1, 6-naphthyridine amine compound as well as preparation method and application thereof

Abstract

The invention relates to the technical fields of medicines and luminescent materials. The invention discloses a 1, 6-naphthyridine amine compound as shown in a formula (I), a preparation method thereof, a pharmaceutical composition taking the compound as an active ingredient, application of the 1, 6-naphthyridine amine compound in preparation of a medicine for treating cancer, application of the 1, 6-naphthyridine amine compound in preparation of a medicine for treating and / or preventing infectious diseases caused by mycobacterium tuberculosis and application of the 1, 6-naphthyridine amine compound in preparation of a fluorescent dye. Wherein R1, R2, R3 and A ring are described in the specification.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical technology and luminescent materials technology. In particular, it relates to 1,6-naphthidineamine compounds of general formula (I), methods for their preparation, pharmaceutical compositions with the compound as an active ingredient, their use in the preparation of drugs for treating cancer, their use in the preparation of drugs for treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis, and their use in the preparation of fluorescent dyes. Background Technology

[0002] In recent years, small-molecule organic fluorescent materials have been widely used in organic light-emitting diodes, solar-sensitized cells, and biosensing imaging analysis. Commonly used traditional fluorescent dyes such as coumarin, anthocyanins, hemicyanins, BODIPY dyes, rhodamine, fluorescein, and benzothiadiazoles have been extensively studied and commercialized in various fields based on their structural characteristics and different properties. Developing dyes with novel core structures remains a current research hotspot.

[0003] Tuberculosis (TB) is a chronic, fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that threatens human health and causes death. According to the World Health Organization (WHO) (Global Tuberculosis Report 2023), 7.5 million new TB cases were diagnosed worldwide in 2022, with 1.3 million deaths. The situation regarding drug resistance is also concerning; an estimated 410,000 cases developed into multidrug-resistant / rifampicin-resistant TB in 2022. The WHO has proposed the End TB Strategy, but data from 2022 shows that it is far from reaching the 2025 milestone. Therefore, the development of anti-TB drugs with novel structures and mechanisms is particularly urgent.

[0004] Cancer remains one of the most difficult diseases to conquer worldwide. Current cancer treatment employs multi-drug combination strategies, but drug resistance is easily developed, leading to treatment failure. Developing anti-tumor drugs with novel structures and mechanisms has always been a relentless pursuit for scientists.

[0005] The literature (Novel Tacrine Analogues for Potential Use against Alzheimer's Disease: Potent and Selective Acetylcholinesterase Inhibitors and 5-HT Uptake Inhibitors. Journal of Medicinal Chemistry, 1997, 40(22): 3516-3523) discloses compound a with the following structure:

[0006]

[0007] However, the literature only mentions its inhibitory effect on norepinephrine uptake, and does not teach that 1,6-naphthidine-4-amine compounds have effects against tumors and Mycobacterium tuberculosis, nor does it report that these compounds have fluorescent properties.

[0008] US10023599 B2 discloses a class of platinum-benzo[a]acridine] derivative hybrids, specifically involving compound bf with the following structure (compound b is a reaction intermediate, and compound cf is a compound listed in the patent document that can be synthesized):

[0009]

[0010] However, the patent does not contain data to support the claim that these compounds possess anticancer activity, and those skilled in the art cannot infer such activity from the patent data. Furthermore, the patent does not provide any guidance on the anti-tuberculosis activity of these compounds, nor does it provide guidance on their fluorescent properties. Summary of the Invention

[0011] The technical problem this invention aims to solve is to provide a novel 1,6-naphthidineamine derivative. This class of compounds exhibits fluorescent properties and has broad application prospects in optoelectronic materials and fluorescent probe design. Furthermore, these compounds possess anti-tuberculosis activity and can be used for the treatment of tuberculosis. In addition, they possess anti-tumor activity and have application value in anti-cancer applications. This invention is based on the above findings. Invention Overview

[0013] The first aspect of the present invention provides a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0014]

[0015] in,

[0016] R1, R2, and R3 are independently selected from hydrogen, hydroxyl, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, trifluoromethyl, -NR4R5, phenyl;

[0017] R4 and R5 are independently selected from hydrogen, C 1-6 alkyl;

[0018] Ring A is a benzene ring or does not exist;

[0019] Compounds that do not include the following structures:

[0020]

[0021] In another preferred embodiment, the compound is represented by general formula (II):

[0022]

[0023] in,

[0024] R1 is selected from hydrogen, halogen, C 1-3 Alkyl, -NR4R5, phenyl;

[0025] R2 is selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, trifluoromethyl;

[0026] R4 and R5 are C 1-6 alkyl;

[0027] The following structures are not included:

[0028]

[0029] In another preferred embodiment, as shown in equation (II), wherein,

[0030] R1 is selected from hydrogen, Br, methyl, diethylamino, and phenyl;

[0031] R2 is selected from hydrogen, F, Br, methyl, trifluoromethyl, and methoxy.

[0032] R1 and R2 are not both hydrogen.

[0033] In another preferred embodiment, the compound is as shown in general formula (III).

[0034]

[0035] in,

[0036] R1, R2, and R3 are independently selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3Alkoxy, trifluoromethyl, -NR4R5, phenyl;

[0037] R4 and R5 are C 1-6 alkyl.

[0038] In another preferred embodiment, the compound is as shown in general formula (III), wherein,

[0039] R1, R2, and R3 are independently selected from hydrogen, F, Cl, Br, methyl, methoxy, trifluoromethyl, diethylamino, and phenyl.

[0040] The pharmaceutically acceptable salts described in this invention are salts formed by the compounds of this invention with an acid selected from the following: sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, fumaric acid, succinic acid, malic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid, acetic acid, or trifluoroacetic acid.

[0041] According to any one of the compounds of the first aspect of the present invention, the compound is selected from:

[0042]

[0043]

[0044] A second aspect of the present invention provides a method for preparing the compound according to any one of the first aspects of the present invention, comprising the following steps:

[0045]

[0046] The compound with the structure shown in Formula IV was placed in an acidic medium and cyclized under stirring at 0-100°C to obtain the compound shown in Formula I.

[0047] The acidic medium is selected from one or more of sulfonic acid, sulfuric acid, perchloric acid, trifluoroacetic acid, and acetic acid, or a combination of one or more of the aforementioned acids and a solvent.

[0048] The sulfonic acid is preferably trifluoromethanesulfonic acid, benzenesulfonic acid, or methanesulfonic acid, and more preferably trifluoromethanesulfonic acid;

[0049] The solvent is preferably chloroform, 1,2-dichloroethane, dichloromethane, ethyl acetate, toluene, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, and more preferably chloroform, 1,2-dichloroethane, dichloromethane, and even more preferably dichloromethane;

[0050] The temperature is preferably 0-100℃, more preferably 0-70℃, in some embodiments room temperature, and in some embodiments 60℃;

[0051] The definitions of R1, R2, R3 and ring A are as described in the first aspect of this invention.

[0052] A third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically and / or preventively effective amount of any of the compounds of the first aspect or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0053] The fourth aspect of this invention provides the use of any of the compounds described in the first aspect of this invention or their pharmaceutically acceptable salts, or any of the pharmaceutical compositions described in the third aspect of this invention, in the preparation of a medicament for treating cancer. The cancers are selected from lung cancer, colorectal cancer, liver cancer, breast cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, leukemia, non-Hodgkin's lymphoma, brain tumors, bladder cancer, ovarian cancer, oral cancer, kidney cancer, multiple myeloma, pharyngeal cancer, uterine cancer, gallbladder cancer, nasopharyngeal carcinoma, melanoma, oropharyngeal cancer, thyroid cancer, laryngeal carcinoma, mesothelioma, salivary gland cancer, Hodgkin's lymphoma, etc. Preferred cancers include stomach cancer, liver cancer, glioma, lung cancer, and breast cancer.

[0054] The fifth aspect of the present invention provides the use of any of the compounds of the first aspect of the present invention or pharmaceutically acceptable salts thereof, or any of the pharmaceutical compositions of the third aspect of the present invention, in the preparation of medicaments for treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis.

[0055] The sixth aspect of the present invention provides the use of any of the compounds described in the first aspect of the present invention or pharmaceutically acceptable salts thereof in the preparation of organic light-emitting materials, organic fluorescent dyes, fluorescent probes and fluorescent dyes for cell imaging. Detailed description of the invention:

[0057] The various aspects and features of the present invention will be further described below.

[0058] All references cited in this invention are incorporated herein by reference in their entirety, and in the event of any inconsistency between the meanings expressed in these references and those expressed herein, the meanings expressed herein shall prevail. Furthermore, the various terms and phrases used in this invention have their general meanings known to those skilled in the art; however, this invention still intends to provide a more detailed explanation and interpretation of these terms and phrases. In the event of any inconsistency between the mentioned terms and their known meanings and those expressed herein, the meanings expressed herein shall prevail. The following are definitions of various terms used in this invention, and these definitions apply to all terms used throughout this specification, unless otherwise specified in the specific context.

[0059] The carbon atom content of various hydrocarbon-containing fractions is indicated by prefixes specifying the minimum and maximum number of carbon atoms in that fraction. C i-j This represents a portion having an integer number of carbon atoms from "i" (inclusive) to "j" (inclusive). Therefore, for example, C 1-4Alkyl refers to an alkyl group having 1 to 4 (including 1 and 4) carbon atoms, particularly methyl, ethyl, C3 alkyl and C4 alkyl.

[0060] As described herein, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which is either straight-chain or branched, and may include its daughter groups, such as those mentioned above. 1-4 When "alkyl" is used, it may also include C 1-3 Alkyl, C 1-2 Alkyl, C 2-4 Alkyl, C 3-4 The term "alkyl" refers to a subrange of groups, including specific groups such as methyl, ethyl, n-propyl, and isopropyl. The terms "alkoxy" and "alkylamine" are conventional expressions referring to alkyl groups, respectively, attached to the remainder of a molecule via an oxygen atom or an amino group, as described in this invention. Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, etc. Alkamine groups include, but are not limited to, methylamino, ethylamino, isopropylamino, n-propylamino, etc.

[0061] As described herein, the terms “halogen,” “halogen,” “halogen atom,” “halogenated,” etc., refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0062] The substructure shown in formula (V) indicates the presence or absence of ring A. When ring A is present, the R3 group is also present, as shown in formula (VI). When ring A is absent, the compound is shown in formula (VII), in which case R1 can be substituted at a substituted position on the benzene ring in the structure shown.

[0063]

[0064] As described herein, the term "effective amount" refers to a dosage of medicine that can achieve the desired therapeutic effect on the disease or condition described in this invention in a subject.

[0065] As described herein, the term "pharmaceutically acceptable," for example, when describing "pharmaceutically acceptable salt," indicates that the salt is not only physiologically acceptable to the subject but can also refer to a synthetic substance with pharmaceutical value, such as a salt formed as an intermediate during chiral resolution, although such intermediate salt cannot be directly given to the subject, but can play a role in obtaining the end product of the present invention.

[0066] As described herein, the term "pharmaceutical composition" can also refer to a "composition" that can be used to treat the disease or condition described in this invention in subjects, particularly mammals.

[0067] The term "cancer" can also refer to "tumor," including lung cancer, colorectal cancer, liver cancer, breast cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, leukemia, non-Hodgkin's lymphoma, brain tumors, bladder cancer, ovarian cancer, oral cancer, kidney cancer, multiple myeloma, pharyngeal cancer, uterine cancer, gallbladder cancer, nasopharyngeal cancer, melanoma, oropharyngeal cancer, thyroid cancer, laryngeal cancer, mesothelioma, salivary gland cancer, Hodgkin's lymphoma, etc.

[0068] The “treatment” of the disease includes:

[0069] (1) Prevention of the disease, that is, preventing the development of clinical symptoms of the disease in mammals that are exposed to or susceptible to the disease but do not experience or show symptoms of the disease.

[0070] (2) Inhibit the disease, that is, stop or reduce the progression of the disease or its clinical symptoms.

[0071] (3) To alleviate the disease, that is, to restore the disease or its clinical symptoms.

[0072] "Therapeutic effective amount" refers to the amount of a compound sufficient to treat a disease when administered to a mammal. Therapeutic effective amount will vary depending on the compound, the disease to be treated and its severity, and factors such as the mammal's age, weight, and sex. Therapeutic effective amount can also refer to any amount of a compound sufficient to achieve the desired beneficial effect, including disease prevention, disease inhibition, or disease ablation as described in (1)-(3) above. For example, the amount of the compound may be between 0.1-250 mg / kg, or preferably, 0.5-100 mg / kg, or more preferably, 1-50 mg / kg, or even more preferably, 2-20 mg / kg. Preferably, the amount of the compound is administered to the mammal twice daily. More preferably, the amount of the compound is administered to the mammal once daily. More preferably, the amount of the compound is administered to the mammal once weekly or once every two weeks.

[0073] As described herein, the term "disease and / or symptom" refers to a physical condition of the subject that relates to the disease and / or symptom described in this invention. For example, the disease and / or symptom described in this invention refers to a tuberculosis infection.

[0074] As described herein, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., that receives a compound of Formula I of the present invention or a pharmaceutical composition thereof to treat the disease or condition described herein.

[0075] Another aspect of the invention relates to pharmaceutical compositions using compounds of the invention as active ingredients. These pharmaceutical compositions can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0076] The compounds or pharmaceutical compositions containing them in this invention can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0077] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0078] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0079] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and cosolvents can be talc, silica, magnesium stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0080] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0081] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a solubilizer, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and solubilizers used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0082] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0083] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0084] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0085] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0086] Beneficial technical effects

[0087] The inventors have discovered that the compounds of this invention possess fluorescent properties, showing broad application prospects in the fields of optoelectronic materials and fluorescent probe design. Furthermore, these compounds exhibit anti-tuberculosis activity and can be used for the treatment of tuberculosis. Additionally, these compounds possess anti-tumor activity and have application value in anti-cancer applications. Attached Figure Description

[0088] Figure 1 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 1 are shown.

[0089] Figure 2 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 2 are shown.

[0090] Figure 3 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 3 are shown.

[0091] Figure 4 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 4 are shown.

[0092] Figure 5 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 5 are shown.

[0093] Figure 6 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 6 are shown.

[0094] Figure 7 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 7 are shown.

[0095] Figure 8 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 8 are shown.

[0096] Figure 9 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 9 are shown.

[0097] Figure 10 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 10 are shown.

[0098] Figure 11 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 11 are shown.

[0099] Figure 12 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 12 are shown.

[0100] Figure 13 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 13 are shown.

[0101] Figure 14 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 14 are shown.

[0102] Figure 15 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 15 are shown.

[0103] Figure 16 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 16 are shown.

[0104] Figure 17The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 17 are shown.

[0105] Figure 18 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 18 are shown.

[0106] Figure 19 The UV-Vis absorption spectrum (blue dashed line) and fluorescence emission spectrum (red solid line) of compound 19 are shown. Detailed Implementation

[0107] The present invention will be described in detail through the following embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0108] For all the following examples, standard operating and purification methods known to those skilled in the art were used. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds were determined by nuclear magnetic resonance (NMR) spectroscopy and / or mass spectrometry (MS). Melting points (Mp) are given in °C without temperature correction.

[0109] Preparation Examples

[0110] The structure of the compound was determined by nuclear magnetic resonance (NMR) hydrogen spectrum (1H NMR). 1 The NMR spectrum was determined by 1H NMR or high-resolution mass spectrometry (HR-MS). The 1H NMR shift (δ) is given in parts per million (ppm). The coupling constant (J) is in Hertz (Hz). NMR spectra were determined using a QOne-400, JEOL-500, or AVANCE NEO 700 NMR spectrometer, with deuterated acetic acid (CD3COOD) or deuterated dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as internal standard. Melting points were determined using an MP470 fully automated video melt analyzer from Jinan Haineng Instrument Co., Ltd., without temperature correction. High-resolution mass spectrometry was performed using a ThermoFisher Exactive Plus mass spectrometer (ESI, ThermoFisher Scientific, Bremen, Germany). An electronic balance was used, specifically a Yanaco LY-300 electronic balance from Japan. Column chromatography typically used 200–300 mesh or 300–400 mesh silica gel as the support. All anhydrous solvents were processed using standard methods. All other reagents were commercially available analytical grade.

[0111] Example

[0112] Example 1

[0113]

[0114] Preparation of 4-chloro-7-methoxyquinoline-3-carboxynitrile A1

[0115] 2.5 g of methyl 2-amino-4-methoxybenzoate and 1.8 mL of DMF-DMA were added to a double-necked flask and heated under reflux for 12 h. The reaction was monitored by TLC until completion. 1.12 g of sodium methoxide was added, followed by 1.1 mL of ultra-dry acetonitrile and 30 mL of anhydrous toluene under argon protection. The mixture was heated under reflux for 12 h, and the starting material disappeared under TLC. Ethyl acetate and water were added to the reaction mixture, and the solution was extracted with water. The aqueous phases were combined, and the pH was adjusted to acidic with 2N HCl. A solid precipitated, was filtered, and dried to obtain a brown solid. 10 mL of the brown solid and SOCl2 were added to a single-necked flask and heated under reflux for 8 h. The reaction was monitored by TLC until completion. The reactants were concentrated, 30 mL of water was added, the pH was adjusted to neutral with saturated K2CO3 solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 300 mg of white solid, with a yield of 14%. 1 H-NMR (400MHz, DMSO-d6): δ9.07 (s, 1H), 8.16 (d, J = 8.8Hz, 1H), 7.52-7.48 (m, 2H), 3.99 (s, 3H).

[0116] Preparation of 7-methoxy-4-aniline-quinoline-3-carboxynitrile B1

[0117] 4-Chloro-7-methoxyquinoline-3-carboxynitrile (150 mg), aniline (0.069 mL), and isopropanol (4 mL) were added to a single-necked flask and heated under reflux for 8 h. The reaction was monitored by TLC until it was complete. 15 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 80 mg of a yellow solid, with a yield of 43%. 1 ¹H-NMR (400MHz, DMSO-d⁶): δ 9.71 (s, 1H), 8.54 (s, 1H), 8.36 (d, J = 9.6Hz, 1H), 7.40 (t, J = 7.6Hz, 2H), 7.34 (s, 1H), 7.30–7.20 (m, 4H), 3.94 (s, 3H). Preparation of 3-methoxydibenzo[b,h][1,6]naphthyl-7-amine (compound 1).

[0118] B1 (60 mg) was dissolved in 1.8 mL of DCM, and trifluoromethanesulfonic acid (0.192 mL, 10 equivalents) was added. The mixture was stirred at room temperature for 0.5 hours, and the reaction was confirmed to be complete by TLC. The solution was concentrated to remove dichloromethane, and the pH was adjusted to alkaline by adding saturated K2CO3 aqueous solution. A large amount of solid precipitated out. After filtration, washing, and drying, 50 mg of a yellow solid was obtained, with a yield of 83%. 1 H-NMR (700MHz, CD3COOD-d4): δ9.47(s,1H),8.60(d,J=9.1Hz,1H),8.31(d,J=8.4Hz,1H),7.96(d, J=8.4Hz,1H),7.82(t,J=7.7Hz,1H),7.53-7.49(m,2H),7.18(dd,J=9.1,2.8Hz,1H),3.99(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3O: 276.1131; Measured value: 276.1125. Melting point > 280℃.

[0119] Example 2

[0120]

[0121] Referring to Example 1, 6-methoxy-4-aniline-quinoline-3-carboxynitrile B2 can be obtained from methyl 2-amino-5-methoxybenzoate as a raw material. It is a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ11.05(s,1H),8.93(s,1H),8.15(d,J=2.8Hz,1H),7.98(d,J=9 .2Hz,1H),7.70(dd,J=9.2,2.4Hz,1H),7.57-7.49(m,2H),7.47-7.38(m,3H),3.97(s,3H).

[0122] Feeding with B2 (15 mg) yields 12 mg of 2-methoxydibenzo[b,h][1,6]naphthidine-7-amine (compound 2), a yellow solid, with a yield of 80%. 1H-NMR (400MHz, DMSO-d6): δ9.62(s,1H),8.52-8.46(m,2H),8.28(s,2H),8.02(d,J=8.8Hz,1H),7.93(d ,J=8.8Hz,1H),7.81(t,J=6.8Hz,1H),7.48(t,J=7.2Hz,1H),7.41(dd,J=9.2,2.8Hz,1H).4.00(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3O: 276.1131; Measured value: 276.1128. Melting point: 182.8℃.

[0123] Example 3

[0124]

[0125] Referring to Example 1, 7-methyl-4-anilinequinoline-3-carboxynitrile B3 can be obtained from methyl 2-amino-4-methylbenzoate as a raw material. It is a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ11.45(s,1H), δ9.04(s,1H),8.73(d,J=8.8Hz,1H),7.86(s,1H),7.70(d,J=8.6Hz,1H),7.56-7.40(m,5H),2.58(s,3H).

[0126] Feeding with B3 (70 mg) yields 65 mg of 3-methyldibenzo[b,h][1,6]naphthidine-7-amine (compound 3), a yellow solid, with a yield of 93%. 1 H-NMR (400MHz, DMSO-d6): δ9.71(s,1H),8.96(d,J=8.2Hz,1H),8.50(d,J=8.4Hz,1H), 8.32(s,2H),7.98(d,J=8.4Hz,1H),7.83-7.79(m,2H),7.54-7.43(m,2H),2.55(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3: 260.1182; Measured value: 260.1175. Melting point > 280℃.

[0127] Example 4

[0128]

[0129] Referring to Example 1, 6-methyl-4-aniline-quinoline-3-carboxynitrile B4 can be obtained from methyl 2-amino-5-methylbenzoate as a raw material. It is a white solid. 1 H-NMR (400MHz, DMSO-d6): δ9.90 (s, 1H), δ8.57 (s, 1H), 8.33 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.72 (dd, J=10.8, 1.6Hz, 1H), 7.46-7.40 (m, 2H), 7.32-7.24 (m, 3H), 2.53 (s, 3H).

[0130] Feeding with B4 (100 mg) yields 75 mg of 2-methyldibenzo[b,h][1,6]naphthidine-7-amine (compound 4), a yellow solid, with a yield of 75%. 1 H-NMR (500MHz, CD3COOD-d4): δ9.54(s,1H),8.54(s,1H),8.39(d,J=8.5Hz,1H),8.08(d,J=8.0Hz,1H), 7.96(d,J=8.5Hz,1H),7.87(t,J=7.5Hz,1H),7.67(d,J=8.5Hz,1H),7.58(t,J=8.0Hz,1H),2.53(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3: 260.1182; Measured value: 260.1177. Melting point > 280℃.

[0131] Example 5

[0132]

[0133] Referring to Example 1, 7-bromo-4-aniline-quinoline-3-carboxylonite B5 can be obtained from methyl 2-amino-4-bromobenzoate as a raw material. It is a yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ11.59(s,1H), δ9.02(s,1H), 8.83(d,J=9.2Hz,1H), 8.34(d,J=2.0Hz,1H), 8.00(dd,J=9.2,2.0Hz,1H), 7.54-7.38(m,5H).

[0134] Feeding with B5 (70 mg) yields 65 mg of 3-bromodibenzo[b,h][1,6]naphthidine-7-amine (compound 3), a yellow solid, with a yield of 93%. 1H-NMR (400MHz, DMSO-d6): δ9.74(s,1H),8.93(d,J=8.8Hz,1H),8.74(brs,2H),8.52(d,J= 8.4Hz, 1H), 8.18 (s, 1H), 8.01 (d, J = 8.4Hz, 1H), 7.92-7.82 (m, 2H), 7.55 (t, J = 7.6Hz, 1H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 BrN3: 324.0131; Measured value: 324.0127. Melting point > 280℃.

[0135] Example 6

[0136]

[0137] Referring to Example 1, 6-bromo-4-aniline-quinoline-3-carboxynitrile B6 can be obtained from methyl 2-amino-5-bromobenzoate as a raw material. It is a light yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.91(s,1H),8.78(d,J=2.2Hz,1H),8.60(s,1H),7.97(dd ,J=8.8,2.0Hz,1H),7.87(d,J=8.8Hz,1H),7.42(t,J=7.8Hz,2H),7.36-7.20(m,3H).

[0138] Feeding with B6 (70 mg) yields 63 mg of 2-bromodibenzo[b,h][1,6]naphthidine-7-amine (compound 6), a yellow solid, with a yield of 90%. 1 H-NMR (400MHz, DMSO-d6): δ9.76 (s, 1H), 9.18 (s, 1H), 8.52 (d, J = 8.6Hz, 1H), 8.42 (s, 2H) ,8.03(d,J=8.4Hz,1H),7.98-7.90(m,2H),7.84(t,J=7.6Hz,1H),7.51(t,J=7.6Hz,1H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 BrN3: 324.0131; Measured value: 324.0125. Melting point > 280℃.

[0139] Example 7

[0140]

[0141] Preparation of 4-chloro-6-fluoroquinoline-3-carboxynitrile A7

[0142] 2.5 g of 6-fluoro-4-hydroxyquinoline-3-carboxylic acid was added to a reaction flask, along with 20 mL of SOCl2. The mixture was heated under reflux for 8 h, and the reaction solution was concentrated. The solution was dissolved in 10 mL of THF and added dropwise to a THF solution saturated with ammonia at room temperature. The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC until it was complete. The reaction mixture was then concentrated, and 40 mL of water was added to wash the solid. The solid was filtered and dried to obtain 2.5 g of white solid, with a yield of 92%. 1 H-NMR (400MHz, DMSO-d6): δ8.86 (s, 1H), 8.26-8.17 (m, 2H), 8.03-7.96 (m, 2H), 7.85 (td, J = 8.8, 2.8Hz, 1H).

[0143] The above solid (1.5 g) and triethylamine (1.86 mL) were added to a dry double-necked flask. Under argon protection, 15 mL of anhydrous dichloromethane was added, and the system was cooled in an ice-water bath. 1.7 mL of trifluoromethanesulfonic anhydride was slowly added dropwise. After stirring for 30 min, the mixture was transferred to room temperature and stirred for another 6 h. The reaction was monitored by TLC until complete. 50 mL of water was added to the reaction solution to quench excess trifluoromethanesulfonic anhydride. The mixture was extracted with DCM, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain A7, a white solid of 1.25 g, with a yield of 91%. 1 H-NMR (400MHz, DMSO-d6): δ9.21 (s, 1H), 8.32-8.38 (m, 1H), 8.09 (dd, J = 9.4, 2.8Hz, 1H), 8.02 (td, J = 8.4, 2.8Hz, 1H).

[0144] Preparation of 6-fluoro-4-aniline-quinoline-3-carboxynitrile B7

[0145] 4-Chloro-6-fluoroquinoline-3-carboxynitrile (500 mg), aniline (0.24 mL), and isopropanol were added to a reaction flask and heated under reflux for 8 h. The reaction was monitored by TLC until it was complete. 15 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 162 mg of a pale yellow solid, with a yield of 25%. 1H-NMR (400MHz, DMSO-d6): δ9.76 (s, 1H), 8.57 (s, 1H), 8.32 (dd, J = 6.4, 1.6Hz, 1H), 8.02-8.00 (m, 1H ),7.77(td,J=5.2,1.6Hz,1H),7.43(t,J=4.8Hz,2H),7.32(d,J=4.0Hz,2H),7.28(t,J=4.4Hz,1H).

[0146] Preparation of 2-fluorodibenzo[b,h][1,6]naphthidine-7-amine (compound 7)

[0147] Following the preparation method of compound 1 in Example 1, using B7 (80 mg) as a raw material, 72 mg of 2-fluorodibenzo[b,h][1,6]naphthidine-7-amine (compound 7) was obtained as a yellow solid with a yield of 90%. 1 H-NMR (700MHz, DMSO-d6): δ9.73(s,1H),8.69(dd,J=9.8,2.8Hz,1H),8.52(dd,J=8.4,1.4Hz,1H),8.40(s,2H),8 .07-8.05(m,1H),8.01(dd,J=8.4,1.4Hz,1H),7.85-7.82(m,1H),7.67(td,J=8.4,2.8Hz,1H),7.54-7.49(m,1H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 FN3: 264.0932; Measured value: 264.0943. Melting point > 280℃.

[0148] Example 8

[0149]

[0150] Referring to Example 7, 7-trifluoromethyl-4-hydroxyquinoline-3-carboxylic acid was used as a raw material to obtain 7-trifluoromethyl-4-aniline-quinoline-3-carboxynitrile B8. It is a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ10.12(s,1H),8.81-8.67(m,2H),8.24(s,1H),7.95(d,J=8.8Hz,1H),7.44(t,J=8.0Hz,2H),7.37-7.27(m,3H).

[0151] Using B8 (26 mg) as a starting material, 21 mg of 3-trifluoromethyldibenzo[b,h][1,6]naphthidine-7-amine (compound 8) was obtained as a yellow solid with a yield of 85%.1 H-NMR (400MHz, DMSO-d6): δ9.85(s,1H),9.27(d,J=8.4Hz,1H),8.54(d,J=8.4Hz,1H),8.49(s,2H),8.29 (s, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.96 (dd, J = 8.4, 2.0Hz, 1H), 7.86 (t, J = 7.2Hz, 1H), 7.54 (t, J = 7.6Hz, 1H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 11 F3N3: 314.0884; Measured value: 314.0894. Melting point > 280℃.

[0152] Example 9

[0153]

[0154] Referring to Example 7, 8-methyl-4-hydroxyquinoline-3-carboxylic acid was used as a raw material to obtain 8-methyl-4-aniline-quinoline-3-carboxynitrile B9. It is a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.75(s,1H),8.62(s,1H),8.31(d,J=8.4Hz,1H),7.71(d,J=7 .2Hz,1H),7.52(t,J=7.6Hz,1H),7.41(t,J=8.0Hz,2H),7.31-7.20(m,3H),2.67(s,3H).

[0155] Using B9 (100 mg) as a starting material, 90 mg of 4-methyldibenzo[b,h][1,6]naphthidine-7-amine (compound 9) can be obtained as a yellow solid with a yield of 90%. 1 H-NMR (500MHz, CD3COOD-d4): δ9.59(d,J=2.5Hz,1H),8.58(d,J=8.0Hz,1H),8.33(d,J=8.5Hz,1H),8. 03(d,J=8.5Hz,1H),7.81(t,J=7.0Hz,1H),7.66(d,J=7.0Hz,1H),7.51(t,J=6.4Hz,2H),2.72(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3: 260.1182; Measured value: 260.1191. Melting point > 280℃.

[0156] Example 10

[0157]

[0158] Referring to Example 1, 8-bromo-4-aniline-quinoline-3-carboxynitrile B10 can be obtained from methyl 2-amino-3-bromobenzoate as a raw material. It is a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ8.53-8.44 (m, 2H), 8.11 (d, J = 7.6Hz, 1H), 7.47-7.13 (m, 7H).

[0159] Using B10 (70 mg) as a starting material, 64 mg of 4-bromodibenzo[b,h][1,6]naphthidine-7-amine (compound 10) was obtained as a yellow solid with a yield of 91%. 1 H-NMR (400MHz, DMSO-d6): δ9.80(s,1H),9.09(d,J=8.0Hz,1H),8.62(brs,2H),8.54(d,J=8.4H z, 1H), 8.15 (d, J = 7.6Hz, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.87 (t, J = 7.6Hz, 1H), 7.65-7.48 (m, 2H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 BrN3: 324.0131; Measured value: 324.0157. Melting point > 280℃.

[0160] Example 11

[0161]

[0162] Referring to Example 7, 8-fluoro-4-hydroxyquinoline-3-carboxylic acid was used as a raw material to obtain 8-fluoro-4-aniline-quinoline-3-carboxynitrile B11. It is a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.77(s,1H),8.92-8.85(m,1H),8.53(d,J=8.4Hz,1H),8.46(s,2 H), 8.01 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.87-7.82 (m, 1H), 7.69-7.58 (m, 2H), 7.55-7.49 (m, 1H).

[0163] Using B11 (100 mg) as a raw material, 95 mg of 4-fluorodibenzo[b,h][1,6]naphthidine-7-amine (compound 11) was obtained as a yellow solid with a yield of 95%. 1H-NMR (400MHz, DMSO-d6): δ9.77(s,1H),8.95-8.83(m,1H),8.53(d,J=8.8Hz,1H),8.45(s, 2H), 8.01 (d, J = 8.4Hz, 1H), 7.85 (t, J = 7.6Hz, 1H), 7.71-7.59 (m, 2H), 7.52 (t, J = 7.6Hz, 1H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 FN3: 264.0932; Measured value: 264.0926. Melting point > 280℃.

[0164] Example 12

[0165]

[0166] Preparation of 4-chloro-quinoline-3-carboxynitrile A12

[0167] 2 g of 4-hydroxyquinoline-3-carboxylic acid was added to a reaction flask, along with 6 mL of SOCl2. The mixture was heated under reflux for 8 h, and the reaction solution was concentrated. The solution was dissolved in 40 mL of THF and added dropwise to a THF solution saturated with ammonia at room temperature. The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC until it was complete. The reactants were then concentrated, and the solid was washed with 40 mL of water. After filtration and drying, 1.84 g of white solid was obtained, with a yield of 84%. 1 H-NMR (400MHz, DMSO-d6): δ8.88(s,1H),8.31(d,J=8.4Hz,1H),8.20(s,1H),8.14(d,J=8.4Hz,1H),8.03-7.96(m,2H),7.85(td,J=8.8,2.8Hz,1H).

[0168] The above solid (2.7 g) and triethylamine (5.4 mL) were added to a dry double-necked flask. Under argon protection, 7.5 mL of anhydrous dichloromethane was added, and the system was cooled in an ice-water bath. 3.3 mL of trifluoromethanesulfonic anhydride was slowly added dropwise. After stirring for 30 min, the mixture was transferred to room temperature and stirred for another 6 h. The reaction was monitored by TLC until complete. 100 mL of water was added to the reaction solution, and the mixture was extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 1.5 g of A12, a white solid, in 61% yield. 1 H-NMR (400MHz, DMSO-d6): δ9.20(s,1H),8.33(d,J=9.6Hz,1H),8.20(d,J=8.8Hz,1H),8.08(t,J=6.8Hz,1H),7.93(t,J=7.2Hz,1H).

[0169] Preparation of 4-o-methylaniline-3-formonitrile B12

[0170] 4-Chloroquinoline-3-carboxynitrile (150 mg), o-methylaniline (0.093 mL), and isopropanol (4 mL) were added to a single-necked flask and heated under reflux for 6 hours. A solid precipitated out. The reaction was confirmed to be complete by TLC. The mixture was filtered and washed with water to give 172 mg of a light brown solid, with a yield of 83%. 1 H-NMR(400M Hz, DMSO-d6): δ9.71(s,1H).8.55(d,J=8.4Hz,1H),8.47(s,1H),7.92(d,J=8.4Hz, 1H),7.84(t,J=7.2Hz,1H),7.64(t,J=7.6Hz,1H),7.38-7.23(m,4H),2.20(s,3H).

[0171] Preparation of 11-methyldibenzo[b,h][1,6]naphthidine-7-amine (compound 12)

[0172] Following the preparation method of compound 7 in Example 7, using B12 (80 mg) as a raw material, 79 mg of 11-methyldibenzo[b,h][1,6]naphthidine-7-amine (compound 12) was obtained as a yellow solid with a yield of 99%. 1 H-NMR (400MHz, DMSO-d6): δ9.75(s,1H),9.16(d,J=8.0Hz,1H),8.35(d,J=8.6Hz,1H),8.24(s,2H) ,8.00(d,J=8.0Hz,1H),7.82-7.77(m,1H),7.72-7.67(m,2H),7.38(t,J=7.6Hz,1H),2.85(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3: 260.1182; Measured value: 260.1195. Melting point > 280℃.

[0173] Example 13

[0174]

[0175] Referring to Example 12, using A12 and p-methylaniline as raw materials, 4-p-methylaniline-quinoline-3-carboxylonite B13, a pale yellow solid of 176 mg, with a yield of 85%, can be obtained. 1H-NMR(400M Hz, DMSO-d6): δ9.85(s,1H),8.57(s,1H),8.50(d,J=8.4Hz,1H),7.93(d,J=8.8Hz, 1H),7.86(t,J=8.8Hz,1H),7.65(t,J=8.4Hz,1H),7.26-7.20(m,4H),2.35(s,3H).

[0176] Using B13 (70 mg) as a starting material, 65 mg of 9-methyldibenzo[b,h][1,6]naphthidine-7-amine (compound 13) was obtained as a yellow solid with a yield of 93%. 1 H-NMR (400MHz, DMSO-d6): δ9.73(s,1H),9.07(d,J=8.0Hz,1H),8.31(s,1H),8.20(s,2H),7.99(d ,J=8.0Hz,1H),7.92(d,J=8.6Hz,1H),7.78(t,J=7.6Hz,1H),7.66(t,J=6.8Hz,2H),2.55(s,3H). HR-MS(ESI):m / z[M+H] + Calculated value C 17 H 14 N3: 260.1182; Measured value: 260.1194. Melting point > 280℃.

[0177] Example 14

[0178]

[0179] Referring to Example 12, using A12 and o-bromoaniline as raw materials, 4-o-bromoaniline-quinoline-3-carboxylonite B14, an off-white solid of 178 mg, was obtained, with a yield of 69%. 1 H-NMR(400M Hz, DMSO-d6): δ11.86(brs,1H),9.12(s,1H),8.98(d,J=8.4Hz,1H),8.19(d,J=8.4Hz,1H),8.11(t,J=6.8Hz,1H),7.89(t,J=8 .0Hz, 1H), 7.83 (dd, J=8.0, 1.2Hz, 1H), 7.67 (dd, J=7.6, 1.6Hz, 1H), 7.55 (td, J=7.6, 1.6Hz, 1H), 7.47 (td, J=7.6, 1.6Hz, 1H).

[0180] 100 mg of raw material B14 was added to 1.2 mL of concentrated sulfuric acid and stirred at room temperature for 4 h. The mixture was then poured into water, and the pH was adjusted to alkaline with saturated potassium carbonate solution, resulting in the precipitation of a solid. After filtration, washing with water, and drying, 83 mg of 11-bromodibenzo[b,h][1,6]naphthyl-7-amine (compound 14) was obtained as a yellow solid, with a yield of 83%. 1 H-NMR (400MHz, DMSO-d6): δ9.79(s,1H),9.17(d,J=8.0Hz,1H),8.61-8.52(m,3H),8.23(d,J=7.6H z, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.85 (t, J = 7.6Hz, 1H), 7.75 (t, J = 7.6Hz, 1H), 7.39 (t, J = 8.0Hz, 1H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 BrN3: 324.0131; Measured value: 324.0124. Melting point > 280℃.

[0181] Example 15

[0182]

[0183] Referring to the preparation method of B12 in Example 12, using A12 and p-bromoaniline as raw materials, 4-p-bromoaniline-quinoline-3-carboxylonitrile B15, a pale yellow solid of 252 mg, with a yield of 98%, can be obtained. 1 H-NMR (400MHz, DMSO-d6): 9.86 (s, 1H), 8.64 (s, 1H), 8.44 (d, J = 8.8Hz, 1H), 7.96 (d, J = 8.0Hz, 1 H), 7.87 (t, J = 8.0Hz, 1H), 7.67 (t, J = 8.0Hz, 1H), 7.57 (d, J = 7.6Hz, 2H), 7.26 (d, J = 7.6Hz, 2H).

[0184] Following the preparation method of compound 14 in Example 14, using B15 (100 mg) as a raw material, 98 mg of 9-bromodibenzo[b,h][1,6]naphthidine-7-amine (compound 15) was obtained as a yellow solid with a yield of 98%. 1H-NMR (400MHz, DMSO-d6): δ9.75(s,1H),9.08(d,J=8.0Hz,1H),8.81(d,J=2.0Hz,1H),8.44 (s, 2H), 8.01 (d, J = 8.0Hz, 1H), 7.98-7.87 (m, 2H), 7.85-7.79 (m, 1H), 7.69 (t, J = 8.4Hz, 1H). HR-MS(ESI):m / z[M+H] + Calculated value C 16 H 11 BrN3: 324.0131; Measured value: 324.0121. Melting point > 280℃.

[0185] Example 16

[0186]

[0187] Referring to Example 12, using A12 and o-aminobiphenyl as raw materials, 4-([1,1'-biphenyl]-2-amino)quinoline-3-carboxynitrile B16, a yellow solid of 338 mg, with a yield of 99%. 1 H-NMR(400M Hz, DMSO-d6): δ10.63(s,1H),8.84(s,1H),8.66(d,J=8.4Hz,1H),8.03(d,J=8.4Hz,1H ),7.97(t,J=8.0Hz,1H),7.72-7.80(m,5H),7.45-7.52(m,4H),7.38(t,J=7.2Hz,1H).

[0188] Using B16 (80 mg) as a starting material, 73 mg of 11-phenyldibenzo[b,h][1,6]naphthidine-7-amine (compound 16) was obtained as a yellow-green solid with a yield of 91%. 1 H-NMR (400MHz, DMSO-d6): 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),9.10(d,J=8.4Hz,1H),8.86(s,1H),8.54(brs,2H),8.21(d,J=8.8Hz,1H),8.10(d,J=8.8Hz,1H) ,8.02(d,J=8.0Hz,1H),7.95(d,J=7.2Hz,2H),7.82(t,J=7.6Hz,1H),7.71(t,J=7.6Hz,1H),7.59-7.53(m,2H),7.43(t,J=6.8Hz,1H). HR-MS(ESI):m / z[M+H] + Calculated value C 22 H16 N3: 322.1339; Measured value: 322.1353. Melting point > 280℃.

[0189] Example 17

[0190]

[0191] Referring to Example 12, using A12 and p-aminobiphenyl as raw materials, 4-([1,1'-biphenyl]-4-amino)quinoline-3-carboxylonitrile B17, 272 mg of yellow solid, yield 80%. 1 H-NMR(400M Hz, DMSO-d6): δ10.14(s,1H),8.71(s,1H),8.54(d,J=8.8Hz,1H),7.98(d,J=8.4Hz,1H ),7.90(t,J=7.2Hz,1H),7.78-7.66(m,5H),7.48(t,J=7.6Hz,2H),7.44-7.34(m,3H).

[0192] Using B17 (80 mg) as a starting material, 72 mg of 9-phenyldibenzo[b,h][1,6]naphthidine-7-amine (compound 17) can be obtained as a yellow-green solid with a yield of 90%. 1 H-NMR (400MHz, DMSO-d6): δ9.77(s,1H),9.10(d,J=8.0Hz,1H),8.86(s,1H),8.56(brs,2H),8.21(d,J=8.8Hz,1H),8.10(d,J=8.8Hz,1H) ,8.02(d,J=8.0Hz,1H),7.95(d,J=7.6Hz,2H),7.83(t,J=8.0Hz,1H),7.71(t,J=8.0Hz,1H),7.56(t,J=7.6Hz,2H),7.43(t,J=7.2Hz,1H). HR-MS(ESI):m / z[M+H] + Calculated value C 22 H 16 N3: 322.1339; Measured value: 322.1330. Melting point > 280℃.

[0193] Example 18

[0194]

[0195] Referring to Example 12, using A12 and 4-diethylaminoaniline as raw materials, 245 mg of 4-((4-(diethylamino)phenyl)amino)quinoline-3-carboxynitrile B18, a pale yellow solid, was obtained, with a yield of 73%. 1H-NMR (400MHz, DMSO-d6): δ9.61(s,1H),8.48(d,J=8.4Hz,1H),8.43(s,1H),7.87(d,J=8.0Hz,1H),7.80(t,J=7.2Hz, 1H), 7.59 (t, J = 7.2Hz, 1H), 7.12 (d, J = 8.4Hz, 2H), 6.70 (d, J = 8.4Hz, 2H), 3.36 (q, J = 7.2Hz, 4H), 1.10 (t, J = 6.8Hz, 6H).

[0196] B18 (80 mg) was dissolved in 1.2 mL of concentrated sulfuric acid and heated and stirred at 60 °C for 2 hours. The reaction was confirmed to be complete by TLC. After cooling, the solution was poured into water, and a saturated K2CO3 aqueous solution was added to adjust the pH to alkaline. A large amount of solid precipitated out. The solid was filtered, washed with water, washed once with DCM, and dried to obtain N. 9 N 9 -Diethylbenzo[b,h][1,6]naphthidine-7,9-diamine (compound 18), 33 mg red solid, 41% yield. 1 H-NMR (400MHz, DMSO-d6): δ9.70(s,1H),9.01(d,J=8.0Hz,1H),8.03-7.92(m,3H),7.89(d,J=9.2Hz,1H),7.72(t,J= 7.6Hz, 1H), 7.63 (t, J = 7.6Hz, 1H), 7.51 (d, J = 9.2Hz, 1H), 7.30 (s, 1H), 3.53 (q, J = 7.2Hz, 4H), 1.18 (d, J = 6.8Hz, 6H). HR-MS(ESI):m / z[M+H] + Calculated value C 20 H 21 N4: 317.1761; Measured value: 317.1756. Melting point: 108-109℃.

[0197] Example 19

[0198]

[0199] Referring to Example 12, using A12 and 1-naphthylamine as raw materials, 4-(naphthyl-1-amino)quinoline-3-carboxylonitrile B19, a pale yellow solid of 260 mg, with a yield of 84%, can be obtained. 1H-NMR (400MHz, DMSO-d6): δ11.75(brs,1H),9.08(d,J=8.4Hz,1H),8.94(s,1H),8.18(d,J=8.0Hz,1H),8.1 1(t,J=7.2Hz,3H),7.96(d,J=8.2Hz,1H),7.90(t,J=7.6Hz,1H),7.73(d,J=7.2Hz,1H),7.68-7.53(m,3H).

[0200] Using B19 (100 mg) as a starting material, 79 mg of benzo[h]naphtho[1,2-b][1,6]naphthidine-7-amine (compound 19) was obtained as an orange solid with a yield of 70%. 1 H-NMR (400MHz, DMSO-d6): δ9.87 (s, 1H), 9.56 (t, J = 5.2Hz, 1H), 9.38 (d, J = 8.0Hz, 1H), 8.38 (d, J = 9.2Hz, 1H), 8.30 (brs, 2H), 8.13-7.99 (m, 2H), 7.91-7.73 (m, 5H). HR-MS(ESI):m / z[M+H] + Calculated value C 20 H 14 N3: 296.1182; Measured value: 296.1194. Melting point > 280℃.

[0201] Experimental Example: Photophysical Properties and Activity Testing

[0202] Experimental Example 1: Photophysical property testing of the compound of the present invention

[0203] A 10 μmol / L stock solution was prepared using DMSO, and then diluted 100-fold with DMSO to obtain a solution for measuring the UV-Vis absorption and fluorescence emission spectra of the compounds. The instrument used was a Tecan Spark 10M multi-functional microplate analyzer. A solution obtained by diluting the stock solution 2000-fold with DMSO was used to test the fluorescence quantum yield, ensuring an absorbance A of less than 0.1, measured at 365 nm. The fluorescence quantum yield was measured using an Edinburgh FLS1000 steady-state transient fluorescence spectrometer, with slit widths set as follows: excitation 2.5 nm, emission 0.25 nm, achieving a signal intensity of approximately 1 million, and a scan range of 348-700 nm. The photophysical properties of the compounds in DMSO are summarized in Table 1.

[0204] Table 1: Photophysical properties of the compounds of the present invention

[0205]

[0206]

[0207] Table 1 shows that the compounds of this invention have high molar extinction coefficients and fluorescence quantum yields ranging from 0.12 to 0.89. The UV-Vis absorption and fluorescence emission spectra of the compounds are detailed in the appendix. Figure 1-19 These compounds have application value in fields such as optoelectronic materials and bioimaging.

[0208] Experimental Example 2: In vitro anti-tuberculosis activity test of the compound of the present invention

[0209] In vitro anti-tuberculosis activity assay. The microplate alamar blue assay (MABA) method was used to determine the in vitro anti-tuberculosis activity.

[0210] Experimental Methods: Sterile 96-well plates were used. The experimental compound was dissolved in DMSO to prepare an initial solution with a concentration of 5 mg / mL. For the well with the highest concentration, 199 μL of 7H9 medium and 1 μL of the initial compound solution were added and mixed thoroughly. This mixture was then sequentially diluted 2-fold to the remaining wells, resulting in final compound concentrations of: 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, and 0.025 μg / mL. Mycobacterium tuberculosis H... 37 R v After 2-3 weeks of culture, the culture was prepared into a bacterial suspension and inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC. The culture was then statically cultured at 37°C for 1-2 weeks until the turbidity reached McFarland 1 (equivalent to 10⁻⁶). 7 When the concentration is CFU / mL, dilute 1:20 and add 100 μL to each well to achieve a final bacterial concentration of 10. 6 CFU / mL. Two growth control wells without antibiotics were included on each plate. The 96-well plate was incubated at 37°C. After 7 days, 20 μL of a mixture of 10× Alamar Blue and 5% Tween 80 was added to the growth control wells, and the plates were incubated at 37°C for 24 hours. If the color changed from blue to pink, the same amount of Alamar Blue and Tween 80 mixture was added to the wells containing the experimental drug, and the plates were incubated at 37°C for 24 hours. The color of each well was recorded, and the fluorescence value at 590 nm was measured using a microplate reader. The MIC was calculated. 90 .

[0211] Table 2: In vitro anti-tuberculosis activity of the compounds of this invention

[0212]

[0213] The results in Table 2 show that the compounds of this invention have anti-tuberculosis activity and can be used in the research of anti-tuberculosis drugs.

[0214] Experimental Example 3: In vitro antitumor activity test of the compounds of the present invention

[0215] The IC50 of the compound against HGC27, T98G, HepG2, A549, and MCF-7 cell lines was determined using the MTT assay. 50 Values. The concentration gradient was set at 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM, and 0.0032 μM. Tumor cells in the logarithmic growth phase were digested with trypsin and prepared to a concentration of 2.5 × 10⁻⁶ μM / mL. 4 Cell sap of 2500 cells per well was seeded into 96-well plates at 100 μl per well. The following day, 100 μl of fresh culture medium (DMSO final concentration <0.5%) with different concentrations of the compound and corresponding solvent controls were added to each well. Three parallel wells were set up for each group. The plates were incubated at 37°C in a 5% CO2 incubator for 72 h. Then, 20 μl of MTT (50 μg·mL⁻¹) was added to each well, for a total volume of 220 μl. After incubation at 37°C for 4 h, the supernatant was discarded, and 100 μl of DMSO was added. The mixture was shaken and the absorbance (A) was measured at 570 nm using a microplate reader. The IC50 was calculated. 50 value.

[0216] Table 3: In vitro antitumor activity of the compounds of this invention

[0217]

[0218] Table 3 shows that the compounds of this invention possess antitumor activity, especially compound 11, which exhibits 0.0508 μM activity against human gastric cancer cells, indicating that this class of compounds can be used for research on antitumor drugs. In contrast, compound c shows activity greater than 10 μM in various tumor cell lines.

[0219] Experimental Example 4: Cytotoxicity Test of the Compounds of the Present Invention

[0220] Cytotoxicity assays were performed on Vero cells using the MTT assay. Cell viability was determined by the reduction of oxidized 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide (trade name: thiazolyl) / MTT [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide] to a poorly soluble blue formazan compound by mitochondrial dehydrogenases (such as succinate dehydrogenase). The formazan compound was dissolved in dimethyl sulfoxide (DMSO) and then reacted with the solution to produce a colorimetric result. The amount of transformation was positively correlated with the number of viable cells. The specific method is as follows: 1. Preparation of cell suspension. Vero cells cultured to the logarithmic growth phase were digested with 0.25% trypsin for 2–3 min. The digestion solution was discarded, and an appropriate amount of culture medium was added. After mixing, 20 μL of the solution was taken and counted under a microscope using a hemocytometer to prepare a cell suspension of appropriate concentration for later use. Simultaneously, prepare a 5 g / L MTT solution using PBS (phosphate buffered solution), filter and sterilize, then set aside. 2. Drug preparation and cytotoxicity assay. Dissolve the test drug in DMSO, dilute 50-fold with culture medium to prepare the highest test concentration, then serially dilute with culture medium at a 1:3 ratio in 96-well plates, setting 6 concentrations for each compound, with a maximum concentration of 64 μg / mL. Each concentration is tested in 6 parallel wells (50 μL / well). Seed the prepared cell suspension into 96-well plates (50 μL / well), cell concentration 4 × 10⁶ cells / well. 5 Cells / mL. Control wells without drug and blank control wells containing culture medium were also included. After 48 hours of culture, 10 μL of MTT per well was added, and culture continued for another 4 hours. The culture plate was removed, the culture medium in the wells was carefully discarded, and 100 μL of DMSO was added to each well. The mixture was shaken until the formazan particles were completely dissolved, and the optical density (OD) was measured at 570 nm using an enzyme-linked immunosorbent assay (ELISA) reader. 570 3. Data Processing. Cell inhibition percentage (%) = [(cell control OD)] 570 Value - OD of the drug-treated group 570 (value) / (cell control OD) 570 Value - Blank OD 570 [Value] × 100%. The dose-response curve was fitted using Origin 7.0 software to calculate the concentration (IC50) of each compound at which the cell inhibition rate was 50%. 50 ).

[0221] Table 4: Vero cytotoxicity of the compounds of this invention

[0222]

[0223] The results in Table 4 show that the compounds of this invention have no significant cytotoxicity to Vero cells and have good safety.

[0224] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, R1, R2, and R3 are independently selected from hydrogen, hydroxyl, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, trifluoromethyl, -NR4R5, phenyl; R4 and R5 are independently selected from hydrogen, C 1-6 alkyl; Ring A is a benzene ring or does not exist; Compounds that do not include the following structures:

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (II): R1 is selected from hydrogen, halogen, C 1-3 Alkyl, -NR4R5, phenyl; R2 is selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, trifluoromethyl; R4 and R5 are C 1-6 alkyl; The following structures are not included:

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, in, R1 is selected from hydrogen, Br, methyl, diethylamino, and phenyl; R2 is selected from hydrogen, F, Br, methyl, trifluoromethyl, and methoxy. R1 and R2 are not both hydrogen.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (III): in, R1, R2, and R3 are independently selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, trifluoromethyl, -NR4R5, phenyl; R4 and R5 are C 1-6 alkyl.

5. The compound according to claim 4, in, R1, R2, and R3 are independently selected from hydrogen, F, Cl, Br, methyl, methoxy, trifluoromethyl, diethylamino, and phenyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

7. A method for preparing the compound according to any one of claims 1-6, comprising the following steps: The compound with the structure shown in Formula IV was placed in an acidic medium and cyclized under stirring at 0-100°C to obtain the compound shown in Formula I. The definitions of R1, R2, R3 and ring A are as described in any one of claims 1-6.

8. A pharmaceutical composition comprising a therapeutically and / or preventively effective amount of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

9. The use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating cancer.

10. The application according to claim 9, characterized in that, The cancers mentioned are selected from stomach cancer, liver cancer, glioma, lung cancer, and breast cancer.

11. The use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis.

12. The use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof in the preparation of organic light-emitting materials, organic fluorescent dyes, fluorescent probes and fluorescent dyes for cell imaging.

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