; the number of heteroatoms is 1; R' ₁₂ ~ R' ₁₃ are independently selected from hydrogen, hydroxyl, C ₁ ~ C ₃ alkoxy, substituted C ₁ to C ₃ alkyl, unsubstituted C ₂ to C ₄ alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocyclic group; the number of the substituents is 1, and the substituents are respectively Independently selected from hydroxyl, C ₁ ~C ₃ alkoxy, halogen, carboxyl, ester or carboxymethyl ester group; the heteroatom of the saturated heterocyclic group is O; the number of heteroatoms is 1; R' ₁₀ ～ _R'15 are not selected from hydrogen at the same time;

Or, in 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;

Or, in 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;

Further, the compound has the structure shown in formula III-A:

in,

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;

Or 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 -;

X ₂ is -O- or -CR ₁₆ R ₁₇ -;

Preferably,

Or 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' 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 hydroxyl group, C ₁ ~C ₃ alkoxy group, halogen, carboxyl group, ester group or methyl carboxylate group; the heteroatom of the saturated heterocyclic group is O, S or N; the heteroatom The number of atoms is 1; R' ₁₀ ~ R' ₁₅ are not selected from hydrogen at the same time;

Or, in 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;

Or, in 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;

Further, the compound has the structure shown in formula III-B:

in,

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 the same time;

Preferably,

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 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-, 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 Any one of ₁₇ cannot be selected from methyl at the same time;

Alternatively, in 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;

Further, the compound has the structure shown in formula III-C:

in,

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 ;

Preferably,

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;

Alternatively, in 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 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;

Further, the compound has the structure shown in formula III-D:

in,

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;

Alternatively, in 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;

Preferably,

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;

Alternatively, in 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 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 said heteroatom is 1.

Further, the compound has the structure shown in formula III-E:

in,

Preferably,

R ₁ to R ₅ are independently selected from C ₁ to C ₂ alkyl groups and 3 to 6 membered cycloalkyl groups;

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.

Further, the compound is shown in formula III-F-1:

in,

R ₁₀ to R ₁₇ are independently selected from hydrogen or unsubstituted C ₁ to C ₄ alkyl;

Or, the compound is shown in formula III-F-2:

Or, the compound is shown in formula III-F-3:

R ₁₀ to R ₁₇ are independently selected from hydrogen or unsubstituted C ₁ to C ₄ alkyl groups.

Further, the compound is shown in formula IV:

R ₁₀ to R ₁₇ are independently selected from hydrogen or unsubstituted C ₁ to C ₃ alkyl groups.

Further, the compound is shown in formula V:

in,

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 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 ~ R' ₁₅ are not simultaneously selected from hydrogen;

Preferably,

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 hydroxyl group, C ₁ ~C ₃ alkoxy group, halogen, carboxyl group, ester group or methyl carboxylate group; the heteroatom of the saturated heterocyclic group is O, S or N; the heteroatom The number of atoms is 1; R' ₁₀ ~ R' ₁₅ are not selected from hydrogen at the same time;

Alternatively, in 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.

Further, the compound is shown in formula VI:

in,

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;

Or, in 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.

Preferably,

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;

Or, in 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 carboheterocycle, the heteroatom of the saturated carboheterocycle is O, S or N; the number of the heteroatom is 1.

Further, 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;

Preferably, 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;

Preferably, 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;

Preferably, 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.

Definition of terms used in the present invention: Unless otherwise stated, the initial definition provided by a group or term herein applies to the group or term throughout the specification; for terms that are not specifically defined herein, they should be based on the disclosure and context , giving the meanings a person skilled in the art can assign to them.

In the present invention, the structure of the compound refers to a structure that can exist stably.

In the present invention, the "substitution" means that the hydrogen atoms in the molecule are replaced by other different atoms or molecules.

In the present invention, "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.

In the present invention, 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 . Thus, for example, 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.

In the present invention, halogen refers to fluorine, chlorine, bromine, and iodine.

In the present invention, the ester group is selected from methyl formate, methyl acetate, ethyl acetate and the like.

In the present invention, a saturated carbocycle is a cycloalkyl group, and a saturated carboheterocycle is a saturated heterocyclic group.

In the present invention, 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:

In the present invention, 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 . Preferably, 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

In the present invention, the structural formula of "CR ₁₄ R ₁₅ " is

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. However, it has the following disadvantages: the effect of "anti-injury effect" is unknown, and OFA lacks universality; the scope of application is limited and multi-drug combination is required; the use of opioid substitute drugs may not be useful for the complications of the original disease. Many studies have clearly pointed out that perioperative intravenous lidocaine has clinical effects such as reducing pain, nausea, and intestinal paralysis time, reducing the need for opioids, and shortening the length of hospital stay. It may be one of the effective means to speed up recovery. However, due to reasons such as low therapeutic index and poor safety, it is difficult to develop as an intravenous drug in clinical application.

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. As an analgesic and anesthesia drug, the compound of the present invention can provide better safety guarantee for intravenous analgesia, general anesthesia, anesthesia induction, auxiliary anesthesia and other anesthesia drugs. At the same time, 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.

In summary, 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). Moreover, 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.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Description of drawings

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.

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.

detailed description

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.

The solvents used in this experiment were analytically pure. 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.

The preparation of embodiment 1, intermediate 2I

Dissolve 20g of 2,6-dimethylaniline (1) and 54mL of N,N-diisopropylethylamine (DIPEA) in 200mL of dichloromethane (DCM), place in an ice bath, add dropwise 1~ Dichloromethane dilution (40mL) of 2 times the molar amount (33.1～66.2g) of bromoacetyl bromide (M-Br), the concentration of bromoacetyl bromide in the dilution is 35% (v/v). After the dropwise addition, return to room temperature to react for 10 min, and the silica gel thin-layer chromatography plate shows that the reaction of the raw materials is complete. The 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%.

Intermediate 2I: ¹ H NMR (400MHz, CDCl ₃ ) δ7.76(s, 1H), 7.17–7.06(m, 3H), 4.07(s, 2H), 2.24(s, 6H).

According to the above method, different raw materials 1 and different raw materials M-Br were synthesized into different intermediates 2, and the specific structure is as follows in Table 1:

Table 1. Synthetic starting materials and characterization information for different intermediates 2

Embodiment 2, the preparation of compound LD-1

1g of intermediate 2I, 0.54g of 2,3,6-trimethylmorpholine, and 1.14g of potassium carbonate were added to 10mL of acetonitrile, and reacted at room temperature for 2h. Silica gel thin-layer chromatography showed that the reaction was complete. After filtration and concentration under reduced pressure, the white solid LD-1 was obtained by column chromatography

1.05 g, yield 88.2%. Purity: 98.7%, melting point: 191.0-191.4°C.

Compound LD-1: ¹ H 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 ₁₇ H ₂₆ N ₂ O ₂ ] ⁺ ,290.1994.

Embodiment 3, the preparation of compound LD-2～LD-16, LD-33～LD-41, LD-43

The compounds in the following table 2 are first synthesized intermediate 2I according to Example 1, and then synthesize the corresponding final product according to the method of Example 2 with different nitrogen-containing raw materials:

Table 2. Synthetic information of other compounds of the present invention

Embodiment 4, the preparation of compound LD-18

Add 1g of intermediate 2II, 0.56g of 2,3,5,6-tetramethylmorpholine, and 1.08g of potassium carbonate into 10mL of acetonitrile, and react at room temperature for 2h. Silica gel thin-layer chromatography showed that the reaction was complete. After filtration and concentration under reduced pressure, the white solid LD-18 was obtained by column chromatography

1.14 g, yield 92.0%. Purity: 99.2%, melting point: 168.2-168.7°C.

Compound LD-18: ¹ H 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 ₁₉ H ₃₀ N ₂ O ₂ ] ⁺ ,318.2307.

Embodiment 5, the preparation of compound LD-17, LD-19～LD-32, LD-42

The compounds in the following table 3 are first synthesized intermediate 2II according to Example 1, and then synthesize the corresponding final product according to the method of Example 4 with different nitrogen-containing raw materials:

Table 3. Synthetic information of other compounds of the present invention

Embodiment 6, the preparation of compound LD-45, LD-46

Add 1 g of raw material LD-OH, 287.86 mg of acetic acid, 989.05 mg of DCC and 48.80 mg of DMAP into 10 mL of dichloromethane, and react at room temperature for 8 hours. Silica gel thin layer chromatography shows that the reaction is complete. Dissolve in 50mL of dichloromethane after vacuum distillation, wash with water 3 times and purify by silica gel column chromatography to obtain white solid LD-45

1.04 g, 89.4% yield. Purity: 99.0%, melting point: 189.1-189.8°C.

Compound LD-45: ¹ H 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 ₁₆ H ₂₄ N ₂ O ₃ ] ⁺ ,292.1787.

The compounds in the following table 4 were prepared according to step 1 of embodiment 8, first synthesized intermediate 2III, and then synthesized intermediate according to embodiment 2 with nitrogen-containing raw materials

Then add 2 times the molar amount of acetic acid, DCC and DMAP to 20mL of dichloromethane according to the above method of this example to synthesize the final product LD-46:

Table 4. Synthesis information of other compounds of the present invention

Embodiment 7, the preparation of compound LD-47

Add 1 g of raw material LD-OH and 473.96 mg of pyridine into 10 mL of dichloromethane, add 734.28 mg of isopropyl chloroformate dropwise under ice-cooling, and react at room temperature for 3 hours. Silica gel thin-layer chromatography plate shows that the reaction is complete. The crude product after vacuum distillation was purified by silica gel column chromatography to obtain yellow oil LD-47

1.61 g, yield 86.84%. Purity: 99.1%.

Compound LD-47: ¹ H 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 ₁₈ H ₂₈ N ₂ O ₄ ] ⁺ ,336.2049.

Embodiment 8, the preparation of compound LD-44

step 1:

Dissolve 0.49g of N-hydroxysuccinimide and 9.22g of triethylamine in 200mL of dry tetrahydrofuran (THF), and add dichloromethane diluent (50mL) of bromoacetyl bromide dropwise under ice-bath conditions to dilute The concentration of bromoacetyl bromide in the solution was 35% (v/v), stirred at low temperature for 1 h, and then turned to room temperature for 4 h. The above reaction solution was added dropwise to a THF solution of 10 g of 3,5-dimethyl-4-aminophenol under an ice bath, and reacted for 2 hours. Silica gel thin-layer chromatography plate showed complete reaction of starting material. After concentration under reduced pressure, it was purified by silica gel column chromatography to obtain 11.2 g of brown oil (Intermediate 2III), with a yield of 59.53%.

Step 2:

Add 450mg of intermediate 2III, 191.27mg of diethylamine, and 361.42mg of potassium carbonate into 5mL of acetonitrile, and react at room temperature for 2 hours. Silica gel thin-layer chromatography plate shows that the reaction is complete. After filtration and concentration under reduced pressure, the brown solid M-1 was obtained by column chromatography

300 mg, yield 68.74%. Purity: 98.8%, melting point: 201.0-201.9°C.

Step 3:

Dissolve 1g of intermediate M-1 and 0.59mL of N,N-diisopropylethylamine (DIPEA) in 10mL of dichloromethane (DCM), place it in an ice bath, and add bromoacetyl bromide in dichloromethane dropwise Diluent (1 mL), the concentration of bromoacetyl bromide in the diluent is 35% (v/v). After the dropwise addition, return to room temperature to react for 10 min, and the silica gel thin-layer chromatography plate shows that the reaction of the raw materials is complete. The 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.

Step 4:

Add 1 g of intermediate M-2, 393.99 mg of diethylamine, and 557.54 mg of potassium carbonate into 10 mL of acetonitrile, and react at room temperature for 2 h. Silica gel thin-layer chromatography shows that the reaction is complete. After filtration and concentration under reduced pressure, the brown solid LD-44 was obtained by column chromatography

756 mg, yield 77.25%. Purity: 96.9%, melting point: 218.5-219.3°C.

¹ H 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 ₂₀ H ₃₃ N ₃ O ₃ ] ⁺ ,363.2522.

Embodiment 9, the preparation of compound LD-48, LD-52, LD-55, LD-57

1 g of intermediate 2III, 506.30 mg of morpholine, and 803.16 mg of potassium carbonate were added to 10 mL of acetonitrile, and reacted at room temperature for 2 h. Silica gel thin-layer chromatography showed that the reaction was complete. After filtration and concentration under reduced pressure, the white solid LD-48 was obtained by column chromatography

768 mg, yield 75.0%. Purity: 98.4%, melting point: 226.2.0-226.9°C.

¹ H 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.

The compounds in the following Table 5 were prepared according to step 1 of Example 8. Firstly, intermediate 2III was synthesized, and then the corresponding final product was synthesized according to the above-mentioned method of Example 9 with different nitrogen-containing raw materials:

Table 5. Synthetic information of other compounds of the present invention

Embodiment 10, the preparation of compound LD-49, LD-53

step 1:

1g of intermediate 2III, 669.33mg of 2,6-dimethylmorpholine, and 803.16mg of potassium carbonate were added to 10mL of acetonitrile, and reacted at room temperature for 2h. Silica gel thin-layer chromatography showed that the reaction was complete. After filtration and concentration under reduced pressure, the white solid M-3 was obtained by column chromatography

850 mg, yield 75.04%. Purity: 97.2%, melting point: 221.0-221.9°C.

Step 2:

Dissolve 1 g of intermediate M-3 and 0.57 mL of N,N-diisopropylethylamine (DIPEA) in 10 mL of dichloromethane (DCM), place in an ice bath, and dilute with acetyl chloride dropwise solution (1 mL), the concentration of acetyl chloride in the diluent was 35% (v/v). After the dropwise addition, return to room temperature to react for 10 min, and the silica gel thin-layer chromatography plate shows that the reaction of the raw materials is complete. Directly wash the reaction solution with 1M hydrochloric acid solution, dry the organic layer with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown yellow solid LD-49

0.81 g, yield 70.99%. Purity: 95.8%, melting point: 235.5-236.2°C. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 6.89 (s, 2H), 3.86 (qt, J = 5.2, 2.8 Hz, 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 ₁₈ H ₂₆ N ₂ O ₄ ] ⁺ ,334.1893.

The compounds in the following Table 6 were prepared according to step 1 of Example 8. First, intermediate 2III was synthesized, and then the corresponding final product LD-53 was synthesized according to the above method of Example 10 with different nitrogen-containing raw materials:

Table 6. Synthesis information of other compounds of the present invention

Example 11, Preparation of Compounds LD-50, LD-51, LD-54, LD-56, LD-58

step 1:

Dissolve 1 g of compound LD-48 and 0.63 mL of N,N-diisopropylethylamine (DIPEA) in 10 mL of dichloromethane (DCM), place in an ice bath, and dilute with bromoacetyl bromide dropwise solution (1 mL), the concentration of bromoacetyl bromide in the diluent was 35% (v/v). After the dropwise addition, return to room temperature to react for 10 min, and the silica gel thin-layer chromatography plate shows that the reaction of the raw materials is complete. Directly wash the reaction solution with 1M hydrochloric acid solution, dry the organic layer with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown yellow solid M-4

0.90 g, yield 61.75%. Purity: 96.4%, melting point: 217.7-218.5°C.

Step 2:

Add 1 g of intermediate M-4, 339.21 mg of 2,6-dimethylmorpholine, and 538.10 mg of potassium carbonate into 10 mL of acetonitrile, and react at room temperature for 2 hours. Silica gel thin-layer chromatography shows that the reaction is complete. After filtration and concentration under reduced pressure, the white solid LD-50 was obtained by column chromatography

660 mg, yield 64.95%. Purity: 98.0%, melting point: 228.8-229.6°C. ¹ H 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 ₂₀ H ₂₉ N ₃ O ₅ ] ⁺ ,391.4680.

The compounds in the following Table 7 were prepared according to step 1 of Example 8. First, intermediate 2III was synthesized, and then the corresponding final product was synthesized with different nitrogen-containing raw materials according to the above method of Example 11:

Table 7. Synthesis information of other compounds of the present invention

Example 12, Preparation of Compounds LDO-1～10, LDO-13～37, LDO-39～63, LDO-65～76

step 1:

Dissolve 20g of 2,6-dimethylphenol and 54mL of DIPEA in 200mL of dichloromethane, place in an ice bath, add dichloromethane dilution (50mL) of bromoacetyl bromide (2eq.) dropwise, dropwise Turn to room temperature and react for 10 minutes. Spotting on a silica gel plate shows that the reaction of the raw materials is complete. The 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 32 g of a white solid (intermediate compound 2A), with a yield of 81.0%. Purity: 99.5%, melting point: 97.4-97.8°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.17–7.06 (m, 3H), 4.07 (s, 2H), 2.24 (s, 6H).

Step 2:

1 g of intermediate compound 2A, 0.86 g of N,N-diethanolamine, and 1.14 g of potassium carbonate were added to 10 mL of acetonitrile, and reacted at room temperature for 2 h, and the reaction was complete when spotted on a silica gel plate. After filtration and concentration under reduced pressure, 780 mg of a white solid (compound LDO-1) was obtained by column chromatography, with a yield of 70.9%. Purity: 98.1%, melting point: 148.9-149.4°C. HRMS: [C ₁₄ H ₂₁ NO ₄ ] ⁺ ,267.1471.

¹ H 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).

The compounds in the following Table 8 were prepared according to step 1 of this example, using different raw materials 1 to synthesize corresponding intermediates 2A-n, and then synthesizing corresponding final products with different nitrogen-containing raw materials:

Table 8. Synthesis information of other compounds of the present invention

Embodiment 13, preparation of compound LDO-11

step 1:

Dissolve 20g of 2,6-dimethylphenol and 54mL of DIPEA in 200mL of dichloromethane, place in an ice bath, add dropwise dichloromethane dilution (50mL) of 2-bromopropionyl bromide (2eq.), After the dropwise addition, turn to room temperature to react for 10 minutes, and point the silica gel plate to show that the raw materials have completely reacted. The reaction solution was directly washed with 1M hydrochloric acid solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 33.8 g of a white solid (intermediate compound 2B), with a yield of 80.4%. Purity: 97.8%, melting point: 104.7-105.1°C.

¹ H 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).

Step 2:

1 g of intermediate compound 2B, 0.48 g of 2,5-dimethylmorpholine, and 1.14 g of potassium carbonate were added to 10 mL of acetonitrile, and reacted at room temperature for 2 h, and the reaction was complete when spotted on a silica gel plate. After filtration and concentration under reduced pressure, 1048 mg of a white solid (compound LDO-11) was obtained by column chromatography with a yield of 87.5%. Purity: 97.7%, melting point: 107.1-107.6°C. HRMS: [C ₁₇ H ₂₅ NO ₃ ] ⁺ ,291.1834.

¹ H 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).

Embodiment 14, the preparation of compound LDO-12

step 1:

Dissolve 20g of 2,6-dimethylphenol and 54mL of DIPEA in 200mL of dichloromethane, place in an ice bath, add dropwise a dichloromethane dilution of 2-bromoisobutyryl bromide (2eq.) (50mL ), after the dropwise addition, turn to room temperature to react for 10 minutes, and point the silica gel plate to show that the raw materials have reacted completely. The 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 34.1 g of a white solid (intermediate compound 2C), with a yield of 76.8%. Purity: 98.1%, melting point: 116.5-116.9°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.26 (m, 3H), 2.18 (s, 6H), 2.06 (s, 6H).

Step 2:

1g of intermediate compound 2C, 0.43g of 2,6-dimethylmorpholine, and 1.14g of potassium carbonate were added to 10mL of acetonitrile, and reacted at room temperature for 2h, and the reaction was complete when spotted on a silica gel plate. After filtration and concentration under reduced pressure, 975 mg of a white solid (compound LDO-12) was obtained by column chromatography, with a yield of 86.6%. Purity: 96.9%, melting point: 118.2-118.8°C. HRMS: [C ₁₈ H ₂₇ NO ₃ ] ⁺ , 305.1991.

¹ H 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).

Embodiment 15, preparation of compound LDO-44～45

1g compound LDO-41

Dissolve in 10mL of dichloromethane, add 0.65g m-chloroperoxybenzoic acid in batches under ice bath, react overnight, and point the silica gel plate to show that the reaction is complete. After concentration under reduced pressure, 713 mg of white solid (compound LDO-44) was obtained by column chromatography, with a yield of 67.2%. Purity: 96.9%, melting point: 165.4-165.9°C.

¹ H 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 ₁₄ H ₁₉ NO ₃ S] ⁺ ,281.1086.

Compounds in the following table 9 are synthesized corresponding intermediates obtained in

steps

1 and 2 in Example 12

Then synthesize the corresponding final product LDO-45 according to the method of this example:

Table 9. Synthesis information of other compounds of the present invention

Embodiment 16, the preparation of compound LDO-46

1g compound LDO-41

Dissolve in 10mL of dichloromethane, add 0.65g m-chloroperoxybenzoic acid in batches under ice bath, react overnight, and point the silica gel plate to show that the reaction is complete. After concentration under reduced pressure, 750 mg of white solid (compound LDO-46) was obtained by column chromatography with a yield of 66.9%. Purity: 97.7%, melting point: 181.4-182.0°C.

¹ H 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 ₁₄ H ₁₉ NO ₄ S] ⁺ ,297.1035.

Example 17, Preparation of Compound LDO-77, LOD-78

step 1:

Dissolve 1g of 2,6-dimethyl-3-nitrophenol and 2.4mL of DIPEA in 10mL of dichloromethane, place in an ice bath, add bromoacetyl bromide (2eq., 2.4g) dropwise in dichloromethane Diluent (10mL), after the dropwise addition, let it react at room temperature for 10min, and spotting the silica gel plate showed that the reaction of the raw materials was complete. The 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 a pale yellow solid 2D, 0.69 g, with a yield of 41.5%. Purity: 96.3%, melting point: 85.7-86.6°C.

¹ H 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).

Step 2:

1 g of intermediate compound 2D, 0.26 g of diethylamine, and 0.95 g of potassium carbonate were added to 10 mL of acetonitrile, and reacted at room temperature for 2 h. A silica gel plate showed that the reaction was complete. After filtration and concentration under reduced pressure, 703 mg of a white solid (compound LDO-77) was obtained by column chromatography, with a yield of 72.3%. Purity: 96.4%, melting point: 168.4-168.9°C. HRMS: [C ₁₄ H ₂₀ N ₂ O ₄ ] ⁺ ,280.1424.

¹ H 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).

The compounds in the following table 10 were prepared according to step 1 of this example with different raw materials 1

Synthetic corresponding intermediates

Then synthesize the corresponding final product LOD-78 with diethylamine:

Table 10. Synthesis information of other compounds of the present invention

Embodiment 18, preparation of compound LDO-79

step 1:

1 g of intermediate compound 2A, 0.37 g of diethanolamine, and 1.14 g of potassium carbonate were added to 10 mL of acetonitrile, and reacted at room temperature for 2 h. A silica gel plate showed that the reaction was complete. After filtration and concentration under reduced pressure, 698 mg of a white intermediate was obtained by column chromatography with a yield of 67.7%. Purity: 97.1%, melting point: 96.7-97.5°C. HRMS: [C ₁₄ H ₂₁ NO ₃ ] ⁺ ,251.1520.

¹ H 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).

Step 2:

1g of the above white intermediate

242mg of acetic acid, 821mg of DCC and 48.9mg of DMAP were added into 10mL of dichloromethane, and reacted at room temperature for 8h, and the silica gel thin layer chromatography plate showed that the reaction was complete. After vacuum distillation, it was dissolved in 50 mL of dichloromethane, washed 3 times with water and purified by silica gel column chromatography to obtain white solid LDO-79

0.78g, yield 66.3%. Purity: 98.2%, melting point: 112.1-112.6°C.

Compound LDO-78: ¹ H 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 ₁₆ H ₂₃ NO ₄ ] ⁺ ,293.1627.

Embodiment 19, preparation of compound LDO-80

1g of the intermediate obtained in Example 18

474mg of pyridine was added to 10mL of dichloromethane, and 651mg of ethyl chloroformate was added dropwise under ice-cooling, and reacted at room temperature for 3 hours. Silica gel thin-layer chromatography plate showed that the reaction was complete. The crude product after vacuum distillation was purified by silica gel column chromatography to obtain light yellow solid LDO-80

1.02 g, yield 79.2%. Purity: 98.6%, melting point: 101.2-101.8°C.

Compound LDO-80: ¹ H 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 ₁₇ H ₂₅ NO ₅ ] ⁺ ,323.1735.

Example 20, Preparation of Compound LDO-81

step 1:

1g of the intermediate obtained in Example 18

678 mg of potassium tert-butoxide was added to 10 mL of dichloromethane, and 925 mg of diethyl phosphate (dissolved in 10 mL of dichloromethane) was added dropwise under ice cooling, and reacted at room temperature for 12 hours. Silica gel thin-layer chromatography showed that the reaction was complete. Add 40mL of water to quench the reaction, extract with ethyl acetate (30mL*2), combine the dried organic phases and purify the crude product by silica gel column chromatography to obtain a yellow intermediate

1.52 g, yield 98.0%. Purity: 98.8%.

Step 2:

Dissolve 0.1 g of the above intermediate in 1 mL of anhydrous chloroform solvent, slowly add 734 mg of TMSBr dropwise in a nitrogen-protected environment, stir at room temperature for 8 h, add 0.2 ml of water and 2 ml of methanol to quench the reaction, and continue stirring at room temperature for 0.5 h. Immediately added 42.5mg of anhydrous sodium carbonate and continued to stir at room temperature for 1h. After concentrating under reduced pressure to remove all solvents, a yellow solid LDO-81 was obtained, 148 mg, with a yield of 98.7%. Purity: 98.2%, melting point: 167.1-167.7°C.

Compound LDO-81: ¹ H 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 ₁₄ H ₂₀ NNa ₂ O ₆ P] ⁺ ,375.2684.

The beneficial effects of the present invention will be demonstrated through specific test examples below.

experimental animals

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. Unit qualification license: SYXK (Sichuan) 2015-030. This study was approved by the Animal Ethics Committee of the West China Clinical College of Sichuan University, and all animal feeding methods and facility environments were carried out in accordance with the guidelines of the National Research Council Life Sciences Committee Laboratory Animal Resources Institute (National Academy of Sciences Press, Washington DC) (2010). 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.

Experimental example 1, using the sequential method to determine the lethality of the compounds in the present invention including but not limited to the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs to mice Quantity (LD ₅₀ )

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). and literature Nelson , KE, Rauch, T., Terebuh, V.&D'Angelo, RA comparison of intrathecal fentanyl and sufentanil for labor analgesia. Anesthesiology.96, 1070-1073 (2002).) concluded that the best dosage arrangement is between 4-5 Move up and down between each dosage group, dosing starts from the middle dosage group, observes the survival situation of mouse immediately after administration, the dosage group setting among the test groups of _LD50 is the same as above, as the death of the first mouse is recorded as (+), The next mouse was given a lower dose; otherwise, the survival of the mouse was recorded as (-), and the next mouse was given a higher dose. 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.

The mouse was fixed with a fixer, and the tail was exposed, and the tail vein of the mouse was expanded by gently wiping it with a cotton ball of 75% alcohol. KM mice tail vein bolus administration lidocaine (Lidocaine, Lid) and 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.

Table 11. The median lethal dose (LD ₅₀ ) of the compounds of the present invention to mice

Note: The greater the LD ₅₀ value in Table 11, the greater the dose of the drug that causes death, and/or the smaller the dose of the effective drug, the safer the drug.

From the results in Table 11, it can be seen 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, 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. Dose Pharmacodynamic Evaluation

Adult ICR mice were selected for the experiment, half male and half male were weighed, and randomly divided into groups according to different drug treatments, with 8 mice in each group. In this experiment, the classic glacial acetic acid-induced mouse writhing model was used. The model was established by intraperitoneal injection of 0.6% glacial acetic acid solution (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.). 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". Then inject 0.6% glacial acetic acid solution into the left abdominal cavity of the mouse according to the amount of 0.1mL/10g, and record the time point at this time as "10", and then start recording the latency time when the mouse begins to writhe, and record The number of times of writhing within 15 minutes after the 5th minute (this time point is recorded as "15") (the end time point is recorded as "30"). That is, the latency time was recorded from time point "10", and the number of writhing times was recorded from time point "15"-"30". And calculate the inhibition rate and analgesic rate: 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 results are shown in Table 12.

Table 12. 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

According to Table 12, 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

Adult SD mice were selected for the experiment, and half male and half male were weighed. Modeling method: 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. After the ligation, the muscles and fascia were sutured continuously with catgut, and the skin was sutured with a single knot with 4-0# suture. Mechanical stimulation was measured by von Frey, and the first three consecutive occurrences were taken as the pain threshold. Infrared thermal stimulation was measured at 60°C, and the average value of three times was taken, with at least 3 minutes between each measurement.

The results are shown in Figure 1. 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). and literature Nelson , KE, Rauch, T., Terebuh, V.&D'Angelo, RA comparison of intrathecal fentanyl and sufentanil for labor analgesia. Anesthesiology.96, 1070-1073 (2002).) concluded that the best dosage arrangement is between 4-5 Move up and down between the dosage groups, administration starts from the middle dosage group, observe the situation of mouse righting reflex immediately after administration, as the righting disappears 10s after the administration of the first mouse, the death of the mouse is recorded as (+), The next mouse uses a lower level of dose; otherwise, if there is no righting reflex or the righting reflex is less than 10s, it is recorded as (-), the next mouse uses a higher level of dose, and so on, and the onset time is recorded. LD ₅₀ The dose group setting between test groups is the same as above, as the death of the first mouse is recorded as (+), and the next mouse is used with a lower level of dose; otherwise, the survival of the mouse is recorded as (-), and the next small mouse Rats use a higher dose. 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.

The mouse was fixed with a fixer, and the tail was exposed, and the tail vein of the mouse was expanded by gently wiping it with a cotton ball of 75% alcohol. KM mice tail vein bolus administration lidocaine (Lidocaine, Lid) and 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. 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.

Table 13. General anesthesia effect of compounds of the present invention on mice

Note: TI in Table 13 is the therapeutic index, which is the ratio of LD ₅₀ to ED ₅₀ . The larger the TI value, the greater the drug dose that causes death, and/or the smaller the effective drug dose, the safer the drug.

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). 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

1. Setting of infusion rate and time

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 . According to the experimental result analysis of 5 half-lives of the continuous infusion of medicine, and the pharmacological principle of the steady state of the blood concentration of the medicine in combination, the distribution half-life of propofol is 2-8min, so the pumping time of the present invention is designed for 60min.

Combined with 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). And literature Yue, ZYet al. Propofol prevents neuronal mtDNA deletion and cerebral damage due to ischemia/reperfusion injury in rats. Brain research 1594, 108-114 (2015).) Consult to determine the commonly used minimum infusion rate of propofol group 1.0mg/kg/min , the value of this minimum infusion rate is about 10% of the rat ED value, so the value of the infusion rate refers to the compound, or its salt, or its stereoisomer, or its 10% ED ₅₀ of the solvate, or its prodrug. 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%. If in the middle of the test, the body movement of the rats occurs, 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. After 60 minutes of infusion, 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).

2. Test method

Male and female SD rats were divided into half and half, weighed and randomly divided into groups of 8 rats. The rats were injected with a single dose of 1.3×ED ₅₀ of Propofol and the drugs of the present invention including but not limited to the above examples through the tail vein. Continuously infuse propofol and the compounds of the present invention including and not limited to the above-mentioned examples, or their salts, or their stereoisomers, or their solvates, or their prodrugs with a micropump syringe according to the above-mentioned results , adjust the pumping rate according to the tail pinch reaction.

3. Sedation score observation

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.

If 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.

4. Results

It can be seen from Fig. 2 that 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 results show 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 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. Therefore, 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.; In addition, 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. 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. Experimental random grouping: ①According to the table 13 The calculated propofol dosage is carried out continuous infusion with normal saline (Pro group), ② the propofol dosage calculated according to Table 13 is combined with the compound or its salt or its three-dimensional Isomers, or their solvates, or 10% of their prodrugs were continuously infused at the same time (Pro+LD-X group), ③The dose of propofol combined with the dose of lidocaine calculated in Table 13 10% were carried out continuous infusion (Pro+Lid group). Experimental results: Carry out mixed infusion according to the above method. Finally, the calculated dosage of propofol is respectively ①Pro group: 35.0±7.2mg, ②Pro+LD-X group: 16.8±3.3mg, ③Pro+Lid group: 27.3±4.8mg.

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

The mouse was fixed with a fixer, and the tail was exposed, and the tail vein of the mouse was expanded by gently wiping it with a cotton ball of 75% alcohol. ICR mice tail vein bolus administration 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 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. Table 14 shows the general anesthesia effects of the compounds in the above examples, or their salts, or stereoisomers, or solvates, or their prodrugs, including but not limited to, the compounds of the present invention on mice.

Table 14. 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

Note: TI in Table 14 is the therapeutic index, which is the ratio of LD ₅₀ to ED ₅₀ . The larger the TI value, the greater the dose of the drug that causes death, and/or the smaller the dose of the effective drug, the safer the drug.

From the results in Table 14, it can be seen 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, compared with lidocaine, Not only can achieve a similar effect of general anesthesia, but also have a greater therapeutic index (TI). 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. According to the method described in Test Example 6, 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. For the isomer, or its solvate, or its prodrug, 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.

Literature (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.) have studied other general anesthetics Propofol with tail pinch stimulation , ethhanal, thiopental and fentanyl on the anesthesia of mice and rats, the experiment shows that it is more feasible to determine the anesthesia effect of intravenous anesthetics with tail pinch stimulation. The more severe the tail pinch reaction (the higher the positive tail pinch reaction), the worse the effect of general anesthesia. The present invention also uses tail pinch stimulation to judge the anesthetic effect of compounds. The test results are shown in Table 15.

Table 15. 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

Note: 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. However, 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. Stable, high safety (mortality rate: 0), high recovery quality score, which means good postoperative delirium.

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. Among them, the definitions and test methods are the same as in Test Example 6, except that ICR mice are replaced by SD rats.

Put the SD rats in the fixer, expose the tail and fix it, gently wipe it with 75% alcohol cotton ball, or soak it in warm water at 45°C for 1-2min, soften the tail cuticle of the rat, expand the tail vein, and use a 24G intravenous indwelling needle The tail vein of the rat was punctured and placed, and the indwelling needle was properly fixed with adhesive tape. Draw back before injecting the medicine, and see the blood as the standard of successful catheterization. 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.

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 test results illustrate: 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. And 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. 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. Combined with 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. Brain research 1594, 108-114 (2015).) Check to determine the commonly used minimum infusion rate of propofol group 1.0mg/kg/min, the value of this minimum infusion rate It is about 10% of the rat ED value measured in Test Example 8, and the combined infusion rate value refers to the compound, or its salt, or its stereoisomer, or its solvent in the above-mentioned examples included and not limited by the present invention 1% ED ₅₀ of the compound or its prodrug. 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).Experimental random grouping: 1. carry out continuous infusion (Pro group) with normal saline by the above-mentioned propofol dose of calculation, 2. by the above-mentioned 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). Experimental results: ①The survival rate of SD rats in the Pro group was 75%, the mortality rate was 25%, the disappearance rate of the tail pinching reaction was 100%, and 1 rat had dyspnea (12.5%) among the adverse reactions; ②The SD rats in the Pro+LDO-X group The survival rate of rats was 100%, and dyspnea in adverse reactions was less than or equal to 1 (≤12.5%); ③The survival rate of SD rats in Pro+Lid group was 75%, and the mortality rate was 25%. Difficulty 4 only (50%). After mixed infusion according to the above method, the calculated doses of propofol were ①Pro group: 35.0±7.2mg, ②Pro+LD-X group: 17.8±3.3mg, ③Pro+Lid group: 26.4±3.7mg.

To sum up, when 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%). And 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. 3), and because 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%). Most importantly, during anesthesia, as shown in Figure 4, 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. Dose Pharmacodynamic Evaluation

Adult ICR mice were selected for the experiment, half male and half male were weighed, and randomly divided into groups according to different drug treatments, with 8 mice in each group. In this experiment, the classic glacial acetic acid-induced mouse writhing model was used. The model was established by intraperitoneal injection of 0.6% glacial acetic acid solution (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.). 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". Then inject 0.6% glacial acetic acid solution into the left abdominal cavity of the mouse according to the amount of 0.1mL/10g, and record the time point at this time as "10", and then start recording the latency time when the mouse begins to writhe, and record The number of times of writhing within 15 minutes after the 5th minute (this time point is recorded as "15") (the end time point is recorded as "30"). That is, the latency time was recorded from time point "10", and the number of writhing times was recorded from time point "15"-"30". And calculate the inhibition rate and analgesic rate: 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 results are shown in Table 17.

Table 17. 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 research of the present invention finds that the inhibition rate of the mice in the lidocaine group to the writhing model induced by glacial acetic acid is 31.19%, and the analgesic rate is 47.99%, which has 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 53.40-96.80%, which is increased by 0.7-2 times; the analgesic rate is 61.13-78.85%, which is increased by 24.5%-64.3%.

In summary, the compounds of the present invention, or their salts, or their stereoisomers, or their solvates, or their prodrugs have good analgesic and/or anesthetic effects for intravenous injection. Through 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. And 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. It can significantly reduce the dosage of propofol and reduce the dosage of opioids, and can be used as an ideal analgesic and anesthetic for intravenous injection at the same time. Therefore, 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. The use of anesthesia and other clinical anesthesia fields provides better safety assurance and reduces the use of opioid anesthesia (ORA) or opioid-free anesthesia (OFA). Furthermore, 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.

Claims

The compound shown in formula I, or its salt, or its stereoisomer, or its solvate, or its prodrug:

in,

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;

Or 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 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;

Alternatively, in 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.
The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II:

in,

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;

Or 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;

Alternatively, in 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.
The compound according to claim 2, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-A:

in,

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;

When 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;

When R 3 is selected from substituted or unsubstituted ester groups, 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.
The compound according to claim 2, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-B:

in,

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;

Preferably, the compound is shown in formula II-B1:

in,

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 according to claim 2, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-C:

in,

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;

When X 1 is selected from -O-, 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 ;

Alternatively, when 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 When 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;

Alternatively, when X 1 and Y 1 are selected from none, R 2 , R 4 , R 7 , R 10 , R 11 , R 14 , R 15 are selected from hydrogen, R 1 is 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, and when one of R 12 and R 13 is selected from hydrogen, the other is not selected from hydroxyl or amino; neither R 12 nor R 13 is selected from For hydrogen, R 12 and R 13 are not selected from methyl at the same time; when one of R 12 and R 13 is selected from methyl, the other is not selected from hydroxyl or methyl;

Alternatively, when one of X 1 and Y 1 is selected from none, and one is selected from -CR 16 R 17 -, and R 10 to R 17 are two substituents on the same carbon atom connected to form a ring, 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

Preferably,

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.
The compound according to claim 5, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-C1:

in,

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;

Preferably,

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 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.
The compound according to claim 6, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-D1:

in,

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;

Alternatively, the compound is shown in formula II-D2:

in,

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.
The compound according to claim 5, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-C2:

in,

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;

Preferably,

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 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.
The compound according to claim 5, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula II-C3:

in,

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;

Preferably,

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.
The compound according to claim 5, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: the compound is shown in formula II-C4:

in,

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;

Preferably,

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 ～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.
The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula III:

in,

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;

Or 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 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;

Alternatively, in 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;

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 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;

When X 1 and Y 1 are both absent, R 10 to R 15 are not simultaneously selected from hydrogen; or, R 12 and R 13 are not selected from unsubstituted methyl;

When X 1 is -CR 16 R 17 - and Y 1 is none, R 10 to R 17 are not simultaneously selected from hydrogen;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form
The compound according to claim 11, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that:

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;

Or 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 the same time;

Alternatively, in 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 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; R' 10 to R' 15 are not simultaneously selected from hydrogen;

Or, in 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;

Or, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form

Preferably,

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;

Or 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;

Alternatively, in 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; the number of heteroatoms is 1; R' 12 ~ R' 13 are independently selected from hydrogen, hydroxyl, C 1 ~ C 3 alkoxy, substituted C 1 to C 3 alkyl, unsubstituted C 2 to C 4 alkyl, 3 to 6 membered cycloalkyl or 3 to 6 membered saturated heterocyclic group; the number of the substituents is 1, and the substituents are respectively Independently selected from hydroxyl, C 1 ~C 3 alkoxy, halogen, carboxyl, ester or carboxymethyl ester group; the heteroatom of the saturated heterocyclic group is O; the number of heteroatoms is 1; R' 10 ～ R'15 are not selected from hydrogen at the same time;

Or, in 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 ~R” 15 , R 16 ~ R 17 are independently selected from hydrogen, hydroxyl, C 1 ~C 3 alkoxy, substituted or unsubstituted C 1 ~C 3 alkyl, 3 ~ 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;

Or, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form
The compound according to claim 11, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: the compound has the structure shown in formula III-A:

in,

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;

Or 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 the same time;

Alternatively, in 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 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; R' 10 to R' 15 are not simultaneously selected from hydrogen;

Or, in 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 to R” 15 , R 16 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 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;

Or, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form

Preferably,

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;

Or 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;

Alternatively, in 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 hydroxyl group, C 1 ~C 3 alkoxy group, halogen, carboxyl group, ester group or methyl carboxylate group; the heteroatom of the saturated heterocyclic group is O, S or N; the heteroatom The number of atoms is 1; R' 10 ~ R' 15 are not selected from hydrogen at the same time;

Or, in 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 ~R” 15 , R 16 ~ R 17 are independently selected from hydrogen, hydroxyl, C 1 ~C 3 alkoxy, substituted or unsubstituted C 1 ~C 3 alkyl, 3 ~ 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;

Or, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form
The compound according to claim 11, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound has the structure shown in formula III-B:

in,

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 the same time;

Alternatively, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form

Preferably,

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 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-, 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 Any one of 17 cannot be selected from methyl at the same time;

Alternatively, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form
The compound according to claim 14, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has a structure as shown in formula III-C:

in,

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 ;

Alternatively, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form

Preferably,

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;

Alternatively, in 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 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form
The compound according to claim 15, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has a structure as shown in formula III-D:

in,

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;

Alternatively, in 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;

Preferably,

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;

Alternatively, in 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 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 said heteroatom is 1.
The compound according to claim 15, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has a structure as shown in formula III-E:

in,

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;

Alternatively, in 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;

When R 1 and R 5 are selected from the same substituent at the same time, R 8 and R 9 cannot be connected to form

Preferably,

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.
The compound, or its salt, or its stereoisomer, or its solvate, or its prodrug according to claim 15, characterized in that: said compound is shown in formula III-F-1:

in,

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;

Or, the compound is shown in formula III-F-2:

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;

Or, the compound is shown in formula III-F-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 17 are independently selected from hydrogen or unsubstituted C 1 to C 4 alkyl groups.
The compound according to claim 14, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, wherein the compound is as shown in formula IV:

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.
The compound according to claim 13, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, wherein the compound is as shown in formula V:

in,

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 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 ~ R' 15 are not simultaneously selected from hydrogen;

Or, in 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;

Preferably,

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 hydroxyl group, C 1 ~C 3 alkoxy group, halogen, carboxyl group, ester group or methyl carboxylate group; the heteroatom of the saturated heterocyclic group is O, S or N; the heteroatom The number of atoms is 1; R' 10 ~ R' 15 are not selected from hydrogen at the same time;

Alternatively, in 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.
The compound according to claim 13, or its salt, or its stereoisomer, or its solvate, or its prodrug, is characterized in that: said compound is shown in formula VI:

in,

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 to R” 15 , R 16 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 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;

Or, in 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;

Preferably,

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 ~R” 15 , R 16 ~ R 17 are independently selected from hydrogen, hydroxyl, C 1 ~C 3 alkoxy, substituted or unsubstituted C 1 ~C 3 alkyl, 3 ~ 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;

Or, among 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 carbocyclic ring or 3-6 A saturated carboheterocycle, the heteroatom of the saturated carboheterocycle is O, S or N; the number of the heteroatom is 1.
The compound, or its salt, or its stereoisomer, or its solvate, or its prodrug according to any one of claims 1-21, characterized in that: the compound is one of the following compounds:
Use of the compound described in any one of claims 1-22, or its salt, or its stereoisomer, or its solvate, or its prodrug in the preparation of analgesic drugs;

Preferably, the analgesic drug is a drug that produces analgesic effect on animals or humans through intravenous injection.
The medicine of the compound described in any one of claims 1-22, or its salt, or its stereoisomer, or its solvate, or its prodrug in the preparation of general anesthetic medicine;

Preferably, the anesthetic drug is a drug that produces general anesthesia on animals or humans through intravenous injection.
Use of the compound described in any one of claims 1 to 22, or its salt, or its stereoisomer, or its solvate, or its prodrug in the preparation of other clinical anesthetic drugs;

Preferably, the anesthetic drug is a drug that produces other clinically used anesthetic effects on animals or humans through intravenous injection.
A medicine, characterized in that: it is the active ingredient of the compound described in any one of claims 1-22, or its salt, or its stereoisomer, or its solvate, or its prodrug, A preparation prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients.
A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 22, or its salt, or its stereoisomer, or its solvate, or its prodrug and other drugs .