Benzodiazepine derivative based on AI design and application thereof

Abstract

The invention discloses a benzodiazepine derivative based on AI design and application of the benzodiazepine derivative. The benzodiazepine derivative has a structure as shown in a formula I, wherein the definitions of all groups are described in the specification. The benzodiazepine derivative with the benzene ring at the tail end is used as an active component of a medicine for preventing myopia and / or inhibiting myopia development, the selectivity on M2 receptors can be remarkably improved, the inhibiting effect on M3 receptors is remarkably reduced, the IC50 ratio of M3 / M2 is remarkably increased, the myopia can be effectively treated under the condition that the pupil size is not influenced, and the application prospect is wide. And the pertinence of treatment and the comfort level of a patient can be improved.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to an AI-designed benzodiazepine derivative and its uses. Background Technology

[0002] Myopia, medically known as nearsightedness or shortsightedness, is a common vision problem and a refractive error characterized by decreased distance vision. It manifests as blurred vision when looking at distant objects, while near vision is better. This condition is usually caused by an excessively long anteroposterior axis of the eyeball, or an excessively large curvature of the cornea or lens, causing light to focus in front of the retina instead of directly on it, resulting in blurred distance vision.

[0003] Myopia disrupts the balance between accommodation and convergence, leading to symptoms such as double vision, blurred vision, eye pain, headache, nausea, eye fatigue, and dryness. Based on disease progression and pathological changes, it can be divided into two categories: simple myopia and pathological myopia. Simple myopia generally does not involve fundus changes. Pathological myopia often presents with symptoms such as protruding eyeballs, a deeper anterior chamber, large pupils with slow response, and narrow palpebral fissures. Pathological myopia also increases the risk of macular degeneration, retinal detachment, cataracts, open-angle glaucoma, and even severely impairs vision (Haarman A. et al., Invest Ophthalmol Vis Sci, 2020, 61(4):49).

[0004] In recent years, myopia has shown a trend of high incidence and younger age of onset, and has become a major public health problem in modern society (PNBaird et al., Nature reviews, 2020, 6(99): 1-20). The high incidence and younger age of onset of myopia is closely related to the popularization of video tools such as computers, mobile phones, and tablets, which leads to a significant increase in screen time and poses a serious threat to the visual health of children and adolescents.

[0005] According to a 2020 study by PNBaird et al. published in *Nature Reviews*, and the WHO's 2020 *World Report on Vision*, the number of people with myopia worldwide has reached 2.6 billion. The *China Eye Health White Paper* shows that the overall incidence of myopia among children and adolescents in my country is 53.6%, and the overall incidence among university students exceeds 90%.

[0006] Currently, methods for controlling myopia include optical correction, refractive surgery, and anticholinergic drug therapy. Among drug treatments, muscarinic receptor antagonists, represented by atropine, are considered relatively effective (Walline JJ et al., Cochrane Database Syst Rev, 2020, 1:D4916). However, reports have shown that the use of 0.01%, 0.025%, and 0.05% atropine resulted in adverse reactions such as pupillary dilation and changes in accommodation (Joachimsen L. et al., Int Ophthalmol, 2021, 41(6):2001-2008). Therefore, there is an urgent need to find drugs that can significantly reduce or completely prevent the side effects caused by mydriasis for the prevention of myopia and / or inhibition of myopia progression.

[0007] In conclusion, there is an urgent need for myopia prevention and control, but existing drugs present a trade-off between effectiveness and safety. Summary of the Invention

[0008] The purpose of this invention is to provide an active ingredient in a drug for preventing and / or inhibiting the development of myopia, which can significantly reduce or prevent mydriatic side effects, in order to provide a safer and more effective solution for the prevention and / or treatment of myopia.

[0009] To achieve the above objectives, this invention provides an AI-designed benzodiazepine derivative having the structure of Formula I:

[0010]

[0011] Wherein, A is a benzene ring or a heteroaromatic ring;

[0012] R1 is any one of hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl;

[0013] R2 is any one of hydrogen, C2-C5 alkenyl or C3-C6 cyclic hydrocarbon group;

[0014] L1 is -CH2CH2CO- or -(CH2) n -, -CH2NHCO-, -NHCH2CO-, -CH2CH2SO-, -CH2CH2O- or Any one of the following; n is any integer from 1 to 3;

[0015] L2 is -CH2CH2- or -CH2CO-;

[0016] L3 is -CH2- or -CO-;

[0017] X is a nitrogen atom or a carbon atom;

[0018] Y can be -N(R3)-, an oxygen atom, or -CH2-;

[0019] R3 is any one of H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 deuteralkyl.

[0020] Optionally, one of the methylene groups of R1 and L2 can form a C4-C7 cycloalkyl or heterocyclic structure together with the X atom to which it is attached.

[0021] Optionally, the benzodiazepine derivative has the structure of formula II:

[0022]

[0023] Wherein, R1 is any one of C1-C3 alkyl groups and C1-C3 haloalkyl groups;

[0024] R2 is any one of hydrogen, a C2-C5 alkenyl group, or a C3-C6 cyclic hydrocarbon group;

[0025] L1 is any one of -CH2CH2CO-, -(CH2)3-, -CH2NHCO-, and -NHCH2CO-; L2 is either -CH2CH2- or -CH2CO-.

[0026] L3 is -CH2- or -CO-;

[0027] R3 is any one of C1-C3 alkyl or C1-C3 deuterated alkyl.

[0028] Optionally, the benzodiazepine derivative comprises:

[0029]

[0030]

[0031] Any one of them.

[0032] The present invention also provides a pharmaceutical composition comprising: the above-mentioned AI-designed benzodiazepine derivative as an active ingredient.

[0033] Optionally, the pharmaceutical composition further comprises: pharmaceutical excipients.

[0034] The present invention also provides the use of AI-designed benzodiazepine derivatives for the preparation of drugs for preventing myopia and / or inhibiting the progression of myopia.

[0035] Optionally, the myopia includes at least one of the following: axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extremely high myopia, severe myopia, high myopia, moderate myopia, low myopia, myopia combined with glaucoma, myopia with risk of developing glaucoma, or myopia accompanied by high intraocular pressure.

[0036] Compared with the prior art, the technical solution of the present invention has at least the following beneficial effects:

[0037] Experiments have demonstrated that the benzodiazepine derivative with a terminal benzene ring, designed based on AI, provided by this invention, as the active ingredient in a drug for preventing the occurrence and / or inhibiting the development of myopia, exhibits high selectivity for M2 cells, significantly inhibiting Human M2 cells while showing little inhibition of Human M3 cells. The IC50 ratio of M3 / M2 is [not specified in the original text]. 50 The ratio is significantly higher than that of AFDX-116, an existing clinical drug for myopia. Therefore, the benzodiazepine derivative of the present invention holds promise for preventing the onset of myopia and / or inhibiting its further deterioration without causing mydriatic side effects. Detailed Implementation

[0038] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0039] M2 receptors are mainly distributed in the ciliary muscle and retina of the eye and are related to regulating the eye's focusing and refractive state. Barathi et al. (Barathi V.A. et al. Dis. Model. Mech. 2013, 6(5): 1146-1158) knocked out the muscarinic M2 receptor gene in mice. After 4-8 weeks of negative lens induction, the control group mice showed significant increases in axial length, lens depth, and vitreous cavity depth, exhibiting myopia symptoms; while the M2 gene knockout mice did not show myopia symptoms. In M2 receptor gene knockout mice, scleral collagen type I increased and type V decreased, i.e., scleral fibrosis increased, thereby inhibiting axial elongation of the eye. It can be seen that myopia can be treated or prevented by inhibiting the activity of M2 receptors. The literature also disclosed two examples of selective M2 receptor inhibitors used to inhibit the development of myopia, including AFDX-116.

[0040] M3 receptors, or muscarinic type 3 receptors, are mainly distributed on the pupillary sphincter muscle of the eye. M3 receptors are associated with the contraction of the pupillary sphincter muscle, affecting pupil size. When these receptors are activated, they cause the pupillary sphincter muscle to contract, thus constricting the pupil—a process called mydriasis. Conversely, when the activity of M3 receptors is reduced or inhibited, the contraction of the pupillary sphincter muscle weakens, causing the pupil to dilate—a process called mydriasis.

[0041] Therefore, in treating or preventing myopia, this invention aims to minimize mydriasis by maximizing the selectivity of the drug for the M2 receptor. Ideally, the drug should primarily act on the M2 receptor while having minimal impact on other muscarinic receptors (such as the M3 receptor), i.e., the IC50 ratio of M3 / M2 should be minimized. 50 The higher the ratio, the better.

[0042] In the latest developments in AI technology, artificial intelligence can be used for the discovery, screening, and optimization of small molecule drugs. By integrating AI computing tools, databases (such as the CAS compound library), and receptor-ligand complex interaction information into efficient molecular / atomic training sets and AI digital workflows, and combining them with BT technologies (bioinformatics, in vitro target cell bioactivity detection, etc.), new therapeutic drugs can be invented.

[0043] As is well known, in the process of drug development, traditional small molecule compounds (drugs) require a lot of time to go from seed compounds to lead compounds and then to candidate compounds (usually taking 5-6 years or even longer). However, drug development driven by artificial intelligence (AIDrug Discovery & Design, AIDD) can perform data cross-comparison, molecular docking, molecular dynamics simulation, etc. in a shorter time (usually only 3-5 months), thereby accelerating the screening or de novo design of new compounds. Its core value lies in pioneering innovation and efficiency improvement.

[0044] Based on relatively well-defined mechanisms (such as the Schrödinger equation and Gibbs free energy change), AI can search multiple, broader, and more comprehensive databases of different compounds and proteomics, quickly completing searches and cross-matches, saving significant resources previously used for wet experiments. Wet experimental data can then be fed back into the AI ​​for iterative optimization of compound structures.

[0045] This invention is based on a computational structural biology technology platform built independently using an AI (dry experiment) + BT (wet experiment) interactive fusion R&D model. It combines various cutting-edge algorithms in medicinal chemistry and quantum chemistry with deep learning, natural language processing, and pre-trained models of various neural network frameworks to generate novel molecular structures with expected functional properties. Then, based on the target-drug related binding interface, molecular modeling, molecular docking, and molecular dynamics simulation are performed to obtain the optimal receptor-ligand binding free energy function, binding constant, and dissociation constant. This optimizes the screening of candidate compounds with the best in vitro cell activity and the most suitable overall evaluation. Meanwhile, through in-depth analysis of disease / drug correlation networks, AI servers, and workstations, drug deep learning and multi-threaded collaborative simulation can be performed simultaneously and independently. Alternatively, an AI computing power cluster can be formed to process large data of libraries and candidate compounds, deeply mining libraries, structure-pharmacodynamic group relationships (QSAR), and novel drug targets, saving innovative drug development costs and shortening R&D time. This forms a new R&D path of "dry and wet combination, seamless connection" for new drug development, which is expected to become a scientific paradigm for future innovative drug development, bringing a new breakthrough in thinking and experimental innovation to the past drug development process that was extremely dependent on wet experiments, which was time-consuming, laborious, and cumbersome.

[0046] Through multiple rounds of iterative dry and wet closed-loop experiments, this invention ultimately yielded a series of benzodiazepine derivatives with the structure of Formula I:

[0047]

[0048] Wherein, A is a benzene ring or a heteroaromatic ring;

[0049] R1 is any one of hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl;

[0050] R2 is any one of hydrogen, C2-C5 alkenyl or C3-C6 cyclic hydrocarbon group;

[0051] L1 is -CH2CH2CO- or -(CH2) n -, -CH2NHCO-, -NHCH2CO-, -CH2CH2SO-, -CH2CH2O- or Any one of the following; n is any integer from 1 to 3;

[0052] L2 is -CH2CH2- or -CH2CO-;

[0053] L3 is -CH2- or -CO-;

[0054] X is a nitrogen atom or a carbon atom;

[0055] Y can be -N(R3)-, an oxygen atom, or -CH2-;

[0056] R3 is any one of H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 deuteralkyl.

[0057] Optionally, one of the methylene groups of R1 and L2 can form a C4-C7 cycloalkyl or heterocyclic structure together with the X atom to which it is attached.

[0058] Optionally, the benzodiazepine derivative has the structure of formula II:

[0059]

[0060] Wherein, R1 is any one of C1-C3 alkyl groups and C1-C3 haloalkyl groups;

[0061] R2 is any one of hydrogen, a C2-C5 alkenyl group, or a C3-C6 cyclic hydrocarbon group;

[0062] L1 is any one of -CH2CH2CO-, -(CH2)3-, -CH2NHCO-, and -NHCH2CO-;

[0063] L2 is -CH2CH2- or -CH2CO-;

[0064] L3 is -CH2- or -CO-;

[0065] R3 is any one of C1-C3 alkyl or C1-C3 deuterated alkyl.

[0066] The present invention also provides a pharmaceutical composition comprising: the above-mentioned AI-designed benzodiazepine derivative as an active ingredient, and pharmaceutical excipients.

[0067] The present invention also provides the use of AI-designed benzodiazepine derivatives, which can be used to prepare drugs for preventing myopia and / or inhibiting the progression of myopia.

[0068] Terminology Definition

[0069] The term "C1-C3 alkyl" as used in this invention refers to straight-chain, branched, or cyclic alkyl groups having 1 to 3 carbon atoms. Examples of straight-chain alkyl groups include methyl, ethyl, and n-propyl; examples of branched alkyl groups include, but are not limited to, isopropyl; and examples of cyclic alkyl groups include, but are not limited to, cyclopropyl.

[0070] The "C2-C5 alkenyl" as described in this invention refers to a hydrocarbon group containing 2 to 5 carbon atoms and at least one carbon-carbon double bond. The alkenyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from one or more substituents selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0071] The "C3-C6 cyclic hydrocarbon group" mentioned in this invention refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent containing 3 to 6 carbon atoms. Non-limiting examples of cyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl.

[0072] The "heteroaromatic ring" as described in this invention refers to a heteroaromatic system containing 1 to 3 heteroatoms and 5 to 8 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaromatic rings include furanyl, thiopheneyl, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.

[0073] In this invention, "substituted" means that an organic group (containing one or more bonds bonded to a hydrogen atom) as defined herein is replaced by one or more bonds bonded to a non-hydrogen atom or group of atoms, wherein the non-hydrogen atom or group of atoms is a substituent.

[0074] This invention further provides isotope-labeled compounds of the compounds of this invention. The term "isotope-labeled compound" refers to the compound described herein, wherein one or more atoms are replaced by isotope atoms whose atomic mass or mass number differs from that of naturally occurring atoms. Suitable radionuclides may include, but are not limited to, 2H (deuterium, also written as D), 3H (tritium, also written as T), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, and 131I. The type of radioisotope contained in the isotope-labeled compound will depend on the specific application of the isotope-labeled compound. For example, for labeling and competition assays of in vitro IDO enzymes, compounds containing 3H, 14C, 82Br, 125I, 131I, or 35S are generally most useful. For isotope imaging applications, 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br, or 77Br are generally most useful.

[0075] The methods known in the prior art for labeling organic compounds with radioactive isotopes are also applicable to the compounds of the present invention.

[0076] When administered as a drug, the compound can be delivered in the form of a pharmaceutical composition. Therefore, in another aspect, this application provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0077] The term "composition" as used herein means a product containing a compound disclosed in this application or a pharmaceutically acceptable salt thereof as a specific active ingredient, as well as any other product directly or indirectly combined with said active ingredient.

[0078] Typically, the pharmaceutical composition contains at least one pharmaceutically acceptable carrier or excipient. The term "pharmaceutically acceptable" means that the carrier or excipient is compatible with other components in the formulation and is harmless to the subject. The carrier referred to herein is a substance used to improve the selectivity, efficacy, and / or safety of the drug during delivery. The carrier is primarily used to control drug release and may also be used to improve the pharmacokinetic properties of the drug, particularly bioavailability. The excipient refers to any substance in the pharmaceutical formulation other than the active ingredient, primarily used for long-term stability, filling solid dosage forms (fillers), or enhancing product efficacy (e.g., promoting absorption, reducing viscosity, or increasing solubility).

[0079] The term "myopia" as used in this article includes at least one of the following: axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, high myopia, severe myopia, high myopia, moderate myopia, low myopia, myopia combined with glaucoma, myopia with a risk of developing glaucoma, or myopia accompanied by high intraocular pressure. Among these, high myopia, severe myopia, high myopia, moderate myopia, and low myopia are categories of myopia based on differences in refractive error. In this article, high myopia is defined as having a refractive error of -10.00D or lower; severe myopia as having a refractive error between -6.00D and -9.99D; high myopia as having a refractive error between -4.00D and -5.99D; moderate myopia as having a refractive error between -2.00D and -3.99D; and low myopia as having a refractive error between -0.50D and -1.99D.

[0080] Unless otherwise specified, the experimental methods used in the following examples were performed under conventional or manufacturer-recommended conditions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0081] The full names of the reagent abbreviations used in the examples are as follows:

[0082] TEA: Triethylamine

[0083] DMSO: Dimethyl sulfoxide

[0084] TFA: Trifluoroacetic acid

[0085] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate

[0086] DIEA: N,N-Diisopropylethylamine.

[0087] Example 1: Preparation of Compound 1

[0088]

[0089] Synthetic route of compound 1:

[0090]

[0091] Step 1: Preparation of intermediate 1a

[0092] Oxaloyl chloride (960 mg, 7.6 mmol) was dissolved in dichloromethane (10 mL). Dimethyl sulfoxide (720 mg, 9.2 mmol) dissolved in dichloromethane (2 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 25 min. Then, ethyl(2-hydroxyethyl)carbamate tert-butyl ester (1 g, 5.4 mmol) dissolved in dichloromethane (8 mL) was added dropwise. The mixture was stirred at -78 °C for another 25 min. Triethylamine (1.86 g, 18.4 mmol) dissolved in dichloromethane (2 mL) was then added dropwise. The mixture was then allowed to rise to room temperature and react for 2 h. The reaction mixture was cooled to 0 °C, and benzylamine (235 mg, 2.2 mmol), acetic acid (1.94 g, 32.4 mmol), and sodium triacetoxyborohydride (1.64 g, 7.6 mmol) were added. The mixture was allowed to react at room temperature for 1 h.

[0093] Quenching was performed with 1N sodium hydroxide aqueous solution (100 mL), followed by extraction three times with ethyl acetate (50 mL). The organic phases were combined, washed twice with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 460 mg of a yellow oily intermediate 1a (yield: 30%).

[0094] LCMS:[Ms+H-Boc] + =279.2.

[0095] Step 2: Preparation of intermediate 1b

[0096] Intermediate 1a (200 mg, 0.7 mmol) was dissolved in N,N-dimethylformamide (6 mL), and deuterated iodomethane (99 mg, 0.7 mmol) and potassium carbonate (193 mg, 1.4 mmol) were added. The mixture was reacted at room temperature for 2 hours.

[0097] The reaction was quenched with water (30 mL), followed by extraction three times with ethyl acetate (20 mL). The organic phases were combined and washed three times with brine (20 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to give 104 mg of a yellow oily intermediate 1b (yield: 50%).

[0098] LCMS:[Ms+H] + =296.3.

[0099] Step 3: Preparation of intermediate 1c

[0100] Intermediate 1b (104 mg, 0.35 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise at 0 °C. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was evaporated to dryness, and the residue was azeotropically reacted with dichloromethane (30 mL) three times. Without further purification, the residue was evaporated to dryness to give 104 mg of crude yellow oily intermediate 1c, which was used directly in the next step.

[0101] LCMS:[Ms+H] + =196.2.

[0102] Step 4: Preparation of intermediate 1d

[0103] 5,11-dihydro-6H-benzopyrido[3,2-b][1,4]diazaphen-6-one (2 g, 12 mmol) and triethylamine (1.6 mL, 6 mmol) were dissolved in 1,4-dioxane (40 mL), then heated to 80 °C and ethyl 4-chloro-4-oxobutyrate (2.4 g, 11.3 mmol) was added. The mixture was reacted at 100 °C for 4 hours under nitrogen atmosphere.

[0104] The reaction was quenched with water (30 mL), followed by extraction three times with ethyl acetate (20 mL). The organic phases were combined and washed three times with brine (20 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to give 1.1 g of a white solid intermediate 1d (yield: 27%).

[0105] LCMS:[Ms+H] + =340.2.

[0106] Step 5: Preparation of intermediate 1e

[0107] Intermediate 1d (166 mg, 0.53 mmol) was dissolved in ethanol (3 mL), and 1N sodium hydroxide aqueous solution (1.5 mL) was added. The reaction mixture was reacted at room temperature for 0.5 h. The reaction mixture was then neutralized with 1N hydrochloric acid aqueous solution (1.5 mL) and evaporated to dryness. N,N-dimethylformamide was then added, and the mixture was filtered to obtain a solution of crude intermediate 1e in N,N-dimethylformamide. The filtrate was used directly in the next reaction without further purification.

[0108] LCMS:[Ms+H] + =312.1.

[0109] Step 6: Preparation of Compound 1

[0110] Intermediate 1e (166 mg, 0.53 mmol) and intermediate 1c (104 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (344 mg, 2.66 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (405 mg, 1.06 mmol) were added sequentially. The reaction was carried out at room temperature for 4 hours under nitrogen protection.

[0111] The solution was diluted with water (30 mL), then extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed three times with brine (20 mL). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by pre-HPLC to give 69 mg of compound 1 (yield: 26%).

[0112] LCMS:[Ms+H] + =489.5.

[0113] 1 H NMR (400MHz, DMSO) δ10.81 (s, 1H), 8.31 (s, 1H), 7.80 (d, J = 7.5Hz, 1H), 7. 76–7.60(m,2H),7.53–7.36(m,3H),7.32–7.11(m,5H),3.60–3.40(m,2H), 3.30–3.22(m,2H),3.16(dd,J=13.9,7.1Hz,1H),2.85–2.70(m,1H),2.48– 2.40(m,1H),2.41–2.26(m,1H),2.20–2.00(m,1H),0.98(t,J=7.0Hz,3H).

[0114] Example 2: Preparation of Compound 2

[0115]

[0116] Synthetic route of compound 2:

[0117]

[0118] Step 1: Preparation of intermediate 2a

[0119] (4-Bromobenzyl)carbamate tert-butyl ester (1 g, 3.5 mmol), cyclopropylboronic acid (361 mg, 4.2 mmol), and potassium carbonate (1.5 g, 105 mmol) were dissolved in dioxane (12 mL) and water (4 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (766 mg, 4.2 mmol). The mixture was reacted at 100 °C for 12 h under nitrogen atmosphere.

[0120] Dilute with water (40 mL), then extract three times with ethyl acetate (30 mL), combine the organic layers, wash three times with brine (30 mL), dry to anhydrous sodium sulfate, and evaporate to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give 367 mg of intermediate 2a (yield: 43%).

[0121] LCMS:[Ms+H-56] + =192.1.

[0122] Step 2: Preparation of intermediate 2b

[0123] Intermediate 2a (367 mg, 1.5 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for 1 hour under nitrogen protection. The reaction solution was evaporated to dryness. Without further purification, 220 mg of crude yellow oily intermediate 2b was obtained by evaporation. This was used directly in the next step.

[0124] LCMS:[Ms+H] + =148.2.

[0125] Step 3: Preparation of intermediate 2c

[0126] Oxaloyl chloride (333 mg, 2.6 mmol) was dissolved in ultra-dry dichloromethane (5 mL). A solution of dimethyl sulfoxide (249 mg, 3.2 mmol) in dichloromethane (3 mL) was added dropwise at -60 °C. The reaction was then carried out under nitrogen at -60 °C for 25 min. Next, a solution of ethyl(2-hydroxyethyl)carbamate tert-butyl (355 mg, 1.9 mmol) in dichloromethane (3 mL) was added dropwise, and the reaction was continued at this temperature for another 25 min. Then, a solution of triethylamine (645 mg, 6.4 mmol) in dichloromethane (3 mL) was added dropwise. The resulting mixture was reacted at room temperature under nitrogen protection for 2 h. The reaction solution was then cooled to 0 °C, and intermediate 2b (220 mg, 1.5 mmol), acetic acid (676 mg, 11.3 mmol), and sodium borohydride acetate (572 mg, 2.7 mmol) were added. The reaction was carried out under nitrogen protection at room temperature for 1 h.

[0127] The reaction mixture was diluted with 20 mL of dichloromethane and 20 mL of saturated sodium chloride solution, and the aqueous layer was washed three times with 10 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by normal-phase column chromatography (eluent: dichloromethane / methanol = 20:1) to give 181 mg of yellow oily intermediate 2c (yield: 38%).

[0128] LCMS:[Ms+H] + =319.2.

[0129] Step 4: Preparation of intermediate 2d

[0130] Intermediate 2c (181 mg, 0.6 mmol) and paraformaldehyde (512 mg, 5.7 mmol) were dissolved in methanol (5 mL), and acetic acid (171 mg, 2.9 mmol) and sodium cyanoborohydride (144 mg, 2.3 mmol) were added. The resulting mixture was reacted at room temperature under nitrogen atmosphere for 12 hours.

[0131] The reaction mixture was diluted with water (40 mL), then extracted three times with ethyl acetate (30 mL). The organic layers were combined and washed three times with brine (30 mL). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by normal-phase column chromatography (eluent: dichloromethane / methanol = 20:1) to give 187 mg of a yellow solid intermediate 2d (yield: 98%).

[0132] LCMS:[Ms+H] + =333.2.

[0133] Step 5: Preparation of intermediate 2e

[0134] Intermediate 2d (187 mg, 0.56 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was reacted at room temperature under nitrogen atmosphere for 1 hour. The reaction solution was evaporated to dryness. Without further purification, evaporation gave 220 mg of crude yellow oily intermediate 2e. This was used directly in the next step.

[0135] LCMS:[Ms+H] + =233.2.

[0136] Step 6: Preparation of Compound 2

[0137] Compound 2 was prepared from intermediate 2e (130 mg, 0.56 mmol) and intermediate 1e (174 mg, 0.56 mmol) according to step 6 of Example 1, with a yield of 17%.

[0138] LCMS:[Ms+H] + =526.4.

[0139] 1 H NMR (400MHz, DMSO) δ10.82(brs,1H),8.31(s,1H),7.81(d,J=6.6Hz,1H),7.76–7.59( m,2H),7.63–7.31(m,3H),7.12(d,J=7.1Hz,2H),6.98(d,J=7.7Hz,2H),3.59–3.40(m ,3H),3.37–3.20(m,3H),3.16(d,J=6.6Hz,1H),2.77(s,1H),2.49–2.25(m,3H),2.20 –1.98(m,4H),1.86(s,1H),1.06(t,J=6.7Hz,2H),0.91(s,3H),0.61(d,J=4.1Hz,2H).

[0140] Example 3: Preparation of Compound 3

[0141]

[0142] Synthetic route of compound 3:

[0143]

[0144] Step 1: Preparation of intermediate 3a

[0145] Intermediate 3a was prepared from tert-butyl (3-bromobenzyl)carbamate (1 g, 3.5 mmol) and cyclopropylboronic acid (361 mg, 4.2 mmol) according to the method in step 1 of Example 2, yield: 45%.

[0146] LCMS:[Ms+H-56] + =192.2.

[0147] Step 2: Preparation of intermediate 3b

[0148] Intermediate 3b was prepared from intermediate 3a (389 mg, 1.6 mmol) according to step 2 of Example 2. 231 mg of crude product was used directly in the next step without further purification.

[0149] LCMS:[Ms+H] + =148.2.

[0150] Step 3: Preparation of intermediate 3c

[0151] Intermediate 3c was prepared from tert-butyl ethyl (2-hydroxyethyl)carbamate (297 mg, 1.6 mmol) and intermediate 3b (231 mg, 1.6 mmol) according to step 3 of Example 2, yield: 55%.

[0152] LCMS:[Ms+H] + =319.2.

[0153] Step 4: Preparation of 3D intermediates

[0154] Intermediate 3d was prepared from intermediate 3c (281 mg, 0.9 mmol) and paraformaldehyde (794 mg, 8.8 mmol) according to step 4 of Example 2, with a yield of 57%.

[0155] LCMS:[Ms+H] + =333.2.

[0156] Step 5: Preparation of intermediate 3e

[0157] Intermediate 3e was prepared from intermediate 3d (166 mg, 0.5 mmol) according to step 5 of Example 2. 116 mg of crude product was used directly in the next step without further purification.

[0158] LCMS:[Ms+H] + =233.2.

[0159] Step 6: Preparation of Compound 3

[0160] Compound 3 was prepared from intermediate 3e (116 mg, 0.5 mmol) and intermediate 1e (156 mg, 0.5 mmol) according to step 6 of Example 1, with a yield of 9%.

[0161] LCMS:[Ms+H] + =526.4.

[0162] 1 H NMR (400MHz, CDCl3) δ9.05–8.67(m,1H),8.34(s,1H),7.97(d,J=7.1Hz,1H),7.58(dd,J=26.3,7.4Hz,3H ),7.42(s,1H),7.29(dd,J=7.6,4.8Hz,1H),7.22–7.10(m,1H),7.09–6.96(m,2H),6.92(d,J=7.4Hz,1H), 3.63–3.20(m,6H),3.14–2.87(m,1H),2.85–2.67(m,1H),2.68–2.33(m,4H),2.24(d,J=8.9Hz,3H),1.92– 1.80(m,1H),1.13(t,J=7.0Hz,1.7H),1.00(t,J=7.0Hz,1.3H),0.95–0.83(m,2H),0.67(d,J=4.8Hz,2H).

[0163] Example 4: Preparation of Compound 4

[0164]

[0165] Synthetic route of compound 4:

[0166]

[0167] Step 1: Preparation of intermediate 4a

[0168] Intermediate 4a was prepared from intermediate 1a (200 mg, 0.7 mmol) and paraformaldehyde (630 mg, 7 mmol) according to step 4 of Example 2, with a yield of 79%.

[0169] LCMS:[Ms+H] + =293.2.

[0170] Step 2: Preparation of intermediate 4b

[0171] Intermediate 4b was prepared from intermediate 4a (150 mg, 0.52 mmol) according to step 5 of Example 2. The 150 mg crude product was used directly in the next step without further purification.

[0172] LCMS:[Ms+H]+=193.1.

[0173] Step 3: Preparation of intermediate 4c

[0174] Intermediate 4b (166 mg, 0.78 mmol) and (tert-butoxycarbonyl)glycine (136 mg, 0.78 mmol) were dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (500 mg, 3.9 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (600 mg, 1.56 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours under nitrogen protection.

[0175] Water (30 mL) was added, followed by extraction three times with dichloromethane (20 mL). The organic phases were combined and washed three times with brine (20 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1) to give 200 mg of intermediate 4c (yield: 73%).

[0176] LCMS:[Ms+H]=350.3.

[0177] Step 4: Preparation of intermediate 4d

[0178] Intermediate 4d was prepared from intermediate 4c (200 mg, 0.57 mmol) according to step 5 of Example 2. The 200 mg crude product was used directly in the next step without further purification.

[0179] LCMS:[Ms+H]=250.1.

[0180] Step 5: Preparation of intermediate 4e

[0181] 5,11-dihydro-6H-benzopyrido[3,2-b][1,4]diazaphen-6-one (500 mg, 2.4 mmol) and N,N-diisopropylethylamine (620 mg, 4.8 mmol) were dissolved in 1,4-dioxane (8 mL), and 20% triphosgene (1.25 g, 4.2 mmol) dissolved in toluene was added dropwise. The mixture was reacted at 85 °C for 2 hours under nitrogen atmosphere.

[0182] Add 30 mL of 1 N sodium dihydrogen phosphate aqueous solution to the reaction solution and stir at room temperature for 1 hour. Then, evaporate the organic solvent in the system and filter. The resulting 44 mg crude product was used directly in the next step without further purification (yield: 37%).

[0183] LCMS:[Ms+H] + =274.0.

[0184] Step 6: Preparation of Compound 4

[0185] Intermediate 4e (220 mg, 0.8 mmol) and intermediate 4d (200 mg, 0.8 mmol) were dissolved in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (206 mg, 1.6 mmol) was added. The mixture was reacted at room temperature for 16 hours under nitrogen protection.

[0186] The reaction mixture was directly evaporated to dryness. The resulting residue was purified by Pre-HPLC to give 67 mg of compound 4 (yield: 17%).

[0187] LCMS:[Ms+H] + =487.3.

[0188] 1 H NMR(400MHz, CDCl3)δ9.10–8.85(m,1H),8.40(t,J=4.7Hz,1H),7.91(d,J=7.8Hz,1H), 7.67–7.53(m,2H),7.49(d,J=8.0Hz,1H),7.38(t,J=7.4Hz,1H),7.34–7.18(m,6H),7. 02–6.90(m,1H),4.15(dd,J=10.6,3.9Hz,2H),3.54(d,J=12.5Hz,3H),3.41–3.18(m,3 H), 2.70–2.48 (m, 2H), 2.28 (s, 3H), 1.16 (t, J = 7.1Hz, 1.8H), 1.04 (t, J = 7.1Hz, 1.2H).

[0189] Example 5: Preparation of Compound 5

[0190]

[0191] Synthetic route of compound 5:

[0192]

[0193] Step 1: Preparation of intermediate 5a

[0194] 5,11-dihydro-6H-benzopyrido[3,2-b][1,4]diazaphen-6-one (50 mg, 0.24 mmol) was dissolved in ultra-dry dioxane (10 mL), and triethylamine (32 mg, 0.31 mmol) and 3-chloropropionyl chloride (33 mg, 0.26 mmol) were added dropwise at 80 °C. The reaction was carried out at 100 °C for 2 hours under nitrogen protection.

[0195] The reaction was quenched by adding 10 mL of saturated sodium chloride aqueous solution to the reaction solution. Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 43 mg of intermediate 5a (yield: 67%).

[0196] LCMS:[Ms+H] + =266.1.

[0197] Step 2: Preparation of intermediate 5b

[0198] Intermediate 5a (43 mg, 0.16 mmol) was dissolved in methanol (5 mL), and ethylamine (0.24 mL, 0.48 mmol, 2 mol / L tetrahydrofuran solution) was added. The reaction mixture was reacted at room temperature for 12 hours under nitrogen protection. The reaction solution was then evaporated to dryness. Without further purification, 45 mg of crude intermediate 5b was obtained by evaporation and used directly in the next step.

[0199] LCMS:[Ms+H] + =311.1.

[0200] Step 2: Preparation of Compound 5

[0201] Intermediate 5b (45 mg, 0.15 mmol), 3-(benzyl(methyl)amino)propionic acid (30 mg, 0.15 mmol), and N,N-diisopropylethylamine (58 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (114 mg, 0.3 mmol) were added. The mixture was reacted at room temperature for 2 hours under nitrogen protection.

[0202] The reaction solution was evaporated to dryness. The resulting residue was purified by Pre-HPLC to give 20 mg of compound 5 (yield: 27%).

[0203] LCMS:[Ms+H] + =486.3.

[0204] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.29(dd,J=9.2,3.5Hz,1H),7.80(d,J=6.9Hz,1H),7.77–7.58(m,2H),7.56–7.35(m,3H),7.28(t,J=8.5Hz, 5H),3.66–3.42(m,4H),3.24–2.97(m,2H),2.77–2.53(m,2H),2.46–2.26 (m,3H),2.25–1.88(m,4H),1.00(t,J=6.5Hz,2H),0.90(t,J=6.5Hz,1H).

[0205] Example 6: Preparation of Compound 6

[0206]

[0207] Synthetic route of compound 6:

[0208]

[0209] Step 1: Preparation of intermediate 6a

[0210] 2-(benzyl(methyl)amino)ethane-1-ol (2 g, 12.1 mmol) and carbon tetrabromide (12 g, 36.3 mmol) were dissolved in dichloromethane (20 mL), and triphenylphosphine (9.5 g, 36.3 mmol) was added dropwise at 0 °C. The resulting mixture was reacted at room temperature under nitrogen atmosphere for 2 hours.

[0211] The reaction was quenched by adding water (10 mL), and then filtered through diatomaceous earth. The filtrate was dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by column chromatography to give 1.4 g of intermediate 6a (yield: 51%).

[0212] LCMS:[Ms+H-100]=230.0.

[0213] Step 2: Preparation of intermediate 6b

[0214] Intermediate 6a (500 mg, 2.2 mmol) and cyclopropylamine (150 mg, 2.6 mmol) were dissolved in acetonitrile (10 mL), followed by the addition of potassium carbonate (607 mg, 4.4 mmol). The resulting mixture was reacted at room temperature for 12 hours.

[0215] Water (40 mL) was added, followed by extraction three times with ethyl acetate (30 mL). The organic phases were combined and washed three times with brine (30 mL). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography to give 106 mg of intermediate 6b (yield: 24%).

[0216] LCMS:[Ms+H]=205.1.

[0217] Step 3: Preparation of Intermediate 6

[0218] Compound 6 was prepared from intermediate 1e (162 mg, 0.52 mmol) and intermediate 6b (106 mg, 0.52 mmol) according to step 6 of Example 1, with a yield of 18%.

[0219] LCMS:[Ms+H] + =498.4.

[0220] 1 H NMR(400MHz, CDCl3)δ8.83(s,1H),8.35(s,1H),7.97(d,J=7.5Hz,1H),7.73–7.50(m,3H),7.42(s,1H),7.34–7.27(m,4H),7 .24–7.17(m,1H),3.49(s,4H),3.12–2.72(m,3H),2.68–2.39(m,4H),2.21(s,3H),0.81(d,J=6.7Hz,2H),0.75–0.59(m,2H).

[0221] Example 7: Preparation of Compound 7

[0222]

[0223] Synthetic route of compound 7:

[0224]

[0225] Step 1: Preparation of intermediate 7a

[0226] Intermediate 7a was prepared from tert-butyl (2-(benzylamino)ethyl)carbamate (1 g, 3.99 mmol) and paraformaldehyde (240 mg, 7.99 mmol) according to step 4 of Example 2, yield: 95%.

[0227] LCMS:[Ms+H]=265.0.

[0228] Step 2: Preparation of intermediate 7b

[0229] Intermediate 7b was prepared from intermediate 7a (800 mg, 3.03 mmol) according to step 5 of Example 2. 910 mg of crude product was used directly in the next step without further purification.

[0230] LCMS:[Ms+H]=165.2.

[0231] Step 3: Preparation of intermediate 7c

[0232] Intermediate 7b (910 mg, 5.55 mmol) was dissolved in a mixed solvent of tetrahydrofuran and N,N-dimethylformamide (30 mL: 6 mL), followed by the addition of N,N-diisopropylethylamine (3.59 g, 27.75 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.29 g, 5.55 mmol). The resulting mixture was reacted at room temperature for 20 hours.

[0233] The reaction mixture was evaporated to dryness. The resulting residue was purified by column chromatography to give 460 mg of intermediate 7c (yield: 34%).

[0234] LCMS:[Ms+H]=247.0.

[0235] Step 4: Preparation of Compound 7

[0236] Compound 7 was prepared from intermediate 6b (460 mg, 1.87 mmol) and intermediate 1e (1.16 g, 3.74 mmol) according to step 6 of Example 1, yield: 3%.

[0237] LCMS:[Ms+H]=540.3.

[0238] 1 H NMR(400MHz, CDCl3)δ8.60(s,1H),8.35(s,1H),7.97(d,J=6.8Hz,1H),7.72–7.38(m,5H),7.35–7.17(m,5H),4.21– 3.80(m,2H),3.74–3.43(m,4H),2.98(brs,1H),2.85–2.69(m,1H),2.68–2.51(m,3H),2.39(brs,1H),2.27(s,3H).

[0239] Example 8: Preparation of Compound 8

[0240]

[0241] Synthetic route of compound 8:

[0242]

[0243] Step 1: Preparation of intermediate 8a

[0244] 3 g (10.45 mmol) of 11-(2-chloroacetyl)-5,11-dihydro-6H-benzopyrido[3,2-b][1,4]diazaphen-6-one was dissolved in a methanol solution of ammonia (30 mL, 210 mmol, 7 mol / L in methanol). The resulting system was reacted at 50 °C for 2 h under nitrogen atmosphere. The reaction solution was evaporated to dryness. The residue was purified by normal column chromatography to give 460 mg of intermediate 8a (yield 16%).

[0245] LCMS:[Ms+H] + =269.0.

[0246] Step 2: Preparation of Compound 8

[0247] N,N'-carbonyldiimidazole (101 mg, 0.63 mmol), intermediate 8a (168 mg, 0.63 mmol), and N,N-diisopropylethylamine (242 mg, 1.89 mmol) were dissolved in dichloromethane (10 mL) at 0 °C and reacted under nitrogen at 0 °C for 1.5 h. The reaction mixture was then added dropwise to a solution of intermediate 4b (120 mg, 0.63 mmol) and N,N-diisopropylethylamine (242 mg, 1.89 mmol) in dichloromethane (5 mL), and the resulting system was reacted under nitrogen at room temperature for 2 h. The reaction mixture was evaporated to dryness. The residue was purified by reversed-phase preparative chromatography to give 24.63 mg of compound 8 (yield 11%).

[0248] LCMS:[Ms+H] + =487.3.

[0249] 1 H NMR (400MHz, CDCl3) δ10.08(s,1H),8.30(s,1H),7.95(d,J=7.4Hz,1H),7.73–7.51(m,3H),7.43(s,1H),7.38–7.20(m,6H),6.65(s,1H),4. 39(d,J=14.2Hz,1H),3.94–3.62(m,3H),3.49–3.28(m,2H),3.20(dd,J=13.7,6.6Hz,2H),2.71(s,2H),2.38(s,3H),1.03(t,J=7.0Hz,3H).

[0250] Example 9: Preparation of Compound 9

[0251]

[0252] Synthetic route of compound 9:

[0253]

[0254] Step 1: Preparation of intermediate 9a

[0255] 2,2,2-trifluoroethyl trifluoromethanesulfonate (334 mg, 1.44 mmol) was dissolved in tetrahydrofuran (4 mL) and N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (928 mg, 7.2 mmol) and (2-(benzylamino)ethyl)(ethyl)carbamate tert-butyl ester (200 mg, 0.72 mmol) were added. The mixture was reacted at room temperature for 16 hours.

[0256] Dilute with dichloromethane (50 mL), then wash three times with water (50 mL), followed by one wash with brine (30 mL), dry to anhydrous sodium sulfate, and evaporate to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to give 140 mg of intermediate 9a (yield: 54%).

[0257] LCMS:[Ms+HB℃] + =361.2.

[0258] Step 2: Preparation of intermediate 9b

[0259] 200 mg (0.56 mmol) of tert-butyl (2-(benzyl(2,2,2-trifluoroethyl)amino)ethyl)(ethyl)carbamate was dissolved in 10 mL of dioxane. 3 mL (12 mmol) of 4N dioxane hydrochloride was added at 0 °C, and the reaction was carried out at room temperature for 4 hours under nitrogen protection. The reaction solution was evaporated to dryness. No further purification was required to obtain crude intermediate 9b, which was used directly in the next step.

[0260] LCMS:[Ms+H]=261.0.

[0261] Step 3: Preparation of Compound 9

[0262] Compound 9 was prepared from intermediate 9b (153 mg, 0.59 mmol) and intermediate 1e (183 mg, 0.59 mmol) according to step 6 of Example 1, with a yield of 13.8%.

[0263] LCMS:[Ms+H] + =554.2.

[0264] 1 H NMR (400MHz, CDCl3) δ9.64 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 6.9Hz, 1H), 7.82–6.90 ( m,9H),4.07–3.66(m,2H),3.56–3.09(m,5H),3.04–1.91(m,7H),1.62–0.75(m,3H).

[0265] 19 F NMR (377MHz, CDCl3) δ-69.60,-70.82,-72.71.

[0266] Example 10: Preparation of Compound 10

[0267]

[0268] Synthetic route of compound 10:

[0269]

[0270] Step 1: Preparation of intermediate 10a

[0271] p-Bromobenzaldehyde (500 mg, 2.70 mmol) was dissolved in toluene (15 mL) and water (3 mL), followed by the addition of cyclobutylboronic acid (324 mg, 3.24 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (198 mg, 0.27 mmol), and potassium carbonate (1.49 g, 10.81 mmol). The resulting system was reacted at 110 °C for 16 h under nitrogen protection.

[0272] The reaction mixture was filtered, and the filter cake was washed twice with ethyl acetate (20 mL). The filtrate was then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 4 / 1) to give 150 mg of intermediate 10a (yield: 34.6%).

[0273] 1 H NMR(400MHz, CDCl3)δ9.90(s,1H),7.74(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),3.72–3.38(m ,1H),2.40–2.27(m,2H),2.20–2.05(m,2H),2.05–1.97(m,1H),1.82(dd,J=18.9,9.0Hz,1H).

[0274] Step 2: Preparation of intermediate 10b

[0275] Intermediate 10a (150 mg, 0.94 mmol) was dissolved in dichloromethane (5 mL), and tert-butyl-2-aminoethyl(ethyl)carbamate (176 mg, 0.94 mmol) and acetic acid (56 mg, 0.94 mmol) were added. The mixture was reacted at room temperature under nitrogen protection for 1 hour. Then sodium triacetoxyborohydride (992 mL, 4.68 mmol) was added, and the mixture was reacted at room temperature under nitrogen protection for 16 hours.

[0276] The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL), and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, and evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 20 / 1) to give 180 mg of intermediate 10b (yield: 57.8%).

[0277] LCMS:[Ms+H] + =333.2.

[0278] Step 3: Preparation of intermediate 10c

[0279] Intermediate 10c was prepared from intermediate 10b (180 mg, 0.54 mmol) and paraformaldehyde (163 mg, 5.41 mmol) according to step 4 of Example 2, with a yield of 96.0%.

[0280] LCMS:[Ms+H] + =347.2.

[0281] Step 4: Preparation of intermediate 10d

[0282] Intermediate 10d was prepared from intermediate 10c (180 mg, 0.52 mmol) according to step 5 of Example 2. 128 mg of crude product was used directly in the next step without further purification.

[0283] LCMS:[Ms+H] + =247.2.

[0284] Step 5: Preparation of Compound 10

[0285] Compound 10 was prepared from intermediate 10d (128 mg, 1.52 mmol) and intermediate 1e (162 mg, 0.52 mmol) according to step 6 of Example 1, with a yield of 40.3%.

[0286] LCMS:[Ms+H] + =540.3.

[0287] 1 H NMR(400MHz,DMSO)δ10.83(s,1H),8.33(s,1H),7.92–7.61(m,3H),7.60–

[0288] 7.15(m,7H),4.41(s,1H),4.16(s,1H),3.70–3.46(m,4H),3.43–3.00(m,4H),2.91–2.55(m, 5H), 2.29 (d, J = 8.5Hz, 2H), 2.21–1.92 (m, 4H), 1.83 (t, J = 8.7Hz, 1H), 1.01 (t, J = 6.5Hz, 3H).

[0289] Example 11: Preparation of Compound 11

[0290]

[0291] Synthetic route of compound 11:

[0292]

[0293] Step 1: Preparation of intermediate 11a

[0294] Intermediate 11a was prepared from (4-bromobenzyl)carbamate tert-butyl ester (2 g, 7 mmol) and cyclopent-1-ene-1-boronic acid (854 mg, 7.7 mmol) according to the method of step 1 in Example 2, yield: 45%.

[0295] 1 H NMR (400MHz, CDCl3) δ7.39(d,J=8.1Hz,2H),7.22(d,J=8.0Hz,2H),6.17(s,1H),4.29(d,J= 5.3Hz,2H),2.73–2.63(m,2H),2.52(td,J=7.7,2.4Hz,2H),2.06–1.95(m,2H),1.46(s,9H).

[0296] Step 2: Preparation of intermediate 11b

[0297] (500 mg, 1.83 mmol) tert-butyl carbamate was dissolved in 10 mL of ethanol, and palladium on carbon (180 mg) was added. The mixture was reacted at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness. Crude intermediate 11b (yield: 98%) was obtained and used directly in the next step without purification.

[0298] 1H NMR (400MHz, CDCl3) δ7.20 (s, 4H), 4.28 (d, J = 5.5Hz, 2H), 3.02–2.88 (m, 1H), 2.12–1.98 (m, 2H),1.84–1.75(m,2H),1.68(ddd,J=12.2,8.1,4.5Hz,2H),1.62–1.54(m,2H),1.46(s,9H).

[0299] Step 3: Preparation of intermediate 11c

[0300] Intermediate 11c was prepared from intermediate 11b (600 mg, 2.2 mmol) according to step 2 of Example 2. The 600 mg crude product was used directly in the next step without further purification.

[0301] LCMS:[Ms+H+ACN]=217.1.

[0302] Step 4: Preparation of intermediate 11d

[0303] Intermediate 11d was prepared from tert-butyl ethyl (2-hydroxyethyl)carbamate (490 mg, 2.6 mmol) and intermediate 11c (500 mg, 2.6 mmol) according to step 3 of Example 2, with a yield of 73%.

[0304] LCMS:[Ms+H] + =347.2.

[0305] Step 5: Preparation of intermediate 11e

[0306] Intermediate 11e was prepared from intermediate 11d (600 mg, 1.7 mmol) and paraformaldehyde (510 mg, 17 mmol) according to step 4 of Example 2, with a yield of 32%.

[0307] LCMS:[Ms+H] + =361.1.

[0308] Step 5: Preparation of intermediate 11f

[0309] Intermediate 11f was prepared from intermediate 11e (200 mg, 0.55 mmol) according to step 5 of Example 2. The 200 mg crude product was used directly in the next step without further purification.

[0310] LCMS:[Ms+H] + =261.3.

[0311] Step 6: Preparation of Compound 11

[0312] Compound 11 was prepared from intermediate 11f (200 mg, 0.55 mmol) and intermediate 1e (190 mg, 0.55 mmol) according to step 6 of Example 1, with a yield of 46%.

[0313] LCMS:[Ms+H] + =554.9.

[0314] 1 H NMR (400MHz, CDCl3) δ10.42–9.37(m,1H),8.33(d,J=3.9Hz,1H),8.12–7.83(m, 1H),7.79–7.47(m,3H),7.46–6.98(m,6H),5.08(brs,2H),4.56–4.05(m,2H),4 .00–3.55(m,1H),3.53–3.09(m,3H),3.07–2.63(m,5H),2.68–2.15(m,2H),2.0 3(s,2H),1.92–1.62(m,4H),1.53(s,2H),1.39–1.19(m,1H),1.18–0.78(m,3H).

[0315] Example 12: Preparation of Compound 12

[0316]

[0317] Synthetic route of compound 12:

[0318]

[0319] Step 1: Preparation of intermediate 12a

[0320] Intermediate 12a was prepared from (4-bromobenzyl)carbamate tert-butyl ester (2 g, 7 mmol) and cyclohexyl-1-en-1-ylboronic acid (969 mg, 7.7 mmol) according to the method in step 1 of Example 2, yield: 85%.

[0321] 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.2Hz,2H),7.23–7.17(m,2H),6.10(s,1H),4.29(d,J=5.3Hz,2H),2.39(dd,J=7.9,6 .0Hz,2H),2.20(dt,J=6.1,3.6Hz,2H),1.77(ddd,J=8.4,7.7,4.2Hz,2H),1.71–1.64(m,2H),1.44(d,J=14.6Hz,9H).

[0322] Step 2: Preparation of intermediate 12b

[0323] Intermediate 12b was prepared from intermediate 12a (500 mg, 1.74 mmol) according to the method in step 1 of Example 2, with a yield of 98%.

[0324] 1 H NMR (400MHz, CDCl3) δ7.18 (q, J=8.2Hz, 4H), 4.27 (d, J=5.5Hz, 2H), 2.53–

[0325] 2.41 (m, 1H), 1.83 (d, J = 9.2Hz, 4H), 1.69 (dd, J = 38.4, 19.6Hz, 2H), 1.46 (s, 9H), 1.37 (dt, J = 15.6, 7.3Hz, 4H).

[0326] Step 3: Preparation of intermediate 12c

[0327] Intermediate 12c was prepared from intermediate 12b (500 mg, 1.73 mmol) according to step 2 of Example 2. The 500 mg crude product was used directly in the next step without further purification.

[0328] LCMS:[Ms+H+ACN]=231.2.

[0329] Step 4: Preparation of intermediate 12d

[0330] Intermediate 12d was prepared from tert-butyl ethyl (2-hydroxyethyl)carbamate (490 mg, 2.6 mmol) and intermediate 12c (500 mg, 2.6 mmol) according to step 3 of Example 2, with a yield of 21.2%.

[0331] LCMS:[Ms+H] + =361.2.

[0332] Step 5: Preparation of intermediate 12e

[0333] Intermediate 12e was prepared from intermediate 12d (160 mg, 0.44 mmol) and paraformaldehyde (132 mg, 4.4 mmol) according to step 4 of Example 2, with a yield of 50%.

[0334] LCMS:[Ms+H] + =367.3.

[0335] Step 5: Preparation of intermediate 12f

[0336] Intermediate 12f was prepared from intermediate 12e (80 mg, 0.21 mmol) according to step 5 of Example 2. The 80 mg crude product was used directly in the next step without further purification.

[0337] LCMS:[Ms+H] + =312.0.

[0338] Step 6: Preparation of Compound 12

[0339] Compound 12 was prepared from intermediate 12f (80 mg, 0.21 mmol) and intermediate 1e (66 mg, 0.21 mmol) according to step 6 of Example 1, with a yield of 36%.

[0340] LCMS:[Ms+H] + =568.9.

[0341] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.34(d,J=3.7Hz,1H),7.80(d,J=7.4Hz,1H),7.74(d, J=8.2Hz,1H),7.65(s,1H),7.55–7.43(m,2H),7.45–7.15(m,5H),4.41(dd,J=13.4,4.8Hz,1H ),4.13(dd,J=12.5,6.7Hz,1H),3.73–3.61(m,1H),3.60–3.47(m,1H),3.38–3.04(m,5H),2. 97–2.43(m,6H),2.34–1.91(m,1H),1.86–1.61(m,5H),1.63–1.27(m,5H),1.16–0.84(m,3H).

[0342] Example 13: Preparation of Compound 13

[0343]

[0344] Synthetic route of compound 13:

[0345]

[0346] Step 1: Preparation of intermediate 13a

[0347] 3 g (10.5 mmol) of tert-butyl (4-bromobenzyl)carbamate was dissolved in 20 mL of N,N-dimethylformamide, followed by the addition of tris(o-methylphenyl)phosphine (1 g, 3.29 mmol), triethylamine (5.3 g, 52.5 mmol), 3-methoxypropyl-1-ene (1.51 g, 21 mmol), and tris(dibenzylideneacetone)dipalladium (0.96 g, 1.05 mmol), and the mixture was reacted overnight at 90 °C under nitrogen protection.

[0348] The sample was filtered, the filtrate was diluted with dichloromethane (300 mL), washed five times with brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 190 mg of intermediate 13a (yield: 6.53%).

[0349] 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.1Hz,2H),7.23(d,J=8.1Hz,2H),6.59(d,J=16.0Hz,1H),6.27(dt,J=1 6, 6.0Hz, 1H), 4.83 (s, 1H), 4.30 (d, J = 7.1Hz, 2H), 4.09 (dd, J = 6.0, 1.3Hz, 2H), 3.39 (s, 3H), 1.46 (s, 9H).

[0350] Step 2: Preparation of intermediate 13b

[0351] Intermediate 13b was prepared from intermediate 13a (190 mg, 0.686 mmol) according to step 2 of Example 2. 96 mg of crude product was used directly in the next step without further purification.

[0352] LCMS:[Ms+H-17]+=161.2.

[0353] Step 3: Preparation of intermediate 13c

[0354] Intermediate 13c was prepared from tert-butyl ethyl (2-hydroxyethyl)carbamate (96 mg, 0.51 mmol) and intermediate 12c (121 mg, 0.686 mmol) according to step 3 of Example 2, with a yield of 78.8%.

[0355] LCMS:[Ms+H] + =349.1.

[0356] Step 4: Preparation of intermediate 13d

[0357] Intermediate 13d was prepared from intermediate 13c (140 mg, 0.4 mmol) and paraformaldehyde (120 mg, 4 mmol) according to step 4 of Example 2, with a yield of 19.3%.

[0358] LCMS:[Ms+H] + =363.2.

[0359] Step 5: Preparation of intermediate 13e

[0360] Intermediate 13e was prepared from intermediate 13d (28 mg, 0.077 mmol) according to step 5 of Example 2. 20 mg of crude product was used directly in the next step without further purification.

[0361] LCMS:[Ms+H] + =263.1.

[0362] Step 6: Preparation of Compound 13

[0363] Compound 13 was prepared from intermediate 13e (20 mg, 0.077 mmol) and intermediate 1e (36 mg, 0.116 mmol) according to step 6 of Example 1, with a yield of 52.3%.

[0364] LCMS:[Ms+H] + =556.1.

[0365] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),8.01–7.45(m,6H),7.43–7.31(m,5H),6.59(d,J=15.7Hz,1H),6.32(dt,J=15.1,5.4Hz ,1H),4.33–4.09(m,3H),4.00–3.80(m,1H),3.43–3.22(m,6H),2.99–2.91(m,1H),2.73–2.35(m,10H),1.35–1.24(m,3H).

[0366] Example 14: Preparation of Compound 14

[0367]

[0368] Synthetic route of compound 14:

[0369]

[0370] Step 1: Preparation of intermediate 14a

[0371] 1.00 g (4.73 mmol) of 5,11-dihydro-6H-pyrido[2,3-B][1,4]benzodiazepine-6-one was dissolved in 1,4-dioxane (100 mL), and then triethylamine (527 mg (5.21 mmol) and 4-bromobutylchloric acid (966 mg (5.21 mmol)) were added at 80 °C. The mixture was then reacted at 100 °C for 4 h under nitrogen protection.

[0372] The reaction mixture was evaporated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1). The product was then dissolved in EtOAc (300 mL), washed twice with 1 M hydrochloric acid (150 mL), and the organic phase was concentrated to give 600 mg of intermediate 14a (yield: 35.1%).

[0373] LCMS:[Ms+H] + =360.1.

[0374] Step 2: Preparation of intermediate 14b

[0375] N-(tert-butoxycarbonyl)-N-ethylglycine (1.00 g, 4.92 mmol) and N-methylbenzylamine (596 mg, 4.92 mmol) were dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (3.18 g, 24.60 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.25 g, 5.90 mmol) were added. The mixture was reacted at room temperature for 16 hours under nitrogen protection.

[0376] The reaction mixture was diluted with water (30 mL) and extracted three times with ethyl acetate (30 mL). The organic phase was washed three times with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by normal-phase column chromatography (eluent: dichloromethane / methanol = 20:1) to give 1.70 g of crude intermediate 14b.

[0377] LCMS:[Ms+H] + =307.2.

[0378] Step 3: Preparation of intermediate 14c

[0379] Intermediate 14c was prepared from intermediate 14b (390 mg, 1.27 mmol) according to step 2 of Example 2. 263 mg of crude product was used directly in the next step without further purification.

[0380] LCMS:[Ms+H]=207.2.

[0381] Step 4: Preparation of Compound 14

[0382] Intermediate 14a (450 mg, 1.25 mmol) and intermediate 14c (258 mg, 1.25 mmol) were dissolved in 1,4-dioxane (20 mL), and triethylamine (1.26 g, 12.49 mmol) and tetrabutylammonium iodide (923 mg, 2.50 mmol) were added sequentially. The mixture was reacted at 100 °C for 16 hours under nitrogen protection.

[0383] The reaction solution was directly concentrated and evaporated to dryness. The resulting residue was first purified by Pre-TLC (dichloromethane / methanol = 10 / 1) to obtain 600 mg of crude product, and then purified by Pre-HPLC to obtain 20 mg of compound 14 (yield: 3.3%).

[0384] LCMS:[Ms+H] + =486.1.

[0385] 1 H NMR (400MHz, CDCl3) δ9.46 (s, 1H), 8.38–8.23 (m, 1H), 7.92 (d, J = 5.0Hz, 1H), 7.7 4–7.58(m,2H),7.54(d,J=7.5Hz,1H),7.44(d,J=6.1Hz,1H),7.38–7.27(m,4H),7 .17(t,J=8.0Hz,2H),4.81–4.37(m,2H),4.13–3.85(m,2H),3.33–3.01(m,4H),2. 96(s,3H),2.80–2.62(m,1H),2.27(s,1H),2.04–1.83(m,2H),1.30–1.07(m,3H).

[0386] Example 15: Preparation of Compound 15

[0387]

[0388] Synthetic route of compound 15:

[0389]

[0390] Step 1: Preparation of intermediate 15a

[0391] 1-Boc-2-aminomethylpiperidine (200 mg, 0.93 mmol) was dissolved in dichloromethane (5 mL), then benzaldehyde (99 mg, 0.93 mmol) and acetic acid (28 mg, 0.47 mmol) were added. The resulting system was reacted at room temperature for 1 hour under nitrogen protection. Then sodium triacetoxyborohydride (989 g, 4.67 mmol) was added, and the resulting system was reacted at room temperature for another 5 hours under nitrogen protection.

[0392] The reaction solution was quenched with 10 mL of saturated sodium bicarbonate aqueous solution, then filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to give 230 mg of intermediate 15a (yield: 80.9%).

[0393] LCMS:[Ms+H] + =305.1.

[0394] Step 2: Preparation of intermediate 15b

[0395] Intermediate 15b was prepared from intermediate 15a (230 mg, 0.76 mmol) and paraformaldehyde (227 mg, 7.56 mmol) according to step 4 of Example 2, yielding 260 mg of crude product.

[0396] LCMS:[Ms+H] + =319.2.

[0397] Step 3: Preparation of intermediate 15c

[0398] Intermediate 15c was prepared from intermediate 15b (260 mg, 0.82 mmol) according to step 5 of Example 2. 89 mg of crude product was used directly in the next step without further purification.

[0399] LCMS:[Ms+H]+=219.1.

[0400] Step 4: Preparation of Compound 15

[0401] Compound 15 was prepared from intermediate 15c (89 mg, 0.41 mmol) and intermediate 1e (127 mg, 0.41 mmol) according to step 6 of Example 1, with a yield of 44.9%.

[0402] LCMS:[Ms+H] + =512.3.

[0403] 1 H NMR (400MHz, CDCl3) δ8.36(d,J=4.4Hz,1H),7.92(d,J=7.8Hz,1H),7.75–

[0404] 7.50(m,3H),7.48–7.28(m,7H),5.42–4.93(m,1H),4.78–3.90(m,6H),3.81 –3.44(m,2H),2.98–2.64(m,6H),2.45(d,J=13.6Hz,2H),1.52–1.11(m,3H).

[0405] Example 16: Preparation of Compound 16

[0406]

[0407] Synthetic route of compound 16:

[0408]

[0409] Step 1: Preparation of intermediate 16a

[0410] Intermediate 16a was prepared from 5,11-dihydro-6H-benzo[e]pyrido[3,2-b][1,4]diaza-6-one (3.00 g, 14.2 mmol) and 4-chlorobutyryl chloride (2.20 g, 15.6 mmol) according to step 1 of Example 14, with a yield of 68.5%.

[0411] LCMS:[Ms+H] + =316.0.

[0412] Step 2: Preparation of intermediate 16b

[0413] Intermediate 16b was prepared from (2-aminoethyl)(ethyl)carbamate tert-butyl ester (500 mg, 2.66 mmol) and benzoic acid (357 mg, 2.92 mmol) according to step 2 of Example 14, yield: 98%.

[0414] LCMS:[Ms+H] + =293.1.

[0415] Step 3: Preparation of intermediate 16c

[0416] Intermediate 16b (2.1 mg, 7.18 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (575 mg, 14.36 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0 °C, and iodomethane (2.04 g, 14.36 mmol) was added. The resulting mixture was reacted at room temperature under nitrogen atmosphere for 1 hour.

[0417] The reaction was quenched by adding ammonium chloride solution (50 mL), extracted three times with ethyl acetate (200 mL), washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by normal-phase column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 1.76 g of intermediate 16c (yield: 79.97%).

[0418] LCMS:[Ms+2+Na] + =307.1.

[0419] Step 4: Preparation of intermediate 16d

[0420] Intermediate 16d was prepared from intermediate 16c (1.76 g, 5.72 mmol) according to step 2 of Example 2. 600 mg of crude product was used directly in the next step without further purification.

[0421] LCMS:[Ms+H]=207.2.

[0422] Step 5: Preparation of Compound 16

[0423] Compound 16 was prepared from intermediate 16a (130 mg, 2.46 mmol) and intermediate 16d (600 mg, 2.46 mmol) according to step 4 of Example 14, yield: 3.88%.

[0424] LCMS:[Ms+H] + =486.1.

[0425] 1 H NMR (400MHz, CDCl3) δ8.32(s,1H),7.94(d,J=7.4Hz,1H),7.71–7.53(m,3H),7.49–7.27(m,7H),3.76–3.11(m,3H),3.05–2.92( m,2H),2.64(s,1H),2.55–2.13(m,7H),1.90–1.71(m,1H),1.39–1.17(m,1H),1.09(s,1H),0.96(t,J=6.9Hz,1H),0.73(s,1H).

[0426] Example 17: Preparation of Compound 17

[0427]

[0428] Synthetic route of compound 17:

[0429]

[0430] Step 1: Preparation of intermediate 17a

[0431] 2-Chloro-3-nitropyridine (4.00 g, 25.23 mmol) was dissolved in tert-butanol (50 mL), followed by the addition of methyl 4-amino-5-methylthiophene-3-carboxylate (2.16 g, 12.62 mmol) and trifluoroacetic acid (8.63 g, 75.69 mmol). The resulting mixture was reacted at 100 °C for 22 hours under nitrogen atmosphere.

[0432] The reaction solution was directly evaporated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 800 mg of intermediate 17a (yield: 21.60%).

[0433] LCMS:[Ms+H] + =294.0.

[0434] Step 2: Preparation of intermediate 17b

[0435] Intermediate 17a (800 mg, 2.73 mmol) was dissolved in acetic acid (30 mL), and iron powder (1.52 g, 27.28 mmol) was added. The resulting mixture was reacted at 60 °C for 16 hours under nitrogen atmosphere.

[0436] The reaction mixture was quenched with water (50 mL), followed by extraction three times with dichloromethane (50 mL). The organic layers were combined and washed once with brine (100 mL). The mixture was dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by normal-phase column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give 300 mg of intermediate 17b (yield: 47.56%).

[0437] LCMS:[Ms+H] + =232.0.

[0438] Step 3: Preparation of intermediate 17c

[0439] Intermediate 17c was prepared from intermediate 17b (300 mg, 1.30 mmol) and succinic acid monoethyl ester chloride (235 mg, 1.43 mmol) according to the method in step 1 of Example 14, with a yield of 98.7%.

[0440] LCMS:[Ms+2+Na] + =360.0.

[0441] Step 4: Preparation of intermediate 17d

[0442] Intermediate 17c (150 mg, 0.42 mmol) was dissolved in dichloromethane (10 mL), and a 1 N boron tribromide solution (6.26 mL, 6.26 mmol) in dichloromethane was added. The mixture was reacted at room temperature for 20 hours.

[0443] The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (20 mL) and discarded. The aqueous phase was adjusted to pH 5 with concentrated hydrochloric acid and then extracted three times with dichloromethane (30 mL). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give 70 mg of crude intermediate 17d. No further purification was performed, and it was used directly in the next reaction.

[0444] LCMS:[Ms+H]+ =332.0.

[0445] Step 5: Preparation of Compound 17

[0446] Compound 17 was prepared from intermediate 17d (75 mg, 0.23 mmol) and intermediate 4b (60 mg, 0.39 mmol) according to step 6 of Example 1, with a yield of 18.5%.

[0447] LCMS:[Ms+H] + =506.1.

[0448] 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.54(d,J=5.2Hz,1H),8.22(t,J=5.6Hz,2H),7.29–7.16(m,5H),6.70(td,J=7.2,3.5Hz,1H),3.52(d,J=6.2Hz ,1H),3.47–3.39(m,5H),3.26–3.21(m,1H),2.83(d,J=4.7Hz,3H),2.79– 2.66(m,4H),2.42(t,J=6.7Hz,1H),2.22–2.07(m,3H),1.15–0.94(m,3H).

[0449] Example 18: Preparation of Compound 18

[0450]

[0451] Synthetic route of compound 18:

[0452]

[0453] Step 1: Preparation of intermediate 18a

[0454] 5-Fluoro-2-nitrobenzoic acid (10 g, 54 mmol) and 2-chloropyridin-3-amine (7 g, 54 mmol) were dissolved in ultra-dry dichloromethane (250 mL). Pyridine (42.66 g, 540 mmol) and phosphorus oxychloride (41.3 g, 270 mmol) were added at 0 °C. The resulting system was reacted at room temperature under nitrogen atmosphere for 2 hours.

[0455] The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by normal-phase column chromatography (PE / EA = 4 / 1) to give 5 g of intermediate 18a (yield: 31%).

[0456] LCMS:[Ms+H]=295.9.

[0457] Step 2: Preparation of intermediate 18b

[0458] Intermediate 18a (296 mg, 1 mmol) and ammonium chloride (265 mg, 5 mmol) were dissolved in methanol (5 mL) and water (5 mL), and iron powder (280 g, 5 mmol) was added. The resulting mixture was reacted at 70 °C for 1.5 hours under nitrogen atmosphere.

[0459] The filtrate was filtered, and the methanol in the filtrate was evaporated to dryness. The pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness. No further purification was required to obtain 235 mg of intermediate 18b, which was used directly in the next step.

[0460] LCMS:[Ms+H]=266.0.

[0461] Step 3: Preparation of intermediate 18c

[0462] Intermediate 18b (235 mg, 0.884 mmol) was dissolved in n-butanol (13 mL), and sulfuric acid (0.57 mL) was added dropwise to the reaction solution at 0 °C. The system was reacted at 120 °C for 1.5 h. The reaction solution was diluted with ethyl acetate (100 mL), and the organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by normal-phase column chromatography (DCM / MeOH = 40 / 1) to give 167 mg of intermediate 18c (yield: 82.6%).

[0463] LCMS:[Ms+H]=230.1.

[0464] Step 4: Preparation of intermediate 18d

[0465] Intermediate 18d was prepared from intermediate 18c (300 mg, 1.30 mmol) and succinic acid monoethyl ester chloride (102 mg, 0.62 mmol) according to the method in step 1 of Example 14, with a yield of 98%.

[0466] LCMS:[Ms+H] + =358.0.

[0467] Step 5: Preparation of intermediate 18e

[0468] Intermediate 18e was prepared from intermediate 18d (150 mg, 0.42 mmol) according to step 5 of Example 1. A DMF solution containing 138 mg of intermediate 18e was used directly in the next step.

[0469] LCMS:[Ms+H]=330.0.

[0470] Step 6: Preparation of Compound 18

[0471] Compound 18 was prepared from intermediate 18e (138 mg, 0.42 mmol) and intermediate 2e (97.4 mg, 0.42 mmol) according to step 6 of Example 1, with a yield of 11.4%.

[0472] LCMS:[Ms+H]=544.1.

[0473] 1 H NMR(400MHz, CDCl3)δ9.74(s,1H),8.65–8.39(m,2H),8.03(dd,J=8.4,2.4Hz,1H),7.82(dt,J=9.1,4.5Hz,1H),7 .66–7.50(m,1H),7.15(dd,J=13.4,8.0Hz,2H),6.99(dd,J=10.0,8.2Hz,2H),6.88(td,J=7.4,2.7Hz,1H),3.51(d d,J=13.6,9.7Hz,3H),3.44–3.27(m,3H),2.99–2.85(m,2H),2.78(dt,J=18.1,6.4Hz,2H),2.56(t,J=7.0Hz,2H), 2.25(s,3H),1.85(ddd,J=13.4,8.5,5.1Hz,1H),1.13(t,J=7.1Hz,3H),0.97–0.87(m,2H),0.65(q,J=4.9Hz,2H).

[0474] Example 19: Preparation of Compound 19

[0475]

[0476] Synthetic route of compound 19:

[0477]

[0478] Step 1: Preparation of intermediate 19a

[0479] 14 g (50.02 mmol) of 3,5-dibromobenzoic acid was dissolved in 100 mL of concentrated sulfuric acid, and then fuming nitric acid (4.73 g (75.02 mmol) was slowly added at room temperature. The reaction was carried out at room temperature for 2 hours under nitrogen protection. The reaction solution was then slowly poured into 1 L of stirred ice water, and a large amount of pale yellow solid precipitated.

[0480] The solid was filtered, rinsed twice with water (200 ml), and the filter cake was dried to obtain 15 g of intermediate 19a (yield: 92.3%).

[0481] LCMS:[Ms+H] + =323.7.

[0482] Step 2: Preparation of intermediate 19b

[0483] Intermediate 19b was prepared from intermediate 19a (5.00 g, 15.39 mmol) and 3-amino-2-chloropyridine (1.98 g, 15.39 mmol) according to step 1 of Example 18, with a yield of 73.1%.

[0484] LCMS:[Ms+H] + =435.8.

[0485] Step 3: Preparation of intermediate 19c

[0486] Intermediate 19c was prepared from intermediate 19b (4.90 g, 11.25 mmol) according to step 2 of Example 18, with a yield of 39.4%.

[0487] LCMS:[Ms+2+H] + =405.8.

[0488] Step 4: Preparation of intermediate 19d

[0489] Intermediate 19d was prepared from intermediate 19c (1.00 g, 2.47 mmol) according to step 3 of Example 18, with a yield of 48.8%.

[0490] LCMS:[Ms+2+H] + =369.9.

[0491] Step 5: Preparation of intermediate 19e

[0492] Intermediate 19e was prepared from intermediate 19d (400 mg, 1.08 mmol) and succinic acid monoethyl ester chloride (196 mg, 1.19 mmol) according to the method in step 1 of Example 14, yield: 89%.

[0493] LCMS:[Ms+Na] + =519.9.

[0494] Step 6: Preparation of intermediate 19f

[0495] Intermediate 19f was prepared from intermediate 19e (150 mg, 0.30 mmol) according to step 5 of Example 1. A DMF solution containing 141 mg of intermediate 19f was used directly in the next step.

[0496] LCMS:[Ms+H]+ =470.0.

[0497] Step 7: Preparation of Compound 19

[0498] Compound 19 was prepared from intermediate 19f (141 mg, 0.30 mmol) and intermediate 2e (70 mg, 0.30 mmol) according to step 6 of Example 1, with a yield of 15.15%.

[0499] LCMS:[Ms+2+H] + =684.1.

[0500] 1 H NMR (400MHz, CDCl3) δ9.71(d,J=6.4Hz,1H),8.66(t,J=6.8Hz,1H),8.54(dd,J=5.8,1.7Hz,2H),8.22(d,J =2.2Hz,1H),7.18(d,J=8.1Hz,2H),7.04–6.94(m,3H),3.64–3.51(m,1H),3.46–3.39(m,1.5H),3.34(q,J= 7.1Hz,0.5H),2.99–2.87(m,2H),2.86–2.71(m,2H),2.58(t,J=6.7Hz,0.5H),2.30(s,2.5H),1.92–1.79( m,1H),1.76–1.53(m,1H),1.40–1.17(m,4H),1.06(t,J=7.1Hz,1H),0.98–0.90(m,2H),0.75–0.61(m,2H).

[0501] Example 20: Preparation of Compound 20

[0502]

[0503] Synthetic route of compound 20:

[0504]

[0505] Step 1: Preparation of intermediate 20a

[0506] 1 g of 2-chloro-6-nitrobenzoic acid (5 mmol) was dissolved in thionyl chloride (5 mL) and reacted at 70 °C for 2 h under nitrogen atmosphere. The mixture was evaporated to dryness, then dissolved in dichloromethane (25 mL), and a methanol solution of ammonia (7 mol / L, 7.14 mL) was added at 0 °C. The resulting system was reacted at room temperature under nitrogen atmosphere for 2 h. The mixture was evaporated to dryness. Without further purification, 1.27 g of intermediate 19a was given and used directly in the next step.

[0507] LCMS:[Ms+H]=201.0.

[0508] Step 2: Preparation of intermediate 20b

[0509] 2-Chloro-6-nitrobenzamide (1.16 g, 5.8 mmol) was dissolved in dioxane (40 mL), followed by the sequential addition of 2-chloro-3-iodopyridine (7 g, 54 mmol), ethylenediamine (52.2 mg, 0.87 mmol), potassium phosphate (2.46 g, 11.6 mmol), and cuprous iodide (165.3 mg, 0.87 mmol). The resulting system was reacted overnight at 105 °C under nitrogen atmosphere. The reaction mixture was evaporated to dryness. The residue was purified by normal column chromatography to give 200 mg of intermediate 20b (yield: 11.08%).

[0510] LCMS:[Ms+H]=312.0.

[0511] Step 3: Preparation of intermediate 20c

[0512] Intermediate 20c was prepared from intermediate 20b (220 mg, 0.705 mmol) according to step 2 of Example 18, with a yield of 98%.

[0513] LCMS:[Ms+H]=281.9.

[0514] Step 4: Preparation of intermediate 20d

[0515] Intermediate 20d was prepared from intermediate 20c (235 mg, 0.833 mmol) according to step 3 of Example 18, with a yield of 73.3%.

[0516] LCMS:[Ms+H]=246.0.

[0517] Step 5: Preparation of intermediate 20e

[0518] Intermediate 20e was prepared from intermediate 20d (174 mg, 0.7 mmol) and succinic acid monoethyl ester chloride (128.4 mg, 0.778 mmol) according to the method in step 1 of Example 14, yield: 98%.

[0519] LCMS:[Ms+H] + =374.0.

[0520] Step 6: Preparation of intermediate 20f

[0521] Intermediate 20f was prepared from intermediate 20e (100 mg, 0.267 mmol) according to step 5 of Example 1. A DMF solution containing 92 mg of intermediate 20f was used directly in the next step.

[0522] LCMS:[Ms+H] + =470.0.

[0523] Step 7: Preparation of Compound 20

[0524] Compound 20 was prepared from intermediate 20f (92 mg, 0.267 mmol) and intermediate 2e (62 mg, 0.267 mmol) according to step 6 of Example 1, with a yield of 23.22%.

[0525] LCMS:[Ms+H]=560.0.

[0526] 1 H NMR(400MHz, CDCl3) δ9.58(s,1H),8.56(dd,J=11.4,4.0Hz,2H),7.77–7.58(m,2H),7.48(dd,J=7.1,1 .6Hz,1H),7.24(d,J=8.1Hz,2H),7.04(d,J=8.1Hz,2H),6.88(t,J=7.4Hz,1H),4.36(s,1H),4.06(s,1H ),3.90–3.70(m,2H),3.45(dd,J=14.2,7.1Hz,2H),3.37–3.12(m,3H),2.95(t,J=6.0Hz,2H),2.86–2.7 6(m,2H),2.70(s,3H),1.93–1.77(m,1H),1.24(t,J=7.1Hz,3H),1.05–0.91(m,2H),0.71–0.55(m,2H).

[0527] Example 21: Preparation of compound 21

[0528]

[0529] Synthetic route of compound 21:

[0530]

[0531] Step 1: Preparation of intermediate 21a

[0532] (2-(benzyloxy)ethyl)(ethyl)carbamate tert-butyl ester (378 mg, 2 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (96 mg, 4 mmol) was added at 0 °C, and then the mixture was stirred at room temperature for 1 hour. Benzyl bromide (512 mg, 3 mmol) was then added, and the resulting mixture was reacted at room temperature under nitrogen atmosphere for 1 hour.

[0533] The reaction was quenched by adding ammonium chloride solution (10 mL), followed by extraction with dichloromethane. The organic layer was washed five times with brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by column chromatography to give 325 mg of intermediate 21a (yield: 58%).

[0534] LCMS:[Ms+H]=280.1.

[0535] Step 2: Preparation of intermediate 21b

[0536] Intermediate 21b was prepared from intermediate 21a (100 mg, 0.358 mmol) according to step 2 of Example 2. 64 mg of crude product was used directly in the next step without further purification.

[0537] LCMS:[Ms+H]=180.2.

[0538] Step 3: Preparation of Compound 21

[0539] Compound 21 was prepared from intermediate 21b (64 mg, 0.358 mmol) and intermediate 1e (111.5 mg, 0.358 mmol) according to step 6 of Example 1, with a yield of 31.26%.

[0540] LCMS:[Ms+H]=473.1.

[0541] 1 H NMR (400MHz, CDCl3) δ8.91(s,1H),8.35(s,1H),7.95(d,J=6.6Hz,1H),7.62(d,J=9.8Hz,3H),7.43(d,J=4.8Hz,1H),7.31(dd,J=14.9, 8.8Hz,5H),4.47(s,2H),3.57(d,J=5.3Hz,2H),3.51(s,1H),3.47–3.34(m,2H),2.97–2.52(m,3H),2.21(s,2H),1.10(d,J=6.8Hz,3H).

[0542] Example 22: Preparation of compound 22

[0543]

[0544] Synthetic route of compound 22:

[0545]

[0546] Step 1: Preparation of intermediate 22a

[0547] 4-Phenylacet-1-amine (2 g, 13.4 mmol) was dissolved in ultradry dichloromethane (8 mL), triethylamine (4.07 g, 40.2 mmol) was added, and then acetyl chloride (2.1 g, 26.8 mmol) was added at 0 °C. The resulting mixture was reacted at room temperature under nitrogen atmosphere for 2 hours.

[0548] The reaction mixture was poured into a saturated sodium chloride solution (50 mL), and then extracted three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 1.1 g of intermediate 22a (yield: 42.9%).

[0549] LCMS:[Ms+H] + =192.2.

[0550] Step 2: Preparation of intermediate 22b

[0551] Intermediate 22a (899 mg, 4.7 mmol) was dissolved in ultra-dry tetrahydrofuran (15 mL), and lithium aluminum hydride (893 mg, 23.5 mmol) was added at 0 °C. The resulting mixture was reacted overnight at 60 °C under nitrogen atmosphere.

[0552] The reaction solution was cooled to 0°C, and the reaction was quenched by adding sodium sulfate decahydrate (10 g). The mixture was extracted with ethyl acetate (50 mL), and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 428 mg of intermediate 22b (yield: 51.36%).

[0553] LCMS:[Ms+H]=178.2.

[0554] Step 3: Preparation of Compound 22

[0555] Compound 22 was prepared from intermediate 22b (100 mg, 0.565 mmol) and intermediate 1e (176 mg, 0.565 mmol) according to step 6 of Example 1, with a yield of 13.72%.

[0556] LCMS:[Ms+H]=471.2.

[0557] 1H NMR (400MHz, CDCl3) δ9.50 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 7.1Hz, 1H), 7.62 (s, 3H), 7.41 (s, 1H), 7.28 (s, 1H), 7.26 –7.06(m,5H),3.27(dd,J=14.5,7.3Hz,4H),3.09–2.55(m,5H),2.45(s,1H),1.64–1.48(m,4H),1.20–0.98(m,3H).

[0558] Example 23: Detection of the inhibitory activity of the compound against Human M2 and M3 receptors

[0559] Experimental Principle

[0560] Using CHO cell lines that stably express Human M2 and Human M3 respectively, the effects of compounds on the activity of Human M2 and Human M3 receptors were determined using the FLIPR Calcium6Assay Kit. The effects of the test substances on Human M2 and Human M3 were studied based on changes in cell signal intensity, and the corresponding concentration-response curves were calculated.

[0561] Experimental reagents, consumables and instruments are shown in Tables 1 and 2.

[0562] Table 1: Information on the Sources of Reagents and Consumables

[0563]

[0564] Table 2: Instrument Information

[0565]

[0566]

[0567] Cell Information

[0568] 1. Human M2-CHO and Human M3-CHO cell lines were cultured in F-12 medium containing 10% fetal bovine serum (Fetal Bovine Serum, AusGeneX, FBS500-S) and 0.2 mg / mL Hygromycin B (Solarbio, H8080-1g) at 37°C and 5% carbon dioxide.

[0569] 2. Cell passage: Remove the old culture medium in a biosafety cabinet and wash once with PBS. Then add 1 mL of 0.25% Trypsin-EDTA (Gibco, 25200-072) solution and incubate at 37°C for 2 minutes. When the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 minutes.

[0570] 3. To maintain the physiological activity of the cells, the confluence of the experimental cells was controlled at around 80% under an inverted microscope (Olympus, CKX53).

[0571] Experimental steps

[0572] 1. Cell Plating: Human M2-CHO and Human M3-CHO cells were digested and collected, resuspended, counted, and seeded into 384-well cell culture plates (Corning, 3764) at a density of 1.2 × 10⁻⁶ cells / well. 4 Cells / 25μL / well. Then incubate the cell plate at 37°C in a 5% CO2 incubator for approximately 16-20 hours;

[0573] 2. Day 2: Prepare the Assay Buffer (20mM HEPES + 1×HBSS) according to the FLIPR Calcium 6 Assay Kit (Molecular Devices, R8191) instructions. After freezing and thawing 20×Component A to room temperature, dilute it to 1×loading buffer with the Assay Buffer and store at room temperature.

[0574] 3. Remove the culture medium from the cell plate, quickly add 35 μL of the above 1× loading buffer to each well, centrifuge using a microplate centrifuge at low speed, and then incubate the cell plate at 37°C in the dark for 120 minutes.

[0575] 4. Prepare working solutions of positive and test compounds in 96-well dilution plates (Biosen, P-0.6-BSA-96-S), and transfer 5 μL into the corresponding cell wells. Incubate at 37°C in the dark for 30 minutes.

[0576] 5. Prepare the agonist working solution and transfer 20 μL / well to a 384-well compound plate (Corning, 264573);

[0577] 6. Place the cell culture plate (Corning, 3764), the 384-well compound plate (Corning, 264573), and the pipette tip into the corresponding positions on the FLIPR instrument, and use... Penta added the 10 μL of agonist diluted in step 5 to each experimental well and collected data at wavelengths of 515 nm to 575 nm.

[0578] 7. By plotting the signal value against the compound concentration, curve fitting and IC50 analysis were performed using the nonlinear regression method in GraphPad Prism software. 50 calculate.

[0579] Data Analysis

[0580] 1) Z'factor = 1 - 3 * (SD) Max +SD Min ) / (AVG Max -AVG Min )

[0581] 2) CV Max = (SD Max / AVG Max )*100%

[0582] 3) CV Min = (SD Min / AVG Min )*100%

[0583] 4) Signal-to-noise ratio S / B = AVG Max / AVG Min

[0584] 5) Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 :

[0585] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0586] 6) Inhibition rate formula:

[0587]

[0588] The average value of the positive control group.

[0589] The mean value of the negative control (0.1% DMSO).

[0590] Experimental results

[0591] Based on the above experimental method, using AFDX-116 as a positive control compound, the inhibitory activity of the compound described in this invention on Human M2 and M3 receptors was detected. The data summary is shown in Table 3 below.

[0592] Table 3: Inhibitory selectivity of compounds 1-14 prepared in Examples 1-22 for Human M2 and M3

[0593]

[0594]

[0595] As can be seen from Table 3, the compounds prepared in the embodiments of the present invention (except for compounds 9, 16, 17, 20-22) all have significant M2 inhibition and M3 / M2 selectivity, proving that the benzodiazepine derivatives with a benzene ring at the end prepared in the present invention can effectively prevent myopia and / or inhibit the development of myopia, and do not cause mydriatic side effects.

[0596] In summary, the benzodiazepine derivatives with a terminal benzene ring provided by this invention, when used as active components in pharmaceutical compositions, can significantly improve selectivity for M2 receptors, significantly reduce inhibitory effects on M3 receptors, and increase the IC50 of M3 / M2. 50 The ratio increases significantly, which can effectively prevent or inhibit the development of myopia without affecting pupil size, and helps to improve the targeting of treatment and patient comfort.

[0597] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A benzodiazepine derivative designed based on AI, characterized in that, It has the structure of Formula I: Wherein, A is a benzene ring or a heteroaromatic ring; R1 is any one of hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl; R2 is any one of hydrogen, C2-C5 alkenyl or C3-C6 cyclic hydrocarbon group; L1 is -CH2CH2CO- or -(CH2) n -, -CH2NHCO-, -NHCH2CO-, -CH2CH2SO-, -CH2CH2O- or Any one of the following, where n is an integer from 1 to 3; L2 is -CH2CH2- or -CH2CO-; L3 is -CH2- or -CO-; X is a nitrogen atom or a carbon atom; Y can be -N(R3)-, an oxygen atom, or -CH2-; R3 is any one of H, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 deuteralkyl.

2. The AI-designed benzodiazepine derivative as described in claim 1, characterized in that, One of the methylene groups in R1 and L2 can form a C4-C7 cycloalkyl or heterocyclic structure together with the X atom to which it is attached.

3. The AI-designed benzodiazepine derivative as described in any one of claims 1, characterized in that, It has the structure of Formula II: Wherein, R1 is any one of C1-C3 alkyl groups and C1-C3 haloalkyl groups; R2 is any one of hydrogen, a C2-C5 alkenyl group, or a C3-C6 cyclic hydrocarbon group; L1 is any one of -CH2CH2CO-, -(CH2)3-, -CH2NHCO-, and -NHCH2CO-; L2 is -CH2CH2- or -CH2CO-; L3 is -CH2- or -CO-; R3 is any one of C1-C3 alkyl or C1-C3 deuterated alkyl.

4. The AI-designed benzodiazepine derivative as described in claim 1, characterized in that, Include: Any one of them.

5. A pharmaceutical composition, characterized in that, It contains: an AI-designed benzodiazepine derivative as described in any one of claims 1-4 as an active ingredient.

6. The pharmaceutical composition according to claim 5, characterized in that, It also includes: pharmaceutical excipients.

7. The use of an AI-designed benzodiazepine derivative, characterized in that, It is used to prepare drugs for preventing and / or inhibiting the development of myopia.

8. The use as described in claim 7, characterized in that, The myopia includes at least one of the following: axial myopia, refractive myopia, pseudomyopia, pathological myopia, simple myopia, extremely high myopia, severe myopia, high myopia, moderate myopia, low myopia, myopia combined with glaucoma, myopia with risk of developing glaucoma, or myopia accompanied by high intraocular pressure.

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