Tetrahydronaphthyridine selenoether derivatives, processes for their preparation and medical uses thereof

Abstract

The application provides a tetrahydronaphthyridine selenoether derivative, a preparation method and medical application thereof, and belongs to the field of medicines. The tetrahydronaphthyridine selenoether derivative has the following general formula I: wherein R is selected from one of C1-C3 alkyl, phenyl, methylphenyl, methoxyphenyl and monohalogenated phenyl; R 1 is selected from one of 4-halogenated phenyl, methylphenyl and C1-C3 alkyl; R 2 is selected from one of C1-C5 alkyl, phenyl, monohalogenated phenyl, dihalogenated phenyl, methoxyphenyl, chloromethylphenyl, trifluoromethylphenyl, allyl, furanyl and tert-butyl (2-oxopropyl) carbonate. The compound is prepared by taking tetrahydronaphthyridine as a mother nucleus, introducing a selenium-containing functional group, and introducing different substituents on the mother nucleus structure. When the substituent is 4-chloromethylphenyl, the 6-position substituent is phenylselenyl, and the 7-position substituent is p-fluorophenyl, the anti-tumor cell activity is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a tetrahydronaphthyl selenide derivative, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Cancer, characterized by the rapid proliferation of abnormal cells, has become one of the leading causes of death worldwide. Chemotherapy is a commonly used clinical method that can kill metastatic tumors. However, most chemotherapy drugs have serious adverse reactions; for example, most anti-tumor drugs, while destroying or inhibiting the growth of cancer cells, also affect normal cells and tissues. Therefore, finding and developing novel, clinically effective, and targeted anti-tumor drugs has always been a focus of medical research.

[0003] 1,8-Naphthidine compounds belong to the class of nitrogen-containing fused-ring compounds. Their main basic skeleton, the 1,8-naphthidine core, is found in many natural substances and exhibits good biological activity when isolated. Its broad biological properties make it a commonly used skeleton in clinical treatments and medical research. Selenium is a very important trace element with antioxidant and anticancer effects in vivo. Clinically, organoselenium compounds are chemopreventive agents for cancer treatment. Therefore, utilizing the splicing principle in drug synthesis, and using tetrahydronaphthidine as the basic skeleton of the target compound, the direct and efficient construction of tetrahydronaphthidine selenium ether derivatives through carbon-selenium coupling, and the study of their anticancer activity, is of profound significance. Summary of the Invention

[0004] The purpose of this invention is to provide a novel tetrahydronaphthyl selenide derivative, its preparation method, and its pharmaceutical applications.

[0005] In a first aspect, the present invention provides a tetrahydronaphthyl selenide derivative having the structure of general formula I:

[0006]

[0007] Wherein, R is selected from one of C1-C3 alkyl, phenyl, methylphenyl, methoxyphenyl and monohalophenyl;

[0008] R 1 Selected from one of 4-halophenyl, methylphenyl, and C1-C3 alkyl groups;

[0009] R 2 It is selected from one of C1-C5 alkyl, phenyl, monohalogenated phenyl, dihalogenated phenyl, methoxyphenyl, chloromethylphenyl, trifluoromethylphenyl, allyl, furanyl, and tert-butyl (2-oxopropyl) carbonate.

[0010] Preferably, in the structure of general formula I, R is preferably selected from one of phenyl, methyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl;

[0011] R 1 Preferably, it is selected from one of 4-fluorophenyl, 4-methylphenyl and methyl;

[0012] R 2 Preferably, it is selected from one of phenyl, 4-chlorophenyl, 4-chloromethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, allyl, methyl, n-propyl, n-butyl, furan-2-yl, and tert-butyl(2-oxopropyl) carbonate.

[0013] The preferred compound designations and their corresponding structures for the above general formula I are shown in Table 1:

[0014] Table 1 Chemical structures of preferred compounds of general formula I

[0015]

[0016]

[0017] A second aspect of the present invention provides a method for preparing a compound of general formula I, comprising the following steps:

[0018] First, starting with 2-amino-3-pyridinecarboxaldehyde, ketone compounds with different substituents were reacted with Al dol to obtain naphthidine compound 2. The compound 3 was then reduced with palladium on carbon and H2. Selenium ethers with different substituents were introduced at the 6-position via carbon (sp2)-selenium coupling to obtain compound 4. Based on this, acylation reaction was carried out with acyl chlorides with different substituents to obtain compound I containing an amide bond.

[0019]

[0020] R is selected from one of phenyl, methyl, benzyl, 4-methoxyphenyl and 4-chlorophenyl.

[0021] R 1 It is selected from one of 4-fluorophenyl, 4-methylphenyl and methyl.

[0022] R 2 It is selected from one of phenyl, 4-chlorophenyl, 4-chloromethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, allyl, methyl, propyl, butyl, furanyl, and tert-butyl (2-oxopropyl) carbonate.

[0023] A third aspect of the present invention provides a pharmaceutical composition comprising the above-described tetrahydronaphthyl selenide derivative or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0024] In a fourth aspect, the present invention provides the use of a tetrahydronaphthyl selenide derivative of general formula I or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for the treatment and / or prevention of malignant tumors.

[0025] Furthermore, the malignant tumor can be either a sensitive malignant tumor or a drug-resistant malignant tumor.

[0026] Tetrahydronaphthyl selenide derivatives or medically acceptable salts thereof exhibit tumor-selective inhibitory activity with minimal damage to normal cells. Furthermore, the drugs treat and / or prevent malignancies by selectively inhibiting tumor cell proliferation.

[0027] Furthermore, the term "commonly sensitive malignant tumors" refers to liver cancer, stomach cancer, breast cancer, colon cancer, lung cancer, nasopharyngeal carcinoma, etc., while "drug-resistant malignant tumors" refers to liver cancer, stomach cancer, colon cancer, nasopharyngeal carcinoma, etc.

[0028] The compounds of this invention can be formulated into pharmaceutical preparations, alone or in combination with one or more pharmaceutically acceptable carriers, for drug delivery. For example, solvents, diluents, etc., can be administered in oral dosage forms such as tablets, capsules, dispersible powders, granules, etc. Various dosage forms of the pharmaceutical compositions of this invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations may contain, for example, 0.05% to 90% by weight of the active ingredient in combination with a carrier, more commonly about 15% to 60% by weight of the active ingredient. The dosage of the compounds of this invention can be from 0.005 to 5000 mg / kg / day, and may exceed this range depending on the severity of the disease or the dosage form.

[0029] The compounds of this invention can be used in combination with other antitumor drugs such as alkylating agents (e.g., cyclophosphamide or cisplatin), antimetabolites (e.g., 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (e.g., camptothecin), mitotic inhibitors (e.g., paclitaxel or vincristine), and DNA inserters (e.g., doxorubicin), and can also be used in combination with radiotherapy. These other antitumor drugs or radiotherapy can be administered simultaneously with or at different times from the compounds of this invention. These combined treatments can produce a synergistic effect, thereby helping to improve treatment efficacy.

[0030] Beneficial effects of this invention:

[0031] This invention combines the structural characteristics of tetrahydronaphthidine skeletons with the biological characteristics of selenium ethers, employing a carbon-selenium coupling method to efficiently construct tetrahydronaphthidine selenium ether compounds. Its anticancer activity was studied, leading to the design and synthesis of novel tetrahydronaphthidine selenium ether derivatives. No reports on such compounds have been found to date. The compounds of this invention use tetrahydronaphthidine as the parent core, introducing selenium-containing functional groups and different substituents into the core structure. When the substituent is 4-chloromethylphenyl, the 6-position substituent is phenylselenoyl, and the 7-position substituent is p-fluorophenyl, its antitumor cell activity is enhanced. Activity tests on various types of cancer cells revealed that these compounds selectively and strongly inhibit the proliferation of various tumor cells (including liver cancer, gastric cancer, breast cancer, colon cancer, lung cancer, etc.) while causing minimal damage to normal cells. Therefore, the compounds of this invention have significant potential for pharmaceutical applications. Detailed Implementation

[0032] To further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention. They should not be construed as limiting the present invention.

[0033] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as embodiments) can be combined with each other to form preferred technical solutions.

[0034] Example 1

[0035] Preparation of (7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(phenyl)methyl ketone (5a)

[0036] Compound 7-(4-fluorophenyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine (0.5 g, 1.3 mmol) was added to a 50 mL Schelenk tube. Benzoyl chloride (0.37 g, 2.5 mmol) and triethylamine (0.39 g, 3.9 mmol) were injected separately using a 2.5 mL syringe. The reaction was carried out under nitrogen protection with DCM as the solvent at room temperature for 5 hours. After the reaction was complete as detected by TLC, the mixture was quenched with methanol, extracted with ethyl acetate, and the organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography (prtroleum ether:EtOAc = 20:1, Rf = 0.2) gave 0.38 g of a white solid, with a yield of 60%. 1H NMR(400MHz, CDCl3)δ8.06(d,J=7.6Hz,1H),7.36(t,J=5.6Hz,6H),7.31-7.26(m,4H),6.82(t,J=8 .4Hz,2H),6.71-6.62(m,2H),4.03(t,J=6.0Hz,2H),2.77(t,J=6.8Hz,2H),2.13-2.03(m,2H).13C NMR (101MHz, CDCl3) δ169.87,161.54,153.78,149.82,141.86,138.45,136.52,133.79,130 .94,134.11,129.63,128.20,128.13,123.49,116.53,114.33,45.13,28.42,26.21,22.92.

[0037] Example 2

[0038] Preparation of (7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(4-chlorophenyl)methyl ketone (5b)

[0039] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, p-chlorobenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 76%. 1HNMR (400MHz, CDCl3) δ8.08(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.40(d,J=7.6Hz,2H),7.31(d,J=6.0Hz,6H),7.26(s ,1H),6.90(t,J=8.4Hz,2H),6.72(dd,J=8.4,5.6Hz,2H),4.05-3.97(m,2H),2.77(t,J=6.4Hz,2H),2.15-2.01(m,2H).13C NMR (101MHz, CDCl3) δ169.87,153.78,149.85,141.62,137.05,135.64,134.11,131.87,131.55,130.72, 130.63,129.65,129.48,128.86,128.28,128.25,123.30,122.67,114.68,114.47,43.82,26.18,22.81.

[0040] Example 3

[0041] Preparation of (4-chloromethylphenyl)(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthidium-1(2H)-yl)methyl ketone (5c)

[0042] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, 4-chloromethylbenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid in 70% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.38 (m, 3H), 7.37–7.36 (m, 3H), 7.34–7.29 (m, 4H), 6.88 (t, J = 8.4 Hz, 2H), 6.65 (dd, J = 8.4, 5.6 Hz, 2H), 4.61 (s, 2H), 4.16–3.77 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.22–2.01 (m, 2H). ¹³C NMR (101 MHz) , CDCl3)δ170.23,164.06,161.59,153.86,149.96,141.54,139.06,138.57,135.26,135.23,134.08,130.78,1 30.70,129.94,129.67,128.56,128.43,128.24,123.39,122.64,114.79,114.57,45.67,43.78,26.20,22.87.

[0043] Example 4

[0044] Preparation of (3-fluorophenyl)(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5d)

[0045] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, 3-fluorobenzoyl chloride, triethylamine, N2 protection, DCM as reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 65%. 1HNMR (400MHz, CDCl3) δ7.31 (dd, J=7.6, 2.0Hz, 2H), 7.28-7.21 (m, 5H), 7.19 (s, 1H), 7.08-7.06 (m, 1H), 7.00 (dd, J=9.4 ,1.6Hz,1H),6.80(t,J=8.7Hz,2H),6.70-6.64(m,2H),4.04-3.89(m,2H),2.71(t,J=6.5Hz,2H),2.11-1.94(m,2H).13C NMR (101MHz, CDCl3) δ169.51,164.09,163.80,153.90,149.79,141.86,140.77,140.70,135.26, 133.94,130.74,130.65,130.04,129.68,128.20,123.74,123.46,122.69,43.84,26.14,22.83.

[0046] Example 5

[0047] Preparation of (4-fluorophenyl)(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5e)

[0048] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, p-fluorobenzoyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 72% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.33 (m, 8H), 7.29 (s, 1H), 7.06 (t, J = 8.4 Hz, 2H), 6.91 (t, J = 8.8 Hz, 2H), 6.79 (dd, J = 8.8, 5.6 Hz, 1H), 4.07–4.01 (m, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.11–2.13 (m, 2H). ¹³C NMR (101MHz, CDCl3) δ169.89,153.87,150.16,141.74,134.00,130.70,130.61,130.40,130.32, 129.63,128.20,126.23,123.35,122.40,115.10,114.89,114.66,114.45,43.89,26.16,22.88.

[0049] Example 6

[0050] Preparation of (2,4-difluorophenyl)(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5f)

[0051] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, 2,4-difluorobenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid in 68% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J = 8.4, 6.4 Hz, 1H), 7.35–7.31 (m, 2H), 7.27–227 (m, 3H), 7.21 (s, 1H), 6.94–6.75 (m, 5H), 6.55–6.50 (m, 1H), 4.20–3.86 (m, 2H), 2.71 (t, J = 6.4 Hz, 2H), 2.00–1.96 (m, 2H). ¹³C NMR (1 01MHz, CDCl3) δ165.14,164.07,161.60,153.67,149.32,141.58,135.34,134.02,131.71,130.53,130.44 ,129.96,129.67,128.23,123.87,123.08,114.71,114.50,111.78,111.56,103.54,43.82,26.21,22.65.

[0052] Example 7

[0053] Preparation of (7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(4-(trifluoromethyl)phenyl)methyl ketone (5g)

[0054] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, p-trifluoromethylbenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 80%. 1HNMR (400MHz, CDCl3) δ7.54(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),7.33(d,J=6.8Hz,2H),7.26-7.22(m,3H),7.19 (s,1H),6.76(t,J=8.8Hz,2H),6.55-6.44(m,2H),4.44-3.64(m,2H),2.72(t,J=6.4Hz,2H),2.06-2.01(m,2H)..13C NMR (101MHz, CDCl3) δ172.25,161.52,155.02,153.62,141.42,140.53,138.95,135.63, 134.36,130.46,129.69,128.41,128.17,125.12,123.28,114.48,45.36,22.74,22.36.

[0055] Example 8

[0056] Preparation of (7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(4-methoxyphenyl)methyl ketone (5h)

[0057] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, p-methoxybenzoyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 54% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.37 (m, 2H), 7.36–7.34 (m, 2H), 7.33–7.29 (m, 4H), 7.26 (s, 1H), 6.89–6.75 (m, 5H), 4.04–3.96 (m, 2H), 3.86 (s, 3H), 2.78 (t, J = 6.4 Hz, 2H), 2.18–1.93 (m, 2H).

[0058] Example 9

[0059] Preparation of 1-(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthid-1(2H)-yl)prop-2-en-1-one (5i)

[0060] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, acryloyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 70% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 8.4, 5.6 Hz, 2H), 7.42–7.32 (m, 3H), 7.28–7.22 (m, 4H), 7.19 (s, 1H), 6.96–6.84 (m, 1H), 6.28–6.25 (m, 1H), 5.55–5.52 (m, 1H), 3.90–3.84 (m, 2H), 2.68–2.54 (m, 2H), 1.91–1.83 (m, 2H).

[0061] Example 10 Preparation of 1-(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthidium-1(2H)-yl)ethyl-1-one (5j)

[0062] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, acetyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.57 (m, 2H), 7.50–7.44 (m, 2H), 7.34 (d, J = 7.2 Hz, 3H), 7.29 (s, 1H), 7.14 (t, J = 8.8 Hz, 2H), 4.23–3.79 (m, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.56 (s, 3H), 2.04–1.85 (m, 2H).

[0063] Example 11

[0064] Preparation of 1-(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)prop-1-one (5k)

[0065] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, propionic anhydride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 62% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.66–7.53 (m, 2H), 7.48–7.40 (m, 2H), 7.33–7.30 (m, 3H), 7.26 (s, 1H), 7.15–7.09 (m, 2H), 3.96–3.77 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 1.94–1.88 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0066] Example 12

[0067] Preparation of 1-(7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthidium-1(2H)-yl)but-1-one (5l)

[0068] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, butyric anhydride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 66% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, J = 8.4, 5.6 Hz, 2H), 7.45 (dd, J = 7.6, 1.6 Hz, 2H), 7.38–7.30 (m, 3H), 7.26 (s, 1H), 7.12 (t, J = 8.8 Hz, 2H).

[0069] 3.90-3.87(m,2H),2.98-2.79(m,2H),2.67(t,J=6.4Hz,2H),1.94-1.87(m,2H),1.72-1.66(m,2H),0.99-0.73(m,3H).13C NMR (101MHz, CDCl3) δ174.43,154.21,150.34,141.66,134.19,130.80,130.72,129.6 3,128.21,124.28,122.36,115.04,114.83,42.95,39.49,26.65,22.78,19.25,13.89.

[0070] Example 13

[0071] Preparation of (7-(4-fluorophenyl)-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(furan-2-yl)methyl ketone (5m)

[0072] In a 50 mL round-bottom flask, 7-(4-fluorophenyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine (0.5 g, 1.3 mmol), furanoic acid (0.29 g, 2.6 mmol), and DCC (0.54 g, 2.6 mmol) were added. Under nitrogen protection, toluene was used as the reaction solvent. The reaction was carried out overnight at 70 °C. The reaction was monitored by TLC until completion. The toluene was removed by concentration, followed by dilution with ethyl acetate, washing with water (20 mL × 3), drying over anhydrous sodium sulfate, filtration, and concentration to obtain a pale yellow oil. Column chromatography (prtroleum ether:EtOAc = 30:1) yielded 65%. 1H NMR (400MHz, CDCl3) δ7.46-7.38(m,3H),7.35-7.26(m,3H),7.19-7.12(m,3H),7.02-6.90( m,3H),6.49-6.48(m,1H),4.02-3.83(m,2H),2.75(t,J=6.4Hz,2H),2.04(t,J=6.4Hz,2H).

[0073] Example 14

[0074] Preparation of tert-butyl (3-(7-(4-fluorophenyl)-6-phenylseleno-3,4-dihydro-1,8-naphthid-1(2H)-yl)-2-oxopropyl)carbamate (5n)

[0075] Following the synthetic method of compound 5m, 7-(4-fluorophenyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, Boc-glycine, DCC, N2 protection, toluene as the reaction solvent, were reacted overnight at 70°C to give a white solid with a yield of 46%. 1HNMR (400MHz, CDCl3) δ7.63 (dd, J=8.4, 5.6Hz, 2H), 7.49-7.44 (m, 2H), 7.37-7.31 (m, 3H), 7.28 (s, 1H), 7.16 (t, J=8.8Hz, 2H), 4 .52(d,J=5.2Hz,2H),4.01(d,J=5.2Hz,1H),3.97-3.90(m,2H),2.67(t,J=6.4Hz,2H),1.94-1.89(m,4H),1.44-1.43(m,9H).13C NMR (101MHz, CDCl3) δ153.20,149.14,141.91,134.34,130.90,129.66,128.30,123.76,123.15,115.22,1 15.00,58.32,49.93,43.43,32.53,30.67,28.38,28.30,26.56,26.21,25.49,25.24,24.65,22.20,18.38.

[0076] Example 15

[0077] Preparation of (4-(chloromethyl)phenyl)(6-(phenylselenoyl)-7-(p-tolyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5o)

[0078] Following the synthetic method of compound 5a, 7-(p-tolyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, 4-chloromethylbenzoyl chloride, triethylamine, N2 protection, DCM as reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 70%. 1H NMR (400MHz, CDCl3) δ7.46-7.41(m,2H),7.38(t,J=5.6Hz,4H),7.33(t,J=5.7Hz,3H),7.26(d,J=2.8Hz,2H),7.00(d,J=7 .6Hz,2H),6.58(d,J=8.0Hz,1H),4.62(s,2H),4.05-3.94(m,2H),2.75(t,J=6.4Hz,2H),2.30(s,3H),2.11-2.01(m,2H).

[0079] Example 16

[0080] Preparation of (6-(phenylselenoyl)-7-(p-tolyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(phenyl)methyl ketone (5p)

[0081] Following the synthetic method of compound 5a, 7-(p-tolyl)-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, benzoyl chloride, triethylamine, N2 protection, DCM as reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 80%. 1HNMR (400MHz, CDCl3) δ8.06(d,J=7.6Hz,1H),7.41-7.36(m,3H),7.32(d,J=6.4Hz,3H),7.27(d,J=6.4Hz,2H),7.24(s,1H),7.21 (s,1H),,6.92(d,J=7.6Hz,2H),6.54(d,J=8.0Hz,2H),4.09-3.90(m,2H),2.71(t,J=6.4Hz,2H),2.25(s,3H),2.05-1.99(m,2H).

[0082] Example 17

[0083] Preparation of (4-chlorophenyl)(6-(phenylselenoyl)-7-(p-tolyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5q)

[0084] Following the synthetic method for compound 5a, 7-(p-Tolyl)-6-phenylselenoyl-1,2,3,4-tetrahydro-1,8-naphthidine, 4-chlorobenzoyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 76% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.48–7.43 (m, 2H), 7.35–7.29 (m, 8H), 7.26 (s, 2H), 7.04–7.02 (m, 2H), 4.15–3.91 (m, 2H), 2.75 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 2.09–2.05 (m, 2H).

[0085] Example 18 Preparation of (4-fluorophenyl)(7-(4-fluorophenyl)-6-(4-methylphenylselenoyl)-3,4-dihydro-1,8-naphthidium-1(2H)-yl)methyl ketone (5r)

[0086] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-(4-methylbenzenesenyl)-1,2,3,4-tetrahydro-1,8-naphthidine, p-fluorobenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 66%. 1HNMR (400MHz, CDCl3) δ8.12(dd,J=8.8,5.6Hz,2H),7.34(d,J=7.6Hz,2H),7.25(d,J=7.6Hz,2H),7.17-7.11(m,3H),7 .03(t,J=8.4Hz,2H),6.89(t,J=8.8Hz,2H),4.06-3.98(m,2H),2.76(t,J=6.4Hz,2H),2.37(s,3H),2.11-2.01(m,2H).

[0087] Example 19

[0088] Preparation of (4-fluorophenyl)(7-(4-fluorophenyl)-6-(methenyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5S)

[0089] Following the synthetic method for compound 5a, 7-(4-fluorophenyl)-6-methylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, p-fluorobenzoyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent were reacted at room temperature for 5 hours to give a white solid in 50% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, 1H), 7.36 (dd, J = 8.4, 5.6 Hz, 2H), 7.02 (t, J = 8.6 Hz, 2H), 6.90 (t, J = 8.4 Hz, 2H), 6.78 (dd, J = 8.4, 5.6 Hz, 2H), 4.06–4.00 (m, 2H), 2.92 (t, J = 6.4 Hz, 2H), 2.21 (d, J = 6.4 Hz, 3H), 2.16–2.11 (m, 2H).

[0090] Example 20

[0091] Preparation of (4-fluorophenyl)(7-(4-fluorophenyl)-6-((4-methoxyphenyl)selenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5t)

[0092] Following the synthetic method of compound 5a, 7-(4-fluorophenyl)-6-(4-methoxyphenylselenoyl)-1,2,3,4-tetrahydro-1,8-naphthidine, p-fluorobenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 65%. 1HNMR (400MHz, CDCl3) δ7.43 (d, J = 8.7Hz, 2H), 7.35 (dd, J = 8.6, 5.2Hz, 2H), 7.12 (s, 1H), 7.04-6.99 (m, 2H), 6.94-6. 86(m,4H),6.79(dd,J=8.6,5.2Hz,2H),4.00-3.97(m,2H),3.84(s,3H),2.74(t,J=6.4Hz,2H),2.08-2.02(m,2H).13C NMR (101MHz, CDCl3) δ169.81,160.36,152.20,149.41,139.28,137.57,135.27,135.24,134.55,130.44 ,130.36,124.70,123.58,118.71,115.51,115.19,114.98,114.90,114.68,55.43,43.87,26.26,22.95.

[0093] Example 21

[0094] Preparation of (6-((4-chlorophenyl)selenoyl)-7-(4-fluorophenyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)(4-fluorophenyl)methyl ketone (5u)

[0095] Compound 5u was synthesized according to the method of 5a, using 7-(4-fluorophenyl)-6-(4-chlorophenylselenoyl)-1,2,3,4-tetrahydro-1,8-naphthidine, p-fluorobenzoyl chloride, triethylamine, N2 protection, and DCM as the reaction solvent. The reaction was carried out at room temperature for 5 hours to give a white solid in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.39 (m, 3H), 7.36–7.34 (m, 1H), 7.28 (s, 2H), 7.20–7.11 (m, 4H), 7.03 (t, J = 8.4 Hz, 2H), 5.62–5.54 (m, 1H), 3.52–3.38 (m, 2H), 2.75 (t, J = 6.4 Hz, 2H), 1. 98-1.94(m,2H).13CNMR(101MHz,CDCl3)δ158.23,156.01,144.94,132.58,132.15,131.9 4,131.00,130.92,129.80,129.42,127.96,116.88,114.92,114.71,41.64,26.37,21.04.

[0096] Example 22

[0097] Preparation of (4-(chloromethyl)phenyl)(7-methyl-6-(phenylselenoyl)-3,4-dihydro-1,8-naphthid-1(2H)-yl)methyl ketone (5v)

[0098] Following the synthetic method of compound 5a, 7-methyl-6-phenylseleno-1,2,3,4-tetrahydro-1,8-naphthidine, p-chloromethylbenzoyl chloride, triethylamine, N2 protection, DCM as the reaction solvent, were reacted at room temperature for 5 hours to give a white solid with a yield of 76%. 1HNMR(400MHz,CDCl3)δ7.38(s,1H,),7.32-7.24(m,9H),4.55(s,2H,),4.05 -3.97(m,2H),2.76(t,J=6.4Hz,2H),1.98(s,3H),1.26(s,2H).13CNMR(101M Hz, CDCl3) δ160.72,143.11,131.00,129.98,128.49,127.97,127.57,127.1 2,126.80,126.34,44.79,44.07,24.93,22.42,21.92.HRMS(ESI):Calcd.For C23H21ClN2OSe[M+H]+:457.0508; found:457.0576.

[0099] Example 23: In vitro antitumor activity study

[0100] The in vitro proliferation inhibitory activity of the target compound 5a-v against three types of human tumor cells (HGC-27, HepG2, and HCT-116) and normal human hepatocytes (LO2) was detected using the MTT assay. Detailed test results are shown in Table 2.

[0101] Table 2. IC50 of target compound 5a-v against three types of human tumor cells. 50 value

[0102]

[0103]

[0104] ND:Notdetected

[0105] The test results showed that most of the compounds of this invention had significant anti-cell proliferation activity, which was superior to the control drug fluorouracil (5-FU). In particular, the IC50 values ​​of compounds 5a-c, 5e, 5g, and 5v against the three types of tumor cells were all in the single digits. In particular, compound 5c, with the 1-substituent 4-ClCH2Ph, the 6-substituent selenylphenyl, and the 7-substituent 4-FPh, had an IC50 value of 0.73 μM against HCT-116 cells, showing strong anti-tumor activity. However, its activity against normal cells was significantly weaker than that against tumor cells, showing selective inhibitory activity against tumor cells.

Claims

1. A tetrahydronaphthyridine selenoether derivative, characterized by, The tetrahydronaphthyridine selenoether derivative has the following general structure: : , wherein R is selected from one of C1-C3 alkyl, phenyl, methylphenyl, methoxyphenyl and monohalophenyl; R 1 one selected from 4-halophenyl, methylphenyl and C1-C3alkyl; R 2 one selected from the group consisting of C1-C5 alkyl, phenyl, monohalo- phenyl, dihalo-phenyl, methoxyphenyl, chloromethylphenyl, trifluoromethylphenyl, allyl, and furanyl.

2. The tetrahydronaphthyridine selenoether derivative according to claim 1, characterized in that, R is selected from one of phenyl, methyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl; R 1 one selected from the group consisting of 4-fluorophenyl, 4-methylphenyl and methyl; R 2 one selected from the group consisting of phenyl, 4-chlorophenyl, 4- chloromethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4- trifluoromethylphenyl, 4-methoxyphenyl, allyl, methyl, n-propyl, n-butyl, and furan-2-yl.

3. The tetrahydronaphthyridine selenoether derivative according to claim 1, characterized in that, the tetrahydronaphthyridine selenoether derivative is any one of the following compounds: (7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)(4- chlorophenyl)methanone; (7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)(4- chlorophenyl)methanone; (4-chloromethylphenyl)(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8- naphthyridin-1 (2H)-yl)methanone; (3-fluorophenyl)(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)- yl)methanone; (4-fluorophenyl)(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)- yl)methanone; (2,4-difluorophenyl)(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)- yl)methanone; (7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)(4- (trifluoromethyl)phenyl)methanone; (7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)(4- methoxyphenyl)methanone; 1 -(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)prop-2-en-1 - one; 1 -(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)ethan-1 -one; 1 -(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)propan-1 -one; 1 -(7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)butan-1 -one; (7-(4-fluorophenyl)-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)(furan-2- yl)methanone; (4-(chloromethyl)phenyl)(6-(phenylseleno)-7-(p-tolyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)- yl)methanone; (6-(phenylseleno)-7-(p-tolyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-yl)(phenyl)methanone; (4-chlorophenyl)(6-(phenylseleno)-7-(p-tolyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)- yl)methanone; (4-Fluorophenyl)(7-(4-fluorophenyl)-6-(4-methylphenylseleno)-3,4-dihydro-1,8- naphthyridin-1(2H)-yl)methanone; (4-Fluorophenyl)(7-(4-fluorophenyl)-6-(methylseleno)-3,4-dihydro-1,8-naphthyridin-1(2H)- yl)methanone; (4-Fluorophenyl)(7-(4-fluorophenyl)-6-((4-methoxyphenyl)seleno)-3,4-dihydro-1,8-naphthyridin- 1(2H)-yl)methanone; (6-((4-Chlorophenyl)seleno)-7-(4-fluorophenyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)(4- fluorophenyl)methanone; (4-(Chloromethyl)phenyl)(7-methyl-6-(phenylseleno)-3,4-dihydro-1,8-naphthyridin-1(2H)- yl)methanone.

4. A process for the preparation of the tetrahydronaphthyridine selenoether derivative of claim 1, characterized by, The preparation method comprises the following steps: S1. Using 2-amino-3-pyridine formaldehyde as a starting material, and carrying out Aldol condensation reaction with ketone compounds with different substituents to obtain naphthyridine compound 2; S2. Reducing the naphthyridine compound 2 with palladium-carbon and H2 to obtain compound 3; S3. Introducing selenide with different substituents at the 6-position of compound 3 through carbon (sp2)-selenium coupling to obtain compound 4; S4. Acylating compound 4 with acyl chlorides of different substituents to obtain compounds containing amide bond ; The synthetic route of the preparation method is shown in the following formula: , wherein R is selected from one of C1-C3 alkyl, phenyl, methylphenyl, methoxyphenyl and monohalogenated phenyl; R 1 one selected from 4-halophenyl, methylphenyl and C1-C3alkyl; R 2 one selected from the group consisting of C1-C5 alkyl, phenyl, monohalo- phenyl, dihalo-phenyl, methoxyphenyl, chloromethylphenyl, trifluoromethylphenyl, allyl, and furanyl.

5. A pharmaceutical composition, characterized by, The tetrahydronaphthyridine selenide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1-3 and a pharmaceutically acceptable carrier or excipient.

6. Use of the tetrahydronaphthyridine selenide derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1-3 as an active ingredient in the preparation of a medicament for treating and / or preventing a malignant tumor, which is one of liver cancer, gastric cancer and colon cancer.

7. Use according to claim 6, characterized in that, The medicament treats and / or prevents the malignant tumor by selectively inhibiting proliferation of tumor cells.

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