CN116102558A - A class of novel benzodiazepine compounds, preparation method and use thereof - Google Patents

Abstract

类化合物具有快速起效、作用时间短、深度强、代谢快和苏醒快等特点。在对小鼠和大鼠麻醉实验中，本发明化合物起效时间和瑞马唑仑相当，但作用时间和苏醒时间均显著缩短，且部分化合物作用深度明显加强，具有起效更快、作用时间更短、作用强度更大、代谢更快和苏醒更快等特点，且同时具有较好的心脏安全性；对大鼠的长期输注麻醉实验中，相比于瑞马唑仑，本发明的短效苯二氮

类衍生物的苏醒时间和恢复时间均显著缩短，具有苏醒更快、恢复更快等特点。

The invention discloses a novel compound represented by formula (I), its preparation method and application. Belong to medicinal chemistry field; Benzodiazepine described in the present invention

The compound has the characteristics of rapid onset of action, short action time, strong depth, fast metabolism and quick recovery. In the anesthesia experiment on mice and rats, the onset time of the compound of the present invention is equivalent to that of remimazolam, but the action time and recovery time are significantly shortened, and the depth of action of some compounds is obviously strengthened, with faster onset and longer action time. Shorter, greater action intensity, faster metabolism and faster recovery, and at the same time have better cardiac safety; in the long-term infusion anesthesia experiment on rats, compared with remimazolam, the present invention short-acting benzodiazepines

The awakening time and recovery time of derivatives are significantly shortened, and it has the characteristics of faster awakening and faster recovery.

Description

A novel benzodiazepine compound, preparation method and use thereof

类化合物、其制备方法及其用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。This invention claims the patent application number 202111322521.5 filed with the State Intellectual Property Office of China on November 9, 2021, entitled "A new type of benzodiazepine

The entire text of the prior application is incorporated into the present invention by reference.

Technical Field

衍生物、包含其的药物组合物、包含其的药盒、其制备方法、使用其的镇静和麻醉方法及其在制备镇静和麻醉药物中的用途。The present invention relates to benzodiazepines of formula (I) as short-acting anesthetics

Derivatives, pharmaceutical compositions containing the same, kits containing the same, preparation methods thereof, sedation and anesthesia methods using the same, and uses thereof in preparing sedation and anesthesia drugs.

Background Art

Anesthetic drugs can cause temporary and reversible loss of consciousness and pain sensation in the body or local parts of the body, helping patients reduce pain and other uncomfortable symptoms. They are essential auxiliary drugs in clinical surgery.

类衍生物(benzodiazepines)是GABA_A受体(又称作γ-氨基丁酸A型受体)激活剂。GABA_A受体是氯离子通道的门控受体，由两个α和两个β亚单位(α2β2)构成氯离子通道。β亚单位上有GABA受点，当GABA与之结合时，氯离子通道开放，使得氯离子内流，从而使神经细胞超极化，产生抑制效应。在α亚单位上则有苯并二氮

受体，当苯并二氮

与之结合时，能够通过促进GABA与GABAA受体的结合而使氯离子通道开放的频率增加(而不是使氯离子通道开放时间延长或使氯离子流增大)，从而使更多的氯离子内流。这使得苯并二氮

类衍生物能够增强GABA神经传递功能和突触抑制效应，从而在临床实践中发挥诱导麻醉、催眠、抗焦虑、及减轻中枢神经系统病变或癫痫引发的痉挛等多种疗效。Benzodiazepines

Derivatives of the benzodiazepine class are GABA _A receptor (also known as γ-aminobutyric acid type A receptor) activators. GABA _A receptors are gated receptors for chloride channels, which are composed of two α and two β subunits (α2β2). There are GABA receptor sites on the β subunits. When GABA binds to them, the chloride channel opens, allowing chloride ions to flow in, thereby hyperpolarizing the nerve cells and producing an inhibitory effect. There are benzodiazepines on the α subunits.

receptors, when benzodiazepines

When combined with it, it can increase the frequency of chloride channel opening by promoting the binding of GABA to GABAA receptors (rather than prolonging the opening time of chloride channels or increasing the chloride ion flow), thereby allowing more chloride ions to flow in. This makes benzodiazepines

Derivatives of this type can enhance the neurotransmission function and synaptic inhibition effect of GABA, thereby playing a variety of therapeutic effects in clinical practice, such as inducing anesthesia, hypnosis, anti-anxiety, and alleviating spasms caused by central nervous system lesions or epilepsy.

类药物最为近年来发展迅速的一类镇静麻醉药物，具有良好的遗忘、抗焦虑和镇静等药效，因此被广泛用于镇静麻醉领域。第一个苯并二氮

类药物氯氮

(利眠宁)于1960年面市。此后，不断有新型苯并二氮

类药物涌现：包括超短效(瑞马唑仑)、短效(三唑仑/咪达唑仑)、中效(劳拉西泮/艾司唑仑)和长效(地西泮)等。临床常用的苯并二氮

类衍生物有20余种，虽结构相似，但不同衍生物之间在临床上的适应症则各不相同。原因在于，GABA与GABA受体的结合部位和作用呈现不均一性，不同神经的GABA门控氯通道是由不同种类的亚单位构成，不同的亚单位的组成可导致这些通道和别构调节剂的相互作用发生细微变化，产生不同的镇静麻醉效应。咪达唑仑在20世纪80年代初作为第一个具有水溶性的苯并二氮

类化合物被引入市场中，并作为静脉注射剂为短期手术或重症监护室提供镇静麻醉手段。然而，咪达唑仑会产生有活性的体内代谢产物，从而导致患者从咪达唑仑诱导的镇静麻醉的状态恢复清醒需要较长时间。另外由于咪达唑仑的代谢依赖于肝酶细胞色素P₄₅₀3A4，肝功能受损的患者给药后，则可能会产生药物间相互作用的问题。瑞马唑仑于2019年12月被批准作为新型超短效的GABA_A受体激动剂上市，是在苯并二氮

母核结构上引入一个可以快速代谢的丙酸甲酯侧链。由于其丙酸甲酯侧链可以被酯酶快速代谢，且主要代谢产物唑仑丙酸几乎无镇静麻醉活性，因此药效维持时间很短，属于超短效苯并二氮

类药物。但其长时间输注仍会产生苏醒延迟和药物蓄积等问题，目前仅被批准用于胃镜检查的镇静和全麻手术。Benzodiazepines

Benzodiazepines are a type of sedative and anesthetic drugs that have developed rapidly in recent years. They have good amnesia, anti-anxiety and sedative effects, so they are widely used in the field of sedation and anesthesia.

Chlordiazepoxide

(Chlordiazepoxide) was launched in 1960. Since then, new benzodiazepines have been introduced.

The emergence of new drugs: including ultra-short-acting (remimazolam), short-acting (triazolam/midazolam), medium-acting (lorazepam/estazolam) and long-acting (diazepam).

There are more than 20 derivatives of this type. Although they have similar structures, the clinical indications of different derivatives are different. The reason is that the binding sites and actions of GABA and GABA receptors are heterogeneous. The GABA-gated chloride channels of different nerves are composed of different types of subunits. The different subunit compositions can lead to subtle changes in the interaction between these channels and allosteric modulators, resulting in different sedative and anesthetic effects. Midazolam was introduced in the early 1980s as the first water-soluble benzodiazepine.

Compounds of this type were introduced into the market and used as intravenous injections to provide sedation and anesthesia for short-term surgery or intensive care units. However, midazolam produces active metabolites in the body, which can cause patients to take a long time to recover from midazolam-induced sedation and anesthesia. In addition, since the metabolism of midazolam depends on the liver enzyme cytochrome P ₄₅₀ 3A4, drug interactions may occur after administration to patients with impaired liver function. Remimazolam was approved for marketing as a new ultra-short-acting GABA _A receptor agonist in December 2019. It is a benzodiazepine

A methyl propionate side chain that can be rapidly metabolized is introduced into the core structure. Since the methyl propionate side chain can be rapidly metabolized by esterases and the main metabolite, zolam propionate, has almost no sedative and anesthetic activity, the drug effect lasts for a very short time, and it is an ultra-short-acting benzodiazepine.

However, its long-term infusion will still cause problems such as delayed awakening and drug accumulation. It is currently only approved for sedation and general anesthesia for gastroscopy.

类麻醉药物使用时常伴随依赖性成瘾性，且其中大多药物代谢产物仍具有一定药效从而无法使患者迅速恢复常态，长期使用易导致药物蓄积作用，阻碍了其进一步发展。因此开发起效快、恢复时间短、无蓄积作用的苯并二氮

类药物是亟待解决的问题。In summary, benzodiazepines

The use of anesthetic drugs is often accompanied by dependence and addiction, and most of the drug metabolites still have a certain efficacy, so patients cannot quickly return to normal. Long-term use can easily lead to drug accumulation, which hinders its further development. Therefore, it is necessary to develop benzodiazepines with fast onset, short recovery time and no accumulation.

Drugs are an urgent problem to be solved.

Summary of the invention

类化合物、其制备方法及其用途。In order to improve the above problems, the present invention provides a new type of benzodiazepine

Compounds, preparation methods and uses thereof.

类化合物，其药学上可药用的盐、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物或前药：The present invention provides a benzodiazepine represented by formula (I)

Compounds of the type described herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs thereof:

_R1 is selected from _C1-6 alkyl, _C1-6 alkyl substituted by 3-8 membered heterocyclyl, _C1-6 alkyl substituted by 3-8 membered cycloalkyl, _C1-6 alkyl substituted by _C6-14 aryl, _C1-6 alkyl substituted by 5-14 membered heteroaryl;

R ₂ is selected from C _1-6 alkyl, halogen;

R ₃ is selected from H, C _1-6 alkyl, halogen; R ₃ is preferably attached at the 2-position or the 6-position;

_R4 is selected from H, _C1-6 alkyl, C(O), 5-14 heteroaryl, _C6-14 aryl, which is unsubstituted or optionally substituted by one, two or more R _a ; each R _a is the same or different and is independently selected from _C1-6 alkyl, _C3-8 cycloalkyl, oxo (=O), NR _a1 R _a2 , 3-8 heterocyclyl, 5-8 heteroaryl; R _a1 and R _a1 are the same or different and are independently selected from _C1-6 alkyl; each R _{b is} the same or different and is independently selected from OH, _C1-6 alkyl, halogen; those skilled in the art should understand that when _R4 is hydrogen, -SH can resonate with the connected triazole ring to form a =S structure;

X is selected from CH or N. When X is CH, R ₃ may be attached to X.

According to an embodiment of the present invention, R ₁ may be selected from C _1-3 alkyl, C _1-3 alkyl substituted by a 6-membered heterocyclic group;

_R2 may be selected from halogen;

R ₃ can be selected from H, halogen;

_R4 can be selected from H, _C1-3 alkyl, C(O), 5-6 membered heteroaryl, unsubstituted or optionally substituted by one, two or more R _a ; each R _a can be the same or different and are independently selected from _C1-3 alkyl, _C3-6 cycloalkyl, oxo (=O), NR _a1 R _a2 , 5-6 membered heterocyclyl, 5-6 membered heteroaryl; R _a1 and R _a1 can be the same or different and are independently selected from C _{1-3 alkyl} ; each R _b can be the same or different and are independently selected from OH, C _1-3 alkyl, halogen.

According to an embodiment of the present invention, _R1 can be selected from methyl,

R ₂ can be selected from Cl, Br;

R ₃ can be selected from H, F, Cl;

R ₄ can be selected from H, methyl, ethyl, propyl, C(O), N-methylimidazolyl, which are unsubstituted or optionally substituted by one, two or more _Ra ; each _Ra can be the same or different and are independently selected from cyclopropyl, _oxo (=O), morpholinyl, dimethylamino, diethylamino, methyl(ethyl)amino, pyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, 4,5-dihydro-1H-imidazolyl; each R _b can be the same or different and are independently selected from OH, F, methyl.

According to an embodiment of the present invention, _R4 can be selected from the following structures: H, methyl, ethyl,

According to an embodiment of the present invention, the compound represented by formula (I) can be selected from the structure represented by formula (II) or formula (III):

Wherein, R ₁ , R ₂ , R ₃ , R ₄ and X have the same meanings as described above.

According to an embodiment of the present invention, the compound is selected from:

-4-基)丙酸甲酯(化合物1)、(S) 3-(8-Bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 1),

-4-基)丙酸甲酯(化合物2)、(S) 3-(8-Bromo-6-(pyridin-2-yl)-1-ethylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 2),

-4-基)丙酸甲酯(化合物3)、(S) 3-(8-Bromo-6-(pyridin-2-yl)-1-((cyclopropylmethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 3),

-4-基)丙酸甲酯(化合物4)、(S) 3-(8-Bromo-6-(pyridin-2-yl)-1-((2-morpholinoethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl) methyl propionate (Compound 4),

-4-基)丙酸甲酯(化合物5)、(S) 3-(8-Bromo-6-(pyridin-2-yl)-1-(3-((dimethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 5),

-4-基)丙酸甲酯(化合物6)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl) methyl propionate (Compound 6),

-4-基)丙酸甲酯(化合物7)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 7),

-4-基)丙酸甲酯(化合物8)、(S) 3-(8-Bromo-6-(2-chlorophenyl)-1-((2-(pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 8),

-4-基)丙酸甲酯(化合物9)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 9),

-4-基)丙酸甲酯(化合物10)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 10),

-4-基)丙酸甲酯(化合物11)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 11),

-4-基)丙酸甲酯(化合物12)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 12),

-4-基)丙酸甲酯(化合物13)、(S) 3-(8-Bromo-6-(pyridin-2-yl)-1-(((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 13),

-4-基)丙酸甲酯(化合物14)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 14),

-4-基)丙酸甲酯(化合物15)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio))-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 15),

-4-基)丙酸甲酯(化合物16)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-((2-(4-methylpiperazin-1-yl)2-oxoethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 16),

-4-基)丙酸甲酯(化合物17)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 17),

-4-基)丙酸甲酯(化合物18)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio))-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 18),

-4-基)丙酸甲酯(化合物19)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(3-((diethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 19),

-4-基)丙酸甲酯(化合物20)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 20),

-4-基)丙酸甲酯(化合物21)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 21),

-4-基)丙酸甲酯(化合物22)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 22),

-4-基)丙酸甲酯(化合物23)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-methylpiperidin-2-carbonyl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 23),

-4-基)丙酸-2-吗啉乙酯(化合物24)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid 2-morpholinoethyl ester (Compound 24),

-4-基)丙酸甲酯(化合物25)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 25),

-4-基)丙酸甲酯(化合物26)、(S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 26),

-4-基)丙酸甲酯(化合物27)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((1H-pyrrol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 27),

-4-基)丙酸甲酯(化合物28)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl) methyl propionate (Compound 28),

-4-基)丙酸甲酯(化合物29)、(S) 3-(8-Chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 29),

-4-基)丙酸甲酯(化合物30)、(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(3-((dimethylamino)-3-oxopropyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 30),

-4-基)丙酸甲酯(化合物31)。(S) 3-(8-chloro-6-(2-chlorophenyl)-1-(((4,5-dihydro-1H-imidazol-2-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propanoic acid methyl ester (Compound 31).

According to an embodiment of the present invention, the structure of the compound is selected from:

The present invention also provides a method for preparing the compound, comprising the following steps: Compound A reacts with R ₄ X ₁ to obtain a compound represented by formula (I); wherein R ₄ has the definition described above, and X ₁ is selected from halogen;

According to an embodiment of the present invention, the reaction may be carried out under the action of a base, and the base may be an inorganic base, such as at least one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide.

Further, the content or dosage of the compound of the present invention in the pharmaceutical composition can be about 10 mg to about 3000 mg, suitably 25-3000 mg, preferably 60-2700 mg, more preferably 60-1500 mg, particularly preferably 60-1000 mg, for example 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg or 500 mg.

The pharmaceutically acceptable carrier is selected from water, oil and other injectable solvents.

The drug additive used is selected from starch, glucose, lactose, brown sugar, gelatin, maltose, self-made, silica gel, sodium stearate, glyceryl monostearate, talc, sodium oxide, skimmed milk powder, glycerol, propylene glycol, ethanol, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethyl cellulose, gelatin, pectin, albumin, trehalose, dextran;

Further, its pharmaceutically acceptable salt is selected from acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride/oxide, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate , methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate and xinafoate, aluminum, arginine, benzathine penicillin salt, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, sodium, potassium, ammonium, tromethamine, and zinc salts.

Furthermore, the compound or composition is used in the preparation of sedative and anesthetic drugs, including conscious sedation during short-term diagnosis, surgery or endoscopic procedures, induction and maintenance of general anesthesia, and ICU sedation.

Further, a method of sedation and anesthesia comprises administering an effective amount of the compound of any one of claims 1 or the pharmaceutical composition of claim 2 intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.

Further, a pharmaceutical preparation comprising a compound according to any one of claims 1 or a pharmaceutically acceptable salt thereof as an active agent and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to one or more inert, non-toxic solid or liquid fillers, diluents, adjuvants, etc., which do not adversely interact with the active compound or the patient.

Furthermore, the dosage form can be a suspension, emulsion, injection, lyophilized powder injection and other dosage forms commonly used in pharmacy.

Further, the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dosage can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that the dosage value can vary with the type and severity of the condition to be alleviated, and can include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs.

According to an embodiment of the present invention, the pharmaceutical composition also includes one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water, oil and other injectable solvents, including those oils of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.; when the pharmaceutical composition is administered intravenously, water is an exemplary carrier; physiological saline, glucose, glycerol aqueous solution, ethanol, propylene glycol, polyethylene glycol, glycerol can also be used as liquid carriers, particularly for injection or emulsion. Suitable pharmaceutical additives include starch, glucose, lactose, brown sugar, gelatin, maltose, autonomous, silica gel, sodium stearate, monostearate glyceryl ester, talc, sodium oxide, skim milk powder, glycerol, propylene glycol, ethanol, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethyl cellulose, gelatin, pectin, albumin, trehalose, dextran, etc. The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffer.

The pharmaceutical composition of the present invention can be administered by any suitable route. Preferably, the pharmaceutical composition of the present invention is administered by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

Another object of the present invention is to provide a pharmaceutical kit comprising the compound or pharmaceutical composition of the present invention.

Another object of the present invention is to provide a sedation and anesthesia method, which comprises administering, preferably administering an effective amount of the compound or pharmaceutical composition of the present invention by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes. The sedation and anesthesia method is preferably used in the following clinical treatment schemes: preoperative sedation during surgery; conscious sedation during short-term diagnosis, surgery or endoscopic procedures; induction and maintenance of general anesthesia before and/or simultaneously with the administration of other anesthetics and analgesics; ICU sedation, use in the preparation of sedative-hypnotic and anxiolytic drugs, including sedation, hypnosis, anxiolysis and amnesia for early awakening insomnia caused by disorders of the excitation and inhibition of the brain.

Another object of the present invention is to provide a compound of the present invention, which is used as a sedative or anesthetic drug, wherein the sedative or anesthetic method is preferably used for intravenous administration in the following clinical treatment schemes: preoperative sedation during surgery; conscious sedation during short-term diagnosis, surgery or endoscopic procedures; induction and maintenance of general anesthesia before and/or simultaneously with the administration of other anesthetics and analgesics; ICU sedation, and use in the preparation of sedative-hypnotic and antianxiety drugs, including sedation, hypnosis, antianxiety and amnesia for early awakening insomnia caused by disorders of the excitation and inhibition of the brain.

The present invention also provides the use of the compound represented by formula (I), its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug in the preparation of drugs.

According to an embodiment of the present invention, the drug is a sedative or anesthetic drug.

According to an embodiment of the present invention, the sedative and anesthetic drugs are preferably used for intravenous administration in the following clinical treatment schemes: preoperative sedation during surgery; conscious sedation during short-term diagnosis, surgery or endoscopic procedures; induction and maintenance of general anesthesia before and/or simultaneously with the administration of other anesthetics and analgesics; ICU sedation, use in the preparation of sedative-hypnotic and antianxiety drugs, including sedation, hypnosis, antianxiety and amnesia for early awakening insomnia caused by disorders of the excitation and inhibition functions of the brain.

The amount of the compound of the present invention administered will depend on the individual treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg person, this will add up to about 0.007mg/day to about 3500mg/day, for example, about 0.7mg/day to about 700mg/day. In some cases, the dosage level lower than the lower limit of the aforementioned range may be sufficient, and in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

Beneficial Effects

类衍生物具有快速起效、作用时间短、深度强、代谢快和苏醒快等特点。在对小鼠和大鼠麻醉实验中，本发明的短效苯并二氮

类衍生物起效时间和瑞马唑仑相当，但作用时间和苏醒时间均显著缩短，且部分化合物作用深度明显加强，具有起效更快、作用时间更短、作用强度更大、代谢更快和苏醒更快等特点；对大鼠的长期输注麻醉实验中，相比于瑞马唑仑，本发明的短效苯二氮

类衍生物的苏醒时间和恢复时间均显著缩短，具有苏醒更快、恢复更快等特点；本发明的苯并二氮

类化合物不但保持对GABA_A受体的高亲和力和选择性，而且通过对苯并二氮

的结构修饰和对羧酸酯基团的调整而具有以下优点：达到镇静麻醉的可预测的快速发作时间、有效作用时间短、作用深度强、苏醒时间短，从而降低对心血管和呼吸系统的不良抑制反应，以及减少给病人神经系统造成的副作用，包括嗜睡、头晕等问题，而且本发明的化合物表现出较好的心脏安全性，对心脏的毒性更小，且对肝脏代谢影响小，具有更广泛的成药前景。The short-acting benzodiazepine of the present invention

The derivatives have the characteristics of rapid onset, short duration of action, strong depth, rapid metabolism and rapid awakening. In the anesthesia experiments on mice and rats, the short-acting benzodiazepines of the present invention

The onset time of the derivatives is comparable to that of remimazolam, but the duration of action and the recovery time are significantly shortened, and the depth of action of some compounds is significantly enhanced, with the characteristics of faster onset, shorter duration of action, greater intensity of action, faster metabolism and faster recovery; in the long-term infusion anesthesia experiment on rats, compared with remimazolam, the short-acting benzodiazepine of the present invention

The awakening time and recovery time of the derivatives are significantly shortened, and the benzodiazepines of the present invention have the characteristics of faster awakening and faster recovery.

The compounds not only maintain high affinity and selectivity for GABA _A receptors, but also

The structural modification and adjustment of the carboxylate group have the following advantages: predictable rapid onset time of sedation and anesthesia, short effective action time, strong action depth, and short awakening time, thereby reducing adverse inhibitory reactions to the cardiovascular and respiratory systems, and reducing side effects on the patient's nervous system, including drowsiness, dizziness and other problems. In addition, the compounds of the present invention show better cardiac safety, less toxicity to the heart, and little effect on liver metabolism, and have a wider prospect for drug development.

Definition and explanation of terms

Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and/or claims of this application.

Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to recording each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. In addition, when certain numerical ranges are defined as "numbers", it should be understood that the two endpoints of the range, each integer in the range, and each decimal in the range are recorded.

It should be understood that herein, when describing one, two or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "C _1-6 alkyl" means a straight chain and branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.

The term "C _3-8 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g., bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7 or 8 carbon atoms. The C _3-10 cycloalkyl may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term "3-8 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, which contains one or more heteroatoms independently selected from N, O and S and has a total ring number of 3-8 (such as 3, 4, 5, 6, 7, 8 atoms). For example, it is a 4-, 5-, 6- or 7-membered monocyclic ring, a 7- or 8-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a tricyclic ring system, and contains at least one, such as 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) ₂ -states. The heterocyclyl can be connected to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). The heterocyclyl can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. When the 3-8-membered heterocyclic group is connected to other groups to form the compound of the present invention, the carbon atoms on the 3-8-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms on the 3-8-membered heterocyclic group may be connected to other groups. For example, when the 3-8-membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl may be connected to other groups. Or when the 3-8-membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom on the para position thereof may be connected to other groups.

The term "C _6-14 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C _6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl or biphenyl, or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. When the C _6-14 aryl is substituted, it may be mono- or polysubstituted. Furthermore, there is no limitation on the substitution site, and for example, substitution may be at the ortho, para or meta position.

The term "5-14 membered heteroaryl" is understood to include monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing one or more (e.g. 1 to 5) heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, additionally, may be benzo-fused. "Heteroaryl" also refers to radicals in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. When the 5-14 membered heteroaryl is connected to other groups to form the compound of the present invention, the carbon atom on the 5-14 membered heteroaryl ring may be connected to other groups, or the heteroatom on the 5-14 membered heteroaryl ring may be connected to other groups. When the 5-14 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. In addition, there is no limitation on the substitution site, for example, the hydrogen connected to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen connected to the heteroatom on the heteroaryl ring may be substituted.

The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

The term "fused ring" refers to a ring system in which two rings share two ring atoms.

The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

DETAILED DESCRIPTION

The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The abbreviations used in this document have the following meanings:

The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR, ¹³ C NMR) and mass spectrometry (MS); the reaction was monitored by thin layer chromatography (TLC) or LCMS, and the developing solvent systems used were: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system.

Column chromatography generally uses 200-300 mesh silica gel as the stationary phase; the eluent system includes: dichloromethane and methanol system, n-hexylene and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

In the following examples, unless otherwise specified, the reaction temperature is room temperature (20° C. to 30° C.).

-4-基)丙酸-2-吗啉乙酯(化合物24)的合成Example 1: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Synthesis of 2-morpholinoethyl propionate (Compound 24)

-4-基)丙酸的制备：Step 1: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Preparation of -4-yl) propionic acid:

-4-基)丙酸甲酯(化合物1a，3.00g，0.0067mol)溶于DCM，加入LiOH，常温反应6小时至LCMS显示反应结束，抽滤取滤液并减压蒸馏除去反应溶剂，残留产物经柱层析(二氯甲烷/甲醇,150:1,v/v)纯化得到白色固体(S)-3-(8-氯-6-(2-氯苯基)-1-硫代-2,4-二氢-1H-苯并[f][1,2,4]三唑[4,3-a][1,4]二氮杂

-4-基)丙酸(化合物1b，2.16g，产率：74.4％)。Compound (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

4-yl)propionic acid methyl ester (compound 1a, 3.00 g, 0.0067 mol) was dissolved in DCM, LiOH was added, and the reaction was carried out at room temperature for 6 hours until LCMS showed that the reaction was completed. The filtrate was filtered and the reaction solvent was removed by distillation under reduced pressure. The residual product was purified by column chromatography (dichloromethane/methanol, 150:1, v/v) to obtain a white solid (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazol[4,3-a][1,4]diazepine

-4-yl)propanoic acid (Compound 1b, 2.16 g, yield: 74.4%).

-4-基)丙酸-2-吗啉乙酯的制备：Step 2: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Preparation of 2-morpholinoethyl propionate:

-4-基)丙酸(化合物1b，2.16g，0.005mol)溶于DCM,加入DCC(1.24g,0.006mol)和催化量的DMAP，常温反应12小时至LCMS显示反应结束，抽滤取滤液并减压蒸馏除去反应溶剂，残留产物经柱层析(石油醚/乙酸乙酯,2:1,v/v)纯化得到白色固体(S)3-(8-氯-6-(2-氯苯基)-1-硫基-2,4-二氢-1H-苯并[f][1,2,4]三唑[4,3-a][1,4]二氮杂

-4-基)丙酸-2-吗啉乙酯(化合物1c，1.81g，产率：63.2％)。Compound (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

2-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid-2-morpholinoethyl ester (Compound 1c, 1.81 g, yield: 63.2%).

¹ H NMR (300MHz, CDCl ₃ -d ₁ )δ: 7.80 (d, J=8.5Hz, 1H), 7.58–7.50 (m, 2H), 7.50–7.45 (m, 1H), 7.45–7.36 (m, 2H),7.34(d,J＝2.4Hz,1H),4.56(t,J＝6.0,8.4Hz,2H),4.22(t,J＝6.5,7.1Hz,2H),3.60–3.48(m,4H ),2.85(t,J＝6.4,9.6Hz,2H),2.72–2.57(m,4H),2.53–2.45(m,2H),2.43–2.28(m,2H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ:173.82,172.99,145.29,143.07,143.02,132.79,130.64,130.52,129.38,129.37,129.30,128.94,128.72,128.62,124.74,122.85,66.04,6 5.90,55.35,54.26,53.77,30.86,30.56.LC -MS(ESI)m/z:546.11[M+H] ⁺ .

-4-基)丙酸甲酯(化合物6)的合成Example 2: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Synthesis of methyl 4-(4-yl)propionate (Compound 6)

-4-基)丙酸甲酯的制备：Step 1: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Preparation of methyl propionate:

-4-基)丙酸甲酯(化合物1a，0.1g，0.22mmol)溶于5ml THF中，加入异丙醇钠(0.021g,0.22mmol)后室温搅拌30分钟，旋蒸除去溶剂后得到相应钠盐，加入1-(2-氯乙基)吡咯烷(0.058g，0.44mmol)，室温反应8小时后，减压浓缩柱层析(PE:EA＝3:1)得白色固体(化合物6，0.072g，产率：59.2％)。(S)-3-(8-chloro-6-(2-chlorophenyl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (compound 1a, 0.1 g, 0.22 mmol) was dissolved in 5 ml of THF, sodium isopropoxide (0.021 g, 0.22 mmol) was added and stirred at room temperature for 30 minutes, and the solvent was removed by rotary evaporation to obtain the corresponding sodium salt, 1-(2-chloroethyl)pyrrolidine (0.058 g, 0.44 mmol) was added, and the reaction was carried out at room temperature for 8 hours, and the mixture was concentrated under reduced pressure and column chromatography (PE:EA=3:1) was performed to obtain a white solid (compound 6, 0.072 g, yield: 59.2%).

¹ H NMR (300MHz, CDCl ₃ -d ₁ )δ: 7.91 (d, J＝2.0Hz, 1H), 7.61 (dd, J＝7.1, 2.2Hz, 1H), 7.51–7.37 (m, 4H), 7.29 (d,J＝7.5Hz,1H),5.22(s,1H),3.68(s,3H),3.48(d,J＝0.9Hz,2H),2.68–2.58(m,4H),2.49(s, 2H), 2.44–2.31 (m, 2H), 2.30–2.19 (m, 2H), 1.80 (d, J = 12.5Hz, 4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.30,160.77,154.13,148.12,138.12,135.83,134.71,132.61,130.82,130.51,130.43,129.29,129.04,128.19,126.36,122.81,57.76,55 .23,54.02,51.98,32.51,29.56,29.39,23.39.LC -MS(ESI)m/z:544.1[M+H] ⁺ .

Examples 3-17 (compounds 9, 11, 14, 16, 17, 19, 20, 22, 23, 25, 27-31) were synthesized according to the corresponding methods in the above examples, and the specific NMR and mass spectrometry characterization data are as follows:

-4-基)丙酸甲酯(化合物9)Example 3: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 9)

¹ H NMR (300MHz, CDCl ₃ -d ₁ )δ:7.77(d,J＝8.7Hz,1H),7.61(dd,J＝2.4Hz,8.7Hz,1H),7.57–7.53(m,1H), 7.41(dd,J＝5.6,3.0Hz,2H),7.37(d,J＝3.6Hz,1H),7.17(d,J＝2.4Hz,1H),4.26(t,J＝6.9Hz,1H), 3.67(s,3H),3.50(t,J＝7.1Hz,2H),2.83(t,J＝3.7Hz,4H),2.74(t,J＝7.1Hz,2H),2.47(s,4H), 1.62–1.56(m,4H),1.45(s,2H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ ) δ173.63,160.77,154.20,148.15,138.23,135.93,134.66,132.61,130.83,130.54,130.43,129.22,129.10,128.13,12 6.35,122.71,57.76,54.95,54.06, 51.97,32.18,29.54,29.39,26.64,23.96.LC-MS(ESI)m/z:558.2[M+H] ⁺ .

-4-基)丙酸甲酯(化合物11)Example 4: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 11)

¹ H NMR (300MHz, CDCl ₃ -d ₁ )δ:8.47(d,J＝5.2Hz,2H),7.93–7.83(m,1H),7.78(d,J＝8.7Hz,1H),7.67–7.56 (m,1H),7.56–7.47(m,2H),7.46–7.34(m,3H),7.23–7.09(m,1H),4.64–4.43(m,2H),4.30(t,J＝6.2Hz ,1H),3.59(s,3H),2.67–2.57(m,4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.65,161.70,154.16,149.79,147.48,146.26,138.07,135.66,134.71,132.61,130.82,130.51,130.43,129.36,129.04,128.19,126.36,1 24.08,122.76,57.76,51.96,39.84,29.54,29.39.LC -MS(ESI)m/z:538.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物14)Example 5: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 14)

¹ H NMR (300MHz, CDCl ₃ -d ₁ )δ:7.68–7.59(m,2H),7.62–7.52(m,2H),7.53–7.45(m,1H),7.41–7.32(m,2H), 6.11(t,J＝5.2Hz,1H),3.66(s,3H),3.46(t,J＝5.2Hz,2H),2.74–2.62(m,6H),2.65–2.51(m,4H),2.25 –2.12(m,4H). ¹³ C NMR(75MHz, CDCl ₃ -d ₁ )δ172.98,160.92,154.16,148.12,137.98,135.93,134.65,132.65,131.03,130.83,130.56,129.18,129.10,128.07,126.30,122.69,118.58,5 7.87,54.60,51.78,48.83,32.57,31.95,9.54,29.49 .LC-MS(ESI)m/z:594.4[M+H] ⁺ .

-4-基)丙酸甲酯(化合物16)Example 6: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-((2-(4-methylpiperazin-1-yl)2-oxoethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 16)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ7.72(d,J＝8.4Hz,1H),7.64–7.57(m,2H),7.55(d,J＝2.4Hz,1H),7.53–7.45 (m,1H),7.41–7.32(m,2H),6.11(t,J＝5.2Hz,1H),4.08(d,J＝2.7Hz,2H),3.66(s,3H),3.49(t, J＝5.3Hz, 4H), 2.65–2.50 (m, 8H), 2.23 (s, 3H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.37,171.54,160.92,154.17,147.98,137.98,136.05,134.72,132.65,131.16,130.83,130.56,129.18,129.10,128.33,126.44,122.74,5 6.97,54.43,51.80,46.07,45.25,35.71,29.47,29.78 .LC-MS(ESI)m/z:587.5[M+H] ⁺ .

-4-基)丙酸甲酯(化合物17)Example 7: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 17)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ7.69 (d, J＝8.3Hz, 1H), 7.61–7.54 (m, 2H), 7.54–7.45 (m, 2H), 7.41–7.30 (m, ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.22,164.87,160.77,154.72,143.84,137.98,136.55,134.71,132.60,130.83,130.54,130.43,129.20,129.10,128.16,126.36,122.85,5 7.81,54.27,52.08,47.39,45.36,29.54,29.57.LC -MS(ESI)m/z:573.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物19)Example 8: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(3-((diethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 19)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ: 7.91 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 7.2, 2.2 Hz, 1H), 7.51–7.37 (m, 5H), 5.32 ( s,1H),3.68(s,3H),3.25(d,J＝2.5Hz,2H),2.65–2.49(m,6H),2.44–2.28(m,4H),1.99(d,J＝2.2Hz ,2H),0.99(s,6H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.62,145.70,144.01,141.27,138.92,132.79,130.73,130.17,129.99,129.43,129.37,128.94,128.72,128.62,124.77,1 20.33,54.20,53.56,51.40,47.08, 33.51,33.02,31.91,30.11,11.83.LC-MS(ESI)m/z:560.16[M+H] ⁺ .

-4-基)丙酸甲酯(化合物20)Example 9: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 20)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ7.75 (d, J = 8.7Hz, 1H), 7.59 (dd, J = 8.7, 2.4Hz, 1H), 7.55 (dd, J = 5.8, 3.4Hz, 1H),7.45–7.39(m,2H),7.37–7.32(m,1H),7.17(d,J＝2.3Hz,1H),4.26(t,J＝6.0Hz,1H),3.67(s,3H ),3.62–3.40(m,2H),2.91–2.78(m,4H),2.72(h,J＝6.1Hz,2H),2.30(s,6H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.88,145.68,144.42,143.87,138.88,133.17,130.68,130.54,129.82,129.72,129.46,129.41,128.74,124.66,122.11,5 4.20,52.83,51.40,42.92,37.46, 33.02,31.93.LC-MS(ESI)m/z:518.11[M+H] ⁺ .

-4-基)丙酸甲酯(化合物22)Example 10: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 22)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ: 7.91 (d, J = 2.0Hz, 1H), 7.66 (dd, J = 7.0, 2.4Hz, 1H), 7.50–7.35 (m, 4H), 7.29 ( d,J＝7.5Hz,1H),5.25(s,1H),3.68(s,3H),3.63–3.51(m,2H),3.48(d,J＝0.9Hz,2H),2.62(d,J ＝2.4Hz,4H),2.55(s,2H),2.44–2.32(m,2H),2.33(d,J＝7.0Hz,1H),2.25(d,J＝12.5Hz,1H),1.79(d ,J＝7.5Hz,4H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.61,145.63,145.00,143.04,138.86,132.79,130.72,130.15,129.99,129.37,128.72,128.60,128.19,124.67,119.77,6 7.85,54.33,51.50,50.74,50.54, 33.99,33.02,32.94,31.92.LC-MS(ESI)m/z:574.14[M+H] ⁺ .

-4-基)丙酸甲酯(化合物23)Example 11: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-methylpiperidin-2-carbonyl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 23)

¹ H NMR (300MHz, CDCl3-d ₁ )δ:7.98(d,J＝2.0Hz,1H),7.66–7.59(m,1H),7.50–7.44(m,1H),7.46–7.33(m,3H),7.29(d,J＝7.5Hz,1H),5.25(s,1H),4.42(s,1H),3.68(s,3H),2.6 2(d,J＝10.6Hz,2H),2.49(d,J＝12.3Hz,1H),2.41–2.30(m,5H),2.25(d,J＝12.5Hz,1H),2.02(d,J＝21.1Hz,2H),1.65(s,1H),1.59(d,J＝4.6Hz,2H),1.53 (s,1H). ¹³ C NMR(75MHz, CDCl3-d1)δ:175.67,173.61,148.74,145.69,143.49,138.91,132.79,130.71,130.16,129.99,129.84,129.37,128.72,128.60,128.19,1 24.68,122.11,62.34,54.53,54.33,51.45,41.64,33.02,31.91,28.57,26.60,22.95.LC-MS(ESI)m/z:571.12[M+H] ⁺ .

-4-基)丙酸甲酯(化合物25)Example 12: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 25)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ: 7.85 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.59–7.51 (m, 3H), 7.47 (dd, J = 7.7, 1.7Hz,1H),7.38(td,J＝23.6,7.4,1.6Hz,2H),7.03(s,2H),6.10(t,J＝5.2Hz,1H),4.27(td,J＝5.0,1.6 Hz, 2H), 3.66–3.60 (m, 5H), 2.66–2.51 (m, 4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ:173.87,145.66,145.05,143.04,139.39,138.93,133.92,132.79,130.68,130.55,129.71,129.46,129.44,129.37,129.31,128.94,128.62, 124.73,120.33,54.20,51.40,49.21,36.04,33.07 ,31.90.LC-MS(ESI)m/z:541.09[M+H] ⁺ .

-4-基)丙酸甲酯(化合物27)Example 13: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((1H-pyrrol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 27)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ7.87 (dd, J = 8.7, 2.4Hz, 1H), 7.78 (d, J = 8.7Hz, 1H), 7.65 (dd, J = 5.9, 3.3Hz, 1H),7.55–7.49(m,2H),7.49–7.42(m,1H),7.18(d,J＝2.3Hz,1H),6.76(t,J＝2.1Hz,2H),5.99(t,J ＝2.1Hz,2H),4.32(t,J＝6.4Hz,1H),4.24(t,J＝6.5Hz,2H),3.60(s,3H),2.68(t,J＝6.4Hz,2H), 2.52-2.50(m,4H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.90,145.62,145.01,143.04,138.89,132.79,130.67,130.54,129.72,129.46,129.44,129.37,128.94,128.62,125.93,1 24.70,120.33,119.18,54.20,53.61, 51.39,36.04,33.00,31.89.LC-MS(ESI)m/z:540.09[M+H] ⁺ .

-4-基)丙酸甲酯(化合物28)Example 14: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 28)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ: 8.03 (s, 1H), 7.97–7.90 (m, 2H), 7.61 (dd, J = 7.5, 2.0Hz, 1H), 7.53–7.34 (m, 5H) ),5.17(s,1H),3.68(s,6H),2.56–2.45(m,2H),2.30–2.19(m,2H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.94,156.53,145.64,145.36,144.40,138.85,137.66,133.15,132.20,130.65,130.54,129.82,129.70,129.46,129.44,1 28.94,128.70,124.72,122.11,54.20, 51.40, 33.80, 33.05, 30.26; LC-MS (ESI) m/z: 527.07[M+H] ⁺ .

-4-基)丙酸甲酯(化合物29)Example 15: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 29)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ7.75 (d, J＝8.4Hz, 1H), 7.60–7.51 (m, 3H), 7.50 (dd, J＝7.8, 1.4Hz, 1H), 7.41 ( td,J＝7.7,1.8Hz,1H),7.34(td,J＝7.5,1.4Hz,1H),4.30(t,J＝8.2Hz,1H),3.64(s,3H),3.45(q,J ＝7.2Hz,2H),3.02(s,3H),2.75–2.59(m,2H),2.59-2.53(m,2H),1.22(t,J＝7.2Hz,3H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.90,162.05,148.74,146.39,143.80,138.87,133.16,130.61,130.53,129.82,129.75,129.46,129.45,129.25,128.74,1 24.69,124.25,54.19,51.41,43.61, 34.27,32.98,30.26,12.47.LC-MS(ESI)m/z:532.09[M+H] ⁺ .

-4-基)丙酸甲酯(化合物30)Example 16: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(3-((dimethylamino)-3-oxopropyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 30)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ: 7.89 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 7.1, 2.2 Hz, 1H), 7.54–7.37 (m, 6H), 5.32 ( s,1H),3.68(s,3H),3.39(s,2H),2.86(s,5H),2.80–2.69(m,2H),2.44–2.28(m,3H),2.25(d,J＝ 12.5Hz,1H). ^13C NMR(75MHz, CDCl3-d1)δ:173.78,172.42,145.67,144.02,143.04,138.84,132.79,130.60,130.55,129.74,129.46,129.37,129.02,128.93,128.62,1 24.74,120.33,54.22,51.42,36.42, 35.74,33.03,31.88,31.67.LC-MS(ESI)m/z:546.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物31)Example 17: (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(((4,5-dihydro-1H-imidazol-2-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 31)

¹ H NMR (300MHz, CDCl3-d ₁ ) δ: 7.91 (d, J = 2.0Hz, 1H), 7.61 (dd, J = 7.2, 2.3Hz, 1H), 7.54–7.37 (m, 4H), 7.31 ( d,J＝7.5Hz,1H),6.83(s,1H),5.17(s,1H),4.32(s,2H),3.68(s,3H),3.59–3.50(m,4H),2.49(d ,J＝12.5Hz,1H),2.40(d,J＝12.5Hz,1H),2.30–2.19(m,2H). ¹³ C NMR(75MHz, CDCl3-d1)δ:173.87,159.44,145.60,143.90,141.65,138.93,133.18,130.69,130.56,129.82,129.73,129.46,129.44,128.91,128.70,1 24.73,122.11,54.18,51.38,44.30, 44.27,41.81,33.04,31.95.LC-MS(ESI)m/z:529.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物1)的合成Example 18: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Synthesis of methyl 4-hydroxypropionate (compound 1)

Step 1: Preparation of (S)-5-((4-bromo-2-pyridinylphenyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (Compound 2c):

2-(2-amino-5-bromo-benzoyl)pyridine (compound 2a, 10.00 g, 0.036 mol) and compound N-tert-butyloxycarbonyl-L-glutamic acid-5-methyl ester (compound 2b, 7.86 g, 0.030 mol) were dissolved in DCM (100 mL). The mixture was cooled to 0 ° C, DCC (7.44 g, 0.036 mmol) was added, and stirred for 12 hours. LCMS showed that the reaction was complete. The filtrate was filtered and the reaction solvent was evaporated under reduced pressure. The residual product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to obtain a white solid (S)-5-((4-bromo-2-pyridinecarbonylphenyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (compound 2c, 10.55 g, yield: 56.2%).

Step 2: Preparation of (S)-4-amino-5-((5-bromo-2-pyridinylphenyl)amino)-5-oxopentanoic acid methyl ester (Compound 2d):

(S)-5-((4-bromo-2-pyridinylphenyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (Compound 2c, 10.55 g) was dissolved in DCM (100 mL). TFA (100 mL) was added and stirred for 20 minutes until LCMS showed that the reaction was complete. The reaction solution was concentrated to obtain a crude residue of (S)-4-amino-5-((5-bromo-2-pyridinylphenyl)amino)-5-oxopentanoic acid methyl ester (Compound 2d, 9.6 g), which was directly used in the next step.

-3-基)丙酸甲酯(化合物2e)的制备：Step 3: (S)-3-(7-bromo-2-oxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

Preparation of methyl 2-(3-yl)propionate (compound 2e):

-3-基)丙酸甲酯(化合物2e，5.72g，产率：32.1％)。(S)-4-amino-5-((5-bromo-2-pyridinylphenyl)amino)-5-oxopentanoic acid methyl ester (compound 2d, 9.6 g) was dissolved in MeOH (100 mL), NaHCO ₃ was added to adjust the pH to about 10, and stirred for 24 hours. LCMS showed that the reaction was complete. The reaction solution was filtered, the filtrate was poured into ice water, extracted with ethyl acetate, the organic phase was washed with water 3 times, dried and concentrated, and the residual product was purified by column chromatography (petroleum ether/ethyl acetate, 2:1, v/v) to give white (S)-3-(7-bromo-2-oxo-5-(2-pyridinyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (Compound 2e, 5.72 g, yield: 32.1%).

-3-基)丙酸甲酯(化合物2f)的制备：Step 4: (S)-3-(7-bromo-2-thioxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

Preparation of methyl 2-(3-yl)propionate (compound 2f):

-3-基)丙酸甲酯(化合物2e,5.72g)溶于甲苯(110mL)，加入劳森试剂(4.86g,0.012mol)，将化合物加热到100℃，搅拌1.5小时，直至LCMS显示反应结束。加入饱和碳酸氢钠溶液除去过量的劳森试剂，乙酸乙酯(20ml×3)萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除反应溶剂，残留产物经柱层析(石油醚/乙酸乙酯,7:1,v/v)纯化得淡黄色固体(S)-3-(7-溴-2-硫代-5-(2-吡啶基)-2,3-二氢-lH-苯并[e][l,4]二氮杂

-3-基)丙酸甲酯(化合物2f，3.10g，产率：53.4％)。(S)-3-(7-bromo-2-oxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl) methyl propionate (compound 2e, 5.72g) was dissolved in toluene (110mL), Lawesson's reagent (4.86g, 0.012mol) was added, the compound was heated to 100°C, and stirred for 1.5 hours until LCMS showed that the reaction was complete. Saturated sodium bicarbonate solution was added to remove the excess Lawesson's reagent, and ethyl acetate (20ml×3) was used for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and the reaction solvent was evaporated under reduced pressure. The residual product was purified by column chromatography (petroleum ether/ethyl acetate, 7:1, v/v) to obtain a light yellow solid (S)-3-(7-bromo-2-thioxo-5-(2-pyridyl)-2,3-dihydro-lH-benzo[e][l,4]diazepine

-3-yl)propionic acid methyl ester (Compound 2f, 3.10 g, yield: 53.4%).

-3-基)丙酸甲酯(化合物2g)的制备：Step 5: (S)-3-(7-bromo-5-(2-pyridyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine

Preparation of methyl 2-(3-yl)propionate (compound 2g):

-3-基)丙酸甲酯(化合物2f，3.10g)溶于30ml THF，将混合物冷却至0℃，加入80％水合肼(1.56g,0.031mol)，并搅拌30分钟直至LCMS显示反应结束，用饱和NaCl除去多余的水合肼，用DCM萃取合并有机相，干燥并浓缩，得到粗品(S)-3-(7-溴-5-(2-吡啶基)-2-肼基-2,3-二氢-1H-苯并[e][1,4]二氮杂

-3-基)丙酸甲酯(化合物2g,3.00g)，将其直接用于下一步反应。(S)-3-(7-bromo-2-thioxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (compound 2f, 3.10 g) was dissolved in 30 ml THF, the mixture was cooled to 0°C, 80% hydrazine hydrate (1.56 g, 0.031 mol) was added, and stirred for 30 minutes until LCMS showed that the reaction was complete, and the excess hydrazine hydrate was removed with saturated NaCl, and the organic phases were combined by extraction with DCM, dried and concentrated to give a crude product (S)-3-(7-bromo-5-(2-pyridyl)-2-hydrazine-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (Compound 2g, 3.00g), which was directly used in the next step reaction.

-4-基)丙酸甲酯(化合物2h)的制备：Step 6: (S)-3-(7-bromo-5-(pyridin-2-yl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Preparation of methyl 4-(4-yl)propanoate (compound 2h):

-3-基)丙酸甲酯(化合物2g,3.00g)溶于80ml THF中，加TEA(1.77g，0.018mol)，将混合物冷至0℃，加硫光气(1.0g，0.009mol)，并搅拌2h直至LCMS显示反应结束，抽滤取滤液并减压蒸除反应溶剂，残留产物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化得到白色固体(S)-3-(7-溴-5-(吡啶-2-基)-1-硫代-2,4-二氢-1H-苯并[f][1,2,4]三唑[4,3-a][1,4]二氮杂

-4-基)丙酸甲酯(化合物2h，1.46g，产率：42.5％)。(S)-3-(7-bromo-5-(2-pyridyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl) propionic acid methyl ester (compound 2g, 3.00g) was dissolved in 80ml THF, TEA (1.77g, 0.018mol) was added, the mixture was cooled to 0°C, thiophosgene (1.0g, 0.009mol) was added, and the mixture was stirred for 2h until LCMS showed that the reaction was complete, the filtrate was filtered and the reaction solvent was evaporated under reduced pressure, and the residual product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to obtain a white solid (S)-3-(7-bromo-5-(pyridin-2-yl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (compound 2h, 1.46 g, yield: 42.5%).

-4-基)丙酸甲酯(化合物1)的制备：Step 7: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Preparation of methyl propionate (compound 1):

-4-基)丙酸甲酯(化合物2h)(0.1g，0.22mmol)溶于5ml THF中，加入叔丁醇钠(0.021g,0.22mmol)后室温搅拌30分钟，旋蒸除去溶剂后得到相应钠盐，加碘甲烷(0.062g，0.44mmol)，室温反应8h后，减压浓缩柱层析(PE:EA＝3:1)得白色固体(S)3-(8-溴-6-(吡啶-2-基)-1-甲硫基-4H-苯并[f][1,2,4]三唑[4,3-a][1,4]二氮杂

-4-基)丙酸甲酯(化合物1，0.071g，产率：68.9％)(S)-3-(7-bromo-5-(pyridin-2-yl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

4-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid methyl ester (Compound 1, 0.071 g, yield: 68.9%)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.79 (dd, J＝3.5, 1.2Hz, 1H), 7.86–7.75 (m, 3H), 7.70–7.65 (m, 1H), 7.54 (dd, J＝7.8,1.5Hz,1H),7.33-7.30(m,1H),6.13(t,J＝5.3Hz,1H),3.66(s,2H),2.72(s,3H),2.66(td,J ＝7.8,1.2Hz,3H),2.62–2.51(m,2H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.38,162.32,155.83,153.99,150.80,147.41,137.47,136.64,136.60,134.48,127.86,125.25,122.80,122.65,120.45,57.05,52.01,29. 61,29.27,16.69.LC-MS(ESI)m/z :474.3[M+H] ⁺ .

Examples 19-23 (compounds 2-5, 13) were synthesized according to the corresponding methods in the above examples, and the specific NMR and mass spectrometry characterization data are as follows:

-4-基)丙酸甲酯(化合物2)Example 19: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-ethylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 2)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.78 (dd, J＝3.5, 1.3Hz, 1H), 7.85–7.74 (m, 3H), 7.67 (t, J＝1.3Hz, 1H), 7.54 (dd,J＝7.9,1.3Hz,1H),7.33-7.30(m,1H),6.13(t,J＝5.2Hz,1H),3.65(s,3H),3.29–3.18(m,2H), 2.70–2.52(m,4H),1.40(t,J=7.2Hz,3H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.72,160.73,157.51,153.83,151.63,147.12,137.61,137.47,136.40,134.75,125.25,124.56,123.44,122.65,120.39,66.22,57.42,52. 01,29.61,29.23,14.70.LC-MS(ESI)m /z:486.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物3)Example 20: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-((cyclopropylmethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 3)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.79 (dd, J＝3.6, 1.3Hz, 1H), 7.82 (td, J＝7.6, 1.2Hz, 1H), 7.80–7.71 (m, 2H) ,7.67(d,J＝2.2Hz,1H),7.56(dd,J＝7.9,1.4Hz,1H),7.33-7.31(m,1H),6.13(t,J＝5.2Hz,1H),3.66( s, 3H), 3.02 (d, J = 4.8Hz, 2H), 2.70–2.51 (m, 4H), 1.40–1.24 (m, 5H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.58,162.37,156.38,154.59,149.57,147.13,137.57,137.28,136.60,134.78,127.93,125.30,122.76,122.64,120.55,59.05,51.80,39. 41,29.45,29.28,10.89,6.19.LC-MS(ESI )m/z:512.4[M+H] ⁺ .

-4-基)丙酸甲酯(化合物4)Example 21: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-((2-morpholinoethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 4)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.58(d,J＝4.2Hz,1H),8.18(d,J＝7.9Hz,1H),7.85(dd,J＝7.2,1.3Hz,1H ),7.79(dd,J＝6.5,4.2Hz,1H),7.66(d,J＝8.8Hz,2H),7.41-7.37(m,1H),4.27(t,J＝5.1Hz,1H),3.69 (s,3H),3.64(t,J＝4.8Hz,4H),3.52-3.41(m,2H),2.91-2.82(m,4H),2.74(t,J＝6.7Hz,2H),2.46( t,J＝4.5Hz,4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ ) δ173.62,162.11,156.69,154.59,148.12,147.31,137.47,137.09,136.60,135.16,128.24,125.26,122.73,122.59,120.96 ,65.69,58.05,54.45,53.31,51.93, 32.18,29.54,29.28.LC-MS(ESI)m/z:571.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物5)Example 22: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-(3-((dimethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 5)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.79 (dd, J＝3.6, 1.2Hz, 1H), 7.81 (td, J＝7.6, 1.2Hz, 1H), 7.78–7.72 (m, 2H) ,7.67(dd,J＝1.7,0.9Hz,1H),7.56(dd,J＝7.9,1.4Hz,1H),7.33-7.30(m,1H),6.13(t,J＝5.4Hz,1H), 3.65(s,3H),3.27(t,J＝6.4Hz,2H),2.73–2.62(m,2H),2.60–2.48(m,4H),2.25(s,6H),1.93(pd,J＝ 6.5,1.1Hz,2H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.33,162.11,156.72,154.49,147.89,146.31,137.30,137.09,136.67,135.32,128.24,125.26,122.74,122.32,120.9 4,58.49,58.05,51.96,44.90,32.55 ,29.54,29.28,26.44.LC-MS(ESI)m/z:543.2[M+H] ⁺ .

-4-基)丙酸甲酯(化合物13)Example 23: (S) 3-(8-bromo-6-(pyridin-2-yl)-1-(((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 13)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.62–8.58(m,1H),8.53–8.46(m,2H),8.18(d,J＝7.9Hz,1H),7.84(td,J＝ 7.8,1.7Hz,1H),7.75(dd,J＝8.7,2.2Hz,1H),7.67(d,J＝2.2Hz,1H),7.54(d,J＝8.7Hz,1H),7.42-7.38( ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.41,161.93,156.42,154.52,149.59,147.48,147.33,146.06,137.37,137.19,136.60,135.48,128.31,125.25,124.08,122.76,122 .61,120.94,58.05,51.96,39.84,29.54,29.34. LC-MS(ESI)m/z:549.4[M+H] ⁺ .

-4-基)丙酸甲酯(化合物7)Example 24: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 7)

Step 1: Preparation of (S)-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (Compound BF-02):

2-Amino-5-bromo-2'-fluorobenzophenone (compound BF-01, 9.82 g, 0.034 mol) and compound N-tert-butyloxycarbonyl-L-glutamic acid-5-methyl ester (7.01 g, 0.027 mol) were dissolved in DCM (120 mL). The mixture was cooled to 0°C, DCC (10.26 g, 0.040 mmol) was added, and stirred for 12 hours. LCMS showed that the reaction was complete. The filtrate was filtered and the reaction solvent was evaporated under reduced pressure. The residual product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to obtain a white solid (S)-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (compound BF-02, 10.56 g, yield: 70.90%)

Step 2: Preparation of (S)-4-amino-5-((2-fluorobenzoyl-4-bromophenyl)amino)-5-oxopentanoic acid methyl ester (Compound BF-03):

(S)-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (Compound BF-02, 10.56 g) was dissolved in DCM (50 mL). TFA (50 mL) was added and stirred for 20 minutes until LCMS showed that the reaction was complete. The reaction solution was concentrated to obtain a crude residue of (S)-4-amino-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-5-oxopentanoic acid methyl ester (Compound BF-03, 8.41 g), which was used directly in the next step.

-3-基)丙酸甲酯(化合物BF-04)的制备：Step 3: (S)-3-(7-bromo-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

Preparation of methyl propionate (compound BF-04):

-3-基)丙酸甲酯(化合物BF-04，7.5g，)(S)-4-amino-5-((2-fluorobenzoyl-4-bromophenyl)amino)-5-oxopentanoic acid methyl ester (compound BF-03, 8.41 g) was dissolved in MeOH (100 mL), NaHCO ₃ was added to adjust the pH to about 10, and stirred for 24 hours. LCMS showed that the reaction was complete. The reaction solution was filtered, the filtrate was poured into ice water, extracted with ethyl acetate, the organic phase was washed with water 3 times, dried and concentrated, and the residual product was purified by column chromatography (petroleum ether/ethyl acetate, 2:1, v/v) to give white (S)-3-(7-bromo-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)methyl propionate (compound BF-04, 7.5 g,)

-3-基)丙酸甲酯(化合物BF-05)的制备：Step 4: (S)-3-(7-bromo-5-(2-fluorophenyl)-2-thioxo-2,3-dihydro-1H-benzo[e][1,4]diazepine

Preparation of methyl propionate (compound BF-05):

-3-基)丙酸甲酯(化合物BF-04,7.5g)溶于甲苯(200mL)，加入劳森试剂(4.86g,0.012mol)，将化合物加热到100℃，搅拌1.5小时，直至LCMS显示反应结束。加入饱和碳酸氢钠溶液除去过量的劳森试剂，乙酸乙酯(20mL×3)萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除反应溶剂，残留产物经柱层析(石油醚/乙酸乙酯,7:1,v/v)纯化得淡黄色固体(S)-3-(7-溴-5-(2-氟苯基)-2-硫代-2,3-二氢-1H-苯并[e][1,4]二氮杂

-3-基)丙酸甲酯(化合物BF-05，4.07g，产率：52.1％)(S)-3-(7-bromo-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl) methyl propionate (compound BF-04, 7.5 g) was dissolved in toluene (200 mL), Lawesson's reagent (4.86 g, 0.012 mol) was added, the compound was heated to 100 ° C, and stirred for 1.5 hours until LCMS showed that the reaction was complete. Saturated sodium bicarbonate solution was added to remove the excess Lawesson's reagent, and ethyl acetate (20 mL × 3) was used for extraction. The organic layers were combined and dried over anhydrous sodium sulfate. The reaction solvent was evaporated under reduced pressure, and the residual product was purified by column chromatography (petroleum ether/ethyl acetate, 7:1, v/v) to obtain a light yellow solid (S)-3-(7-bromo-5-(2-fluorophenyl)-2-thio-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (compound BF-05, 4.07 g, yield: 52.1%)

-3-基)丙酸甲酯(化合物BF-06)的制备：Step 5: (S)-3-(7-bromo-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine

Preparation of methyl propionate (compound BF-06):

-3-基)丙酸甲酯(化合物BF-05，4.07g)溶于50mL THF，将混合物冷却至0℃，加入80％水合肼(1.56g,0.031mol)，并搅拌30分钟直至LCMS显示反应结束，用饱和NaCl除去多余的水合肼，用DCM萃取合并有机相，干燥并浓缩，得到粗品(S)-3-(7-溴-5-(2-氟苯基)-2-肼基-2,3-二氢-1H-苯并[e][1,4]二氮杂

-3-基)丙酸甲酯(化合物BF-06,3.1g)，将其直接用于下一步反应。(S)-3-(7-bromo-5-(2-fluorophenyl)-2-thioxo-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (compound BF-05, 4.07 g) was dissolved in 50 mL THF, the mixture was cooled to 0 ° C, 80% hydrazine hydrate (1.56 g, 0.031 mol) was added, and stirred for 30 minutes until LCMS showed that the reaction was complete, and the excess hydrazine hydrate was removed with saturated NaCl, and the organic phases were combined by extraction with DCM, dried and concentrated to give a crude product (S)-3-(7-bromo-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (compound BF-06, 3.1 g), which was directly used in the next step reaction.

-4-基)丙酸甲酯(化合物BF-07互变异构体)的制备：Step 6: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-thioxo-2-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

Preparation of methyl-4-yl)propanoate (compound BF-07 tautomer):

-3-基)丙酸甲酯(化合物BF-06,3.1g)溶于80ml THF中，加TEA(1.77g，0.018mol)，将混合物冷却至0℃，加硫光气(1.0g，0.009mol)，并搅拌2h直至LCMS显示反应结束，抽滤取滤液并减压蒸除反应溶剂，残留产物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化得到白色固体(S)-3-(8-溴-6-(2-氟苯基)-1-硫代-2-2,4-二氢-1H-苯并[f][1,2,4]三唑[4,3-a](化合物BF-07互变异构体，1.46g，产率：42.5％)。(S)-3-(7-bromo-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine

-3-yl)propionic acid methyl ester (compound BF-06, 3.1 g) was dissolved in 80 ml THF, TEA (1.77 g, 0.018 mol) was added, the mixture was cooled to 0°C, thiophosgene (1.0 g, 0.009 mol) was added, and the mixture was stirred for 2 h until LCMS showed that the reaction was completed, the filtrate was filtered and the reaction solvent was evaporated under reduced pressure, and the residual product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to obtain a white solid (S)-3-(8-bromo-6-(2-fluorophenyl)-1-thio-2-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a] (compound BF-07 tautomer, 1.46 g, yield: 42.5%).

Step 7: Compound BF-07 (0.1 g, 0.22 mmol) was dissolved in 5 ml THF, sodium tert-butoxide (0.021 g, 0.22 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by rotary evaporation to obtain the corresponding sodium salt, 1-(2-chloroethyl)pyrrolidine (0.062 g, 0.44 mmol) was added, and the reaction was carried out at room temperature for 8 hours, and the mixture was concentrated under reduced pressure and column chromatography (PE:EA=3:1) was performed to obtain a white solid (compound 7, 0.071 g, yield: 68.9%).

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ7.72 (dd, J＝8.4, 2.6Hz, 1H), 7.61–7.56 (m, 2H), 7.55–7.43 (m, 2H), 7.28 (td, J＝7.5,1.5Hz,1H),7.21(dd,J＝7.8,1.5Hz,1H),6.10(t,J＝5.2Hz,1H),3.64(s,3H),3.45(t,J＝5.1 Hz, 2H), 2.74 (t, J = 4.9 Hz, 4H), 2.65–2.51 (m, 6H), 1.89-182 (m, 4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.65,163.32,159.17,154.22,147.98,136.64,136.54,132.59,131.54,130.23,128.57,127.70,124.00,121.79,120.47,115.76,58.29,55 .23,54.02,51.93,32.18,29.54,29.30,23.40.LC -MS(ESI)m/z:572.1[M+H] ⁺ .

Examples 25-31 (Compounds 8, 10, 12, 15, 18, 21, 26) were synthesized according to the corresponding methods in the above examples, and the specific NMR and mass spectrometry characterization data are as follows:

-4-基)丙酸甲酯(化合物8)Example 25: (S) 3-(8-bromo-6-(2-chlorophenyl)-1-((2-(pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 8)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ7.75 (dd, J＝8.4, 2.6Hz, 1H), 7.68–7.58 (m, 2H), 7.55 (dd, J＝7.7, 1.6Hz, 1H) ,7.49(dd,J＝7.8,1.6Hz,1H),7.40(td,J＝7.6,1.6Hz,1H),7.33(td,J＝7.5,1.5Hz,1H),6.11(t,J＝5.2 Hz,1H),3.64(s,3H),3.45(t,J＝5.1Hz,2H),2.74(t,J＝4.9Hz,4H),2.65–2.51(m,6H),1.86(td,J ＝4.9,2.7Hz,4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ ) δ173.57,160.33,154.78,149.12,137.49,136.40,136.44,134.71,133.11,131.17,130.63,129.36,128.19,126.09,121.84 ,120.47,57.87,55.33,54.02,51.93, 32.14,29.54,29.39,23.33.LC-MS(ESI)m/z:588.0[M+H] ⁺ .

-4-基)丙酸甲酯(化合物10)Example 26: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 10)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ7.73 (dd, J＝8.4, 2.6Hz, 1H), 7.62–7.56 (m, 2H), 7.53–7.43 (m, 2H), 7.29 (td, J＝7.5,1.5Hz,1H),7.17(dd,J＝7.9,1.5Hz,1H),6.10(t,J＝5.2Hz,1H),3.64(s,3H),3.45(t,J＝5.1 Hz,2H),2.68–2.51(m,10H),1.58-1.54(m,4H),1.48–1.37(m,2H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.60,163.21,159.19,154.15,148.12,136.35,136.54,132.44,131.52,130.23,128.53,127.70,124.00,121.85,120.25,115.78,58.29,54 .90,54.06,51.93,32.18,29.54,29.30,26.83,24.03 .LC-MS(ESI)m/z:586.1[M+H] ⁺ .

-4-基)丙酸甲酯(化合物12)Example 27: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 12)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ8.62–8.57(m,2H),7.73(dd,J＝8.4,2.6Hz,1H),7.59(d,J＝2.5Hz,1H),7.58 –7.51(m,2H),7.47(td,J＝7.7,1.6Hz,1H),7.33–7.26(m,3H),7.26–7.20(m,1H),6.10(t,J＝5.2Hz,1H ),4.53(s,2H),3.64(s,3H),2.67–2.57(m,2H),2.57–2.51(m,2H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.62,163.35,159.17,154.16,149.79,147.48,146.26,136.60,136.54,132.67,131.51,130.23,128.53,127.70,124.09,124.00,121.79,1 20.47,115.76,58.29,51.92,39.84,29.54,29.30.LC -MS(ESI)m/z:566.4[M+H] ⁺ .

-4-基)丙酸甲酯(化合物15)Example 28: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio))-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 15)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ7.74 (dd, J＝8.4, 2.4Hz, 1H), 7.62–7.54 (m, 2H), 7.54–7.44 (m, 2H), 7.33–7.21 ( m,2H),4.32(t,J＝5.3,7.4Hz,1H),3.66(s,3H),3.46(t,J＝5.2,6.7Hz,2H),2.74–2.68(m,3H),2.68 –2.62(m,4H),2.61(dd,J＝1.9,1.2Hz,1H),2.61–2.51(m,2H),2.25–2.12(m,4H). ¹³ C NMR (75MHz, CDCl ₃ -d ₁ )δ173.33,163.02,159.33,154.16,148.12,136.55,136.54,132.67,131.53,130.23,128.58,127.70,123.91,121.85,120.45,118.58,115.77,5 8.29,54.60,51.94,48.71,32.61,32.23,29.34,29.63 .LC-MS(ESI)m/z:622.5[M+H] ⁺ .

-4-基)丙酸甲酯(化合物18)Example 29: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio))-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 18)

-4-基)丙酸甲酯(化合物21) ¹ H NMR (300MHz, CDCl ₃ -d ₁ )δ: 7.75 (dd, J＝8.4, 2.6Hz, 1H), 7.59 (d, J＝2.5Hz, 1H), 7.56–7.44 (m, 3H), 7.28 (td,J＝7.6,1.4Hz,1H),7.22(dd,J＝7.7,1.3Hz,1H),6.12(t,J＝5.4Hz,1H),3.77–3.68(m,2H),3.68– ¹³ C NMR(75MHz,CDCl ₃ -d ₁ )δ:173.61,167.58,160.70,148.74,143.80,143.14,132.49,131.38,131.10,129.83,129.44,129.40,124.54,124.20,121.80,115.88, 115.73,54.33,54.18,51.71,51.50,44.98 ,33.02,31.91.LC-MS(ESI)m/z:601.10[M+H] ⁺ . Example 30: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][ 1,2,4]triazole[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 21)

¹ H NMR (300MHz, CDCl ₃ -d ₁ ) δ: 7.73 (dd, J＝8.5, 2.5Hz, 1H), 7.61–7.55 (m, 2H), 7.54–7.43 (m, 2H), 7.29 (td, J＝7.7,1.5Hz,1H),7.23(dd,J＝7.9,1.5Hz,1H),4.30(t,J＝5.2Hz,1H),3.64(s,3H),3.46(t,J＝5.2 ¹³ C NMR(75MHz, CDCl3-d1)δ:173.78,160.38,145.61,144.39,143.49,134.16,131.97,130.87,130.41,130.05,129.44,124.54,124.20,122.40,115.82,1 15.55,54.33,52.69,51.40,42.92, 37.46,33.02,30.26.LC-MS(ESI)m/z:546.09[M+H] ⁺ .

-4-基)丙酸甲酯(化合物26)Example 31: (S) 3-(8-bromo-6-(2-fluorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 26)

¹ H NMR (300 MHz, CDCl ₃ -d ₁ )δ: 7.85 (s, 1H), 7.72 (dd, J = 8.4, 2.6 Hz, 1H), 7.61–7.54 (m, 2H), 7.52 (dd, J ＝7.9,1.5 Hz,1H),7.47(td,J＝7.7,1.6 Hz,1H),7.28(td,J＝7.5,1.5 Hz,1H),7.21(dd,J＝7.8,1.5 Hz,1H) ,7.03(s,2H),6.10(t,J＝5.2 Hz,1H),4.27(td,J＝5.0,1.7 Hz,2H),3.66–3.60(m,5H),2.67–2.51(m,4H ). ^13C NMR (75MHz, CDCl ₃ -d ₁ ) δ172.39,160.89,154.16,148.42,137.37,136.33,136.43,134.20,132.08,131.13,130.83,129.13,128.19,126.39,121.84 ,120.47,57.37,55.24,54.02,51.93, 32.18,28.94,29.34,23.27.LC-MS(ESI)m/z:569.1[M+H] ⁺ .

Pharmacological activity experiments:

In anesthetic experiments, the incubation period generally refers to the time from the start of drug administration to the loss of consciousness of the subject. The shorter the incubation period, the better, indicating that the drug can take effect quickly after administration. The duration of anesthesia generally refers to the duration from the loss of consciousness of the subject to the recovery of consciousness. The duration of drugs in different animal models or animal species will vary. If the duration of anesthesia is too long, it may have adverse inhibitory reactions on the cardiovascular and respiratory systems, such as causing side effects to the patient's nervous system, including drowsiness and dizziness; at the same time, if the duration of anesthesia is too short, it may affect the anesthetic effect and cause problems such as increased anesthetic dosage during surgery.

Example 32. Drug-induced loss of righting reflex in mice:

KM mice (female, 18-25 g) were randomly divided into groups, and after a single rapid injection of the drug via the tail vein, the latency and duration of the disappearance of the righting reflex of the mice were recorded. The experimental results are shown in Table 1 below.

Table 1. Drug-induced loss of righting reflex in mice

As shown in Table 1, in the mouse experiment, the compound of the present invention has an anesthetic effect with a rapid onset and a faster recovery.

Example 33. Drug-induced loss of righting reflex in rats

SD rats (male, 200-280 g) were randomly divided into groups and given a single dose via tail vein rapid injection. The latency and duration of the righting reflex of the rats were recorded.

Table 2. Drug-induced loss of righting reflex in rats

Table 2 above shows that in the rat experiment, the compound of the present invention has an anesthetic effect with rapid onset and rapid recovery.

Example 34. Continuous drug infusion for 20 minutes to induce anesthesia in rats

SD rats (male, 200-280 g) were randomly divided into groups. After an initial dose was rapidly injected via the tail vein, a maintenance dose was continuously infused. After 20 minutes of stopping the infusion, the duration of the righting reflex and the time from awakening to recovery of the rats were recorded.

Table 3. Drug continuous infusion for 20 minutes to induce anesthesia in rats

Table 3 above shows that the compounds of the present invention can maintain anesthesia in animals during continuous infusion, and once the continuous infusion ends, the animals have the characteristics of faster awakening and faster recovery.

Example 35. Cell patch clamp test of the effect of drugs on cell GABA-activated current

The test compound was dissolved in the external solution (NaCl 140mM, KCl 4.7mM, HEPES 10mM, CaCl ₂ 2mM, glucose 10mM, MgCl ₂ 1mM, pH 7.4) at different concentrations. HEK 293T cells were seeded on coverslips and cultured in DMEM medium at 37°C and 5% CO ₂ for 24h. GABA Cl ^- current was recorded in whole cells using a HEKA EPC 10USB patch clamp amplifier. 2μM GABA was used to stimulate Cl ^- current, and the membrane potential was clamped at -60mV. The test compound and 2μM GABA were treated simultaneously to treat the cells, and the induction effect on the Cl ^- current of the same cell and E _max were recorded.

Table 4. Effects on GABA-activated currents in cells

The maximum enhancement percentage E _max and its corresponding concentration (μM) of 2μM GABA current: 100% for normal people. The larger the percentage, the lower the corresponding concentration, and the stronger the depth of anesthesia.

Table 5. Effects on GABA-activated currents in cells

Note: EC ₅₀ (μM) of the positive enhancement of the current induced by 2μM GABA: The concentration of the drug required to achieve a certain depth of anesthesia. The lower the value, the better.

As shown in Tables 4 and 5 above, the compounds of the present invention have a suitable anesthetic depth, indicating that the compounds of the present invention have excellent anesthetic effects.

Example 36. Rate of drug passage through the blood-brain barrier in vitro

A Transwell device (pore size 5.0 μm) was placed in a 24-well cell culture well, and then 1×10 ⁵ /ml hCMEC/D3 cells were transferred to the upper microwell of the Transwell, 150 μL/well, and cell culture medium was added to the lower microwell. When the cells were covered with a monolayer, the culture medium in the well was replaced with EBM-2 complete culture medium containing 1% FBS, and cultured in a CO ₂ incubator for 10 days until it grew into a completely dense monolayer. When the cells were a dense monolayer, 0.1 mg/ml of the compound was added to the lower culture medium, and the concentration of the compound in the upper culture medium was detected after 5 minutes, and the permeability was calculated:

P _compound % = C _{upper layer compound} / C _{lower layer compound} × 100%

Table 6. Test of drug penetration rate through blood-brain barrier

Table 6 above shows that the compound has the effect of quickly breaking through the blood-brain barrier.

Example 37. In vitro plasma half-life test of drugs

Preparation of plasma: After SD rats were fasted but not watered for 12 hours, blood was collected through the orbital venous plexus. The freshly collected blood was placed in a centrifuge tube containing sodium heparin, centrifuged at 5000 rpm for 10 minutes at 4°C, the supernatant was slowly aspirated and aliquoted. Finally, the collected SD rat plasma was sealed and labeled and stored at -20°C for later use.

Prepare target compound samples: accurately weigh the target compound using an analytical balance and prepare a mother solution with a concentration of 2 mg/mL (solvent: V acetone: V Tween 80: V saline = 1:1:3) for later use.

In vitro half-life determination of target compound samples: 20 μL of the mother solution of the test compound and 80 μL of rat plasma were taken and mixed. Nine parallel ep tubes were taken and the corresponding test tubes marked as 0, 1, 2, 3, 5, 10, 15, 20, and 30 min were placed in a 37°C water bath and incubated for 0, 1, 2, 3, 5, 10, 15, 20, and 30 min, respectively. At each time point, 50 μL of the mixed solution was taken out from the corresponding ep tube, 100 mL of acetonitrile was added to precipitate the protein, and the mixture was vortexed for 10 min using a mixer and centrifuged at 12000 rpm for 15 min. The supernatant was taken and centrifuged at 12000 rpm for 10 min again. The Intellistat software in UPLC-MS/MS was used to determine the optimal detection method for the MRM mode of the target compound, the corresponding mass spectrometry peak area was integrated, and its plasma half-life was calculated.

Table 7. Results of in vitro plasma half-life tests of drugs

Table 7 above shows that the compound has the effect of quickly breaking through the blood-brain barrier.

Example 38. Fluorescence polarization technique to detect whether a drug has a potential inhibitory effect on the voltage-gated potassium channel hERG

This experiment measures the effect of eight concentrations of compounds on hERG channel current and calculates the IC ₅₀ . The operation was strictly carried out according to the Predictor ^TM hERG fluorescence polarization assay kit. Before measuring fluorescence polarization, the assay plate was covered to protect the reagent from light and evaporation. After incubation at room temperature for 2-4 hours, the sample plate was centrifuged and the fluorescence polarization value was read. The excitation light was 540nm and the emission light was 573nm. The results showed that the IC ₅₀ values for hERG channel current were all greater than or equal to 30μM, with almost no toxicity. Representative compounds are shown in Table 8 below.

Table 8. Effects of drugs on hERG channel currents

Example 39. LC-MS detection of whether a drug has a potential inhibitory effect on human liver P450s enzymes

The compounds of the present invention at seven concentrations (final concentration of the incubation system) were selected, human liver microsomes and mixed probe substrates (final concentration of the compound/system: midazolam: 5 μmol/L, tolbutamide: 50 μmol/L, omeprazole: 20 μmol/L, phenacetin 50 μmol/L, dextromethorphan 5 μmol/L, testosterone 70 μmol/L, bupropion 20 μmol/L, paclitaxel 5 μmol/L, chlorzoxazone 50 μmol/L) were preheated for 5 min, and then the NADPH energy regeneration system (system components and final concentrations were: MgCl ₂ /10mmol/L, NADP+/1mmol/L, G-6-P/10mmol/L, PDH/2Unit/mL) was added to start the reaction, and the incubation time was 20 min. The content of the organic solvent in the entire reaction system was controlled to be ≤1%. After the incubation, the reaction was terminated in an ice-water bath at 0°C, and the protein was directly precipitated with an acetonitrile solution (1:5, v/v) containing an internal standard (o-methylbenzylamine, 30 ng/mL), fully shaken for 5 min, and 400 μL of supernatant was quantitatively transferred after centrifugation at 18000 rpm*5 min (4°C), and then centrifuged again at 18000 rpm*5 min (4°C), 100 μL of supernatant was quantitatively transferred, and 10 μL was injected. The logarithm of the molar concentration of the drug to be tested was used as the horizontal coordinate, and the ratio of the amount of the corresponding subtype metabolite generated at this concentration level to the amount of the metabolite generated in the corresponding blank solvent group (i.e., the remaining percentage of the subenzyme activity measured at this drug concentration level) was used as the vertical coordinate. The data show that the compounds of the present invention have little effect on drug-drug interactions and little effect on liver metabolism.

Table 9. Effects of drugs on human liver P450s enzymes

The above pharmacological data show that the compound of general formula (I) of the present invention has the characteristics of rapid onset of action, strong depth of action, and rapid awakening, and the preferred compound has almost no accumulation, and its toxicity to the heart is significantly improved, it is almost non-toxic, and has little effect on liver metabolism.

Example 40. Lyophilized powder injection containing active agent compound 32:

Compound 32 (10 g) and glycine (100 g) were added to a bottle, water for injection was added to 1 L, and the pH value of the solution was adjusted to 3.5. The solution was divided into 1000 bottles and prepared into freeze-dried powder injection by conventional freeze-drying method.

The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A benzodiazepine represented by formula (I)

Compounds of the type described herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs thereof:

_R1 is selected from _C1-6 alkyl, _C1-6 alkyl substituted by 3-8 membered heterocyclyl, _C1-6 alkyl substituted by 3-8 membered cycloalkyl, _C1-6 alkyl substituted by _C6-14 aryl, _C1-6 alkyl substituted by 5-14 membered heteroaryl; R ₂ is selected from C _1-6 alkyl, halogen; R ₃ is selected from H, C _1-6 alkyl, halogen; _R4 is selected from H, _C1-6 alkyl, C(O), 5-14 heteroaryl, _C6-14 aryl, which is unsubstituted or optionally substituted by one, two or more R _a ; each R _a is the same or different and is independently selected from _C1-6 alkyl, _C3-8 cycloalkyl, oxo (=O), NR _a1 R _a2 , 3-8 heterocyclyl, 5-8 heteroaryl; R _a1 and R _a1 are the same or different and are independently selected from _{C1-6 alkyl} ; each R _b is the same or different and is independently selected from OH, _C1-6 alkyl, halogen; when _R4 is hydrogen, -SH can resonate with the connected triazole ring to form a =S structure; X is selected from CH or N. When X is CH, R ₃ may be attached to X. 2. The compound according to claim 1, characterized in that R ₁ is selected from C _1-6 alkyl, C _1-6 alkyl substituted with 3-8 membered heterocyclic group; R ₂ is selected from C _1-6 alkyl, halogen; R ₃ is selected from H, C _1-6 alkyl, halogen; _R4 is selected from H, _C1-6 alkyl, C(O), 5-14 membered heteroaryl, unsubstituted or optionally substituted by one, two or more R _a ; each R _a is the same or different and is independently selected from _C1-6 alkyl, _C3-8 cycloalkyl, oxo (=O), NR _a1 R _a2 , 3-8 membered heterocyclyl, 5-8 membered heteroaryl; R _a1 and R _a1 are the same or different and are independently selected from _C1-6 alkyl; each R _b is the same or different and is independently selected from OH, _C1-6 alkyl, halogen; when _R4 is hydrogen, -SH _can resonate with the connected triazole ring to form a =S structure; X is selected from CH or N. When X is CH, R ₃ may be attached to X. 3. The compound according to claim 1 or 2, characterized in that R ₁ is selected from C _1-3 alkyl, C _1-3 alkyl substituted with a 6-membered heterocyclic group; _R2 is selected from halogen; _R3 is selected from H, halogen; _R4 is selected from H, _C1-3 alkyl, C(O), 5-6 membered heteroaryl, unsubstituted or optionally substituted by one, two or more R _a ; each R _a may be the same or different and are independently selected from _C1-3 alkyl, _C3-6 cycloalkyl, oxo (=O), NR _a1 R _a2 , 5-6 membered heterocyclyl, 5-6 membered heteroaryl, unsubstituted or optionally substituted by one, two or more R _b ; R _a1 and R _a1 are the same or different and are independently selected from _C1-3 alkyl; each R _b is the same or different and is independently selected from OH, _C1-3 alkyl, halogen; Preferably, _R1 is selected from methyl,

_R2 is selected from Cl, Br; _R3 is selected from H, F, Cl; R ₄ is selected from H, methyl, ethyl, propyl, C(O), N-methylimidazolyl, which are unsubstituted or optionally substituted by one, two or more _Ra ; each _Ra is the same or different and is independently selected from cyclopropyl, _oxo (=O), morpholinyl, dimethylamino, diethylamino, methyl(ethyl)amino, pyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyridinyl, imidazolyl, 4,5-dihydro-1H-imidazolyl; each R _b is the same or different and is independently selected from OH, F, methyl. 4. The compound according to any one of claims 1 to 3, characterized in that R ₄ is selected from the following groups: H, methyl, ethyl,

5. The compound according to any one of claims 1 to 4, characterized in that the compound represented by formula (I) is selected from the structure represented by formula (II) or formula (III):

Wherein, R ₁ , R ₂ , R ₃ , R ₄ and X have the definitions as described in any one of claims 1-4. 6. The compound according to any one of claims 1 to 5, characterized in that the compound is selected from: (S) 3-(8-Bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 1), (S) 3-(8-Bromo-6-(pyridin-2-yl)-1-ethylthio-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 2), (S) 3-(8-Bromo-6-(pyridin-2-yl)-1-((cyclopropylmethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 3), (S) 3-(8-Bromo-6-(pyridin-2-yl)-1-((2-morpholinoethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl) methyl propionate (Compound 4), (S) 3-(8-Bromo-6-(pyridin-2-yl)-1-(3-((dimethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 5), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl) methyl propionate (Compound 6), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 7), (S) 3-(8-Bromo-6-(2-chlorophenyl)-1-((2-(pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 8), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 9), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 10), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 11), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 12), (S) 3-(8-Bromo-6-(pyridin-2-yl)-1-(((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 13), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 14), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio))-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 15), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-((2-(4-methylpiperazin-1-yl)2-oxoethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 16), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 17), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio))-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 18), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(3-((diethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 19), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 20), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 21), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 22), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-methylpiperidin-2-carbonyl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 23), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)propionic acid 2-morpholinoethyl ester (Compound 24), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 25), (S) 3-(8-Bromo-6-(2-fluorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 26), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-(2-((1H-pyrrol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl) methyl propionate (Compound 27), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 28), (S) 3-(8-Chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 29), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(3-((dimethylamino)-3-oxopropyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 30), (S) 3-(8-chloro-6-(2-chlorophenyl)-1-(((4,5-dihydro-1H-imidazol-2-yl)methyl)thio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

-4-yl)methyl propionate (Compound 31); The structure of the compound is selected from:

7. The compound according to any one of claims 1 to 6, characterized in that its pharmaceutically acceptable salt is selected from acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride/oxide, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate salts of: 1,2-dihydrogen phosphate, ... 8. A method for preparing the compound according to any one of claims 1 to 6, characterized in that it comprises the following steps: Compound A reacts with R ₄ X ₁ to obtain a compound of formula (I); wherein R ₄ has the definition as described in any one of claims 1 to 6, and X ₁ is selected from halogen;

Preferably, the reaction is carried out under the action of a base, and the base is an inorganic base, such as at least one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide. 9. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof. 10. Use of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof in the preparation of a medicament; Preferably, the drug is a sedative or anesthetic drug.