WO2023083191A1

WO2023083191A1 - Benzodiazepine compound, and preparation method therefor and medical use thereof

Info

Publication number: WO2023083191A1
Application number: PCT/CN2022/130695
Authority: WO
Inventors: 刘进; 柯博文
Original assignee: 四川大学华西医院
Priority date: 2021-11-09
Filing date: 2022-11-08
Publication date: 2023-05-19
Also published as: CN116102557A; CN116102557B

Abstract

Provided are a benzodiazepine compound, and a preparation method therefor and a medical use thereof, relating to the field of chemical medicines. The benzodiazepine compound is a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or an eutectic thereof, or a composition thereof. The compound has a good intravenous sedative anesthesia effect, and the anesthesia effect thereof is comparable to that of Remimazolam and even better than that of Remimazolam; and it is specifically embodied that an effective dose is significantly reduced, and a duration and a recovery time are significantly reduced. In addition, in rat and mouse caudal venous anesthesia models, the waking-up quality of the compound is significantly improved compared with Remimazolam. The compound has rapid onset of action, is short in duration, rapid in wake-up, and good in tolerance, can be applied to anesthesia induction, anesthesia maintenance, and day surgery anesthesia, and has a good application prospect.

Description

Benzodiazepines and their preparation and use in medicine

technical field

The invention belongs to the field of chemical medicine, and in particular relates to a benzodiazepine compound, a preparation method thereof and a medical application thereof.

Background technique

Midazolam is the most commonly used benzodiazepine drug, which is relatively safe and acts mainly by binding to central γ-aminobutyric acid (GABAA) receptors. The onset is relatively rapid, and it has the effect of reducing intracranial pressure and brain metabolism. It is often used in pre-anesthesia administration, induction and maintenance of general anesthesia, adjuvant medication in spinal anesthesia and local anesthesia, diagnostic or therapeutic operations such as cardiovascular angiography, Sedation of ICU patients during cardioversion, bronchoscopy, gastrointestinal endoscopy, etc. However, because its metabolism depends on the liver and kidneys, long-term continuous infusion will cause drug accumulation in the body, usually causing adverse reactions such as excessive sedation, respiratory and circulatory depression, and drug tolerance, and it cannot be used for a long time in patients with liver and kidney dysfunction.

The parent structure of Remimazolam is midazolam, which is an ultra-short-acting intravenous benzodiazepine sedative/anesthetic that acts on GABA receptors, especially GABA-α. The drug combines the safety of midazolam with the effectiveness of propofol (propofol). In humans, Remimazolam is rapidly metabolized by tissue esterases into inactive metabolites and is not affected by cytochrome-dependent hepatic pathways. Metabolism is an ultra-short-acting benzodiazepine drug. As an intravenous general anesthesia drug, it has the characteristics of fast onset, short duration, fast recovery and good tolerance. Remimazolam is used for anesthesia induction, maintenance of anesthesia and day surgery anesthesia. Compared with other products, it has certain advantages when applied to patients with cardiovascular disease, respiratory system disease, liver disease and elderly patients.

However, it has been reported that remimazolam has a lower potency than other sedative drugs, and it is necessary to increase the dosage in clinical application to increase the potential toxicity; meanwhile, the free base structure of remimazolam is unstable, and the by-products are quite toxic, and It will further affect the activity of drug-metabolizing enzymes in the body, resulting in problems such as high blood drug concentration and drug accumulation during continuous medication. Therefore, it is expected to develop new ultra-short-acting sedative and anesthetic drugs with better safety and higher potency.

Contents of the invention

The object of the present invention is to provide a kind of benzodiazepine compound and its preparation method and the application in medicine.

The present invention mentions the compound represented by formula I, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition:

in,

Each _R is independently selected from hydrogen, a short-chain hydrocarbon group, a _C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R ₁ is a short-chain hydrocarbon group or hydrogen;

Each _R is independently selected from hydrogen, short-chain hydrocarbon group, C _3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R ₂ is hydrogen or a short-chain hydrocarbon group;

Or R ₁ and R ₂ on the same carbon atom respectively form a C _3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;

m is an integer selected from 0 to 6;

_M is selected from none or selected from O, S, NH or C _1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy substituent substitution;

_M2 is selected from none or selected from O, S, NH or C _1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy substituent substitution;

_M3 is selected from none or selected from O, S, NH or C _1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy A substituent is substituted, and the NH is substituted by a short-chain hydrocarbon group;

R ₃ is selected from hydrogen, short-chain hydrocarbon group, C _1-8 alkoxy, -C(O)-M ₄ -R ₅ , C _3-10 cycloalkyl, 6-10 membered aryl or 5-10 membered hetero Aryl, the heteroaryl includes 1 to 3 heteroatoms selected from N, O, or S;

_M4 is selected from none or selected from O, S, NH or C _1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy substituent substitution;

_R is selected from short-chain hydrocarbon groups or C _1-8 alkoxy groups;

a is an integer selected from 0 to 6;

R ₄ is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R ₄ is pyridine with nitrogen at 2 positions;

X are independently selected from halogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is an integer selected from 1 to 4;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is O or S or NH or C _1-5 alkylene, m is 1, R ₃ is -C(O)-M ₄ -R ₅ , when M ₄ is O, R ₅ is not selected from short-chain hydrocarbon groups;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is O or S or NH or C _1-5 alkylene, m is 1, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is none, R ₅ is not selected from C _1-8 alkoxy;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is none, m is 1-5, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is O, R ₅ is not selected from short chain hydrocarbon groups;

When M ₁ is nothing, a is 1, M ₂ is O, M ₃ is nothing, m is 1-5, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is nothing, R ₅ is not selected from C _1-8 alkoxy.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, substituted or unsubstituted C _1-8 alkyl, substituted or unsubstituted C _3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R ₁ and R ₂ on the same carbon atom respectively constitute a substituted or unsubstituted C _3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C _1-8 alkyl, C _1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

_M3 is selected from none or selected from O, S, NH or C _1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy A substituent is substituted, and the NH is substituted by C _1-8 alkyl;

R ₃ is selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy, -C(O)-M ₄ -R ₅ , C _3-10 cycloalkyl, 6-10 membered aryl or 5- 10-membered heteroaryl, which includes 1 to 3 heteroatoms selected from N, O, or S;

_R is selected from C _1-8 alkyl or C _1-8 alkoxy;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

n is selected from 1, 2, 3, 4;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is O or S or NH or C _1-5 alkylene, m is 1, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is O, R ₅ is not selected from C _1-8 alkyl;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is none, m is 1-5, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is O, R ₅ is not Selected from C _1～8 alkyl groups;

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

_M3 is selected from none or selected from O, S, NH or C _1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy A substituent is substituted, and the NH is substituted by C _1-4 alkyl;

R ₃ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, -C(O)-M ₄ -R ₅ , C _3-6 cycloalkyl, phenyl, thienyl, pyridyl, imidazolyl;

_R is selected from C _1-4 alkyl or C _1-4 alkoxy;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is O or S or NH or C _1-5 alkylene, m is 1, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is O, R ₅ is not selected from C _1-4 alkyl;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is O or S or NH or C _1-5 alkylene, m is 1, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is none, R ₅ is not selected from C _1-4 alkoxy;

When M ₁ is none, a is 1, M ₂ is O, M ₃ is none, m is 1-5, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is O, R ₅ is not selected from C _1-4 alkyl;

When M ₁ is nothing, a is 1, M ₂ is O, M ₃ is nothing, m is 1-5, R ₃ is -C(O)-M ₄ -R ₅ , M ₄ is nothing, R ₅ is not selected from C _1-4 alkoxy;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH ₃ , -OCH ₃ , -CF ₃ , -OCF ₃ .

Further, the compound is shown in formula II:

in,

m is an integer selected from 1 to 5;

_M2 is selected from O, S, NH or C _1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C _1-6 alkoxy;

_M3 is selected from O, S, NH or C _1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C _1-6 alkoxy;

_R is selected from short-chain hydrocarbon groups;

a is an integer selected from 0 to 6;

n is an integer selected from 1 to 4;

When a is 1, M ₂ is O, M ₃ is O or S or NH or C _1-5 alkylene, m is 1, M ₄ is not O;

When a is 1, _M2 is O, _M3 is none, and m is 1-5, _M4 is not O.

further,

m is selected from 1, 2, 3, 4, 5;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1,2,3,4.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 1, 2, 3, 4, 5;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

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

in,

m is selected from 1, 2, 3, 4, 5;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1, 2, 3, 4;

When a is 1 and m is 1, M ₄ is not O.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 1, 2, 3, 4, 5;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

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

in,

m1 is selected from 0, 1, 2, 3, 4;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1, 2, 3, 4;

When a is 1 and m1 is 0, M ₄ is not O.

further,

m1 is selected from 0, 1, 2, 3, 4;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

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

in,

m1 is selected from 0, 1, 2, 3, 4;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

When a is 1 and m1 is 0, M ₄ is not O.

further,

m1 is selected from 0, 1, 2, 3, 4;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.

Further, the compound is shown in formula III:

in,

m is an integer selected from 0 to 6;

_M1 is selected from O, S, NH or C _1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C _1-6 alkoxy;

_M3 is selected from none or selected from O, S, NH or C _1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C _1-6 alkoxy substituent substitution;

_R is selected from short-chain hydrocarbon groups;

a is an integer selected from 0 to 6;

n is an integer selected from 1-4.

further,

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1,2,3,4.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

Further, the compound is shown in formula III-a:

in,

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1,2,3,4.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

Further, the compound is shown in formula III-b:

in,

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.

Further, the compound is shown in formula IV:

in,

m is an integer selected from 0 to 6;

_R is selected from short-chain hydrocarbon groups;

a is an integer selected from 0 to 6;

n is an integer selected from 1-4.

further,

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1,2,3,4.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

Further, the compound is shown in formula IV-a:

in,

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

n is selected from 1,2,3,4.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R ₄ is selected from pyridine rings with nitrogen at the 2-position;

n is selected from 1;

Preferably,

Further, the compound is shown in formula IV-b:

in,

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.

further,

Each R ₁ or R ₂ is independently selected from hydrogen, C _1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

R ₅ is selected from C _1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.

Further, the compound is shown in formula V-a:

in,

R ₃ is selected from C _1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.

Further, the compound is shown in formula V-b:

in,

R ₃ is selected from C _1-8 alkyl, C _3-6 cycloalkyl, phenyl, thienyl, pyridyl, imidazolyl; a is selected from 0, 1, 2, 3, 4, 5, 6.

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 cocrystal, or its composition in the preparation of sedatives and/or anesthetics;

Preferably, the sedative and/or anesthetic is a sedative and/or anesthetic for intravenous sedation and/or anesthesia.

The present invention also provides a medicine, which uses the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its co-crystal, or its composition as an active ingredient, plus pharmaceutically Preparations prepared from acceptable excipients or auxiliary ingredients;

Preferably, the drug is a sedative and/or anesthetic;

More preferably, the sedative and/or anesthetic is a sedative and/or anesthetic for intravenous sedation and/or anesthesia.

In the present invention, the room temperature is 25±5°C, and overnight is 12±2h.

The compounds and derivatives provided in this invention are named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

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

In the present invention, the minimum and maximum values of carbon atoms in hydrocarbon groups are represented by prefixes, for example, C _a~b alkyl means any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C _1-10 alkyl refers to straight chain or branched chain alkyl containing 1-10 carbon atoms; C _1-10 alkoxy refers to alkoxy containing 1-10 carbon atoms.

The short-chain hydrocarbon group in the present invention is a straight-chain or branched-chain alkyl group containing 1 to 10 carbon atoms.

In the present invention, C _3-10 cycloalkyl refers to a saturated cycloalkyl group consisting of 3-10 carbon atoms.

In the present invention, the 3-10 membered heterocyclic group refers to a saturated heterocyclic group, the heterocyclic group is composed of 3-10 atoms, at least one of which is selected from O, S or substituted nitrogen atom, silicon atom .

In the present invention, aryl refers to a group containing aromatic unsaturation without ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems), such as phenyl, anthracenyl, naphthyl. Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein heteroatom refers to nitrogen atom, oxygen atom, sulfur atom. Such as thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, etc.

In the present invention, halogen is fluorine, chlorine, bromine or iodine.

The compound of the present invention has good intravenous sedation and anesthesia effect, and its anesthesia effect is equivalent to that of remimazolam, or even better than that of remimazolam, and is specifically manifested in that the effective dose is significantly reduced, and the duration and recovery time are significantly reduced. At the same time, in the tail vein anesthesia model of rats and mice, the compound of the present invention significantly reduces the occurrence of side effects compared with remimazolam, and the quality of recovery is significantly improved. The compound of the present invention has quick onset of action, short duration, quick recovery, low toxicity and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, 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.

Detailed ways

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

Example 1

500mg (1.18mmol, 1eq) of 3-((4S)-8-bromo-6-(4,5-dihydropyridin-2-yl)-1-methyl-4H-benzo[f]imidazol[1 ,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, and 367.2 mg (1.76 mmol, 1.5 eq) of bromomethyl acetate and 325 mg (2.36 mmol, 2 eq) of potassium carbonate were added , stirred at room temperature for 5 hours. Point the board, and the raw materials basically react completely. After the reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 500 mg of light yellow oil was obtained by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.57(d, J=5.5Hz, 1H), 8.15(d, J=7.9Hz, 1H), 7.80(td, J= 7.8,1.7Hz,1H),7.72(dd,J=8.7,2.3Hz,1H),7.63(d,J=2.2Hz,1H),7.35(dd,J=7.5,4.9Hz,1H),7.30( d,J=8.7Hz,1H),6.88–6.84(m,1H),5.77–5.70(m,2H),4.04(t,J=6.7Hz,1H),2.83(dt,J=17.2,6.8Hz ,4H),2.33(s,3H),2.06(d,J=3.2Hz,3H)..MS: m/z:497.32(M+1)

Example 2

500mg (1.18mmol, 1eq) of 3-((4S)-8-bromo-6-(4,5-dihydropyridin-2-yl)-1-methyl-4H-benzo[f]imidazol[1 ,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, added 367.2mg (1.76mmol, 1.5eq) of 2-bromoethyl acetate and 325mg (2.36mmol, 2eq ) potassium carbonate, stirred at room temperature for 5 hours. Point the board, and the raw materials basically react completely. After the reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 550 mg of light yellow oil was obtained by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.56(d, J=4.8Hz, 1H), 8.16(d, J=8.0Hz, 1H), 7.79(t, J= 7.7Hz, 1H), 7.71(dd, J=8.7, 2.3Hz, 1H), 7.63(dd, J=4.2, 2.3Hz, 1H), 7.34(dd, J=7.5, 3.7Hz, 1H), 7.29( d, J=8.7Hz, 1H), 6.84(q, J=4.9Hz, 2H), 4.11(q, J=7.1Hz, 1H), 2.79(dt, J=15.6, 7.4Hz, 4H), 2.33( s,3H),2.00(d,J=2.2Hz,3H),1.43(dd,J=5.4,3.4Hz,3H)..MS: m/z:511.21(M+1)

Example 3

500mg (1.18mmol, 1eq) of 3-((4S)-8-bromo-6-(4,5-dihydropyridin-2-yl)-1-methyl-4H-benzo[f]imidazol[1 ,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, and 294.5 mg (1.76 mmol, 1.5 eq) of 1-bromoethyl acetate and 325 mg (2 eq) of potassium carbonate were added , stirred at room temperature for 5 hours. Point the board, and the raw materials basically react completely. After the reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 530 mg of light green oil was obtained by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.55(d, J=4.0Hz, 1H), 8.26(d, J=7.8Hz, 0H), 8.15(d, J= 8.0Hz, 1H), 7.80(dd, J＝7.8, 1.7Hz, 1H), 7.70(dd, J＝8.7, 2.3Hz, 1H), 7.62(d, J＝2.3Hz, 1H), 7.35–7.31( m,1H),7.29(d,J=8.7Hz,1H),6.85(d,J=1.0Hz,1H),4.28–4.21(m,4H),2.85–2.75(m,4H),2.33(s ,3H),2.02(s,3H)..MS: m/z: 511.21(M+1)

Example 4

Dissolve 3g (25.86mmol, 1eq) of compound 1 in 40ml of acetonitrile, add 5.31g (31.03mmol, 1.2eq) of benzyl bromide, 7.14g (51.72mmol, 2eq) of potassium carbonate, mix well, heat to reflux at 90°C overnight, point plate (PE/EA=3:1), after the raw materials were basically reacted, filtered and spin-dried, and passed through the column with petroleum ether ethyl acetate (0%-10%) to obtain 3.6g of compound 2 with a yield of 67.54%.

Dissolve 3.2g of compound 2 in 40ml of anhydrous tetrahydrofuran, add 12.5ml of 2.5M lithium aluminum tetrahydrogen tetrahydrofuran solution dropwise at 0°C under nitrogen protection, react overnight at room temperature, spot the plate (PE/EA=3:1), and the reaction is complete Finally, place at 0°C, add 1.2ml of water, 1.2ml of 15% sodium hydroxide solution, and 3.6ml of water dropwise in order to quench lithium tetrahydrogen aluminum, stir for 20min, add anhydrous sodium sulfate to dry, filter and spin dry, The column was passed through petroleum ether ethyl acetate (0%-15%) to obtain 1.9 g of compound 3 with a yield of 61.29%.

Dissolve 500mg (2.8mmol, 1eq) of compound 3 in 15ml of dichloromethane, add 20mg (0.16mmol, 0.05eq) of DMAP, dropwise add 0.53mL of acetic anhydride, react at room temperature for 5h, spot the plate (PE/EA=5:1) After the raw materials were basically reacted, they were spin-dried and passed through the column with petroleum ether ethyl acetate (0%-8%) to obtain 576 mg of compound 4 with a yield of 93.35%.

Dissolve 500 mg of compound 4 in 20 ml of ethyl acetate, add 50 mg of 10% palladium carbon, react overnight with hydrogen at room temperature, spot the plate, after the raw materials are basically reduced, filter, and concentrate at low temperature to obtain compound 5, which is directly used in the next reaction.

Dissolve 200mg (0.47mmol, 1eq) of compound 10 in 10ml of dichloromethane, add 124mg (2eq) of compound 5, 135mg (1.5eq) of DCC, 5.6mg (0.1eq) of DMAP, mix well, react at room temperature for 5h, spot the plate ( DCM/MeOH=15:1), after the reaction of the raw materials was basically complete, the mixture was filtered and spin-dried, and passed through the column with petroleum ether ethyl acetate (10%-70%) to obtain 170 mg of the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, CDCl3) δ8.56 (d, J = 4.2Hz, 1H), 8.18 (d, J = 7.8Hz, 1H), 7.80 (td, J = 7.8, 1.6Hz,1H),7.72(dd,J＝8.8,2.4Hz,1H),7.64(d,J＝2.2Hz,1H),7.38–7.32(m,1H),7.30(d,J＝8.6Hz, 1H), 6.86(d, J=0.8Hz, 1H), 4.30(s, 2H), 4.04(dd, J=8.2, 5.0Hz, 1H), 2.88–2.68(m, 4H), 2.34(s, 3H ),2.03(s,3H),0.98–0.82(m,4H)ppm..MS: m/z:537.11(M+1)

Example 5

Dissolve 500mg (2.8mmol, 1eq) of compound 3 in 30ml of dichloromethane, add 777μl (2eq) of triethylamine, add dropwise 519.7mg (2eq, firstly dissolved in DCM) propionyl chloride under ice bath, react at room temperature for 5h, point After the basic reaction of the raw materials, the plate was washed with water for 1-2 times, dried, filtered and spin-dried, and passed through the column with petroleum ether ethyl acetate (0%-8%) to obtain compound 6, 630 mg, with a yield of 95.7%.

Dissolve 500 mg of compound 6 in 20 ml of ethyl acetate, add 50 mg of 10% palladium carbon, react overnight with hydrogen at room temperature, spot the plate, and after the raw materials are basically reduced, filter and spin dry to obtain compound 7, which is directly used in the next reaction.

Dissolve 200mg (0.47mmol, 1eq) of compound 10 in 10ml of dichloromethane, add 100mg (1.5eq) of compound 7, 143mg (1.5eq) of DCC, 6mg (0.1eq) of DMAP, mix well, react at room temperature for 5h, spot the plate, After the reaction of the raw material was basically complete, it was filtered and spin-dried, and passed through the column with petroleum ether ethyl acetate (10%-70%) to obtain 160 mg of the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, CDCl3) δ8.60–8.56 (m, 1H), 8.18 (d, J = 7.8Hz, 1H), 7.80 (td, J = 7.8, 1.6Hz, 1H),7.72(dd,J=8.6,2.4Hz,1H),7.64(d,J=2.2Hz,1H),7.35(ddd,J=7.6,4.8,1.2Hz,1H),7.30(d,J =8.6Hz,1H),6.86(d,J=1.0Hz,1H),4.30(s,2H),4.04(dd,J=8.2,5.2Hz,1H),2.86–2.72(m,4H),2.30 (dd,J=15.2,7.6Hz,5H),1.12(t,J=7.6Hz,3H),0.98–0.82(m,4H)ppm..MS: m/z:551.12(M+1)

Example 6

Dissolve 1g (1eq) remimazolam in 20mL tetrahydrofuran solution, add 1.6mL 1M/L lithium aluminum hydride tetrahydrofuran solution (0.7eq) at -20°C, stir for 2 hours, then add water (1eq ), 15% NaOH (4eq) aqueous solution to quench the reaction, then purified by chromatographic column to obtain intermediate 1-2, then take 300mg intermediate 1-2 (1eq) and 134mg n-propyl chloroformate (1.5eq) in pyridine (2eq) was reacted with dichloromethane for 5h to obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.89–8.85 (m, 1H), 8.53 (td, J=7.9, 1.6Hz, 1H), 8.25 (d, J= 8.0Hz,1H),8.14(dd,J=8.8,2.2Hz,1H),8.06(ddd,J=7.7,5.5,1.1Hz,1H),8.00(d,J=2.2Hz,1H),7.92( d,J=8.8Hz,1H),7.54(d,J=1.1Hz,1H),4.58(dd,J=10.2,4.3Hz,1H),4.38–4.24(m,2H),4.06(t,J ＝6.4Hz, 2H), 2.68(dtd, J＝15.1, 10.0, 5.0Hz, 1H), 2.53(d, J＝1.0Hz, 3H), 2.49–2.41(m, 1H), 2.25(ddq, J＝ 16.4, 11.4, 5.6Hz, 1H), 2.01–1.92(m, 1H), 1.65(h, J=7.3Hz, 2H), 0.93(t, J=7.4Hz, 3H). MS: m/z: 497.11 (M+1)

Example 7

Dissolve 1g (1eq) remimazolam in 20mL tetrahydrofuran solution, add 1.6mL 1M/L lithium aluminum hydride tetrahydrofuran solution (0.7eq) at -20°C, stir and react for 2 hours, then add water (1eq ), 15% NaOH (4eq) aqueous solution to quench the reaction, then purified by chromatographic column to obtain intermediate 1-2, then take 300mg intermediate 1-2 (1eq) and 134mg isopropyl chloroformate (1.5eq) in pyridine (2eq) was reacted with dichloromethane for 5h to obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.83–8.81 (m, 1H), 8.63 (td, J=7.7, 1.6Hz, 1H), 8.15 (d, J= 8.0Hz,1H),8.03(dd,J=8.8,2.2Hz,1H),8.00(ddd,J=7.7,5.5,1.1Hz,1H),7.98(d,J=2.2Hz,1H),7.95( d,J=8.8Hz,1H),7.43(d,J=1.1Hz,1H),5.24(p,J=6.8Hz,1H),4.63(td,J=12.2,3.3Hz,1H),4.54( t, J＝6.6Hz, 1H), 4.45(td, J＝12.2, 3.2Hz, 1H), 2.40(s, 3H), 1.92(dt, J＝9.8, 6.3Hz, 2H), 1.78(dddq, J =14.8,9.1,6.2,3.0Hz,1H),1.60(dtq,J=15.5,9.4,3.2Hz,1H),1.32(d,J=6.8Hz,3H),1.27(d,J=6.8Hz, 3H).MS: m/z: 497.11 (M+1)

Example 8

Dissolve 1g (1eq) remimazolam in 20mL tetrahydrofuran solution, add 1.6mL 1M/L lithium aluminum hydride tetrahydrofuran solution (0.7eq) at -20°C, stir and react for 2 hours, then add water (1eq ), 15% NaOH (4eq) aqueous solution to quench the reaction, and then purified by chromatographic column to obtain intermediate 1-2, then take 300mg intermediate 1-2 (1eq) and 150mg isobutyl chloroformate (1.5eq) in pyridine (2eq) was reacted with dichloromethane for 5h to obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50(d, J=4.3Hz, 1H), 8.12(d, J=7.9Hz, 1H), 7.80–7.60(m, 3H), 7.29(t, J=9.1Hz, 2H), 6.94(s, 1H), 4.22(tt, J=7.1, 3.7Hz, 2H), 3.85(d, J=6.7Hz, 1H), 3.81( dd,J＝6.7,1.0Hz,2H),2.40(s,3H),2.04–1.89(m,2H),1.85–1.72(m,2H),1.59–1.49(m,1H),0.95(dd, J＝25.0,6.8Hz,6H)..MS: m/z:511.12(M+1)

Example 9

Take 300mg of intermediate 1-2 (1eq) and 150mg of chloroethyl chloroformate (1.5eq), add pyridine (1.5eq) and react in dichloromethane for 5h, then wash and dry with acidic water to obtain intermediate 1-3, After reacting with acetic acid (1eq) and K ₂ CO ₃ (3eq) in DMF for 6h, add ice water to the system, extract with ethyl acetate, wash with water twice, combine the organic phases, dry, and perform column chromatography to obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.13–8.08 (m, 1H), 7.73 (td, J =7.8,1.8Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.3Hz,1H),7.27(ddd,J=7.5,4.8,1.1Hz,1H) ,7.21(d,J=10.2Hz,1H),6.79(q,J=1.1Hz,1H),5.16(ddd,J=12.1,10.3,1.8Hz,1H),4.68(td,J=12.2,2.7 Hz,1H),4.64–4.57(m,2H),4.51(dt,J=12.2,1.6Hz,1H),4.39(td,J=12.0,4.0Hz,1H),4.28(dt,J=12.5, 1.4Hz,1H),2.40(s,3H),2.02(s,3H),1.92(td,J＝7.4,2.8Hz,2H),1.78(ddq,J＝11.9,9.3,3.0Hz,1H), 1.68(ttd,J=12.2,7.9,4.0Hz,1H)..MS: m/z:541.10(M+1)

Example 10

Take 300mg of intermediate 1-2 (1eq) and chloromethyl chloroformate (1.5eq), add pyridine (1.5eq) and react in dichloromethane for 5h, wash and dry with acid water to obtain intermediate 1-4, and then After reacting with acetic acid (1eq) and K ₂ CO ₃ (3eq) in DMF for 6h, add ice water to the system, extract with ethyl acetate, wash twice with water, combine the organic phases, dry, and obtain by column chromatography the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.61–8.57 (m, 1H), 7.67 (td, J=7.9, 1.1Hz, 1H), 7.64–7.61 (m, 1H ),7.58(dd,J=7.5,2.0Hz,1H),7.55(ddd,J=7.9,5.1,1.1Hz,1H),7.53–7.50(m,2H),6.99(s,1H),6.42( d,J=12.5Hz,1H),6.32(d,J=12.5Hz,1H),5.19–5.11(m,1H),4.49(dd,J=10.9,2.3Hz,1H),3.88(tt,J ＝12.2,2.9Hz, 1H),2.40(s,3H),2.11(s,3H),1.90–1.73(m,3H),1.56–1.43(m,1H)..MS: m/z:527.10( M+1)

Example 11

Take 300mg of intermediate 1-2 (1eq) and chloroethyl chloroformate (1.5eq), add pyridine (1.5eq) and react in dichloromethane for 5h, wash and dry with acidic water to obtain intermediate 1-5, and then After reacting with acetic acid (1eq) and K ₂ CO ₃ (3eq) in DMF for 6h, add ice water to the system, extract with ethyl acetate, wash twice with water, combine the organic phases, dry, and obtain by column chromatography the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50 (d, J = 4.7Hz, 1H), 8.13–8.07 (m, 1H), 7.73 (td, J = 7.8, 1.7 Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.61–7.56(m,1H),7.27(ddd,J=7.5,4.8,1.1Hz,1H),7.21(d,J= 11.9Hz, 1H), 6.79(d, J=1.0Hz, 1H), 6.39–6.30(m, 1H), 4.60(td, J=12.2, 2.9Hz, 1H), 4.49(dd, J=11.5, 1.1 Hz, 1H), 4.39(td, J=12.1, 3.4Hz, 1H), 2.40(s, 3H), 2.08(s, 3H), 2.02–1.92(m, 2H), 1.75(d, J=6.8Hz ,3H),1.69(d,J=12.9Hz,1H),1.57–1.47(m,1H).MS: m/z:541.10(M+1)

Example 12

Take 300mg of intermediate 1-2 (1eq) and 58mg of acetic acid (2eq), K ₂ CO ₃ (3eq) and react in DMF for 5h, add ice water to the system, then extract with ethyl acetate, wash twice with water, and combine The organic phase was dried and the compound was obtained by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.51 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.73 ( td,J=7.8,1.8Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.57(d,J=2.3Hz,1H),7.28(ddd,J=7.5,4.8,1.1Hz ,1H),7.21(d,J=10.5Hz,1H),6.82(d,J=1.1Hz,1H),4.14(t,J=6.6Hz,2H),3.87(dd,J=9.0,5.3Hz ,1H),2.62–2.39(m,2H),2.27(d,J＝0.9Hz,3H),2.07–2.00(m,1H),1.96(s,3H),1.84(dtd,J＝13.7,6.5 ,3.8Hz,1H).MS: m/z: 453.11(M+1)

Example 13

Take 300mg of intermediate 1-2 (1eq) and 63mg of cyclopropyl formic acid (2eq), K ₂ CO ₃ (3eq) in DMF at room temperature and stir for 5h, add ice water to the system, then extract with ethyl acetate, and then Washed twice with water, combined the organic phases, dried, and obtained the compound by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.51 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.73 ( td,J=7.8,1.8Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.57(d,J=2.2Hz,1H),7.28(ddd,J=7.5,4.9,1.1Hz ,1H),7.22(s,1H),6.82(d,J=1.0Hz,1H),4.58(dd,J=11.7,2.0Hz,1H),4.37–4.30(m,1H),4.05(td, J＝12.1, 3.3Hz, 1H), 2.40(s, 3H), 2.01(ddd, J＝11.4, 9.0, 2.8Hz, 1H), 1.78–1.71(m, 1H), 1.70–1.66(m, 1H) ,1.64(dd,J=8.8,3.8Hz,2H),1.08(tt,J=8.4,4.3Hz,2H),0.84(tt,J=7.2,4.3Hz,2H).MS: m/z:479.10 (M+1)

Example 14

Take 300mg of intermediate 1-2 (1eq) and 62mg of isobutyric acid (2eq), K ₂ CO ₃ (3eq) and DMF to react for 5h, add ice water to the system, then extract with ethyl acetate, and wash with water twice , combined the organic phases, dried, and obtained the compound by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50 (d, J = 4.3Hz, 1H), 8.13–8.08 (m, 1H), 7.73 (td, J = 7.7, 1.4 Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.2Hz,1H),7.27(ddd,J=7.5,4.8,1.0Hz,1H),7.21(d ,J=10.5Hz,1H),6.79(s,1H).2.67(hept,J=6.8Hz,1H),2.40(s,3H),2.04–1.94(m,1H),1.72(ddd,J= 14.6, 12.2, 3.1Hz, 1H), 1.68–1.63(m, 1H), 1.62–1.55(m, 1H), 1.26(d, J＝6.8Hz, 3H), 1.21(d, J＝6.9Hz, 3H ).MS: m/z: 481.11 (M+1)

Example 15

Take 300mg of intermediate 1-2 (1eq) and 71mg of isovaleric acid (2eq), K ₂ CO ₃ (3eq) and react in DMF for 5h, add ice water to the system, then extract with ethyl acetate, and wash with water twice , combined the organic phases, dried, and obtained the compound by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.61–8.56(m,1H),7.80–7.69(m,2H),7.61–7.54(m,2H),7.53–7.48 (m,2H),6.99(s,1H),4.53–4.46(m,2H),4.18(td,J=12.3,1.9Hz,1H),2.44(dd,J=12.4,7.1Hz,1H), 2.40(s,3H),2.30(dd,J=12.4,7.0Hz,1H),2.13(dp,J=13.7,6.8Hz,1H),1.96–1.89(m,2H),1.76(dtt,J= 15.5,7.6,3.9Hz,1H),1.50–1.41(m,1H),1.00(d,J=6.8Hz,3H),0.94(d,J=6.8Hz,3H).MS: m/z:495.13 (M+1)

Example 16

Take 310mg of intermediate 1-2 (1eq) and 228mg of bromoacetyl bromide (1.5eq), pyridine (2eq) reacted in dichloromethane for 5h, washed with acid water and dried to obtain intermediate 1-6, and then mixed with acetic acid ( 1eq), K ₂ CO ₃ (3eq) reacted in DMF for 6h, added ice water to the system, extracted with ethyl acetate, washed twice with water, combined the organic phases, dried, and obtained the compound by column chromatography.

¹ H NMR (400MHz, Chloroform-d) δ8.51(dd, J=4.4,1.3Hz,1H),8.10(d,J=7.9Hz,1H),7.73(td,J=7.8,1.8Hz,1H ),7.66(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.2Hz,1H),7.28(ddd,J=7.5,4.8,1.2Hz,1H),7.24(d,J= 8.7Hz, 1H), 6.80(d, J=1.0Hz, 1H).5.21(d, J=12.5Hz, 1H), 4.57(d, J=12.5Hz, 1H), 4.52(dd, J=12.2, 2.4Hz, 1H), 4.48–4.42(m, 1H), 3.82(ddd, J=12.2, 9.3, 3.3Hz, 1H), 2.40(s, 3H), 2.18(s, 3H), 1.90–1.82(m ,1H),1.78–1.64(m,2H),1.44–1.33(m,1H).MS: m/z:511.11(M+1)

Example 17

Take 272mg of intermediate 1-2 (1eq) and 214mg of 2-bromopropionyl bromide (1.5eq), pyridine (2eq), react in dichloromethane for 5h, wash and dry with acid water to obtain intermediate 1-7, After reacting with acetic acid (1eq) and K ₂ CO ₃ (3eq) in DMF for 6h, add ice water to the system, extract with ethyl acetate, wash with water twice, combine the organic phases, dry, and obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50 (d, J = 4.3Hz, 1H), 8.14–8.07 (m, 1H), 7.73 (td, J = 7.7, 1.4 Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.2Hz,1H),7.27(ddd,J=7.5,4.8,1.0Hz,1H),7.21(d ,J=10.5Hz,1H),6.79(q,J=1.0Hz,1H),4.98(qd,J=7.1,2.8Hz,1H),4.23(td,J=6.4,2.0Hz,2H),3.87 (dd,J=9.1,5.1Hz,1H),2.60–2.39(m,2H),2.27(s,3H),2.05(d,J=1.1Hz,3H),1.81–1.70(m,2H), 1.40 (dd, J=7.1, 2.4Hz, 3H). MS: m/z: 525.11 (M+1)

Example 18

Take 300mg of intermediate 1-2 (1eq) and 252mg of 2-bromoisobutyryl bromide (1.5eq), pyridine (2eq), react in dichloromethane for 5h, wash and dry with acid water to obtain intermediate 1-8 , then reacted with acetic acid (1eq), K ₂ CO ₃ (3eq) in DMF for 6h, added ice water to the system, extracted with ethyl acetate, washed twice with water, combined the organic phases, dried, and subjected to column chromatography to obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.60-8.54 (d, J = 4.3Hz, 1H), 8.24–8.17 (m, 1H), 7.56 (dd, J = 7.3 ,1.4Hz,1H),7.55(dd,J=8.3,2.3Hz,1H),7.45(d,J=2.2Hz,1H),7.30(ddd,J=7.6,4.3,1.0Hz,1H),7.11 (d, J = 10.5Hz, 1H), 6.83 (q, J = 1.0Hz, 1H), 4.62 (dd, J = 11.6, 2.0Hz, 1H), 4.54 (td, J = 11.8, 2.4Hz, 1H) ,3.84(td,J=12.2,3.5Hz,1H),2.40(s,3H),2.12(s,3H),2.08(ddd,J=11.8,9.1,3.0Hz,1H),1.78–1.71(m ,1H),1.66(s,3H),1.63(d,J=3.2Hz,1H),1.61(s,4H).MS: m/z:539.11(M+1)

Example 19

Take 300mg of intermediate 1-2 (1eq) and 188mg of 3-bromopropionyl chloride (1.5eq), pyridine (2eq), react in dichloromethane for 5h, wash and dry with acid water to obtain intermediate 1-9, and then After reacting with acetic acid (1eq), K ₂ CO ₃ (3eq) in DMF for 6h, add ice water to the system, extract with ethyl acetate, wash with water twice, combine the organic phases, dry, and obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.73-8.54 (d, J = 4.3Hz, 1H), 8.26–8.19 (m, 1H), 7.73 (dd, J = 7.3 ,1.4Hz,1H),7.65(dd,J=8.3,2.3Hz,1H),7.55(d,J=2.2Hz,1H),7.36(ddd,J=7.6,4.3,1.0Hz,1H),7.23 (d,J=10.5Hz,1H),6.76(q,J=1.0Hz,1H)5.34–5.26(m,1H),4.59–4.50(m,2H),4.44(dt,J=12.3,2.4Hz ,1H),3.85–3.77(m,1H),2.66(td,J＝12.1,2.4Hz,1H),2.45(ddd,J＝12.2,2.4,1.1Hz,1H),2.39(s,3H), 2.06(ddd, J＝11.2, 8.5, 2.6Hz, 1H), 2.02(s, 3H), 1.76(tt, J＝11.3, 5.0Hz, 1H), 1.64–1.50(m, 2H).MS: m/ z: 525.11(M+1)

Example 20

Take 300mg of intermediate 1-2 (1eq) and 203mg of 3-bromopropionyl chloride (1.5eq), pyridine (2eq), react in dichloromethane for 5h, wash and dry with acid water to obtain intermediate 1-10, and then After reacting with acetic acid (1eq), K ₂ CO ₃ (3eq) in DMF for 6h, add ice water to the system, then extract with ethyl acetate, wash with water twice, combine the organic phases, dry, and obtain the compound.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.52–8.49 (m, 1H), 8.10 (d, J = 7.9Hz, 1H), 7.73 (td, J = 7.8, 1.8 Hz,1H),7.66(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.3Hz,1H),7.28(ddd,J=7.5,4.8,1.2Hz,1H),7.24(d ,J=8.7Hz,1H),6.80(d,J=1.0Hz,1H).4.51–4.43(m,2H),4.23(td,J=12.6,2.2Hz,1H),4.19–4.09(m, 2H), 2.54(td, J=12.8, 2.5Hz, 1H), 2.40(s, 3H), 2.28(td, J=12.7, 2.6Hz, 1H), 2.02(s, 4H), 1.92(ddt, J =9.1,6.6,2.9Hz,2H),1.79–1.65(m,2H),1.47(tt,J=12.7,2.5Hz,1H).MS: m/z:539.12(M+1)

Example 21

Take 330mg of intermediate 1-2 (1eq) and 105mg of malonic acid (2eq), add DCC (1.5eq), DMAP (0.1eq), react in dichloromethane for 5h, filter, dry and obtain by column chromatography Intermediate 1-11 was reacted with methanol (1.5eq), DCC (1.5eq), DMAP (0.1eq) in dichloromethane for 6h, filtered and dried to obtain the compound by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.73 ( td,J=7.8,1.8Hz,1H),7.66(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.2Hz,1H),7.28(ddd,J=7.5,4.8,1.2Hz ,1H),7.24(d,J=8.7Hz,1H),6.80(d,J=1.0Hz,1H).4.54(dd,J=11.6,1.6Hz,1H),4.35(td,J=12.2, 3.2Hz, 1H), 4.13(td, J=12.0, 3.2Hz, 1H), 4.03(d, J=12.3Hz, 1H), 3.76(d, J=12.5Hz, 1H), 3.73(s, 3H) ,2.40(s,3H),2.00–1.90(m,1H),1.78–1.69(m,1H),1.69–1.63(m,1H),1.62–1.53(m,1H).MS: m/z: 511.11(M+1)

Example 22

Take 410mg of intermediate 1-2 (1eq) and 235.6mg of succinic acid (2eq), add DCC (1.5eq), DMAP (0.1eq), react in dichloromethane for 5h, filter and dry to obtain the column layer The intermediate 1-12 was obtained by analysis, and then reacted with methanol (1.5eq), DCC (1.5eq), DMAP (0.1eq) in dichloromethane for 6h, filtered and dried to obtain the compound by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.63 (ddd, J = 4.8, 1.7, 0.8Hz, 1H), 8.21 (d, J = 7.8Hz, 1H), 7.76 ( dd,J=7.8,1.8Hz,1H),7.66(dd,J=8.7,2.3Hz,1H),7.60(d,J=2.2Hz,1H),7.32(ddd,J=7.5,4.8,1.2Hz ,1H),7.26(d,J=8.3Hz,1H),6.92(d,J=1.0Hz,1H).4.62(td,J=12.2,3.0Hz,1H),4.47(dd,J=11.6, 1.8Hz, 1H), 3.63(s, 4H), 3.24–3.12(m, 2H), 2.64–2.50(m, 2H), 2.40(s, 3H), 1.82(qd, J＝12.1, 2.4Hz, 1H ),1.72–1.64(m,1H),1.63–1.53(m,1H),1.39(qt,J＝12.4,2.2Hz,1H).MS: m/z:525.11(M+1)

Example 23

The reaction operation is the same as in Example 3, 500mg (1.18mmol, 1eq) 3-((4S)-8-bromo-6-(4,5-dihydropyridin-2-yl)-1-methyl-4H- Benzo[f]imidazol[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, and 320.5mg (1.76mmol, 1.5eq) of acetic acid-1-bromopropane was added ester and 325mg (2eq) of potassium carbonate, stirred at room temperature for 5 hours. Point the board, and the raw materials basically react completely. After the reaction solution was filtered, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 530 mg of light green oil was obtained by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.70(d, J=4.8Hz, 1H), 8.26(td, J=7.8, 1.4Hz, 1H), 8.20(d ,J=7.9Hz,1H),8.08(dd,J=8.7,2.2Hz,1H),7.90–7.76(m,3H),7.52(s,1H),4.55(dd,J=9.9,3.9Hz, 1H), 4.25–4.05(m,3H), 2.91–2.60(m,4H), 2.52(s,3H), 2.05–1.71(m,5H).MS: m/z: 525.11(M+1)

Example 24

Take 300mg of intermediate 1-2 (1eq), add 136.5mg (2eq) of propionyl chloride, stir in dichloromethane under an ice bath, add 115mg (2eq) of pyridine dropwise, and then move to room temperature for 2 hours. Wash with water for about 5 minutes, combine the organic phases, and obtain the product by column chromatography.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.57 (ddd, J = 4.2, 1.6, 0.8 Hz, 1H), 8.20 (d, J = 6.9 Hz, 1H), 7.73 ( td,J=6.8,1.8Hz,1H),7.85(dd,J=8.6,2.3Hz,1H),7.67(d,J=3.3Hz,1H),7.48(ddd,J=6.5,4.8,1.1Hz ,1H),7.31(d,J=10.2Hz,1H),6.92(d,J=1.1Hz,1H),4.24(t,J=6.6Hz,2H),3.87(dd,J=9.0,5.3Hz ,1H),2.62–2.39(m,2H),2.27(d,J＝0.9Hz,3H),2.07–2.00(m,1H),1.96(s,3H),1.84(dt,J＝13.7,6.5 ,3.8Hz,1H).1.12(t,J=8.0Hz,3H).MS: m/z:467.12(M+1)

Example 25

The reaction operation is the same as in Example 24.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.51 (d, J = 5.5Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.73 (td, J = 7.8,1.8Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.3Hz,1H),7.28(ddd,J=7.5,4.8,1.1Hz,1H), 7.21 (d, J = 10.4Hz, 1H), 6.82 (d, J = 1.0Hz, 1H), 4.15 (t, J = 6.6Hz, 2H), 3.88 (dd, J = 9.0, 5.3Hz, 1H), 2.56(dtd, J=14.5,9.6,5.4Hz,1H),2.45(ddd,J=19.5,10.6,5.7Hz,1H),2.27(s,3H),2.18(t,J=7.5Hz,2H) ,2.00(dtd,J=12.2,9.7,8.4,6.1Hz,1H),1.85(ddd,J=13.7,10.0,6.4Hz,1H),1.62–1.56(m,2H),0.86(t,J= 7.4Hz,3H).MS: m/z: 481.12(M+1)

Example 26

The reaction operation is the same as in Example 24.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.51 (d, J = 5.5Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.73 (td, J = 7.8,1.8Hz,1H),7.65(dd,J=8.7,2.3Hz,1H),7.58(d,J=2.3Hz,1H),7.28(ddd,J=7.5,4.8,1.1Hz,1H), 7.21 (d, J = 10.4Hz, 1H), 6.82 (d, J = 1.0Hz, 1H), 4.15 (t, J = 6.6Hz, 2H), 3.88 (dd, J = 9.0, 5.3Hz, 1H), 2.40(s,3H),2.07–1.99(m,1H),1.98–1.88(m,3H),1.78–1.69(m,1H),1.68–1.62(m,1H),1.60–1.53(m,1H ),1.53–1.45(m,2H),0.85–0.76(m,6H).MS: m/z:509.15(M+1)

Example 27

The reaction operation is the same as in Example 24.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50(d, J=4.8Hz, 1H), 8.12(d, J=8.0Hz, 1H), 7.73(td, J= 7.7,1.6Hz,1H),7.67(d,J=3.7Hz,1H),7.64(dd,J=8.7,2.2Hz,1H),7.55(d,J=2.2Hz,1H),7.44(d, J＝5.0Hz, 1H), 7.27(dd, J＝7.5, 4.9Hz, 1H), 7.20(d, J＝6.1Hz, 1H), 7.02–6.97(m, 1H), 6.80(s, 1H), 4.45–4.30(m,2H),3.96(dd,J=8.9,5.5Hz,1H),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS: m/z: 521.10(M+1)

Example 28

The reaction operation is the same as in Example 24.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50(d, J=4.8Hz, 1H), 8.12(d, J=8.0Hz, 1H), 7.73(td, J= 7.7,1.6Hz,1H),7.67(d,J=3.7Hz,1H),7.64(dd,J=8.7,2.2Hz,1H),7.55(d,J=2.2Hz,1H),7.44(d, J＝5.0Hz, 1H), 7.27(dd, J＝7.5, 4.9Hz, 1H), 6.80(s, 1H), 4.45–4.30(m, 2H), 3.96(dd, J＝8.9, 5.5Hz, 1H ),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS: m/z:505.10(M+1)

Example 29

The reaction operation is the same as in Example 24.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.50(d, J=4.8Hz, 1H), 8.12(d, J=8.0Hz, 1H), δ8.02(dd, J=7.5,1.9Hz,2H),7.79(tt,J=7.8,1.9Hz,1H),7.73(td,J=7.7,1.6Hz,1H),7.67(d,J=3.7Hz,1H), 7.55(d, J=2.2Hz, 1H), 7.42(t, J=7.5Hz, 2H), 7.27(dd, J=7.5, 4.9Hz, 1H), 6.80(s, 1H), 4.45–4.30(m ,2H),3.96(dd,J＝8.9,5.5Hz,1H),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS: m/z:515.10 (M+1)

Example 30

The reaction operation is the same as in Example 24.

The proton nuclear magnetic resonance spectrum of the compound: ¹ H NMR (400MHz, Chloroform-d) δ8.90(d, J=5.2Hz, 2H), δ8.50(d, J=4.8Hz, 1H), 8.12(d, J＝8.0Hz, 1H), 8.00(d, J＝5.2Hz, 2H), 7.79(tt, J＝7.8, 1.9Hz, 1H), 7.67(d, J＝3.7Hz, 1H), 7.55(d, J＝2.2Hz, 1H), 7.27(dd, J＝7.5, 4.9Hz, 1H), 6.80(s, 1H), 4.45–4.30(m, 2H), 3.96(dd, J＝8.9, 5.5Hz, 1H ),2.69–2.49(m,2H),2.27(s,3H),2.16–2.00(m,2H).MS: m/z:516.40(M+1)

The beneficial effects of the compounds of the present invention are demonstrated below through specific test examples.

The compounds of the present invention are evaluated for their pharmacological activity, efficacy and safety.

In clinical application, it is necessary to strictly control the effect of anesthetic drugs, so as to ensure the smooth progress of the operation, diagnosis and other processes, and to terminate the anesthesia as soon as possible after the operation, so that the patient can wake up quickly. If the anesthesia lasts too long, it may cause some adverse effects on the cardiovascular system and respiratory system, such as drowsiness and dizziness. Therefore, an ideal anesthetic drug should have the advantages of quick onset, quick recovery, and high safety.

Test Example 1. Pharmacodynamic study of remimazolam derivatives in mice

1. Test method

Using the sequential method (Dixon-Mood Method) single tail vein administration, each compound was subjected to loss of righting reflex (LORR) experiment in mice, and the anesthesia half effective dose (ED ₅₀ ) of the compound was determined.

ED ₅₀ determination: male Kunming mice (25-30g) were randomly selected, the compound was prepared with PEG-400: pure water (3:7), and the administration volume was 0.2mL. According to the preliminary experiment results, between the highest and the lowest dose Set the other three doses according to the geometric sequence. Start administration from the middle dose (the tail vein injection time is about 10s), and observe the disappearance of righting reflex in mice. If the duration of righting reflex disappearance of the first mouse is more than 30s, it is positive, then the second mouse is given a lower dose; if the first mouse’s righting reflex disappears for less than 30s or the If it disappears, it is negative, and the second mouse is given a higher dose; the experiment is repeated until 8 cycles of positive-negative or negative-positive are crossed to end the experiment.

2. Test results

The test results are shown in Table 1

Table 1. Pharmacodynamic study results of each compound

In Table 1, the duration of anesthesia is the time from the disappearance of the righting reflex to the recovery of the righting reflex, and the recovery quality is the time from the recovery of the righting reflex to the ability to crawl freely; the recovery quality "+" means <1 min, and "++" means greater than or equal to Between 1min and less than 3min, "+++" means greater than or equal to 3min and less than 5min, "++++" means greater than or equal to 5min to less than 10min, "++++" means ≥10min .

From the above test results, it can be seen that compared with remimazolam, the compound of the present invention can reduce the effective dosage, and has the characteristics of quick onset, short recovery time, higher quality of recovery, and as an anesthetic, the effect is obviously better than that of remazolam Zolam.

In summary, the compound of the present invention has good intravenous sedation and anesthesia effects, and its anesthesia effect is comparable to that of remimazolam, or even better than that of remimazolam, specifically manifested in a significant reduction in effective dose, and a significant reduction in duration and recovery time. At the same time, in the rat tail vein anesthesia model, the awakening quality of the compound of the present invention is significantly improved compared with remimazolam. The compound of the present invention has quick onset, short duration, quick recovery and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has a good application prospect.

Claims

A compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof:

in,

Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;

Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;

Or R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;

m is an integer selected from 0 to 6;

M is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M2 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy A substituent is substituted, and the NH is substituted by a short-chain hydrocarbon group;

R 3 is selected from hydrogen, short-chain hydrocarbon group, C 1-8 alkoxy, -C(O)-M 4 -R 5 , C 3-10 cycloalkyl, 6-10 membered aryl or 5-10 membered hetero Aryl, the heteroaryl includes 1 to 3 heteroatoms selected from N, O, or S;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R is selected from short-chain hydrocarbon groups or C 1-8 alkoxy groups;

a is an integer selected from 0 to 6;

R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is an integer selected from 1 to 4;

When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , when M 4 is O, R 5 is not selected from short-chain hydrocarbon groups;

When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is none, R 5 is not selected from C 1-8 alkoxy;

When M 1 is none, a is 1, M 2 is O, M 3 is none, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from short chain hydrocarbon groups;

When M 1 is nothing, a is 1, M 2 is O, M 3 is nothing, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is nothing, R 5 is not selected from C 1-8 alkoxy.
The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M2 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy A substituent is substituted, and the NH is substituted by C 1-8 alkyl;

R 3 is selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, -C(O)-M 4 -R 5 , C 3-10 cycloalkyl, 6-10 membered aryl or 5- 10-membered heteroaryl, which includes 1 to 3 heteroatoms selected from N, O, or S;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R is selected from C 1-8 alkyl or C 1-8 alkoxy;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1, 2, 3, 4;

When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from C 1-8 alkyl;

When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is none, R 5 is not selected from C 1-8 alkoxy;

When M 1 is none, a is 1, M 2 is O, M 3 is none, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not Selected from C 1～8 alkyl groups;

When M 1 is nothing, a is 1, M 2 is O, M 3 is nothing, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is nothing, R 5 is not selected from C 1-8 alkoxy.
The compound according to claim 2, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M2 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy A substituent is substituted, and the NH is substituted by C 1-4 alkyl;

R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, -C(O)-M 4 -R 5 , C 3-6 cycloalkyl, phenyl, thienyl, pyridyl, imidazolyl;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R is selected from C 1-4 alkyl or C 1-4 alkoxy;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from C 1-4 alkyl;

When M 1 is none, a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, R 3 is -C(O)-M 4 -R 5 , M 4 is none, R 5 is not selected from C 1-4 alkoxy;

When M 1 is none, a is 1, M 2 is O, M 3 is none, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is O, R 5 is not selected from C 1-4 alkyl;

When M 1 is nothing, a is 1, M 2 is O, M 3 is nothing, m is 1-5, R 3 is -C(O)-M 4 -R 5 , M 4 is nothing, R 5 is not selected from C 1-4 alkoxy;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula II:

in,

Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;

Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;

Or R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;

m is an integer selected from 1 to 5;

M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M3 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R is selected from short-chain hydrocarbon groups;

a is an integer selected from 0 to 6;

R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is an integer selected from 1 to 4;

When a is 1, M 2 is O, M 3 is O or S or NH or C 1-5 alkylene, m is 1, M 4 is not O;

When a is 1, M2 is O, M3 is none, and m is 1-5, M4 is not O.
The compound according to claim 4, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 1, 2, 3, 4, 5;

M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M3 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1,2,3,4.
The compound according to claim 5, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 1, 2, 3, 4, 5;

M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M3 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 4, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula II-a :

in,

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 1, 2, 3, 4, 5;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1, 2, 3, 4;

When a is 1 and m is 1, M 4 is not O.
The compound according to claim 7, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 1, 2, 3, 4, 5;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 7, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula II-b :

in,

m1 is selected from 0, 1, 2, 3, 4;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1, 2, 3, 4;

When a is 1 and m1 is 0, M 4 is not O.
The compound according to claim 9, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

m1 is selected from 0, 1, 2, 3, 4;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 9, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula II-c :

in,

m1 is selected from 0, 1, 2, 3, 4;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

When a is 1 and m1 is 0, M 4 is not O.
The compound according to claim 11, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

m1 is selected from 0, 1, 2, 3, 4;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula III:

in,

Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;

Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;

Or R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;

m is an integer selected from 0 to 6;

M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R is selected from short-chain hydrocarbon groups;

a is an integer selected from 0 to 6;

R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is an integer selected from 1-4.
The compound according to claim 13, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1,2,3,4.
The compound according to claim 14, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 13, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof, wherein the compound is represented by formula III-a :

in,

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1,2,3,4.
The compound according to claim 16, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 16, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof, wherein the compound is represented by formula III-b :

in,

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to claim 18, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to claim 1, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula IV:

in,

Each R is independently selected from hydrogen, a short-chain hydrocarbon group, a C3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0 to 4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 1 is a short-chain hydrocarbon group or hydrogen;

Each R is independently selected from hydrogen, short-chain hydrocarbon group, C 3-10 cycloalkyl group or 3-10 membered heterocyclic group, and the short-chain hydrocarbon group, cycloalkyl group or heterocyclic group is selected from 0-4 Substituents from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heterocycles selected from N, O, or S Atom, preferably R 2 is hydrogen or a short-chain hydrocarbon group;

Or R 1 and R 2 on the same carbon atom respectively form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the cycloalkyl group or heterocyclic group is replaced by 0 to 4 members selected from halogen, trifluoro Substituted by methyl, cyano, nitro, short-chain alkyl, or alkoxy, and the heterocycle includes 1 to 3 heteroatoms selected from N, O, or S;

m is an integer selected from 0 to 6;

M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;

M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R is selected from short-chain hydrocarbon groups;

a is an integer selected from 0 to 6;

R 4 is selected from pyridine rings with nitrogen at 2, 3, and 4 positions, preferably R 4 is pyridine with nitrogen at 2 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is an integer selected from 1-4.
The compound according to claim 20, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;

M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1,2,3,4.
The compound according to claim 21, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M1 is selected from O, S, NH or C 1-5 alkylene, said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy;

M2 is selected from O, S, NH or C 1-5 alkylene, and said alkylene is substituted by 0 to 4 substituents selected from halogen, trifluoromethyl, and C 1-6 alkoxy;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 20, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is represented by formula IV-a :

in,

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2, 3, and 4 positions;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1,2,3,4.
The compound according to claim 23, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6;

R 4 is selected from pyridine rings with nitrogen at the 2-position;

X are independently selected from halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy; the substituent of the alkyl or alkoxy is halogen;

n is selected from 1;

Preferably,

X is independently selected from -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 .
The compound according to claim 23, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof, wherein the compound is represented by formula IV-b :

in,

Each R 1 or R 2 is independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocycle or R 1 and R 2 on the same carbon atom respectively constitute a substituted or unsubstituted C 3-10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocyclic group; the substituted alkyl, substituted The number of substituents of the cycloalkyl or substituted heterocyclic group is 1, 2, 3 or 4, and the substituents of the substituted alkyl, substituted cycloalkyl or substituted heterocyclic group are selected from halogen, trifluoro Methyl, cyano, nitro, C 1-8 alkyl, C 1-8 alkoxy; the heteroatoms of the heterocyclic group are selected from N, O, S, and the number of the heteroatoms is 1, 2 or 3;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to claim 25, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that:

Each R 1 or R 2 is independently selected from hydrogen, C 1-4 alkyl;

m is selected from 0, 1, 2, 3, 4, 5, 6;

M3 is selected from none or selected from O, S, NH or C 1-5 alkylene, and said alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

M4 is selected from none or selected from O, S, NH or C 1-5 alkylene, and the alkylene is replaced by 0 to 4 selected from halogen, trifluoromethyl, C 1-6 alkoxy substituent substitution;

R 5 is selected from C 1-4 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof, wherein the compound is represented by formula V-a:

in,

R 3 is selected from C 1-8 alkyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof, wherein the compound is represented by formula V-b:

in,

R 3 is selected from C 1-8 alkyl, C 3-6 cycloalkyl, phenyl, thienyl, pyridyl, imidazolyl;

a is selected from 0, 1, 2, 3, 4, 5, 6.
The compound according to any one of claims 1 to 28, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition, is characterized in that: the compound is as follows One of the compounds:
Use of the compound according to any one of claims 1 to 29, or its salt, or its stereoisomer, or its solvate, or its cocrystal, or its composition in the preparation of sedatives and/or anesthetics;

Preferably, the sedative and/or anesthetic is a sedative and/or anesthetic for intravenous sedation and/or anesthesia.
A medicine, characterized in that: it is the compound described in any one of claims 1 to 29, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof A preparation prepared from the active ingredient plus pharmaceutically acceptable excipients or auxiliary ingredients;

Preferably, the drug is a sedative and/or anesthetic;

More preferably, the sedative and/or anesthetic is a sedative and/or anesthetic for intravenous sedation and/or anesthesia.