CN116102557B

CN116102557B - Benzodiazepine compound, preparation method and medical application thereof

Info

Publication number: CN116102557B
Application number: CN202211392447.9A
Authority: CN
Inventors: 刘进; 柯博文
Original assignee: West China Hospital of Sichuan University
Current assignee: West China Hospital of Sichuan University
Priority date: 2021-11-09
Filing date: 2022-11-08
Publication date: 2024-04-26
Anticipated expiration: 2042-11-08
Also published as: WO2023083191A1; CN116102557A

Abstract

The invention provides a benzodiazepine compound, a preparation method thereof and application thereof in medicine, and belongs to the field of chemical medicine. The benzodiazepine compound is a compound shown in a formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a eutectic crystal thereof, or a composition thereof. The compound has good intravenous sedation and anesthesia effect, the anesthesia effect is equivalent to that of Rayleigh Malun and even better than that of Rayleigh Malun, and the effective dose is obviously reduced, and the duration and recovery time are obviously reduced. Meanwhile, in a rat tail vein anesthesia model, compared with a rui Malun awakening quality, the compound provided by the invention is obviously improved. The compound has the advantages of quick response, short duration, quick recovery and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has good application prospect.

Description

Benzodiazepine compound, preparation method and medical application thereof

Technical Field

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

Background

Midazolam is the most commonly used benzodiazepine drug and has better safety and mainly acts by binding to the central gamma-aminobutyric acid (GABAA) receptor. Has rapid onset of action, has effect in lowering intracranial pressure and cerebral metabolism, and is commonly used for administration before anesthesia, induction and maintenance of general anesthesia, auxiliary administration during intraspinal anesthesia and local anesthesia, diagnosis or therapeutic operation such as angiocardiography, cardioversion, bronchoscopy, gastrointestinal endoscopy, etc., and ICU patient sedation. However, since the metabolism depends on the liver and kidney, long-time continuous infusion causes accumulation of the drug in the body, adverse reactions such as excessive sedation, respiratory cycle inhibition, drug tolerance and the like usually occur, and the drug cannot be used for a long time for patients with liver and kidney dysfunction.

The parent structure of Rayleigh Malun (Remimazolam) is midazolam, an ultra-short acting intravenous benzodiazepine sedative/anesthetic, which acts on GABA receptors, especially GABA-alpha. The drug combines the safety of midazolam and the effectiveness of propofol, remimazolam is rapidly metabolized into inactive metabolites by tissue esterase and is not metabolized by cytochrome dependent liver pathways in human body, and the drug is an ultra-short-acting benzodiazepine drug which is used as a general intravenous anesthetic drug and has the characteristics of quick effect, short duration, quick awakening and good tolerance. Rayleigh Malun is used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has certain advantages when being applied to patients with cardiovascular diseases, respiratory diseases, liver diseases and the elderly compared with other products.

However, the related report contains Malun which has lower potency than other sedative drugs, and the clinical application needs to increase the dosage and the potential toxicity; meanwhile, the free alkali structure of the rui Malun is unstable, the byproducts have considerable toxicity, and the activity of in-vivo drug metabolizing enzyme can be further influenced, so that the problems of higher blood concentration, drug accumulation and the like during continuous administration are caused. Therefore, development of novel ultra-short-acting sedative and anesthetic drugs with better safety and higher potency is expected.

Disclosure of Invention

The invention aims to provide a benzodiazepine compound, a preparation method thereof and application thereof in medicine.

The invention provides a compound shown in a formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a eutectic crystal thereof, or a composition thereof:

wherein,

Each R ₁ is independently selected from hydrogen, a short chain hydrocarbyl, a C _3-10 cycloalkyl, or a 3-to 10-membered heterocyclic group, said short chain hydrocarbyl, cycloalkyl, or heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, or alkoxy, and said heterocyclic ring including 1-3 heteroatoms selected from N, O, or S, preferably R ₁ is short chain hydrocarbyl or hydrogen;

Each R ₂ is independently selected from hydrogen, a short chain hydrocarbyl, a C _3-10 cycloalkyl, or a 3-to 10-membered heterocyclic group, said short chain hydrocarbyl, cycloalkyl, or heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, or alkoxy, and said heterocyclic ring including 1-3 heteroatoms selected from N, O, or S, preferably R ₂ is hydrogen or short chain hydrocarbyl;

Or R ₁ and R ₂ on the same carbon atom respectively form C _3-10 cycloalkyl or 3-10 membered heterocyclic group, wherein the cycloalkyl or heterocyclic group is substituted by 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl or alkoxy, and the heterocyclic ring comprises 1-3 hetero atoms selected from N, O or S;

m is selected from integers of 0 to 6;

m ₁ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy;

M ₂ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy;

m ₃ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy, said NH being substituted with a short chain hydrocarbyl group;

R ₃ is selected from hydrogen, short chain hydrocarbyl, C _1-8 alkoxy, -C (O) -M ₄-R₅、C_3-10 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl, including 1-3 heteroatoms selected from N, O, or S;

M ₄ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy;

R ₅ is selected from short chain hydrocarbyl or C _1-8 alkoxy;

a is selected from integers of 0 to 6;

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

X is 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 from 1 to 4;

When M ₁ is absent, 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-R₅、M₄ is O, R ₅ is not selected from short chain hydrocarbyl;

When M ₁ is absent, 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-R₅、M₄ is absent, R ₅ is not selected from C _1-8 alkoxy;

when M ₁ is absent, a is 1, M ₂ is O, M ₃ is absent, M is 1-5, R ₃ is-C (O) -M ₄-R₅、M₄ is O, R ₅ is not selected from short chain hydrocarbyl groups;

When M ₁ is absent, a is 1, M ₂ is O, M ₃ is absent, M is 1-5, R ₃ is-C (O) -M ₄-R₅、M₄ is absent, R ₅ is not selected from C _1-8 alkoxy.

Further, the method comprises the steps of,

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-to 10-membered heterocyclyl; or R ₁ and R ₂ on the same carbon atom respectively form a substituted or unsubstituted C _3-10 cycloalkyl group and a substituted or unsubstituted 3-10 membered heterocyclic group; the number of the substituents of the substituted alkyl, the substituted cycloalkyl or the substituted heterocyclic group is 1,2, 3 or4, and the substituents of the substituted alkyl, the substituted cycloalkyl or the substituted heterocyclic group are selected from halogen, trifluoromethyl, cyano, nitro, C _1-8 alkyl and C _1-8 alkoxy; the hetero atom of the heterocyclic group is N, O, S, and the number of the hetero atom is 1,2 or 3;

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

M ₃ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy, said NH being substituted with C _1-8 alkyl;

R ₃ is selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy, -C (O) -M ₄-R₅、C_3-10 cycloalkyl, 6-to 10-membered aryl or 5-to 10-membered heteroaryl, wherein the heteroaryl comprises 1-3 heteroatoms selected from N, O, or S;

R ₅ 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 2,3 and 4 positions;

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

When M ₁ is absent, 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-R₅、M₄ is O, R ₅ is not selected from C _1-8 alkyl;

When M ₁ is absent, a is 1, M ₂ is O, M ₃ is absent, M is 1-5, R ₃ is-C (O) -M ₄-R₅、M₄ is O, R ₅ is not selected from C _1～8 alkyl;

Further, the method comprises the steps of,

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 ₃ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy, said NH being substituted with C _1-4 alkyl;

R ₃ is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, -C (O) -M ₄-R₅、C_3-6 cycloalkyl, phenyl, thienyl, pyridinyl, imidazolyl;

r ₅ 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 absent, 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-R₅、M₄ is O, R ₅ is not selected from C _1-4 alkyl;

When M ₁ is absent, 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-R₅、M₄ is absent, R ₅ is not selected from C _1-4 alkoxy;

When M ₁ is absent, a is 1, M ₂ is O, M ₃ is absent, M is 1-5, R ₃ is-C (O) -M ₄-R₅、M₄ is O, R ₅ is not selected from C _1-4 alkyl;

When M ₁ is absent, a is 1, M ₂ is O, M ₃ is absent, M is 1-5, R ₃ is-C (O) -M ₄-R₅、M₄ is absent, R ₅ is not selected from C _1-4 alkoxy;

preferably, the method comprises the steps of,

X is independently selected from-F, -Cl, -Br, -CH ₃、-OCH₃、-CF₃、-OCF₃.

Further, the compound is represented by formula II:

wherein,

m is selected from integers of 1 to 5;

m ₂ is selected from O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, C _1-6 alkoxy;

M ₃ is selected from O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, C _1-6 alkoxy;

R ₅ is selected from short chain hydrocarbyl;

a is selected from integers of 0 to 6;

n is an integer 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, M ₂ is O, M ₃ is absent, and M is 1 to 5, M ₄ is not O.

Further, the method comprises the steps of,

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;

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

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

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by the formula II-a:

wherein,

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;

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

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

When a is 1 and M is 1, M ₄ is not O.

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by the formula II-b:

wherein,

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;

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

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

when a is 1 and M1 is 0, M ₄ is not O.

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by the formula II-c:

wherein,

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, the method comprises the steps of,

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 represented by formula III:

wherein,

m is selected from integers of 0 to 6;

M ₁ is selected from O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, C _1-6 alkoxy;

M ₃ is selected from the group consisting of no or O, S, NH or C _1-5 alkylene, said alkylene being substituted with 0 to 4 substituents selected from the group consisting of halogen, trifluoromethyl, C _1-6 alkoxy;

R ₅ is selected from short chain hydrocarbyl;

a is selected from integers of 0 to 6;

n is an integer from 1 to 4.

Further, the method comprises the steps of,

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;

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

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

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by formula III-a:

wherein,

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;

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

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

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by the formula III-b:

wherein,

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, the method comprises the steps of,

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 represented by formula IV:

wherein,

m is selected from integers of 0 to 6;

R ₅ is selected from short chain hydrocarbyl;

a is selected from integers of 0 to 6;

n is an integer from 1 to 4.

Further, the method comprises the steps of,

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;

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

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

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by formula IV-a:

wherein,

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;

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

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

Further, the method comprises the steps of,

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, the method comprises the steps of,

Further, the compound is represented by formula IV-b:

wherein,

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, the method comprises the steps of,

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 represented by formula V-a:

wherein,

R ₃ is selected from C _1-8 alkyl;

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

Further, the compound is represented by formula V-b:

wherein,

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 invention also provides the use of the aforementioned compounds, or salts thereof, or stereoisomers thereof, or solvates thereof, or co-crystals thereof, or compositions thereof, for the preparation of sedatives and/or anesthetics;

Preferably, the sedative and/or anesthetic is a sedative and/or anesthetic administered intravenously.

The invention also provides a medicine, which is a preparation prepared by taking the compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a eutectic thereof, or a composition thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients;

preferably, the medicament is a sedative and/or anesthetic;

more preferably, the sedative and/or anesthetic is a sedative and/or anesthetic administered intravenously.

In the invention, the room temperature is 25+/-5 ℃ and the overnight time is 12+/-2 hours.

The compounds and derivatives provided in the present invention are named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.

"Substituted" in the context of the present invention means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

In the present invention, the minimum and maximum values of the carbon atom content of the hydrocarbon group are indicated by a prefix, for example, a C _a～b alkyl group indicates any alkyl group having from "a" to "b" carbon atoms. Thus, for example, C _1～10 alkyl refers to straight or branched chain alkyl groups containing from 1 to 10 carbon atoms; c _1～10 alkoxy means an alkoxy group containing 1 to 10 carbon atoms.

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

In the present invention, C _3～10 cycloalkyl means saturated cycloalkyl, which is composed of 3 to 10 carbon atoms.

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

Aryl in the context of the present invention means aromatic unsaturated groups containing no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems), such as phenyl, anthracyl, 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 the hetero atom refers to nitrogen atom, oxygen atom and sulfur atom. Such as thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, and the like.

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

The compound has good intravenous sedation and anesthesia effect, the anesthesia effect is equivalent to that of Rayleigh Malun and even better than that of Rayleigh Malun, and the effective dose is obviously reduced, and the duration and recovery time are obviously reduced. Meanwhile, compared with the rui Malun, the compound obviously reduces the occurrence of side effects in a rat and mouse tail vein anesthesia model, and the awakening quality is obviously improved. The compound has the advantages of quick response, short duration, quick recovery, low toxicity and good tolerance when being used for anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has good application prospect.

It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.

Detailed Description

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

Example 1

500Mg (1.18 mmol,1 eq) of 3- ((4S) -8-bromo-6- (4, 5-dihydropyridin-2-yl) -1-methyl-4H-benzo [ f ] imidazo [1,2-a ] [1,4] diaza-4-yl) propionic acid are dissolved in 10mL of DMF, 367.2mg (1.76 mmol,1.5 eq) of bromomethyl acetate and 325mg (2.36 mmol,2 eq) of potassium carbonate are added and stirred at room temperature for 5 hours. And (3) spotting the plate, wherein the raw materials are basically reacted completely. The reaction solution was filtered, washed with 50mL of water, extracted with 100mL of methylene chloride, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, concentrated under reduced pressure, and subjected to column chromatography to obtain 500mg of pale yellow oily substance.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 (1.18 mmol,1 eq) of 3- ((4S) -8-bromo-6- (4, 5-dihydropyridin-2-yl) -1-methyl-4H-benzo [ f ] imidazo [1,2-a ] [1,4] diaza-4-yl) propionic acid are dissolved in 10mL of DMF, 367.2mg (1.76 mmol,1.5 eq) of 2-bromoethyl acetate and 325mg (2.36 mmol,2 eq) of potassium carbonate are added and stirred at room temperature for 5 hours. And (3) spotting the plate, wherein the raw materials are basically reacted completely. The reaction solution was filtered, washed with 50mL of water, extracted with 100mL of methylene chloride, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, concentrated under reduced pressure, and subjected to column chromatography to obtain 550mg of a pale yellow oily substance.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 (1.18 mmol,1 eq) of 3- ((4S) -8-bromo-6- (4, 5-dihydropyridin-2-yl) -1-methyl-4H-benzo [ f ] imidazo [1,2-a ] [1,4] diaza-4-yl) propionic acid are dissolved in 10mL of DMF, 294.5mg (1.76 mmol,1.5 eq) of acetic acid-1-bromoethyl ester and 325mg (2 eq) of potassium carbonate are added and stirred at room temperature for 5 hours. And (3) spotting the plate, wherein the raw materials are basically reacted completely. The reaction solution was filtered, washed with 50mL of water, extracted with 100mL of methylene chloride, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, concentrated under reduced pressure, and subjected to column chromatography to obtain 530mg of pale green oily substance.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

3G (25.86 mmol,1 eq) of Compound 1 were dissolved in 40ml acetonitrile, 5.31g (31.03 mmol,1.2 eq) of benzyl bromide, 7.14g (51.72 mmol,2 eq) of potassium carbonate were added, mixed well, heated under reflux overnight at 90℃and the plates (PE/EA=3:1) were spotted, after the basic reaction of the starting materials was complete, the mixture was dried by filtration and passed through a column with ethyl petroleum ether acetate (0% -10%) to give Compound 2.6 g in 67.54% yield.

3.2G of compound 2 was dissolved in 40ml of anhydrous tetrahydrofuran, 12.5ml of a 2.5M solution of lithium aluminum hydride tetrahydrofuran was added dropwise at 0℃under the protection of nitrogen gas, reacted overnight at normal temperature, and after completion of the reaction, 1.2ml of water, 1.2ml of a 15% sodium hydroxide solution, 3.6ml of water were added dropwise in this order at 0℃to quench lithium aluminum hydride, stirred for 20 minutes, dried over anhydrous sodium sulfate, filtered and dried by spin-drying, and column-packed with ethyl petroleum ether acetate (0% -15%) to give 3.9 g of compound in 61.29% yield.

500Mg (2.8 mmol,1 eq) of Compound 3 are dissolved in 15mL of dichloromethane, 20mg (0.16 mmol,0.05 eq) DMAP are added, 0.53mL of acetic anhydride are added dropwise, the reaction is carried out at room temperature for 5h, the reaction is carried out on a spot plate (PE/EA=5:1), the starting material is dried by spin-drying after the basic reaction, and the mixture is passed through a column with petroleum ether ethyl acetate (0% -8%) to give Compound 4 576mg in 93.35% yield.

500Mg of compound 4 is dissolved in 20ml of ethyl acetate, 50mg of 10% palladium carbon is added, hydrogen is reacted at normal temperature overnight, the reaction is performed by spotting a plate, after the raw material is basically reduced, the filtration and the low-temperature concentration are performed to obtain compound 5, and the compound 5 is directly thrown into the next reaction.

200Mg (0.47 mmol,1 eq) of compound 10 was dissolved in 10ml of dichloromethane, 124mg (2 eq) of compound 5,135mg (1.5 eq) of DCC,5.6mg (0.1 eq) of DMAP were added, mixed well, reacted at room temperature for 5h, spotted plates (DCM/MeOH=15:1), after the basic reaction of the starting materials was completed, the mixture was dried by filtration and passed through a column with petroleum ether ethyl acetate (10% -70%) to give 170mg of compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

500Mg (2.8 mmol,1 eq) of Compound 3 was dissolved in 30ml of dichloromethane, 777. Mu.l (2 eq) of triethylamine was added, 519.7mg (2 eq, dissolved first in DCM) of propionyl chloride was added dropwise under ice bath, reacted for 5h at room temperature, spotted on a plate, after the starting material had substantially reacted, washed with water 1-2 times, dried, filtered and spun dry, and passed through a column with petroleum ether ethyl acetate (0% -8%) to give Compound 6, 630mg, 95.7% yield.

500Mg of compound 6 is dissolved in 20ml of ethyl acetate, 50mg of 10% palladium carbon is added, hydrogen is reacted at normal temperature overnight, the reaction is performed by spotting a plate, after the raw materials are basically reduced, the filtration and spin drying are performed to obtain compound 7, and the compound 7 is directly put into the next reaction.

200Mg (0.47 mmol,1 eq) of compound 10 was dissolved in 10ml of methylene chloride, 100mg (1.5 eq) of compound 7,143mg (1.5 eq) of DCC,6mg (0.1 eq) of DMAP were added, and the mixture was uniformly mixed, reacted at room temperature for 5 hours, spotted, and after the raw materials were substantially reacted completely, the mixture was dried by filtration and passed through a column with petroleum ether ethyl acetate (10% -70%) to obtain 160mg of compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

1G (1 eq) of the derivative Malun is dissolved in 20mL of tetrahydrofuran solution, 1.6mL of 1M/L lithium aluminum hydride tetrahydrofuran solution (0.7 eq) is added under the condition of-20 ℃, water (1 eq) and 15% NaOH (4 eq) aqueous solution are sequentially added after stirring for reaction for 2 hours, quenching reaction is carried out, intermediate 1-2 is purified by a chromatographic column, and 300mg of intermediate 1-2 (1 eq) and 134mg of n-propyl chloroformate (1.5 eq) are taken to react for 5 hours in pyridine (2 eq) and dichloromethane, so that the compound is obtained.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Methanol-d₄)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

1G (1 eq) of the derivative Malun is dissolved in 20mL of tetrahydrofuran solution, 1.6mL of 1M/L lithium aluminum hydride tetrahydrofuran solution (0.7 eq) is added under the condition of-20 ℃, water (1 eq) and 15% NaOH (4 eq) aqueous solution are sequentially added after stirring for reaction for 2 hours, quenching reaction is carried out, intermediate 1-2 is purified by a chromatographic column, and 300mg of intermediate 1-2 (1 eq) and 134mg of isopropyl chloroformate (1.5 eq) are taken to react in pyridine (2 eq) and dichloromethane for 5 hours to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Methanol-d₄)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

1G (1 eq) of the derivative Malun is dissolved in 20mL of tetrahydrofuran solution, 1.6mL of 1M/L lithium aluminum hydride tetrahydrofuran solution (0.7 eq) is added at the temperature of minus 20 ℃, water (1 eq) and 15% NaOH (4 eq) aqueous solution are added in sequence after stirring for reaction for 2 hours to quench the reaction, then a chromatographic column is used for purifying the reaction product to obtain an intermediate 1-2, and 300mg of the intermediate 1-2 (1 eq) and 150mg of isobutyl chloroformate (1.5 eq) are taken to react in pyridine (2 eq) and dichloromethane for 5 hours to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

300Mg of intermediate 1-2 (1 eq) and 150mg of chloroethyl chloroformate (1.5 eq) are taken and added with pyridine (1.5 eq) to react for 5 hours in methylene dichloride, and then the intermediate 1-3 is obtained after washing and drying with acid water, and then the compound is obtained after reacting with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added into the system, extraction is carried out with ethyl acetate, washing is carried out for 2 times again, organic phases are combined, and the compound is obtained after drying and column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.50(ddd,J＝4.8,1.7,0.8Hz,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＝12.2,2.7Hz,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

300Mg of intermediate 1-2 (1 eq) and chloromethyl chloroformate (1.5 eq) are taken, pyridine (1.5 eq) is added to react for 5 hours in methylene dichloride, acid water is used for washing and drying to obtain intermediate 1-4, then the intermediate 1-4 reacts with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added to the system, extraction is carried out by ethyl acetate, water is used for washing for 2 times, organic phases are combined, and the compound is obtained through column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

300Mg of intermediate 1-2 (1 eq) and chloroethyl chloroformate (1.5 eq) are taken, pyridine (1.5 eq) is added to react for 5 hours in methylene dichloride, acid water is used for washing and drying to obtain intermediate 1-5, then the intermediate 1-5 reacts with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added to the system, extraction is carried out by ethyl acetate, water is used for 2 times, organic phases are combined, and the compound is obtained through column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.7Hz,1H),8.13–8.07(m,1H),7.73(td,J＝7.8,1.7Hz,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＝11.5,1.1Hz,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

300Mg of intermediate 1-2 (1 eq) and 58mg of acetic acid (2 eq) were taken and reacted with K ₂CO₃ (3 eq) in DMF for 5h, ice water was added to the system, extraction was performed with ethyl acetate, washing with water was performed for 2 times, the organic phases were combined, dried and column chromatography was performed to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.51(ddd,J＝4.8,1.6,0.8Hz,1H),8.10(d,J＝7.9Hz,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

300Mg of intermediate 1-2 (1 eq) and 63mg of cyclopropylformic acid (2 eq) are taken and reacted with K ₂CO₃ (3 eq) under stirring at DMF normal temperature for 5h, ice water is added into the system, extraction is carried out with ethyl acetate, washing is carried out for 2 times, the organic phases are combined, dried and subjected to column chromatography to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.51(ddd,J＝4.8,1.6,0.8Hz,1H),8.11(d,J＝7.9Hz,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

300Mg of intermediate 1-2 (1 eq) and 62mg of isobutyric acid (2 eq), K ₂CO₃ (3 eq) were taken and reacted with DMF for 5h, ice water was added to the system, extraction was performed with ethyl acetate, washing with water was performed for 2 times, the organic phases were combined, dried and column chromatography was performed to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.3Hz,1H),8.13–8.08(m,1H),7.73(td,J＝7.7,1.4Hz,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

300Mg of intermediate 1-2 (1 eq) and 71mg of isovaleric acid (2 eq) were taken and reacted with K ₂CO₃ (3 eq) in DMF for 5h, ice water was added to the system, extraction was performed with ethyl acetate, washing with water was performed for 2 times, the organic phases were combined, dried and column chromatography was performed to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

310Mg of intermediate 1-2 (1 eq) and 228mg of bromoacetyl bromide (1.5 eq) are taken to react for 5 hours in methylene dichloride, pyridine (2 eq) is washed and dried by acid water to obtain intermediate 1-6, then the intermediate 1-6 reacts with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added into the system, extraction is carried out by ethyl acetate, the organic phases are combined, and the compound is obtained by column chromatography.

¹H 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

272Mg of intermediate 1-2 (1 eq) was taken and reacted with 214mg of 2-bromopropionyl bromide (1.5 eq) and pyridine (2 eq) in methylene chloride for 5 hours, then the intermediate 1-7 was obtained after washing and drying with acid water, and then reacted with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water was added to the system, extraction was performed with ethyl acetate, washing was performed for 2 times again, the organic phases were combined, dried and column chromatography was performed to obtain the compound.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.50(d,J＝4.3Hz,1H),8.14–8.07(m,1H),7.73(td,J＝7.7,1.4Hz,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

300Mg of intermediate 1-2 (1 eq) is taken to react with 252mg of 2-bromoisobutyryl bromide (1.5 eq) and pyridine (2 eq) in methylene dichloride for 5 hours, then the intermediate 1-8 is obtained after washing and drying with acid water, then the intermediate is reacted with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added into the system, extraction is carried out with ethyl acetate, the organic phases are combined, and the compound is obtained after drying and column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

300Mg of intermediate 1-2 (1 eq) is taken to react with 188mg of 3-bromopropionyl chloride (1.5 eq) and pyridine (2 eq) in methylene dichloride for 5 hours, then the intermediate 1-9 is obtained after washing and drying with acid water, then the intermediate is reacted with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added into the system, extraction is carried out with ethyl acetate, washing is carried out for 2 times again, organic phases are combined, and the compound is obtained after drying and column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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

300Mg of intermediate 1-2 (1 eq) is taken to react with 203mg of 3-bromobutyryl chloride (1.5 eq) and pyridine (2 eq) in methylene dichloride for 5 hours, then the intermediate 1-10 is obtained after washing and drying by acid water, then the intermediate is reacted with acetic acid (1 eq) and K ₂CO₃ (3 eq) in DMF for 6 hours, ice water is added into the system, extraction is carried out by ethyl acetate, the organic phases are combined for 2 times, and the compound is obtained after drying and column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.52–8.49(m,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＝2.3Hz,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

330Mg of intermediate 1-2 (1 eq) and 105mg of malonic acid (2 eq) were taken and added with DCC (1.5 eq) and DMAP (0.1 eq), after reacting for 5h in methylene dichloride, the mixture was filtered and dried to obtain intermediate 1-11 by column chromatography, and after reacting with methanol (1.5 eq) and DCC (1.5 eq) and DMAP (0.1 eq) in methylene dichloride for 6h, the mixture was filtered and dried to obtain the compound by column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.51(ddd,J＝4.8,1.7,0.8Hz,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).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

410Mg of intermediate 1-2 (1 eq) and 235.6mg of succinic acid (2 eq) are taken, DCC (1.5 eq) and DMAP (0.1 eq) are added, after reaction for 5h in dichloromethane, filtration and drying are carried out, thus obtaining intermediate 1-12 through column chromatography, after reaction with methanol (1.5 eq), DCC (1.5 eq) and DMAP (0.1 eq) in dichloromethane for 6h, filtration and drying are carried out, thus obtaining the compound through column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 was carried out in the same manner as in example 3 except that 500mg (1.18 mmol,1 eq) of 3- ((4S) -8-bromo-6- (4, 5-dihydropyridin-2-yl) -1-methyl-4H-benzo [ f ] imidazo [1,2-a ] [1,4] diazepin-4-yl) propionic acid was dissolved in 10mL of DMF, 320.5mg (1.76 mmol,1.5 eq) of acetic acid-1-bromopropyl ester and 325mg (2 eq) of potassium carbonate were added and stirred at room temperature for 5 hours. And (3) spotting the plate, wherein the raw materials are basically reacted completely. The reaction solution was filtered, washed with 50mL of water, extracted with 100mL of methylene chloride, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain a filtrate, concentrated under reduced pressure, and subjected to column chromatography to obtain 530mg of pale green oily substance.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Methanol-d₄)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

300Mg of intermediate 1-2 (1 eq) is taken, 136.5mg (2 eq) of propionyl chloride is added, and then stirred in methylene dichloride under ice bath, 115mg (2 eq) of pyridine is added dropwise, after the completion of the dropwise addition, the reaction is carried out at room temperature for 2h, water with pH of about 5 is used for washing, the organic phases are combined, and the product is obtained through column chromatography.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H NMR(400MHz,Chloroform-d)δ8.57(ddd,J＝4.2,1.6,0.8Hz,1H),8.20(d,J＝6.9Hz,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 was carried out as in example 24.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 was carried out as in example 24.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 was carried out as in example 24.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 was carried out as in example 24.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 was carried out as in example 24.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 was carried out as in example 24.

Nuclear magnetic resonance hydrogen spectrum of the compound ：¹H 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 invention are demonstrated below by specific test examples.

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

In clinical application, the action of anesthetic is required to be strictly controlled, so that the smooth operation, diagnosis and other processes are ensured, and anesthesia can be terminated as soon as possible after the operation is finished, so that a patient can wake up quickly. If the anesthesia is too long, it may cause some adverse effects on the cardiovascular system and respiratory system, such as sleepiness, dizziness, etc. Therefore, the ideal anesthetic should have the advantages of quick effect, quick recovery, high safety and the like.

Test example 1 pharmacodynamics study of Rayleigh Malun derivative in mice

1. Test method

The half-dose effective for anesthesia (ED ₅₀) of the compounds was determined by a single tail vein administration using sequential methods (Dixon-Mood Method) and mice were tested for loss of orthostatic reflection (Loss of righting reflex, LORR).

ED ₅₀ assay: male Kunming mice (25-30 g) were randomly selected and the compound was treated with PEG-400: pure water (3:7) was formulated to give a dosing volume of 0.2mL, and three additional doses were set in an equal ratio series between the highest and lowest doses according to pre-experimental results. Mice were observed for loss of everlasting reflection from the start of the intermediate dose (tail vein bolus time of about 10 s). If the first mouse shows positive after the duration of the specular reflection disappearance is more than 30 seconds, the second mouse is given one dose lower; if the duration of the disappearance of the specular reflection of the first mouse is less than 30 seconds or the specular reflection of the first mouse is not disappeared, the second mouse is given one dose higher; the experiment was repeated until 8 cycle crossings of positive-negative or negative-positive occurred to end the experiment.

2. Test results

The test results are shown in Table 1

TABLE 1 pharmacodynamic study results of the respective Compounds

In table 1, the anesthesia duration is the time from disappearance of the specular reflection to recovery of the specular reflection, and the recovery quality is the time from recovery of the specular reflection to free crawling; the wakeup quality "+" indicates < 1min, "++" indicates between greater than or equal to 1min and less than 3min, "+++" means greater than or equal to between 3min and less than 5min, "+++" means greater than or equal to between 5min and less than 10min, for 5min to less than between 10 minutes of the time of the preparation.

From the above test results, it can be seen that: compared with the rui Malun, the compound can reduce the effective administration dosage, has the characteristics of quick response and short recovery time, has higher recovery quality, and has obviously better effect than the rui Malun when being used as an anesthetic.

In conclusion, the compound of the invention has good intravenous sedation and anesthesia effect, and the anesthesia effect is equivalent to that of Rayleigh Malun and even better than that of Rayleigh Malun, and the specific effect shows that the effective dose is obviously reduced, and the duration and recovery time are obviously reduced. Meanwhile, in a rat tail vein anesthesia model, compared with a rui Malun awakening quality, the compound provided by the invention is obviously improved. The compound has the advantages of quick response, short duration, quick recovery and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has good application prospect.

Claims

1. A compound or salt thereof, characterized in that: the compound is shown in a formula III-b:

wherein,

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

m is selected from 1, 2 and 3;

M ₃ is selected from none or from O;

M ₄ is selected from none or from O;

R ₅ is selected from C _1-4 alkyl;

a is selected from 1, 2 and 3.

2. A compound or salt thereof, characterized in that: the compound is shown in a formula IV-b:

wherein,

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

m is selected from 1, 2 and 3;

m ₃ is selected from O;

M ₄ is selected from none;

R ₅ is selected from C _1-4 alkyl;

a is selected from 1, 2 and 3.

3. A compound or salt thereof, characterized in that: the compound is represented by the formula V-a:

wherein,

R ₃ is selected from C _1-8 alkyl;

a is selected from 1, 2 and 3.

4. A compound or salt thereof, characterized in that: the compound is shown as a formula V-b:

wherein,

a is selected from 1, 2 and 3.

5. A compound or salt thereof, characterized in that: the compound is one of the following compounds:

6. use of a compound according to any one of claims 1 to 5 or a salt thereof for the preparation of a sedative and/or anaesthetic.

7. Use according to claim 6, characterized in that: the sedative and/or anesthetic is a sedative and/or anesthetic administered intravenously.

8. A medicament, characterized in that: the medicine is a preparation prepared by taking the compound or the salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials;

the medicament is a sedative and/or anesthetic.

9. A medicament according to claim 8, characterized in that: the sedative and/or anesthetic is a sedative and/or anesthetic administered intravenously.