Benzodinitrogen compound and application thereof

Abstract

The invention discloses a benzodiazepine # imgabs0 # compound with a structure as shown in a formula I or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorphic substance, a solvate, a metabolite or a prodrug of the benzodiazepine # imgabs0 # compound. The benzodiazepine # imgabs 1 # compound disclosed by the invention has the characteristics of low toxicity, high safety, quick action, short action time, stable anesthesia, quick metabolism, quick reviving and the like. The invention further discloses application of the benzodiazepine # imgabs2 # compound or pharmaceutically acceptable salt, stereoisomer, tautomer, polymorphic substance, solvate, metabolite or prodrug thereof in preparation of sedative or anesthetic drugs, and further discloses application of the benzodiazepine # imgabs2 # compound or pharmaceutically acceptable salt, stereoisomer, tautomer, polymorphic substance, solvate, metabolite or prodrug thereof in preparation of sedative or anesthetic drugs. # imgabs3 #

Description

Technical Field

[0001] The present invention relates to a novel benzodiazepine Compounds, in particular, benzodiazepines as short-acting anesthetics Derivatives, pharmaceutical compositions containing the same, kits containing the same, sedation and anesthesia methods using the same, and uses thereof in preparing sedation and anesthesia drugs. Background Art

[0002] Anesthesia is a reversible inhibition of the central nervous system and / or peripheral nervous system produced by drugs or other methods, which causes the patient to lose consciousness and temporarily lose sensation in the whole or part of the body, so as to achieve painless surgical treatment. With the clinical demand for comfortable diagnosis and treatment in scenarios such as endoscopy, intensive care units (ICU), cancer pain, and labor analgesia, the service scope of modern anesthesia has gradually expanded, and the clinical demand for anesthetic drugs has also increased. Benzodiazepines 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 the chloride ion channel, which is composed of two α and two β subunits (α2β2). There is a GABA receptor on the β subunit. When GABA binds to it, the chloride ion channel opens, allowing chloride ions to flow in, thereby hyperpolarizing the nerve cells and producing an inhibitory effect. 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 channel or increasing the chloride ion flow), thereby allowing more chloride ions to flow in. Derivatives of this type can enhance the neurotransmission function and synaptic inhibition effect of GABA, thereby exerting multiple therapeutic effects in clinical practice, such as inducing anesthesia, hypnosis, anti-anxiety, and alleviating spasms caused by central nervous system lesions or epilepsy.

[0003] Benzodiazepines Benzodiazepines are a type of sedative and anesthetic drug that has developed rapidly in recent years. They have good amnesia, anxiolysis and sedation effects, so they are widely used in the field of sedation and anesthesia. Chlorpheniramine (Chlordiazepoxide) was launched in 1960. Since then, new benzodiazepines have been A new class of drugs has emerged: including ultra-short-acting (remimazolam), short-acting (triazolam, midazolam), medium-acting (lorazepam, estazolam) and long-acting (diazepam). There are over 20 derivatives of this type. Although structurally similar, their clinical indications vary. This is because the binding sites and actions of GABA and GABA receptors are heterogeneous. GABA-gated chloride channels in different nerves are composed of different subunits. The different subunit compositions can lead to subtle changes in the interactions between these channels and allosteric modulators, resulting in different sedative and anesthetic effects.

[0004] Midazolam was introduced in the early 1980s as the first water-soluble benzodiazepine Compounds of this type have been introduced into the market and used as intravenous agents 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, when administered to patients with impaired liver function, drug interactions may occur. In addition, midazolam has a strong hERG potassium channel inhibitory effect. The inhibition of hERG can lead to QT interval prolongation and is directly related to the occurrence of ventricular tachycardia (TdP). A rapidly metabolized methyl propionate side chain was introduced into the core structure and was approved as a new ultra-short-acting GABA in December 2019. A Since the methyl propionate side chain of remimazolam can be rapidly metabolized by esterases, and the main metabolite, zolam propionate, has almost no sedative and anesthetic activity, the duration of its efficacy is very short, making it an ultra-short-acting benzodiazepine. However, long-term infusion of sedatives can still cause problems such as delayed awakening and drug accumulation. Currently, they are only approved for sedation during gastroscopy and general anesthesia.

[0005] Anesthetic drugs are different from other drugs and have obvious technical barriers. According to the "Regulations on the Administration of Narcotic Drugs and Psychotropic Drugs", the state implements a designated production system for anesthetic drugs and psychotropic drugs. Among the new drugs (new molecular entities) approved by the FDA between 2015 and 2021, there was only one sedative, one disease-related analgesic, and one surgery-related opioid analgesic. This shows that the development of new drugs for analgesia and sedation is relatively slow. The main reason why drugs have difficulty in exerting their pharmacological effects in the CNS is that the tight junctions of the BBB (blood-brain barrier) make it difficult for drugs to penetrate. Compared with other cells or tissues in the human body, the high expression of LAT1 (large neutral amino acid transporter 1) in brain microvascular endothelial cells and brain tissue cells makes it an important transporter for the delivery of drugs for the treatment of CNS (central nervous system) diseases. Some amino acid compounds can enhance the activity of this type of benzodiazepines through LAT1. The blood-brain barrier penetration ability of drugs.

[0006] In summary, benzodiazepines As a popular anesthetic drug in the field of anesthesia, derivatives have broad market prospects and obvious therapeutic advantages, but benzodiazepines The use of anesthetic drugs is often accompanied by dependence and addiction, and most of the drug metabolites still have a certain effect, which makes it difficult for patients to quickly recover. Long-term use can easily lead to drug accumulation and may cause certain cardiotoxicity, which hinders its further development. Therefore, it is necessary to develop benzodiazepines with low toxicity, high safety, fast onset, short recovery time and no accumulation. Drugs are an urgent problem to be solved. Summary of the Invention

[0007] In order to improve the above problems, the present invention provides a new type of benzodiazepine Compounds, preparation methods and uses thereof.

[0008] The purpose of the present invention is achieved through the following technical solutions:

[0009] Benzodiazepines with the structure shown in formula (I) Compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs thereof:

[0010]

[0011] in:

[0012] R1 is selected from hydrogen or OR6, NR7R8; R6 is selected from hydrogen, C1-C5 straight or branched alkyl, morpholino-substituted C1-C6 alkyl R7 is selected from hydrogen, C1-C5 straight or branched alkyl, R8 is selected from R9 is selected from hydrogen, substituted or unsubstituted C1-C5 straight chain or branched alkyl, the substituent of C1-C5 straight chain or branched alkyl is phenyl, indolyl, methylthio (-SCH3), or R7, R8 and N form a 5-6 membered saturated or unsaturated heterocyclic ring, and the 5-6 membered saturated or unsaturated heterocyclic ring is substituted by methyl formate;

[0013] R2 is selected from hydrogen, chlorine, bromine, nitro, cyano, amino;

[0014] X is selected from C or N; when X is selected from C, R3 is selected from hydrogen, fluorine, chlorine, bromine; when X is selected from N, R3 is a covalent bond;

[0015] R4 is selected from hydrogen, chlorine, and fluorine substituted at the 4' or 6' position;

[0016] R5 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl, acetyl 2-propynyl, N-methylpiperidinyl, 3-methylpyridin-2-yl N-methylimidazol-4-yl, The substituents of the C1-C5 straight-chain or branched alkyl group are hydroxy, amino (-NH2), cyclopropyl, morpholinyl, piperidinyl, 4,4-difluoropiperidinyl, N-methylpiperidinyl, 4-hydroxypiperidinyl, 1,4-dioxa-8-azaspiro[4.5]decyl, piperazinyl, N-methylpiperazinyl, N-phenylpiperazinyl, N-hydroxyethylpiperazinyl, pyrrolyl, tetrahydropyrrolyl, 3-fluorotetrahydropyrrolyl, 3-hydroxytetrahydropyrrolyl, pyridinyl, imidazolyl, 2-methylpyridinyl, 3-methylpyridinyl, pyrimidinyl, phosphonooxy, NR 10 R 11 ; R 10 、R 11 Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl;

[0017] But excluding: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from 4-morpholinylmethyl, 3-(diethylamino)propyl; R1 is selected from methoxy, R2 is selected from hydrogen, X is selected from C, R3 is selected from hydrogen, R4 is selected from fluorine substituted at the 4' position, R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from C, R3 is selected from chlorine, R4 is selected from hydrogen, R5 is selected from cyclopropylmethyl; R1 is selected from methoxy, R2 is selected from chlorine, X is selected from C, R3 is selected from hydrogen, R4 is selected from chlorine substituted at the 6' position, R5 is selected from chloromethyl, 2-chloroethyl, 3-chloropropyl, 2-(cyclopropyl(methyl)amino)ethyl.

[0018] Preferably, R1 is selected from hydrogen or OR6, NR7R8; R6 is selected from methyl, ethyl, 2-morpholinylethyl R7 is selected from R8 is selected from hydrogen, R9 is selected from hydrogen, methyl, 2-methylpropyl 1-Methylpropyl Isopropyl benzyl 3-Indolylmethyl Methyl methyl sulfide (-CH2SCH3), or R7, R8 and N form pyrrolyl-2-alkanecarboxylic acid methyl ester

[0019] R2 is selected from hydrogen, chlorine, bromine, nitro;

[0020] X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond;

[0021] R4 is selected from hydrogen, 4'-substituted chlorine, 6'-substituted fluorine or chlorine;

[0022] R5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl, acetyl, 2-propynyl, N-methylpiperidinyl, 3-methylpyridin-2-yl, N-methylimidazol-4-yl, The substituents of C1-C3 alkyl are hydroxy, amino, cyclopropyl, morpholinyl, piperidinyl, 4,4-difluoropiperidinyl, N-methylpiperidinyl, 4-hydroxypiperidinyl, 1,4-dioxa-8-azaspiro[4.5]decyl, piperazinyl, N-methylpiperazinyl, N-phenylpiperazinyl, N-hydroxyethylpiperazinyl, pyrrolyl, tetrahydropyrrolyl, 3-fluorotetrahydropyrrolyl, 3-hydroxytetrahydropyrrolyl, pyridinyl, imidazolyl, 2-methylpyridinyl, 3-methylpyridinyl, pyrimidinyl, phosphonooxy, NR 10 R 11 ; R 10 、R 11 Each independently selected from methyl and ethyl;

[0023] But excluding: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from 4-morpholinylmethyl, 3-(diethylamino)propyl; R1 is selected from methoxy, R2 is selected from hydrogen, X is selected from C, R3 is selected from hydrogen, R4 is selected from fluorine substituted at the 4' position, R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from C, R3 is selected from chlorine, R4 is selected from hydrogen, R5 is selected from cyclopropylmethyl; R1 is selected from methoxy, R2 is selected from chlorine, X is selected from C, R3 is selected from hydrogen, R4 is selected from chlorine substituted at the 6' position, R5 is selected from chloromethyl, 2-chloroethyl, 3-chloropropyl, 2-(cyclopropyl(methyl)amino)ethyl.

[0024] More preferably, the following compounds further exhibit the advantages of "deeper anesthesia depth and higher in vitro blood-brain barrier permeability":

[0025] R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl;

[0026] R2 is selected from chlorine, bromine, and nitro;

[0027] X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond;

[0028] R4 is selected from hydrogen, chlorine substituted at the 6' position;

[0029] R5 is selected from hydrogen, methyl, cyclopropylmethyl Morpholinylmethyl (1-Methylpiperidin-4-yl)methyl Pyridin-4-ylmethyl Pyridin-2-ylmethyl Pyridin-3-ylmethyl (6-Methylpyridin-2-yl)methyl Ethyl, 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl 2-((3R)-3-Fluoropyrrolidin-1-yl)ethyl 2-((3R)-3-Hydroxypyrrolidin-1-yl)ethyl 2-(Piperazin-1-yl)ethyl 1-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl 3-(dimethylamino)propyl, ((3R)-3-fluoropyrrolidin-1-yl)propyl, (1,4-dioxa-8-azaspiro[4.5]decane-8-yl)propyl, 3-methylpyridin-2-yl,

[0030] But excluding: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from 4-morpholinylmethyl, 3-(diethylamino)propyl; R1 is selected from methoxy, R2 is selected from bromine, X is selected from C, R3 is selected from chlorine, R4 is selected from hydrogen, R5 is selected from cyclopropylmethyl.

[0031] More preferably, the following compounds, in addition to exhibiting the advantages of "deeper anesthesia depth and high in vitro blood-brain barrier permeability", further exhibit the advantages of "shorter in vitro plasma half-life and rapid recovery to normal state after drug withdrawal":

[0032] R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl;

[0033] R2 is selected from chlorine, bromine, and nitro;

[0034] X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond;

[0035] R4 is selected from hydrogen, chlorine substituted at the 6' position;

[0036] R5 is selected from hydrogen, methyl, cyclopropylmethyl, (1-methylpiperidin-4-yl)methyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl, ethyl, 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, 2-((3R)-3-fluoropyrrolidin-1-yl)ethyl, 2-((3R)-3-hydroxypyrrolidin-1-yl)ethyl, 2-(piperazin-1-yl)ethyl, 1-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl, 3-(dimethylamino)propyl, ((3R)-3-fluoropyrrolidin-1-yl)propyl, (1,4-dioxa-8-azaspiro[4.5]decan-8-yl)propyl, 3-methylpyridin-2-yl,

[0037]

[0038] But it does not include: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from 4-morpholinylmethyl and 3-(diethylamino)propyl.

[0039] More preferably, the following compounds further exhibit the advantages of “low inhibitory effect on hERG potassium ion channels and low cardiotoxicity”:

[0040] R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl;

[0041] R2 is selected from chlorine, bromine;

[0042] X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond;

[0043] R4 is selected from hydrogen, chlorine substituted at the 6' position;

[0044] R5 is selected from hydrogen, methyl, cyclopropylmethyl, (1-methylpiperidin-4-yl)methyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl, ethyl, 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, 3-(dimethylamino)propyl, (1,4-dioxa-8-azaspiro[4.5]decan-8-yl)propyl;

[0045] But not including: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, R5 is selected from 3-(diethylamino)propyl.

[0046] Most preferably, the following compounds further exhibit the beneficial effects of “low inhibition of liver microsomal CYP450 enzymes and minimal drug-drug interactions”:

[0047] R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl;

[0048] R2 is selected from bromine;

[0049] X is selected from N, R3 is a covalent bond;

[0050] R4 is selected from hydrogen;

[0051] R5 is selected from hydrogen, ethyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl.

[0052] When R5 is selected from hydrogen, the benzodiazepine represented by formula (I) The tautomers of the compound are shown in formula (II):

[0053]

[0054] wherein R1, R2, X, R3, and R4 are as described above;

[0055] But not including: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, and R4 is selected from hydrogen.

[0056] Specifically, the benzodiazepine The compound or its tautomer is selected from the following compounds:

[0057] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 1);

[0058] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 1 tautomer);

[0059] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 2);

[0060] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 2 tautomer);

[0061] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 4);

[0062] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 4 tautomer);

[0063] (S)-3-(6-phenyl-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 5);

[0064] (S)-3-(6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 5 tautomer);

[0065] (S)-3-(6-(4-Fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 6 tautomer)

[0066] (S)-3-(8-chloro-6-phenyl-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 7);

[0067] (S)-3-(8-chloro-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate (compound 7 tautomer);

[0068] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 8);

[0069] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 9);

[0070] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 10);

[0071] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 11);

[0072] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 12);

[0073] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 13);

[0074] (S)-3-(8-Chloro-6-(2-fluorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 14);

[0075] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 15);

[0076] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 16);

[0077] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 17);

[0078] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 18);

[0079] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 19);

[0080] (S)-3-(8-Chloro-6-(2-fluorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 20);

[0081] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 21);

[0082] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 22);

[0083] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 23);

[0084] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 24);

[0085] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 25);

[0086] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 26);

[0087] (S)-3(8-Bromo-6-(2-chlorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 27);

[0088] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 28);

[0089] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 29);

[0090] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 30);

[0091] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 31);

[0092] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 32);

[0093] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 33);

[0094] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 34);

[0095] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 35);

[0096] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 36);

[0097] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 37);

[0098] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(acetyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 38);

[0099] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(acetyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 39);

[0100] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(acetyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 40);

[0101] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)ethyl propionate (Compound 41);

[0102] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)ethyl propionate (Compound 41 tautomer);

[0103] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)ethyl propionate (Compound 42);

[0104] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)ethyl propionate (Compound 43);

[0105] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)ethyl propionate (Compound 44);

[0106] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 45);

[0107] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 46);

[0108] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 47);

[0109] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 48);

[0110] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 49);

[0111] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 50);

[0112] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 51);

[0113] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 52);

[0114] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 53);

[0115] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 54);

[0116] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 55);

[0117] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 56);

[0118] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 57);

[0119] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 58);

[0120] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 59);

[0121] (S)-3-(8-Chloro-6-(2-fluorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 60);

[0122] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 61);

[0123] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 62);

[0124] (S)-3-(8-Chloro-6-(2-fluorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 63);

[0125] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 64);

[0126] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 65);

[0127] (S)-3-(8-Chloro-6-(2-fluorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 66);

[0128] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 67);

[0129] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 68);

[0130] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 69);

[0131] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 70);

[0132] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 71);

[0133] (S)-3-(8-Chloro-6-(2-fluorophenyl)-1-((4-phenylpiperazin-1-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 72);

[0134] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((4-phenylpiperazin-1-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 73);

[0135] (S)-3-(8-Nitro-6-(2-fluorophenyl)-1-((4-phenylpiperazin-1-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 74);

[0136] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 75);

[0137] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 76);

[0138] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 77);

[0139] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 78);

[0140] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 79);

[0141] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 80);

[0142] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 81);

[0143] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 82);

[0144] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 83);

[0145] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 84);

[0146] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 85);

[0147] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 86);

[0148] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 87);

[0149] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 88);

[0150] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 89);

[0151] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 90);

[0152] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 91);

[0153] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 92);

[0154] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 93);

[0155] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 94);

[0156] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 95);

[0157] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 96);

[0158] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 97);

[0159] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 98);

[0160] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 99);

[0161] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 100);

[0162] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 101);

[0163] (S)-3-(8-chloro-1-(methyloxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 102);

[0164] (S)-3-(8-Bromo-1-(methyloxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 103);

[0165] (S)-3-(8-Nitro-1-(methoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 104);

[0166] (S)-3-(8-chloro-1-(2-morpholinoethoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 105);

[0167] (S)-3-(8-Bromo-1-(2-morpholinoethoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 106);

[0168] (S)-3-(8-Nitro-1-(2-morpholinoethoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 107);

[0169] (S)-3-(8-chloro-1-(3-(dimethylamino)propoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 108);

[0170] (S)-3-(8-Bromo-1-(3-(dimethylamino)propoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 109);

[0171] (S)-3-(8-Nitro-1-(3-(dimethylamino)propoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 110);

[0172] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((phosphonooxy)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 111);

[0173] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-((phosphonooxy)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 112);

[0174] (S)-3-(8-Nitro-6-(2-chlorophenyl)-1-((phosphonooxy)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 113);

[0175] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-methoxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 114);

[0176] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-ethoxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 115);

[0177] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 116);

[0178] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(2-morpholinethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 117);

[0179] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 118);

[0180] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(pyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 119);

[0181] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 120);

[0182] (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-(pyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 121);

[0183] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(piperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 122);

[0184] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(piperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 123);

[0185] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(pyridin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 124);

[0186] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(pyridin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 125);

[0187] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(2-(pyridin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 126);

[0188] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 127);

[0189] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 128);

[0190] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 129);

[0191] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 130);

[0192] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(4-methylpiperazin-1-yl)-1-oxomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 131);

[0193] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(diethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 132);

[0194] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(dimethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 133);

[0195] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(dimethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 134);

[0196] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 135);

[0197] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((1-methylpiperidin-1-yl)-1-oxomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 136);

[0198] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxy-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionic acid-2-morpholinoethyl ester (Compound 137);

[0199] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(1H-imidazol-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 138);

[0200] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(1H-imidazol-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 139);

[0201] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(1H-pyrrol-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 140);

[0202] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 141);

[0203] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 142);

[0204] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(dimethylamino)-3-oxopropoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 143);

[0205] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((4,5-dihydro-1H-imidazol-2-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 144);

[0206] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 148);

[0207] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 149);

[0208] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-fluoropyrrolidin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 150);

[0209] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-hydroxypyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 151);

[0210] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 152);

[0211] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(cyclopropyl(methyl)amino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 155);

[0212] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 156);

[0213] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(piperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 157);

[0214] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 158);

[0215] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 159);

[0216] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-ethoxy-2,4-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionic acid-2-morpholinoethyl ester (Compound 160);

[0217] (S)-3-(1-(2-(1H-imidazol-1-yl)ethoxy)-8-bromo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 163);

[0218] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((3-methylpyridin-2-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 164);

[0219] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(pyridin-2-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 165);

[0220] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(pyridin-3-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 166);

[0221] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(pyridin-2-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 167);

[0222] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(pyridin-3-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 168);

[0223] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-((6-methylpyridin-2-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 169);

[0224] (S)-3-(8-Bromo-1-(aminoacetoxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 170);

[0225] (S)-3-(8-Bromo-1-(2-aminopropionyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 171);

[0226] (S)-3-(8-Bromo-1-(2-amino-4-methylpentanoyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 172);

[0227] (S)-8-Bromo-4-(3-methoxy-3-oxopropyl)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -1-yl 2-amino-3-methylpentanoate (Compound 173);

[0228] (S)-3-(8-Bromo-1-(2-amino-3-methylbutyryloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 174);

[0229] (S)-3-(8-Bromo-1-(pyrrolidin-2-yloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 175);

[0230] (S)-3-(8-Bromo-1-(2-amino-3-phenylpropionyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 176);

[0231] (S)-3-(8-Bromo-1-(2-amino-4-methylthiobutyryloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 177);

[0232] (S)-3-(8-Bromo-1-(2-amino-3-indolylpropionyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 178);

[0233] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(aminoacetoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 179);

[0234] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-aminopropionyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 180);

[0235] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-4-methylpentanoyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 181);

[0236] (S)-8-Chloro-6-(2-chlorophenyl)-4-(3-methoxy-3-oxopropyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -1-yl 2-amino-3-methylpentanoate (Compound 182);

[0237] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-3-methylbutyryloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 183);

[0238] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(pyrrolidin-2-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 184);

[0239] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-3-phenylpropionyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 185);

[0240] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-4-methylthiobutyryloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 186);

[0241] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-3-indolylpropionyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (Compound 187);

[0242] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)acetic acid methyl ester (Compound 188);

[0243] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)propionic acid methyl ester (Compound 189);

[0244] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-4-methylpentanoic acid methyl ester (Compound 190);

[0245] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-methylpentanoic acid methyl ester (Compound 191);

[0246] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-indolylpropionic acid methyl ester (Compound 192);

[0247] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionyl)-3-indolylpropionic acid methyl ester (Compound 193);

[0248] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-methylbutanoic acid methyl ester (Compound 194);

[0249] (S)-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionyl)pyrrolidin-2-yl-carboxylate (Compound 195);

[0250] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-phenylpropionic acid methyl ester (Compound 196);

[0251] (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-4-methylthiobutanoic acid methyl ester (Compound 197);

[0252] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)acetic acid methyl ester (Compound 198);

[0253] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)propionic acid methyl ester (Compound 199);

[0254] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-4-methylpentanoic acid methyl ester (Compound 200);

[0255] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-methylpentanoic acid methyl ester (Compound 201);

[0256] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-methylbutanoic acid methyl ester (Compound 202);

[0257] (S)-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionyl)pyrrolidin-2-ylcarboxylate (Compound 203);

[0258] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-3-phenylpropionic acid methyl ester (Compound 204);

[0259] (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionamido)-4-methylthiobutanoic acid methyl ester (Compound 205);

[0260] The above-mentioned benzodiazepines The structural formula of the compound or its tautomer is as follows:

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270] The benzodiazepine Pharmaceutically acceptable salts of the compounds are selected from acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate or carbonate, bisulfate or sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride or chloride, hydrobromide or bromide, hydroiodide or iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, Methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, naphthoate, phosphate / hydrogenphosphate / dihydrogenphosphate, 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, or zinc salts.

[0271] Another object of the present invention is to provide the benzodiazepine Use of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof in the preparation of a sedative or anesthetic drug.

[0272] Furthermore, the application is in the preparation of sedative drugs for consciousness during short-term diagnosis, surgery or endoscopic procedures, induction and maintenance drugs for general anesthesia, and ICU sedative drugs.

[0273] Another object of the present invention is to provide a pharmaceutical composition, which is based on the benzodiazepine A pharmaceutically acceptable dosage form comprising a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof as an active ingredient or main active ingredient and a pharmaceutically acceptable carrier.

[0274] The dosage form can be a suspension, emulsion, injection, freeze-dried powder injection and other commonly used dosage forms in pharmacy.

[0275] 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.

[0276] Furthermore, the pharmaceutically acceptable carrier is selected from water, oil or other injectable solvents, and pharmaceutical additives.

[0277] Oils include those of natural or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like.

[0278] When the pharmaceutical composition is administered intravenously, water is an exemplary carrier; physiological saline, dextrose, aqueous glycerol solution, ethanol, propylene glycol, polyethylene glycol, glycerol can also be used as liquid carriers, particularly for injection solutions or emulsions.

[0279] The pharmaceutical additive is selected from starch, lactose, gelatin, maltose, silica gel, sodium stearate, glyceryl monostearate, talc, sodium oxide, skimmed milk powder, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethyl cellulose, pectin, albumin, trehalose, and dextran.

[0280] The pharmaceutical composition may also contain a small amount of a wetting agent, emulsifier or pH buffering agent as needed.

[0281] The benzodiazepine The content of the compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug in the pharmaceutical composition can be 10 to 3000 mg, suitably 15 to 3000 mg, preferably 15 to 2500 mg, more preferably 15 to 1000 mg, and particularly preferably 15 to 500 mg, for example 15 mg, 30 mg, 45 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg or 300 mg.

[0282] The benzodiazepine The dosage of a class compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug depends on the individual being 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 an individual weighing 70 kg, the effective dose amounts to about 0.007 mg / day to about 3500 mg / day, for example, about 0.7 mg / day to about 3500 mg / day. In some cases, the dosage level below the lower limit of the aforementioned range can be sufficient, and in other cases, a larger dose can 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.

[0283] Furthermore, the dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, which can be divided into several doses over time, or the dosage can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It should be noted that dosage values ​​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's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0284] The pharmaceutical composition can be administered by any suitable route. Preferably, the pharmaceutical composition is administered intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.

[0285] Another object of the present invention is to provide the use of the pharmaceutical compound of the present invention in the preparation of sedative or anesthetic drugs.

[0286] Another object of the present invention is to provide a medicine box comprising the benzodiazepine The present invention relates to a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug or pharmaceutical composition thereof.

[0287] Another object of the present invention is to provide a sedation or anesthesia method comprising administering an effective amount of the benzodiazepine via intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal route. The present invention relates to a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the pharmaceutical composition.

[0288] The sedation and anesthesia methods are preferably used in the following clinical treatment options: 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 anxiolytic drugs, including sedation, hypnosis, anxiolysis and amnesia for early-awakening insomnia caused by disorders of brain excitation and inhibition.

[0289] Beneficial effects of the present invention:

[0290] The short-acting benzodiazepine of the present invention These derivatives have the characteristics of low toxicity, high safety, rapid onset, short duration of action, stable anesthetic effect, rapid metabolism and rapid awakening.

[0291] In the anesthesia experiments on mice and rats, the benzodiazepines of the present invention The onset time of the benzodiazepine 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 benzodiazepine derivatives of the present invention The awakening time and recovery time of the derivatives are significantly shortened, and they have the characteristics of faster awakening and faster recovery. Compounds not only maintain the effect of GABA A receptors with high affinity and selectivity, and through the 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, short recovery 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; at the same time, the benzodiazepine of the present invention The derivatives have good water solubility, retain the advantage of fast metabolism while improving drug safety, and expand the application prospects of amino acids in clinical drug research; in the hERG inhibition experiment, the benzodiazepines of the present invention The inhibitory effect of this type of derivative on hERG potassium ion channels is small, and the drug has high cardiac safety.

[0292] Definitions and Explanations of Terms

[0293] "C1-C6 alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms, specifically selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-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 isomers thereof.

[0294] The "C1-C5 straight or branched chain alkyl group" is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. DETAILED DESCRIPTION

[0295] In order to make the purpose and technical solution of the present invention clearer, the technical solution of the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, the specific experimental methods not mentioned in the following examples are all carried out according to conventional experimental methods.

[0296] The abbreviations used in this invention have the following meanings:

[0297]

[0298]

[0299] The structures of the compounds were determined by nuclear magnetic resonance spectroscopy ( 1 H NMR, 13 CNMR) and mass spectrometry (MS) for confirmation; the reaction is monitored by thin layer chromatography (TLC) or LCMS, and the developing solvent systems used are: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system.

[0300] Column chromatography generally uses 200-300 mesh silica gel as the stationary phase; the eluent system includes: 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.

[0301] Unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

[0302] Example 1

[0303] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 1 tautomer)

[0304]

[0305] Step 1: Preparation of (S)-5-((2-fluoro-benzoyl-4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid methyl ester (Compound 1c):

[0306] 2-Amino-5-chloro-2'-fluorobenzophenone (compound 1a, 10.00 g, 0.040 mol) and N-tert-butoxycarbonyl-L-glutamic acid-5-methyl ester (compound 1b, 8.73 g, 0.033 mol) were dissolved in DCM (120 mL), cooled to 0°C, and DCC (8.28 g, 0.040 mol) was added. The mixture was stirred for 24 hours. LC-MS showed that the reaction was complete. The mixture was filtered, and the filtrate was evaporated under reduced pressure to remove the reaction solvent. The residual product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1, v / v) to obtain (S)-5-((2-fluoro-benzoyl-4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid methyl ester (compound 1c, 11.25 g, yield: 68.3%) as a white solid.

[0307] Step 2: Preparation of (S)-4-amino-5-((2-fluorobenzoyl-4-chlorophenyl)amino)-5-oxopentanoic acid methyl ester (Compound 1d):

[0308] Methyl (S)-5-((2-fluoro-benzoyl-4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (compound 1c, 11.25 g) was dissolved in DCM (50 mL), TFA (50 mL) was added, and the mixture was stirred for 20 minutes until LC-MS showed completion of the reaction. The reaction solution was concentrated to obtain a crude residue, methyl (S)-4-amino-5-((2-fluorobenzoyl-4-chlorophenyl)amino)-5-oxopentanoate (compound 1d, 9.20 g), which was used directly in the next reaction.

[0309] Step 3: (S)-3-(7-chloro-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine Preparation of methyl 2-(3-yl)propionate (Compound 1e):

[0310] Methyl (S)-4-amino-5-((2-fluorobenzoyl-4-chlorophenyl)amino)-5-oxopentanoate (Compound 1d, 9.20 g) was dissolved in MeOH (100 mL), and NaHCO3 was added to adjust the pH to about 10. The mixture was stirred for 24 hours. LC-MS showed that 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 silica gel column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to give (S)-3-(7-chloro-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine as a white solid. -3-yl)propionic acid methyl ester (Compound 1e, 7.52 g, yield: 85.7%).

[0311] Step 4: (S)-3-(7-chloro-5-(2-fluorophenyl)-2-thioxo-2-3,3-dihydro-1H-benzo[e][1,4]diazepine Preparation of methyl 2-(3-yl)propionate (compound 1f):

[0312] (S)-3-(7-chloro-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine Methyl 7-(7-chloro-5-(2-fluorophenyl)-2-thioxo-2-3,3-dihydro-1H-benzo[e][1,4]diazepine was dissolved in toluene (100 mL) and Lawesson's reagent (4.86 g, 0.012 mol) was added. The mixture was heated to 100°C and stirred for 1.5 hours until the reaction was completed as shown by LC-MS. Saturated sodium bicarbonate solution was added to remove the excess Lawesson's reagent, 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 evaporated under reduced pressure, and the residual product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1, v / v) to obtain a light yellow solid (S)-3-(7-chloro-5-(2-fluorophenyl)-2-thioxo-2-3,3-dihydro-1H-benzo[e][1,4]diazepine -3-yl)propionic acid methyl ester (compound 1f, 4.07 g, yield: 52.1%).

[0313] Step 5: (S)-3-(7-chloro-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine Preparation of methyl 2-(3-yl)propionate (Compound 1g)

[0314] (S)-3-(7-chloro-5-(2-fluorophenyl)-2-thioxo-2-3,3-dihydro-1H-benzo[e][1,4]diazepine -3-yl) propionic acid methyl ester (compound 1f, 4.07 g, 0.010 mol) was dissolved in 50 mL of THF and cooled to 0 ° C. 80% hydrazine hydrate (1.56 g, 0.030 mol) was added and stirred for 30 minutes until LC-MS showed that the reaction was complete. The excess hydrazine hydrate was removed with saturated NaCl solution and extracted with DCM. The organic phases were combined, dried and concentrated to give crude (S)-3-(7-chloro-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine -3-yl)propionic acid methyl ester (compound 1g, 2.92g) was directly used in the next step reaction.

[0315] Step 6: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (compound 1 tautomer) (compound 1 tautomer)

[0316] (S)-3-(7-chloro-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepine Methyl 1-(8-chloro-6-(fluorophenyl)-1-carbonyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1, v / v) to obtain a white solid (S)-3-(8-chloro-6-(fluorophenyl)-1-carbonyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine). -4-yl)propionic acid methyl ester (Compound 1 tautomer, 1.72 g, yield: 55.3%).

[0317] 1 H NMR (300MHz, DMSO-d6) δ: 14.17 (s, 1H), 8.46 (d, J = 8.7Hz, 1H), 7.96-7.62 (m, 3H), 7.36-7 .28(m,2H),7.23(d,J=3.0Hz,1H), 4.26(t,J=6.1Hz,1H),3.62(s,3H),2.70-2.45(m,4H); 13C NMR(75MHz,DMSO-d6)δ:173.95,166.35,164.33,161.76,158.48,153.86,133.76,133.55,132.21,131.81, 131.28,129.13,127.87,127.02,125.17,116.48,55.16,51.55,31.19,25.26; LC-MS(ESI)m / z:415.12[M+H] + .

[0318] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 1)

[0319]

[0320] (S)-3-(8-chloro-6-(fluorophenyl)-1-carbonyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Methyl 4-(8-chloro-6-(2-fluorophenyl)propanoate (compound 1 tautomer, 0.50 g, 1.21 mmol) was dissolved in 5 mL of THF, and K2CO3 (0.33 g, 2.41 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes, extracted three times with 60 mL of EA, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA=5:1, v / v) to obtain a white solid (S)-3-(8-chloro-6-(2-fluorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionic acid methyl ester (Compound 1, 250 mg, yield 50%).

[0321] 1 H NMR(300MHz, CDCl3)δ8.87(s,1H),7.80(d,J=1.9Hz,1H),7.70–7.63(m,2H),7.49-7.47(m,1H),7.44–7.34(m,2H),7.22 (dd,J=7.4,2.1Hz,1H),5.33(s,1H),3.69(s,3H),2.56(d,J=3.3Hz,2H),2.40(d,J=12.3Hz,1H),2.23(d,J=12.5Hz,1H). 13C NMR (75MHz, CDCl3) δ173.95,160.35,152.11,148.45,136.97,136.37,131.44,130.78,130.43,129.97,1 28.43,127.92,126.29,125.34,124.54,115.80,70.25,52.50,33.02,29.80.LC-MS(ESI)m / z:414.1[M+H] + .

[0322] Example 2

[0323] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl-4-yl)propionate (compound 2 tautomer)

[0324] The tautomer of Compound 2 was prepared by replacing 2-amino-5-chloro-2'-fluorobenzophenone (Compound 1a) in Example 1 with an equal molar amount of 2-amino-5-chloro-2'-chlorobenzophenone, while remaining the same as Example 1.

[0325] 1 H NMR(300MHz,DMSO-d6)δ:12.15(s,1H),8.56(d,J=8.8Hz,1H),7.81(d,J=7.4Hz,1H),7 .62-7.51(m,4H),7.17(s,1H),4.33(t,J=5.8Hz,1H),3.61(s,3H),2.60-2.45(m,4H); 13 C NMR(75MHz,DMSO-d6)δ:172.54,167.87,167.21,153.61,138.83,133.42,132.68,132.72,131.84,131.53, 130.64,130.07,129.21,128.32,127.34,127.10,55.10,51.75,30.12,26.56; LC-MS(ESI)m / z:431.27[M+H] + .

[0326] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 2)

[0327] Compound 2 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 2, with the remainder being the same as in Example 1.

[0328] 1 H NMR (300MHz, CDCl3) δ9.11 (s, 1H), 7.85–7.79 (m, 2H), 7.59 (dd, J = 7.1, 2.3Hz, 1H), 7.52–7.35 ( m,5H),5.33(s,1H),3.69(s,3H),2.57(s,2H),2.34(d,J=12.5Hz,1H),2.25(d,J=12.5Hz,1H). 13 C NMR (75MHz, CDCl3) δ173.78,152.07,147.10,144.05,139.27,132.85,131.55,130.78,130.50,130.18,1 29.90,128.92,128.43,126.29,125.34,124.71,70.25,51.45,33.02,29.80.LC-MS(ESI)m / z:430.1[M+H] + .

[0329] Example 3

[0330]

[0331] (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate (compound 3 tautomer)

[0332] The tautomer of Compound 3 was prepared by replacing 2-amino-5-chloro-2'-fluorobenzophenone (Compound 1a) in Example 1 with an equal molar amount of 2-(2-amino-5-bromo-benzoyl)pyridine, while the rest of the reaction was the same as in Example 1.

[0333] 1 H NMR(300MHz, DMSO-d6)δ:14.27(s,1H),8.59(d,J=4.3Hz,1H),8.27(d,J=8.8Hz,1H),8.11(d,J=7.9H z,1H),8.01-7.97(m,2H),7.61-7.53(m,2H),4.31(t,J=5.8Hz,1H),3.64(s,3H),2.68-2.45(m,4H); 13CNMR(75MHz,DMSO-d6)δ:173.70,167.81,166.51,160.32,157.68,155.34,149.03,136.91,134.69,134.01, 132.24,130.18,126.91,125.28,124.90,123.99,55.09,51.71,30.17,26.18; LC-MS(ESI)m / z:442.27[M+H] + .

[0334] (S)-3-(8-Bromo-1-hydroxy-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 3)

[0335] Compound 3 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 3, with the rest being the same as in Example 1.

[0336] 1 H NMR (300MHz, CDCl3) δ9.11 (s, 1H), 8.70 (dd, J = 5.0, 1.3Hz, 1H), 7.85 (td, J = 8. 0,1.3Hz,1H),7.67(dd,J=7.5,2.0Hz,1H),7.61(d,J=1.9Hz,1H),7.51(d,J=7 .5Hz,1H),7.45(dd,J=8.0,1.0Hz,1H),7.29-7.25(m,1H),5.33(s,1H),3.67( s,3H),2.52(d,J=1.0Hz,2H),2.42(d,J=12.3Hz,1H),2.25(d,J=12.3Hz,1H). 13 C NMR (75MHz, CDCl3) δ173.78,152.07,148.45,144.61,143.26,142.62,140.78,136.63,131.82,129.6 9,124.74,123.85,120.84,119.46,115.73,70.25,51.48,33.02,29.42.LC-MS(ESI)m / z:441.0[M+H] + .

[0337] Example 4

[0338] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (compound 4 tautomer)

[0339] The tautomer of Compound 4 was prepared by replacing 2-amino-5-chloro-2'-fluorobenzophenone (Compound 1a) in Example 1 with 2-amino-5-bromo-2'-fluorobenzophenone in equal moles, with the rest being the same as Example 1.

[0340] 1 H NMR(300MHz, DMSO-d6)δ:11.24(s,1H),8.34(d,J=9.1Hz,1H),7.98(d,J=8.9Hz,1H),7.62-7.47(m,2H),7.33 (s,1H),7.25(t,J=7.5Hz,1H),7.13(t,J=9.8Hz,1H),4.23(t,J=6.7Hz,1H),3.61(s,3H),2.71-2.43(m,4H); 13 C NMR(75MHz,DMSO-d6)δ:173.60,166.91,164.26,161.78,158.48,153.87,134.09,133.46,132.45,131.93, 131.60,128.02,127.05,125.28,120.85,116.80,55.14,51.87,30.20,26.27; LC-MS(ESI)m / z:459.28[M+H] + .

[0341] (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (compound 4)

[0342] Compound 4 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 4, with the rest being the same as in Example 1.

[0343] 1H NMR (300MHz, CDCl3) δ9.11(s,1H),7.69(dd,J=7.4,2.1Hz,1H),7.61(d,J=1.9Hz,1H),7.55(dd,J=7.5,2.0Hz,1H),7.41-7.37(m,4H),7.22(dd ,J=7.4,2.1Hz,1H),5.33(s,1H),3.68(s,3H),2.52(d,J=12.4Hz,1H),2.46(d,J=12.5Hz,1H),2.34(d,J=12.4Hz,1H),2.25(d,J=12.5Hz,1H). 13 C NMR (75MHz, CDCl3) δ173.78,160.38,152.07,147.10,136.97,136.37,131.81,131.44,130.43,129.00,1 26.73,125.40,124.54,119.05,115.88,115.29,70.25,51.43,33.02,29.80.LC-MS(ESI)m / z:458.0[M+H] + .

[0344] Example 5

[0345] (S)-3-(6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (compound 5 tautomer)

[0346] The tautomer of Compound 5 was prepared by replacing 2-amino-5-chloro-2'-fluorobenzophenone (Compound 1a) in Example 1 with 2-amino-benzophenone in equal moles, with the rest being the same as Example 1.

[0347] 1 H NMR (300MHz, DMSO-d6) δ: 14.16 (s, 1H), 8.23 ​​(d, J = 8.0Hz, 1H), 7.81 (t, J = 7.3Hz ,1H),7.61-7.42(m,7H),4.14(t,J=5.7Hz,1H),3.61(s,3H),2.76-2.45(m,4H); 13CNMR(75MHz, CDCl3)δ:173.69,168.62,167.25,154.27,138.37,133.47,131.68,131.11,131.02,129.8 1(2C),129.54,128.32(2C),127.78,125.57,54.71,51.82,30.26,26.71; LC-MS(ESI)m / z:363.13[M+H] + .

[0348] (S)-3-(6-phenyl-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 5)

[0349] Compound 5 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 5, with the rest being the same as in Example 1.

[0350] 1 H NMR(300MHz, CDCl3)δ7.74–7.65(m,4H),7.56(td,J=7.5,2.0Hz,1H),7.49–7.41(m,1H),7.43–7.35(m,2H),7.26(t d,J=7.5,2.0Hz,1H),5.33(s,1H),3.68(s,3H),2.58–2.48(m,2H),2.40(d,J=12.3Hz,1H),2.23(d,J=12.5Hz,1H). 13 C NMR (75MHz, CDCl3) δ173.89,154.55,152.11,148.55,142.57,138.16,130.11,129.72,129.16,1 28.64,128.48,122.60,121.85,121.22,64.68,52.29,33.02,29.80.LC-MS(ESI)m / z:362.4[M+H] + .

[0351] Example 6

[0352] (S)-3-(6-(4-Fluorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (compound 6 tautomer)

[0353] The tautomer of Compound 6 was prepared by replacing 2-amino-5-chloro-2'-fluorobenzophenone (Compound 1a) in Example 1 with 2-amino-4'-fluorobenzophenone in equal moles, while the rest of the reaction was the same as in Example 1.

[0354] 1 H NMR (300MHz, CDCl3) δ8.87(s,1H),7.75(dd,J=7.5,2.0Hz,1H),7.68–7.61(m,3H),7.52(td,J=7.5,2.0Hz,1H),7.26(td,J=7. 5,2.0Hz,1H),7.20–7.14(m,2H),5.22(s,1H),3.68(s,2H),2.58–2.48(m,2H),2.33(d,J=12.5Hz,1H),2.23(d,J=12.5Hz,1H). 13 CNMR(75MHz, CDCl3)δ173.95,164.04,152.74,152.11,148.55,142.57,133.26,130.11,129.91,1 25.08,123.50,121.14,120.93,116.03,64.68,51.69,33.02,29.80.LC-MS(ESI)m / z:380.2[M+H] + .

[0355] (S)-3-(6-(4-Fluorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 6)

[0356]

[0357] Compound 6 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 6, with the rest being the same as in Example 1.

[0358] 1 H NMR (300MHz, CDCl3) δ8.87(s,1H),7.75(dd,J=7.5,2.0Hz,1H),7.68–7.61(m,3H),7.52(td,J=7.5,2.0Hz,1H),7.26(td,J=7. 5,2.0Hz,1H),7.20–7.14(m,2H),5.22(s,1H),3.68(s,3H),2.58–2.48(m,2H),2.33(d,J=12.5Hz,1H),2.23(d,J=12.5Hz,1H).13 CNMR(75MHz, CDCl3)δ173.95,164.04,152.74,152.11,148.55,142.57,133.26,130.11,129.91,1 25.08,123.50,121.14,120.93,116.03,64.68,51.69,33.02,29.80.LC-MS(ESI)m / z:380.1[M+H] + .

[0359] Example 7

[0360] (S)-3-(8-Chloro-6-phenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (compound 7 tautomer)

[0361] The tautomer of Compound 7 was prepared by replacing 2-amino-5-chloro-2′-fluorobenzophenone (Compound 1a) in Example 1 with 2-amino-5-chlorobenzophenone in equal moles, with the rest being the same as in Example 1.

[0362] 1 H NMR (300MHz, DMSO-d6) δ: 11.24 (s, 1H), 8.51 (d, J = 8.8Hz, 1H), 7.71-7.31 (m, 7H), 4.17 (t, J = 5.8Hz, 1H), 3.63 (s, 3H), 2.81-2.63 (m, 4H); 13 C NMR(75MHz,DMSO-d6)δ:173.62,167.25,166.82,154.07,138.40,132.31,132.24,131.44,131.20, 130.96,130.45,129.54,128.91,127.86,55.36,51.84,30.23,26.34; LC-MS(ESI)m / z:397.15[M+H] + .

[0363] (S)-3-(8-chloro-6-phenyl-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 7)

[0364] Compound 7 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 7, with the rest being the same as in Example 1.

[0365] 1 H NMR (300MHz, CDCl3) δ8.87(s,1H),7.94(d,J=2.0Hz,1H),7.89(d,J=7.5Hz,1H),7.66–7.59(m,2H),7.52– 7.35(m,5H),5.33(s,1H),3.68(s,3H),2.60–2.49(m,2H),2.40(d,J=12.3Hz,1H),2.23(d,J=12.5Hz,1H). 13 C NMR (75MHz, CDCl3) δ173.95,152.11,150.66,147.10,140.62,138.65,130.18,130.17,129.70,1 28.90,128.55,127.99,127.46,125.34,64.68,52.28,33.02,29.80.LC-MS(ESI)m / z:396.1[M+H] + .

[0366] Example 8: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 8)

[0367]

[0368] (S)-3-(8-chloro-6-(2-fluorophenyl)-1-oxo-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Methyl (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionic acid methyl ester (Compound 8, 0.39 g, yield: 75.4%).

[0369] 1H NMR(300MHz, CDCl3)δ:7.79-7.61(m,3H),7.48(q,J=6.1Hz,1H),7.34-7.24(m,2 H),7.05(t,J=9.6Hz,1H),4.23(t,J=5.7Hz,1H),3.68(s,3H),2.90-2.72(m,7H); 13 C NMR (75MHz, CDCl3) δ174.88,163.67,161.96,159.65,157.58,151.07,133.73,132.71,132.60,131.62,131.2 7,130.35,129.78,127.05,124.63,116.46,55.06,51.63,30.18,26.55,15.28; LC-MS(ESI)m / z:429.14[M+H] + .

[0370] Example 9: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 9)

[0371] Compound 9 was prepared by replacing compound 1 in Example 8 with compound 4 and referring to the method of Example 8.

[0372] 1 H NMR (300MHz, CDCl3) δ7.84(d,J=2.4Hz,1H),7.76(d,J=8.4Hz,1H),7.64(dd,J =8.4,2.6Hz,1H),7.57(dd,J=7.8,1.6Hz,1H),7.51(dd,J=7.7,1.6Hz,1H),7.3 1(dd,J=7.5,1.3Hz,1H),7.24(dd,J=7.8,1.3Hz,1H),4.71–4.63(m,1H),3.65 (s,3H),2.68(s,3H),2.72–2.62(m,1H),2.56–2.44(m,2H),2.39–2.28(m,1H); 13C NMR (75MHz, CDCl3) δ172.78,160.03,150.29,147.02,140.17,138.02,131.75,129.62,129.44,129.40,125.5 1,125.40,122.44,118.85,117.15,115.82,54.38,51.46,32.25,27.63,14.05; LC-MS(ESI)m / z:473.30[M+H] + .

[0373] Example 10: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 10)

[0374] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine The method of Example 8 was used to prepare compound 10.

[0375] 1 H NMR (300MHz, CDCl3) δ8.26(dd,J=7.5,2.0Hz,1H),8.15(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.64(dd,J=7.2,2.3Hz,1H),7.50–7.31(m,2H ),7.27(dd,J=7.2,2.4Hz,1H),5.15(s,1H),3.68(s,3H),2.56(s,3H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H); 13C NMR (75MHz, CDCl3) δ173.61,160.03,150.29,148.47,146.96,143.52,141.28,129.83,129.75,128.39,124.8 7,124.15,123.29,122.44,120.52,115.88,57.87,51.40,32.25,27.60,14.05; LC-MS(ESI)m / z:440.14[M+H] + .

[0376] Example 11: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 11)

[0377] In Example 8, iodomethane was replaced by iodoethane, and compound 11 was prepared according to the method of Example 8.

[0378] 1 H NMR (300MHz, CDCl3) δ: 8.11 (d, J = 8.3Hz, 1H), 7.66 (dd, J = 8.4, 2.6Hz, 1H), 7.57 (td, J = 7.8 ,5.0,1.6Hz,1H),7.50(td,J=7.7,5.0,1.6Hz,1H),7.40(d,J=2.5Hz,1H),7.31(td,J=7.5, 1.3Hz,1H),7.24(td,J=7.9,1.3Hz,1H),4.72–4.64(m,1H),3.65(s,3H),3.24(t,J=14.5,7 .3Hz,2H),2.77–2.66(m,1H),2.57–2.43(m,2H),2.40–2.28(m,1H),1.38(t,J=7.2Hz,3H); 13 C NMR(75MHz, CDCl3)δ:173.48,163.70,162.02,158.68,157.41,150.20,133.69,132.71,131.51,131.26,130.40, 129.65,127.06,125.08,124.56,116.45,55.10,51.63,30.20,27.81,26.54,14.66; LC-MS(ESI)m / z:443.18[M+H] + .

[0379] Example 12: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 12)

[0380] Compound 12 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with iodoethane.

[0381] 1 H NMR (300MHz, CDCl3) δ7.81 (dd, J=7.2, 2.4Hz, 1H), 7.59 (d, J=2.0Hz, 1H), 7.55-7.29 (m, 4H), 7.22 (dd, J=7.0, 2.5Hz, 1H) ,5.22(s,1H),3.68(s,3H),3.18(s,2H),2.50(d,J=12.4Hz,1H),2.39(d,J=12.4Hz,1H),2.37-2.19(m,2H),1.39(s,3H); 13 C NMR (75MHz, CDCl3) δ175.78,160.03,147.02,144.40,140.17,138.02,131.75,129.69,129.44,129.40,127.05,1 24.20,122.44,119.90,116.44,115.82,54.38,51.46,32.25,28.40,27.60,14.23; LC-MS(ESI)m / z:487.16[M+H] + .

[0382] Example 13: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 13)

[0383] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with iodoethane, and following the method of Example 8 to prepare compound 13.

[0384] 1H NMR (300MHz, CDCl3) δ8.27(dd,J=7.5,2.0Hz,1H),8.17(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.66-7.56(m,1H),7.47–7.31(m,2H),7. 32-7.22(m,1H),5.15(s,1H),3.68(s,3H),3.18(s,2H),2.53(d,J=12.4Hz,1H),2.45-2.33(m,2H),2.23(d,J=12.4Hz,1H),1.40(s,3H); 13 C NMR (75MHz, CDCl3) δ173.65,160.03,148.47,146.96,144.00,143.52,141.28,129.50,129.44,128.71,124.87,1 24.15,122.86,122.44,120.52,115.88,54.38,51.43,32.25,28.40,27.60,14.23; LC-MS(ESI)m / z:453.43[M+H] + .

[0385] Example 14: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 14)

[0386] In Example 8, iodomethane was replaced with 1-iodopropane, and compound 14 was prepared according to the method of Example 8.

[0387] 1 H NMR(300MHz, CDCl3)δ:7.78-7.61(m,3H),7.48(q,J=8.3Hz,1H),7.34-7.24(m,2H),7.05(t,J=9.0Hz,1H),4.23(t, J=6.2Hz,1H),3.68(s,3H),3.22(t,J=7.0Hz,2H),2.90-2.72(m,4H),1.77(q,J=7.1Hz,2H),1.01(t,J=7.2Hz,3H); 13C NMR(75MHz, CDCl3)δ:173.89,163.69,162.02,158.68,157.40,150.42,133.67,132.70,131.50,131.27,130.42,129 .65,127.06,125.11,124.57,116.45,55.11,51.63,35.33,30.21,26.54,22.68,13.17; LC-MS(ESI)m / z:457.11[M+H] + .

[0388] Example 15: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 15)

[0389] Compound 15 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 1-iodopropane.

[0390] 1 H NMR (300MHz, CDCl3) δ7.78 (dd, J=7.0, 2.4Hz, 1H), 7.62-7.29 (m, 6H), 7.21 (dd, J=6.9, 2.5Hz, 1H), 5.17 (s, 1 H),3.68(s,3H),3.24(s,2H),2.50(d,J=12.4Hz,1H),2.45-2.19(m,3H),1.80(d,J=0.4Hz,2H),1.01(s,2H); 13 C NMR (75MHz, CDCl3) δ175.78,160.03,147.02,145.70,140.80,138.02,131.75,129.84,129.69,129.44,127.05,124. 20,122.44,121.80,116.44,115.82,54.38,51.45,32.86,32.25,27.67,27.60,14.10; LC-MS(ESI)m / z:501.15[M+H] + .

[0391] Example 16: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 16)

[0392] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 1-iodopropane, and referring to the method of Example 8 to prepare compound 16.

[0393] 1 H NMR(300MHz, CDCl3) δ8.32(dd,J=7.5,2.0Hz,1H),8.17(d,J=1.9Hz,1H),7.75( d,J=7.5Hz,1H),7.64(dd,J=5.7,3.8Hz,1H),7.40(dd,J=5.6,3.9Hz,2H),7.28( dd,J=5.6,3.9Hz,1H),5.15(s,1H),3.68(s,3H),3.28(s,2H),2.53(d,J=12.4H z,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H),1.79(s,2H),1.03(s,3H); 13 C NMR (75MHz, CDCl3) δ171.70,160.03,148.47,145.70,144.82,143.03,142.03,129.44,128.90,128.71,124.87,124. 15,122.86,122.44,120.52,115.82,54.33,51.46,33.02,32.86,27.67,27.60,14.09; LC-MS(ESI)m / z:468.24[M+H] + .

[0394] Example 17: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 17)

[0395] In Example 8, iodomethane was replaced with 2-iodoethanol, and compound 17 was prepared according to the method of Example 8.

[0396] 1H NMR(300MHz, CDCl3)δ:7.81-7.64(m,3H),7.44(d,J=7.3Hz,1H),7.34-7.24(m,2H),7.05(t,J=10.0H z,1H),4.25-4.13(m,2H),3.99(q,J=5.6Hz,2H),3.68(s,3H),3.49-3.35(m,2H),2.90-2.72(m,4H); 13 CNMR(75MHz, CDCl3)δ173.81,163.79,162.01,158.67,157.51,150.84,133.95,132.78,131.69,131.27,130.17, 129.77,126.92,125.06,124.58,116.50,61.90,54.99,51.66,36.08,30.13,26.46; LC-MS(ESI)m / z:459.10[M+H] + .

[0397] Example 18: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazolyl Preparation of methyl (4-hetero-4-yl) propionate (Compound 18)

[0398] Compound 18 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 2-iodoethanol, according to the method of Example 8.

[0399] 1 H NMR (300MHz, CDCl3) δ7.78(dd,J=7.0,2.4Hz,1H),7.62–7.46(m,2H),7.47-7.29(m,2H),7.21(dd,J=6.9,2.5Hz,1H),7.11(d,J=7.5Hz,1H),5.15 (s,1H),4.58(t,J=5.5Hz,1H),3.71-3.49(m,6H),3.43(d,J=12.4Hz,1H),2.50(d,J=12.4Hz,1H),2.39(d,J=12.4Hz,1H),2.24(d,J=1.6Hz,2H); 13C NMR (75MHz, CDCl3) δ174.28,160.03,147.02,145.12,140.80,138.02,131.75,129.84,129.65,129.44,127.05,1 24.20,122.44,121.80,116.44,115.82,61.40,54.38,51.45,34.93,32.03,27.60; LC-MS(ESI)m / z:503.12[M+H] + .

[0400] Example 19: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazolyl Methyl 4-(4-(2-Methyl-2-nitropropionate))propanoate (Compound 19)

[0401] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-iodoethanol, and following the method of Example 8 to prepare Compound 19.

[0402] 1 H NMR (300MHz, CDCl3) δ8.32 (dd, J=7.5, 2.0Hz, 1H), 8.13 (d, J=2.0Hz, 1H), 7.75 (d ,J=7.5Hz,1H),7.64(dd,J=5.7,3.8Hz,1H),7.40(dd,J=5.6,3.9Hz,2H),7.41-7 .23(m,1H),5.15(s,1H),4.27(t,J=5.5Hz,1H),3.71-3.54(m,6H),3.51(d,J=12 .4Hz,1H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.6Hz,2H); 13C NMR (75MHz, CDCl3) δ176.90,160.03,148.47,145.70,144.82,143.03,142.03,129.44,128.90,128.71,124.87,1 24.15,122.86,122.44,121.02,115.82,61.63,54.33,51.46,35.01,33.02,27.60; LC-MS(ESI)m / z:470.13[M+H] + .

[0403] Example 20: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 20)

[0404] In Example 8, methyl iodide was replaced with 2-chloroethylamine, and compound 20 was prepared according to the method of Example 8.

[0405] 1 H NMR(300MHz, CDCl3)δ:7.82-7.67(m,3H),7.48(d,J=5.4Hz,1H),7.34-7.24(m,2H),7.05 (t,J=9.0Hz,1H),4.38-4.21(m,3H),3.68(s,3H),3.46-3.22(m,4H),2.90-2.72(m,4H); 13 C NMR(75MHz, CDCl3)δ:174.82,163.79,162.00,158.65,157.61,150.05,133.93,132.74,131.74,131.24,130.09, 129.69,126.95,125.11,124.56,116.48,54.98,51.65,40.72,31.58,30.15,26.45; LC-MS(ESI)m / z:458.18[M+H] + .

[0406] Example 21: (S)-3-(8-bromo-6-(2-fluorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 21)

[0407] Compound 21 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 2-chloroethylamine.

[0408] 1 H NMR (300MHz, CDCl3) δ7.86(dd,J=7.0,2.5Hz,1H),7.62-7.46(m,2H),7.47-7.29(m,2H),7.21(dd,J=6.9,2.5Hz,1H),7.04(d,J=7.5Hz,1H),5.15(s,1H ),4.49(d,J=0.7Hz,1H),4.37(d,J=0.7Hz,1H),3.71-3.51(m,5H),2.95(s, 2H), 2.50 (d, J = 12.4Hz, 1H), 2.39 (d, J = 12.4Hz, 1H), 2.24 (d, J = 1.5Hz, 2H); 13 CNMR (75MHz, CDCl3) δ174.72,160.03,147.02,145.12,140.80,138.02,131.75,129.84,129.69,129.44,127.05, 124.20,122.44,121.80,116.44,115.82,54.38,51.45,39.99,34.13,32.03,27.60; LC-MS(ESI)m / z:502.34[M+H] + .

[0409] Example 22: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 22)

[0410] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-chloroethylamine, and following the method of Example 8 to prepare Compound 22.

[0411] 1H NMR (300MHz, CDCl3) δ8.12 (dd, J=7.5, 2.0Hz, 1H), 8.17 (d, J=2.0Hz, 1H), 7.75 (d, J=7. 5Hz,1H),7.64(dd,J=5.7,3.8Hz,1H),7.40(dd,J=5.6,3.9Hz,2H),7.41-7.23(m,1H), 5.15(s,1H),4.49(d,J=0.7Hz,1H),4.37(d,J=0.7Hz,1H),3.65(d,J=17.9Hz,5H),3.0 0-2.82(m,2H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.6Hz,2H); 13 C NMR (75MHz, CDCl3) δ173.43,160.03,148.47,145.70,144.82,143.03,142.03,129.44,128.90,128.71,124.87,1 24.15,122.86,122.44,120.52,115.82,54.33,51.46,39.99,34.37,33.02,27.60; LC-MS(ESI)m / z:469.23[M+H] + .

[0412] Example 23: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 23)

[0413] Compound 23 was prepared by replacing compound 1 in Example 8 with compound 2 and referring to the method of Example 8.

[0414] 1 H NMR(300MHz, CDCl3)δ:7.97(d,J=8.6Hz,1H),7.64-7.54(m,2H),7.43-7.33 (m,3H),7.19(s,1H),4.28(t,J=6.4Hz,1H),3.68(s,3H),2.90-2.76(m,7H); 13C NMR (75MHz, CDCl3) δ: 175.83, 170.45, 157.49, 151.12, 138.02, 133.68, 132.84, 131.57, 131.35, 131.30, 131. 00,130.94,130.25,129.49,127.19,124.62,55.10,51.63,30.18,26.50,15.25; LC-MS(ESI)m / z:445.30[M+H] + .

[0415] Example 24: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 24)

[0416] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine The method of Example 8 was used to prepare compound 24.

[0417] 1 H NMR (300MHz, CDCl3) δ7.69 (dd, J=7.4, 1.9Hz, 1H), 7.62-7.44 (m, 3H), 7.51-7.27 (m, 3H), 7.34-7.24 (m,1H),5.32(s,1H),3.68(s,3H),2.53(d,J=8.9Hz,3H),2.45-2.26(m,2H),2.25(d,J=12.4Hz,1H); 13C NMR (75MHz, CDCl3) δ174.78,150.29,149.26,147.02,140.80,133.13,132.57,131.75,130.86,129.62,128.9 7,128.62,125.51,124.07,118.85,118.19,54.38,51.46,32.25,27.63,14.05; LC-MS(ESI)m / z:489.75[M+H] + .

[0418] Example 25: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 25)

[0419] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Compound 25 was prepared by referring to the method of Example 8.

[0420] 1 H NMR(300MHz, CDCl3)δ8.20(dd,J=7.5,2.0Hz,1H),8.17(d,J=2.1Hz,1H),7.68-7.54(m,2H),7.54-7.31(m,3H ),5.22(s,1H),3.68(s,3H),2.56(s,3H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.35-2.17(m,2H); 13C NMR (75MHz, CDCl3) δ172.71,150.96,150.29,148.47,143.37,141.28,134.20,130.98,130.35,129.35,128.7 1,128.62,124.17,123.83,122.86,121.02,54.38,51.43,32.25,27.60,14.05; LC-MS(ESI)m / z:456.19[M+H] + .

[0421] Example 26: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 26)

[0422] Compound 26 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with iodoethane.

[0423] 1 H NMR (300MHz, CDCl3) δ: 7.72 (d, J = 8.5Hz, 1H), 7.64-7.54 (m, 2H), 7.43-7.33 (m, 3H), 7.19 (s, 1H), 4 .28(t,J=6.2Hz,1H),3.68(s,3H),3.34(q,J=7.6Hz,2H),2.90-2.72(m,4H),1.42(t,J=7.1Hz,3H); 13 C NMR(75MHz, CDCl3)δ:173.81,166.46,157.23,150.27,138.05,133.63,132.82,131.46,131.32,131.30,130.98, 130.95,130.21,129.36,127.19,125.04,55.14,51.63,30.20,27.68,26.49,14.77; LC-MS(ESI)m / z:459.33[M+H] + .

[0424] Example 27: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 27)

[0425] The compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoic acid methyl ester, and iodomethane was replaced by iodoethane. Compound 27 was prepared by referring to the method of Example 8.

[0426] 1 H NMR (300MHz, CDCl3) δ7.80-7.67(m,1H),7.60(d,J=2.0Hz,1H),7.57-7.25(m,5H),5.32(s,1H),3.68 (s,3H),3.18(s,2H),2.50(d,J=12.4Hz,1H),2.45-2.26(m,2H),2.25(d,J=12.4Hz,1H),1.39(s,3H); 13 C NMR (75MHz, CDCl3) δ172.78,149.26,147.02,144.40,140.17,133.47,132.57,131.75,130.98,129.65,128.97,1 28.62,127.05,124.07,122.26,116.44,54.38,51.48,32.03,29.80,28.40,14.23; LC-MS(ESI)m / z:503.78[M+H] + .

[0427] Example 28: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 28)

[0428] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoic acid methyl ester, and iodomethane was replaced by iodoethane. The compound 28 was prepared according to the method of Example 8.

[0429] 1H NMR (300MHz, CDCl3) δ8.30(dd,J=7.5,2.0Hz,1H),8.19(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.61(dd,J=7.4,2.0Hz,1H),7.54-7. 31(m,3H),5.22(s,1H),3.68(s,3H),3.18(s,2H),2.53(d,J=12.4Hz,1H),2.40(d,J=12.4Hz,1H),2.24(d,J=1.5Hz,2H),1.40(s,3H); 13 C NMR (75MHz, CDCl3) δ173.90,150.96,147.02,144.00,143.37,141.28,133.92,130.98,130.35,129.31,128.71,1 28.54,124.07,123.83,122.86,121.02,54.38,51.46,32.25,28.40,27.60,14.23; LC-MS(ESI)m / z:470.12[M+H] + .

[0430] Example 29: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 29)

[0431] Compound 29 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-iodopropane.

[0432] 1 H NMR(300MHz, CDCl3)δ:7.86-7.27(m,7H),4.28(t,J=5.7Hz,1H),3.68(s,3H),3.30 (t,J=13.8Hz,2H),2.90-2.72(m,4H),1.81(q,J=6.7Hz,2H),1.04(t,J=6.9Hz,3H); 13C NMR(75MHz, CDCl3)δ:173.55,166.46,157.22,150.50,138.06,133.61,132.84,131.47,131.35,131.29,130.99,130 .95,130.22,129.35,127.18,125.09,55.19,51.64,35.17,30.23,26.52,22.73,13.23; LC-MS(ESI)m / z:473.12[M+H] + .

[0433] Example 30: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 30)

[0434] The compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 1-iodopropane, and following the method of Example 8 to obtain compound 30.

[0435] 1 H NMR (300MHz, CDCl3) δ7.96-7.85 (m, 2H), 7.79 (dd, J = 8.4, 2.5Hz, 1H), 7.59-7.4 9(m,1H),7.51-7.39(m,2H),7.41-7.27(m,1H),6.06-5.90(m,1H),3.62(s,3H), 3.32(dt,J=14.5,6.4Hz,1H),3.17(dt,J=14.5,6.4Hz,1H),2.79-2.62(m,1H), 2.58-2.40(m,2H),2.44-2.24(m,1H),1.93-1.58(m,2H),1.02(t,J=7.6Hz,3H); 13C NMR (75MHz, CDCl3) δ174.45,162.53,154.57,153.88,138.65,136.35,134.47,133.31,132.86,130.41,129.64,129. 59,128.37,126.63,122.44,119.72,55.11,51.90,34.69,29.81,29.59,22.63,13.16; LC-MS(ESI)m / z:517.16[M+H] + .

[0436] Example 31: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(propyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 31)

[0437] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 1-iodopropane, and following the method of Example 8 to prepare compound 31.

[0438] 1 H NMR (300MHz, CDCl3) δ8.44(dd,J=8.5,2.1Hz,1H),8.36(d,J=2.1Hz,1H),8.25(d,J=8.5Hz,1H),7.57(dd,J=7.8,1.5Hz,1H),7.54-7.36(m,2H),7.35(td ,J=7.6,1.5Hz,1H),5.12-4.94(m,1H),3.61(s,3H),3.38-3.13(m,2H),2.7 0-2.46(m,3H),2.35-2.17(m,1H),1.92-1.58(m,2H),1.03(t,J=7.6Hz,3H); 13 CNMR (75MHz, CDCl3) δ174.50,162.06,154.57,153.88,146.01,138.70,137.82,134.63,130.41,129.65,128.42,128 .36,128.20,126.67,125.98,123.39,55.11,51.90,34.69,29.70,29.62,22.63,13.16; LC-MS(ESI)m / z:484.16[M+H]+ .

[0439] Example 32: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 32)

[0440] Compound 32 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-iodoethanol.

[0441] 1 H NMR (300MHz, CDCl3) δ: 7.72 (d, J = 8.6Hz, 1H), 7.64-7.55 (m, 2H), 7.45-7.33 (m, 3H), 7.19 (s, 1H) ),4.28(t,J=5.3Hz,1H),4.11-3.96(m,3H),3.68(s,3H),3.51-3.42(m,2H),2.90-2.72(m,4H); 13 C NMR(75MHz, CDCl3)δ:173.74,166.57,157.42,150.92,137.91,133.98,132.83,131.65,131.39,131.29,130.98, 130.71,130.27,129.48,127.22,125.07,62.20,55.08,51.68,36.05,30.15,26.42; LC-MS(ESI)m / z:475.33[M+H] + .

[0442] Example 33: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 33)

[0443] The compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-iodoethanol, and following the method of Example 8 to prepare compound 33.

[0444] 1H NMR (300MHz, CDCl3) δ7.97-7.85 (m, 2H), 7.81 (dd, J = 8.4, 2.5Hz, 1H), 7.59-7. 48(m,1H),7.51-7.39(m,2H),7.39-7.27(m,1H),6.07-5.90(m,1H),4.40(t,J =7.2Hz,1H),3.75(q,J=7.0Hz,2H),3.62(s,3H),3.67–3.51(m,1H),3.39(dt, J=15.0,6.8Hz,1H),2.78-2.60(m,1H),2.60-2.38(m,2H),2.41-2.22(m,1H); 13 C NMR (75MHz, CDCl3) δ173.32,162.52,154.54,153.87,138.65,136.35,134.89,133.44,132.85,130.33,129.69,1 29.62,128.28,126.66,122.43,119.94,60.25,55.10,51.89,35.35,29.70,29.59; LC-MS(ESI)m / z:519.03[M+H] + .

[0445] Example 34: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(2-hydroxyethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 34)

[0446] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-iodoethanol, and following the method of Example 8 to prepare compound 34.

[0447] 1H NMR (300MHz, CDCl3) δ8.46-8.33(m,2H),8.26(d,J=8.4Hz,1H),7.57(dd,J=7.8,1.4Hz,1H),7.54-7.38(m,2H),7.34(td,J=7.5,1.5Hz,1H),5.09 -4.93(m,1H),4.40(t,J=7.2Hz,1H),3.82-3.63(m,2H),3.61(s,3H),3.6 8-3.40(m,2H),2.77-2.60(m,1H),2.61-2.42(m,2H),2.35-2.16(m,1H); 13 C NMR (75MHz, CDCl3) δ173.25,162.06,154.59,153.87,146.02,138.70,137.80,134.47,130.33,129.69,128.29,1 28.18,127.85,126.71,125.90,123.39,60.27,55.10,51.90,35.34,29.65,29.60; LC-MS(ESI)m / z:486.11[M+H] + .

[0448] Example 35: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 35)

[0449] Compound 35 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-chloroethylamine.

[0450] 1 H NMR (300MHz, CDCl3) δ: 7.85 (d, J = 8.7Hz, 1H), 7.62-7.51 (m, 2H), 7.41-7.31 (m, 3H), 7 .15(s,1H),6.46(s,2H),4.24(t,J=7.8Hz,1H),3.77-3.52(m,7H),2.82-2.73(m,4H); 13C NMR(75MHz, CDCl3)δ:175.80,166.72,157.62,150.17,137.84,134.11,132.82,131.95,131.37,131.23,130.93, 130.39,130.27,129.39,127.18,125.15,54.93,51.71,40.16,31.60,30.15,26.31; LC-MS(ESI)m / z:474.34[M+H] + .

[0451] Example 36: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 36)

[0452] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-chloroethylamine, and following the method of Example 8 to prepare compound 36.

[0453] 1 H NMR (300MHz, CDCl3) δ7.96-7.85 (m, 2H), 7.81 (dd, J = 8.3, 2.5Hz, 1H), 7.59-7.4 9(m,1H),7.51-7.39(m,2H),7.39-7.27(m,1H),6.06-5.89(m,1H),3.74(t,J=6. 1Hz,2H),3.62(s,3H),3.48(dt,J=15.6,5.8Hz,1H),3.34(dt,J=15.6,5.9Hz,1 H),3.18-2.88(m,2H),2.79-2.61(m,1H),2.59-2.37(m,2H),2.41-2.22(m,1H); 13C NMR (75MHz, CDCl3) δ173.41,162.53,154.45,153.86,138.65,136.35,134.80,133.38,132.85,130.33,129.69,1 29.62,128.28,126.66,122.43,119.94,55.10,51.89,40.95,35.18,29.70,29.59; LC-MS(ESI)m / z:518.05[M+H] + .

[0454] Example 37: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 37)

[0455] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-chloroethylamine, and following the method of Example 8 to obtain compound 37.

[0456] 1 H NMR (300MHz, CDCl3) δ8.53 (dd, J=8.5, 2.1Hz, 1H), 8.37 (d, J=2.1Hz, 1H), 8.27 (d, J=8. 4Hz,1H),7.56(dd,J=7.7,1.5Hz,1H),7.56-7.38(m,2H),7.34(td,J=7.5,1.5Hz,1H), 5.08-4.90(m,1H),3.74(t,J=6.1Hz,2H),3.64-3.33(m,4H),3.14(dt,J=14.6,6.0Hz, 1H),2.98(dd,J=14.6,5.9Hz,1H),2.74-2.57(m,1H),2.62-2.42(m,2H),2.26(m,2H); 13C NMR (75MHz, CDCl3) δ173.45,162.06,154.50,153.88,146.02,138.70,137.80,134.48,130.33,129.69,128.29,1 28.17,127.79,126.71,125.90,123.39,55.10,51.90,40.95,35.19,29.65,29.60; LC-MS(ESI)m / z:485.13[M+H] + .

[0457] Example 38: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(acetyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 38)

[0458] Compound 38 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing methyl iodide with acetyl iodide.

[0459] 1 H NMR(300MHz, CDCl3)δ:8.43(d,J=8.8Hz,1H),7.64(d,J=9.5Hz,1H),7.51-7.39(m,4H),7 .15(d,J=3.2Hz,1H),4.28(t,J=5.8Hz,1H),3.68(s,3H),2.80-2.62(m,4H),2.30(s,3H); 13 C NMR(75MHz, CDCl3)δ:173.43,168.18,167.82,166.20,151.61,141.72,137.59,134.00,133.16,132.08,131.51,1 31.07,130.85,130.49,129.00,127.37,127.07,54.77,51.81,29.81,25.73,20.63; LC-MS(ESI)m / z:473.07[M+H] + .

[0460] Example 39: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(acetyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 39)

[0461] The compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with acetyl iodide, and following the method of Example 8 to prepare Compound 39.

[0462] 1 H NMR (300MHz, CDCl3) δ8.14(d,J=8.3Hz,1H),7.96(d,J=2.5Hz,1H),7.79(dd,J=8.4,2.5Hz,1H),7.57 -7.27(m,4H),6.06-5.93(m,1H),3.62(s,3H),2.71-2.44(m,3H),2.45-2.22(m,4H); 13 C NMR (75MHz, CDCl3) δ183.25,173.42,162.53,154.37,148.67,138.65,136.35,134.79,133.71,132.84,130.33,1 29.63,129.62,128.28,126.66,122.42,119.94,55.10,51.89,30.14,29.65,29.59; LC-MS(ESI)m / z:517.02[M+H] + .

[0463] Example 40: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(acetyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 40)

[0464] The compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with acetyl iodide, and following the method of Example 8 to prepare compound 40.

[0465] 1H NMR (300MHz, CDCl3) δ8.51-8.33(m,2H),8.34(d,J=2.0Hz,1H),7.55(dt,J=7.7,6.0Hz,2H),7.53-7.3 2(m,2H),5.99(dt,J=8.2,7.4Hz,1H),3.61(s,3H),2.71-2.40(m,3H),2.42(s,3H),2.44-2.25(m,1H); 13 C NMR (75MHz, CDCl3) δ182.25,173.39,162.06,154.37,148.19,146.02,138.70,138.07,134.47,130.33,129.69,1 28.29,128.21,128.17,126.71,125.90,123.40,55.10,51.90,30.14,29.65,29.60; LC-MS(ESI)m / z:484.09[M+H] + .

[0466] Example 41

[0467] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxo-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of ethyl 4-aminopropionate (compound 41 tautomer)

[0468]

[0469] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine The mixture of methyl 2-(8-chloro-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine was dissolved in 4 ml of THF, and 2 ml of 2M LiOH was added. The mixture was stirred at 60°C for 6 hours, and the mixture was concentrated under reduced pressure and subjected to column chromatography (DCM:MeOH=20:1) to give a white solid (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-Chloro-6-(2-chlorophenyl)propionic acid (386.5 mg) was dissolved in 4 ml of DMF, and K2CO3 (133.5 mg, 0.97 mmol) and ethyl chloride (112 mg, 1.5 mmol) were added. The mixture was stirred at 55°C for 6 hours, and the reaction solution was diluted with water. The mixture was extracted three times with 60 ml of EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA=3:1, v / v) to give (S)3-(8-chloro-6-(2-chlorophenyl)-1-oxo-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine as a white solid. -4-yl)propionic acid ethyl ester (Compound 41 tautomer, 248.1 mg, yield 60%).

[0470] 1 H NMR (300MHz, CDCl3) δ: 12.39 (s, 1H), 8.52 (d, J = 8.7Hz, 1H), 7.62 (d, J = 8.6Hz, 1H), 7.64-7.38 (m, 4H) ,7.14(s,1H),4.28(t,J=6.3Hz,1H),4.14(q,J=7.0Hz,2H),2.76-2.57(m,4H),1.23(t,J=7.1Hz,3H); 13 C NMR(75MHz, CDCl3)δ:173.32,168.00,167.13,153.25,137.67,133.88,133.07,131.81,131.39,131.17,130. 91,130.82,130.40,129.14,127.01,60.70,54.92,37.23,30.18,25.84,14.19; LC-MS(ESI)m / z:445.30[M+H] + .

[0471] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-hydroxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of ethyl 4-aminopropionate (Compound 41)

[0472] Compound 41 was prepared by replacing the tautomer of Compound 1 in Example 1 with an equal molar amount of the tautomer of Compound 41, with the remainder being the same as in Example 1.

[0473] 1H NMR(300MHz, CDCl3)δ9.11(s,1H),7.85–7.79(m,3H),7.59(dd,J=7.3,2.1Hz,1H),7.53–7.36(m,6H),5.33(s,1H),4.0 7(s,2H),2.56(d,J=12.4Hz,1H),2.43(d,J=12.5Hz,1H),2.34(d,J=12.4Hz,1H),2.25(d,J=12.5Hz,1H),1.21(s,3H). 13 C NMR (75MHz, CDCl3) δ173.37,152.07,147.10,144.05,139.27,132.85,131.55,131.03,130.50,130.02,129.7 2,128.92,128.43,126.29,125.34,124.71,70.25,60.75,33.02,29.42,14.28.LC-MS(ESI)m / z:446.31[M+H] + .

[0474] Example 42: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of ethyl 4-aminopropionate (Compound 42)

[0475] Compound 42 was prepared by replacing compound 1 in Example 8 with compound 41 and following the method of Example 8.

[0476] 1 H NMR (300MHz, CDCl3) δ: 7.75 (d, J = 8.5Hz, 1H), 7.64-7.56 (m, 2H), 7.43-7.31 (m, 3H), 7.19 (s ,1H),4.28(t,J=5.6Hz,1H),4.14(q,J=7.0Hz,2H),2.90-2.76(m,5H)1.24(t,J=6.6Hz,3H); 13 C NMR(75MHz, CDCl3)δ:173.44,166.45,157.55,151.14,138.05,133.70,132.88,131.60,131.38,131.02,130.28 ,129.51,127.22,124.63,60.43,55.14,37.36,30.46,26.54,23.33,15.27,14.24; LC-MS(ESI)m / z:459.09[M+H]+ .

[0477] Example 43: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(methyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of ethyl 4-aminopropionate (Compound 43)

[0478] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 41 was replaced by compound (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Compound 43 was prepared by referring to the method of Example 8.

[0479] 1 H NMR (300MHz, CDCl3) δ7.99-7.87(m,2H),7.80(dd,J=8.4,2.5Hz,1H),7.53(dd,J=8.0,1.6Hz,1H),7.51-7.39(m,2H),7.39 -7.27(m,1H),5.02(ddd,J=8.3,7.6,0.7Hz,1H),4.21-3.97(m,2H),2.64(s,3H),2.73–2.26(m,4H),1.18(t,J=6.9Hz,3H); 13 C NMR (75MHz, CDCl3) δ172.72,162.53,154.47,153.45,138.65,136.35,134.56,133.15,132.85,130.33,129.69,1 29.62,128.28,126.67,122.44,119.73,60.67,55.10,30.27,29.68,16.53,14.18; LC-MS(ESI)m / z:503.04[M+H] + .

[0480] Example 44: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of ethyl 4-aminopropionate (Compound 44)

[0481] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 41 was replaced by compound (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine The method of Example 8 was used to prepare compound 44.

[0482] 1 H NMR (300MHz, CDCl3) δ8.51-8.33(m,2H),8.25(d,J=8.4Hz,1H),7.56(dd,J=7.7,1.5Hz,1H),7.53-7.39(m,2H),7.33(td,J=7.5,1.5Hz, 1H),5.02-4.87(m,1H),4.21-3.97(m,2H),2.75-2.58(m,1H),2.64(s,3H),2.61-2.39(m,2H),2.33-2.15(m,1H),1.18(t,J=6.9Hz,3H); 13 C NMR (75MHz, CDCl3) δ172.73,161.98,154.47,153.47,146.09,138.70,137.56,134.51,130.33,129.67,128.29,1 28.17,127.79,126.66,125.92,123.39,60.68,55.10,30.29,29.68,16.53,14.17; LC-MS(ESI)m / z:470.12[M+H] + .

[0483] Example 45: (S)-3-(8-chloro-1-(cyclopropylmethoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 45)

[0484] Compound 45 was prepared by replacing potassium iodide in Example 8 with (iodomethyl)cyclopropane.

[0485] 1 H NMR (300MHz, CDCl3) δ: 7.90 (s, 2H), 7.62 (dt, J = 25.3, 7.0Hz, 2H), 7.37 (d, J = 14.2Hz, 2H), 7.22 (t, J = 9.6Hz, 1H), 4.28 (t, J =6.4Hz,1H),3.62(s,3H),3.07(d,J=7.2Hz,2H),2.77-2.57(m,4H),1.05(s,1H),0.45(d,J=7.9Hz,2H),0.24-0.12(m,2H); 13 CNMR(75MHz, CDCl3)δ:173.57,163.45,161.94,161.87,161.44,156.52,153.90,134.08,133.03,132.44,132.38,131.36, 130.59,130.53,129.90,124.71,122.90,116.37,116.21,55.18,51.94,38.04,29.28,11.77; LC-MS(ESI)m / z:469.14[M+H] + .

[0486] Example 46: (S)-3-(8-Bromo-1-(cyclopropylmethoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 46)

[0487] Compound 46 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with (iodomethyl)cyclopropane.

[0488] 1H NMR (300MHz, CDCl3) δ7.97-7.83 (m, 2H), 7.80 (dd, J = 8.4, 2.5Hz, 1H), 7.53 ( m,J=15.6,7.6,5.0,1.6Hz,2H),7.28(dt,J=16.5,7.7,1.4Hz,2H),4.70-4.5 3(m,1H),3.61(s,3H),3.36-3.21(m,1H),3.09-2.96(m,1H),2.71-2.53(m,1 H),2.58-2.42(m,2H),2.36(dt,J=10.9,8.4,7.6Hz,1H),1.40-1.20(m,5H); 13 C NMR (75MHz, CDCl3) δ173.43,163.16,162.00,161.89,159.80,154.35,153.86,136.35,133.54,132.91,131.57,131.46,1 28.86,128.82,126.92,126.66,124.26,119.98,55.26,51.89,37.41,29.65,29.60,13.37; LC-MS(ESI)m / z:513.09[M+H] + .

[0489] Example 47: (S)-3-(8-nitro-1-(cyclopropylmethoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 47)

[0490] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, potassium iodide was replaced by (iodomethyl)cyclopropane, and compound 47 was prepared according to the method of Example 8.

[0491] 1H NMR(300MHz, CDCl3)δ8.56(dd,J=8.5,2.1Hz,1H),8.35–8.19(m,2H),7.63-7.44(m,2H),7.30(dt,J=13.2,7.7,1.4Hz,2H),4.9 3(t,J=8.1Hz,1H),3.61(s,3H),3.42-3.29(m,1H),3.05-2.91(m,1H),2.71-2.50(m,2H),2.55-2.27(m,2H),1.39-1.20(m,5H); 13 CNMR(75MHz, CDCl3)δ172.39,163.12,161.47,161.36,159.76,154.35,153.88,146.14,137.98,130.48,130.37,128.16, 127.07,126.81,126.00,123.39,115.95,115.68,55.26,51.90,37.41,29.65,29.61,13.37; LC-MS(ESI)m / z:480.16[M+H] + .

[0492] Example 48: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 48)

[0493] Compound 48 was prepared by replacing potassium iodide in Example 8 with 3-bromopropyne.

[0494] 1 H NMR(300MHz, CDCl3)δ:7.90-7.81(m,2H),7.68-7.53(m,2H),7.42-7.30(m,2H),7.28-7.18(m,1H),4.30(d d,J=8.0,5.5Hz,1H),3.98(qd,J=16.4,2.6Hz,2H),3.62(s,3H),3.17(t,J=2.6Hz,1H),2.80-2.54(m,4H); 13C NMR(75MHz, CDCl3)δ:175.35,163.77,161.23,156.64,153.26,134.21,132.95,131.36,130.71,129.34,127.76,127 .58,124.83,123.25,116.64,116.33,79.82,72.44,55.37,51.62,29.43,29.30,20.68; LC-MS(ESI)m / z:453.11[M+H] + .

[0495] Example 49: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 49)

[0496] Compound 49 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 3-bromopropyne.

[0497] 1 H NMR (300MHz, CDCl3) δ7.91 (d, J = 8.4Hz, 1H), 7.88-7.74 (m, 2H), 7.63-7.44 (m, 2H), 7.37-7.19 (m, 2H), 4.90 ( t,J=8.0Hz,1H),4.07(dd,J=12.4,3.0Hz,1H),3.85(dd,J=12.4,3.0Hz,1H),3.62(s,3H),2.71-2.27(m,5H); 13 C NMR (75MHz, CDCl3) δ173.39,163.17,162.00,161.89,159.80,154.01,153.86,136.35,133.51,132.85,130.43,128. 86,126.93,124.29,122.43,119.81,115.71,72.66,55.26,51.89,29.65,29.59,20.39; LC-MS(ESI)m / z:497.05[M+H] + .

[0498] Example 50: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 50)

[0499] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, potassium iodide was replaced by 3-bromopropyne, and compound 50 was prepared according to the method of Example 8.

[0500] 1 H NMR (300MHz, CDCl3) δ8.48(dd,J=8.5,2.1Hz,1H),8.33(d,J=2.1Hz,1H),8.22(d,J=8.5Hz,1H),7.63-7.45(m,2H),7.29(dtd,J=16.4 ,7.7,1.4Hz,2H),4.90(t,J=8.1Hz,1H),4.08(dd,J=12.3,3.0Hz,1H),3.87(dd,J=12.3,3.0Hz,1H),3.61(s,3H),2.73-2.26(m,5H); 13 C NMR (75MHz, CDCl3) δ173.41,163.13,161.36,159.77,154.02,146.14,131.58,131.46,130.43,130.33,128.17,127.36, 127.07,126.05,124.29,123.39,115.71,79.07,72.67,55.26,51.90,29.65,29.61,20.39; LC-MS(ESI)m / z:464.16[M+H] + .

[0501] Example 51: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 51)

[0502] Compound 51 was prepared by replacing potassium iodide in Example 8 with 2-(4-morpholino)ethyl bromide.

[0503] 1 H NMR(300MHz, CDCl3)δ:7.93(s,2H),7.75-7.52(m,2H),7.45-7.31(m,2H),7.30-7.18(m,1H),4.31(d, J=5.9Hz,1H),3.63(s,3H),3.55-3.45(m,4H),3.35(d,J=6.7Hz,2H),2.86-2.55(m,6H),2.36(m,4H); 13 C NMR(75MHz, CDCl3)δ:173.54,163.45,161.75,161.17,153.67,134.62,133.22,132.15,131.46,130.22,127.83,127.72,127.61 ,124.84,124.71,122.83,116.41,116.33,66.57,55.24,53.94,53.56,51.78,30.26,29.56,29.35; LC-MS(ESI)m / z:528.17[M+H] + .

[0504] Example 52: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 52)

[0505] Compound 52 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 2-(4-morpholino)ethyl bromide.

[0506] 1 H NMR (300MHz, CDCl3) δ8.06(dd,J=8.7,2.2Hz,1H),7.85(d,J=8.7Hz,1H),7.74-7.47(m,3H),7.37(t,J=7.5Hz,1H),7.25(dd,J= 10.6,8.6Hz,1H),4.30(t,J=6.6Hz,1H),3.64(s,3H),3.53-3.46(m,4H),3.35(d,J=6.8Hz,2H),2.89-2.56(m,6H),2.36(s,4H); 13C NMR (75MHz, CDCl3) δ173.40,163.21,162.00,161.89,159.85,154.56,153.8 6,136.19,133.51,132.95,131.61,131.50,130.38,130.28,128.98,128.94, 126.92,126.66,124.32,124.28,122.44,119.83,115.98,115.71,65.42,55 .26,53.50,52.67,51.93,30.41,29.65,29.61; LC-MS(ESI)m / z:572.44[M+H] + .

[0507] Example 53: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 53)

[0508] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 2-(4-morpholino)ethyl bromide was used in place of methyl 2-(4-morpholino)ethyl propionate, potassium iodide was replaced by 2-(4-morpholino)ethyl bromide, and compound 53 was prepared according to the method of Example 8.

[0509] 1H NMR (300MHz, CDCl3) δ8.52(dd,J=8.5,2.1Hz,1H),8.38(d,J=2.1Hz,1H),8.22(d,J=8.4Hz,1H),7.64-7.46(m,2H),7.37-7.20(m,2H),6. 13C NMR (75MHz, CDCl3) δ173.37,163.30,161.48,161.38,159.94,154.57,153.8 8,146.17,137.95,131.60,131.49,130.54,130.43,128.17,127.60,127.56, 127.08,126.81,125.94,124.26,124.22,123.35,115.98,115.71,65.46,55 .26,53.55,52.62,51.89,30.41,29.67,29.61; LC-MS(ESI)m / z:539.20[M+H] + .

[0510] Example 54: (S)-3-(8-chloro-1-(2-(diethylamino)ethoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 54)

[0511] Compound 54 was prepared by replacing potassium iodide in Example 8 with 2-bromo-N,N-diethylethanamine and referring to the method of Example 8.

[0512] 1H NMR (300MHz, CDCl3) δ: 7.91 (d, J=2.0Hz, 1H), 7.67–7.60 (m, 1H), 7.50 (dd, J= 7.5,2.0Hz,1H),7.46–7.35(m,2H),7.29(d,J=7.5Hz,1H),7.26–7.19(m,1H), 5.15(s,1H),3.68(s,3H),3.48(d,J=0.9Hz,2H),2.67(s,2H),2.54(s,4H),2. 47(d,J=12.3Hz,1H),2.40(d,J=12.5Hz,1H),2.30–2.19(m,2H),1.00(s,6H); 13 C NMR (75MHz, CDCl3) δ: 173.49, 163.48, 161.84, 161.77, 161.52, 156.36, 153. 37,134.73,133.25,132.58,132.39,131.41,130.67,130.46,129.73,127.74 ,127.62,127.58,127.39,124.68,124.51,122.76,116.45,116.26,55.22,51 .83,51.53,47.82,30.37,29.51,29.33,11.51; LC-MS(ESI)m / z:514.00[M+H] + .

[0513] Example 55: (S)-3-(8-Bromo-1-(2-(diethylamino)ethoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 55)

[0514] Compound 55 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 2-bromo-N,N-diethylethylamine, according to the method of Example 8.

[0515] 1H NMR (300MHz, CDCl3) δ7.96-7.84(m,2H),7.79(dd,J=8.4,2.5Hz,1H),7.53(m,J=16.9 ,7.6,5.0,1.6Hz,2H),7.28(m,2H),6.05-5.89(m,1H),3.62(s,3H),3.51(dt,J=14.1, 5.2Hz,1H),3.35(dt,J=14.1,5.2Hz,1H),2.84(dt,J=12.2,5.2Hz,1H),2.77-2.60(m ,2H),2.66-2.47(m,4H),2.53-2.40(m,2H),2.43-2.24(m,1H),1.01(t,J=7.2Hz,6H); 13 CNMR (75MHz, CDCl3) δ173.41,163.21,162.00,161.89,159.85,154.56,153. 86,136.19,133.43,132.95,131.62,131.52,130.53,130.42,128.86,128.82 ,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.71,55.26,51 .93,50.88,47.11,30.42,29.65,29.61,11.17; LC-MS(ESI)m / z:558.14[M+H] + .

[0516] Example 56: (S)-3-(8-nitro-1-(2-(diethylamino)ethoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 56)

[0517] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionic acid methyl ester, potassium iodide was replaced by 2-bromo-N,N-diethylethanamine, and compound 56 was prepared according to the method of Example 8.

[0518] 1 H NMR (300MHz, CDCl3) δ8.49(dd,J=8.5,2.1Hz,1H),8.32(d,J=2.1Hz,1H),8.21(d,J=8.5Hz,1H),7.54(m,2H),7.37-7.20(m,2H),4.89(m,1H),3 .62(s,3H),3.47(dt,J=14.1,5.2Hz,1H),3.33(dt,J=14.1,5.2Hz,1H), 2.87(dt,J=12.1,5.2Hz,1H),2.79-2.26(m,9H),1.01(t,J=7.2Hz,6H); 13 C NMR (75MHz, CDCl3-d1) δ173.42,163.09,161.48,161.38,159.73,154.51,153 .88,146.17,137.95,131.60,131.49,130.49,130.38,128.17,127.60,127.5 6,127.08,126.81,126.00,124.26,124.22,123.37,115.98,115.71,55.26,5 1.91,50.88,47.11,30.42,29.67,29.61,11.17; LC-MS(ESI)m / z:525.22[M+H] + .

[0519] Example 57: (S)-3-(8-chloro-1-(3-(dimethylamino)propoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 57)

[0520] Compound 57 was prepared by replacing potassium iodide in Example 8 with 3-bromo-N,N-dimethyl-1-propylamine and referring to the method of Example 8.

[0521] 1H NMR(300MHz, CDCl3)δ:7.92-7.84(m,2H),7.65(td,J=7.6,1.8Hz,1H),7.58(tdd,J=7.5,5.2,1.8Hz,1H),7.42-7.31(m,2H),7.22(dd,J=10.9 ,8.3Hz,1H),4.28(dd,J=7.7,5.5Hz,1H),3.61(s,3H),3.24-3.06(m,2H),2.78-2.52(m,4H),2.39(m,2H),2.18(s,6H),1.79(q,J=7.1Hz,2H); 13 C NMR (75MHz, CDCl3) δ: 173.72, 163.68, 161.90, 161.82, 161.54, 156.38, 153. 73,134.21,133.12,132.51,132.36,131.73,130.66,130.48,129.41,127.88 ,127.60,127.47,127.39,124.63,124.49,122.88,116.47,116.28,58.73,55 .48,51.63,45.28,31.91,29.53,29.33,26.74; LC-MS(ESI)m / z:500.18[M+H] + .

[0522] Example 58: (S)-3-(8-Bromo-1-(3-(dimethylamino)propoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 58)

[0523] Compound 58 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 3-bromo-N,N-dimethyl-1-propylamine.

[0524] 1 H NMR (300MHz, CDCl3) δ7.97-7.83(m,2H),7.79(dd,J=8.4,2.5Hz,1H),7.53(m,2H),7.28(dtd,J=13.1,7.7,1.4Hz,2H),6.06-5. 91(m,1H),3.62(s,3H),3.37-3.12(m,2H),2.70-2.53(m,2H),2.58-2.40(m,2H),2.45-2.24(m,3H),2.21(s,5H),1.94(m,2H);13 CNMR (75MHz, CDCl3) δ173.41,163.21,162.00,161.89,159.85,154.56,153. 86,136.19,133.43,132.95,131.57,131.46,130.53,130.42,128.86,128.82 ,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.72,57.69,55 .26,51.89,44.74,30.52,29.65,29.61,27.44; LC-MS(ESI)m / z:544.13[M+H] + .

[0525] Example 59: (S)-3-(8-nitro-1-(3-(dimethylamino)propoxy)-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 59)

[0526] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 3-bromo-N,N-dimethyl-1-propylamine was used in place of methyl 4-amino-2-nitropropanoate, and the method of Example 8 was followed to prepare Compound 59.

[0527] 1H NMR (300MHz, CDCl3) δ8.48(dd,J=8.5,2.1Hz,1H),8.31(d,J=2.1Hz,1H),8.22(d,J=8.5Hz,1H),7.63-7.45(m,2H),7.37-7.20(m,2H),4.95(t,J=8.1 Hz,1H),3.62(s,3H),3.30(dt,J=14.4,6.4Hz,2H),2.21(dd,5H),1.91(m, J=10.6,13.0,6.5Hz,2H),3.15(dt,J=14.4,6.4Hz,1H),2.71-2.26(m,6H); 13 C NMR (75MHz, CDCl3) δ173.43,163.12,161.48,161.38,159.76,154.59,153.8 8,146.17,137.96,131.60,131.49,130.51,130.41,128.17,127.29,127.25, 127.08,126.81,126.00,124.26,124.22,123.37,115.95,115.68,57.69,55 .26,51.91,44.74,30.52,29.65,29.61,27.43; LC-MS(ESI)m / z:511.20[M+H] + .

[0528] Example 60: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 60)

[0529] Compound 60 was prepared by replacing potassium iodide in Example 8 with 1-(2-bromoethyl)-4-methylpiperazine.

[0530] 1 H NMR(300MHz, CDCl3) δ7.94(d,J=1.9Hz,1H),7.71–7.64(m,1H),7.47–7.37(m,3H),7.29(d,J=7.5Hz,1H),7.19–7.12( m,1H),5.15(s,1H),3.68(s,3H),3.51(s,2H),2.51(s,2H),2.48–2.39(m,9H),2.41–2.30(m,3H),2.29–2.22(m,3H); 13C NMR(75MHz, CDCl3)δ:173.69,163.57,161.84,161.73,161.56,156.48,153.38 ,134.67,133.55,132.47,132.34,131.73,130.35,130.13,129.57,127.65,12 7.58,127.37,127.29,124.67,124.61,122.48,116.37,116.24,55.32,53.46, 52.78,52.55,51.78,45.84,30.26,29.74,29.36; LC-MS(ESI)m / z:541.23[M+H] + .

[0531] Example 61: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 61)

[0532] Compound 61 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 1-(2-bromoethyl)-4-methylpiperazine.

[0533] 1 H NMR (300MHz, CDCl3) δ7.67(dd,J=7.4,2.2Hz,1H),7.60(d,J=2.0Hz,1H),7.54(dd,J=7.4,1.9Hz,1H),7.46–7.34(m,2H),7.18(d,J=7.5Hz,1H ),7.07(dd,J=7.4,2.2Hz,1H),5.15(s,1H),3.68(s,3H),3.51(s,2H),2.51(s,2H),2.48–2.39(m,9H),2.41–2.30(m,3H),2.29–2.22(m,3H). 13C NMR (75MHz, CDCl3) δ173.36,163.19,162.00,161.89,159.83,154.56,153.86, 136.38,133.51,132.95,131.61,131.50,130.38,130.28,128.98,128.94,126 .92,126.66,124.32,124.28,122.44,119.83,115.98,115.71,55.26,53.62,5 2.88,52.57,51.93,45.16,30.41,29.67,29.59; LC-MS(ESI)m / z:585.15[M+H] + .

[0534] Example 62: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 62)

[0535] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 1-(2-bromoethyl)-4-methylpiperazine, potassium iodide was replaced by 1-(2-bromoethyl)-4-methylpiperazine, and compound 62 was prepared according to the method of Example 8.

[0536] 1H NMR (300MHz, CDCl3) δ8.52(dd,J=8.4,2.1Hz,1H),8.37(d,J=2.1Hz,1H),8.20(d,J=8.5Hz,1H),7.64-7.46(m,2H),7.28(dtd,J=18.3,7.7,1.4Hz,2 H),5.98(m,1H),3.66-3.49(m,4H),3.29(dt,J=14.1,5.2Hz,1H),2.84(d t,J=12.1,5.2Hz,1H),2.80-2.45(m,8H),2.52-2.29(m,5H),2.25(s,3H); 13 C NMR (75MHz, CDCl3) δ173.36,163.30,161.48,161.38,159.94,154.51,153.88, 146.17,138.11,131.60,131.49,130.54,130.43,128.17,127.60,127.56,127 .08,126.81,125.94,124.26,124.22,123.35,115.98,115.71,55.26,53.62,5 2.88,52.57,51.93,45.16,30.41,29.67,29.61; LC-MS(ESI)m / z:552.23[M+H] + .

[0537] Example 63: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 63)

[0538] Compound 63 was prepared by replacing potassium iodide in Example 8 with N-methyl-4-bromopiperidine.

[0539] 1H NMR(300MHz, CDCl3)δ:7.94(d,J=1.9Hz,1H),7.67–7.60(m,1H),7.60(d,J=7.4Hz,1H),7.49–7.35(m,3H),7.26–7.19(m,1H),5.22(s ,1H),3.68(s,3H),3.59(s,1H),2.56(s,2H),2.54–2.43(m,3H),2.40(d,J=12.5Hz,1H),2.35–2.22(m,5H),1.98(s,2H),1.90(s,2H); 13 C NMR (75MHz, CDCl3) δ: 173.62, 163.43, 161.72, 161.63, 161.53, 154.68, 153. 31,133.68,133.10,132.42,132.23,131.41,130.63,130.48,129.88,127.82 ,127.79,127.73,127.45,124.68,124.56,123.36,116.38,116.23,55.16,53 .81,51.92,45.91,39.48,31.55,29.39,29.25; LC-MS(ESI)m / z:512.18[M+H] + .

[0540] Example 64: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 64)

[0541] Compound 64 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with N-methyl-4-bromopiperidine.

[0542] 1 H NMR (300MHz, CDCl3) δ7.95-7.85(m,2H),7.80(dd,J=8.4,1.9Hz,1H),7.64-7.45(m,2H),7.28(dd,J=7.7,1.3Hz,2H),6.05-5.91(m,1H),3 .62(s,3H),3.27(p,J=5.8Hz,1H),2.74(m,2H),2.68-2.51(m,1H),2.58-2.42(m,3H),2.48-2.32(m,2H),2.29(s,3H),2.04-1.79(m,4H).13 C NMR (75MHz, CDCl3) δ173.41,163.21,162.00,161.89,159.85,153.44,153.0 1,136.19,133.07,132.95,131.60,131.49,130.53,130.42,128.86,128.82, 126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.71,55.26,54 .28,51.93,45.68,34.94,31.76,29.65,29.61; LC-MS(ESI)m / z:566.13[M+H] + .

[0543] Example 65: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 65)

[0544] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)propionic acid methyl ester, potassium iodide was replaced by N-methyl-4-bromopiperidine, and compound 65 was prepared according to the method of Example 8.

[0545] 1H NMR (300MHz, CDCl3) δ8.51 (dd, J=8.4, 1.9Hz, 1H), 8.40 (d, J=1.9Hz, 1H), 8.2 2(d,J=8.5Hz,1H),7.55(dd,J=17.0,7.6,5.0,1.7Hz,2H),7.29(m,J=14.3,7. 7,1.4Hz,2H),6.06-5.90(m,1H),3.62(s,3H),3.28(m,J=5.8Hz,1H),2.77(m ,J=12.2,7.8,5.8Hz,2H),2.71-2.24(m,6H),2.29(s,3H),2.06-1.80(m,4H). 13 C NMR (75MHz, CDCl3) δ173.37,163.09,161.48,161.38,159.73,153.42,153.0 3,146.17,137.52,131.60,131.49,130.51,130.41,128.17,127.60,127.56, 127.08,126.81,126.05,124.26,124.22,123.35,115.98,115.71,55.26,54 .28,51.91,45.68,34.92,31.67,29.67,29.61; LC-MS(ESI)m / z:523.20[M+H] + .

[0546] Example 66: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 66)

[0547] Compound 66 was prepared by replacing potassium iodide in Example 8 with 4-(3-chloropropyl)piperazine-1-ethanol and referring to the method of Example 8.

[0548] 1H NMR(300MHz, CDCl3)δ7.97(d,J=2.0Hz,1H),7.71–7.64(m,1H),7.57(d,J=7.5Hz ,1H),7.51–7.39(m,3H),7.12–7.06(m,1H),5.26(s,1H),4.33(t,J=5.5Hz,1H),3 .69(s,3H),3.49(d,J=5.4Hz,2H),3.20(q,J=12.5Hz,2H),2.53(d,J=0.7Hz,2H) ,2.47(d,J=3.3Hz,8H),2.46–2.33(m,4H),2.35–2.22(m,2H),2.02–1.91(m,2H); 13 C NMR(75MHz, CDCl3)δ:173.51,163.39,161.74,161.67,161.24,156.51,153.86,13 4.09,133.33,132.18,132.28,131.50,130.54,130.47,129.88,127.75,127.58,1 27.72,127.61,124.72,124.66,122.55,116.36,116.02,59.79,57.51,55.23,55. 12,52.68,52.08,51.89,31.15,29.43,29.18,27.65; LC-MS(ESI)m / z:585.23[M+H] + .

[0549] Example 67: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 67)

[0550] Compound 67 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 4-(3-chloropropyl)piperazine-1-ethanol.

[0551] 1H NMR (300MHz, CDCl3) δ7.67 (dd, J=7.5, 2.1Hz, 1H), 7.63–7.53 (m, 2H), 7.46 (td, J=7.5, 2.0Hz, 1H),7.38(td,J=7.4,2.1Hz,2H),7.12(dd,J=7.5,2.1Hz,1H),5.26(s,1H),4.33(t,J=5.5Hz,1 H),3.69(s,3H),3.49(d,J=5.4Hz,2H),3.20(q,J=12.5Hz,2H),2.53(d,J=0.7Hz,2H),2.47(d, J=3.3Hz,8H),2.41(d,J=3.5Hz,2H),2.42–2.33(m,2H),2.35–2.22(m,2H),2.02–1.91(m,2H). 13 C NMR (75MHz, CDCl3) δ173.40,163.37,162.00,161.89,160.00,154.56,153.86,136 .38,133.59,132.95,131.61,131.50,130.39,130.28,128.98,128.94,126.93,12 6.66,124.21,124.17,122.44,119.76,115.91,115.64,59.24,58.71,55.29,55.1 1,52.38,52.36,51.93,30.47,29.67,29.59,27.31; LC-MS(ESI)m / z:629.18[M+H] + .

[0552] Example 68: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 68)

[0553] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-(3-chloropropyl)piperazine-1-ethanol, potassium iodide was replaced by 4-(3-chloropropyl)piperazine-1-ethanol, and compound 68 was prepared according to the method of Example 8.

[0554] 1 H NMR (300MHz, CDCl3) δ8.41(dd,J=7.5,2.0Hz,1H),8.19(d,J=2.0Hz,1H),7.75(d,J=7.5Hz,1H),7.64(dd,J =7.4,2.0Hz,1H),7.49(td,J=7.5,2.0Hz,1H),7.42(td,J=7.4,2.0Hz,1H),7.14(dd,J=7.4,2.0Hz,1H),5.1 5(s,1H),4.21(t,J=5.5Hz,1H),3.69(s,3H),3.49(d,J=5.4Hz,2H),3.20(q,J=12.5Hz,2H),2.52(d,J=2.7H z,2H),2.53–2.39(m,11H),2.39(s,1H),2.35(d,J=12.3Hz,1H),2.25(d,J=12.5Hz,1H),2.02–1.91(m,2H). 13 CNMR (75MHz, CDCl3) δ173.36,163.30,161.56,161.45,159.94,154.60,153.88,14 6.16,138.12,131.61,131.50,130.46,130.35,128.16,127.78,127.74,127.08,1 26.81,125.94,124.35,124.31,123.35,115.91,115.64,59.24,58.71,55.26,55. 11,52.44,52.41,51.94,30.45,29.67,29.59,27.31; LC-MS(ESI)m / z:596.26[M+H] + .

[0555] Example 69: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 69)

[0556] Compound 69 was prepared by replacing potassium iodide in Example 8 with 4-(chloromethyl)morpholine.

[0557] 1 H NMR (300MHz, CDCl3) δ8.04(d,J=2.0Hz,1H),7.64(dd,J=6.9,2.7Hz,1H),7.60(d,J=7.5Hz,1H),7.47–7.33(m,3H),7.23(dd,J=6.9,2.7Hz,1 H),5.17(s,1H),3.81(d,J=12.4Hz,1H),3.72–3.62(m,9H),2.78(s,3H),2.50(d,J=12.4Hz,1H),2.42(d,J=12.5Hz,1H),2.35–2.22(m,2H); 13 C NMR(75MHz, CDCl3)δ:173.44,163.43,161.90,161.83,161.34,153.79,153 .74,134.22,133.01,132.43,132.37,131.35,130.53,130.46,129.92,127 .75,127.65,127.51,127.49,124.71,124.61,123.02,116.42,116.01,66. 71,58.33,55.58,51.74,43.81,29.41,29.17; LC-MS(ESI)m / z:514.16[M+H] + .

[0558] Example 70: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 70)

[0559] Compound 70 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with 4-(chloromethyl)morpholine.

[0560] 1H NMR (300MHz, CDCl3) δ7.97-7.83(m,2H),7.81(dd,J=8.4,2.5Hz,1H),7.53(m,2H),7.36-7.19(m,2H),6.04-5.90(m,1H) ,4.24(d,J=13.4Hz,1H),3.99(d,J=13.4Hz,1H),3.75-3.56(m,7H),2.93(m,2H),2.80-2.40(m,5H),2.41-2.23(m,1H). 13 C NMR (75MHz, CDCl3) δ173.41,163.21,162.00,161.89,159.85,153.86,149. 17,136.19,133.62,132.95,131.62,131.52,130.53,130.42,128.86,128. 82,126.92,126.66,124.26,124.22,122.42,119.83,115.98,115.71,66.3 1,58.28,55.26,52.38,51.93,29.65,29.61; LC-MS(ESI)m / z:558.11[M+H] + .

[0561] Example 71: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 71)

[0562] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-(chloromethyl)morpholine was used in place of methyl 4-(chloromethyl)morpholine, and compound 71 was prepared according to the method of Example 8.

[0563] 1H NMR(300MHz, CDCl3)δ8.50(dd,J=8.4,2.1Hz,1H),8.33(d,J=2.1Hz,1H),8.23(d,J=8 .5Hz,1H),7.65-7.46(m,2H),7.29(m,J=14.4,7.7,1.4Hz,2H),4.75(t,J=8.2Hz,1H), 4.20(d,J=13.4Hz,1H),4.06(d,J=13.4Hz,1H),3.74-3.54(m,7H),2.93(m,J=12.7,6. 8,5.3Hz,2H),2.73(m,J=12.7,6.9,5.2Hz,2H),2.72–2.48(m,2H),2.53-2.27(m,2H). 13 CNMR (75MHz, CDCl3) δ173.37,163.09,161.48,161.38,159.73,153.86,149 .17,146.17,137.95,131.60,131.49,130.51,130.41,128.17,127.65,127 .61,127.08,126.81,126.05,124.26,124.22,123.35,115.98,115.71,66. 32,58.28,55.26,52.43,51.91,29.67,29.61; LC-MS(ESI)m / z:525.18[M+H] + .

[0564] Example 72: (S)-3-(8-chloro-6-(2-fluorophenyl)-1-((4-phenylpiperazin-1-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 72)

[0565] Compound 72 was prepared by replacing potassium iodide in Example 8 with N-phenylpiperazine.

[0566] 1H NMR(300MHz, CDCl3)δ8.47(d,J=8.9Hz,1H),7.92-7.83(m,1H),7.68-7.51(m,2H),7 .40-7.30(m,2H),7.29-7.14(m,3H),6.93(t,J=9.3Hz,2H),6.76(t,J=7.2Hz,1H),5. 28(d,J=13.4Hz,1H),5.10(d,J=13.4Hz,1H),4.37-4.23(m,1H),3.33(s,3H),3.13( t,J=4.9Hz,3H),3.02-2.85(m,4H),2.82-2.56(m,4H),2.45(dd,J=10.1,6.7Hz,1H); 13 C NMR(75MHz, CDCl3)δ:173.46,163.40,161.84,161.81,161.33,153.79,153.34,150 .64,134.18,133.22,132.16,132.12,131.39,130.49,130.33,129.94,129.11,127 .75,127.63,127.53,127.49,124.63,124.45,123.18,118.61,116.59,116.44,116 .31,58.36,55.28,51.91,51.72,48.41,29.39,29.19; LC-MS(ESI)m / z:589.21[M+H] + .

[0567] Example 73: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((4-phenylpiperazin-1-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 73)

[0568] Compound 73 was prepared by replacing compound 1 in Example 8 with compound 4 and potassium iodide with N-phenylpiperazine.

[0569] 1H NMR (300MHz, CDCl3) δ7.87(d,J=2.4Hz,1H),7.80-7.62(m,2H),7.57(m,J=7.6,6.7,3.9,1.4H z,2H),7.29(td,J=7.5,1.4Hz,1H),7.23-7.11(m,3H),6.90-6.81(m,3H),6.02-5.87(m,1H),4 .34-4.09(m,2H),3.76(s,3H),3.34(m,J=11.8,6.4,4.2Hz,2H),3.22(m,J=11.8,6.5,4.2Hz,2 H),2.76(m,J=11.7,6.4,4.2Hz,2H),2.61-2.52(m,1H),2.60-2.32(m,4H),2.41-2.15(m,1H); 13 C NMR(75MHz, CDCl3)δ:173.34,163.22,162.45,161.76,160.45,153.56,151.31,149 .21,136.45,133.70,132.32,131.37,131.67,130.78,130.43,129.23,128.68,128 .45,126.57,126.34,124.23,124.12,122.45,119.56,118.50,116.12,115.91,115 .64,58.79,55.33,51.53,51.74,48.44,29.32,29.52; LC-MS(ESI)m / z:633.15[M+H] + .

[0570] Example 74: (S)-3-(8-nitro-6-(2-fluorophenyl)-1-((4-phenylpiperazin-1-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 74)

[0571] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-fluorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-fluorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, potassium iodide was replaced by N-phenylpiperazine, and compound 74 was prepared according to the method of Example 8.

[0572] 1 H NMR (300MHz, CDCl3) δ8.48-8.37(m,2H),8.00(d,J=8.2Hz,1H),7.56-7.38(m,2H),7.23(td,J=7.6,1.3Hz,1H ),7.14-7.01(m,3H),6.88-6.73(m,3H),4.56(m,J=8.2,7.2,0.7Hz,1H),4.13(d,J=13.4Hz,1H),4.01(d,J=13 .3Hz,1H),3.43(s,3H),3.21(m,J=11.8,6.3,4.2Hz,2H),3.01(m,J=11.8,6.5,4.2Hz,2H),2.74(m,J=11.8,6. 4,4.2Hz,2H),2.65-2.54(m,1H),2.60-2.47(m,2H),2.53-2.42(m,1H),2.48-2.33(m,1H),2.34-2.16(m,1H); 13 C NMR(75MHz, CDCl3)δ:173.34,163.54,161.56,161.36,160.78,153.98,151.45,149 .54,146.16,137.22,131.51,131.65,130.54,130.76,129.17,128.20,127.55,127 .12,127.01,126.71,126.02,124.43,124.23,123.45,118.08,116.11,115.87,115 .45,58.56,55.68,51.45,51.67,48.44,29.78,29.68; LC-MS(ESI)m / z:600.23[M+H] + .

[0573] Example 75: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 75)

[0574] Compound 75 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with (iodomethyl)cyclopropane.

[0575] 1 H NMR(300MHz, CDCl3)δ:7.93-7.81(m,2H),7.66(dd,J=6.0,3.3Hz,1H),7.53(dq,J=6.1,4.0,3.4Hz,2H),7.51-7.42(m,1H),7.19(d,J=2.3Hz,1 H),4.31(dd,J=7.9,5.5Hz,1H),3.26-3.07(m,3H),3.01(d,J=6.1,2H) ,2.79-2.57(m,4H),1.11(m,1H),0.58-0.45(m,2H),0.34-0.21(m,2H); 13 C NMR(75MHz, CDCl3)δ:173.43,162.78,156.44,153.88,137.85,134.75,133.44,133.26,131.45,131.39,129.69,129 .45,128.57,128.38,127.21,122.56,54.73,51.82,38.13,29.58,29.14,11.63,6.31; LC-MS(ESI)m / z:485.11[M+H] + .

[0576] Example 76: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 76)

[0577]

[0578] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with (iodomethyl)cyclopropane, and following the method of Example 8 to obtain Compound 76.

[0579] 1 H NMR (300MHz, CDCl3) δ7.81 (d, J = 2.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.70-7.5 5(m,2H),7.53-7.41(m,2H),7.32(dt,J=7.8,5.1,3.8Hz,1H),4.79-4.50(m, 1H),3.70(s,3H),3.43(dd,J=13.5,4.8Hz,1H),3.13(dd,J=13.6,4.8Hz,1H) ,2.71-2.43(m,3H),2.53-2.28(m,1H),1.50-1.33(m,1H),1.42-1.14(m,4H); 13 CNMR(75MHz, CDCl3)δ:173.45,162.31,154.35,153.57,138.87,136.17,134.12,133.45,132.28,130.98,129.34,12 9.47,128.38,126.68,122.44,119.76,55.43,51.67,37.43,29.81,29.62,13.54,6.60; LC-MS(ESI)m / z:529.06[M+H] + .

[0580] Example 77: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 77)

[0581] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with (iodomethyl)cyclopropane, and following the method of Example 8 to obtain Compound 77.

[0582] 1 H NMR (300MHz, CDCl3) δ8.49(d,J=2.1Hz,1H),8.37(dd,J=8.5,2.1Hz,1H),8.02(d,J=8.5Hz,1H),7.67-7.48(m,3H),7.30(dt,J=8.0,6.9,1.7Hz,1H) ,4.67-4.43(m,1H),3.34(s,3H),3.10-3.01(m,1H),2.90-2.85(m,1H),2. 59-2.33(m,2H),2.39-2.23(m,1H),2.20-2.05(m,1H),1.46-1.21(m,5H); 13 C NMR(75MHz, CDCl3)δ:173.50,162.65,154.76,153.55,146.81,138.09,137.32,134.46,130.71,129.98,128.12,128 .23,128.46,126.87,125.67,123.75,55.43,51.56,37.56,29.65,29.23,13.45,6.76; LC-MS(ESI)m / z:496.13[M+H] + .

[0583] Example 78: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 78)

[0584] Compound 78 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 3-bromopropyne.

[0585] 1 H NMR (300MHz, CDCl3) δ7.94-7.80(m,2H),7.69-7.60(m,1H),7.58-7.48(m,2H),7.45(m,1H),7.20(d,J=2.4Hz ,1H),4.33(dd,J=7.9,5.4Hz,1H),4.15-3.96(m,2H),3.60(s,3H),3.21(t,J=2.5Hz,1H),2.78-2.54(m,4H); 13C NMR(75MHz, CDCl3)δ:173.25,162.95,156.03,153.88,137.76,134.79,133.90,133.06 ,131.54,131.29,129.88,129.65,128.82,128.67,127.31,123.03,79.13,72.19,54.94 51.94,29.57,29.24,20.22; LC-MS(ESI)m / z:469.08[M+H] + .

[0586] Example 79: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 79)

[0587] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 3-bromopropyne was used in place of iodomethane, and compound 79 was prepared according to the method of Example 8.

[0588] 1 H NMR (300MHz, CDCl3) δ7.97(d,J=2.5Hz,1H),7.76(d,J=8.4Hz,1H),7.55(dd,J=8.5,2.4Hz,1H),7.48-7.31(m,3H),7.18(dt,J=7.8,5.7,3. 2Hz,1H),4.67-4.52(m,1H),4.01(dd,J=12.3,3.0Hz,1H),3.89(dd,J=12.4,3.0Hz,1H),3.71(s,3H),2.65-2.32(m,3H),2.29-2.05(m,2H); 13C NMR(75MHz, CDCl3)δ:173.12,162.65,154.30,153.09,138.23,136.76,134.09,133.19,132.65,130.65,129.45,129 .76,128.78,126.13,122.56,119.73,79.01,72.66,55.11,51.70,29.57,29.76,20.41; LC-MS(ESI)m / z:513.03[M+H] + .

[0589] Example 80: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(prop-2-yn-1-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 80)

[0590] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 3-bromopropyne was used in place of iodomethane, and compound 80 was prepared according to the method of Example 8.

[0591] 1 H NMR (300MHz, CDCl3) δ8.49-8.34(m,2H),8.09(d,J=8.4Hz,1H),7.55-7.40(m,3H),7.30(dt,J=7.7,7.2,1.7Hz,1H),4.89(t,J=8.0Hz,1H),4.12(d d,J=12.4,3.0Hz,1H),3.89(dd,J=12.4,3.0Hz,1H),3.60(s,3H),2.87-2 .63(m,2H),2.49-2.33(m,1H),2.37-2.29(m,1H),2.21(t,J=3.0Hz,1H); 13C NMR(75MHz, CDCl3)δ:173.50,162.06,154.02,153.88,146.01,138.70,137.82,134.63,130.41,129.65,128.39,128 .36,128.20,126.67,125.98,123.39,79.06,72.67,55.11,51.90,29.70,29.62,20.40; LC-MS(ESI)m / z:480.10[M+H] + .

[0592] Example 81: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 81)

[0593] Compound 81 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-(4-morpholino)ethyl bromide.

[0594] 1 H NMR (300MHz, CDCl3) δ: 7.92 (d, J = 1.8 Hz, 2H), 7.72-7.64 (m, 1H), 7.58-7.46 (m, 3H), 7.27-7.16 (m, 1H), 4.34 (t, J = 6 .6Hz,1H),3.62(s,3H),3.55(t,J=4.5Hz,4H),3.43(s,2H),2.81-2.67(m,2H),2.63(t,J=6.6Hz,4H),2.40(s,4H); 13 C NMR(75MHz, CDCl3)δ:173.34,162.85,156.47,153.39,137.34,134.56,133.33,133.10,131.49,131.36,129.24,129.11 ,128.87,128.59,127.39,122.55,66.23,54.88,53.99,53.54,51.78,30.35,29.88,29.68; LC-MS(ESI)m / z:544.14[M+H] + .

[0595] Example 82: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 82)

[0596] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine methyl 2-(4-morpholino)ethyl bromide, replacing iodomethane with 2-(4-morpholino)ethyl bromide, and following the method of Example 8 to prepare Compound 82.

[0597] 1 H NMR (300MHz, CDCl3) δ8.04(dd,J=8.7,2.3Hz,1H),7.83(d,J=8.7Hz,1H),7.68(dd,J=6.0,3.3Hz,1H),7.60-7.45(m,3H),7.33(d,J=2.2Hz,1H ),4.33(t,J=6.6Hz,1H),3.62(s,3H),3.56-3.51(m,4H),3.39(d,J=6.2Hz,2H),2.82-2.66(m,2H),2.62(t,J=6.7Hz,4H),2.45-2.32(m,4H); 13 C NMR(75MHz, CDCl3)δ:173.54,162.56,154.86,153.45,138.96,136.11,134.57,133.69,132.98,130.01,129.24,129.30 ,128.45,126.35,122.57,119.97,65.12,55.45,53.55,52.57,51.98,30.65,29.80,29.89; LC-MS(ESI)m / z:588.09[M+H] + .

[0598] Example 83: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(2-morpholinoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 83)

[0599] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 2-(4-morpholino)ethyl bromide was used in place of iodomethane, and compound 83 was prepared according to the method of Example 8.

[0600] 1 H NMR (300MHz, CDCl3) δ8.56-8.43(m,2H),8.13(d,J=8.3Hz,1H),7.59-7.47(m,1H),7.52-7.38(m,2H),7.37-7.25(m,1H),5. 11-4.96(m,1H),3.54-3.33(m,8H),3.19(dt,J=14.1,5.2Hz,1H),2.89-2.65(m,3H),2.57-2.32(m,6H),2.20-2.11(m,1H); 13 C NMR(75MHz, CDCl3)δ:173.11,162.45,154.44,153.90,146.22,138.67,137.48,135.92,130.33,129.68,128.45,128.85 ,128.68,126.15,125.68,123.42,65.82,55.15,53.47,52.98,51.75,30.09,29.61,29.01; LC-MS(ESI)m / z:555.17[M+H] + .

[0601] Example 84: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 84)

[0602] Compound 84 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-bromo-N,N-diethylethylamine.

[0603] 1 H NMR(300MHz, CDCl3)δ:8.15(d,J=8.4Hz,1H),7.63(dd,J=8.4,2.4Hz,1H),7.53– 7.43(m,3H),7.41(d,J=2.5Hz,1H),7.30(td,J=7.9,7.0,1.8Hz,1H),4.69(t,J=8 .0Hz,1H),3.67–3.56(m,3H),3.45(dt,J=14.3,5.1Hz,1H),2.94(dt,J=12.1,5. 2Hz,1H),2.76–2.44(m,9H),2.37(dq,J=11.3,8.1Hz,1H),1.02(t,J=7.2Hz,6H); 13 C NMR(75MHz, CDCl3)δ:173.45,162.23,156.68,153.44,137.88,134.21,133.45,133.88,131.73,131.46,129.96,129.78 ,128.75,128.53,127.38,122.45,54.59,51.83,51.67,47.65,30.57,29.99,29.43,11.87; LC-MS(ESI)m / z:530.16[M+H] + .

[0604] Example 85: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 85)

[0605] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with 2-bromo-N,N-diethylethanamine, and following the method of Example 8 to prepare Compound 85.

[0606] 1 H NMR (300MHz, CDCl3) δ7.95 (d, J = 2.4Hz, 1H), 7.79-7.61 (m, 2H), 7.55-7.40 (m, 3H),7.28(td,J=7.7,6.4,2.4Hz,1H),4.76-4.62(m,1H),3.68-3.51(m,4H),3. 43(dt,J=14.2,5.2Hz,1H),2.87(dt,J=12.1,5.2Hz,1H),2.79-2.56(m,3H),2 .63-2.46(m,4H),2.52-2.39(m,1H),2.43-2.24(m,1H),1.03(t,J=7.2Hz,6H); 13 C NMR(75MHz, CDCl3)δ:173.47,162.55,154.56,153.88,138.65,136.19,134.57,133.30,132.51,130.41,129.80,129.31 ,128.32,126.70,122.48,119.74,55.12,51.92,50.90,47.11,30.42,29.81,29.62,11.17; LC-MS(ESI)m / z:574.11[M+H] + .

[0607] Example 86: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(2-(diethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 86)

[0608] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-amino-5-nitropropionic acid methyl ester, replacing iodomethane with 2-bromo-N,N-diethylethanamine, and following the method of Example 8 to prepare Compound 86.

[0609] 1 H NMR (300MHz, CDCl3) δ8.54 (dd, J=8.5, 2.1Hz, 1H), 8.41 (d, J=2.1Hz, 1H), 8.29 (d, J=8.3Hz,1H),7.60(dd,J=7.7,1.5Hz,1H),7.56-7.39(m,2H),7.31(td,J=7.5,1. 4Hz,1H),5.98(m,1H),3.76-3.56(m,4H),3.33(dt,J=14.3,5.2Hz,1H),2.81(dt, J=12.1,5.2Hz,1H),2.63-2.49(m,8H),2.32-2.14(m,1H),1.01(t,J=7.3Hz,6H); 13 C NMR(75MHz, CDCl3)δ:173.23,162.11,154.63,153.23,146.87,138.86,137.98,134.58,130.23,129.96,128.42,128.18 ,128.49,126.26,125.86,123.14,55.75,51.87,50.97,47.31,30.65,29.43,29.61,11.32; LC-MS(ESI)m / z:541.19[M+H] + .

[0610] Example 87: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 87)

[0611] Compound 87 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 3-bromo-N,N-dimethyl-1-propylamine, according to the method of Example 8.

[0612] 1H NMR (300MHz, CDCl3) δ: 7.93-7.80 (m, 2H), 7.66 (dd, J = 5.9, 3.4Hz, 1H), 7.53 (dq,J=6.1,3.9,3.5Hz,2H),7.50-7.42(m,1H),7.19(d,J=2.3Hz,1H),4.31 (dd,J=7.9,5.5Hz,1H),3.60(s,3H),3.31-3.23(m,1H),3.16(dt,J=13.4,7 .2Hz,1H),2.78-2.57(m,4H),2.36(s,2H),2.17(s,6H),1.86-1.73(m,2H); 13 C NMR(75MHz, CDCl3)δ:173.98,162.36,156.78,153.43,137.67,134.84,133.56,133.42,131.86,131.46,129.86,129.08 ,128.68,128.49,127.17,122.98,58.03,54.10,51.27,45.55,31.36,29.71,29.59,26.59; LC-MS(ESI)m / z:516.15[M+H] + .

[0613] Example 88: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 88)

[0614] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 3-bromo-N,N-dimethyl-1-propylamine was used in place of methyl iodide, and compound 88 was prepared according to the method of Example 8.

[0615] 1H NMR (300MHz, CDCl3) δ7.99(d,J=8.4Hz,1H),7.87-7.70(m,2H),7.67(dd,J=7.6,1.8Hz,1H),7.56(dd,J=7.6,1.6Hz,1H),7.39(m,2H),6.01-5.91(m,1H ),3.65(s,3H),3.38(dt,J=14.4,6.4Hz,1H),3.10(dt,J=14.4,6.5Hz,1H), 2.67-2.34(m,6H),2.22(m,6H),2.01(dp,J=12.9,6.4Hz,1H),1.88(m,1H); 13 CNMR(75MHz, CDCl3)δ:173.14,162.23,154.50,153.43,138.22,136.18,134.79,133.26,132.96,130.16,129.09,129.34 ,128.98,126.12,122.43,119.21,57.64,55.86,51.43,44.53,30.15,29.70,29.34,27.78; LC-MS(ESI)m / z:560.10[M+H] + .

[0616] Example 89: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 89)

[0617] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 3-bromo-N,N-dimethyl-1-propylamine was used in place of methyl iodide, and compound 89 was prepared according to the method of Example 8.

[0618] 1H NMR (300MHz, CDCl3) δ8.58(dd,J=8.5,2.1Hz,1H),8.43(d,J=2.1Hz,1H),8.34(d,J=8.5Hz,1H),7.55(dd,J=7.7,1.4Hz,1H),7.50–7.38(m,2H),7.3 2(td,J=7.5,1.5Hz,1H),4.99(t,J=8.1Hz,1H),3.61(s,3H),3.26–3.04(m ,2H),2.83–2.37(m,6H),2.31(m,6H),1.95(dt,J=17.5,12.8,6.3Hz,2H); 13 CNMR(75MHz, CDCl3)δ:173.14,162.40,154.60,153.77,146.41,138.33,137.69,134.87,130.44,129.82,128.58,128.69 ,127.77,126.86,125.93,123.39,57.73,55.26,51.98,44.99,30.58,29.88,29.09,27.54; LC-MS(ESI)m / z:527.17[M+H] + .

[0619] Example 90: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 90)

[0620] Compound 90 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)-4-methylpiperazine.

[0621] 1 H NMR (300MHz, CDCl3) δ8.49(dd,J=7.2,1.5Hz,1H),8.37(d,J=1.5Hz,1H),7.81(d,J=7.7Hz,1H),7.69-7.57(m,1H),7.57-7.33(m,3H),5.9 5-5.89(m,1H),3.58(s,3H),3.50-3.18(m,2H),2.88-2.50(m,2H),2.67-2.49(m,7H),2.55-2.41(m,4H),2.50-2.41(m,1H),2.30(s,3H); 13C NMR(75MHz, CDCl3)δ:173.76,162.91,156.09,153.49,137.91,134.24,133.76,133.42,131.90,131.11,129.46,129.36,12 8.87,128.71,127.90,122.23,54.29,53.70,52.40,52.22,51.53,45.66,30.98,29.56,29.29; LC-MS(ESI)m / z:557.18[M+H] + .

[0622] Example 91: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 91)

[0623] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 1-(2-chloroethyl)-4-methylpiperazine, replacing iodomethane with 1-(2-chloroethyl)-4-methylpiperazine, and following the method of Example 8 to prepare Compound 91.

[0624] 1 H NMR (300MHz, CDCl3) δ8.43(dd,J=7.2,1.5Hz,1H),8.31(d,J=1.5Hz,1H),7.82(d,J=7.7Hz,1H),7.69-7.59(m,1H),7.56-7.33(m,3H),5.9 5-5.83(m,1H),3.52(s,3H),3.50-3.18(m,2H),2.88-2.50(m,2H),2.67-2.49(m,7H),2.55-2.41(m,4H),2.50-2.41(m,1H),2.30(s,3H); 13C NMR(75MHz, CDCl3)δ:173.23,162.76,154.34,153.67,138.98,136.34,134.59,133.16,132.90,130.46,129.51,129.33,12 8.40,126.10,122.21,119.70,55.37,53.48,52.69,52.16,51.95,45.17,30.34,29.11,29.60; LC-MS(ESI)m / z:601.13[M+H] + .

[0625] Example 92: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(2-(4-methylpiperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 92)

[0626] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 1-(2-chloroethyl)-4-methylpiperazine, replacing iodomethane with 1-(2-chloroethyl)-4-methylpiperazine, and following the method of Example 8 to prepare Compound 92.

[0627] 1 H NMR (300MHz, CDCl3) δ8.56(dd,J=7.2,1.5Hz,1H),8.33(d,J=1.5Hz,1H),7.87(d,J=7.7Hz,1H),7.69-7.59(m,1H),7.56-7.33(m,3H),5.9 5-5.83(m,1H),3.56(s,3H),3.50-3.28(m,2H),2.88-2.60(m,2H),2.67-2.49(m,7H),2.55-2.45(m,4H),2.50-2.42(m,1H),2.30(s,3H); 13C NMR(75MHz, CDCl3)δ:173.36,162.07,154.51,153.88,146.14,138.72,137.95,134.98,130.33,129.65,128.27,128.25,12 8.17,126.71,125.83,123.35,55.10,53.62,52.88,52.57,51.93,45.16,30.41,29.67,29.61; LC-MS(ESI)m / z:568.20[M+H] + .

[0628] Example 93: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 93)

[0629] Compound 93 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with N-methyl-4-bromopiperidine.

[0630] 1 H NMR (300MHz, CDCl3) δ7.92-7.78(m,2H),7.70-7.60(m,1H),7.58-7.41(m,3H),7.18( d,J=2.4Hz,1H),4.31(dd,J=7.8,5.5Hz,1H),3.36(d,J=18.0Hz,4H),2.79-2.54(m,5 H),2.51-2.33(m,4H),2.13(s,3H),2.10-1.92(m,3H),1.90-1.79(m,1H),1.66(dt,J =13.2,10.2,9.7,3.5Hz,1H),1.51(dt,J=13.8,10.3,3.8Hz,1H),1.19-0.97(m,1H); 13 C NMR(75MHz, CDCl3)δ:173.56,162.78,154.34,153.98,137.09,134.34,133.39,133.14,131.98,131.01,129.84,129.37 ,128.81,128.58,127.23,123.67,54.45,53.76,51.43,45.98,39.09,31.34,29.71,29.01; LC-MS(ESI)m / z:528.15[M+H] + .

[0631] Example 94: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 94)

[0632] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with N-methyl-4-bromopiperidine, and following the method of Example 8 to prepare Compound 94.

[0633] 1 H NMR(300MHz, CDCl3) δ7.93(d,J=1.8Hz,1H),7.74(d,J=8.5Hz,1H),7.65(dd,J=8.4,1.8Hz,1H),7.54–7.43(m,3H),7.29(td,J=7.5,1.6Hz,1H),6.04–5 .94(m,1H),3.65(s,3H),3.32(p,J=5.8Hz,1H),2.78(m,2H),2.66–2.54(m, 2H),2.57–2.45(m,1H),2.41–2.29(m,3H),2.35(s,3H),2.07–1.89(m,4H); 13 CNMR (75MHz, CDCl3) δ173.44,162.92,154.83,153.07,136.68,136.32,134.54,132.69,130.92,129.67,129.29,128 .62,126.95,122.39,118.51,55.15,52.59,51.85,45.28,39.32,30.13,29.31,29.03; LC-MS(ESI)m / z:572.10[M+H] + .

[0634] Example 95: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 95)

[0635] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with N-methyl-4-bromopiperidine, and following the method of Example 8 to prepare Compound 95.

[0636] 1 H NMR (300MHz, CDCl3) δ8.43–8.37(m,2H),8.07(d,J=8.2Hz,1H),7.51(dd,J=7.7,1.4Hz, 1H),7.47–7.39(m,2H),7.33–7.26(m,1H),5.03(t,J=8.0Hz,1H),3.65(s,3H),3.32(p, J=5.8Hz,1H),2.80(dd,J=12.1,8.0,2H),2.63(dt,J=15.4,7.7Hz,1H),2.60–2.46(m,2 H),2.41–2.34(m,1H),2.36(s,3H),2.38–2.32(m,1H),2.30(m,1H),2.08–1.90(m,4H). 13 C NMR (75MHz, CDCl3) δ173.44,162.54,154.39,153.21,145.72,137.91,137.16,134.54,130.92,129.44,129.27,128.61, 128.47,126.86,125.17,123.04,55.05,52.59,51.85,45.22,39.42,30.26,29.38,29.04; LC-MS(ESI)m / z:539.17[M+H] + .

[0637] Example 96: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 96)

[0638] Compound 96 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 4-(3-chloropropyl)piperazine-1-ethanol.

[0639] 1 H NMR (300MHz, CDCl3) δ7.93(d,J=1.8Hz,1H),7.75–7.61(m,2H),7.54(dd,J=14.9,7.8,1.5Hz,2H),7.46(td,J=7.6,1. 6Hz,1H),7.29(td,J=7.7,1.5Hz,1H),6.03–5.95(m,1H),4.27(t,J=7.3Hz,1H),3.68–3.56(m,4H),3.53(m,1H),3.33( dt,J=14.3,6.4Hz,1H),3.24(dt,J=14.5,6.4Hz,1H),3.00(dt,J=11.7,5.3Hz,2H),2.89(dt,J=11.9,5.4Hz,2H),2.73 (dt,J=12.6,6.9Hz,1H),2.69–2.61(m,1H),2.64–2.43(m,9H),2.39–2.28(m,1H),1.90(dd,J=23.9,13.0,6.5Hz,2H); 13 C NMR(75MHz, CDCl3)δ:173.23,162.34,156.65,153.22,137.74,134.46,133.56,133.06,131.88,131.72,129.74,129.36,128.80,1 28.55,127.38,122.21,59.43,57.76,55.63,54.52,52.37,52.27,51.28,31.15,29.36,29.27,27.46; LC-MS(ESI)m / z:601.20[M+H] + .

[0640] Example 97: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 97)

[0641] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-(3-chloropropyl)piperazine-1-ethanol, replacing iodomethane with 4-(3-chloropropyl)piperazine-1-ethanol, and following the method of Example 8 to prepare Compound 97.

[0642] 1 H NMR(300MHz, CDCl3)δ7.95(d,J=1.8Hz,1H),7.75–7.64(m,2H),7.54(m,2H),7.46(td,J=7.6,1.6Hz,1H),7.29(t d,J=7.7,1.5Hz,1H),6.03–5.95(m,1H),4.27(t,J=7.3Hz,1H),3.68–3.56(m,4H),3.53(m,1H),3.33(dt,J=14.3 ,6.4Hz,1H),3.24(dt,J=14.5,6.4Hz,1H),3.00(dt,J=11.7,5.3Hz,2H),2.89(dt,J=11.9,5.4Hz,2H),2.73(dt, J=12.6,6.9Hz,1H),2.69–2.61(m,1H),2.64–2.43(m,9H),2.39–2.28(m,1H),1.90(dd,J=23.9,13.0,6.5Hz,2H); 13C NMR (75MHz, CDCl3) δ173.41,162.97,156.25,153.66,136.68,136.32,134.34,134.42,132.59,130.92,129.67,129.26,128.51,12 6.45,122.37,118.53,59.43,57.28,55.15,54.51,52.52,51.92,51.75,30.28,29.37,29.07,27.65; LC-MS(ESI)m / z:645.15[M+H] + .

[0643] Example 98: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 98)

[0644] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-(3-chloropropyl)piperazine-1-ethanol, replacing iodomethane with 4-(3-chloropropyl)piperazine-1-ethanol, and following the method of Example 8 to prepare Compound 98.

[0645] 1H NMR (300MHz, CDCl3) δ8.65(dd,J=8.9,2.0Hz,1H),8.46(d,J=2.0Hz,1H),8.20(d,J=8.9Hz,1 H),7.67-7.66(m,1H),7.53-7.34(m,3H),5.75(t,J=8.3Hz,1H),4.11(t,J=6.3Hz,1H),3.65 (s,3H),3.63–3.55(m,2H),3.24(td,J=6.9,1.9Hz,2H),2.78-2.56(m,2H),2.60-2.51(m,1H ),2.56-2.42(m,3H),2.49-2.34(m,7H),2.44-2.35(m,1H),2.39-2.18(m,2H),1.81(m,2H); 13 C NMR (75MHz, CDCl3) δ173.44,162.54,156.32,153.82,145.72,138.32,137.06,134.54,130.92,129.41,129.27,128.61,128.42,12 6.96,125.17,123.04,59.43,57.27,55.05,54.51,52.52,51.92,51.85,30.28,29.37,29.07,27.55; LC-MS(ESI)m / z:611.23[M+H] + .

[0646] Example 99: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 99)

[0647] Compound 99 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 4-(chloromethyl)morpholine.

[0648] 1H NMR (300MHz, CDCl3) δ8.11(d,J=8.4Hz,1H),7.65(dd,J=8.4,2.4Hz,1H),7.52–7.43(m,3H),7.41(d,J=2.5Hz,1H),7.33–7.25(m,1H),6.03 –5.95(m,1H),4.31(d,J=13.3Hz,1H),4.06(d,J=13.3Hz,1H),3.67–3.61(m,7H),2.65–2.57(m,5H),2.61–2.47(m,2H),2.41–2.30(m,1H); 13 C NMR(75MHz, CDCl3)δ:173.36,162.28,153.47,153.28,137.19,134.03,133.47,133.19,131.63,131.57,129.72,129 .56,128.86,128.55,127.05,123.53,66.32,58.17,54.59,51.73,43.82,29.47,29.18; LC-MS(ESI)m / z:530.41[M+H] + .

[0649] Example 100: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 100)

[0650] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-(methyl)morpholine instead of iodomethane, and the method according to Example 8 to prepare compound 100.

[0651] 1H NMR (300MHz, CDCl3) δ7.93(dd,J=1.9,0.7Hz,1H),7.87-7.74(m,2H),7.64-7.51(m,1H),7.53-7.37(m,3H),5.75(t,J=8.3Hz,1H),4. 08(d,J=3.6Hz,2H),3.53(s,3H),3.69-3.52(m,4H),2.68-2.52(m,2H),2.48-2.46(m,4H),2.38-2.29(m,1H),2.33-2.21(m,1H).13C NMR (75MHz, CDCl3) δ173.44,162.92,153.77,153.55,137.68,136.38,134.61,134.54,132.69,130.92,129.73,129. 21,128.61,126.95,122.30,118.53,66.63,56.98,55.05,51.65,46.16,29.48,29.27; LC-MS(ESI)m / z:574.08[M+H] + .

[0652] Example 101: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-(morpholinomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 101)

[0653] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-(chloromethyl)morpholine instead of iodomethane, and the method according to Example 8 to prepare Compound 101.

[0654] 1H NMR(300MHz, CDCl3)δ:8.64(dd,J=9.1,2.1Hz,1H),8.45(d,J=2.2Hz,1H),8.21(d,J=8.9Hz,1H),7.65-7.57(m,1H),7.50-7.36(m,3H),5.71(t,J =8.3Hz,1H),4.10(d,J=3.6Hz,2H),3.63(s,3H),3.60-3.50(m,4H),2.7 3-2.58(m,2H),2.55-2.42(m,4H),2.35-2.25(m,1H),2.21-2.18(m,1H); 13 C NMR(75MHz, CDCl3)δ:173.43,162.54,153.85,153.77,145.74,138.23,137.07,134.57,130.81,129.43,129.37,128 .64,128.47,126.96,125.17,123.03,66.63,56.90,55.04,51.82,46.16,29.38,29.08; LC-MS(ESI)m / z:541.15[M+H] + .

[0655] Example 102: (S)-3-(8-chloro-1-(methyloxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 102)

[0656] Compound 102 was prepared by replacing compound 1 in Example 8 with compound 7 and following the method of Example 8.

[0657] 1 H NMR (300MHz, CDCl3) δ: 7.98-7.85 (m, 2H), 7.58-7.41 (m, 6H), 4.25 (dd, J = 7.6, 5.5Hz, 1H), 3.63 (s, 3H), 2.85-2.51 (m, 7H); 13 C NMR (75MHz, CDCl3) δ: 173.46, 166.48, 153.48, 153.37, 139.60, 133.75, 133.45, 132.62, 130.46, 130. 30,128.69,128.43,128.12,122.65,55.63,51.73,29.83,29.07,16.74; LC-MS(ESI)m / z:411.11[M+H] + .

[0658] Example 103: (S)-3-(8-Bromo-1-(methyloxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 103)

[0659] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-benzophenone in equal moles, and the rest was the same as in Example 1 to prepare (S)-3-(8-bromo-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Compound 103 was prepared by referring to the method of Example 8.

[0660] 1 H NMR(300MHz, CDCl3)δ:7.80-7.73(m,3H),7.62-7.57(m,2H),7.50-7.44(m,3H),5.62(t,J=8.2Hz,1H),3.64( s,3H),2.78(dt,J=15.4,9.0Hz,1H),2.73(s,3H),2.68(dt,J=15.4,9.1Hz,1H),2.34(dt,J=13.5,8.0Hz,2H); 13 C NMR (75MHz, CDCl3) δ: 173.45, 166.20, 153.34, 152.80, 138.58, 136.32, 133.67, 133.29, 129.82, 129. 08,128.50,128.41,122.37,118.45,55.25,51.82,29.37,29.06,16.60; LC-MS(ESI)m / z:455.06[M+H] + .

[0661] Example 104: (S)-3-(8-nitro-1-(methoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 104)

[0662] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-benzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-phenyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-phenyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Compound 104 was prepared by referring to the method of Example 8.

[0663] 1 H NMR(300MHz, CDCl3)δ:8.64(dd,J=9.0,2.0Hz,1H),8.51(d,J=2.1Hz,1H),8.16(d,J=9.0Hz,1H),7.72-7.60(m,2H),7.53-7.42(m,3H),5 .62(t,J=8.3Hz,1H),3.64(s,3H),2.79(dt,J=15.3,8.9Hz,1H),2.72(s,3H),2.66(dt,J=15.4,9.1Hz,1H),2.31(dt,J=13.8,8.3Hz,2H); 13 C NMR(75MHz, CDCl3)δ:173.42,166.07,153.37,153.07,145.64,138.78,137.33,129.81,128.92,128. 42,128.41,128.42,125.74,123.07,55.30,51.81,29.33,29.16,16.61; LC-MS(ESI)m / z:422.14[M+H] + .

[0664] Example 105: (S)-3-(8-chloro-1-(2-morpholinethoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 105)

[0665] Compound 105 was prepared by replacing compound 1 in Example 8 with compound 7 and replacing iodomethane with 2-(4-morpholino)ethyl bromide.

[0666] 1H NMR(300MHz, CDCl3)δ:7.77(d,J=8.2Hz,1H),7.64-7.59(m,3H),7.53-7.42(m,4H),5.66(t,J=8.4Hz,1H),3.64(s,3H),3.59(m ,4H),3.32(td,J=6.5,2.4Hz,2H),2.75(dt,J=15.3,9.1Hz,1H),2.74-2.61(m,3H),2.51(m,4H),2.33(dt,J=13.4,8.0Hz,2H); 13 CNMR(75MHz, CDCl3)δ:172.35,166.71,156.81,153.23,139.60,133.81,133.54,132.55,130.70,130.52,128.65 ,128.37,128.09,122.51,66.71,55.87,53.42,53.31,51.37,30.36,29.52,29.35; LC-MS(ESI)m / z:510.18[M+H] + .

[0667] Example 106: (S)-3-(8-Bromo-1-(2-morpholinethoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 106)

[0668] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-benzophenone in equal moles, and the rest was the same as in Example 1 to prepare (S)-3-(8-bromo-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 2-(4-morpholino)ethyl bromide was used in place of iodomethane, and compound 106 was prepared according to the method of Example 8.

[0669] 1H NMR(300MHz, CDCl3)δ:8.07(d,J=10.6Hz,1H),7.85(d,J=8.8Hz,1H),7.63-7.45(m,6H) ,4.23(t,J=6.4Hz,1H),3.63(s,3H),3.54-3.36(m,6H),2.80-2.55(m,6H),2.32(m,4H); 13 C NMR(75MHz, CDCl3)δ:173.32,165.99,155.27,153.74,138.35,136.51,134.20,133.09,129.82,129.04,128.57 ,128.40,122.35,118.45,66.52,55.23,54.15,52.82,51.83,30.47,29.31,29.06; LC-MS(ESI)m / z:554.13[M+H] + .

[0670] Example 107: (S)-3-(8-nitro-1-(2-morpholinethoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 107)

[0671] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-benzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-phenyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-phenyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 2-(4-morpholino)ethyl bromide was used in place of iodomethane, and compound 107 was prepared according to the method of Example 8.

[0672] 1H NMR (300MHz, CDCl3) δ: 8.60 (dd, J=9.1, 2.2Hz, 1H), 8.53 (d, J=2.4Hz, 1H), 8 .15(d,J=9.3Hz,1H),7.72–7.60(m,2H),7.50–7.40(m,3H),5.63(t,J=8.3Hz ,1H),3.64(s,3H),3.57(m,4H),3.35(td,J=6.2,2.1Hz,2H),2.77(dt,J=15. 3,8.9Hz,1H),2.75–2.61(m,3H),2.50(m,4H),2.32(dt,J=13.5,9.1Hz,2H); 13 CNMR(75MHz, CDCl3)δ:173.40,166.04,155.50,153.77,145.65,138.78,137.68,129.60,128.97,128.49,128.45 ,128.42,125.73,123.07,66.21,55.42,54.10,52.79,51.83,30.47,29.36,29.05; LC-MS(ESI)m / z:521.21[M+H] + .

[0673] Example 108: (S)-3-(8-chloro-1-(3-(dimethylamino)propoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 108)

[0674] Compound 108 was prepared by replacing compound 1 in Example 8 with compound 7 and replacing iodomethane with 3-bromo-N,N-dimethyl-1-propylamine.

[0675] 1 H NMR (300MHz, CDCl3) δ: 7.85-7.80 (m, 2H), 7.58-7.42 (m, 6H), 4.22 (dd, J = 7.8, 5.3Hz, 1H), 3.61 (s, 3H),3.13(td,J=7.1,2.5Hz,2H),2.85-2.52(m,4H),2.25-2.13(m,2H),2.05(s,6H),1.67(m,2H); 13C NMR(75MHz, CDCl3)δ:173.54,166.82,156.32,153.86,139.10,133.50,133.05,132.63,130.70,130.21,128.64 ,128.68,128.43,122.91,58.45,55.26,51.94,45.36,31.11,29.46,29.30,26.45; LC-MS(ESI)m / z:482.19[M+H] + .

[0676] Example 109: (S)-3-(8-Bromo-1-(3-(dimethylamino)propoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 109)

[0677] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-benzophenone in equal moles, and the rest was the same as in Example 1 to prepare (S)-3-(8-bromo-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-phenyl-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 3-bromo-N,N-dimethyl-1-propylamine was used in place of methyl iodide, and compound 109 was prepared according to the method of Example 8.

[0678] 1 H NMR(300MHz, CDCl3)δ:7.80-7.73(m,3H),7.65-7.56(m,2H),7.49-7.40(m,3H),5.62(t,J=8.1Hz,1H),3.64(s,3H),3.22(td,J= 6.0,3.2Hz,2H),2.75(dt,J=15.1,9.3Hz,1H),2.66(dt,J=14.9,8.9Hz,1H),2.65-2.54(m,2H),2.43-2.22(m,8H),1.82(m,2H); 13C NMR(75MHz, CDCl3)δ:173.46,165.99,156.26,153.75,138.54,136.31,134.10,133.09,129.79,129.05,128.50 ,128.40,122.29,118.45,58.19,55.26,51.83,44.82,30.00,29.35,29.10,26.59; LC-MS(ESI)m / z:526.14[M+H] + .

[0679] Example 110: (S)-3-(8-nitro-1-(3-(dimethylamino)propoxy)-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 110)

[0680] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-benzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-phenyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-phenyl-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine The compound 110 was prepared by the method of Example 8, replacing iodomethane with 3-bromo-N,N-dimethyl-1-propylamine.

[0681] 1 H NMR(300MHz, CDCl3)δ:8.60(dd,J=9.3,2.2Hz,1H),8.49(d,J=2.4Hz,1H),8.15(d,J=9.3Hz,1H),7.69-7.63(m,2H),7 .50-7.43(m,3H),5.64(t,J=8.3Hz,1H),3.64(s,3H),3.22(td,J=6.3,3.1Hz,2H),2.77(dt,J=15.2,8.9Hz,1H),2.68 -2.53(m,3H),2.45-2.25(m,8H),1.83(m,2H); 13C NMR(75MHz, CDCl3)δ:173.42,166.04,156.30,153.75,145.64,138.78,137.79,129.81,129.00,128.49,128 .40,125.61,123.05,58.21,55.40,51.85,44.72,30.10,29.33,29.03,26.59; LC-MS(ESI)m / z:493.21[M+H] + .

[0682] Example 111: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((phosphonooxy)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 111)

[0683] Compound 111 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with dichloromethyl phosphate.

[0684] 1 H NMR(300MHz, CDCl3)δ:7.80(d,J=8.0Hz,1H),7.65(dd,J=7.1,1.9Hz,1H),7.50(dd,J=8.3,2.6Hz,1H),7.51-7.45(m,1H),7.50-7.42( m,3H),5.72(t,J=8.3Hz,1H),5.48-5.38(m,2H),3.64(s,3H),2.75(dt,J=15.3,9.1Hz,1H),2.66(dt,J=15.5,9.2Hz,1H),2.34(m,4H); 13 C NMR(75MHz, CDCl3)δ:173.43,161.14,157.55,157.13,154.08,137.57,134.69,134.19,132.67,131.29,131.24,129. 70,129.59,128.68,128.45,127.31,123.02,66.32,66.25,58.23,51.94,29.93,29.01; LC-MS(ESI)m / z:541.04[M+H] + .

[0685] Example 112: (S)-3-(8-bromo-6-(2-chlorophenyl)-1-((phosphonooxy)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 112)

[0686] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with chloromethyl dihydrogen phosphate, and following the method of Example 8 to prepare Compound 112.

[0687] 1 H NMR(300MHz, CDCl3)δ:7.84(t,J=7.9Hz,1H),7.65(dd,J=7.1,1.8Hz,1H),7.51-7.41(m,4H),5.72(t,J=8.2Hz ,1H),5.48-5.38(m,2H),3.64(s,3H),2.75(dt,J=15.0,9.5Hz,1H),2.68(dt,J=14.8,9.5Hz,1H),2.36(m,4H); 13 C NMR(75MHz, CDCl3)δ:173.33,161.23,157.05,156.93,154.00,136.52,136.21,135.16,133.92,132.76,130.90,129. 32,128.62,128.61,126.93,122.23,118.30,66.01,65.95,58.26,51.57,29.53,29.24; LC-MS(ESI)m / z:584.99[M+H] + .

[0688] Example 113: (S)-3-(8-nitro-6-(2-chlorophenyl)-1-((phosphonooxy)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 113)

[0689] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-nitro-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(6-(2-chlorophenyl)-8-nitro-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl)methyl propionate, replacing iodomethane with chloromethyl dihydrogen phosphate, and following the method of Example 8 to prepare compound 113.

[0690] 1 H NMR (300MHz, CDCl3) δ: 8.63 (dd, J = 8.7, 2.4Hz, 1H), 8.45 (d, J = 2.1Hz, 1H), 8.15 (d, J = 9.0Hz, 1H), 7.65 (dd, J = 7.0, 2. 0Hz,1H),7.51-7.35(m,3H),5.70(t,J=8.3Hz,1H),5.48-5.37(m,2H),3.64(s,3H),2.78-2.68(m,2H),2.34(m,4H). 13 C NMR(75MHz, CDCl3)δ:173.35,160.78,157.03,157.04,154.03,145.70,137.80,136.97,133.91,130.72,129.30,128. 60,128.46,128.42,126.75,124.61,123.21,66.11,65.82,58.25,51.72,29.57,29.52; LC-MS(ESI)m / z:552.06[M+H] + .

[0691] Example 114: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-methoxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 114)

[0692] Compound 114 was prepared by replacing compound 1 in Example 8 with compound 3 and following the method of Example 8.

[0693] 1H NMR(300MHz, CDCl3)δ:8.77(dd,J=3.5,1.2Hz,1H),7.85-7.72(m,3H),7.71-7.62(m,1H),7.53(dd,J=7.8 ,1.5Hz,1H),7.33-7.30(m,1H),3.66(s,3H),2.72(s,3H),2.62(td,J=7.8,1.2Hz,3H),2.61-2.50(m,2H). 13 C NMR(75MHz, CDCl3)δ:173.40,162.32,155.85,153.99,150.79,147.41,137.45,136.64,136.58,134.48,1 27.84,125.25,122.82,122.65,120.43,57.02,52.01,29.59,29.27,16.70.LC-MS(ESI)m / z:456.06[M+H] + .

[0694] Example 115: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-ethoxy-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 115)

[0695] Compound 115 was prepared by replacing compound 1 with compound 3 and replacing iodomethane with iodoethane in Example 8.

[0696] 1 H NMR(300MHz, CDCl3)δ:8.75(dd,J=3.5,1.3Hz,1H),7.84-7.73(m,3H),7.65(t,J=1.3Hz,1H),7.52(dd,J=7.9,1.3Hz,1 H),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). 13C NMR(75MHz, CDCl3)δ:173.70,160.73,157.49,153.83,151.60,147.12,137.58,137.47,136.40,134.72,125. 25,124.53,123.44,122.65,120.37,66.22,57.45,52.01,29.60,29.23,14.73.LC-MS(ESI)m / z:470.07[M+H] + .

[0697] Example 116: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(cyclopropylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 116)

[0698] Compound 116 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with (iodomethyl)cyclopropane.

[0699] 1 H NMR(300MHz, CDCl3)δ:7.82-7.71(m,4H),7.64(d,J=2.2Hz,1H),7.53(dd,J=7.9,1.4Hz,1H),7.33-7.31 (m,1H),6.13(t,J=5.2Hz,1H),3.66(s,3H),3.14(d,J=4.8Hz,2H),2.70-2.51(m,4H),1.40-1.24(m,5H). 13 C NMR(75MHz, CDCl3)δ:173.58,162.37,156.38,154.59,149.57,147.13,137.57,137.28,136.60,134.78,127.93 ,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:496.09[M+H] + .

[0700] Example 117: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(2-morpholinethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 117)

[0701] Compound 117 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 2-(4-morpholino)ethyl bromide.

[0702] 1 H NMR (300MHz, CDCl3) δ: 8.54 (d, J = 4.2Hz, 1H), 8.17 (d, J = 7.9Hz, 1H), 7.82 (dd ,J=7.2,1.3Hz,1H),7.79(dd,J=6.5,4.2Hz,1H),7.66(d,J=8.5Hz,2H),7.41- 7.37(m,1H),4.27(t,J=5.1Hz,1H),3.69(s,3H),3.60(t,J=4.8Hz,4H),3.53- 3.40(m,2H),2.92-2.81(m,4H),2.74(t,J=6.7Hz,2H),2.46(t,J=4.5Hz,4H). 13 C NMR(75MHz, CDCl3)δ:173.62,162.11,156.69,154.59,148.12,147.31,137.47,137.09,136.60,135.16,128.24,125 .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:555.13[M+H] + .

[0703] Example 118: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(3-(dimethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 118)

[0704] Compound 118 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 3-bromo-N,N-dimethyl-1-propylamine.

[0705] 1H NMR(300MHz, CDCl3)δ:8.75(dd,J=3.6,1.2Hz,1H),7.82(td,J=7.6,1.2Hz,1H),7.78-7.72(m,2H),7.65(dd,J=1.7,0.9Hz,1H),7.54(dd,J=7.9,1.4H z,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(m,2H). 13 C NMR(75MHz, CDCl3)δ:173.30,162.11,156.72,154.50,147.89,146.31,137.30,137.11,136.67,135.32,128.24 ,125.26,122.74,120.94,58.49,58.05,52.00,44.90,32.55,29.54,29.28,26.47.LC-MS(ESI)m / z:527.13[M+H] + .

[0706] Example 119: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(pyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 119)

[0707] Compound 119 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with N-(2-chloroethyl)pyrrolidine.

[0708] 1 H NMR(300MHz, CDCl3)δ:7.92(d,J=2.0Hz,1H),7.60(dd,J=7.0,2.4Hz,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),2.65-2.54(m,4H),2.45(s,2H),2.42-2.31(m,2H),2.26-2.19(m,2H),1.80(d,J=12.5Hz,4H). 13C NMR(75MHz, CDCl3)δ:173.30,160.77,154.13,148.12,138.12,135.83,134.71,132.61,130.82,130.51,130.43,129.29 ,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:528.15[M+H] + .

[0709] Example 120: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(pyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 120)

[0710] Compound 120 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with N-(2-chloroethyl)pyrrolidine.

[0711] 1 H NMR (300MHz, CDCl3) δ: 7.74 (dd, J=8.2, 2.6Hz, 1H), 7.61-7.57 (m, 2H), 7.53-7.43 (m, 2H), 7.30 (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). 13 C NMR(75MHz, CDCl3)δ:173.66,163.32,159.17,154.22,147.98,136.65,136.54,132.59,131.53,130.23,128.57,127.70 ,124.00,121.79,120.45,115.76,58.29,55.23,54.00,51.93,32.17,29.54,29.30,23.42.LC-MS(ESI)m / z:556.14[M+H] + .

[0712] Example 121: (S)-3-(8-Bromo-6-(2-chlorophenyl)-1-(2-(pyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 121)

[0713] The 2-amino-5-chloro-2'-fluorobenzophenone (compound 1a) in Example 1 was replaced by 2-amino-5-bromo-2'-chlorobenzophenone in equal moles, and the rest were the same as in Example 1 to prepare (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) methyl propionate, the compound 1 in Example 8 was replaced by (S)-3-(8-bromo-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Compound 121 was prepared by the method of Example 8, using methyl iodide as the base, and replacing N-(2-chloroethyl)pyrrolidine with methyl 4-yl)propionate.

[0714] 1 H NMR(300MHz, CDCl3)δ:7.72(dd,J=8.4,2.6Hz,1H),7.68-7.58(m,2H),7.52(d d,J=7.7,1.6Hz,1H),7.49(dd,J=7.8,1.6Hz,1H),7.40(td,J=7.6,1.6Hz,1H), 7.32(td,J=7.5,1.5Hz,1H),6.10(t,J=5.2Hz,1H),3.64(s,3H),3.43(t,J=5.1 Hz,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)δ:173.55,160.33,154.78,149.12,137.50,136.40,136.42,134.71,133.11,131.17,130.61,129.36 ,128.19,126.09,121.82,120.47,57.87,55.33,54.00,51.93,32.12,29.54,29.39,23.33.LC-MS(ESI)m / z:572.10[M+H] + .

[0715] Example 122: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(piperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 122)

[0716] Compound 122 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)piperidine.

[0717] 1 H NMR (300MHz, CDCl3) δ: 7.75 (d, J = 8.7Hz, 1H), 7.60 (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),3.47(t,J=7.1Hz,2H),2.80(t,J= 3.7Hz,4H),2.74(t,J=7.1Hz,2H),2.46(s,4H),1.62-1.56(m,4H),1.45(s,2H). 13 C NMR(75MHz, CDCl3)δ:173.63,160.77,154.20,148.15,138.23,135.93,134.66,132.61,130.83,130.54,130.43,129.22,12 9.10,128.13,126.35,122.71,57.76,54.95,54.06,51.97,32.18,29.54,29.39,26.64,23.96.LC-MS(ESI)m / z:542.16[M+H] + .

[0718] Example 123: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(piperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 123)

[0719] Compound 123 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 1-(2-chloroethyl)piperidine.

[0720] 1H NMR(300MHz, CDCl3)δ:7.75(dd,J=8.4,2.6Hz,1H),7.63-7.57(m,2H),7.50-7.43(m,2H),7.27(td,J=7.5,1.5Hz,1H),7.1 7(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),2.68-2.50(m,10H),1.58-1.54(m,6H). 13 C NMR(75MHz, CDCl3)δ:173.60,163.21,159.19,154.15,148.12,136.35,136.54,132.44,131.52,130.23,128.53,127.70,12 4.00,121.85,120.25,115.78,58.29,54.90,54.06,51.93,32.18,29.54,29.30,26.83,24.03.LC-MS(ESI)m / z:570.14[M+H] + .

[0721] Example 124: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(pyridin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 124)

[0722] Compound 124 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 4-chloromethylpyridine.

[0723] 1 H NMR(300MHz, CDCl3)δ:8.45(d,J=5.2Hz,2H),7.91-7.81(m,1H),7.75(d,J=8.7Hz,1H),7.64-7.57(m,1H),7.53-7.47( m,2H),7.43-7.34(m,3H),7.20-7.12(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)δ:173.65,161.70,154.16,149.79,147.48,146.26,138.07,135.66,134.71,132.61,130.82,130.51,1 30.43,129.36,129.04,128.19,126.36,124.08,122.76,57.76,51.96,39.84,29.54,29.39.LC-MS(ESI)m / z:522.10[M+H] + .

[0724] Example 125: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(pyridin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 125)

[0725] Compound 125 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 4-chloromethylpyridine.

[0726] 1 H NMR(300MHz, CDCl3)δ:8.62-8.57(m,2H),7.72(dd,J=8.4,2.6Hz,1H),7.59(d,J=2.5Hz,1H),7.59-7.53(m,2H),7.42(td,J =7.7,1.6Hz,1H),7.31-7.25(m,3H),7.26-7.20(m,1H),6.12(t,J=5.2Hz,1H),4.53(s,2H),3.64(s,3H),2.67-2.51(m,4H). 13 C NMR(75MHz, CDCl3)δ:173.65,163.35,159.19,154.16,149.80,147.48,146.24,136.60,136.52,132.67,131.54,130.23,1 28.53,127.73,124.09,124.00,121.81,120.47,115.76,58.27,51.92,39.84,29.54,29.30.LC-MS(ESI)m / z:550.08[M+H] + .

[0727] Example 126: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(2-(pyridin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 126)

[0728] Compound 126 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 4-chloromethylpyridine.

[0729] 1 H NMR(300MHz, CDCl3)δ:8.60-8.56(m,1H),8.53-8.46(m,2H),8.18(d,J=7.9Hz,1H),7.84(td,J=7.8,1.7Hz,1H),7.76(dd,J=8.7,2.2Hz,1H),7.64( d,J=2.2Hz,1H),7.52(d,J=8.7Hz,1H),7.42-7.36(m,1H),7.32-7.27(m,2 H),4.54-4.35(m,2H),4.29-4.21(m,1H),3.69(s,3H),2.92-2.76(m,4H). 13 C NMR(75MHz, CDCl3)δ:173.45,161.93,156.43,154.52,149.61,147.48,147.33,146.08,137.37,137.21,136.60,135. 48,128.29,125.25,124.08,122.76,122.61,120.94,58.05,51.96,39.84,29.54,29.34.LC-MS(ESI)m / z:533.09[M+H] + .

[0730] Example 127: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 127)

[0731] Compound 127 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)-4,4-difluoropiperidine.

[0732] 1H NMR(300MHz, CDCl3)δ:7.68-7.60(m,2H),7.57-7.52(m,2H),7.48-7.45(m,1H),7.41-7.32(m,2H),6.11(t, J=5.2Hz,1H),3.66(s,3H),3.43(t,J=5.2Hz,2H),2.74-2.67(m,6H),2.63-2.51(m,4H),2.25-2.12(m,4H). 13 C NMR(75MHz, CDCl3)δ:172.98,160.92,154.20,148.12,137.96,135.93,134.65,132.67,131.03,130.80,130.56,129.18,12 9.10,128.07,126.30,122.69,118.58,57.87,54.60,51.78,48.83,32.57,31.95,9.54,29.49.LC-MS(ESI)m / z:578.15[M+H] + .

[0733] Example 128: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 128)

[0734] Compound 128 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 1-(2-chloroethyl)-4,4-difluoropiperidine.

[0735] 1 H NMR(300MHz, CDCl3)δ:7.72(dd,J=8.4,2.4Hz,1H),7.62-7.54(m,2H),7.50-7.44(m,2H),7.32-7.21(m,2H),4.33(t,J=5.3,6.8Hz,1H),3.66 (s,3H),3.46(t,J=5.2,7.4Hz,2H),2.74-2.69(m,3H),2.66-2.63(m,4H),2.61(dd,J=1.9,1.2Hz,1H),2.57-2.51(m,2H),2.25-2.12(m,4H). 13C NMR(75MHz, CDCl3)δ:173.33,163.02,159.33,154.16,148.12,136.55,136.54,132.67,131.53,130.23,128.58,127.70,123 .91,121.85,120.45,118.58,115.77,58.29,54.60,51.94,48.71,32.61,32.23,29.34,29.63.LC-MS(ESI)m / z:606.15[M+H] + .

[0736] Example 129: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 129)

[0737] Compound 129 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroacetyl)-4-methylpiperazine hydrochloride.

[0738] 1 H NMR(300MHz, CDCl3)δ:7.73(d,J=8.4Hz,1H),7.64-7.58(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)δ:173.47,171.54,160.89,154.17,147.96,137.98,136.05,134.72,132.65,131.16,130.83,130.56,129 .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:571.15[M+H] + .

[0739] Example 130: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((4-methylpiperazin-1-yl)-1-oxomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 130)

[0740] Compound 130 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 4-methylpiperazine-1-carbonyl chloride.

[0741] 1 H NMR(300MHz, CDCl3)δ:7.698(d,J=8.3Hz,1H),7.61-7.54(m,2H),7.51-7.45(m,2H),7.41-7.30(m,2H),6 .12(t,J=5.4Hz,1H),3.77-3.68(m,4H),3.66(s,3H),2.74-2.63(m,2H),2.60-2.45(m,6H),2.29(s,3H). 13 C NMR(75MHz, CDCl3)δ:173.25,164.87,160.73,154.72,143.84,137.98,136.55,134.69,132.60,130.83,130.51,130.43, 129.20,129.13,128.16,126.36,122.85,57.81,54.27,52.07,47.39,45.36,29.54,29.57.LC-MS(ESI)m / z:557.14[M+H] + .

[0742] Example 131: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((4-methylpiperazin-1-yl)-1-oxomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 131)

[0743] Compound 131 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 4-methylpiperazine-1-carbonyl chloride.

[0744] 1H NMR (300MHz, CDCl3) δ: 7.73 (dd, J=8.4, 2.6Hz, 1H), 7.56 (d, J=2.5Hz, 1H), 7.53-7.44 (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,4H),3.63(s,3H),2.74-2.63(m,2H),2.57(m,2H),2.55-2.45(m,4H),2.29(s,3H). 13 C NMR(75MHz, CDCl3)δ:173.62,167.58,160.72,148.74,143.80,143.14,132.49,131.38,131.10,129.83,129.44,129.40, 124.54,124.20,121.80,115.87,115.73,54.33,54.14,51.71,51.50,44.97,33.02,31.92.LC-MS(ESI)m / z:585.12[M+H] + .

[0745] Example 132: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(diethylamino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 132)

[0746] Compound 132 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 3-diethylaminopropyl chloride hydrochloride.

[0747] 1 H NMR(300MHz, CDCl3)δ:7.89(d,J=1.6Hz,1H),7.61(dd,J=7.2,2.2Hz,1H),7.52-7.37(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). 13C NMR(75MHz, CDCl3)δ:173.62,145.70,144.01,141.27,138.92,132.79,130.73,130.17,129.99,129.43,129.37,128.94,12 8.72,128.62,124.77,120.33,54.20,53.56,51.40,47.08,33.51,33.02,31.91,30.11,11.83.LC-MS(ESI)m / z:544.18[M+H] + .

[0748] Example 133: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(dimethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 133)

[0749] Compound 133 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-bromo-N,N-dimethylethylamine.

[0750] 1 H NMR(300MHz, CDCl3)δ:7.72(d,J=8.7Hz,1H),7.55(dd,J=8.7,2.4Hz,1H),7.52(dd,J=5.8,3.4Hz,1H),7.45–7.39(m,2H),7.37–7.30(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)δ:173.85,145.64,144.42,143.86,138.90,133.17,130.68,130.54,129.82,129.72,129.46, 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:502.13[M+H] + .

[0751] Example 134: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(dimethylamino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 134)

[0752] Compound 134 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 2-bromo-N,N-dimethylethylamine.

[0753] 1 H NMR(300MHz, CDCl3)δ:7.71(dd,J=8.5,2.5Hz,1H),7.62–7.57(m,2H),7.53–7.43(m,2H),7.29(td,J=7.7,1.5Hz,1H),7.23(dd,J=7.9,1.5Hz,1 H),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)δ:173.70,160.40,145.58,144.37,143.46,134.19,131.97,130.87,130.41,130.05,129.44,124 .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:530.11[M+H] + .

[0754] Example 135: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((4-hydroxypiperidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 135)

[0755] Compound 135 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)piperidin-4-ol.

[0756] 1H NMR (300MHz, CDCl3) δ: 7.88 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 7.0, 2.4 Hz, 1H), 7. 50–7.35(m,4H),7.29(d,J=7.5Hz,1H),5.25(s,1H),3.68(s,3H),3.65–3.54( m,2H),3.48(d,J=0.9Hz,2H),2.62(d,J=2.4Hz,4H),2.55(s,2H),2.46–2.31 (m,2H),2.33(d,J=7.0Hz,1H),2.25(d,J=12.5Hz,1H),1.81(d,J=7.5Hz,4H). 13 C NMR(75MHz, CDCl3)δ:173.63,145.59,145.02,143.05,138.86,132.79,130.72,130.15,129.99,129.37,128.72,128.60 ,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:558.16[M+H] + .

[0757] Example 136: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-((1-methylpiperidin-1-yl)-1-oxomethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 136)

[0758] Compound 136 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 1-methylpiperidine-2-carbonyl chloride.

[0759] 1H NMR(300MHz, CDCl3)δ:7.96(d,J=2.0Hz,1H),7.67–7.57(m,1H),7.52–7.47(m,1H) ),7.43–7.32(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)δ:175.69,173.60,148.74,145.67,143.49,138.91,132.76,130.71,130.16,129.95,129.84,129.37,128.72,12 8.60,128.19,124.68,122.11,62.34,54.53,54.33,51.45,41.64,33.02,31.91,28.57,26.60,22.95.LC-MS(ESI)m / z:556.14[M+H] + .

[0760] Example 137: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxyl-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of 2-morpholinoethyl (4-methyl)propionate (Compound 137)

[0761] (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Methyl 2-(8-chloro-6-(2-chlorophenyl)propanoate (compound 2 tautomer, 0.50 g, 1.13 mmol) was dissolved in 8 mL THF, 4 mL 2 M LiOH was added, the reaction was stirred at 60°C for 6 hours, and the mixture was concentrated under reduced pressure and subjected to column chromatography (DCM:MeOH=20:1, v / v) to obtain a white solid, which was dissolved in 6 mL DMF and 2-(4-morpholino)ethyl bromide (0.23 g, 1.13 mmol) was added. The reaction was allowed to proceed for 6 hours, the reaction was quenched with water, and the mixture was extracted three times with 60 mL EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (PE:EA=5:1, v / v) to obtain a white solid, (S)-3-(8-chloro-6-(2-chlorophenyl)-1-oxyl-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine 4-amino-2-morpholinoethyl)propanoate (Compound 137, 0.11 g, yield 36%).

[0762] 1 H NMR (300MHz, CDCl3) δ: 13.8 (s, 1H), 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=6.0Hz,1H),4.22(t,J=6.5Hz,2H),3.60–3.48(m,4H),2.85(t,J=6 .4,8.2Hz,2H),2.73–2.57(m,4H),2.53–2.45(m,2H),2.43–2.28(m,2H). 13 C NMR(75MHz, CDCl3)δ:173.85,172.97,145.29,143.04,143.02,132.78,130.65,130.52,129.38,129.37,129.30,128 .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:530.19[M+H] + .

[0763] Example 138: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(1H-imidazol-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 138)

[0764] Compound 138 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)imidazole hydrochloride.

[0765] 1 H NMR (300MHz, CDCl3) δ: 7.84 (s, 1H), 7.60 (d, J = 8.3Hz, 1H), 7.58–7.50 (m, 3H), 7.45 (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=5.0,1.6Hz,2H),3.66–3.60(m,5H),2.66–2.51(m,4H). 13 C NMR(75MHz, CDCl3)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. 44,129.37,129.31,128.92,128.64,124.73,120.33,54.20,51.38,49.21,36.04,33.07,31.90.LC-MS(ESI)m / z:525.11[M+H] + .

[0766] Example 139: (S)-3-(8-Bromo-6-(2-fluorophenyl)-1-(2-(1H-imidazol-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 139)

[0767] Compound 139 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 1-(2-chloroethyl)imidazole hydrochloride.

[0768] 1H NMR(300MHz, CDCl3)δ:7.84(s,1H),7.70(dd,J=8.4,2.6Hz,1H),7.60–7.52(m,2H),7.50(dd,J=7.9,1.5Hz,1H),7.46(td,J=7.7,1.6Hz,1H),7.28(td, J=7.5,1.5Hz,1H),7.21(dd,J=7.8,1.5Hz,1H),7.03(s,2H),6.10(t,J=5.2 Hz,1H),4.27(td,J=5.0,1.7Hz,2H),3.66–3.60(m,5H),2.67–2.51(m,4H). 13 CNMR(75MHz, CDCl3)δ:172.37,160.85,154.18,148.42,137.35,136.33,136.43,134.20,132.08,131.13,130.83,129.13 ,128.19,126.39,121.84,120.47,57.37,55.24,54.02,51.95,32.18,28.95,29.37,23.28.LC-MS(ESI)m / z:553.09[M+H] + .

[0769] Example 140: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(1H-pyrrol-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 140)

[0770] Compound 140 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)pyrrole.

[0771] 1H NMR (300MHz, CDCl3) δ: 7.85 (dd, J=8.7, 2.4Hz, 1H), 7.76 (d, J=8.7Hz, 1H), 7. 64(dd,J=5.9,3.3Hz,1H),7.55–7.49(m,2H),7.46–7.42(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)δ:173.88,145.60,145.03,143.04,138.89,132.79,130.67,130.54,129.72,129.46,129.44,129.37, 128.94,128.62,125.93,124.70,120.33,119.18,54.20,53.61,51.40,36.03,33.02,31.91.LC-MS(ESI)m / z:524.12[M+H] + .

[0772] Example 141: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1-methyl-1H-imidazol-4-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 141)

[0773] Compound 141 was prepared by replacing compound 1 in Example 8 with compound 4 and replacing iodomethane with 4-chloro-1-methyl-1H-imidazole.

[0774] 1 H NMR(300MHz, CDCl3)δ:7.98(s,1H),7.96–7.90(m,2H),7.61(dd,J=7.5,2.0Hz,1H), 7.52–7.35(m,5H),5.17(s,1H),3.68(s,6H),2.56–2.45(m,2H),2.30–2.19(m,2H). 13CNMR(75MHz, CDCl3)δ:173.90,156.54,145.67,145.35,144.42,138.85,137.66,133.15,132.20,130.65,130.54,129.82, 129.70,129.46,129.44,128.94,128.70,124.72,122.11,54.23,51.38,33.77,33.03,30.24; LC-MS(ESI)m / z:511.10[M+H] + .

[0775] Example 142: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((ethyl(methyl)carbamoyl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 142)

[0776] Compound 142 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with N-methyl-N-ethylcarbamoyl chloride.

[0777] 1 H NMR(300MHz, CDCl3)δ:7.73(d,J=8.4Hz,1H),7.61–7.50(m,3H),7.48(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),2.75–2.62(m,2H),2.59-2.54(m,2H),1.22(t,J=7.2Hz,3H). 13 C NMR(75MHz, CDCl3)δ:173.92,162.07,148.75,146.37,143.83,138.87,133.16,130.61,130.53,129.82,129.75,129.46, 129.45,129.25,128.74,124.69,124.25,54.19,51.41,43.61,34.25,32.94,30.28,12.45.LC-MS(ESI)m / z:516.11[M+H] + .

[0778] Example 143: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(dimethylamino)-3-oxopropoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 143)

[0779] Compound 143 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 3-chloro-N,N-dimethylpropionamide.

[0780] 1 H NMR(300MHz, CDCl3)δ:7.91(d,J=1.9Hz,1H),7.63(dd,J=7.1,2.2Hz,1H),7.51–7.35(m,6H),5.32(s,1H ),3.68(s,3H),3.39(s,2H),2.86(s,5H),2.80–2.69(m,2H),2.45–2.25(m,3H),2.27(d,J=12.5Hz,1H). 13 C NMR(75MHz, CDCl3)δ:173.74,172.43,145.65,144.02,143.04,138.84,132.79,130.60,130.55,129.74,129.46,129.37, 129.02,128.93,128.62,124.74,120.33,54.22,51.42,36.41,35.77,33.00,31.89,31.62.LC-MS(ESI)m / z:530.13[M+H] + .

[0781] Example 144: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((4,5-dihydro-1H-imidazol-2-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 144)

[0782] Compound 144 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-chloromethylimidazoline hydrochloride.

[0783] 1H NMR(300MHz, CDCl3)δ:7.95(d,J=2.0Hz,1H),7.63(dd,J=7.2,2.3Hz,1H),7.53–7.34(m,4H),7.30(d,J=7.5Hz,1H),6.81(s,1H ),5.15(s,1H),4.32(s,2H),3.68(s,3H),3.54–3.47(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)δ:173.85,159.42,145.57,143.96,141.65,138.93,133.18,130.69,130.56,129.82,129.73,129.46, 129.44,128.91,128.70,124.73,122.11,54.18,51.38,44.32,44.23,41.84,33.00,31.92.LC-MS(ESI)m / z:513.11[M+H] + .

[0784] Example 145: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(chloromethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 145)

[0785]

[0786] Compound 145 was prepared by replacing compound 1 with compound 2 and replacing iodomethane with chloroiodomethane in Example 8.

[0787] 1 H NMR (300MHz, CDCl3) δ7.89 (d, J=2.0Hz, 1H), 7.79 (dd, J=7.2, 2.3Hz, 1H), 7.59–7.38 (m, 4H), 7.51 (d, J=7. 5Hz,1H),6.03(s,1H),4.32(s,1H),3.61(s,2H),3.68(s,3H),2.49(d,J=12.5Hz,1H),2.33–2.35(m,2H). 13C NMR(75MHz, CDCl3)δ:173.87,159.44,146.60,143.90,141.65,138.93,133.18,131.69,130.56,129.82,129.73,129.46, 129.44,128.91,128.70,122.73,122.11,54.18,51.38,44.30,44.27,41.81,33.04,31.95.LC-MS(ESI)m / z:479.04[M+H] + .

[0788] Example 146: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-chloroethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 146)

[0789]

[0790] Compound 146 was prepared by replacing compound 1 with compound 2 and replacing iodomethane with 1-chloro-2-iodoethane in Example 8.

[0791] 1 H NMR(300MHz, CDCl3)δ7.91(d,J=2.0Hz,1H),7.79(dd,J=7.2,2.3Hz,1H),7.75–7.51(m,4H),7.38(d,J=7.5Hz,1 H),6.03(s,1H),4.32(s,1H),4.22(m,2H),4.08(s,2H),3.68(s,3H),2.49(d,J=12.5Hz,1H),2.32–2.35(m,2H). 13 C NMR(75MHz, CDCl3)δ:177.87,155.44,146.61,143.90,141.65,138.93,132.18,131.69,130.56,129.88,129.73,129.46, 129.44,128.91,128.70,122.63,122.11,54.18,51.38,44.30,44.27,41.81,43.04,33.96.LC-MS(ESI)m / z:493.05[M+H] + .

[0792] Example 147: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-chloropropoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 147)

[0793]

[0794] Compound 146 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-chloro-3-iodopropane.

[0795] 1 H NMR (300MHz, CDCl3) δ7.69(d,J=8.4Hz,1H),7.62(dd,J=7.3,2.1Hz,1H),7.57(dd,J=8.4,2.6Hz,1H),7.50–7.45(m,2H),7.41–7.33(m,2 H),5.96(dd,J=8.4,7.6Hz,1H),4.37(t,J=6.1Hz,2H),3.74(t,J=3.9Hz,2H),3.67(s,3H),2.69–2.52(m,4H),2.16(m,J=6.1,3.9Hz,2H). 13 C NMR(75MHz, CDCl3)δ:177.79,156.44,146.61,143.90,141.65,138.73,132.28,131.68,130.56,129.88,129.73,129.47 ,129.34,128.81,128.70,122.67,122.11,54.18,51.38,44.32,44.27,41.81,43.04,33.96.LC-MS(ESI)m / z:50.07[M+H] + .

[0796] Example 148: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-aminoethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 148)

[0797] Compound 148 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-chloroethylamine, and referring to the method of Example 8.

[0798] 1H NMR (300MHz, CDCl3) δ7.71 (d, J=8.4Hz, 1H), 7.57 (m, J=6.4, 4.9, 2.6Hz, 2H), 7.51–7.45 (m, 2H), 7.42–7.35 (m, 2H), 5.98–5. 93(m,1H),4.58(m,J=36.1,7.0,6.0Hz,2H),4.35(td,J=5.6,2.8Hz,2H),3.67(s,3H),3.12–3.03(m,2H),2.68–2.51(m,4H). 13 C NMR(75MHz, CDCl3)δ:173.64,159.53,153.40,151.73,138.19,136.06,133.90,132.52,131.70,130.82,129.46, 128.66,128.22,126.53,126.32,123.66,71.51,57.25,52.00,40.93,29.54,29.28.LC-MS(ESI)m / z:474.10[M+H] + .

[0799] Example 149: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 149)

[0800] Compound 149 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with (R)-1-(2-chloroethyl)-3-fluoropyrrolidine.

[0801] 1 H NMR(300MHz, CDCl3)δ:7.94(d,J=2.0Hz,1H),7.78(d,J=7.5Hz,1H),7.69–7.63(m,1H) ,7.52–7.45(m,2H),7.44–7.35(m,2H),5.22(s,1H),5.18(s,1H),4.21(d,J=1.4Hz,2H ),3.68(s,3H),3.21(d,J=9.5Hz,1H),3.14(d,J=9.5Hz,1H),2.91–2.78(m,3H),2.69( d,J=9.5Hz,1H),2.46–2.30(m,3H),2.25(d,J=12.5Hz,1H),2.06(s,1H),2.02(s,1H).13 C NMR(75MHz, CDCl3)δ:173.82,150.56,148.09,144.05,143.49,132.79,131.55,130.65,129.51,129.49,129.44,129.33,129.1 2,128.38,124.71,124.25,86.44,70.25,67.81,53.15,51.40,50.84,49.68,33.02,30.26,29.74.LC-MS(ESI)m / z:546.14[M+H] + .

[0802] Example 150: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-fluoropyrrolidin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 150)

[0803] Compound 150 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with (R)-1-(2-chloropropyl)-3-fluoropyrrolidine.

[0804] 1 H NMR(300MHz, CDCl3)δ:7.94(d,J=1.9Hz,1H),7.71(d,J=7.5Hz,1H),7.70–7.62 (m,1H),7.52–7.45(m,2H),7.44–7.35(m,2H),5.40(s,1H),5.02(s,1H),4.23(s ,2H),3.68(s,3H),3.29(d,J=9.5Hz,2H),3.05(d,J=9.5Hz,1H),2.77–2.70(m,2 H),2.67–2.58(m,2H),2.46–2.22(m,3H),2.13–2.05(m,2H),2.05–1.98(m,2H). 13C NMR(75MHz, CDCl3)δ:173.61,148.42,148.09,144.05,143.49,132.79,130.70,130.54,129.51,129.49,129.44,129.12,129.02,1 28.19,124.71,124.25,86.74,70.25,68.33,53.69,51.40,50.54,49.75,33.02,31.57,30.26,28.40.LC-MS(ESI)m / z:560.16[M+H] + .

[0805] Example 151: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-hydroxypyrrolidin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 151)

[0806] Compound 151 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with (R)-1-(2-chloropropyl)pyrrolidin-3-ol.

[0807] 1 H NMR (300MHz, CDCl3) δ8.03(d,J=8.8Hz,1H),7.58(dd,J=8.8,2.4Hz,1H),7.44(d,J=7.6Hz,1H),7.38(m,3H),7.08(d,J=2.3Hz,1H),4.31(m,1H),4. 21(dd,J=8.6,5.3Hz,1H),4.01(m,2H),3.68(s,3H),3.08–2.83(m,4H),2. 79–2.72(m,2H),2.66–2.54(m,4H),2.43–2.33(m,1H),2.21–2.10(m,1H). 13 C NMR (75MHz, CDCl3) δ173.67,167.68,151.96,146.83,138.41,132.92,132.33,131.88,131.31,131.16,130.92,130.43,130.31 ,129.61,127.04,124.76,70.77,62.36,55.25,53.60,52.53,51.72,34.58,31.57,30.12,25.47.LC-MS(ESI)m / z:544.43[M+H] +.

[0808] Example 152: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-((R)-3-hydroxypyrrolidin-1-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 152)

[0809] Compound 152 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with (R)-1-(2-chloropropyl)pyrrolidin-3-ol.

[0810] 1 H NMR(300MHz, CDCl3)δ:7.94(d,J=1.9Hz,1H),7.71(d,J=6Hz,1H),7.67–7.65(m,1H),7.52–7.45(m,2H),7. 44–7.35(m,2H),5.40(s,1H),4.29(d,J=4.9Hz,1H),4.23(s,2H),3.84(d,J=4.9Hz,1H),3.68(s,3H),3.34 (d,J=1.8Hz,3H),2.82(d,J=12.4Hz,1H),2.69–2.55(m,2H),2.43(d,J=12.3Hz,1H),2.37(d,J=12.5Hz,1H ),2.31(d,J=12.3Hz,1H),2.25(d,J=12.5Hz,1H),2.19(d,J=12.3Hz,1H),2.08–1.99(m,2H),1.56(s,1H). 13 CNMR(75MHz, CDCl3)δ:173.82,148.42,148.09,144.05,143.49,132.79,130.70,130.54,129.51,129.49,129.44,129.12,129.02,1 28.19,124.71,124.25,70.25,69.86,68.33,57.77,53.90,51.40,50.37,33.02,32.94,30.26,28.40.LC-MS(ESI)m / z:558.16[M+H] + .

[0811] Example 153: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(cyclopropyl(methyl)amino)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 154)

[0812]

[0813] Compound 154 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with N-(2-chloroethyl)-N-methylcyclopropylamine.

[0814] 1 H NMR(300MHz, CDCl3)δ:7.94(d,J=2.0Hz,1H),7.78(d,J=7.5Hz,1H),7.69–7.63(m,1H),7.52–7.44(m,2H),7.44–7.36(m,2H),5.22(s,1H),4.18–4 .06(m,2H),3.68(s,3H),2.92(s,2H),2.56–2.49(m,2H),2.40(d,J=12.3 Hz,1H),2.30–2.20(m,5H),1.56(d,J=5.1Hz,2H),1.46(d,J=5.1Hz,2H). 13 C NMR(75MHz, CDCl3)δ:173.89,150.56,148.09,144.05,143.49,132.79,131.55,130.65,129.50,129.48,129.44,129.38 ,128.62,124.95,124.71,70.25,66.36,52.13,51.90,51.40,41.90,33.02,30.26,28.24.LC-MS(ESI)m / z:528.15[M+H] + .

[0815] Example 154: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(3-(cyclopropyl(methyl)amino)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 155)

[0816] Compound 155 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with N-(3-chloropropyl)-N-methylcyclopropylamine.

[0817] 1H NMR(300MHz, CDCl3)δ:7.94(d,J=1.9Hz,1H),7.74–7.63(m,2H),7.54–7.46(m,2H),7.43–7.37(m,2H), 5.33(s,1H),4.26(s,2H),3.68(s,3H),2.67(s,4H),2.46–2.22(m,5H),2.00(s,2H),1.66–1.59(m,5H). 13 C NMR(75MHz, CDCl3)δ:173.98,148.42,148.09,144.05,143.49,132.79,131.55,130.65,129.51,129.49,129.44,129.33,129.1 2,128.38,124.71,124.25,70.25,68.33,56.08,51.40,47.58,40.74,33.02,30.26,28.24,27.95.LC-MS(ESI)m / z:542.16[M+H] + .

[0818] Example 155: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1-methylpiperidin-4-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 156)

[0819] Compound 156 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 4-(chloromethyl)-1-methyl-piperidine.

[0820] 1 H NMR(300MHz, CDCl3)δ:7.94(d,J=1.9Hz,1H),7.74–7.62(m,2H),7.54–7.45(m,2H),7.40(tt,J=5.1,4.4Hz,2H),5.17(s,1H), 4.10(s,2H),3.68(s,3H),2.81(s,2H),2.59(s,2H),2.46–2.37(m,2H),2.38–2.22(m,4H),2.19(s,1H),1.64(d,J=5.3Hz,5H). 13C NMR(75MHz, CDCl3)δ:173.98,151.97,148.09,144.05,143.49,132.79,131.55,130.65,129.51,129.49,129.44,129.33,12 9.12,128.38,124.71,124.25,70.25,69.76,54.52,51.40,45.62,38.77,33.02,30.26,26.93.LC-MS(ESI)m / z:542.16[M+H] + .

[0821] Example 156: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-(piperazin-1-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 157)

[0822] Compound 157 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 1-(2-chloroethyl)piperazine.

[0823] 1 H NMR(300MHz, CDCl3)δ:7.94(d,J=2.0Hz,1H),7.78(d,J=7.5Hz,1H),7.69–7.63(m,1H ),7.52–7.45(m,2H),7.44–7.35(m,2H),5.22(s,1H),4.21(d,J=1.4Hz,2H),3.68(s, 3H),2.79(d,J=3.3Hz,2H),2.48(d,J=10.0Hz,8H),2.43(d,J=12.3Hz,1H),2.37(d,J =12.5Hz,1H),2.33(d,J=12.3Hz,1H),2.25(d,J=12.5Hz,1H),1.97(d,J=0.8Hz,1H). 13 C NMR(75MHz, CDCl3)δ:173.82,150.56,148.09,144.05,143.49,132.79,131.55,130.65,129.51,129.49,129.44,129.33 ,129.12,128.38,124.71,124.25,70.25,67.81,54.14,51.40,50.90,47.14,33.02,30.26.LC-MS(ESI)m / z:543.16[M+H] + .

[0824] Example 157: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 158)

[0825] Compound 158 was prepared by replacing compound 1 in Example 8 with compound 146 and replacing iodomethane with 4-piperidone glycol acetal hydrochloride.

[0826] 1 H NMR(300MHz, CDCl3)δ:7.97(d,J=2.0Hz,1H),7.78(d,J=7.5Hz,1H),7.67(dd ,J=7.2,2.3Hz,1H),7.53–7.35(m,4H),5.29(s,1H),4.29–4.18(m,2H),3.93 (s,4H),3.69(s,3H),2.85(s,2H),2.63(s,4H),2.43(d,J=12.3Hz,1H),2.35 (dd,J=19.7,12.4Hz,2H),2.25(d,J=12.5Hz,1H),2.01(s,2H),1.84(s,2H). 13 C NMR(75MHz, CDCl3)δ:173.61,150.56,148.09,144.54,143.49,131.62,131.15,130.86,130.54,129.51,129.44,129.01,128.79 ,128.50,124.71,119.29,101.40,70.25,68.27,64.17,54.20,51.64,50.79,33.91,33.02,30.26.LC-MS(ESI)m / z:600.17[M+H] + .

[0827] Example 158: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)propoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 159)

[0828] Compound 159 was prepared by replacing compound 1 in Example 8 with compound 147 and replacing iodomethane with 4-piperidone glycol acetal hydrochloride.

[0829] 1 H NMR(300MHz, CDCl3)δ:7.91(d,J=2.0Hz,1H),7.74–7.64(m,2H),7.49(dd,J=7.0,2.4Hz,1H),7.46–7.35(m,2H),7.25(dd,J=7.5,2.0Hz,1H),5.40(s, 1H),4.23(s,2H),3.95(s,4H),3.69(s,3H),2.72(s,2H),2.60(s,4H),2.46 –2.22(m,3H),2.17(d,J=12.4Hz,2H),2.09(d,J=12.3Hz,2H),2.02(s,3H). 13 CNMR(75MHz, CDCl3)δ:173.61,148.42,148.09,144.54,143.49,131.62,130.86,130.76,130.54,129.51,129.44,129.01,128.79,1 28.50,124.71,119.29,101.84,70.25,68.33,64.17,53.87,51.68,49.98,34.35,33.02,30.26,27.42.LC-MS(ESI)m / z:614.19[M+H] + .

[0830] Example 159: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-ethoxy-2,4-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of 2-morpholinoethyl (4-methyl)propionate (Compound 160)

[0831] The tautomer of Compound 2 in Example 137 was replaced by the tautomer of Compound 3, and Compound 160 was prepared according to the method of Example 137.

[0832] 1H NMR (300MHz, CDCl3) δ8.72 (dd, J=5.0, 1.2Hz, 1H), 7.78 (td, J=8.0, 1.3Hz, 1 H),7.68–7.57(m,4H),7.48(dd,J=8.0,1.0Hz,1H),7.29(m,1H),5.17(s,1H) ,4.21–4.11(m,5H),3.59(s,2H),3.55(s,2H),2.83(s,2H),2.54(s,2H),2.4 9–2.36(m,5H),2.31(d,J=12.3Hz,1H),2.25(d,J=12.5Hz,1H),1.33(s,3H). 13 C NMR (75MHz, CDCl3) δ173.15,150.56,148.09,145.36,143.98,142.69,139.79,136.63,132.20,131.10,127.07,123.85 ,122.40,120.50,115.55,66.04,65.90,64.03,57.82,54.26,53.64,32.43,29.80,14.73.LC-MS(ESI)m / z:569.46[M+H] + .

[0833] Example 160: Preparation of (S)-methyl 3-(8-bromo-1-(morpholinomethoxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate (Compound 161)

[0834]

[0835] Compound 161 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 4-(chloromethyl)morpholine.

[0836] 1 H NMR (300MHz, CDCl3) δ8.61(d,J=4.3Hz,1H),8.07(d,J=7.9Hz,1H),7.95(d,J=8.8Hz,1H),7.88–7.71(m,2H),7.5 2(d,J=2.0Hz,1H),7.43–7.35(m,1H),4.78–4.57(m,2H),4.23(dd,J=7.8,5.3Hz,1H),3.71(s,7H),2.75(m,8H). 13C NMR (75MHz, CDCl3) δ173.89,151.97,148.09,145.36,142.69,142.28,141.12,136.63,132.20,130.05,128.89, 123.85,122.71,120.50,115.29,74.30,65.90,54.20,51.40,50.60,32.43,29.80.LC-MS(ESI)m / z:541.11[M+H] + .

[0837] Example 161: Preparation of (S)-methyl 3-(8-bromo-1-(3-(diethylamino)propoxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propanoate (Compound 162)

[0838]

[0839] Compound 162 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 3-chloro-1-diethylaminopropane.

[0840] 1 H NMR (300MHz, CDCl3) δ8.60(d,J=4.2Hz,1H),8.04(d,J=7.9Hz,1H),7.95(d,J=8 .8Hz,1H),7.81(m,1H),7.74(dd,J=8.8,2.3Hz,1H),7.50(d,J=2.2Hz,1H),7.42 –7.34(m,1H),4.22(dd,J=7.8,5.6Hz,1H),3.85(t,J=7.1Hz,2H),3.70(s,3H), 2.82–2.64(m,4H),2.56–2.49(m,6H),2.01–1.86(m,2H),1.00(t,J=7.1Hz,6H). 13 C NMR (75MHz, CDCl3) δ173.78,150.56,148.09,145.36,142.69,142.28,141.12,136.63,132.20,129.76,127.07,123.85 ,122.71,120.50,115.29,68.30,54.20,52.84,51.40,47.28,32.43,29.80,27.69,12.00.LC-MS(ESI)m / z:555.16[M+H] + .

[0841] Example 162: (S)-3-(1-(2-(1H-imidazol-1-yl)ethoxy)-8-bromo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 163)

[0842] Compound 163 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 1-(2-chloroethyl)imidazoline hydrochloride.

[0843] 1 H NMR (300MHz, CDCl3) δ8.60(d,J=4.1Hz,1H),8.06(d,J=7.9Hz,1H),7.86–7.80(m,2H),7.73(d,J=2.2Hz,1H),7.52–7.45(m, 2H),7.12–6.87(m,3H),4.40–4.33(m,2H),4.26–4.18(m,2H),4.10(dd,J=7.8,6.4Hz,1H),3.72(s,3H),2.80–2.61(m,4H). 13 C NMR (75MHz, CDCl3) δ173.89,150.56,148.09,145.36,142.69,142.28,141.12,139.39,136.63,132.07,129.76,128.99,1 27.07,124.06,123.85,122.71,120.50,115.29,66.70,54.20,51.40,49.03,32.43,29.80.LC-MS(ESI)m / z:536.10[M+H] + .

[0844] Example 163: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-((3-methylpyridin-2-yl)oxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 164)

[0845] Compound 164 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-chloro-3-methylpyridine.

[0846] 1H NMR (300MHz, CDCl3) δ8.35 (dd, J=4.9, 1.3Hz, 1H), 8.04 (d, J=2.0Hz, 1H), 7.71 ( d,J=7.4Hz,1H),7.65–7.58(m,1H),7.52–7.45(m,1H),7.47–7.35(m,3H),7.30 (dd,J=7.9,1.3Hz,1H),6.92(dd,J=8.0,5.0Hz,1H),5.17(s,1H),3.68(s,2H), 2.56–2.45(m,2H),2.33(d,J=12.3Hz,1H),2.25(d,J=12.5Hz,1H),2.25(s,3H). 13 C NMR (75MHz, CDCl3) δ173.94,159.12,151.75,148.09,144.05,143.49,141.69,132.79,131.55,130.70,130.65,129.50,1 29.48,129.38,128.62,126.72,125.34,124.71,123.41,54.20,51.40,33.02,30.26,14.70.LC-MS(ESI)m / z:522.10[M+H] + .

[0847] Example 164: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(pyridin-2-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 165)

[0848] Compound 165 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 2-chloromethylpyridine.

[0849] 1 H NMR (300MHz, CDCl3) δ8.53(d,J=5.5Hz,1H),8.03(d,J=8.8Hz,1H),7.87–7.75(m,2H),7.62(dd,J=6.5,2.3Hz,1H),7.52(dd,J=5.9,2.8Hz,3H),7 .35–7.25(m,2H),7.10(d,J=2.4Hz,1H),5.12(s,2H),4.34(dd,J=8.8,5 .2Hz,1H),3.57(s,3H),2.61(dd,J=14.5,8.0Hz,2H),2.44–2.29(m,2H).13 C NMR (75MHz, CDCl3) δ173.94,150.84,148.09,147.79,147.27,144.05,140.84,136.95,132.79,131.55,130.65,129.50,129.4 8,129.38,128.62,127.79,124.95,124.71,123.44,121.45,68.23,54.20,51.40,33.02,30.26.LC-MS(ESI)m / z:522.13[M+H] + .

[0850] Example 165: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(pyridin-3-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 166)

[0851] Compound 166 was prepared by replacing compound 1 in Example 8 with compound 2 and replacing iodomethane with 3-chloromethylpyridine.

[0852] 1 H NMR(300MHz, CDCl3)δ8.69(d,J=1.7Hz,1H),8.62–8.53(m,1H),8.04(d,J=8.8Hz,1H),7.75(d,J=7.9Hz,1H),7.59(dd,J=8.8,2.4Hz,1H),7 .47–7.37(m,4H),7.33–7.29(m,1H),7.10(d,J=2.3Hz,1H),5.15–4.97(m,2H),4.22(dd,J=8.9,5.1Hz,1H),3.68(s,3H),2.79–2.54(m,4H). 13 C NMR (75MHz, CDCl3) δ173.94,150.84,148.41,148.09,144.05,143.49,142.60,132.79,131.55,131.04,130.65,130.09,129.5 0,129.48,129.38,128.62,127.79,124.95,124.71,123.70,68.05,54.20,51.40,33.02,30.26.LC-MS(ESI)m / z:522.09[M+H] + .

[0853] Example 166: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(pyridin-2-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 167)

[0854] Compound 167 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 2-chloromethylpyridine.

[0855] 1 H NMR (300MHz, CDCl3) δ8.64–8.57(m,2H),8.03(dd,J=13.9,8.4Hz,2H),7.83(m,1H),7.76(dd,J=8.8,2.3Hz,1H),7.67(m,1H),7.58 –7.48(m,2H),7.39(dd,J=7.0,5.3Hz,1H),7.24(s,1H),5.17(s,2H),4.25(dd,J=7.7,5.3Hz,1H),3.69(s,3H),2.80–2.62(m,4H). 13 C NMR (75MHz, CDCl3) δ173.89,150.84,148.09,147.79,147.27,145.36,142.69,142.28,141.12,136.95,136.63,132.07,129.7 6,127.07,123.85,123.23,122.71,121.45,120.50,115.29,68.23,54.20,51.40,32.43,29.80.LC-MS(ESI)m / z:533.09[M+H] + .

[0856] Example 167: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-(pyridin-3-ylmethoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 168)

[0857] Compound 168 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 3-chloromethylpyridine.

[0858] 1H NMR (300MHz, CDCl3) δ8.70(dd,J=5.0,1.3Hz,1H),8.57(dd,J=5.0,1.2Hz,1H),8.50(d,J=1.2Hz,1H),7.73(td,J=8.0,1.2Hz,1H),7.71–7.61( m,3H),7.53(dt,J=8.0,1.3Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.33–7.24(m,2H),5.39(s,2H),5.33(s,1H),3.68(s,3H),2.52-2.22(m,4H). 13 C NMR (75MHz, CDCl3) δ173.89,150.84,148.41,148.09,145.36,142.69,142.60,142.28,141.12,136.63,132.07,131.04,130.0 9,129.76,127.07,123.85,123.70,122.71,120.50,115.29,68.05,54.20,51.40,32.43,29.80.LC-MS(ESI)m / z:533.11[M+H] + .

[0859] Example 168: (S)-3-(8-Bromo-6-(pyridin-2-yl)-1-((6-methylpyridin-2-yl)methoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 169)

[0860] Compound 169 was prepared by replacing compound 1 in Example 8 with compound 3 and replacing iodomethane with 2-chloromethyl-6-methylpyridine.

[0861] 1 H NMR (300MHz, CDCl3) δ8.72(dd,J=5.0,1.2Hz,1H),7.81–7.73(m,2H),7.68–7.57(m,4H),7.48(dd,J=8.0,1.0Hz,1H),7.29( m,1H),7.03(dd,J=7.7,1.3Hz,1H),5.32(d,J=3.5Hz,2H),5.17(s,1H),3.68(s,3H),2.47–2.34(m,2H),2.31–2.19(m,5H). 13C NMR (75MHz, CDCl3) δ173.78,154.58,150.84,148.09,145.36,142.69,142.28,139.79,139.12,137.57,136.63,132.20,130.05,1 27.07,123.85,122.71,122.04,120.50,119.66,115.29,68.23,54.20,51.40,32.43,29.80,23.88.LC-MS(ESI)m / z:547.11[M+H] + .

[0862] Example 169: (S)-3-(8-Bromo-1-(aminoacetoxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 170)

[0863]

[0864] (S)-3-(8-bromo-6-(pyridin-2-yl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine -4-yl) propionic acid methyl ester (compound 3 tautomer, 0.50 g, 1.13 mmol) was dissolved in 8 ml DMAP (138.5 mg, 1.13 mmol) was added to DMF and stirred at room temperature for 30 minutes. Boc-glycine (397.2 mg, 2.26 mmol) was then added. The mixture was cooled to 5°C in an ice bath and DCC (233.9 mg, 1.13 mmol) was added dropwise. The mixture was allowed to react naturally at room temperature for 6 hours. The reaction was quenched by adding water and extracted three times with 60 ml of EA. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA=5:1, v / v) to give a white solid. The solid was dissolved in 8 ml of hydrochloric acid and methanol and reacted at room temperature for 6 hours. The filter cake was filtered and dried to give (S)-3-(8-bromo-1-(aminoacetoxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine as a white solid. -4-yl)propionic acid methyl ester (Compound 170, 302 mg, yield 53%).

[0865] 1H NMR(300MHz, CDCl3)δ8.70(dd,J=5.0,1.3Hz,1H),7.78–7.68(m,2H),7.63–7.53(m,2H),7.45(dd,J=7.9,1.0Hz,1H),7.32(m,1H),5 .17(s,1H),4.96(s,1H),4.63(s,1H),3.73(s,2H),3.68(s,3H),2.52(d,J=12.5Hz,1H),2.46(d,J=12.5Hz,1H),2.29–2.20(m,2H); 13 C NMR (75MHz, CDCl3) δ173.89,170.99,148.34,147.19,146.59,142.69,140.78,140.59,136.63,131.75,129. 76,127.25,123.85,122.10,120.05,115.55,54.35,51.46,48.23,33.02,29.80; LC-MS(ESI)m / z:499.3[M+H] + .

[0866] Example 170: (S)-3-(8-Bromo-1-(2-aminopropionyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 171)

[0867] Compound 171 was prepared by replacing Boc-glycine in Example 169 with Boc-alanine and following the method of Example 169.

[0868] 1 H NMR (300MHz, CDCl3) δ8.70(dd,J=5.0,1.3Hz,1H),7.77–7.68(m,2H),7.63(dd,J=7.5,2.0Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.41(d,J=7.5Hz,1H ),7.29(m,1H),5.28(s,2H),5.17(s,1H),3.98(s,1H),3.68(s,3H),2.52( d,J=12.4Hz,1H),2.46(d,J=12.5Hz,1H),2.29–2.20(m,2H),1.44(s,3H); 13C NMR (75MHz, CDCl3) δ173.89,169.57,150.84,148.34,145.36,142.69,140.78,140.59,136.63,131.75,129.76, 127.25,123.85,122.40,120.50,115.55,54.35,51.40,50.17,33.02,29.80,15.60; LC-MS(ESI)m / z:513.4[M+H] + .

[0869] Example 171: (S)-3-(8-Bromo-1-(2-amino-4-methylpentanoyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 172)

[0870] Compound 172 was prepared by replacing Boc-glycine in Example 169 with Boc-leucine and following the method of Example 169. 1 H NMR (300MHz, CDCl3) δ8.70(dd,J=5.0,1.3Hz,1H),7.73(td,J=8.0,1.2Hz,1H),7.67(d,J=1.9Hz,1H ),7.60(dd,J=7.5,2.0Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.41(d,J=7.4Hz,1H),7.29(m,1H),5.17 (s,1H),5.02(s,1H),4.63(s,1H),3.87(s,1H),3.68(s,3H),2.43(d,J=12.4Hz,1H),2.35(d,J=12.5 Hz,1H),2.29–2.20(m,2H),1.60(d,J=19.1Hz,1H),1.54(d,J=6.9Hz,2H),0.94(s,3H),0.89(s,3H); 13 C NMR (75MHz, CDCl3) δ173.78,170.38,151.52,148.34,146.59,142.69,142.28,141.12,136.63,131.97,129.76,126.38 ,123.85,122.71,120.50,115.55,54.20,53.61,51.40,39.44,32.43,29.80,25.24,22.29; LC-MS(ESI)m / z:555.4[M+H] + .

[0871] Example 172: (S)-8-Bromo-4-(3-methoxy-3-oxopropyl)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of 2-amino-3-methylpentanoate (Compound 173)

[0872] Compound 173 was prepared by replacing Boc-glycine in Example 169 with Boc-isoleucine and following the method of Example 169. 1 H NMR(300MHz, CDCl3) δ8.70(dd,J=5.0,1.3Hz,1H),7.73(td,J=8.0,1.2Hz,1H),7.67(d,J=1.9Hz,1H),7 .60(dd,J=7.5,2.0Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.41(d,J=7.4Hz,1H),7.29(m,1H),5.65(s,1H) ,5.17(s,1H),5.02(s,1H),4.21(s,1H),3.68(s,3H),2.43(d,J=12.4Hz,1H),2.35(d,J=12.5Hz,1H),2. 29–2.20(m,2H),1.81(s,1H),1.39(d,J=12.4Hz,1H),1.33(d,J=12.5Hz,1H),0.94(s,3H),0.81(s,3H); 13 C NMR (75MHz, CDCl3) δ173.78,170.09,151.52,148.34,146.59,142.69,142.28,141.12,136.63,131.97,129.76,126.38,12 3.85,122.71,120.50,115.55,58.01,54.20,51.40,35.93,32.43,29.80,25.62,15.40,11.59; LC-MS(ESI)m / z:555.4[M+H] + .

[0873] Example 173: (S)-3-(8-Bromo-1-(2-amino-3-methylbutyryloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 174)

[0874] Compound 174 was prepared by replacing Boc-glycine in Example 169 with Boc-valine and following the method of Example 169.

[0875] 1 H NMR(300MHz, CDCl3) δ8.70(dd,J=5.0,1.3Hz,1H),7.73(td,J=8.0,1.2Hz,1H),7.67(d,J =1.9Hz,1H),7.60(dd,J=7.5,2.0Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.41(d,J=7.4Hz, 1H),7.29(m,1H),5.62(s,2H),5.17(s,1H),4.33(s,1H),3.68(s,3H),2.49(d,J=12.3Hz ,1H),2.38(d,J=12.5Hz,1H),2.29–2.20(m,2H),2.07(s,1H),1.02(s,3H),0.98(s,3H); 13 C NMR (75MHz, CDCl3) δ173.89,169.55,151.52,148.34,146.59,142.69,142.28,140.59,136.63,131.97,130.05,126 .38,123.85,122.71,120.50,115.55,60.49,54.20,51.40,32.43,30.52,29.80,18.85; LC-MS(ESI)m / z:541.4[M+H] + .

[0876] Example 174: (S)-3-(8-Bromo-1-(pyrrolidin-2-yloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 175)

[0877] Compound 175 was prepared by replacing Boc-glycine in Example 169 with Boc-proline and following the method of Example 169.

[0878] 1H NMR (300MHz, CDCl3) δ8.70 (dd, J=5.0, 1.3Hz, 1H), 7.73 (td, J=8.0, 1.2Hz, 1H), 7.67 (d, J=1.9Hz ,1H),7.60(dd,J=7.5,2.0Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.41(d,J=7.4Hz,1H),7.29(m,1 H),5.17(s,1H),4.14(s,1H),3.68(s,3H),3.45(s,1H),3.12(d,J=2.2Hz,2H),2.52(d,J=12.5H z,1H),2.42(d,J=12.5Hz,1H),2.29–2.20(m,2H),2.00(d,J=16.9Hz,2H),1.71(d,J=2.5Hz,2H); 13 C NMR (75MHz, CDCl3) δ173.89,170.24,151.52,148.34,146.59,142.69,142.28,141.12,136.63,131.81,129.76,126.38 ,123.85,122.71,120.50,115.55,55.94,54.20,51.40,48.87,32.43,29.80,26.92,24.92; LC-MS(ESI)m / z:539.4[M+H] + .

[0879] Example 175: (S)-3-(8-Bromo-1-(2-amino-3-phenylpropionyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 176)

[0880] Compound 176 was prepared by replacing Boc-glycine in Example 169 with Boc-phenylalanine and following the method of Example 169.

[0881] 1H NMR (300MHz, CDCl3) δ8.72 (dd, J=5.0, 1.2Hz, 1H), 7.80 (td, J=7.9, 1.2Hz, 1H), 7.70 (d, J=2.0H z,1H),7.60(dd,J=7.5,2.0Hz,1H),7.45(dd,J=8.0,1.0Hz,1H),7.38(d,J=7.5Hz,1H),7.29(m 1H),7.21(m,5H),5.29(s,1H),4.63(s,1H),4.22(s,1H),3.92(s,1H),3.68(s,3H),3.04– 2.93(m,2H),2.43(d,J=12.4Hz,1H),2.34(dd,J=12.4,7.4Hz,2H),2.25(d,J=12.4Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.61,170.38,151.52,148.34,145.36,144.74,143.98,139.79,136.63,136.58,131.97,131.10,130.23, 129.92,128.14,126.91,123.85,122.40,120.50,117.15,57.82,53.65,51.50,36.31,32.43,29.80; LC-MS(ESI)m / z:589.5[M+H] + .

[0882] Example 176: (S)-3-(8-Bromo-1-(2-amino-4-methylthiobutyryloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 177)

[0883] Compound 177 was prepared by replacing Boc-glycine in Example 169 with Boc-methionine and following the method of Example 169.

[0884] 1H NMR (300MHz, CDCl3) δ8.70 (dd, J=5.0, 1.3Hz, 1H), 7.73 (td, J=8.0, 1.2Hz, 1H), 7.67 (d, J=1.9 Hz,1H),7.60(dd,J=7.5,2.0Hz,1H),7.48(dd,J=8.0,1.0Hz,1H),7.41(d,J=7.4Hz,1H),7.29( m,1H),5.17(s,1H),4.83(s,2H),4.36(s,1H),3.68(s,3H),3.38(d,J=12.5Hz,1H),3.26(s,1 H),2.88(d,J=12.5Hz,1H),2.46(d,J=12.3Hz,1H),2.35(d,J=12.5Hz,1H),2.29–2.20(m,2H); 13 C NMR (75MHz, CDCl3) δ173.78,169.91,151.52,148.34,146.59,142.69,142.28,140.59,136.63,131.81,130.05, 126.38,123.85,122.71,120.50,115.55,55.89,54.20,51.40,32.43,30.24,29.80; LC-MS(ESI)m / z:545.4[M+H] + .

[0885] Example 177: (S)-3-(8-Bromo-1-(2-amino-3-indolylpropionyloxy)-6-(pyridin-2-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 178)

[0886] Compound 178 was prepared by replacing Boc-glycine in Example 169 with Boc-tryptophan and following the method of Example 169.

[0887] 1H NMR (300MHz, CDCl3) δ9.10 (s, 1H), 8.70 (dd, J = 4.9, 1.3Hz, 1H), 7.92 (td, J = 8.0, 1.2Hz ,1H),7.67–7.57(m,3H),7.45(dd,J=8.0,1.0Hz,1H),7.41–7.33(m,3H),7.14–7.07(m ,3H),5.29(s,1H),4.63(s,2H),3.90(s,1H),3.68(s,3H),3.20(d,J=12.5Hz,1H),3.1 0(d,J=12.5Hz,1H),2.43(d,J=12.5Hz,1H),2.38–2.30(m,2H),2.25(d,J=12.5Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.61,171.11,153.90,148.34,145.36,144.74,14 3.98,139.79,136.63,136.06,132.20,131.10,127.20,126.91,124.69, 123.88,123.85,122.10,120.50,120.33,118.26,115.73,111.28,110.9 4,68.07,53.36,51.64,32.43,31.18,29.80; LC-MS(ESI)m / z:628.5[M+H] + .

[0888] Example 178: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(aminoacetoxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 179)

[0889] Compound 179 was prepared by replacing compound 3 in Example 169 with compound 2 and referring to the method of Example 169.

[0890] 1H NMR (300MHz, CDCl3) δ8.00(d,J=2.0Hz,1H),7.82(d,J=7.5Hz,1H),7.64(dd,J=5.6,3.8Hz,1H),7.53–7.46(m,2H),7.45– 7.38(m,2H),5.17(s,1H),4.96(s,1H),4.63(s,1H),3.73(s,2H),3.68(s,3H),2.56(d,J=3.3Hz,2H),2.29–2.20(m,2H); 13 C NMR (75MHz, CDCl3) δ173.89,170.63,148.34,147.19,144.05,141.55,132.88,131.55,130.78,130.65,129.78,1 29.48,129.38,128.74,126.73,125.34,124.71,54.35,51.48,48.23,33.02,30.26; LC-MS(ESI)m / z:488.3[M+H] + .

[0891] Example 179: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-aminopropionyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 180)

[0892] Compound 180 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-alanine.

[0893] 1 H NMR(300MHz, CDCl3)δ8.00(d,J=2.0Hz,1H),7.82(d,J=7.5Hz,1H),7.65–7.58(m,1H),7.52–7.42(m,2H),7.44–7.36 (m,2H),5.28(s,2H),5.17(s,1H),3.98(s,1H),3.68(s,3H),2.56(d,J=3.3Hz,2H),2.29–2.20(m,2H),1.44(s,3H); 13C NMR (75MHz, CDCl3) δ173.89,169.57,150.84,148.34,144.51,144.05,132.83,131.55,130.65,130.18,129.78,129. 48,129.38,128.74,126.73,125.34,124.71,54.20,51.48,50.17,33.02,30.26,15.60; LC-MS(ESI)m / z:502.4[M+H] + .

[0894] Example 180: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-4-methylpentanoyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 181)

[0895] Compound 181 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-leucine.

[0896] 1 H NMR(300MHz, CDCl3)δ8.04(d,J=2.0Hz,1H),7.66(d,J=7.5Hz,1H),7.63–7.57(m, 1H),7.52–7.46(m,1H),7.45–7.36(m,3H),5.17(s,1H),5.02(s,1H),4.63(s,1H), 3.87(s,1H),3.68(s,3H),2.49(d,J=12.3Hz,1H),2.36(dd,J=21.1,12.4Hz,2H), 2.25(d,J=12.5Hz,1H),1.61(s,1H),1.60–1.49(m,2H),0.92(s,3H),0.87(s,3H); 13 C NMR (75MHz, CDCl3) δ173.78,170.38,151.52,148.34,144.05,139.95,132.79,131.55,130.65,129.51,129.49,129.33,129 .12,128.62,126.72,124.71,124.25,54.20,53.61,51.40,39.44,33.02,30.26,25.25,22.29; LC-MS(ESI)m / z:544.4[M+H] + .

[0897] Example 181: (S)-8-Chloro-6-(2-chlorophenyl)-4-(3-methoxy-3-oxopropyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of 2-amino-3-methylpentanoate (Compound 182)

[0898] Compound 182 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-isoleucine.

[0899] 1 H NMR (300MHz, CDCl3) δ8.04(d,J=2.0Hz,1H),7.66(d,J=7.5Hz,1H),7.63–7.57(m,1H),7. 52–7.46(m,1H),7.45–7.36(m,3H),5.65(s,1H),5.17(s,1H),5.02(s,1H),4.21(s,1H),3 .68(s,3H),2.49(d,J=12.3Hz,1H),2.36(dd,J=21.1,12.4Hz,2H),2.25(d,J=12.5Hz,1H ),1.81(s,1H),1.39(d,J=12.4Hz,1H),1.33(d,J=12.5Hz,1H),0.93(s,3H),0.83(s,3H); 13 C NMR (75MHz, CDCl3) δ173.78,170.09,151.52,148.34,144.05,139.95,132.79,131.55,130.65,129.51,129.49,129.33,129.12 ,128.62,126.72,124.71,124.25,58.57,54.20,51.40,35.99,33.02,30.26,25.62,15.40,11.52; LC-MS(ESI)m / z:544.4[M+H] + .

[0900] Example 182: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-3-methylbutyryloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 183)

[0901] Compound 183 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-valine, and referring to the method of Example 169.

[0902] 1 H NMR (300MHz, CDCl3) δ8.00(d,J=2.0Hz,1H),7.66(d,J=7.5Hz,1H),7.64–7.56(m,1H),7.52–7.42(m,2H),7.44–7.36(m,2H),5. 62(s,2H),5.17(s,1H),4.33(s,1H),3.68(s,3H),2.56–2.45(m,2H),2.29–2.20(m,2H),2.07(s,1H),1.02(s,3H),0.98(s,3H); 13 CNMR(75MHz, CDCl3)δ173.89,169.55,151.52,148.34,144.51,144.05,132.79,131.55,130.65,129.50,129.48,129 .38,128.62,126.72,124.71,124.25,60.49,54.20,51.40,33.02,30.52,30.26,18.85; LC-MS(ESI)m / z:530.4[M+H] + .

[0903] Example 183: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(pyrrolidin-2-yloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 184)

[0904] Compound 184 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-proline, according to the method of Example 169.

[0905] 1H NMR(300MHz, CDCl3)δ8.04(d,J=2.0Hz,1H),7.66(d,J=7.5Hz,1H),7.64–7.56(m,1H),7.52–7.45(m,1H),7.47–7.36(m,3H),5.17(s,1H),4.14 (s,1H),3.68(s,3H),3.45(s,1H),3.12(d,J=2.2Hz,2H),2.56–2.45(m,2H),2.29–2.20(m,2H),2.00(d,J=16.9Hz,2H),1.71(d,J=2.5Hz,2H); 13 C NMR (75MHz, CDCl3) δ173.89,170.24,151.52,148.34,144.05,139.95,132.79,131.55,130.65,129.50,129.48,129.38 ,128.62,126.72,124.71,124.25,55.94,54.20,51.40,48.87,33.02,30.26,27.48,25.58; LC-MS(ESI)m / z:528.4[M+H] + .

[0906] Example 184: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-3-phenylpropionyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 185)

[0907] Compound 185 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-phenylalanine, according to the method of Example 169.

[0908] 1 H NMR (300MHz, CDCl3) δ7.97 (d, J=2.0Hz, 1H), 7.69–7.61 (m, 2H), 7.49 (dd, J= 7.0,2.4Hz,1H),7.41(m,2H),7.26–7.17(m,1H),7.21(m,5H),5.29(s,1H), 4.63(s,1H),4.22(s,1H),3.92(s,1H),3.69(s,3H),3.04–2.93(m,2H),2.4 9(d,J=12.2Hz,1H),2.36(dd,J=21.1,12.3Hz,2H),2.25(d,J=12.4Hz,1H); 13CNMR (75MHz, CDCl3) δ173.61,170.38,151.52,148.34,144.54,139.95,136.58,132.21,130.76,130.70,130.54,130.26,129.90,129 .51,129.12,129.02,128.50,128.09,126.72,124.71,119.29,57.82,53.36,51.50,36.31,33.02,30.26; LC-MS(ESI)m / z:578.5[M+H] + .

[0909] Example 185: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-4-methylthiobutyryloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 186)

[0910] Compound 186 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-methionine, according to the method of Example 169.

[0911] 1 H NMR(300MHz, CDCl3)δ8.00(d,J=2.0Hz,1H),7.82(d,J=7.5Hz,1H),7.65–7.59(m,1H),7.52–7.44(m,2H),7.44–7.36(m,2H),5.17(s,1H), 4.83(s,2H),4.36(s,1H),3.68(s,3H),3.38(d,J=12.5Hz,1H),3.26(s,1H),2.88(d,J=12.5Hz,1H),2.56–2.45(m,2H),2.29–2.20(m,2H); 13 C NMR (75MHz, CDCl3) δ173.89,169.91,151.52,148.34,144.51,144.05,133.15,131.55,130.65,130.18,129.50,129. 48,129.38,128.74,126.72,124.71,124.25,55.80,54.20,51.40,33.02,30.26,30.17; LC-MS(ESI)m / z:534.4[M+H] + .

[0912] Example 186: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-(2-amino-3-indolylpropionyloxy)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-aminopropionate (Compound 187)

[0913] Compound 187 was prepared by replacing compound 3 in Example 169 with compound 2, and replacing Boc-glycine with Boc-tryptophan.

[0914] 1 H NMR (300MHz, CDCl3) δ9.10 (s, 1H), 7.97 (d, J = 2.0Hz, 1H), 7.70–7.61 (m, 2H), 7.59 (s, 1H),7.52–7.46(m,1H),7.44–7.33(m,3H),7.25(dd,J=7.5,2.0Hz,1H),7.17–7.07(m, 3H),5.29(s,1H),4.63(s,2H),3.90(s,1H),3.69(s,3H),3.20(d,J=12.5Hz,1H),3.10 (d,J=12.5Hz,1H),2.43(d,J=12.5Hz,1H),2.38–2.30(m,2H),2.25(d,J=12.5Hz,1H); 13 CNMR (75MHz, CDCl3) δ173.61,171.11,153.90,148.34,144.54,139.95,136 .06,131.62,130.86,130.76,130.54,129.51,129.01,128.79,128.72,127 .20,126.72,124.54,124.41,123.88,120.33,119.29,118.27,111.59,111 .40,57.82,53.36,51.68,33.92,31.18,30.26; LC-MS(ESI)m / z:617.5[M+H] + .

[0915] Example 187: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl (4-amino)propionamido)acetate (Compound 188)

[0916]

[0917] (S)-3-(8-bromo-6-(pyridin-2-yl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Methyl 4-aminopropionate (compound 3 tautomer, 0.50 g, 1.13 mmol) was dissolved in 8 mL THF, 4 mL 2 M LiOH was added, and the reaction was stirred at 60 ° C for 6 hours, concentrated under reduced pressure, and silica gel column chromatography (DCM: MeOH = 20: 1, v / v) obtained a white solid, which was dissolved in 6 mL To DMF were added HBTU (429.9 mg, 1.13 mmol), HOBT (153.2 mg, 1.13 mmol), and L-glycine methyl ester (201.3 mg, 2.26 mmol), and the mixture was stirred at room temperature for 0.5 h. DIPEA (292 mg, 2.26 mmol) was then added, and the mixture was reacted at 60° C. for 6 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA=5:1, v / v) to give (S)-2-(3-(8-bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine) as a white solid. -4-yl)propionamido)-3-indolylpropionic acid methyl ester (Compound 188, 278 mg, yield 52%).

[0918] 1 H NMR (300MHz, CDCl3) δ10.60(s,1H),8.70(dd,J=5.0,1.3Hz,1H),8.11(s,1H),7.77(td,J=8.0,1.2Hz,1H),7.69–7.62(m,2H),7.45(dd,J=8.0,1.0Hz,1 H),7.32(m,1H),7.06(d,J=7.3Hz,1H),4.77(s,1H),4.20(d,J=12.5Hz,1H) ,4.13(d,J=12.4Hz,1H),3.64(s,3H),2.44–2.32(m,2H),2.17–2.07(m,2H); 13 C NMR (75MHz, CDCl3) δ173.11,172.64,151.50,145.51,141.85,140.78,138.70,137.13,136.63,131.75,129. 76,128.10,123.85,122.10,120.48,120.05,55.35,52.77,42.09,32.65,29.81; LC-MS(ESI)m / z:499.3[M+H] + .

[0919] Example 188: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl (4-amino)propionamido)propionate (Compound 189)

[0920] Compound 189 was prepared by replacing L-glycine methyl ester in Example 187 with L-alanine methyl ester.

[0921] 1 H NMR (300MHz, CDCl3) δ10.60(s,1H),8.70(dd,J=5.0,1.3Hz,1H),8.16(s,1H),7.74(td,J=8.0,1.3Hz,1H),7.69–7.62(m,2H),7.48(dd,J=8.0 ,1.0Hz,1H),7.29(m,1H),7.06(d,J=7.3Hz,1H),4.77(s,1H),4.36(s, 1H),3.64(s,3H),2.44–2.33(m,2H),2.13–2.03(m,2H),1.39(s,3H).; 13 C NMR (75MHz, CDCl3) δ173.30,173.07,151.50,145.51,141.85,140.78,138.70,137.13,136.63,131.75,129.76,1 28.10,123.85,122.40,120.50,120.48,55.35,52.46,51.98,32.73,30.22,17.85.;LC-MS(ESI)m / z:513.4[M+H] + .

[0922] Example 189: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-4-yl)propionamido)-4-methylpentanoate (Compound 190)

[0923] Compound 190 was prepared by replacing L-glycine methyl ester in Example 187 with L-leucine methyl ester.

[0924] 1H NMR (300MHz, CDCl3) δ10.60(s,1H),8.70(dd,J=5.0,1.3Hz,1H),8.14(s,1H),7.74(td,J=8.0 ,1.3Hz,1H),7.69–7.62(m,2H),7.48(dd,J=8.0,1.0Hz,1H),7.29(m,1H),7.06(d,J=7.4Hz,1 H),4.77(s,1H),4.37(s,1H),3.63(s,3H),2.37(d,J=1.0Hz,2H),2.30(d,J=12.3Hz,1H),1.8 0(d,J=12.3Hz,1H),1.71(d,J=12.3Hz,1H),1.63(t,J=6.2Hz,2H),0.92(s,3H),0.87(s,3H); 13 C NMR (75MHz, CDCl3) δ173.49,172.93,151.50,145.51,142.28,141.85,139.00,137.13,136.63,131.97,129.76,128.10 ,123.85,123.47,122.71,120.50,54.12,52.59,51.52,40.32,32.65,30.22,24.85,22.23; LC-MS(ESI)m / z:555.4[M+H] + .

[0925] Example 190: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-3-methylpentanoate (Compound 191)

[0926] Compound 191 was prepared by replacing L-glycine methyl ester in Example 187 with L-isoleucine methyl ester.

[0927] 1H NMR (300MHz, CDCl3) δ10.60 (s, 1H), 8.70 (dd, J = 5.0, 1.3Hz, 1H), 8.07 (s, 1H), 7.74 (td,J=8.0,1.3Hz,1H),7.69–7.62(m,2H),7.48(dd,J=8.0,1.0Hz,1H),7.29(m,1H ),7.06(d,J=7.4Hz,1H),4.77(s,1H),4.27(s,1H),3.64(s,3H),2.37(d,J=1.0Hz, 2H),2.30(d,J=12.3Hz,1H),1.84–1.77(m,2H),1.30(s,2H),0.90(d,J=5.1Hz,6H); 13 C NMR (75MHz, CDCl3) δ173.02,172.80,151.50,145.51,142.28,141.85,139.00,137.13,136.63,131.97,129.76,128.10,12 3.85,123.47,122.71,120.50,57.02,54.12,52.53,36.82,32.65,30.22,26.07,16.60,14.69; LC-MS(ESI)m / z:555.4[M+H] + .

[0928] Example 191: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl (4-yl)propionamido)-3-indolylpropionate (Compound 192)

[0929] Compound 192 was prepared by replacing L-glycine methyl ester in Example 187 with L-tryptophan methyl ester.

[0930] 1H NMR (300MHz, CDCl3) δ10.60(s,1H),9.10(s,1H),8.70(dd,J=4.9,1.3Hz,1H),8.13(s,1H),7.91(td,J=8 .0,1.2Hz,1H),7.71(dd,J=7.5,2.0Hz,1H),7.67–7.60(m,2H),7.45(dd,J=8.0,1.0Hz,1H),7.39–7.33( m,2H),7.22–7.17(m,2H),7.10(d,J=10.3Hz,2H),4.77(s,1H),4.50(s,1H),3.66(s,3H),3.19(d,J=12. 5Hz,1H),3.06(d,J=12.5Hz,1H),2.37(d,J=1.1Hz,2H),2.30(d,J=12.3Hz,1H),1.80(d,J=12.3Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.28,173.00,151.50,147.52,143.98,140.11,13 8.30,137.13,136.63,136.09,132.20,131.10,128.63,127.20,124.69, 124.13,123.85,122.10,121.03,120.50,120.48,118.27,111.40,111.1 0,54.12,53.05,52.45,32.65,30.22,30.15; LC-MS(ESI)m / z:628.5[M+H] + .

[0931] Example 192: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl (4-indole)-3-indolyl)propionyl)-3-indolylpropionate (Compound 193)

[0932] Compound 193 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-tryptophan methyl ester.

[0933] 1H NMR (300MHz, CDCl3) δ9.10 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 2.0Hz, 1H), 7.78 (d, J = 7.5Hz ,1H),7.70–7.60(m,2H),7.52–7.46(m,1H),7.44–7.30(m,5H),7.17(d,J=19.6Hz,2H),7 .09(s,1H),4.71(s,1H),4.50(s,1H),3.66(s,3H),3.19(d,J=12.5Hz,1H),3.06(d,J=12 .5Hz,1H),2.37(d,J=12.5Hz,1H),2.30(dd,J=12.4,5.6Hz,2H),1.80(d,J=12.3Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.28,173.00,151.50,150.22,141.16,137.13,136. 09,131.62,130.86,130.76,130.54,129.51,129.01,128.79,128.72,127. 20,126.43,124.54,124.41,124.13,121.03,120.72,118.27,111.43,111. 28,54.12,53.20,52.37,32.65,30.15,29.74; LC-MS(ESI)m / z:617.5[M+H] + .

[0934] Example 193: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-3-methylpropionyl)propionamido-3-methylbutanoate (Compound 194)

[0935] Compound 194 was prepared by replacing L-glycine methyl ester in Example 187 with L-valine methyl ester and following the method of Example 187.

[0936] 1H NMR (300MHz, CDCl3) δ10.60 (s, 1H), 8.70 (dd, J = 5.0, 1.3Hz, 1H), 8.03 (s, 1H), 7.74 (t d,J=8.0,1.3Hz,1H),7.69–7.62(m,2H),7.48(dd,J=8.0,1.0Hz,1H),7.29(m,1H),7. 06(d,J=7.4Hz,1H),4.77(s,1H),4.29(s,1H),3.64(s,3H),2.37(d,J=1.0Hz,2H),2. 30(d,J=12.3Hz,1H),2.00(s,1H),1.80(d,J=12.3Hz,1H),1.02(s,3H),0.97(s,3H); 13 C NMR (75MHz, CDCl3) δ173.02,172.39,151.50,145.51,142.28,141.85,138.70,137.13,136.63,131.97,130.05,128 .10,123.85,123.47,122.71,120.50,57.94,54.12,52.48,33.40,30.88,30.22,18.38; LC-MS(ESI)m / z:541.4[M+H] + .

[0937] Example 194: (S)-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of 4-(4-yl)propionyl)pyrrolidin-2-yl-carboxylate (Compound 195)

[0938] Compound 195 was prepared by replacing L-glycine methyl ester in Example 187 with L-proline methyl ester.

[0939] 1H NMR (300MHz, CDCl3) δ10.60(s,1H),8.70(dd,J=5.0,1.3Hz,1H),7.74(td,J=8.0,1 .3Hz,1H),7.69–7.62(m,2H),7.48(dd,J=8.0,1.0Hz,1H),7.29(m,1H),7.06(d,J=7 .4Hz,1H),4.77(s,1H),4.34(s,1H),3.63(d,J=13.2Hz,4H),2.55(m,2H),2.48(m, 2H), 2.30 (d, J = 12.3Hz, 1H), 1.95 (dd, J = 34.5, 17.9Hz, 3H), 1.80 (d, J = 12.3Hz, 1H); 13 C NMR (75MHz, CDCl3) δ172.46,171.56,151.50,145.51,142.28,141.85,139.00,137.13,136.63,131.81,129.76,128.10 ,123.85,123.47,122.71,120.50,58.42,54.12,52.39,47.25,33.37,30.27,28.87,24.71; LC-MS(ESI)m / z:539.4[M+H] + .

[0940] Example 195: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-3-phenylpropionyl)propionamido)-3-phenylpropanoate (Compound 196)

[0941] Compound 196 was prepared by replacing L-glycine methyl ester in Example 187 with L-phenylalanine methyl ester and following the method of Example 187.

[0942] 1H NMR (300MHz, CDCl3) δ10.60 (s, 1H), 8.72 (dd, J = 4.9, 1.2Hz, 1H), 8.12 (s, 1H), 7 .80(td,J=7.9,1.2Hz,1H),7.74–7.68(m,2H),7.45(dd,J=8.0,1.0Hz,1H),7.29 (m,1H),7.27–7.16(m,6H),4.77(s,1H),4.49(s,1H),3.63(s,3H),2.96(t,J=0. 9Hz, 2H), 2.37 (d, J = 1.1Hz, 2H), 2.27 (d, J = 12.4Hz, 1H), 1.76 (d, J = 12.4Hz, 1H); 13 C NMR (75MHz, CDCl3) δ173.49,172.68,151.50,147.52,143.98,140.11,138.30,137.13,136.82,136.63,131.97,131.10,130.34, 129.92,128.63,128.24,123.85,122.40,120.50,120.48,54.12,53.31,52.65,37.91,32.65,30.22; LC-MS(ESI)m / z:589.5[M+H] + .

[0943] Example 196: (S)-2-(3-(8-Bromo-1-oxo-6-(pyridin-2-yl)-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-methyl-4-yl)propionamido)-4-methylthiobutanoate (Compound 197)

[0944] Compound 197 was prepared by replacing L-glycine methyl ester in Example 187 with L-methionine methyl ester.

[0945] 1H NMR (300MHz, CDCl3) δ10.60 (s, 1H), 8.70 (dd, J=5.0, 1.3Hz, 1H), 8.17 (s, 1H), 7.74 (td, J= 8.0,1.3Hz,1H),7.69–7.62(m,2H),7.48(dd,J=8.0,1.0Hz,1H),7.29(m,1H),7.06(d,J=7 .4Hz,1H),4.79(d,J=20.0Hz,2H),4.44(s,1H),3.64(s,3H),3.38(d,J=12.5Hz,1H),2.88 (d,J=12.5Hz,1H),2.37(d,J=1.1Hz,2H),2.30(d,J=12.3Hz,1H),1.80(d,J=12.3Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.28,172.80,151.50,145.51,142.28,141.85,138.70,137.13,136.63,131.81,130.05, 128.10,123.85,123.47,122.71,120.50,54.12,53.50,52.48,33.40,29.74,29.33; LC-MS(ESI)m / z:545.4[M+H] + .

[0946] Example 197: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl (4-amino)propionamido)acetate (Compound 198)

[0947] Compound 198 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2 and referring to the method of Example 187.

[0948] 1 H NMR (300MHz, CDCl3) δ9.13(s,1H),8.11(s,1H),7.94(d,J=2.0Hz,1H),7.84(d,J=7.5Hz,1H),7.69–7.63(m,1H),7.50(m,2H),7. 46–7.36(m,2H),4.77(s,1H),4.10(d,J=12.3Hz,1H),4.02(d,J=12.5Hz,1H),3.63(s,3H),2.44–2.33(m,2H),2.17–2.07(m,2H);13 CNMR(75MHz, CDCl3)δ173.11,172.64,151.50,150.08,142.34,137.13,132.88,131.55,130.78,130.65,129.78, 129.48,129.38,128.74,126.43,124.71,122.85,55.35,52.88,42.09,32.65,29.74; LC-MS(ESI)m / z:488.3[M+H] + .

[0949] Example 198: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl (4-amino)propionamido)propionate (Compound 199)

[0950] Compound 199 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-alanine methyl ester.

[0951] 1 H NMR (300MHz, CDCl3) δ9.10 (s, 1H), 8.10 (s, 1H), 7.94 (d, J = 2.0Hz, 1H), 7.7 8(d,J=7.5Hz,1H),7.69–7.63(m,1H),7.51–7.43(m,2H),7.43–7.36(m,2H) ,4.71(s,1H),4.36(s,1H),3.65(s,3H),2.41(d,J=12.5Hz,1H),2.37(d,J =12.5Hz,1H),2.30(d,J=12.3Hz,1H),1.80(d,J=12.3Hz,1H),1.39(s,3H); 13 CNMR(75MHz, CDCl3)δ173.30,173.07,151.50,150.08,142.34,137.13,132.83,131.55,130.65,130.18,129.78,129 .48,129.38,128.74,126.43,124.71,122.85,55.35,52.53,51.98,33.40,29.81,17.85; LC-MS(ESI)m / z:502.4[M+H] + .

[0952] Example 199: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-4-yl)propionamido)-4-methylpentanoate (Compound 200)

[0953] Compound 200 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-leucine methyl ester.

[0954] 1 H NMR (300MHz, CDCl3) δ9.15 (s, 1H), 8.12 (s, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.78 (d ,J=7.5Hz,1H),7.65–7.58(m,1H),7.52–7.45(m,2H),7.44–7.36(m,2H),4.77( s,1H),4.37(s,1H),3.63(s,3H),2.44–2.33(m,2H),2.27(d,J=12.4Hz,1H),1 .74(dd,J=25.9,12.4Hz,2H),1.63(t,J=6.2Hz,2H),0.92(s,3H),0.87(s,3H); 13 C NMR (75MHz, CDCl3) δ173.49,172.93,151.50,150.08,142.34,137.13,132.79,131.55,130.65,129.51,129.49,129.33,129 .12,128.62,126.43,124.71,122.85,54.12,52.48,51.79,40.32,32.65,29.74,24.87,22.23; LC-MS(ESI)m / z:544.4[M+H] + .

[0955] Example 200: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-3-methylpentanoate (Compound 201)

[0956] Compound 201 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-isoleucine methyl ester.

[0957] 1 H NMR (300MHz, CDCl3) δ9.10 (s, 1H), 8.05–7.98 (m, 2H), 7.78 (d, J = 7.5Hz, 1H), 7 .65–7.59(m,1H),7.52–7.45(m,2H),7.44–7.36(m,2H),4.77(s,1H),4.27(s, 1H),3.64(s,3H),2.44(d,J=12.3Hz,1H),2.37(d,J=12.5Hz,1H),2.30(d,J=1 2.3Hz,1H),1.84–1.77(m,2H),1.31(d,J=3.5Hz,2H),0.90(d,J=11.3Hz,6H); 13 C NMR (75MHz, CDCl3) δ173.02,172.80,151.50,150.08,142.34,137.13,132.79,131.55,130.65,129.51,129.49,129.33,129.12 ,128.62,126.43,124.71,122.85,57.02,54.12,52.53,36.20,32.65,29.74,26.07,17.25,14.69; LC-MS(ESI)m / z:544.4[M+H] + .

[0958] Example 201: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-3-methylpropionamido)-3-methylbutanoate (Compound 202)

[0959] Compound 202 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-valine methyl ester.

[0960] 1H NMR (300MHz, CDCl3) δ9.08(s,1H),8.03(s,1H),7.94(d,J=1.9Hz,1H),7.78(d,J= 7.5Hz,1H),7.65–7.59(m,1H),7.54–7.45(m,2H),7.44–7.36(m,2H),4.77(s,1H) ,4.29(s,1H),3.64(s,3H),2.50(d,J=12.4Hz,1H),2.43(d,J=12.3Hz,1H),2.30( d,J=12.3Hz,1H),2.00(s,1H),1.80(d,J=12.3Hz,1H),1.00(s,3H),0.95(s,3H); 13 C NMR (75MHz, CDCl3) δ173.19,172.62,151.50,150.08,142.34,137.13,132.79,131.55,130.65,129.50,129.48,129 .38,128.62,126.43,124.71,122.85,57.94,54.12,52.40,32.65,30.82,29.74,18.38; LC-MS(ESI)m / z:530.4[M+H] + .

[0961] Example 202: (S)-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of 4-(4-yl)propionyl)pyrrolidin-2-ylcarboxylate (Compound 203)

[0962] Compound 203 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-proline methyl ester.

[0963] 1H NMR (300MHz, CDCl3) δ9.05 (s, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.78 (d, J = 7.5Hz, 1H), 7.65–7.59 (m, 1H), 7.53–7.45 (m, 2H), 7.44–7.36 (m, 2H), 4.71 (s,1H),4.36(s,1H),3.62(s,3H),3.56(d,J=9.5Hz,2H),2.63–2.52(m, 2H),2.30(d,J=12.3Hz,2H),2.02–1.88(m,3H),1.80(d,J=12.3Hz,1H); 13 C NMR (75MHz, CDCl3) δ172.46,171.56,151.50,150.08,142.34,137.13,132.79,131.55,130.65,129.50,129.48,129.38 ,128.62,126.43,124.71,122.85,58.28,54.12,52.30,47.25,32.30,30.27,28.87,24.71; LC-MS(ESI)m / z:528.4[M+H] + .

[0964] Example 203: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-amino-3-phenylpropionyl)propionamido)-3-phenylpropanoate (Compound 204)

[0965] Compound 204 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-phenylalanine methyl ester.

[0966] 1H NMR (300MHz, CDCl3) δ9.10 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 2.0Hz, 1H), 7.78 (d ,J=7.5Hz,1H),7.66(dd,J=7.2,2.2Hz,1H),7.49(dd,J=7.0,2.4Hz,1H),7.45 –7.35(m,3H),7.28–7.16(m,5H),4.71(s,1H),4.49(s,1H),3.63(s,3H),2.96 (m,2H),2.37(d,J=1.1Hz,2H),2.27(d,J=12.4Hz,1H),1.76(d,J=12.4Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.49,172.68,151.50,150.43,141.16,137.13,136.83,132.21,130.76,130.70,130.54,130.31,129.90,129. 51,129.12,129.02,128.50,128.24,126.43,124.71,120.72,54.12,53.31,52.65,37.91,32.65,29.74; LC-MS(ESI)m / z:578.5[M+H] + .

[0967] Example 204: (S)-2-(3-(8-chloro-6-(2-chlorophenyl)-1-oxo-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Preparation of methyl 4-methyl-4-yl)propionamido)-4-methylthiobutanoate (Compound 205)

[0968] Compound 205 was prepared by replacing the tautomer of Compound 3 in Example 187 with the tautomer of Compound 2, and replacing L-glycine methyl ester with L-methionine methyl ester.

[0969] 1H NMR (300MHz, CDCl3) δ9.12 (s, 1H), 8.24 (s, 1H), 7.94 (d, J = 1.9Hz, 1H), 7.78 (d, J=7.5Hz,1H),7.65–7.59(m,1H),7.54–7.45(m,2H),7.44–7.36(m,2H),4.77(s, 1H),4.43(s,1H),3.64(s,3H),3.00–2.89(m,2H),2.44(d,J=12.3Hz,1H),2.37 (d,J=12.5Hz,1H),2.30(d,J=12.3Hz,1H),2.05(s,3H),1.80(d,J=12.3Hz,1H); 13 C NMR (75MHz, CDCl3) δ173.70,172.80,151.50,150.08,142.34,137.13,132.79,131.55,130.65,129.50,129.38,129.33, 129.12,128.62,126.43,124.71,122.85,54.12,52.53,52.02,36.60,32.65,29.74,15.34; LC-MS(ESI)m / z:548.4[M+H] + .

[0970] Example 205

[0971] In anesthetic drug experiments, the incubation period generally refers to the time from the start of drug administration to the subject's loss of consciousness. 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 subject's loss of consciousness to the recovery of consciousness. The duration of drugs varies in different animal models or animal species. If the duration of anesthesia is too long, it may cause adverse inhibitory reactions to the cardiovascular and respiratory systems, such as side effects on 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.

[0972] 1. Drug-induced loss of righting reflex in mice

[0973] KM mice (male, 20-25 g) were randomly divided into groups and given a single bolus injection via the tail vein. The latency and duration of the righting reflex of the mice were recorded.

[0974] Table 1. Results of drug-induced loss of righting reflex test in mice

[0975]

[0976]

[0977]

[0978]

[0979] Note: NA means no activity. The solvent system for each compound is: compound + equimolar amount of p-toluenesulfonic acid + physiological saline, and the compound solution is prepared at pH 3-4.

[0980] As shown in Table 1, in the mouse experiment, the benzodiazepine These compounds have a rapid onset of anesthetic effect and an even faster recovery.

[0981] 2. Drug-induced loss of righting reflex in rats

[0982] SD rats (male, 200-280 g) were randomly divided into groups and given a single dose (dose: 45 mg / kg) via tail vein rapid injection. The latency and duration of the righting reflex of the rats were recorded.

[0983] Table 2. Drug-induced loss of righting reflex in rats

[0984]

[0985]

[0986] Note: The solvent system of each compound is: compound + equimolar amount of p-toluenesulfonic acid + normal saline, and the compound solution is prepared with a pH of 3-4.

[0987] Table 2 shows that in the rat experiment, the benzodiazepines of the present invention These compounds also have a rapid onset and rapid recovery anesthetic effect.

[0988] Example 206: Anesthesia test in rats induced by continuous drug infusion for 20 minutes

[0989] SD rats (male, 200-280 g) were randomly divided into groups. After a rapid injection of an initial dose via the tail vein, a maintenance dose was continuously infused for 20 minutes. After stopping the infusion, the duration of the rats' righting reflex and the time from awakening to recovery were recorded.

[0990] Table 3. Drugs continuously infused for 20 minutes to induce anesthesia in rats

[0991]

[0992]

[0993]

[0994] Note: The solvent system of each compound is: compound + equimolar amount of p-toluenesulfonic acid + physiological saline, and the pH of each compound solution is prepared at 3-4.

[0995] Table 3 shows that the benzodiazepines of the present invention These compounds can maintain anesthesia in animals during continuous infusion, and once the continuous infusion ends, they have the characteristics of faster awakening and faster recovery.

[0996] Example 207: Cell patch clamp detection of the effect of drugs on cell GABA-activated current

[0997] The test compounds were dissolved in an external solution (NaCl 140mM, KCl 4.7mM, HEPES 10mM, CaCl2 2mM, glucose 10mM, MgCl2 1mM, pH 7.4) at various concentrations. HEK 293T cells were seeded on coverslips and cultured in DMEM medium at 37°C and 5% CO2 for 24 hours. Whole-cell recordings of GABA Cl were performed using a HEKA EPC 10USB patch clamp amplifier. - 2 μM GABA was used to stimulate Cl - The cell was treated with the compound to be tested and 2μM GABA at the same time, and the Cl - The inductive effect of current and E max .

[0998] Table 4. Effects of compounds on GABA-activated currents in cells

[0999]

[1000]

[1001] Maximum enhancement percentage E of 2 μM GABA current max The corresponding concentration (μM): 100% for normal people. The larger the percentage, the more obvious the drug's enhancement of GABA-activated current, and the stronger the central nervous system inhibition and anesthetic effect.

[1002] Table 5. Effects of compounds on GABA-activated currents in cells

[1003]

[1004]

[1005] Table 5 shows that the compounds have an effect on GABA agonist EC 50 The smaller the value, the smaller the dose required for anesthesia.

[1006] Example 208: Rate of drug passage through the blood-brain barrier in vitro

[1007] A Transwell device (pore size 5.0 μm) was placed in a 24-well cell culture well, and 1×10 5 hCMEC / D3 cells at a concentration of 100 μL / mL were transferred to the upper microwells of the Transwell, with 150 μL / well added to the lower microwells. High-glucose DMEM cell culture medium was added to the lower microwells. Once the cells had formed a complete monolayer, the culture medium in the wells was replaced with EBM-2 complete culture medium containing 1% FBS. Culture was continued in a CO2 incubator for 10 days until a completely dense monolayer was formed. When the cells formed a dense monolayer, a pre-prepared 10 μM compound solution (prepared with DMSO to a 10 mM compound stock solution, then diluted with PBS to a 10 μM compound solution) was added to the lower culture medium. After 5 minutes, the compound concentration in the upper culture medium was measured and the permeability (P) was calculated:

[1008] P 化合物 % = C 上层化合物 / C 下层化合物 ×100%

[1009] Table 6. Test results of drug penetration rate through the blood-brain barrier

[1010]

[1011] Table 7 shows that the benzodiazepines of the present invention These compounds have the ability to quickly penetrate the blood-brain barrier.

[1012] Example 209: In vitro plasma half-life test of drugs

[1013] Plasma preparation: After 12 hours of fasting (but not water deprivation), blood was collected from the orbital venous plexus of SD rats. Freshly collected blood was placed in a centrifuge tube containing sodium heparin and centrifuged at 5000 rpm at 4°C for 10 minutes. The supernatant was slowly aspirated and aliquoted. The collected SD rat plasma was sealed, labeled, and stored at -20°C until ready for use.

[1014] Prepare compound samples: accurately weigh the compound using an analytical balance and prepare a stock solution with a concentration of 2 mg / mL (solvent: acetone: Tween 80: physiological saline volume ratio = 1:1:3) for later use.

[1015] In vitro half-life determination of compound samples: 20 μL of the stock solution of the test compound and 80 μL of SD rat plasma were taken and mixed. Nine parallel ep tubes (corresponding test tubes marked with 0, 1, 2, 3, 5, 10, 15, 20, and 30 min) were taken and incubated in a 37°C water bath for 0, 1, 2, 3, 5, 10, 15, 20, and 30 min, respectively. At each time point, 50 μL of the mixture 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 12,000 rpm for 15 min. The supernatant was taken and centrifuged again at 12,000 rpm for 10 min. The optimal detection method of the target compound in the MRM mode was determined using the Intellistat software in UPLC-MS / MS. The corresponding mass spectrometry peak area was integrated to calculate its plasma half-life.

[1016] Table 7. In vitro plasma half-life test results of drugs

[1017]

[1018] Example 210: Fluorescence polarization technology to detect whether the drug has a potential inhibitory effect on the voltage-gated potassium channel hERG

[1019] IC was calculated by testing the effects of eight compound concentrations on hERG channel current. 50 According to Predictor TM The hERG fluorescence polarization assay kit was used. Before measuring fluorescence polarization, the assay plate was covered to protect the reagent from light and evaporation. After incubation at room temperature for 40 minutes, the sample plate was centrifuged and the fluorescence polarization value was read. The excitation light was 540 nm and the emission light was 573 nm. The results are shown in Table 8, which shows that the benzodiazepines of the present invention The cardiotoxicity of these compounds is significantly lower than that of midazolam.

[1020] Table 8. Effects of drugs on hERG channel currents

[1021]

[1022]

[1023] Example 211: LC-MS detection of whether drugs have potential inhibitory effects on human liver P450s enzymes

[1024] Seven concentrations (final concentration of the incubation system) of the benzodiazepines of the present invention were selected. The compounds were preheated for 5 min with human liver microsomes (and mixed probe substrate (final concentrations of compounds / 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), and then the NADPH energy regeneration system (system components and final concentrations were: MgCl2 / 10 mmol / L, NADP + / 1mmol / L, G-6-P / 10mmol / L, PDH / 2Unit / mL) to start the reaction, and the incubation time is 20min. The content of organic solvent in the entire reaction system is controlled at ≤1%. After the incubation is completed, the reaction is terminated in a 0°C ice-water bath, and the protein is directly precipitated with an acetonitrile solution (1:5, v / v) containing an internal standard (o-methylbenzylamine, 30ng / mL), fully shaken for 5min, centrifuged at 18000rpm for 5min (4°C), and 400μL of supernatant is quantitatively transferred. After that, centrifuged at 18000rpm for 5min (4°C) again, 100μL of supernatant is quantitatively transferred, and 10μL is sampled. The logarithm of the molar concentration of the drug to be tested is used as the horizontal axis, 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) is used as the vertical axis. As shown in Table 9, the benzodiazepines of the present invention These compounds have little effect on drug-drug interactions.

[1025] Table 9. Effects of drugs on human liver P450s enzymes

[1026]

[1027]

[1028] The pharmacological data in Tables 1 to 9 indicate that the benzodiazepine #imgpt662# compounds of the present invention have the characteristics of low toxicity, rapid onset of action, stable anesthesia, and rapid awakening, and the preferred compounds have almost no accumulation.

[1029] Example 212: Lyophilized powder injection containing active agent Compound 81:

[1030] Compound 81 (10 g) and glycine (100 g) were added to a bottle, water for injection was added to 1 L, and the pH of the solution was adjusted to 3.5. The solution was divided into 1000 bottles and prepared into lyophilized powder injections by conventional lyophilization.

[1031] It should be understood that after reading the above content of the present invention, those skilled in the art may make various modifications or changes to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. Benzodiazepines with the structure shown in formula I Compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs thereof: in: R1 is selected from hydrogen or OR6, NR7R8; R6 is selected from hydrogen, C1-C5 straight or branched alkyl, morpholinyl substituted C1-C6 alkyl; R7 is selected from hydrogen, C1-C5 straight or branched alkyl, R8 is selected from R9 is selected from hydrogen, substituted or unsubstituted C1-C5 straight chain or branched alkyl, the substituent of C1-C5 straight chain or branched alkyl is phenyl, indolyl, methylthio, or R7, R8 and N form a 5-6 membered saturated or unsaturated heterocyclic ring, and the 5-6 membered saturated or unsaturated heterocyclic ring is substituted by methyl formate; R2 is selected from hydrogen, chlorine, bromine, nitro, cyano, amino; X is selected from C or N; when X is selected from C, R3 is selected from hydrogen, fluorine, chlorine, bromine; when X is selected from N, R3 is a covalent bond; R4 is selected from hydrogen, chlorine, and fluorine substituted at the 4' or 6' position; R5 is selected from hydrogen, substituted or unsubstituted C1-C5 straight or branched alkyl, acetyl, 2-propynyl, N-methylpiperidinyl, 3-methylpyridin-2-yl, N-methylimidazol-4-yl, The substituents of the C1-C5 straight-chain or branched alkyl group are hydroxy, amino, cyclopropyl, morpholinyl, piperidinyl, 4,4-difluoropiperidinyl, N-methylpiperidinyl, 4-hydroxypiperidinyl, 1,4-dioxa-8-azaspiro[4.5]decyl, piperazinyl, N-methylpiperazinyl, N-phenylpiperazinyl, N-hydroxyethylpiperazinyl, pyrrolyl, tetrahydropyrrolyl, 3-fluorotetrahydropyrrolyl, 3-hydroxytetrahydropyrrolyl, pyridinyl, imidazolyl, 2-methylpyridinyl, 3-methylpyridinyl, pyrimidinyl, phosphonooxy, NR 10 R 11 ; R 10 , R 11 Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl; But not including: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from 4-morpholinylmethyl, 3-(diethylamino)propyl; R1 is selected from methoxy, R2 is selected from hydrogen, X is selected from C, R3 is selected from hydrogen, R4 is selected from fluorine substituted at the 4' position, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from C, R3 is selected from chlorine, R4 is selected from hydrogen, and R5 is selected from cyclopropylmethyl; R1 is selected from methoxy, R2 is selected from chlorine, X is selected from C, R3 is selected from hydrogen, R4 is selected from chlorine substituted at the 6' position, and R5 is selected from chloromethyl, 2-chloroethyl, 3-chloropropyl, 2-(cyclopropyl(methyl)amino)ethyl.

2. The benzodiazepine according to claim 1 A compound characterized by: R1 is selected from hydrogen or OR6, NR7R8; R6 is selected from methyl, ethyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from hydrogen, methyl, 2-methylpropyl, 1-methylpropyl, isopropyl, benzyl, 3-indolylmethyl, methyl methyl sulfide, or R7, R8 and N form methyl pyrrolyl-2-alkanecarboxylate; R2 is selected from hydrogen, chlorine, bromine, nitro; X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond; R4 is selected from hydrogen, 4'-substituted chlorine, 6'-substituted fluorine or chlorine; R5 is selected from hydrogen, substituted or unsubstituted C1-C3 alkyl, acetyl, 2-propynyl, N-methylpiperidinyl, 3-methylpyridin-2-yl, N-methylimidazol-4-yl, The substituents of C1-C3 alkyl are hydroxy, amino, cyclopropyl, morpholinyl, piperidinyl, 4,4-difluoropiperidinyl, N-methylpiperidinyl, 4-hydroxypiperidinyl, 1,4-dioxa-8-azaspiro[4.5]decyl, piperazinyl, N-methylpiperazinyl, N-phenylpiperazinyl, N-hydroxyethylpiperazinyl, pyrrolyl, tetrahydropyrrolyl, 3-fluorotetrahydropyrrolyl, 3-hydroxytetrahydropyrrolyl, pyridinyl, imidazolyl, 2-methylpyridinyl, 3-methylpyridinyl, pyrimidinyl, phosphonooxy, NR 10 R 11 ; R 10 , R 11 Each independently selected from methyl and ethyl; But not including: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from 4-morpholinylmethyl, 3-(diethylamino)propyl; R1 is selected from methoxy, R2 is selected from hydrogen, X is selected from C, R3 is selected from hydrogen, R4 is selected from fluorine substituted at the 4' position, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from C, R3 is selected from chlorine, R4 is selected from hydrogen, and R5 is selected from cyclopropylmethyl; R1 is selected from methoxy, R2 is selected from chlorine, X is selected from C, R3 is selected from hydrogen, R4 is selected from chlorine substituted at the 6' position, and R5 is selected from chloromethyl, 2-chloroethyl, 3-chloropropyl, 2-(cyclopropyl(methyl)amino)ethyl.

3. The benzodiazepine according to claim 2 A compound characterized by: R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl; R2 is selected from chlorine, bromine, and nitro; X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond; R4 is selected from hydrogen, chlorine substituted at the 6' position; R5 is selected from hydrogen, methyl, cyclopropylmethyl, morpholinylmethyl, (1-methylpiperidin-4-yl)methyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl, ethyl, 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, 2-((3R)-3-fluoropyrrolidin-1-yl)ethyl, 2-((3R)-3-hydroxypyrrolidin-1-yl)ethyl, 2-(piperazin-1-yl)ethyl, 1-((1,4-dioxa-8-azaspiro[4.5]decane-8-yl)ethyl, 3-(dimethylamino)propyl, ((3R)-3-fluoropyrrolidin-1-yl)propyl, (1,4-dioxa-8-azaspiro[4.5]decane-8-yl)propyl, 3-methylpyridin-2-yl, But it does not include: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from 4-morpholinylmethyl, 3-(diethylamino)propyl; R1 is selected from methoxy, R2 is selected from bromine, X is selected from C, R3 is selected from chlorine, R4 is selected from hydrogen, and R5 is selected from cyclopropylmethyl.

4. The benzodiazepine according to claim 3 A compound characterized by: R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl; R2 is selected from chlorine, bromine, and nitro; X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond; R4 is selected from hydrogen, chlorine substituted at the 6' position; R5 is selected from hydrogen, methyl, cyclopropylmethyl, (1-methylpiperidin-4-yl)methyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl, ethyl, 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, 2-((3R)-3-fluoropyrrolidin-1-yl)ethyl, 2-((3R)-3-hydroxypyrrolidin-1-yl)ethyl, 2-(piperazin-1-yl)ethyl, 1-((1,4-dioxa-8-azaspiro[4.5]decane-8-yl)ethyl, 3-(dimethylamino)propyl, ((3R)-3-fluoropyrrolidin-1-yl)propyl, (1,4-dioxa-8-azaspiro[4.5]decane-8-yl)propyl, 3-methylpyridin-2-yl, But it does not include: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from 4-morpholinylmethyl and 3-(diethylamino)propyl.

5. The benzodiazepine according to claim 4 A compound characterized by: R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl; R2 is selected from chlorine, bromine; X is selected from C, R3 is selected from hydrogen, fluorine, chlorine or X is selected from N, R3 is a covalent bond; R4 is selected from hydrogen, chlorine substituted at the 6' position; R5 is selected from hydrogen, methyl, cyclopropylmethyl, (1-methylpiperidin-4-yl)methyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl, ethyl, 2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, 3-(dimethylamino)propyl, (1,4-dioxa-8-azaspiro[4.5]decan-8-yl)propyl; But not including: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from hydrogen; R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, R4 is selected from hydrogen, and R5 is selected from 3-(diethylamino)propyl.

6. The benzodiazepine according to claim 5 A compound characterized by: R1 is selected from OR6, NR7R8; R6 is selected from methyl, 2-morpholinylethyl; R7 is selected from R8 is selected from hydrogen, R9 is selected from benzyl; R2 is selected from bromine; X is selected from N, R3 is a covalent bond; R4 is selected from hydrogen; R5 is selected from hydrogen, ethyl, pyridin-4-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, (6-methylpyridin-2-yl)methyl.

7. The benzodiazepine according to claim 1 A compound characterized by: When R5 is selected from hydrogen, the benzodiazepine shown in formula I The tautomers of the compounds are shown in formula II: Wherein, R1, R2, X, R3, and R4 are as described in claim 1; But not including: R1 is selected from methoxy, R2 is selected from bromine, X is selected from N, R3 is a covalent bond, and R4 is selected from hydrogen.

8. Benzodiazepines A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, characterized in that: The benzodiazepine The compound or its tautomer is selected from the following compounds:

9. The benzodiazepine according to any one of claims 1 to 8 Use of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof in the preparation of a sedative or anesthetic drug.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition is a benzodiazepine according to any one of claims 1 to 8. A pharmaceutically acceptable dosage form prepared by using a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof as an active ingredient or main active ingredient and a pharmaceutically acceptable carrier.

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