Naphthalimide compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a naphthalimide compound as well as a preparation method and application thereof. The naphthalimide compound or the pharmaceutically acceptable salt of the naphthalimide compound has a structure as shown in a general formula (I) or a general formula (II), wherein # imgabs0 # n is any integer from 0 to 6; the naphthalimide compound provided by the invention is simple in structure, has good antibacterial activity on various bacteria, and particularly has remarkable antibacterial activity on vancomycin moderate drug-resistant bacteria.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a naphthalimide compound, a preparation method thereof, and an application thereof. Background Art

[0002] A series of antibiotics with powerful antibacterial efficacy for treating microbial infections such as bacteria and fungi, such as aminoglycosides, beta-lactams, and fluoroquinolones, have emerged one after another, which once made pathogen-related infectious diseases well controlled. However, due to the continuous emergence of antibiotic abuse, more and more bacteria have developed resistance to antibiotics, making standard clinical treatments unable to completely eliminate infections. According to reports from the World Health Organization (WHO), for some common infectious diseases such as urinary tract infections, pneumonia, and skin wound infections, the proportion of infections caused by drug-resistant bacteria has been relatively high, and a large part of hospital-acquired infections are caused by highly drug-resistant bacteria, such as Methicillin-resistant S. aureus, Vancomycin-intermediate S. aureus, or multi-drug-resistant Gram-negative bacteria. For infections caused by drug-resistant bacteria, the clinical treatment effect is usually poor, the clinical treatment cost is relatively high, and the death risk of patients is greatly increased. At the same time, the pace of new drug development is very slow and cannot cope with the crisis brought by drug-resistant bacteria to human health.

[0003] Therefore, developing antibacterial drugs with new structures and new mechanisms has great clinical significance and application prospects. Summary of the Invention

[0004] The present invention provides a naphthalimide compound or a pharmaceutically acceptable salt thereof, and the compound can be applied to antibacterial drugs.

[0005] The technical solution of the present invention is as follows:

[0006] A naphthalimide compound or a pharmaceutically acceptable salt thereof has a structure shown in the following general formula (I) or general formula (II):

[0007] Each R1 is independently selected from hydrogen, halogen, nitro, hydroxyl, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted acyloxy;

[0008] R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy;

[0009] Y1, Y2, and Y3 are each independently selected from hydrogen or nitrogen;

[0010] L is selected from a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, a five-membered heterocyclic group, a six-membered heterocyclic group, a C3-C8 alkyl group, or a C3-C8 cycloalkyl group;

[0011] X is selected from one of the following groups:

[0012]

[0013] A is selected from an oxygen-containing five- or six-membered heterocyclic ring, a nitrogen-containing five- or six-membered heterocyclic ring, or a sulfur-containing five- or six-membered heterocyclic ring;

[0014] n is any integer from 0 to 6; represents a connection site.

[0015] In some embodiments, each R1 is independently selected from hydrogen, halogen, nitro, hydroxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted amido, or substituted or unsubstituted acyloxy;

[0016] R2, R3, and R4 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, or substituted or unsubstituted C1-C3 alkoxy;

[0017] L is selected from cyclohexyl, phenyl, benzyl, an oxygen- or nitrogen-containing five-membered heterocyclic group, an oxygen- or nitrogen-containing six-membered heterocyclic group, or a C3-C8 alkylene group;

[0018] A is selected from one of the following groups:

[0019]

[0020] n is 0 or 1.

[0021] In some embodiments, each R1 is independently selected from hydrogen, halogen, nitro, hydroxy, amino, dimethylamino, or methoxy;

[0022] R2, R3, and R4 are each independently selected from hydrogen, halogen, methyl, methoxy, or dimethylamino;

[0023] L is selected from one of the following groups:

[0024]

[0025] X is selected from one of the following groups:

[0026]

[0027] In some of these embodiments, the naphthalimide compound or a pharmaceutically acceptable salt thereof has a structure shown in any of the following:

[0028]

[0029] The present invention also provides a method for preparing the above-mentioned naphthalimide compound or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0030] (a) Preparing an intermediate compound 2 by aminolysis reaction of compound 1 and compound R-L-NH2;

[0031] (b) Preparing the compound by reductive amination reaction or condensation reaction of the intermediate compound 2;

[0032] In the compound R-L-NH2, R is selected from one or more of NH2, NHMe or OH;

[0033] The structural formulas of the compound 1 and the intermediate compound 2 are shown as follows:

[0034] Compound 1, Intermediate compound 2.

[0035] In some of these embodiments, in the compound R-L-NH2, R is selected from NH2; and / or, the intermediate compound 2 undergoes a reductive amination reaction with an aldehyde compound;

[0036] Wherein, the aldehyde compound includes one of the following structural formulas:

[0037]

[0038] In some of these embodiments, in the compound R-L-NH2, R is selected from one of NH2, NHMe or OH; and / or, the intermediate compound 2 undergoes a condensation reaction with a carboxylic acid compound or a halogenated compound;

[0039] Wherein, the carboxylic acid compound includes one of the following structures:

[0040]

[0041] The halogenated compound includes one of the following structures:

[0042] P is selected from halogen.

[0043] The present invention also provides an antibacterial drug, which comprises the above-mentioned naphthalimide compound or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the bacteria include one or more of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, vancomycin-intermediate resistant Staphylococcus aureus, Enterococcus faecalis, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii.

[0045] In some embodiments, the drug is any one of tablets, capsules, aerosols and ointments.

[0046] The beneficial effects of the present invention are as follows:

[0047] The naphthalimide compound provided by the present invention has a simple structure, and the compound has good antibacterial activity against various bacteria, especially significant antibacterial activity against vancomycin-intermediate resistant bacteria. The naphthalimide antibacterial compound of the present invention can be made into antibacterial drugs in various dosage forms, which helps to solve the increasingly serious problem of bacterial drug resistance.

[0048] Other advantages, objectives and features of the present invention will be described to some extent in the subsequent description, and to some extent, will be obvious to those skilled in the art based on the study of the following text, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be realized and obtained through the following description. Detailed Embodiments

[0049] The following specific examples illustrate the embodiments of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that the diagrams provided in the following examples only illustrate the basic concept of the present invention schematically. Without conflict, the following examples and the features in the examples can be combined with each other.

[0050] The terms "preferably", "more preferably", "more desirably", "even more desirably", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention. That is, in the present invention, "preferably", "more preferably", "more desirably", "even more desirably", etc. are only used to describe embodiments or examples with better effects, but do not constitute a limitation on the protection scope of the present invention.

[0051] In the present invention, "further", "even further", "especially", etc. are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the protection scope of the present invention.

[0052] In the present invention, "A and B are each independently selected from x, y or z" means that A and B are independent events, and event A does not affect the occurrence of event B. Therefore, when A is selected from x, B can be selected from any one of x, y or z; when A is selected from y, B can be selected from any one of x, y or z; when A is selected from z, B can be selected from any one of x, y or z.

[0053] In the present invention, "alkyl" may represent straight-chain, branched-chain and / or cyclic alkyl. The number of carbon atoms in the alkyl can be 1 to 50, 1 to 30, 1 to 20, 1 to 10 or 1 to 6. Phrases containing this term, for example, "C1-C9 alkyl" refer to alkyls containing 1 to 9 carbon atoms, and each occurrence can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl or C9 alkyl. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, 2-ethylbutyl, 3,3-dimethylbutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, 1-methylpentyl, 3-methylpentyl, 2-ethylpentyl, 4-methyl-2-pentyl, n-octyl, n-hexyl, 1-methylhexyl, 2-ethylhexyl, 2-butylhexyl, cyclohexyl, 1,1-dimethylbutyl, adamantane, etc.

[0054] The term "cycloalkyl" refers to a cyclic organic group containing only carbon and hydrogen atoms, preferably having 3 to 10 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0055] The term "alkoxy" refers to a group having -O-alkyl, i.e., the alkyl group as defined above is connected to the parent nuclear structure via an oxygen atom. Suitable examples of phrases containing this term include, but are not limited to: methoxy (-O-CH3 or -OMe), ethoxy (-O-CH2CH3 or -OEt), and tert-butoxy (-O-C(CH3)3 or -OtBu). The term "alkylthio" includes branched and straight-chain alkyl groups connected to a bridging sulfur atom, such as methylthio, etc.

[0056] In the present invention, the heterocyclic group and the heterocycle have the same meaning and can be interchanged. The term "heterocyclic group" means that at least one carbon atom in the cycloalkyl group is replaced by a non-carbon atom, and the non-carbon atom can be an N atom, an O atom, an S atom, etc., representing a nitrogen-containing heterocycle, an oxygen-containing heterocycle, and a sulfur-containing heterocycle, respectively, and can be a saturated ring or a partially unsaturated ring. Among them, the "five-membered heterocyclic group" refers to a group formed by a cyclic organic compound composed of carbon atoms and non-carbon atoms, and the sum of the number of carbon atoms and the number of non-carbon atoms is 5. The "six-membered heterocyclic group" refers to a group formed by a cyclic organic compound composed of carbon atoms and non-carbon atoms, and the sum of the number of carbon atoms and the number of non-carbon atoms is 6.

[0057] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0058] In the present invention, the single bond to which the substituent is attached passes through the corresponding ring, indicating that the substituent can be connected to any optional position of the ring. For example in which R can be connected to any substitutable site of the benzene ring.

[0059] The present invention provides a naphthalimide compound or a pharmaceutically acceptable salt thereof, having a structure represented by the following general formula (I) or general formula (II):

[0060]

[0061] Each R1 is independently selected from hydrogen, halogen, nitro, hydroxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted acyloxy;

[0062] R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy;

[0063] Y1, Y2, and Y3 are independently selected from hydrogen or nitrogen;

[0064] L is selected from substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, five-membered heterocyclic group, six-membered heterocyclic group, C3-C8 alkyl, C3-C8 cycloalkyl;

[0065] X is selected from one of the following groups:

[0066]

[0067] A is selected from an oxygen-containing five- or six-membered heterocyclic ring, a nitrogen-containing five- or six-membered heterocyclic ring, or a sulfur-containing five- or six-membered heterocyclic ring;

[0068] n represents the number of R1 substituents on the naphthalene ring, and n is any integer from 0 to 6;

[0069] represents the connection site.

[0070] The naphthalimide compound of the present invention has a simple structure, and this compound has good antibacterial activity against various bacteria, especially significant antibacterial activity against vancomycin-intermediate resistant bacteria. The naphthalimide antibacterial compound of the present invention can be made into antibacterial drugs in various dosage forms, which helps to solve the increasingly serious problem of bacterial drug resistance.

[0071] In some examples, in the structure represented by the general formula (I) or the general formula (II), each of the R1s is independently selected from hydrogen, halogen, nitro, hydroxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted amide group, substituted or unsubstituted acyloxy group, and n is 0 or 1; further, each of the R1s is independently selected from hydrogen, halogen, nitro, hydroxy, amino, dimethylamino or methoxy.

[0072] In some examples, R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy; further, the R2, R3, and R4 are independently selected from hydrogen, halogen, methyl, methoxy or dimethylamino.

[0073] In some examples, L is selected from cyclohexyl, phenyl, benzyl, an oxygen-containing or nitrogen-containing five-membered heterocyclic group, an oxygen-containing or nitrogen-containing six-membered heterocyclic group or C3-C8 alkyl; further, L is selected from one of the following groups:

[0074]

[0075] In some examples, X is selected from one of the following groups:

[0076] In some examples, A is selected from one of the following groups:

[0077]

[0078] In some of these examples, the naphthalimide compound has a structure shown as any of the following:

[0079]

[0080] The present invention also provides a method for preparing the above-mentioned naphthalimide compound, comprising the following steps:

[0081] (a) Preparing intermediate compound 2 by aminolysis reaction of compound 1 with R-L-NH2;

[0082] (b) Preparing the compound by reductive amination reaction or condensation reaction of the intermediate compound 2;

[0083] In the compound R-L-NH2, R is selected from one or more of NH2, NHMe or OH;

[0084] The structural formulas of the compound 1 and the intermediate compound 2 are shown as follows:

[0085] Compound 1, Intermediate compound 2.

[0086] It can be understood that the definitions of R1 and L in the compound 1 and the intermediate compound 2 of the present invention are the same as those above; the definition of R in the intermediate compound 2 is the same as that in the compound R-L-NH2.

[0087] In some of these examples, in the compound R-L-NH2, R is selected from NH2; and / or,

[0088] The intermediate compound 2 undergoes a reductive amination reaction with an aldehyde compound;

[0089] Wherein, the aldehyde compound includes one of the following structural formulas:

[0090]

[0091] In some of these specific examples, the reaction solvent for the aminolysis reaction includes one or more of N,N-dimethylformamide or toluene.

[0092] In some of these specific examples, the reaction solvent for the reductive amination reaction includes one or more of methanol or 1,2-dichloroethane.

[0093] As an example of the reductive amination reaction, the preparation method includes the following steps: (a) Mixing compound 1 and NH2-L-NH2 to prepare intermediate compound 2 through aminolysis reaction; (b) Performing reductive amination reaction on intermediate compound 2 and aldehyde compound in methanol or 1,2-dichloroethane. The synthetic route 1 is shown as follows:

[0094] (Synthetic route 1).

[0095] Furthermore, the naphthalimide compound in the above synthetic route 1 can further undergo reductive amination reaction. As an example, it is shown in the following synthetic route 2:

[0096] (Synthetic route 2).

[0097] As another example of the reductive amination reaction, as shown in synthetic route 3:

[0098] (Synthetic route 3).

[0099] Furthermore, the naphthalimide compound in the above synthetic route 3 can further undergo reductive amination reaction. As an example, it is shown in the following synthetic route 4:

[0100] (Synthetic route 4).

[0101] In some examples, R in the compound R-L-NH2 is selected from one of NH2, NHMe or OH; and / or, the intermediate compound 2 undergoes a condensation reaction with a carboxylic acid compound or a halogenated compound;

[0102] Among them, the carboxylic acid compound includes one of the following structures:

[0103]

[0104] The halogenated compound includes one of the following structures:

[0105] P is selected from halogen

[0106] In some specific examples, the condensing agent for the condensation reaction includes sodium hydride.

[0107] As an example of the condensation reaction, when R is selected from NH2, the preparation method includes the following steps: (a) Mixing compound 1 and NH2-L-NH2 to prepare an intermediate compound through aminolysis reaction; (b) Performing a condensation reaction on the intermediate compound and a carboxylic acid compound. The synthetic route 5 is shown as follows:

[0108] (Synthetic Route 5).

[0109] As another example of the condensation reaction, when R is selected from NH2, as shown in Synthetic Route 6:

[0110] (Synthetic Route 6).

[0111] As another example of the condensation reaction, when R is selected from OH, the preparation method includes the following steps: (a) Mix compound 1 and HO-L-NH2 to prepare an intermediate compound through aminolysis reaction; prepare a brominated compound from an alcohol compound through bromination reaction, (b) Carry out a condensation reaction between the intermediate compound and the brominated compound. Synthetic Route 7 is as follows:

[0112] (Synthetic Route 7).

[0113] The present invention also provides an antibacterial drug, which includes the above-mentioned naphthalimide compounds or their pharmaceutically acceptable salts.

[0114] In some examples, the bacteria include one or more of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, vancomycin-intermediate Staphylococcus aureus, Enterococcus faecalis, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii.

[0115] In some examples, the drug is any one of tablets, capsules, aerosols, and ointments.

[0116] The embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. For the experimental methods without specific conditions in the following examples, priority is given to the guidance given in the present invention, and it can also be carried out according to the experimental manuals or conventional conditions in the art, or according to the conditions recommended by the manufacturers, or referring to the experimental methods known in the art. For the reagents or instruments without indicating the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0117] Example 1

[0118] Prepare compound N1

[0119] Step (a): Weigh 1,8-naphthalic anhydride (1-a) (2 g, 10.09 mmol) and place it in a 100 mL round-bottom flask. Add trans-1,4-diaminocyclohexane (1.73 g, 15.14 mmol) and 15 mL of N,N-dimethylformamide. Then stir and react at 150 °C for 1 hour. After the reaction is completed, filter off the insoluble matter by suction filtration. Wash the filter cake with N,N-dimethylformamide to obtain a filtrate. Add a large amount of deionized water to the filtrate and stir at room temperature for 20 minutes. Solids will precipitate. Filter by suction to obtain a filter cake and dry it in an infrared oven. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 15:1, v / v) to obtain 1.65 g of intermediate compound 2-a, a pale yellow solid, with a yield of 56%. The structural formula of 2-a is shown below, and the test data are as follows: 1 H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 5.07 - 4.99 (m, 1H), 2.90 - 2.84 (m, 1H), 2.72 - 2.61 (m, 2H), 2.01 (d, J = 12.4 Hz, 2H), 1.74 (d, J = 11.2 Hz, 2H), 1.40 - 1.30 (m, 2H).

[0120] Step (b): Weigh intermediate compound 2-a (200 mg, 0.68 mmol) and place it in a 25 mL round-bottom flask. Add 1,4-benzodioxane-6-carbaldehyde (134 mg, 0.82 mmol), 5 mL of 1,2-dichloroethane, and 3 drops of glacial acetic acid. After stirring at 65 °C for 10 min, add sodium triacetoxyborohydride (432 mg, 2.04 mmol) and stir at 65 °C for 1 h. After the reaction is completed, remove the solvent by rotary evaporation. Dissolve it in dichloromethane. Wash the organic phase with sodium bicarbonate solution and deionized water, dry it over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 80:1, v / v) to obtain 80 mg of compound N1, a pale yellow solid, with a yield of 26%. The structural formula of compound N1 is shown below, and the test data are as follows: 11H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 7.6 Hz, 2H), 8.17 (d, J = 8.0 Hz, 2H), 7.73 (t, J = 8.0 Hz, 2H), 6.99 - 6.96 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.25 (s, 4H), 3.86 (s, 2H), 2.84 - 2.79 (m, 1H), 2.67 - 2.57 (m, 2H), 2.23 (d, J = 12.0 Hz, 2H), 1.80 (d, J = 11.6 Hz, 2H), 1.64 - 1.56 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.60, 143.46, 142.49, 134.03, 133.52, 131.45, 131.05, 128.16, 126.93, 123.22, 121.08, 117.16, 116.90, 64.39, 64.36, 55.10, 53.22, 50.56, 33.13, 27.29. HRMS (ESI) (m / z): [M + H] + calcd for C 27 H 26 N2O4, 443.1966; found, 443.1982.

[0121]

[0122] Example 2

[0123] Preparation of Compound N2

[0124] Step (a) is the same as in Example 1;

[0125] Step (b) is basically the same as in Example 1, except that the aldehyde compound is different. The structural formula of the aldehyde compound 2 in Example 2 is shown below. The prepared Compound N2 is a white solid with a yield of 30%. The structural formula of Compound N2 is shown below, and the test data: 1 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 7.2 Hz, 2H), 8.17 (d, J = 8.0 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 5.10 - 5.03 (m, 1H), 3.83 (s, 2H), 2.74 - 2.60 (m, 3H), 2.34 (s, 3H), 2.13 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 10.4 Hz, 2H), 1.43 - 1.33 (m, 2H).13 13C NMR (100 MHz, CDCl3): δ 164.60, 137.38, 136.51, 133.52, 131.46, 131.06, 129.16, 123.18, 128.12, 126.93, 123.23, 55.32, 53.20, 50.90, 33.07, 27.29, 21.08. HRMS (ESI) (m / z): [M+H] + calcd for C 26 H 26 N2O2, 399.2067; found, 399.2082.

[0126]

[0127] Example 3

[0128] Preparation of Compound N3

[0129] Step (a) is the same as in Example 1;

[0130] Step (b) is basically the same as in Example 1, except that the aldehyde compound is different. The structural formula of the aldehyde compound 3 in Example 3 is shown below. The prepared Compound N3 is a white solid with a yield of 25%. The structural formula of Compound N3 is shown below, and the test data are as follows: 1 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.47 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 5.10 - 5.04 (m, 1H), 3.82 (s, 2H), 2.70 - 2.61 (m, 3H), 2.10 (d, J = 11.6 Hz, 2H), 1.77 (d, J = 11.2 Hz, 2H), 1.33 - 1.29 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.62, 141.36, 133.58, 132.41, 131.47, 131.10, 130.66, 130.29, 129.92, 128.17, 127.34, 126.95, 123.19, 55.58, 53.08, 50.13, 33.27, 27.28. HRMS (ESI) (m / z): [M+H] + calcd for C 25 H 22 Cl2N2O2, 453.1131; found, 453.1143.

[0131]

[0132] Example 4

[0133] Preparation of Compound N4

[0134] Step (a) is the same as in Example 1;

[0135] Step (b): Weigh the intermediate compound 2-a (200 mg, 0.68 mmol) and place it in a 25 mL round-bottom flask. Add 5 mL of N,N-dimethylformamide, EDC (150 μL, 0.85 mmol), HBTU (258 mg, 0.68 mmol), DIEA (296 μL, 1.7 mmol), and p-toluic acid (111 mg, 0.82 mmol), and stir at room temperature for 1 h. After the reaction is completed, remove the solvent by rotary evaporation, add a small amount of dichloromethane for pulping, filter by suction to obtain the filter cake, and purify the crude product by silica gel column chromatography (dichloromethane / methanol = 60:1, v / v) to obtain 72 mg of compound N4, a white solid, with a yield of 25%. The structural formula of compound N4 is shown below, and the test data: 1 HNMR(400MHz,CDCl3):δ8.58(d,J=7.2Hz,2H),8.20(d,J=8.0Hz,2H),7.75(t,J=7.6Hz,2H),7.68(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),5.92(d,J=7.6Hz,1H),5.13-5.06(m,1H),4.20-4.13(m,1H),2.89-2.79(m,2H),2.40(s,3H),2.28(d,J=11.6Hz,2H),1.82(d,J=11.2Hz,2H),1.52-1.42(m,2H).HRMS(ESI)(m / z):[M+H] + calcd for C 26 H 24 N2O3,413.1860;found,413.1866.

[0136]

[0137] Example 5

[0138] Preparation of Compound N5

[0139] Step (a) is the same as in Example 1;

[0140] Step (b) is basically the same as that in Example 4, except that the carboxylic acid compound is different. The structure of carboxylic acid compound 2 in Example 5 is shown below. The prepared compound N5 is a white solid with a yield of 53%. The structural formula of compound N5 is shown below, and the test data are as follows: 1 H NMR(400MHz,CDCl3):δ8.73(d,J=7.2Hz,2H),8.20(d,J=8.0Hz,2H),7.88(s,1H),7.75(t,J=7.6Hz,2H),7.61(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),5.95(d,J=7.6Hz,1H),5.13-5.07(m,1H),4.17-4.12(m,1H),2.89-2.79(m,2H),2.27(d,J=11.2Hz,2H),1.83(d,J=11.6Hz,2H),1.54-1.44(m,2H).HRMS(ESI)(m / z):[M+H] + calcd for C 25 H 20 Cl2N2O3,467.0924;found,467.0932.

[0141]

[0142] Example 6

[0143] Preparation of compound N6

[0144] Step (a) is the same as that in Example 1;

[0145] Step (b) is basically the same as that in Example 1, except that the aldehyde compound is different. The structural formula of aldehyde compound 4 in Example 6 is shown below. The prepared compound N6 is a white solid with a yield of 21%. The structural formula of compound N6 is shown below, and the test data are as follows: 1 H NMR(400MHz,CDCl3):δ8.55(d,J=7.2Hz,2H),8.18(d,J=8.4Hz,2H),7.73(t,J=8.0Hz,2H),7.45(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),5.10-5.06(m,1H),3.81(s,2H),2.70-2.63(m,3H),2.10(d,J=12Hz,2H),1.77(d,J=10.8Hz,2H),1.40-1.30(m,2H). 13CNMR(100MHz, CDCl3): δ164.61, 139.89, 133.55, 131.49, 131.47, 131.08, 129.79, 128.17, 126.94, 123.21, 120.61, 55.50, 53.14, 50.61, 33.16, 27.30. HRMS(ESI)(m / z): [M + H] + calcd for C 25 H 23 BrN2O2, 463.1016;found, 463.1029.

[0146]

[0147] Example 7

[0148] Preparation of Compound N7

[0149] Step (a) is the same as in Example 1;

[0150] Step (b) is basically the same as in Example 1, except that the aldehyde compound is different. The structural formula of the aldehyde compound 5 in Example 7 is shown below. The prepared Compound N7 is a white solid with a yield of 28%. The structural formula of Compound N7 is shown below, and the test data are as follows: 1 H NMR(400MHz, CDCl3): δ8.56(d, J = 7.2Hz, 2H), 8.18(d, J = 8.0Hz, 2H), 7.74(t, J = 8.0Hz, 2H), 7.31(dd, J = 8.4, 5.6Hz, 2H), 7.02(t, J = 8.8Hz, 2H), 5.10 - 5.04(m, 1H), 3.82(s, 2H), 2.70 - 2.64(m, 3H), 2.12(d, J = 12Hz, 2H), 1.77(d, J = 10.8Hz, 2H), 1.40 - 1.34(m, 2H). 13 C NMR(100MHz, CDCl3): δ164.61, 163.86(d, J = 149.9Hz), 136.56(d, J = 3.1Hz), 133.55, 131.46, 131.07, 129.58(d, J = 7.8Hz), 128.17, 126.93, 123.21, 115.19(d, J = 21.1Hz), 55.50, 53.17, 50.57, 33.26, 27.30. HRMS(ESI)(m / z): [M + H] + calcd forC 25 H 23 FN2O2, 403.1817;found, 403.1831.

[0151]

[0152] Example 8

[0153] Preparation of Compound N8

[0154] Step (a) is the same as that in Example 1;

[0155] Step (b) is basically the same as that in Example 1, except that the aldehyde compound is different. The structural formula of aldehyde compound 6 in Example 8 is shown as follows. The prepared Compound N8 is a white solid with a yield of 25%. The structural formula of Compound N8 is shown as follows, and the test data: 1 H NMR(400MHz,DMSO-d6):δ8.45(t,J=7.6Hz,2H),7.86(d,J=7.6Hz,2H),7.40-7.37(m,4H),4.93-4.87(m,1H),3.76(s,2H),2.50-2.45(m,3H),2.05(d,J=11.6Hz,2H),1.66(d,J=10.8Hz,2H),1.22-1.15(m,2H). 13 C NMR(100MHz,CDCl3):δ164.61,139.89,133.55,131.49,131.47,131.08,129.79,128.17,126.94,123.21,120.61,55.50,53.14,50.61,33.16,27.30.HRMS(ESI)(m / z):[M+H] + calcd for C 25 H 23 ClN2O2,419.1521;found,419.1539.

[0156]

[0157] Example 9

[0158] Preparation of Compound N9

[0159] Step (a) is the same as that in Example 1;

[0160] Step (b) is basically the same as that in Example 1, except that the aldehyde compound is different. The structural formula of aldehyde compound 7 in Example 9 is shown as follows. The prepared Compound N9 is a white solid with a yield of 20%. The structural formula of Compound N9 is shown as follows, and the test data: 11H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 7.2 Hz, 2H), 8.42 (d, J = 8 Hz, 2H), 7.85 (t, J = 7.6 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 7.19 (d, J = 8 Hz, 2H), 4.93 - 4.87 (m, 1H), 3.72 (s, 2H), 2.45 (m, 2H), 2.03 (d, J = 11.6 Hz, 3H), 1.67 (d, J = 10.8 Hz, 2H), 1.23 - 1.15 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.60, 137.54, 133.55, 131.49, 131.09, 130.23, 128.20, 126.94, 123.22, 55.43, 92.30, 53.04, 50.45, 32.92, 27.24. HRMS (ESI) (m / z): [M + H] + calcd for C 25 H 23 IN2O2, 511.0877; found, 511.0894.

[0161]

[0162] Example 10

[0163] Preparation of Compound N10

[0164] Step (a) is the same as in Example 1;

[0165] Step (b): Weigh the intermediate compound 2-a (200 mg, 0.70 mmol) and place it in a 25 mL round-bottom flask. Add 4-bromo-3-fluorobenzaldehyde (180 mg, 0.88 mmol), 5 mL of methanol, and 3 drops of glacial acetic acid. After stirring at room temperature for 20 min, add sodium cyanoborohydride (128 mg, 2.04 mmol) and stir at room temperature for 5 h. After the reaction is completed, remove the solvent by rotary evaporation, dissolve it in dichloromethane, wash the organic phase with sodium bicarbonate solution and deionized water, dry it over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 80:1, v / v) to obtain 135 mg of Compound N10 as a white solid with a yield of 42%. The structural formula of Compound N10 is shown below, and the test data are as follows: 11H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.2 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.15 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.10 - 5.04 (m, 1H), 3.82 (s, 2H), 2.70 - 2.63 (m, 3H), 2.10 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 10.8 Hz, 2H), 1.39 - 1.29 (m, 2H). 13 13C NMR (100 MHz,): δ 164.60, 159.14, (d, J = 245.7 Hz), 143.13 (d, J = 6.2 Hz), 133.56, 133.25, 131.47, 131.08, 128.18, 126.94, 124.68 (d, J = 3.2 Hz), 123.20, 115.97 (d, J = 22.0 Hz), 106.87 (d, J = 21.0 Hz), 55.53, 53.10, 50.24, 33.30, 27.30. HRMS (ESI) (m / z): [M + H] + calcd for C 25 H 22 BrFN2O2, 481.0922; found, 481.0938.

[0166]

[0167] Example 11

[0168] Preparation of Compound N11

[0169] Step (a) is the same as in Example 1;

[0170] Step (b) is basically the same as in Example 10, except that the aldehyde compound is different. The structural formula of the aldehyde compound 8 in Example 11 is shown below. The prepared Compound N11 is a yellow solid with a yield of 65%. The structural formula of Compound N11 is shown below, and the test data: 11H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.10 - 5.04 (m, 1H), 3.77 (s, 2H), 2.94 (s, 6H), 2.72 - 2.62 (m, 3H), 2.13 (d, J = 12 Hz, 2H), 1.77 (d, J = 10.4 Hz, 2H), 1.45 - 1.34 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.58, 149.93, 133.48, 131.47, 131.04, 129.15, 128.19, 126.91, 123.28, 112.88, 55.21, 53.24, 50.60, 40.76, 32.97, 27.31. HRMS (ESI) (m / z): [M + H] + calcd for C 27 H 29 N3O2, 428.2333; found, 428.2343.

[0171]

[0172] Example 12

[0173] Preparation of Compound N12

[0174] Step (a) is the same as in Example 1;

[0175] Step (b) is basically the same as in Example 10, except that the aldehyde compound is different. The structural formula of the aldehyde compound 9 in Example 12 is shown below. The prepared Compound N12 is a white solid with a yield of 61%. The structural formula of Compound N12 is shown below, and the test data: 1 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 7.2 Hz, 2H), 8.36 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.75 (t, J = 7.6 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.10 - 5.04 (m, 1H), 3.86 (s, 2H), 2.70 - 2.61 (m, 3H), 2.11 (d, J = 12 Hz, 2H), 1.78 (d, J = 11.2 Hz, 2H), 1.40 - 1.30 (m, 2H). 1313C NMR (100 MHz, CDCl3): δ 164.62, 150.02, 149.27, 138.68, 135.35, 133.58, 131.49, 131.11, 128.20, 126.94, 124.01, 123.21, 55.73, 53.04, 47.80, 33.30, 27.28. HRMS (ESI) (m / z): [M+H] + calcd for C 24 H 22 ClN3O2, 420.1474; found, 420.1474.

[0176]

[0177] Example 13

[0178] Preparation of Compound N13

[0179] Step (a) is the same as in Example 1;

[0180] Step (b) is basically the same as in Example 10, except that the aldehyde compound is different. The structural formula of the aldehyde compound 10 in Example 13 is shown below. The prepared Compound N13 is a white solid with a yield of 61%. The structural formula of Compound N13 is shown below, and the test data: 1 1H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 7.2 Hz, 2H), 8.51 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 7.6 Hz, 2H), 7.62 (dd, J = 8.4, 2.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 5.10 - 5.03 (m, 1H), 3.95 (s, 2H), 2.70 - 2.60 (m, 3H), 2.12 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 11.6 Hz, 2H), 1.40 - 1.30 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.58, 158.52, 148.10, 136.11, 133.50, 131.46, 131.04, 130.12, 128.17, 126.91, 123.23, 123.03, 55.77, 53.15, 51.93, 33.22, 27.27. HRMS (ESI) (m / z): [M+H] + calcd for C 24 H 22 ClN3O2, 420.1474; found, 420.1473.

[0181]

[0182] Example 14

[0183] Preparation of Compound N14

[0184] Step (a) is the same as in Example 1;

[0185] Step (b) is basically the same as in Example 10, except that the aldehyde compound is different. The structural formula of the aldehyde compound 11 in Example 14 is shown below. The prepared Compound N14 is a white solid with a yield of 67%. The structural formula of Compound N14 is shown below, and the test data are as follows: 1 H NMR(400MHz,CDCl3):δ8.55(d,J=7.2Hz,2H),8.18(d,J=8.0Hz,2H),7.73(t,J=7.6Hz,2H),7.33(t,J=8.0Hz,1H),7.18(d,J=10.0Hz,1H),7.07(d,J=7.6Hz,1H),5.11-5.03(m,1H),3.83(s,2H),2.70-2.60(m,3H),2.10(d,J=12.4Hz,2H),1.77(d,J=10.8Hz,2H),1.40-1.30(m,2H). 13 C NMR(100MHz,CDCl3):δ164.60,158.14(d,J=247.1Hz),142.24(d,J=6.2Hz),133.54,131.47,131.06,130.35,128.17,126.92,124.18(d,J=3.4Hz),123.20,119.03(d,J=17.5Hz),116.04(d,J=20.9Hz),55.54,53.10,50.22,33.30,27.30.HRMS(ESI)(m / z):[M+H] + calcd for C 25 H 22 ClFN2O2,437.1427;found,437.1424.

[0186]

[0187] Example 15

[0188] Preparation of Compound N15

[0189] Step (a) is the same as in Example 1;

[0190] Step (b) is basically the same as that in Example 10, except that the aldehyde compound is different. The structural formula of aldehyde compound 12 in Example 15 is shown as follows. The prepared compound N15 is a white solid with a yield of 65%. The structural formula of compound N15 is shown as follows, and the test data: 1 H NMR(400MHz,CDCl3):δ8.56(dd,J=7.2,0.8Hz,2H),8.18(dd,J=8.0,0.8Hz,2H),7.74(t,J=7.6Hz,2H),7.67(dd,J=8.0,6.8Hz,1H),7.11(dd,J=8.8,1.6Hz,1H),6.90(dd,J=8.0,1.6Hz,1H),5.10-5.03(m,1H),3.83(s,2H),2.70-2.60(m,3H),2.10(d,J=12.4Hz,2H),1.77(d,J=10.0Hz,2H),1.46-1.30(m,2H). 13 C NMR(100MHz,CDCl3):δ164.59,161.85(d,J=244.1Hz),144.36(d,J=6.3Hz),139.08,133.53,131.48,131.07,128.19,126.93,125.31,125.27,123.22,115.21(d,J=23.5Hz),78.61(d,J=25.5Hz),55.53,53.11,50.23,33.30,27.30.HRMS(ESI)(m / z):[M+H] + calcd for C 25 H 22 FIN2O2,529.0783;found,529.0783.

[0191]

[0192] Example 16

[0193] Preparation of compound N16

[0194] Step (a) is the same as that in Example 1;

[0195] Step (b) is basically the same as that in Example 10, except that the aldehyde compound is different. The structural formula of aldehyde compound 13 in Example 16 is shown as follows. The prepared compound N16 is a white solid with a yield of 53%. The structural formula of compound N16 is shown as follows, and the test data: 11H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 8.4 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 6.91 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.10 - 5.05 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.80 (s, 2H), 2.73 - 2.61 (m, 3H), 2.13 (d, J = 12.4 Hz, 2H), 1.78 (d, J = 10.8 Hz, 2H), 1.42 - 1.30 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.60, 149.10, 148.064, 133.51, 131.47, 131.05, 128.18, 126.92, 123.24, 120.17, 111.53, 111.30, 55.99, 55.91, 55.60, 53.23, 51.19, 33.27, 27.35. HRMS (ESI) (m / z): [M + H] + calcd for C 27 H 28 N2O4, 445.2122; found, 445.2134.

[0196]

[0197] Example 17

[0198] Preparation of Compound N17

[0199] Step (a): Weigh 2-bromo-1,8-naphthalic anhydride (1-b) (300 mg, 1.08 mmol) and place it in a 25 mL round-bottom flask. Add trans-1,4-diaminocyclohexane (186 mg, 1.62 mmol) and 6 mL of toluene, and then stir the reaction at 110 °C for 1 hour. After the reaction is completed, filter off the insoluble matter, wash the filter cake with toluene to obtain the filtrate, and concentrate the filtrate by rotary evaporation to obtain 65 mg of intermediate compound 2-b, a pale yellow solid, with a yield of 16%. The structural formula of 2-b is shown below, and the test data are as follows: 11H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 7.2 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 5.05 - 4.97 (m, 1H), 2.90 - 2.82 (m, 1H), 2.70 - 2.60 (m, 2H), 2.00 (d, J = 12.8 Hz, 2H), 1.74 (d, J = 11.2 Hz, 2H), 1.38 - 1.28 (m, 2H).

[0200] Step (b) is basically the same as that in Example 10, except that intermediate compound 2-b is used and the aldehyde compound is different. The structural formula of the aldehyde compound 14 in Example 17 is shown below. The prepared compound N17 is a pale yellow solid with a yield of 40%. The structural formula of compound N17 is shown below, and the test data are as follows: 1 1H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 6.8 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.2 Hz, 1H), 6.85 - 6.78 (m, 3H), 5.07 - 5.00 (m, 1H), 4.26 (s, 4H), 3.74 (s, 2H), 2.70 - 2.57 (m, 3H), 2.11 (d, J = 12.0 Hz, 2H), 1.76 (d, J = 10.4 Hz, 2H), 1.43 - 1.30 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 163.99, 143.46, 142.49, 134.12, 132.88, 131.89, 131.12, 131.06, 130.49, 129.82, 128.99, 128.07, 123.63, 122.77, 121.04, 117.15, 116.87, 64.40, 64.36, 55.09, 53.44, 50.59, 33.14, 27.28. HRMS (ESI) (m / z): [M + H]+ calcd for C 27 H 25 BrN2O4, 521.1071; found, 521.1072.

[0201]

[0202] Example 18

[0203] Prepare compound N18

[0204] Step (a) is basically the same as that in Example 1, except that the naphthalic anhydride compound is different. The structural formula of the naphthalic anhydride compound 1-c in Example 18 is shown below. The prepared intermediate compound 2-c is a pale yellow solid with a yield of 20%. The structural formula of 2-c is as follows;

[0205] Step (b) is basically the same as that in Example 10, except that the intermediate compound 2-c is used. The compound N18 prepared with the aldehyde compound 14 is a pale yellow solid with a yield of 35%. The structural formula of the compound N18 is shown below, and the test data: 1 H NMR(400MHz,CDCl3):δ9.27(d,J=2.0Hz,1H),9.10(d,J=1.6Hz,1H),8.74(d,J=7.2Hz,1H),8.39(d,J=8.0Hz,1H),7.92(t,J=8.0Hz,1H),6.86-6.79(m,3H),5.09-5.01(m,1H),4.26(s,4H),3.75(s,2H),2.71-2.57(m,3H),2.12(d,J=12.8Hz,2H),1.77(d,J=11.2Hz,2H),1.41-1.29(m,2H). 13 C NMR(100MHz,CDCl3):δ163.48,162.80,146.50,143.49,142.56,135.13,134.29,130.88,130.19,129.06,128.52,125.26,124.13,123.74,121.07,117.19,116.90,64.40,64.36,55.05,53.81,50.54,33.01,27.23.HRMS(ESI)(m / z):[M+H]+calcdfor C 27 H 25 N3O6,488.1816;found,488.1816.

[0206]

[0207] Example 19

[0208] Preparation of compound N19

[0209] Step (a) is basically the same as that in Example 1, except that the naphthalic anhydride compound is different. The structural formula of the naphthalic anhydride compound 1-d in Example 19 is shown below. The prepared intermediate compound 2-d is a pale yellow solid with a yield of 18%, and the structural formula of 2-d is as follows;

[0210] Step (b) is basically the same as that in Example 10, except that intermediate compound 2-d and aldehyde compound 14 are used. The prepared compound N19 is a yellow solid with a yield of 25%. The structural formula of compound N19 is shown below, and the test data are as follows: 1 H NMR(400MHz,DMSO-d6):δ8.21(d,J=4.4Hz,1H),8.19(d,J=5.6Hz,1H),7.99(d,J=2.4Hz,1H),7.71(t,J=8.0Hz,1H),7.62(d,J=2.4Hz,1H),6.86(s,1H),6.81-6.77(m,2H),4.90-4.84(m,1H),4.23(s,4H),3.65(s,2H),2.48-2.39(m,3H),2.03(d,J=11.2Hz,2H),1.65(d,J=10.4Hz,2H),1.22-1.12(m,2H). 13 C NMR(100MHz,DMSO-d6):δ164.41,164.05,156.76,143.53,142.43,134.80,133.67,132.66,127.81,127.77,124.33,122.82,122.62,122.35,121.11,117.00,116.91,115.94,64.53,64.46,55.05,53.08,49.84,33.05,27.40.HRMS(ESI)(m / z):[M+H]+calcd for C 27 H 26 N2O5,459.1915;found,459.1915.

[0211]

[0212] Example 20

[0213] Preparation of compound N20

[0214] Step (a) is basically the same as that in Example 17, except that the naphthalic anhydride compound is different. The structural formula of the naphthalic anhydride compound 1-e in Example 20 is shown below. The prepared intermediate compound 2-e is a light yellow solid with a yield of 16%, and the structural formula of 2-e is as follows;

[0215] Step (b) is basically the same as that in Example 10, except that intermediate compound 2-e and aldehyde compound 14 are used. The prepared compound N20 is a light yellow solid with a yield of 40%. The structural formula of compound N20 is shown below, and the test data are as follows: 11H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 6.8 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 6.85 - 6.78 (m, 3H), 5.07 - 5.00 (m, 1H), 4.26 (s, 4H), 3.74 (s, 2H), 2.69 - 2.57 (m, 3H), 2.10 (d, J = 12.0 Hz, 2H), 1.76 (d, J = 10.4 Hz, 2H), 1.40 - 1.29 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 163.99, 163.97, 143.46, 142.48, 134.20, 132.89, 131.89, 131.12, 131.07, 130.50, 129.83, 129.01, 128.07, 123.65, 122.78, 121.02, 117.14, 116.85, 64.40, 64.36, 55.10, 53.46, 50.61, 33.17, 27.29. HRMS (ESI) (m / z): [M + H]+ calcd for C 27 H 25 BrN2O4, 521.1071; found, 521.1069.

[0216]

[0217] Example 21

[0218] Preparation of Compound N21

[0219] Step (a) is basically the same as that in Example 1, except that the naphthalic anhydride compound is different. The structural formula of the naphthalic anhydride compound 1-f in Example 21 is shown as follows. The prepared intermediate compound 2-f is a pale yellow solid with a yield of 17%. The structural formula of 2-f is as follows;

[0220] Step (b) is basically the same as that in Example 10, except that the intermediate compound 2-f and the aldehyde compound 14 are used. The prepared compound N21 is a pale yellow solid with a yield of 35%. The structural formula of compound N21 is shown as follows, and the test data: 11H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 7.6 Hz, 1H), 7.85 - 7.78 (m, 2H), 6.85 - 6.78 (m, 3H), 5.07 - 5.00 (m, 1H), 4.26 (s, 4H), 3.74 (s, 2H), 2.70 - 2.57 (m, 3H), 2.11 (d, J = 12.0 Hz, 2H), 1.76 (d, J = 10.8 Hz, 2H), 1.39 - 1.29 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.11, 163.85, 143.45, 142.48, 138.65, 134.15, 131.86, 131.00, 130.26, 129.15, 129.07, 127.83, 127.34, 123.62, 122.12, 121.03, 117.14, 116.85, 64.40, 64.36, 55.10, 53.43, 50.60, 33.16, 27.29. HRMS (ESI) (m / z): [M+H]+ calcd for C 27 H 25 ClN2O4, 477.1576; found, 477.1576.

[0221]

[0222] Example 22

[0223] Preparation of Compound N22

[0224] Step (a) is basically the same as that in Example 1, except that the naphthalenedicarboxylic anhydride compound is different. The structural formula of the naphthalenedicarboxylic anhydride compound 1-g in Example 22 is shown below. The prepared intermediate compound 2-g is a yellow solid with a yield of 22%. The structural formula of 2-g is as follows;

[0225] Step (b) is basically the same as that in Example 10, except that the intermediate compound 2-g and the aldehyde compound 14 are used. The prepared compound N22 is a yellow solid with a yield of 28%. The structural formula of compound N22 is shown below. Test data: 11H NMR (400 MHz, CDCl3): δ 8.82 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 7.2 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.97 (t, J = 7.2 Hz, 1H), 6.85 - 6.78 (m, 3H), 5.07 - 4.99 (m, 1H), 4.26 (s, 4H), 3.75 (s, 2H), 2.70 - 2.56 (m, 3H), 2.12 (d, J = 12.0 Hz, 2H), 1.77 (d, J = 10.4 Hz, 2H), 1.40 - 1.30 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 163.66, 162.82, 149.31, 143.47, 142.51, 134.10, 132.31, 129.95, 129.66, 129.11, 129.03, 127.57, 123.91, 123.57, 123.52, 121.02, 117.16, 116.84, 64.40, 64.36, 55.04, 53.85, 50.60, 33.09, 27.25. HRMS (ESI) (m / z): [M + H]+ calcd for C 27 H 25 N3O6, 488.1816; found, 488.1815.

[0226]

[0227] Example 23

[0228] Preparation of Compound N23

[0229] Step (a) is basically the same as that in Example 1, except that the naphthalic anhydride compound is different. The structural formula of the naphthalic anhydride compound 1-h in Example 23 is shown below. The prepared intermediate compound 2-h is a yellow solid with a yield of 20%. The structural formula of 2-h is as follows;

[0230] Step (b) is basically the same as that in Example 10, except that intermediate compound 2-h and aldehyde compound 14 are used. The prepared compound N23 is a yellow solid with a yield of 32%. The structural formula of compound N23 is shown below. Test data: 11H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 7.2 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.85 - 6.79 (m, 3H), 5.09 - 5.03 (m, 1H), 4.26 (s, 4H), 3.74 (s, 2H), 3.09 (s, 6H), 2.69 - 2.60 (m, 3H), 2.01 (d, J = 12.0 Hz, 2H), 1.74 (d, J = 10.8 Hz, 2H), 1.39 - 1.30 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 160.26, 159.76, 151.91, 138.70, 137.73, 129.35, 127.74, 126.11, 126.04, 125.47, 120.46, 120.18, 118.93, 116.33, 112.39, 112.15, 110.92, 108.64, 59.64, 50.408, 48.18, 45.82, 39.99, 28.43, 22.57. HRMS (ESI) (m / z): [M + H]+ calcd for C 29 H 31 N3O4, 486.2388; found, 486.2388.

[0231]

[0232] Example 24

[0233] Preparation of Compound N24

[0234] Step (a) is basically the same as that in Example 1, except that the naphthalic anhydride compound is different. The structural formula of the naphthalic anhydride compound 1-i in Example 24 is shown as follows. The prepared intermediate compound 2-i is a pale yellow solid with a yield of 18%. The structural formula of 2-i is as follows;

[0235] Step (b) is basically the same as that in Example 10, except that the intermediate compound 2-i and the aldehyde compound 14 are used. The prepared compound N24 is a yellow solid with a yield of 28%. The structural formula of compound N24 is shown as follows, and the test data: 11H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 6.99 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 8.0 Hz, 1H), 5.10 - 5.03 (m, 1H), 4.24 (s, 4H), 3.99 (s, 3H), 3.89 (s, 2H), 2.84 - 2.81 (m, 1H), 2.65 - 2.55 (m, 2H), 2.23 (d, J = 12.0 Hz, 2H), 1.80 (d, J = 11.6 Hz, 2H), 1.67 - 1.58 (m, 2H). 13 13C NMR (100 MHz, DMSO-d6): δ 164.60, 164.19, 158.36, 143.66, 143.50, 133.12, 132.26, 128.55, 127.41, 124.54, 123.70, 122.99, 122.34, 122.15, 117.99, 117.63, 112.74, 64.35, 64.31, 55.86, 54.47, 52.43, 38.16, 29.68, 26.86. HRMS (ESI) (m / z): [M + H]+ calcd for C 28 H 28 N2O5, 473.2071; found, 473.2072.

[0236]

[0237] Example 25

[0238] Preparation of Compound N25

[0239] Step (a) is the same as in Example 1;

[0240] Step (b) is basically the same as that in Example 10, except that the aldehyde compound is different. The structural formula of aldehyde compound 15 in Example 25 is shown below. The prepared compound N25 is a white solid with a yield of 54%. The structural formula of compound N25 is shown below. Test data: 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.2 Hz, 2H), 8.19 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.03 (s, 1H), 7.01 (s, 1H), 5.11 - 5.03 (m, 1H), 3.83 (s, 2H), 2.70 - 2.61 (m, 3H), 2.10 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 10.8 Hz, 2H), 1.38 - 1.29 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 164.62, 158.87 (dd, J = 248.7, 3.6 Hz), 142.50 (t, J = 7.7 Hz), 133.58, 131.48, 131.10, 128.18, 126.94, 123.19, 111.14 (d, J = 24.4 Hz), 55.55, 53.03, 50.08, 33.32, 27.28. HRMS (ESI) (m / z): [M + H]+ calcd for C 25 H 21 ClF2N2O2, 455.1333; found, 455.1337.

[0241]

[0242] Example 26

[0243] Preparation of compound N26

[0244] Step (a) is the same as that in Example 1;

[0245] Step (b) is basically the same as that in Example 10, except that the aldehyde compound is different. The structural formula of aldehyde compound 16 in Example 26 is shown below. The prepared compound N26 is a white solid with a yield of 59%. The structural formula of compound N26 is shown below, and the test data: 1H NMR (400 MHz, CDCl3): δ8.56 (d, J = 7.2 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.01 (s, 1H), 6.99 (s, 1H), 5.11 - 5.03 (m, 1H), 3.83 (s, 2H), 2.69 - 2.60 (m, 3H), 2.10 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 10.8 Hz, 2H), 1.39 - 1.29 (m, 2H). 13C NMR (100 MHz, CDCl3): δ164.61, 159.92 (dd, J = 247.2, 4.3 Hz), 143.81 (t, J = 7.6 Hz), 133.58, 131.47, 131.09, 128.18, 126.94, 123.19, 111.13 (dd, J = 25.3, 2.5 Hz), 95.56, 55.55, 53.03, 50.09, 33.32, 27.28. HRMS (ESI) (m / z): [M + H]+ calcd for C 25 H 21 BrF2N2O2, 499.0827; found, 499.0830.

[0246]

[0247] Example 27

[0248] Preparation of compound N27

[0249] Step (a): It is basically the same as that in Example 1, except that cis-1,4-cyclohexanediamine is used instead of trans-1,4-diaminocyclohexane to prepare intermediate compound 2-j, and the structural formula is as follows;

[0250] Step (b) is basically the same as that in Example 10, except that intermediate compound 2-j and aldehyde compound 14 are used. The prepared compound N27 is a white solid with a yield of 58%. The structural formula of compound N27 is shown below, and the test data: 11H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 7.6 Hz, 2H), 8.18 (d, J = 8.4 Hz, 2H), 7.73 (t, J = 8.0 Hz, 2H), 6.95 (s, 1H), 6.91 - 6.83 (m, 2H), 5.11 - 5.02 (m, 1H), 4.26 (s, 4H), 3.75 (s, 2H), 2.93 - 2.78 (m, 3H), 2.00 (d, J = 14.4 Hz, 2H), 1.65 - 1.53 (m, 4H). 13 13C NMR (100 MHz, CDCl3): δ 164.54, 143.37,

[0251] 142.33, 134.51, 133.48, 131.46, 131.07, 128.19, 126.92, 123.28, 121.13, 117.03, 116.94, 64.42, 64.38, 52.97, 50.25, 49.38, 29.81, 22.85. HRMS (ESI) (m / z): [M + H]+ calcd for C 27 H 26 N2O4, 443.1966; found, 443.1967.

[0252]

[0253] Example 28

[0254] Preparation of Compound N28

[0255] Step (a): It is basically the same as Example 1, except that 1,3 - diamino - propane is used instead of trans - 1,4 - diamino - cyclohexane to prepare intermediate compound 2 - k, and the structural formula is as follows;

[0256] Step (b) is basically the same as Example 10, except that intermediate compound 2 - k and aldehyde compound 14 are used. The prepared compound N28 is a light yellow solid with a yield of 52%. The structural formula of compound N28 is shown as follows, and the test data:

[0257] 1 1H NMR (400 MHz, DMSO - d6): δ 8.48 (d, J = 7.2 Hz, 2H), 8.44 (d, J = 8.4 Hz, 2H), 7.86 (t, J =

[0258] 8.0 Hz, 2H), 6.80 (s, 1H), 6.75 - 6.70 (m, 2H), 4.19 (s, 4H), 4.10 (t, J = 7.6 Hz, 2H), 3.58 (s, 2H), 2.56 (t, J = 7.2 Hz, 2H), 1.84 - 1.77 (m, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 163.91, 143.48,

[0259] 142.50, 134.71, 133.98, 131.74, 131.15, 127.63, 122.51, 121.20, 116.99, 116.95, 64.48, 64.42, 52.54, 46.45, 38.54, 28.12. HRMS (ESI) (m / z): [M + H]+ calcd for C 24 H 22 N2O4, 403.1653; found, 403.1654.

[0260]

[0261] Example 29

[0262] Preparation of Compound N29

[0263] Step (a): Basically the same as Example 1, except that 1,4-diaminobutane was used instead of trans-1,4-diaminocyclohexane to prepare intermediate compound 2-l, the structural formula is as follows;

[0264] Step (b) was basically the same as Example 10, except that intermediate compound 2-l and aldehyde compound 14 were used to prepare Compound N29 as a light yellow solid with a yield of 50%. The structural formula of Compound N29 is shown below, and the test data: 1 H

[0265] NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 7.2 Hz, 2H), 8.44 (d, J = 8.4 Hz, 2H), 7.86 (t, J = 8.0

[0266] Hz, 2H), 6.80 (s, 1H), 6.74 (s, 2H), 4.20 (s, 4H), 4.04 (t, J = 7.6 Hz, 2H), 3.57 (s, 2H), 2.51 (t, J = 7.2 Hz, 2H), 1.71 - 1.63 (m, 2H), 1.53 - 1.45 (m, 2H). 1313C NMR(100MHz,DMSO-d6):δ163.84,143.49,142.50,134.71,133.98,131.75,131.15,127.80,127.64,122.51,121.18,116.97,64.48,

[0268] 64.43,52.66,48.58,27.30,26.00.HRMS(ESI)(m / z):[M+H]+calcd for C 25 H 24 N2O4,417.1809;found,417.1809.

[0269]

[0270] Example 30

[0271] Preparation of Compound N30

[0272] Step (a): Basically the same as Example 1, except that a compound with the following structure was used instead of trans-1,4-diaminocyclohexane to prepare Intermediate Compound 2-m, the structural formula of which is as follows;

[0273] Step (b) was basically the same as Example 10, except that Intermediate Compound 2-m and aldehyde compound 14 were used to prepare Compound N30 as a light yellow solid with a yield of 50%. The structural formula of Compound N30 is shown below, and the test data are as follows:

[0274] 1 1H NMR(400MHz,CDCl3):δ8.60(d,J = 7.2Hz,2H),8.21(d,J = 8.0Hz,2H),7.75(t,J = 7.6Hz,2H),6.80 - 6.74(m,3H),4.23(s,4H),4.08(d,J = 7.2Hz,2H),3.68(s,2H),2.50 - 2.44(m,

[0275] 1H),1.97 - 1.88(m,3H),1.79(d,J = 12.4Hz,2H),1.24 - 1.04(m,4H). 13 13C NMR(100MHz,CDCl3):δ164.51,143.40,142.45,133.84,131.60,131.30,128.22,126.93,122.69,121.10,

[0276] 117.09, 116.93, 64.34, 56.01, 45.72, 36.56, 32.78, 29.59. HRMS(ESI)(m / z): [M + H]+ calcd for C 28 H 28 N2O4, 457.2122; found, 457.2120.

[0277]

[0278] Example 31

[0279] Preparation of Compound N31

[0280] Step (a): Basically the same as Example 1, except that is used instead of trans-1,4-diaminocyclohexane to prepare Intermediate Compound 2-n, the structural formula is as follows;

[0281] Step (b) is basically the same as Example 10, except that Intermediate Compound 2-n and aldehyde Compound 14 are used to prepare Compound N31 as a yellow solid with a yield of 52%. The structural formula of Compound N31 is as shown below, and the test data: 1 H NMR(400MHz, CDCl3): δ8.59(d, J = 7.2Hz, 2H), 8.18(d, J = 8.0Hz, 2H), 7.73(t, J = 8.0Hz, 2H), 7.42(d, J = 8.0Hz, 2H), 6.83(s, 1H), 6.78(s, 2H), 6.57(d, J = 8.4Hz, 2H), 5.27(s, 2H), 4.21(s, 4H), 4.16(s, 2H). 13 C NMR(100MHz, CDCl3): δ164.23, 143.55, 142.73, 133.82, 131.57, 131.27, 130.61, 128.18, 126.87, 122.89, 120.52, 117.30, 116.42, 112.90, 112.86, 64.34, 64.31, 47.94, 43.12. HRMS(ESI)(m / z): [M + H]+ calcd for C 28 H 22 N2O4, 451.1653; found, 451.1651.

[0282]

[0283] Example 32

[0284] Preparation of Compound N32

[0285] Step (a): It is basically the same as Example 1, except that p-phenylenediamine is used instead of trans-1,4-diaminocyclohexane to prepare intermediate compound 2-o, and the structural formula is as follows;

[0286] Step (b) is basically the same as that of Example 10, except that intermediate compound 2-o and aldehyde compound 14 are used. The prepared compound N32 is a yellow solid with a yield of 66%. The structural formula of compound N32 is shown as follows, and the test data: 1 H NMR(400MHz,DMSO-d6):δ8.49-8.47(m,4H),7.87(t,J=7.6Hz,2H),6.99(d,J=8.4Hz,2H),6.90(s,1H),6.87(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.65(d,J=8.4Hz,2H),4.22(s,4H),4.20(s,2H). 13 C NMR(100MHz,DMSO-d6):δ164.41,148.60,143.73,142.68,134.71,133.50,131.90,131.16,129.65,128.21,127.67,124.54,123.20,120.51,117.29,116.30,112.70,64.55,64.44,46.45.HRMS(ESI)(m / z):[M+H]+calcd for C 27 H 20 N2O4,437.1496;found,437.1494.

[0287]

[0288] Example 33

[0289] Preparation of compound N33

[0290] Weigh compound N1 and formaldehyde to carry out reductive amination reaction in methanol or 1,2-dichloroethane. The preparation steps are basically the same as those of step (b) in Example 10. The prepared compound N33 is a white solid with a yield of 73%. The structural formula of compound N33 is shown as follows, and the test data: 11H NMR (400 MHz, CDCl3): δ 8.56 (d, J = 7.2 Hz, 2H), 8.21 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 6.97 - 6.90 (m, 3H), 5.05 - 4.99 (m, 1H), 4.26 (s, 4H), 3.92 (s, 2H), 3.16 - 3.09 (m, 1H), 2.74 - 2.64 (m, 2H), 2.56 (s, 3H), 2.24 (d, J = 10.8 Hz, 2H), 1.87 (d, J = 10.8 Hz, 2H), 1.77 - 1.68 (m, 2H). 13 13C NMR (100 MHz, CDCl3): δ 164.63, 143.32, 142.38, 133.54, 131.46, 131.08, 128.18, 126.94, 123.22, 121.67, 117.49, 116.90, 64.38, 61.18, 57.49, 53.40, 37.65, 27.96, 27.86. HRMS (ESI) (m / z): [M + H]+ calcd for C 28 H 28 N2O4, 457.2122; found, 457.2121.

[0291]

[0292] Example 34

[0293] Preparation of Compound N34

[0294] Step (a): Weigh 1,8-naphthalic anhydride (100 mg, 505 μmol) and place it in a 25 mL round-bottom flask. Add trans-4-aminocyclohexanol (76 mg, 656 μmol) and 3 mL of N,N-dimethylformamide, and then stir the reaction at 90 °C for 4 hours. After the reaction is completed, add a large amount of deionized water to the reaction solution, stir at room temperature for 20 minutes, and a solid precipitates. Filter by suction to obtain the filter cake, and dry it in an infrared oven to obtain 102 mg of intermediate compound 2-x, a white solid, with a yield of 67%. The structural formula of compound 2-x is as follows, and the test data: 1 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 7.2 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.75 (t, J = 7.6 Hz, 2H), 5.10 - 5.04 (m, 1H), 3.85 - 3.79 (m, 1H), 2.75 - 2.66 (m, 2H), 2.13 (d, J = 11.2 Hz, 2H), 1.77 (d, J = 11.6 Hz, 2H), 1.57 - 1.48 (m, 2H).

[0295]

[0296] Measure benzodioxan-6-methanol (40 μL, 301 μmol) and place it in a 25 mL round-bottom flask. Add 2 mL of dichloromethane, and add phosphorus tribromide (32 μL, 331 μmol) at 0 °C. React under argon protection for 3 h. After the reaction is completed, pour the reaction solution into a large amount of ice water, adjust the pH to 7 - 8 with sodium hydroxide solution, add dichloromethane to dissolve, wash with deionized water, dry with anhydrous sodium sulfate, and concentrate. 52 mg of intermediate halogenated compound 1, a pale yellow oil, is obtained with a yield of 90%. The structural formula of intermediate halogenated compound 1 is as follows, and the test data: 1 HNMR(400MHz,CDCl3):δ6.91(d,J=2.0Hz,1H),6.87(dd,J=8.4,2.0Hz,1H),6.81(d,J=8.4Hz,1H),4.43(s,2H),4.25(s,4H).

[0297]

[0298] Step (b): Weigh intermediate compound 2-x (409 mg, 1.38 mmol) and place it in a 50 mL round-bottom flask. Add 4 mL of ultra-dry tetrahydrofuran, add sodium hydride (78 mg, 1.94 mmol) under ice bath, stir for 1 h under argon protection, then add intermediate halogenated compound 1 dissolved well in ultra-dry tetrahydrofuran, and stir at room temperature overnight. After the reaction is completed, add saturated ammonium chloride solution to quench the reaction solution, extract with ethyl acetate, wash with deionized water, and collect the organic phase. The organic phase is dried with anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (dichloromethane:methanol = 60:1, v / v) to obtain 218 mg of compound N34, a white solid, with a yield of 48%. The structural formula of N34 is as follows, and the test data: 1 H NMR(400MHz,CDCl3):δ8.56(d,J=7.2Hz,2H),8.19(d,J=8.0Hz,2H),7.74(t,J=7.6Hz,2H),6.90(s,1H),6.84(s,2H),5.10-5.04(m,1H),4.48(s,2H),4.26(s,4H),3.52-3.47(m,1H),2.68-2.59(m,2H),2.22(d,J=12.4Hz,2H),1.78(d,J=11.2Hz,2H),1.56-1.46(m,2H). 1313C NMR (100 MHz, CDCl3): δ 164.61, 143.43, 142.99, 133.59, 132.30, 131.46, 131.12, 128.17, 126.95, 123.17, 120.91, 117.13, 116.80, 76.27, 69.69, 64.38, 52.73, 32.02, 26.71. HRMS (ESI) (m / z): [M+Na]+ calcd for C 27 H 25 NO5, 466.1625; found, 466.1627.

[0299]

[0300] Biological activity test

[0301] The in vitro antibacterial experiments of the above compounds N1 - N35 against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate-resistant Staphylococcus aureus were carried out as follows:

[0302] According to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) of the United States, the antibacterial activities of the synthesized compounds were tested. The test strains included Staphylococcus aureus (S. aureus ATCC29213), methicillin-resistant Staphylococcus aureus (MRSA ATCC43300), and vancomycin-intermediate-resistant Staphylococcus aureus (VISAXN108). The concentration of the bacterial suspension was adjusted to 1×10 6 CFU / mL. The test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution, and the compounds were diluted with the culture medium by the two-fold dilution method. Then, an equal volume of the bacterial suspension was added, and the mixture was cultured at 37 °C for 17 h. The lowest concentration that completely inhibited the growth of bacteria visually was the minimum inhibitory concentration (MIC), and OD 600 was measured at the same time. The test results are shown in Table 1 below.

[0303] Table 1 In vitro antibacterial activities of the compounds

[0304]

[0305]

[0306] As can be seen from Table 1, the naphthalimide compounds provided by the present invention show strong inhibitory activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate-resistant Staphylococcus aureus, and have clear antibacterial application prospects.

[0307] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the present technical solution, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A naphthalimide compound or a pharmaceutically acceptable salt thereof, characterized in that, Has the structure shown by the following general formula (I) or general formula (II): Each R1 is independently selected from hydrogen, halogen, nitro, hydroxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted acyloxy; R2, R3, and R4 are each independently selected from hydrogen, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy; Y1, Y2, and Y3 are each independently selected from hydrogen or nitrogen; L is selected from substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, five-membered heterocyclic group, six-membered heterocyclic group, C3-C8 alkyl, C3-C8 cycloalkyl; X is selected from one of the following groups: A is selected from an oxygen-containing five- or six-membered heterocycle, a nitrogen-containing five- or six-membered heterocycle, a sulfur-containing five- or six-membered heterocycle; n is any integer from 0 to 6; Indicates the connection site.

2. The naphthalimide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that Each R1 is independently selected from hydrogen, halogen, nitro, hydroxy, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C1-C3 alkylthio, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted acyloxy; R2, R3, and R4 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C3 alkyl-substituted or unsubstituted amino, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy; L is selected from cyclohexyl, phenyl, benzyl, an oxygen- or nitrogen-containing five-membered heterocyclic group, an oxygen- or nitrogen-containing six-membered heterocyclic group, or C3-C8 alkylene; A is selected from one of the following groups: n is 0 or 1.

3. The naphthalimide compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that Each R1 is independently selected from hydrogen, halogen, nitro, hydroxy, amino, dimethylamino, or methoxy; R2, R3, and R4 are each independently selected from hydrogen, halogen, methyl, methoxy, or dimethylamino; L is selected from one of the following groups: X is selected from one of the following groups:

4. The naphthalimide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, Has one of the following structures:

5. A method for preparing the naphthalimide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, comprising the following steps: (a) Preparing intermediate compound 2 by aminolysis reaction of compound 1 with compound R-L-NH2; (b) Preparing the compound by reductive amination reaction or condensation reaction of the intermediate compound 2; in the compound R-L-NH2, R is selected from one or more of NH2, NHMe, or OH; The structural formulas of the compound 1 and the intermediate compound 2 are as follows: Compound 1, Intermediate Compound 2.

6. According to the preparation method of claim 5, characterized in that In the compound R-L-NH2, R is selected from NH2; and / or The intermediate compound 2 undergoes a reductive amination reaction with an aldehyde compound; Among them, the aldehyde compound includes one of the following structural formulas:

7. The preparation method according to claim 5, wherein in the compound R-L-NH2, R is selected from one of NH2, NHMe or OH; and / or the intermediate compound 2 undergoes a condensation reaction with a carboxylic acid compound or a halogenated compound; Among them, the carboxylic acid compound includes one of the following structures: The halogenated compound includes one of the following structures: P is selected from halogens.

8. An antibacterial drug, characterized in that, The antibacterial drug includes the naphthalimide compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

9. The antibacterial drug according to claim 8, wherein The bacteria include one or more of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, vancomycin-intermediate Staphylococcus aureus, Enterococcus faecalis, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Acinetobacter baumannii.

10. The antibacterial drug according to any one of claims 8 to 9, characterized in that, The drug is any one of tablets, capsules, aerosols and ointments.

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