Novel benzodiazepine compounds, methods for their preparation and uses thereof

Abstract

The application discloses a novel compound shown in formula (I), a preparation method and application thereof, and belongs to the field of medicinal chemistry. The benzodiazepine compound has the characteristics of rapid effect, short action time, strong depth, fast metabolism and fast recovery. In the anesthesia experiment on mice and rats, the effect time of the compound is equivalent to that of remazepam, but the action time and recovery time are significantly shortened, the action depth of part of the compounds is obviously strengthened, the compound has the characteristics of faster effect, shorter action time, greater action strength, faster metabolism and faster recovery, and has good heart safety. In the long-term infusion anesthesia experiment on rats, compared with remazepam, the recovery time and recovery time of the short-acting benzodiazepine derivative of the application are significantly shortened, and the compound has the characteristics of faster recovery and faster recovery.

Description

[0001] This invention claims the patent filed on November 9, 2021, with China National Intellectual Property Administration, patent application number 202111322521.5, entitled "A Novel Benzodiazepine". Priority is claimed in the prior application concerning "a class of compounds, methods for their preparation, and uses thereof," the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to benzodiazepine of formula (I) as a short-acting anesthetic. Derivatives, pharmaceutical compositions comprising the derivatives, cassettes comprising the derivatives, methods of their preparation, methods of sedation and anesthesia using the derivatives, and their use in the preparation of sedative and anesthetic drugs. Background Technology

[0003] Anesthetic drugs can temporarily and reversibly cause loss of sensation and pain in the body or a local area, helping patients reduce pain and other discomfort symptoms. They are an essential adjuvant drug in clinical surgery.

[0004] benzodiazepine Benzodiazepines are GABA derivatives. A GABA receptor (also known as γ-aminobutyric acid type A receptor) activator. A The receptor is a gated receptor for chloride ion channels, consisting of two α and two β subunits (α2β2). The β subunit has a GABA receptor; when GABA binds to it, the chloride ion channel opens, allowing an influx of chloride ions, which hyperpolarizes the nerve cell and produces an inhibitory effect. The α subunit contains benzodiazepines. Acceptor, when benzodiazepine When combined with this, it can increase the frequency of chloride channel opening (rather than prolonging the chloride channel opening time or increasing the chloride ion flux) by promoting the binding of GABA to GABAA receptors, thereby resulting in a greater chloride ion influx. This allows benzodiazepines... These derivatives can enhance GABA neurotransmission and synaptic inhibition, thus exerting various therapeutic effects in clinical practice, such as inducing anesthesia, hypnosis, anti-anxiety, and relieving spasms caused by central nervous system lesions or epilepsy.

[0005] benzodiazepine Benzodiazepines are a rapidly developing class of sedative and anesthetic drugs in recent years. They possess good amnesic, anti-anxiety, and sedative effects, and are therefore widely used in the field of sedation and anesthesia. The first benzodiazepine... Class II drugs chlordiazepoxide (Librium) was introduced to the market in 1960. Since then, new types of benzodiazepines have been continuously developed. The emergence of drug classes includes ultra-short-acting (remazolam), short-acting (triazolam / midazolam), intermediate-acting (lorazepam / eszolam), and long-acting (diazepam), etc. Benzodiazepam is commonly used clinically. There are more than 20 derivatives of GABA, and although they are structurally similar, their clinical indications vary. This is because the binding sites and functions of GABA to GABA receptors are heterogeneous. GABA-gated channels in different nerves are composed of different types of subunits, and the composition of these subunits can lead to subtle changes in the interaction between these channels and allosteric modulators, producing different sedative and anesthetic effects. Midazolam was first developed as a water-soluble benzodiazepine in the early 1980s. This type of compound has been introduced to the market and is used intravenously as a means of sedation and anesthesia for short surgeries or intensive care units. However, midazolam produces active metabolites in the body, resulting in a prolonged recovery time for patients from midazolam-induced sedation. Furthermore, the metabolism of midazolam depends on the liver enzyme cytochrome P400. 450 3A4. Drug interactions may occur after administration to patients with impaired liver function. Remimazolam was approved in December 2019 as a novel, ultra-short-acting GABAergic agonist. A The market launch of receptor agonists was based on benzodiazepines. A methyl propionate side chain, which can be rapidly metabolized, is introduced into the core structure. Because its methyl propionate side chain can be rapidly metabolized by esterases, and its main metabolite, azolamyric acid, has almost no sedative or anesthetic activity, the drug's effect is very short-lived, classifying it as an ultra-short-acting benzodiazepine. This type of drug. However, prolonged infusion can still cause problems such as delayed awakening and drug accumulation, and it is currently only approved for sedation and general anesthesia in gastroscopy.

[0006] In summary, benzodiazepines Narcotic drugs often lead to dependence and addiction, and many of their metabolites retain some efficacy, making it difficult for patients to quickly return to normal. Long-term use can easily lead to drug accumulation, hindering their further development. Therefore, the development of benzodiazepines that have rapid onset of action, short recovery time, and no accumulation is crucial. The availability of such drugs is an urgent problem to be solved. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a novel type of benzodiazepine. Class of compounds, their preparation methods and uses.

[0008] This invention provides a benzodiazepine represented by formula (I) Class of compounds, including their pharmaceutically usable salts, stereoisomers, tautomers, polymorphs, solvates, metabolites, or prodrugs:

[0009]

[0010] R1 is selected from C 1-6 Alkyl, 3-8 membered heterocyclic substituted C 1-6 Alkyl, 3-8 membered cycloalkyl substituted C 1-6 Alkyl, C 6-14 aryl-substituted C 1-6 alkyl, 5-14-membered heteroaryl substituted C 1-6 alkyl;

[0011] R2 is selected from C 1-6 Alkyl groups, halogens;

[0012] R3 is selected from H and C. 1-6 Alkyl, halogen; R3 is preferably attached at the 2 or 6 position;

[0013] R4 is selected from H, is unsubstituted, or is optionally composed of one, two, or more R4 groups. a Replacement C 1-6 Alkyl, C(O), 5-14 membered heteroaryl, C 6-14 Aryl; each R a They are identical or different, selected independently of each other without substitution or arbitrarily selected by one, two or more Rs. b Replacement C 1-6 Alkyl, C 3-8 Cycloalkyl, oxo (=O), NR a1 R a2 3-8 membered heterocyclic groups, 5-8 membered heteroaryl groups; R a1 R a1 Same or different, selected independently from C 1-6 Alkyl; each R b They are either the same or different, and are independently selected from OH and C. 1-6 Alkyl groups, halogens; those skilled in the art should understand that when R4 is hydrogen, -SH can resonate with the attached triazole ring to form a =S structure;

[0014] X is selected from CH or N. When X is CH, R3 can be connected to X.

[0015] According to an embodiment of the present invention, R1 can be selected from C. 1-3 alkyl, 6-membered heterocyclic substituted C 1-3 alkyl;

[0016] R2 can be selected from halogens;

[0017] R3 can be selected from H or halogens;

[0018] R4 can be selected from H, without substitution, or optionally replaced by one, two, or more R4s.a Replacement C 1-3 Alkyl, C(O), 5-6 membered heteroaryl; each R a They can be the same or different, and can be selected independently of each other without substitution or arbitrarily selected by one, two or more Rs. b Replacement C 1-3 Alkyl, C 3-6 Cycloalkyl, oxo (=O), NR a1 R a2 5-6 membered heterocyclic group, 5-6 membered heteroaryl group; R a1 R a1 They can be the same or different, and can be selected independently from C. 1-3 Alkyl; each R b They can be the same or different, and are independently selected from OH and C. 1-3 Alkyl groups, halogens.

[0019] According to an embodiment of the present invention, R1 may be selected from methyl,

[0020] R2 can be selected from Cl or Br;

[0021] R3 can be selected from H, F, and Cl;

[0022] R4 can be selected from H, without substitution, or optionally replaced by one, two, or more R4s. a Substituted methyl, ethyl, propyl, C(O), N-methylimidazolyl; each R a They can be the same or different, and can be selected independently of each other without substitution or arbitrarily selected by one, two or more Rs. b Substituted cyclopropyl, oxo(=O), morpholino, dimethylamino, diethylamino, methyl(ethyl)amino, pyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, pyridinyl, imidazoleyl, 4,5-dihydro-1H-imidazolyl; each R b They can be the same or different, and can be independently selected from OH, F, and methyl.

[0023] According to an embodiment of the present invention, R4 may be selected from the following structures: H, methyl, ethyl,

[0024] According to an embodiment of the present invention, the compound represented by formula (I) may be selected from the structures represented by formula (II) or formula (III):

[0025]

[0026]

[0027] Among them, R1, R2, R3, R4, and X have the definitions described above.

[0028] According to an embodiment of the present invention, the compound is selected from:

[0029] (S)3-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 1)

[0030] (S)3-(8-bromo-6-(pyridin-2-yl)-1-ethylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 2)

[0031] (S)3-(8-bromo-6-(pyridin-2-yl)-1-((cyclopropylmethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 3)

[0032] (S)3-(8-bromo-6-(pyridin-2-yl)-1-((2-morpholinoethyl)thio)-4H-benzo[f][1,2,4]triazol[4,3-a][1,4]diaza methyl 4-yl)propionate (compound 4)

[0033] (S)3-(8-bromo-6-(pyridin-2-yl)-1-(3-((dimethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 5)

[0034] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza methyl 4-yl)propionate (compound 6)

[0035] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((pyrrolid-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza methyl 4-yl)propionate (compound 7)

[0036] (S)3-(8-bromo-6-(2-chlorophenyl)-1-((2-(pyrrolid-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 8)

[0037] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza 4-yl)methyl propionate (compound 9)

[0038] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 10)

[0039] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 11)

[0040] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 12)

[0041] (S)3-(8-bromo-6-(pyridin-2-yl)-1-(((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 13)

[0042] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 14)

[0043] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 15)

[0044] (S)3-(8-chloro-6-(2-chlorophenyl)-1-((2-(4-methylpiperazin-1-yl)2-oxoethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 16)

[0045] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 17)

[0046] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio))-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 18)

[0047] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(3-((diethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 19)

[0048] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 20)

[0049] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 21)

[0050] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 22)

[0051] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-methylpiperidin-2-carbonyl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 23)

[0052] (S)3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza 2-morpholinoethyl 4-yl)propionic acid (compound 24)

[0053] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 25)

[0054] (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 26)

[0055] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((1H-pyrrolo-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 27)

[0056] (S)3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 28)

[0057] (S)3-(8-chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 29)

[0058] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(3-((dimethylamino)-3-oxopropyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 30)

[0059] (S)3-(8-chloro-6-(2-chlorophenyl)-1-(((4,5-dihydro-1H-imidazol-2-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza 4-yl)methyl propionate (compound 31).

[0060] According to an embodiment of the present invention, the structure of the compound is selected from:

[0061]

[0062]

[0063] The present invention also provides a method for preparing the compound, comprising the following steps: reacting compound A with R4X1 to obtain the compound shown in formula (I); wherein, R4 has the definition described above, and X1 is selected from halogens;

[0064]

[0065] According to an embodiment of the present invention, the reaction can be carried out under the action of an alkali, which can be an inorganic alkali, such as at least one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide or sodium ethoxide.

[0066] Furthermore, the content or amount of the compound of the present invention in the pharmaceutical composition may be from 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.

[0067] The pharmaceutically acceptable carrier is selected from water, oil, and other injectable solvents.

[0068] The pharmaceutical excipients used are selected from starch, glucose, lactose, brown sugar, gelatin, maltose, acetic acid, silica gel, sodium stearate, glyceryl monostearate, talc, sodium oxide, skim milk powder, glycerin, propylene glycol, ethanol, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethyl cellulose, gelatin, pectin, albumin, trehalose, and dextran.

[0069] Furthermore, its pharmaceutically acceptable salts are selected from acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hydrochlorides / oxides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, malates, maleic anhydride, malonate, and methanesulfonates. Methyl sulfate, naphthate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydronaphthalate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, glycoside, stearate, succinate, tannic acid, tartrate, toluenesulfonate, trifluoroacetate and sine, aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, ethanolamine salt, sodium salt, potassium salt, ammonium salt, tromethamine salt and zinc salt.

[0070] Furthermore, the use of the compound or composition in the preparation of sedative and anesthetic drugs includes conscious sedation during short-term diagnostic, surgical, or endoscopic procedures, induction and maintenance of general anesthesia, and ICU sedation.

[0071] Furthermore, a method of sedation and anesthesia includes administering an effective amount of the compound of any one of claims 1 or the pharmaceutical composition of claim 2 via intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.

[0072] Furthermore, a pharmaceutical formulation comprising, as an active agent, the compound of any one of claims 1 or a pharmaceutically acceptable salt thereof 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 react adversely with the active compound or the patient.

[0073] Furthermore, the dosage form can be a commonly used pharmaceutical dosage form such as a suspension, emulsion, injection, or lyophilized powder for injection.

[0074] Furthermore, the dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0075] A pharmaceutical composition comprising at least one of the following: a therapeutically effective amount of the compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph, a solvate, a metabolite, or a prodrug.

[0076] According to embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water, oils, and other injectable solvents, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.; water is an exemplary carrier when the pharmaceutical composition is administered intravenously; physiological saline, glucose, aqueous glycerol solution, ethanol, propylene glycol, polyethylene glycol, and glycerin can also be used as liquid carriers, particularly for injections or emulsions. Suitable pharmaceutical excipients include starch, glucose, lactose, brown sugar, gelatin, maltose, acetic acid, silica gel, sodium stearate, glyceryl monostearate, talc, sodium oxide, skim milk powder, glycerin, propylene glycol, ethanol, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethyl cellulose, gelatin, pectin, albumin, trehalose, dextran, etc. The composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed.

[0077] The pharmaceutical compositions of the present invention can be administered via suitable routes. Preferably, the pharmaceutical compositions of the present invention are administered via intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.

[0078] Another object of the present invention is to provide a medicine box containing the compounds or pharmaceutical compositions of the present invention.

[0079] Another object of the present invention is to provide a method of sedation and anesthesia, comprising administration, preferably by intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or percutaneous route, of an effective amount of the compound or pharmaceutical composition of the present invention, wherein the sedation and anesthesia method is preferably used for the following clinical treatment regimens: preoperative sedation during surgery; conscious sedation during short-term diagnostic, surgical, 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 anti-anxiety drugs, including sedation, hypnosis, anti-anxiety, and amnesia for early awakening-type insomnia caused by dysfunction of excitation and inhibition of the brain.

[0080] Another object of the present invention is to provide the compounds of the invention for use as sedative and anesthetic drugs, wherein the sedation and anesthesia methods are preferably used for intravenous administration in the following clinical treatment regimens: preoperative sedation during surgery; conscious sedation during short-term diagnostic, surgical, 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 anti-anxiety drugs, including for sedation, hypnosis, anti-anxiety, and amnesia in early-morning insomnia caused by dysfunction of the brain's excitation and inhibition mechanisms.

[0081] The present invention also provides the use of the compound of formula (I), its pharmaceutically pharmaceutically usable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug in the preparation of a medicament.

[0082] According to an embodiment of the present invention, the drug is a sedative or anesthetic drug.

[0083] According to embodiments of the present invention, the sedative and anesthetic drugs are preferably used for intravenous administration in the following clinical treatment regimens: preoperative sedation during surgery; conscious sedation during short-term diagnostic, surgical, 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 anti-anxiety drugs, including sedation, hypnosis, anti-anxiety, and amnesia for early awakening insomnia caused by dysfunction of the brain's excitation and inhibition mechanisms.

[0084] The amount of the compound of the present invention administered will depend on the individual being treated, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. Generally, the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, for example, about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would total about 0.007 mg / day to about 3500 mg / day, for example, about 0.7 mg / day to about 700 mg / day. In some cases, dose levels below the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0085] Beneficial effects

[0086] The short-acting benzodiazepine of the present invention The derivatives of this invention are characterized by rapid onset of action, short duration of action, strong depth of action, rapid metabolism, and rapid recovery. In anesthesia experiments on mice and rats, the short-acting benzodiazepine of this invention... The onset time of this derivative is comparable to that of remimazolam, but both the duration of action and recovery time are significantly shortened. Furthermore, some compounds exhibit a markedly enhanced depth of action, demonstrating faster onset, shorter duration of action, greater potency, faster metabolism, and faster recovery. In long-term infusion anesthesia experiments on rats, compared to remimazolam, the short-acting benzodiazepine of this invention... The awakening and recovery times of the derivatives are significantly shortened, exhibiting characteristics such as faster awakening and faster recovery; the benzodiazepine of this invention... These compounds not only maintain their dependence on GABA A The high affinity and selectivity of the receptor, and through benzodiazepines The structural modifications and adjustments to the carboxylic acid ester groups provide the following advantages: predictable rapid onset of sedation and anesthesia, short effective duration of action, strong depth of action, and short recovery time, thereby reducing adverse inhibitory reactions on the cardiovascular and respiratory systems and reducing side effects on the patient's nervous system, including drowsiness and dizziness. Moreover, the compounds of this invention exhibit good cardiac safety, less cardiotoxicity, and minimal impact on liver metabolism, and have broader prospects for drug development.

[0087] Terminology Definitions and Explanations

[0088] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0089] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. Furthermore, when certain numerical ranges are defined as "numbers", it should be understood that they describe the two endpoints of the range, each integer within the range, and each decimal within the range.

[0090] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0091] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0092] Term "C" 1-6"Alkyl" means a straight-chain or 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 their isomers.

[0093] Term "C" 3-8 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) or tricyclic alkanes having 3, 4, 5, 6, 7, or 8 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0094] The term "3-8 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system containing one or more heteroatoms independently selected from N, O, and S, with a total ring atom number of 3-8 (e.g., 3, 4, 5, 6, 7, 8 atoms). For example, it is a 4-, 5-, 6-, or 7-membered monocyclic, a 7-, or 8-membered bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic ring system, containing at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2- states. The heterocyclic group can be connected to the rest of the molecule via any of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirmonobutylene and oxobutylene; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. When the 3-8-membered heterocyclic group is connected to other groups to form the compound of the present invention, the carbon atom on the 3-8-membered heterocyclic group may be connected to other groups, or the heterocyclic atom on the 3-8-membered heterocyclic ring may be connected to other groups. For example, when the 3-8-membered heterocyclic group is selected from piperazineyl, the nitrogen atom on the piperazineyl group 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 at its para position may be connected to other groups.

[0095] Term "C"6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-14 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0096] The term "5-14-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), 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, such as "5-14-membered heteroaryl". "5-14-membered heteroaryl" should also be 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, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzo-fused. "Heteroaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. When the 5-14 membered heteroaryl group is linked with other groups to form the compound of the present invention, the carbon atom on the 5-14 membered heteroaryl ring may be linked with other groups, or the heteroatom on the 5-14 membered heteroaryl ring may be linked with other groups. When the 5-14 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom on the heteroaryl ring linked with a carbon atom may be substituted, or the hydrogen atom on the heteroaryl ring linked with a heteroatom may be substituted.

[0097] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0098] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0099] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms. Detailed Implementation

[0100] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory 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 covered within the scope of protection intended by the present invention.

[0101] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0102] The abbreviations used in this article have the following meanings:

[0103]

[0104]

[0105] The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR). 1 H NMR, 13 The reaction was confirmed by 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, and petroleum ether and ethyl acetate system.

[0106] Column chromatography typically uses 200-300 mesh silica gel as the stationary phase; the eluent systems include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

[0107] In the following examples, unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0108] Example 1: (S)3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Synthesis of 2-morpholinoethyl 4-yl)propionic acid (compound 24)

[0109]

[0110] Step 1: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Preparation of 4-yl)propionic acid:

[0111] The compound (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza) Methyl 4-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza)propionate (compound 1a, 3.00 g, 0.0067 mol) was dissolved in DCM, and LiOH was added. The reaction was carried out at room temperature for 6 hours until LCMS showed the end of the reaction. The filtrate was collected and the reaction solvent was removed by vacuum distillation. The residual product was purified by column chromatography (dichloromethane / methanol, 150:1, v / v) to give a white solid (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza) -4-yl)propionic acid (compound 1b, 2.16 g, yield: 74.4%).

[0112] Step 2: (S)3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Preparation of 2-morpholinoethyl 4-yl)propionic acid:

[0113] The compound (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza) -4-yl)propionic acid (compound 1b, 2.16 g, 0.005 mol) was dissolved in DCM, and DCC (1.24 g, 0.006 mol) and a catalytic amount of DMAP were added. The reaction was carried out at room temperature for 12 hours until LCMS showed the end of the reaction. The filtrate was collected and the reaction solvent was removed by vacuum distillation. The residual product was purified by column chromatography (petroleum ether / ethyl acetate, 2:1, v / v) to give a white solid (S)3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza -4-yl)propionic acid-2-morpholinoethyl ester (compound 1c, 1.81 g, yield: 63.2%).

[0114] 1H NMR(300MHz, CDCl3-d1)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, CDCl3-d1)δ:173.82,172.99,145.29,143.07,143.02,132.79,130.64,130.52,129.38,129.37,129.30,12 8.94,128.72,128.62,124.74,122.85,66.04,65.90,55.35,54.26,53.77,30.86,30.56.LC-MS(ESI)m / z:546.11[M+H] + .

[0115] Example 2: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidine-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Synthesis of methyl 4-yl)propionate (compound 6)

[0116]

[0117] Step 1: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyrrolidine-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Preparation of methyl 4-yl)propionate:

[0118] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (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 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 (0.058 g, 0.44 mmol) was added, and the mixture was reacted at room temperature for 8 hours. After concentration under reduced pressure, column chromatography (PE:EA = 3:1) was performed to give a white solid (compound 6, 0.072 g, yield: 59.2%).

[0119] 1 H NMR(300MHz, CDCl3-d1)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, CDCl3-d1) δ173.30,160.77,154.13,148.12,138.12,135.83,134.71,132.61,130.82,130.51,130.43,129.2 9,129.04,128.19,126.36,122.81,57.76,55.23,54.02,51.98,32.51,29.56,29.39,23.39.LC-MS(ESI)m / z:544.1[M+H] + .

[0120] Examples 3-17 (compounds 9, 11, 14, 16, 17, 19, 20, 22, 23, 25, 27-31) were all synthesized according to the corresponding methods in the above examples. Specific NMR and CMR characterization data are as follows:

[0121] Example 3: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 9)

[0122] 1H NMR(300MHz, CDCl3-d1)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, CDCl3-d1) δ173.63,160.77,154.20,148.15,138.23,135.93,134.66,132.61,130.83,130.54,130.43,129.22,1 29.10,128.13,126.35,122.71,57.76,54.95,54.06,51.97,32.18,29.54,29.39,26.64,23.96.LC-MS(ESI)m / z:558.2[M+H] + .

[0123] Example 4: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 11)

[0124] 1 H NMR(300MHz, CDCl3-d1)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). 13C NMR (75MHz, CDCl3-d1) δ173.65,161.70,154.16,149.79,147.48,146.26,138.07,135.66,134.71,132.61,130.82,130.51 ,130.43,129.36,129.04,128.19,126.36,124.08,122.76,57.76,51.96,39.84,29.54,29.39.LC-MS(ESI)m / z:538.1[M+H] + .

[0125] Example 5: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 14)

[0126] 1 H NMR(300MHz, CDCl3-d1)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, CDCl3-d1) δ172.98,160.92,154.16,148.12,137.98,135.93,134.65,132.65,131.03,130.83,130.56,129.18,1 29.10,128.07,126.30,122.69,118.58,57.87,54.60,51.78,48.83,32.57,31.95,9.54,29.49.LC-MS(ESI)m / z:594.4[M+H] + .

[0127] Example 6: (S)3-(8-chloro-6-(2-chlorophenyl)-1-((2-(4-methylpiperazin-1-yl)2-oxoethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 16)

[0128] 1 H NMR (300MHz, CDCl3-d1) 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, CDCl3-d1) δ173.37,171.54,160.92,154.17,147.98,137.98,136.05,134.72,132.65,131.16,130.83,130.56,1 29.18,129.10,128.33,126.44,122.74,56.97,54.43,51.80,46.07,45.25,35.71,29.47,29.78.LC-MS(ESI)m / z:587.5[M+H] + .

[0129] Example 7: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 17)

[0130] 1 H NMR(300MHz, CDCl3-d1)δ7.69(d,J=8.3Hz,1H),7.61–7.54(m,2H),7.54–7.45(m,2H),7.41–7.30(m ,2H),6.12(t,J=5.4Hz,1H),3.77–3.62(m,7H),2.74–2.63(m,2H),2.60–2.45(m,6H),2.29(s,3H). 13C NMR (75MHz, CDCl3-d1) δ173.22,164.87,160.77,154.72,143.84,137.98,136.55,134.71,132.60,130.83,130.54,130.4 3,129.20,129.10,128.16,126.36,122.85,57.81,54.27,52.08,47.39,45.36,29.54,29.57.LC-MS(ESI)m / z:573.1[M+H] + .

[0131] Example 8: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(3-((diethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 19)

[0132] 1 H NMR(300MHz, CDCl3-d1)δ:7.91(d,J=1.6Hz,1H),7.62(dd,J=7.2,2.2Hz,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:173.62,145.70,144.01,141.27,138.92,132.79,130.73,130.17,129.99,129.43,129.37,128.94,1 28.72,128.62,124.77,120.33,54.20,53.56,51.40,47.08,33.51,33.02,31.91,30.11,11.83.LC-MS(ESI)m / z:560.16[M+H] + .

[0133] Example 9: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((dimethylamino)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 20)

[0134] 1H NMR (300MHz, CDCl3-d1) 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:173.88,145.68,144.42,143.87,138.88,133.17,130.68,130.54,129.82,129.72,129.4 6,129.41,128.74,124.66,122.11,54.20,52.83,51.40,42.92,37.46,33.02,31.93.LC-MS(ESI)m / z:518.11[M+H] + .

[0135] Example 10: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 22)

[0136] 1 H NMR(300MHz, CDCl3-d1)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),3.63–3.5 1(m,2H),3.48(d,J=0.9Hz,2H),2.62(d,J=2.4Hz,4H),2.55(s,2H),2.44–2.3 2(m,2H),2.33(d,J=7.0Hz,1H),2.25(d,J=12.5Hz,1H),1.79(d,J=7.5Hz,4H). 13C 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. 60,128.19,124.67,119.77,67.85,54.33,51.50,50.74,50.54,33.99,33.02,32.94,31.92.LC-MS(ESI)m / z:574.14[M+H] + .

[0137] Example 11: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-methylpiperidin-2-carbonyl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 23)

[0138] 1 H NMR(300MHz, CDCl3-d1)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 ),2.62(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, 128.60,128.19,124.68,122.11,62.34,54.53,54.33,51.45,41.64,33.02,31.91,28.57,26.60,22.95.LC-MS(ESI)m / z:571.12[M+H] + .

[0139] Example 12: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 25)

[0140] 1 H NMR(300MHz, CDCl3-d1)δ:7.85(s,1H),7.63(d,J=8.3Hz,1H),7.59–7.51(m,3H),7.47(dd,J=7.7,1.7Hz,1H),7.38(td,J=2 3.6,7.4,1.6Hz,2H),7.03(s,2H),6.10(t,J=5.2Hz,1H),4.27(td,J=5.0,1.6Hz,2H),3.66–3.60(m,5H),2.66–2.51(m,4H). 13 C NMR(75MHz, CDCl3-d1)δ:173.87,145.66,145.05,143.04,139.39,138.93,133.92,132.79,130.68,130.55,129.71,129.46,12 9.44,129.37,129.31,128.94,128.62,124.73,120.33,54.20,51.40,49.21,36.04,33.07,31.90.LC-MS(ESI)m / z:541.09[M+H] + .

[0141] Example 13: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(2-((1H-pyrrolo-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 27)

[0142] 1H NMR(300MHz, CDCl3-d1)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 ,128.94,128.62,125.93,124.70,120.33,119.18,54.20,53.61,51.39,36.04,33.00,31.89.LC-MS(ESI)m / z:540.09[M+H] + .

[0143] Example 14: (S)3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 28)

[0144] 1 H NMR(300MHz, CDCl3-d1)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). 13C 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 ,129.70,129.46,129.44,128.94,128.70,124.72,122.11,54.20,51.40,33.80,33.05,30.26; LC-MS(ESI)m / z:527.07[M+H] + .

[0145] Example 15: (S)3-(8-chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 29)

[0146] 1 H NMR (300MHz, CDCl3-d1) 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:173.90,162.05,148.74,146.39,143.80,138.87,133.16,130.61,130.53,129.82,129.75,129.4 6,129.45,129.25,128.74,124.69,124.25,54.19,51.41,43.61,34.27,32.98,30.26,12.47.LC-MS(ESI)m / z:532.09[M+H] + .

[0147] Example 16: (S)3-(8-chloro-6-(2-chlorophenyl)-1-(3-((dimethylamino)-3-oxopropyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 30)

[0148] 1 H NMR(300MHz, CDCl3-d1)δ:7.89(d,J=1.9Hz,1H),7.61(dd,J=7.1,2.2Hz,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). 13 C NMR(75MHz, CDCl3-d1)δ:173.78,172.42,145.67,144.02,143.04,138.84,132.79,130.60,130.55,129.74,129.46,129.3 7,129.02,128.93,128.62,124.74,120.33,54.22,51.42,36.42,35.74,33.03,31.88,31.67.LC-MS(ESI)m / z:546.1[M+H] + .

[0149] 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]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 31)

[0150] 1 H NMR(300MHz, CDCl3-d1)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,1 H),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). 13C NMR(75MHz, CDCl3-d1)δ:173.87,159.44,145.60,143.90,141.65,138.93,133.18,130.69,130.56,129.82,129.73,129.4 6,129.44,128.91,128.70,124.73,122.11,54.18,51.38,44.30,44.27,41.81,33.04,31.95.LC-MS(ESI)m / z:529.1[M+H] + .

[0151] Example 18: (S)3-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Synthesis of methyl 4-yl)propionate (compound 1)

[0152]

[0153] Step 1: Preparation of methyl (S)-5-((4-bromo-2-pyridinylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (compound 2c):

[0154] 2-(2-amino-5-bromo-benzoyl)pyridine (compound 2a, 10.00 g, 0.036 mol) and compound N-tert-butoxycarbonyl-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 the mixture was stirred for 12 hours. The reaction was complete as indicated by LCMS. The filtrate was collected, and the reaction solvent was removed under reduced pressure. The remaining product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to give a white solid (S)-5-((4-bromo-2-pyridinylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate methyl ester (compound 2c, 10.55 g, yield: 56.2%).

[0155] Step 2: Preparation of (S)-4-amino-5-((5-bromo-2-pyridinylphenyl)amino)-5-oxovalerate methyl ester (compound 2d):

[0156] Methyl (S)-5-((4-bromo-2-pyridinylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (compound 2c, 10.55 g) was dissolved in DCM (100 mL). TFA (100 mL) was added, and the mixture was stirred for 20 minutes until LCMS showed the reaction was complete. The reaction solution was concentrated, and the residue obtained was crude methyl (S)-4-amino-5-((5-bromo-2-pyridinylphenyl)amino)-5-oxovalerate (compound 2d, 9.6 g), which was used directly in the next reaction.

[0157] Step 3: (S)-3-(7-bromo-2-oxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Preparation of methyl 3-yl)propionate (compound 2e):

[0158] Methyl (S)-4-amino-5-((5-bromo-2-pyridinylphenyl)amino)-5-oxovalerate (compound 2d, 9.6 g) was dissolved in MeOH (100 mL), and the pH was adjusted to approximately 10 with NaHCO3. The mixture was stirred for 24 hours. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was poured into ice water and extracted with ethyl acetate. The organic phase was washed three times with water, dried, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 2:1, v / v) to give a white (S)-3-(7-bromo-2-oxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Methyl 3-yl)propionate (compound 2e, 5.72 g, yield: 32.1%).

[0159] Step 4: (S)-3-(7-bromo-2-thio-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Preparation of methyl 3-yl)propionate (compound 2f):

[0160] (S)-3-(7-bromo-2-oxo-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Methyl (-3-yl)propionate (compound 2e, 5.72 g) was dissolved in toluene (110 mL), and Lawson's reagent (4.86 g, 0.012 mol) was added. The compound was heated to 100 °C and stirred for 1.5 hours until the reaction was complete as indicated by LCMS. Excess Lawson's reagent was removed by adding saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The reaction solvent was removed by vacuum distillation. The residual product was purified by column chromatography (petroleum ether / ethyl acetate, 7:1, v / v) to give a pale yellow solid (S)-3-(7-bromo-2-thio-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl 3-yl)propionate (compound 2f, 3.10 g, yield: 53.4%).

[0161] Step 5: (S)-3-(7-bromo-5-(2-pyridyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diaza Preparation of methyl 3-yl)propionate (compound 2g):

[0162] (S)-3-(7-bromo-2-thio-5-(2-pyridyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Methyl (-3-yl)propionate (compound 2f, 3.10 g) was dissolved in 30 mL THF. The mixture was cooled to 0 °C, and 80% hydrazine hydrate (1.56 g, 0.031 mol) was added. The mixture was stirred for 30 minutes until the reaction was complete as indicated by LCMS. Excess hydrazine hydrate was removed with saturated NaCl, and the organic phases were extracted with DCM. The combined organic phases were dried and concentrated to give crude (S)-3-(7-bromo-5-(2-pyridyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl 3-yl)propionate (compounds 2g and 3.00g) was used directly in the next reaction.

[0163] Step 6: (S)-3-(7-bromo-5-(pyridin-2-yl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Preparation of methyl 4-yl)propionate (compound 2h):

[0164] (S)-3-(7-bromo-5-(2-pyridyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl (-3-yl)propionate (2 g of compound, 3.00 g) was dissolved in 80 mL of THF, and TEA (1.77 g, 0.018 mol) was added. The mixture was cooled to 0 °C, and sulfur phosgene (1.0 g, 0.009 mol) was added. The mixture was stirred for 2 h until the reaction was complete as indicated by LCMS. The filtrate was collected, and the reaction solvent was removed under reduced pressure. The residual product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to give a white solid (S)-3-(7-bromo-5-(pyridin-2-yl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza) Methyl 4-yl)propionate (compound 2h, 1.46g, yield: 42.5%).

[0165] Step 7: (S)3-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Preparation of methyl 4-yl)propionate (compound 1):

[0166] (S)-3-(7-bromo-5-(pyridin-2-yl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza) was dissolved in 5 mL of 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. Iodomethane (0.062 g, 0.44 mmol) was added, and the reaction was carried out at room temperature for 8 hours. The mixture was then concentrated under reduced pressure and subjected to column chromatography (PE:EA = 3:1) to give a white solid (S)3-(8-bromo-6-(pyridin-2-yl)-1-methylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (Compound 1, 0.071 g, yield: 68.9%)

[0167] 1 H NMR(300MHz, CDCl3-d1)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). 13C NMR (75MHz, CDCl3-d1) 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] + .

[0168] Examples 19-23 (compounds 2-5, 13) were synthesized according to the corresponding methods in the above examples. Specific NMR and CMR characterization data are as follows:

[0169] Example 19: (S)3-(8-bromo-6-(pyridin-2-yl)-1-ethylthio-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 2)

[0170] 1 H NMR (300MHz, CDCl3-d1) 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, CDCl3-d1) δ173.72,160.73,157.51,153.83,151.63,147.12,137.61,137.47,136.40,134.75,12 5.25,124.56,123.44,122.65,120.39,66.22,57.42,52.01,29.61,29.23,14.70.LC-MS(ESI)m / z:486.1[M+H] + .

[0171] Example 20: (S)3-(8-bromo-6-(pyridin-2-yl)-1-((cyclopropylmethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 3)

[0172] 1 H NMR (300MHz, CDCl3-d1) 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, CDCl3-d1) δ173.58,162.37,156.38,154.59,149.57,147.13,137.57,137.28,136.60,134.78,127.9 3,125.30,122.76,122.64,120.55,59.05,51.80,39.41,29.45,29.28,10.89,6.19.LC-MS(ESI)m / z:512.4[M+H] + .

[0173] Example 21: (S)3-(8-bromo-6-(pyridin-2-yl)-1-((2-morpholinoethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 4)

[0174] 1 H NMR (300MHz, CDCl3-d1) δ8.58(d,J=4.2Hz,1H),8.18(d,J=7.9Hz,1H),7.85(d d,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). 13C NMR (75MHz, CDCl3-d1) δ173.62,162.11,156.69,154.59,148.12,147.31,137.47,137.09,136.60,135.16,128.24,1 25.26,122.73,122.59,120.96,65.69,58.05,54.45,53.31,51.93,32.18,29.54,29.28.LC-MS(ESI)m / z:571.1[M+H] + .

[0175] Example 22: (S)3-(8-bromo-6-(pyridin-2-yl)-1-(3-((dimethylamino)propyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 5)

[0176] 1 H NMR (300MHz, CDCl3-d1) δ8.79 (dd, J=3.6, 1.2Hz, 1H), 7.81 (td, J=7.6, 1.2Hz, 1 H),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, CDCl3-d1) δ173.33,162.11,156.72,154.49,147.89,146.31,137.30,137.09,136.67,135.32,128.24,1 25.26,122.74,122.32,120.94,58.49,58.05,51.96,44.90,32.55,29.54,29.28,26.44.LC-MS(ESI)m / z:543.2[M+H] + .

[0177] Example 23: (S)3-(8-bromo-6-(pyridin-2-yl)-1-(((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 13)

[0178] 1 H NMR (300MHz, CDCl3-d1) 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(m,1H),7.36–7.32(m, 2H),4.55–4.37(m,2H),4.30–4.21(m,1H),3.69(s,3H),2.93–2.77(m,4H). 13 C NMR (75MHz, CDCl3-d1) 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] + .

[0179] Example 24: (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((pyrrolidine-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 7)

[0180]

[0181] Step 1: Preparation of methyl (S)-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (compound BF-02):

[0182] 2-Amino-5-bromo-2'-fluorobenzophenone (compound BF-01, 9.82 g, 0.034 mol) and N-tert-butoxycarbonyl-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 the mixture was stirred for 12 hours. LC-MS showed that the reaction was complete. The filtrate was collected, and the reaction solvent was removed under reduced pressure. The remaining product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to give a white solid (S)-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate methyl ester (compound BF-02, 10.56 g, yield: 70.90%).

[0183] Step 2: Preparation of (S)-4-amino-5-((2-fluorobenzoyl-4-bromophenyl)amino)-5-oxovalerate methyl ester (compound BF-03):

[0184] Methyl (S)-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxovalerate (compound BF-02, 10.56 g) was dissolved in DCM (50 mL). TFA (50 mL) was added, and the mixture was stirred for 20 minutes until the reaction was complete as indicated by LC-MS. The reaction solution was concentrated, and the residue obtained was crude methyl (S)-4-amino-5-((2-fluoro-benzoyl-4-bromophenyl)amino)-5-oxovalerate (compound BF-03, 8.41 g), which was directly used in the next step of the reaction.

[0185] Step 3: (S)-3-(7-bromo-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Preparation of methyl 3-yl)propionate (compound BF-04):

[0186] Methyl (S)-4-amino-5-((2-fluorobenzoyl-4-bromophenyl)amino)-5-oxopentanoate (compound BF-03, 8.41 g) was dissolved in MeOH (100 mL), and the pH was adjusted to approximately 10 with NaHCO3. The mixture was stirred for 24 hours. LC-MS showed the reaction was complete. The reaction solution was filtered, and the filtrate was poured into ice water and extracted with ethyl acetate. The organic phase was washed three times with water, dried, and concentrated. The residual product was purified by column chromatography (petroleum ether / ethyl acetate, 2:1, v / v) to give a white (S)-3-(7-bromo-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][l,4]diaza)- Methyl 3-yl)propionate (compound BF-04, 7.5g)

[0187] Step 4: (S)-3-(7-bromo-5-(2-fluorophenyl)-2-thio-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of methyl 3-yl)propionate (compound BF-05):

[0188] (S)-3-(7-bromo-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][l,4]diaza Methyl (-3-yl)propionate (compound BF-04, 7.5 g) was dissolved in toluene (200 mL), and Lawson's reagent (4.86 g, 0.012 mol) was added. The compound was heated to 100 °C and stirred for 1.5 hours until the reaction was complete as indicated by LCMS. Excess Lawson's reagent was removed by adding saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The reaction solvent was removed under reduced pressure. The residual product was purified by column chromatography (petroleum ether / ethyl acetate, 7:1, v / v) to give a pale yellow solid (S)-3-(7-bromo-5-(2-fluorophenyl)-2-thio-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl 3-yl)propionate (compound BF-05, 4.07 g, yield: 52.1%)

[0189] Step 5: (S)-3-(7-bromo-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diaza Preparation of methyl 3-yl)propionate (compound BF-06):

[0190] (S)-3-(7-bromo-5-(2-fluorophenyl)-2-thio-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl (-3-yl)propionate (compound BF-05, 4.07 g) was dissolved in 50 mL THF. The mixture was cooled to 0 °C, and 80% hydrazine hydrate (1.56 g, 0.031 mol) was added. The mixture was stirred for 30 minutes until the reaction was complete as indicated by LCMS. Excess hydrazine hydrate was removed with saturated NaCl, and the organic phases were extracted with DCM. The combined organic phases were dried and concentrated to give crude (S)-3-(7-bromo-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl 3-yl)propionate (compound BF-06, 3.1 g) was used directly in the next reaction.

[0191] Step 6: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-thio-2-2,4-dihydro-1H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Preparation of methyl 4-yl)propionate (the tautomer of compound BF-07):

[0192] (S)-3-(7-bromo-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diaza Methyl 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%) was dissolved in 80 mL of THF, and TEA (1.77 g, 0.018 mol) was added. The mixture was cooled to 0 °C, and sulfur phosgene (1.0 g, 0.009 mol) was added. The mixture was stirred for 2 h until the reaction was complete as indicated by LCMS. The filtrate was collected and the reaction solvent was removed under reduced pressure. The residual product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to give 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%).

[0193] Step 7: Compound BF-07 (0.1 g, 0.22 mmol) was dissolved in 5 ml of 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 mixture was reacted at room temperature for 8 h. The mixture was then concentrated under reduced pressure and subjected to column chromatography (PE:EA = 3:1) to give a white solid (compound 7, 0.071 g, yield: 68.9%).

[0194] 1 H NMR (300MHz, CDCl3-d1) 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=5.1Hz,2H),2.74(t,J=4.9Hz,4H),2.65–2.51(m,6H),1.89-182(m,4H). 13C NMR (75MHz, CDCl3-d1) δ173.65,163.32,159.17,154.22,147.98,136.64,136.54,132.59,131.54,130.23,128.57,127.7 0,124.00,121.79,120.47,115.76,58.29,55.23,54.02,51.93,32.18,29.54,29.30,23.40.LC-MS(ESI)m / z:572.1[M+H] + .

[0195] Examples 25-31 (compounds 8, 10, 12, 15, 18, 21, and 26) were all synthesized according to the corresponding methods described in the above examples. Specific NMR and CMR characterization data are as follows:

[0196] Example 25: (S)3-(8-bromo-6-(2-chlorophenyl)-1-((2-(pyrrolidine-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 8)

[0197] 1 H NMR(300MHz, CDCl3-d1)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=5.2Hz,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, CDCl3-d1) δ173.57,160.33,154.78,149.12,137.49,136.40,136.44,134.71,133.11,131.17,130.63,129.3 6,128.19,126.09,121.84,120.47,57.87,55.33,54.02,51.93,32.14,29.54,29.39,23.33.LC-MS(ESI)m / z:588.0[M+H] + .

[0198] Example 26: (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((piperidin-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 10)

[0199] 1 H NMR (300MHz, CDCl3-d1) 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=5.1Hz,2H),2.68–2.51(m,10H),1.58-1.54(m,4H),1.48–1.37(m,2H). 13 C NMR (75MHz, CDCl3-d1) δ173.60,163.21,159.19,154.15,148.12,136.35,136.54,132.44,131.52,130.23,128.53,127.70,1 24.00,121.85,120.25,115.78,58.29,54.90,54.06,51.93,32.18,29.54,29.30,26.83,24.03.LC-MS(ESI)m / z:586.1[M+H] + .

[0200] Example 27: (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((pyridin-4-yl)methyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 12)

[0201] 1H NMR (300MHz, CDCl3-d1) 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, CDCl3-d1) δ173.62,163.35,159.17,154.16,149.79,147.48,146.26,136.60,136.54,132.67,131.51,130.23 ,128.53,127.70,124.09,124.00,121.79,120.47,115.76,58.29,51.92,39.84,29.54,29.30.LC-MS(ESI)m / z:566.4[M+H] + .

[0202] Example 28: (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((4,4-difluoropiperidin-1-yl)ethyl)thio))-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 15)

[0203] 1 H NMR(300MHz, CDCl3-d1)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),3.6 6(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). 13C NMR (75MHz, CDCl3-d1) δ173.33,163.02,159.33,154.16,148.12,136.55,136.54,132.67,131.53,130.23,128.58,127.70,1 23.91,121.85,120.45,118.58,115.77,58.29,54.60,51.94,48.71,32.61,32.23,29.34,29.63.LC-MS(ESI)m / z:622.5[M+H] + .

[0204] Example 29: (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazine-1-carbonyl)thio))-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 18)

[0205] 1 H NMR (300MHz, CDCl3-d1)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,1 H),6.12(t,J=5.4Hz,1H),3.77–3.68(m,2H),3.68–3.63(m,5H),2.74–2.63 (m,2H),2.57(ddd,J=7.9,5.5,1.0Hz,2H),2.55–2.45(m,4H),2.29(s,3H). 13 C NMR(75MHz, CDCl3-d1)δ:173.61,167.58,160.70,148.74,143.80,143.14,132.49,131.38,131.10,129.83,129.44,129.4 0,124.54,124.20,121.80,115.88,115.73,54.33,54.18,51.71,51.50,44.98,33.02,31.91.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]diaza Methyl 4-yl)propionate (compound 21)

[0206] 1 H NMR(300MHz, CDCl3-d1)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=5.2Hz,2H),2.71(dt ,J=12.4,5.2Hz,1H),2.69–2.57(m,3H),2.60–2.51(m,2H),2.29(s,6H). 13 C NMR(75MHz, CDCl3-d1)δ:173.78,160.38,145.61,144.39,143.49,134.16,131.97,130.87,130.41,130.05,129.44,12 4.54,124.20,122.40,115.82,115.55,54.33,52.69,51.40,42.92,37.46,33.02,30.26.LC-MS(ESI)m / z:546.09[M+H] + .

[0207] Example 31: (S)3-(8-bromo-6-(2-fluorophenyl)-1-(2-((1H-imidazol-1-yl)ethyl)thio)-4H-benzo[f][1,2,4]triazole[4,3-a][1,4]diaza Methyl 4-yl)propionate (compound 26)

[0208] 1 H NMR (300 MHz, CDCl3-d1) 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, CDCl3-d1) δ172.39,160.89,154.16,148.42,137.37,136.33,136.43,134.20,132.08,131.13,130.83,129.1 3,128.19,126.39,121.84,120.47,57.37,55.24,54.02,51.93,32.18,28.94,29.34,23.27.LC-MS(ESI)m / z:569.1[M+H] + .

[0209] Pharmacological activity experiments:

[0210] In anesthetic drug experiments, the latency period generally refers to the time from the start of drug administration to the loss of consciousness in the subject. A shorter latency period is better, indicating a rapid onset of action. The duration of anesthesia generally refers to the time from loss of consciousness to regained consciousness in the subject. The duration of anesthesia varies depending on the animal model or species. An excessively long duration of anesthesia may cause adverse inhibitory effects on the cardiovascular and respiratory systems, such as neurological side effects including drowsiness and dizziness; conversely, an excessively short duration of anesthesia may affect the anesthetic effect, leading to problems such as increased intraoperative anesthetic dosage.

[0211] Example 32. Experiment on drug-induced loss of righting reflex in mice:

[0212] KM mice (female, 18-25g) were randomly divided into groups. After a single rapid intravenous injection of the drug via the tail vein, the latency and duration of loss of the righting reflex were recorded. The experimental results are shown in Table 1 below.

[0213] Table 1. Tests showing drug-induced loss of righting reflex in mice

[0214]

[0215]

[0216] As shown in Table 1, in mouse experiments, the compounds of the present invention have an anesthetic effect with rapid onset and even faster recovery.

[0217] Example 33. Test on drug-induced loss of righting reflex in rats

[0218] SD rats (male, 200-280g) were randomly divided into groups. After a single rapid bolus injection of the drug via the tail vein, the latency and duration of the righting reflex were recorded.

[0219] Table 2. Tests showing drug-induced loss of righting reflex in rats

[0220]

[0221] Table 2 above shows that, in rat experiments, the compounds of the present invention have a rapid onset and rapid recovery anesthetic effect.

[0222] Example 34. Rat anesthesia induction experiment by continuous drug infusion for 20 minutes

[0223] SD rats (male, 200-280g) were randomly divided into groups. The initial dose was rapidly injected via the tail vein, followed by a maintenance dose. After 20 minutes, the duration of the righting reflex and the time from awakening to recovery were recorded.

[0224] Table 3. Rat anesthesia induced by continuous drug infusion for 20 minutes

[0225]

[0226] 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, they have the characteristics of faster awakening and faster recovery.

[0227] Example 35. Effect of drugs on cellular GABA activation currents detected by cell patch clamp assay

[0228] The test compounds were dissolved in different concentrations in external solutions (NaCl 140mM, KCl 4.7mM, HEPES 10mM, CaCl2 2mM, glucose 10mM, MgCl2 1mM, pH 7.4). HEK 293T cells were seeded on coverslips and cultured in DMEM medium at 37°C and 5% CO2 for 24 h. GABA Cl - Whole-cell recordings were performed using a HEKA EPC 10USB patch-clamp amplifier. 2 μM GABA was used to excite Cl... - Current and membrane potential were clamped at -60 mV. Cells were simultaneously treated with the analyte compound and 2 μM GABA, and the effect on Cl- in the same cells was recorded. - The induction effect of current and E max .

[0229] Table 4. Effects on cellular GABA activation currents

[0230]

[0231]

[0232] Maximum enhancement percentage E of 2μM GABA current max And its corresponding concentration (μM): 100% for normal individuals. The higher the percentage, the lower the corresponding concentration, and the stronger the depth of anesthesia.

[0233] Table 5. Effects on cellular GABA activation current

[0234]

[0235] Note: The positive enhancement of EC induced by 2μM GABA 50 (μM): The concentration of the drug required to achieve a certain depth of anesthesia; the lower the value, the better.

[0236] As shown in Tables 4 and 5 above, the compounds of the present invention have a suitable depth of anesthesia, indicating that the compounds of the present invention have excellent anesthetic effects.

[0237] Example 36. Rate of drug crossing the blood-brain barrier in vitro

[0238] Place a Transwell apparatus (5.0 μm pore size) into a 24-well cell culture well, then add 1×10 5 hCMEC / D3 cells per ml were transferred to the upper wells of a Transwell microwell at a rate of 150 μL / well, and cell culture medium was added to the lower wells. Once the cells had formed a complete monolayer, the medium was replaced with EBM-2 complete medium containing 1% FBS, and the cells were cultured in a CO2 incubator for 10 days until a completely dense monolayer was formed. After the cell monolayer was formed, 0.1 mg / ml of the compound was added to the lower culture medium, and the compound concentration in the upper culture medium was measured after 5 minutes to calculate the permeability.

[0239] P 化合物 % = C 上层化合物 / C 下层化合物 ×100%

[0240] Table 6. Tests on the rate of drug crossing the blood-brain barrier

[0241]

[0242]

[0243] Table 6 above shows that this compound has the ability to rapidly cross the blood-brain barrier.

[0244] Example 37. In vitro plasma half-life test of drugs

[0245] Plasma preparation: After fasting for 12 hours with unlimited access to water, SD rats were fed and blood was collected via the orbital venous plexus. The freshly collected blood was placed in centrifuge tubes containing heparin sodium and 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, labeled, and stored at -20°C for later use.

[0246] Prepare the target compound sample: Accurately weigh the target compound using an analytical balance and prepare a stock solution with a concentration of 2 mg / mL (solvent is V acetone: V Tween 80: V physiological saline = 1:1:3) for later use.

[0247] Determination of the in vitro half-life of the target compound sample: Take 20 μL of the mother solution of the test compound and 80 μL of rat plasma, respectively, mix well, and take 9 parallel EP tubes, labeled as corresponding test tubes for 0, 1, 2, 3, 5, 10, 15, 20, and 30 min. Incubate in a 37℃ water bath for 0, 1, 2, 3, 5, 10, 15, 20, and 30 min. At each time point, take 50 μL of the mixture from the corresponding EP tube, add 100 mL of acetonitrile to precipitate the protein, vortex for 10 min, centrifuge at 12000 rpm for 15 min, take the supernatant and centrifuge again at 12000 rpm for 10 min. Use Intellistat software in UPLC-MS / MS to determine the optimal detection method of the MRM mode of the target compound, integrate the corresponding mass spectrometry peak areas, and calculate its plasma half-life.

[0248] Table 7. Results of in vitro plasma half-life test for drugs

[0249]

[0250] Table 7 above shows that this compound has the ability to rapidly cross the blood-brain barrier.

[0251] Example 38. Detection of whether a drug has a potential inhibitory effect on voltage-gated potassium ion channels (hERG) using fluorescence polarization technology.

[0252] This experiment calculated the IC by detecting the effect of eight compound concentrations on the hERG channel current. 50 Strictly follow the Predictor TM The hERG fluorescence polarization analysis kit was used for operation. Before measuring fluorescence polarization, the assay plate was covered to protect the reagents from light and evaporation. After incubation at room temperature for 2-4 hours, the sample plate was centrifuged, and the fluorescence polarization values ​​were read. The excitation light was 540 nm, and the emission light was 573 nm. The results showed that for the hERG channel current IC 50 The values ​​are all greater than or equal to 30 μM, indicating that they are almost non-toxic. Representative compounds are shown in Table 8 below.

[0253] Table 8. Results of the effect of drugs on hERG channel currents

[0254]

[0255] Example 39. LC-MS detection of whether the drug has a potential inhibitory effect on human liver P450s enzymes

[0256] Seven concentrations (final concentrations of the incubation system) of the compounds of this invention were selected and reacted with human liver microsomes and a mixed probe substrate (compound / final system concentration: 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). The mixture was preheated for 5 min, then an NADPH energy regeneration system (system components and final concentrations: MgCl2 / 10 mmol / L, NADP+ / 1 mmol / L, G-6-P / 10 mmol / L, PDH / 2 Unit / mL) was added to initiate the reaction. The incubation time was 20 min. The content of organic solvent in the entire reaction system was controlled to be ≤1%. After incubation, the reaction was terminated in an ice-water bath at 0°C. Protein was directly precipitated using acetonitrile solution (1:5, v / v) containing an internal standard (o-methylphenidate, 30 ng / mL), shaken thoroughly for 5 min, centrifuged at 18000 rpm for 5 min (4°C), and 400 μL of supernatant was quantitatively transferred. This was followed by another centrifugation at 18000 rpm for 5 min (4°C), and 100 μL of supernatant was quantitatively transferred and injected in 10 μL. The logarithm of the molar concentration of the analyte was plotted on the x-axis, and the ratio of the amount of the corresponding subtype metabolite produced at that concentration level to the amount of the corresponding metabolite produced in the corresponding blank solvent group (i.e., the remaining percentage of the measured subenzyme activity at that drug concentration level) was plotted on the y-axis. The data indicate that the compounds of this invention have minimal impact on drug-drug interactions and minimal impact on hepatic metabolism.

[0257] Table 9. Results of the effects of drugs on human liver P450s enzymes

[0258]

[0259] 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 recovery. Furthermore, the preferred compound has almost no accumulation, significantly improved cardiotoxicity, is almost non-toxic, and has little impact on liver metabolism.

[0260] Example 40. Lyophilized powder for injection containing active agent compound 32:

[0261] Compound 32 (10g) and glycine (100g) were added to a vial, and water for injection was added to a final volume of 1L. The pH of the solution was adjusted to 3.5. The solution was dispensed into 1000 vials and then lyophilized into a lyophilized powder for injection using conventional lyophilization methods.

[0262] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound as described below: ###0001### or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein a pharmaceutically acceptable salt thereof, selected from the group consisting of acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthoate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, sodium, potassium, ammonium, tromethamine and zinc.

3. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of claim 1 or a pharmaceutically acceptable salt thereof.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a sedative, anesthetic pharmaceutical.

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