CN106565599A - 2-aminomethylpyridylnicotinamides and preparation method and application thereof - Google Patents

Abstract

The invention relates to a compound as shown in the general formula (I) and salt thereof. The compound has the effect of high reversal of tumor multidrug resistance (MDR). The activity is far higher than that of verapamil, and the cytotoxicity is small. The invention further relates to a preparation method of the compound and a pharmaceutic preparation containing the compound. (Please see the specification for the formula)

Description

2-Aminomethylpyridinyl nicotinamide compound and its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a class of P-glycoprotein inhibitors, a preparation method thereof and the application of the compounds in multidrug resistance reversal agents.

Background technique

Tumor is one of the major diseases that threaten human health and life. Chemotherapy plays an irreplaceable role as the main method to treat tumors. However, due to the emergence of multidrug resistance (MDR) in tumor cells, the efficacy of chemical drugs is greatly reduced. The so-called MDR refers to that after cancer patients receive chemotherapy drugs, tumor cells develop resistance to one chemotherapy drug, and at the same time, they also develop cross-resistance to other chemotherapy drugs that have not been exposed to, or have completely different structures and mechanisms of action. As a result, the clinical curative effect is reduced or ineffective. Studies have shown that 90% of tumor chemotherapy failures in cancer patients are caused by the generation of tumor multidrug resistance. Therefore, it has become an urgent problem to be solved in tumor treatment to find drugs that can reverse MDR to inhibit the generation of multidrug resistance.

The generation of tumor multidrug resistance involves many mechanisms, among which the overexpression of P-glycoprotein (P-glycoprotein, P-gp) in the tumor cell membrane is considered to be the main reason for the generation of multidrug resistance. The overexpression of P-gp uses the energy released by ATP hydrolysis to pump the drugs entering the tumor cells out of the cells, resulting in the concentration of anti-tumor drugs in tumor cells being lower than the effective concentration, leading to the generation of multidrug resistance. In the 30 years since the discovery of the first MDR reversal agent, verapamil, the research on P-gp inhibitors has become the main direction of MDR reversal agent research. The research on P-gp inhibitors has gone through three generations. The first generation is represented by verapamil, etc. This generation of inhibitors has serious cardiovascular toxicity and is difficult to be used clinically; the second generation is represented by verapamil derivatives, etc. As a representative, the activity of this generation of inhibitors has been significantly enhanced, and the toxicity and side effects have been reduced, but most of the compounds have obvious inhibitory effects on P450 enzymes, which limits their clinical application. The third-generation inhibitors not only improve the P-gp inhibitory activity, but also overcome the side effects of the second-generation inhibitors interfering with P450 enzymes. Although the research on the third-generation P-gp inhibitors has brought hope for the reversal of tumor multidrug resistance, there is still no MDR reversal agent on the market.

In recent years, researchers have found that a series of tyrosine kinase inhibitors represented by gefitinib, erlotinib, apatinib and motesanib have the activity of reversing tumor multidrug resistance, which also provides The study of MDR reversal agents suggests a new direction.

The present invention is based on the shared structure 2-aminomethylpyridinyl nicotinamide of apatinib and motesanib as the common skeleton for reversing the MDR activity, combined with different aromatic amine substitutions, and completed the design and synthesis of compounds with novel structures , to obtain a series of compounds with higher activity. Compared with verapamil and apatinib, the compound obtained in the present invention not only has stronger MDR reversal activity, but also has almost no cytotoxicity. Therefore, the compound of the general formula (I) and its pharmaceutically acceptable salts have the potential to prevent and treat tumor multidrug resistance.

Contents of the invention

The main purpose of the present invention is to provide a new type of tumor multidrug resistance reversal agent whose core structure is 2-aminomethylpyridyl nicotinamide structure, which has less cytotoxicity and stronger reversal activity, and is used to improve antitumor drug Efficacy.

The purpose of the present invention is also to provide a preparation method of a kind of 2-aminomethylpyridinyl nicotinamide structural tumor multidrug resistance reversal agent.

The detailed invention is as follows:

The present invention has synthesized a series of compounds described in the general structural formula (I) or pharmaceutically acceptable salts thereof:

in:

Ring A is selected from: substituted or unsubstituted phenyl, naphthyl, aromatic condensed ring, aromatic heterocyclic group, and the substituents are selected from: halogen, haloalkyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted Or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted C ₁ -C ₅ alkyl alkoxy; aromatic ring includes an aromatic ring condensed with an aliphatic ring, such as a saturated or partially saturated ring, such as four Hydronaphthalene ring;

n stands for integer 0~2;

R ₁ is H, halogen, haloalkyl, haloalkoxy, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted aryl, aromatic heterocyclic group ;

R ₂ is H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted aryl, or aromatic heterocyclic group.

Preferred compounds of general formula (I) are:

in:

Ring A is selected from: unsubstituted or up to three substituted benzene rings, naphthalene, pyrrolidine, pyrrolidone, piperidine, piperidone, piperazine, morpholine, imidazolidine, pyrazolidine, pyrrole, indole, pyrazole , indazole, triazole, benzotriazole, imidazole, benzimidazole, thiazole, benzothiazole, furan, benzofuran, oxazole, benzoxazole, isoxazole, tetrazole, pyridine, pyrimidine, Tridine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, fluorene;

n stands for integer 0~2;

R ₁ is selected from: H, F, Cl, -OCF ₃ , substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted aryl, aromatic heterocycle base;

R ₂ is H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted aryl, or aromatic heterocyclic group.

More preferred compounds of the present invention having general formula (I) or pharmaceutically acceptable salts thereof, said compounds are selected from:

N-(3-(methoxy)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-1);

2-((pyridine-4-methylene)amino)-N-(3,4,5-(trimethoxy)phenyl)nicotinamide methanesulfonate (I-2);

2-((pyridine-4-methylene)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (I-3);

N-(4-(tert-butyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate (I-4);

N-([1,1'-biphenyl]-4-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-5);

N-(5-(3-(methoxy)phenyl)-1,3,4-thiadiazol-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I -6);

N-(4-(piperidin-1-yl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-7);

N-(4-morpholinephenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-8);

N-(4-(4-methylpiperazin-1-yl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-9);

N-(naphthalene-1-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-10);

2-((pyridine-4-methylene)amino)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)nicotinamide (I-11);

N-(1H-benzimidazol-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-12);

N-(pyridine-4-methylene)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate (I-13);

N-(3,4-(dimethoxy)phenethyl)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate (I-14);

2-((pyridine-4-methylene)amino)-N-(2-(thien-2-yl)ethyl)nicotinamide (I-15);

N,N-Dibenzyl-2-((pyridine-4-methylene)amino)nicotinamide (I-16);

N-(4-(morpholinoethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-17);

N-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-18);

N-(4-(2-(piperidin-1-yl)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-19);

N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2-((pyridine-4- Methylene) amino) nicotinamide (I-20);

N-(3,4-dimethoxybenzyl)-N-methyl-2-((pyridine-4-methylene)amino)nicotinamide (I-21);

N-(4-(2-((3,4-dimethoxybenzyl)(methyl)amino)ethylphenyl)-2-((pyridine-4-methylene)amino)nicotinamide ( I-22);

N,N-bis(3,4-dimethoxybenzyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-23);

N-(9H-fluoren-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-24);

N-(2-Benzoylphenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-25).

In another aspect, the present invention provides a use of the compound or a pharmaceutically acceptable salt thereof for treating tumor multidrug resistance.

Another aspect of the present invention relates to a pharmaceutical composition, which contains a therapeutically effective dose of the compound described in general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient; And the application of the pharmaceutical composition in treating tumor multidrug resistance.

Detailed Description of the Invention

Unless otherwise specified, the terms in the specification and claims have the following meanings.

"C ₁ -C ₅ Alkyl" may mention for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl Base etc.

"C ₁ -C ₆ alkyl" can be mentioned such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl base, hexyl, etc.

"Heteroaromatic ring" can refer to, for example, a 5-13 membered (monocyclic, bicyclic or tricyclic) heterocyclic group, and the atoms constituting the heterocyclic ring contain, in addition to carbon atoms, one or two selected from N, S, 1 to 4 heteroatoms of O, preferably a 5-6 membered aromatic heterocycle and the like. Specifically, aromatic heterocycles include pyrrolidine, pyrrolidone, piperidine, piperidone, piperazine, morpholine, imidazolidine, pyrazolidine, pyrrole, indole, pyrazole, indazole, triazole, benzotri Azole, imidazole, benzimidazole, thiazole, benzothiazole, furan, benzofuran, oxazole, benzoxazole, isoxazole, tetrazole, pyridine, pyrimidine, triridine, quinoline, isoquinoline, quinoline Azoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, fluorene, etc.

"Pharmaceutical composition" means a mixture containing one or more compounds of the general formula (I) of the present invention or pharmaceutically acceptable salts thereof, or prodrugs thereof and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the absorption of the active ingredient by the organism, and facilitate the biological activity of the active ingredient in the organism.

The structures of some compounds are:

According to the present invention, pharmaceutically acceptable salts include addition salts formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, methanesulfonic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, Salt formation of maleic acid, benzenesulfonic acid, succinic acid and similar acids known to be acceptable.

The preparation method of 2-aminomethylpyridyl nicotinamide structure compound of the present invention, the method is as follows:

Under the catalysis of copper oxide, compound 1 and compound 2 react to generate 2-((pyridine-4-methylene)amino)nicotinic acid, namely compound 3, which is further condensed with various aromatic substituted amines to generate the target compound.

The following are the pharmacological experiment data of some compounds of the present invention:

1. Cytotoxicity of compounds

Doxorubicin was used as a positive control. K562 (human leukemia cells), K562/A02 (doxorubicin-resistant human leukemia cells), K562/A02 cells are induced by sensitive K562 cells exposed to increasing concentrations of doxorubicin. The two cell lines were cultured in RPMI 1640 medium containing 10% calf serum and adding a final concentration of 1mg/L doxorubicin at 37°C and 5% CO ₂ saturated humidity conditions, and the drug-resistant cell lines before the experiment Cultured for 14 days without doxorubicin. Take the cells in the logarithmic growth phase, inoculate them in a 96-well culture plate at a density of 1×10 ⁴ cells/ml, and culture them for 24 hours at 37°C with 5% CO ₂ , then add a series of concentration gradients of the test compound and albino Mycin, continue to incubate for 48 hours, add MTT (5mg/ml) to each well, incubate for another 4 hours, centrifuge, absorb the culture medium with a plate washer, add 150 μL DMSO to dissolve in each well, shake on a shaker for 20 minutes, and then Measured above with a wavelength of 570nm, respectively calculate the concentration when the cell growth is inhibited to 50%, expressed as IC ₅₀ value.

The cytotoxic effects of 16 compounds on K562 cells and K562/A02 cells were measured respectively. As shown in Table 1, the compounds were less cytotoxic to the two cell lines than verapamil and apatinib, and most of the compounds were Not cytotoxic (IC ₅₀ >100 μM).

Cytotoxicity of some compounds in table 1 to K562 cells and K562/A02 cells

2. The reversal effect of the compound on doxorubicin-resistant human leukemia cells

Verapamil was used as a positive control. The two cell lines K562 and K562/A02 were cultured in RPMI 1640 medium containing 10% calf serum and adding a final concentration of 1 mg/L doxorubicin at 37°C and 5% CO ₂ saturated humidity, and the experiment The former drug-resistant cell lines were cultured for 14 days without doxorubicin. Cells in the logarithmic growth phase were inoculated in 96-well culture plates at a density of ¹ ×104 cells/ml, and cultured at 37°C for 24 hours under the condition of 5% CO ₂ . Doxorubicin with a series of concentration gradients was continued to incubate for 48 hours, then MTT (5 mg/ml) was added to each well, cultured for another 4 hours, centrifuged, the culture medium was sucked off by a plate washer, 150 μL DMSO was added to each well to dissolve, and shaken for 20 minutes. Then measure with a wavelength of 570nm on a microplate reader, and calculate the concentration when the cell growth is inhibited by 50%, expressed as _IC50 value, and the reversal factor is expressed as _IC50 (ADR)/ _IC50 (ADR+reversal agent).

The reversing activity of 34 compounds at 1 μM concentration to the drug resistance of doxorubicin-resistant leukemia cells was respectively measured as shown in Table 2. The results showed that the compounds all had reversing activity, and the reversing activity of the compounds was significantly higher than that of the positive control product Vera Pammy (verapamil). Among them, the reversal multiple of I-18 was 26.9, much stronger than that of verapamil with a reversal multiple of 1.5. The experimental results are shown in Table 2.

Table 2 Adding reversal agent (1μM) reduces the effect of K562/A02 on doxorubicin IC ₅₀ (μM)

The above pharmacological data show that the compound of the general formula (I) of the present invention has a stronger effect of reversing tumor multidrug resistance than the positive control drug verapamil, and most of the compounds have almost no cytotoxicity.

The present invention also includes a pharmaceutical preparation, which comprises the compound of general formula (I) or a pharmaceutically acceptable salt thereof as an active agent and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to one or more inert, non-toxic solid or liquid fillers, diluents, adjuvants, etc., which do not adversely affect the active compound or the patient.

The dosage forms of the composition of the present invention can be commonly used pharmaceutical dosage forms such as tablets, capsules, pills, suppositories, soft capsules, oral liquids, suspensions, and injections. Pharmaceutical products and capsules for oral use contain traditional excipients such as fillers, diluents, lubricants, dispersants and binders. It can be prepared according to methods well known in the art.

Dosages of the above active agents will vary from formulation to formulation.

In general, the amount which has proven to be advantageous is a total amount of about 0.01-80 mg, preferably a total amount of about 0.1-40 mg/kg, of the compound of formula (I) administered per kilogram of body weight for 24 hours to achieve the desired result. Administer in several single doses, if necessary.

However, if necessary, deviations from the above-mentioned dosages can be made, i.e. it depends on the type and body weight of the subject to be treated, the individual's behavior towards the drug, the nature and severity of the disease, the type of preparation and administration, and the time of administration or interval.

The present invention will be further described below by way of examples.

detailed description:

The present invention will be further described below in conjunction with embodiment. It should be noted that the following examples are only for illustration, but not for limiting the present invention. Various changes made by those skilled in the art according to the teaching of the present invention shall be within the scope of protection required by the claims of the present application.

Example 1

Preparation of 2-((pyridine-4-methylene)amino)nicotinic acid (3)

Add 2-chloronicotinic acid (25.3mmol), copper oxide (catalytic amount), and potassium carbonate (25.3mmol) into a 100ml round bottom flask, stir at room temperature for 20min, add 4-methylaminopyridine (50.6mmol), and heat at 110°C 2h. Then add ethyl acetate and stir to room temperature, filter with suction, wash the filter cake twice with ethyl acetate, dissolve in water (20ml), adjust to pH 5-6 with 4N hydrochloric acid, let stand to precipitate, filter with suction, dry the filter cake, The obtained crude product was further purified by hot beating with ethanol, and filtered with suction to obtain 5.16 g of off-white solid with a yield of 89% and a melting point of 197-199°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 8.61 (d, J=5.8Hz, 1.0H, ArH), 8.48 (s, 2H, ArH), 8.19 (dd, J=4.7, 1.9Hz, 1H, ArH), 8.11 (dd, J=7.7, 1.9Hz, 1H, ArH), 7.29 (d, J=4.7Hz, 2H, ArH), 6.64 (dd, J=7.7, 4.8Hz, 1.0Hz, -NH- ), 4.73 (d, J=5.8Hz, 2H, -NHC H ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 170.78, 159.02, 151.33, 150.46, 149.05, 136.60, 122.79, 114.11, 106.62 , 43.63; ESI-MS m/z: 230.2[M+H]+; Anal.calcd.For C ₁₂ H ₁₁ N ₃ O ₂ : C, 62.87; H, 4.84; N, 18.33; Found: C, 62.56; H, 4.94; N, 18.52.

Example 2

Preparation of N-(3-(methoxy)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-1)

Compound 3 (6mmol), 3-methoxyaniline (5mmol), EDCI (7.2mmol), HOBT (7.2mmol) were dissolved in DMF, stirred at room temperature for 16h, then added 50ml of water to the reaction solution, ethyl acetate ( 30ml×3) extraction, combined organic phases, washed with saturated sodium carbonate solution (20ml×2) and saturated brine (20ml×2), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography (dichloromethane/methanol, 50:1, v/v), purified to obtain 0.88 g of white solid, yield 53%, melting point: 113-115°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.59(s, 1H, -CONH-), 9.23(s, 1H, ArH), 8.87(d, J=5.4Hz, 2H, ArH), 8.41(d , J=7.0Hz, 1H, ArH), 8.07(d, J=5.4Hz, 3H, ArH), 7.45(s, 1H, ArH), 7.32(d, J=6.9Hz, 2H, ArH), 6.97( d, J=5.7Hz, 1H, ArH), 6.74(d, J=6.9Hz, 1H, -NH-), 5.03(s, 2H, -NHC H ₂ -), 3.76(s, 3H, -OCH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 162.25, 160.12, 158.75, 151.41, 150.46, 149.05, 140.25, 134.99, 130.08, 122.79, 116.75, 111.08, 110.71, 109.81, 109.08, 106.02; ES.07 - MS m/z: 335.2[M ₊ H] ⁺ ; _{Anal.calcd.For C19H18N4O2 :} C, 68.25; H, 5.43; N, 16.67; Found: C, 68.03; H, 5.50; N , 16.76.

Example 3

Preparation of 2-((pyridine-4-methylene)amino)-N-(3,4,5-(trimethoxy)phenyl)nicotinamide methanesulfonate (I-2)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) 3,4,5-(trimethoxy)aniline (5mmol) to obtain compound I-2 to obtain 1.21g of white solid with a yield of 61%. Melting point: 216-218°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.32(s, 1H, -CONH-), 8.83(d, J=6.1Hz, 3H, ArH), 8.20(d, J=7.3Hz, 1H, ArH ), 8.10(d, J=4.1Hz, 1H, ArH), 7.97(d, J=5.9Hz, 2H, ArH), 7.20(s, 2H, ArH), 6.85-6.67(m, 1H, -NH- ), 4.94 (s, 2H, -NHC H ₂ -), 3.78 (s, 6H, -OCH ₃ ), 3.65 (s, 3H, -OCH ₃ ), 2.37 (s, 6H, -CH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δ: 162.22, 155.04, 151.12, 149.22, 144.38, 140.57, 137.08, 133.41, 125.26, 116.37, 108.08, 101.24, 60.70, 56.83, 43.29, 36.027, IES m; z: _395.2 [M ₊ H] ⁺ ; _{Anal.calcd.For C23H28N4O10S2 :} C, 47.25; H, 4.83; N, 9.58; S, 10.97; Found: C, 47.27; 4.70; N, 9.71; S, 10.82.

Example 4

Preparation of 2-((pyridine-4-methylene)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (I-3)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 4-(trifluoromethoxy)aniline (5mmol) to obtain compound I-3 to obtain 1.36g of a light yellow solid with a yield of 70%. Melting point: 125-127°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.46 (s, 1H, -CONH-), 8.47-8.08 (m, 3H, ArH), 8.13 (d, J=8.9Hz, 2H, ArH), 7.84 (d, J=8.9Hz, 2H, ArH), 7.38 (d, J=8.6Hz, 2H, ArH), 7.29 (d, J=5.2Hz, 2H, ArH), 6.70 (dd, J=7.5, 4.9 Hz, 1H, -NH-), 4.68 (d, J=5.8Hz, 2H, -NHC H ₂ -); ¹³ CNMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.12, 149.05, 135.41 , 134.99, 123.35, 122.79, 117.70, 110.71, 109.81, 43.75; ESI-MS m/z: 389.2[M+H] ⁺ ; Anal.calcd.For C ₁₉ H ₁₅ F ₃ N ₄ O ₂ : C, 58.76; H, 3.89; F, 14.68; N, 14.43; Found: C, 58.66; H, 3.95; F, 14.72; N, 14.30.

Example 5

Preparation of N-(4-(tert-butyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate (I-4)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 4-(tert-butyl)aniline (5mmol) to obtain compound I-4 to obtain 1.05g of white solid, yield 58%, melting point: 141 -143°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.39(s, 1H, -CONH-), 8.84(d, J=5.7Hz, 3H, ArH), 8.24(d, J=7.2Hz, 1H, ArH ), 8.11 (d, J=4.5Hz, 1H, ArH), 7.98 (d, J=5.6Hz, 2H, ArH), 7.67 (d, J=8.2Hz, 2H, ArH), 7.39 (d, J= 8.2Hz, 2H, ArH), 6.86-6.77(m, 1H, -NH-), 4.96(s, 2H, -NHC H ₂ -), 2.38(s, 6H, -SO ₃ CH ₃ ), 1.29(s , 9H, -CH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.22, 158.25, 149.22, 146.62, 144.38, 141.77, 135.54, 125.93, 123.86, 120.49, 116.37, 105.08, 43.279, 38 , 31.36; ESI-MS m/z: 361.3[M+H] ⁺ ; Anal.calcd.For C ₂₄ H ₃₀ N ₄ O ₇ S ₂ : C, 52.35; H, 5.49; N, 10.17; S, 11.64; Found: C, 51.68; H, 5.32; N, 10.21; S, 11.55..

Example 6

Preparation of N-([1,1'-biphenyl]-4-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-5)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and (1,1'-biphenyl)-4-amine (5mmol) to obtain compound I-5 to obtain 1.49g of white solid with a yield of 78 %, melting point: 190-192°C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δppm: 10.40 (s, 1H, -CONH-), 8.51 (s, 3H, ArH), 8.17 (s, 2H, ArH), 7.77 (m, 7H, ArH) , 7.46(s, 2H, ArH), 7.31(s, 2H, ArH), 6.71(s, 1H, -NH-), 4.72(s, 2H, -NHC H ₂ -); ¹³ C NMR (75MHz, DMSO -d ₆ ) δppm: 162.25, 158.75, 151.41, 150.46, 149.05, 140.35, 137.21, 135.09, 128.91, 127.88, 127.44, 123.66, 122.79, 110.71, 109.81, 43.66; ESI-MS m/ ] ⁺ ; Anal.calcd.For C ₂₄ H ₂₀ N ₄ O: C, 75.77; H, 5.30; N, 14.73; Found: C, 75.67; H, 5.36; N, 14.56.

Example 7

N-(5-(3-(methoxy)phenyl)-1,3,4-thiadiazol-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I -6) Preparation

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 5-(3-(methoxy)phenyl)-1,3,4-thiadiazol-2-amine (5mmol) Compound I-6, 1.36 g of white solid was obtained, the yield was 65%, and the melting point was 221-223°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 8.78-8.40 (m, 3H, ArH), 8.21 (s, 1H, ArH), 7.48 (s, 5H, ArH), 7.10 (s, 1H, ArH) , 6.69 (s, 1H, -NH-), 4.74 (s, 2H, -NHC H ₂ -), 3.84 (s, 3H, -CH ₃ ); ¹³ CNMR (75MHz, DMSO-d ₆ ) δppm: 170.42, 169.48, 161.96, 158.75, 154.43, 151.41, 150.46, 149.05, 134.99, 133.18, 129.14, 122.79, 120.11, 116.14, 110.71, 109.81, 56.08, ^43.70 ; .calcd.For C ₂₁ H ₁₈ N ₆ O ₂ S: C, 60.27; H, 4.34; N, 20.08; S, 7.66; Found: C, 60.15; H, 4.28; N, 20.24; S, 7.57.

Example 8

Preparation of N-(4-(piperidin-1-yl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-7)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6 mmol) and 4-(piperidin-1-yl) aniline (5 mmol) to obtain compound I-7 to obtain 1.42 g of a white solid with a yield of 73%. Melting point: 217-219°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.09 (s, 1H, -CONH-), 8.51-8.11 (m, 3H, ArH), 8.09 (d, J=6.6Hz, 2H, ArH), 7.53 (d, J=8.9Hz, 2H, ArH), 7.28 (d, J=4.9Hz, 2H, ArH), 6.91 (d, J=8.9Hz, 2H, ArH), 6.67 (dd, J=7.4, 4.9 Hz, 1H, -NH-), 4.67 (d, J=5.8Hz, 2H, -NHC H ₂ -), 3.08 (d, J=5.3Hz, 4H, -NCH ₂ -), 1.74-1.37 (m, 6H, -CH ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.46, 149.05, 147.22, 134.99, 129.23, 122.79, 118.56, 110.71, 109.81, 49.5979, 25. , 23.43; ESI-MS m/z: 388.3[M+H] ⁺ ; Anal.calcd.For C ₂₂ H ₂₅ N ₅ O: C, 71.29; H, 6.50; N, 18.07; Found: C, 71.35; H , 6.44; N, 18.01.

Example 9

Preparation of N-(4-morpholinephenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-8)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 4-morpholine aniline (5mmol) to obtain compound I-8 to obtain 1.54g of white solid with a yield of 79% and melting point: 215-217°C .

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.10 (s, 1H, -CONH-), 8.63-8.33 (m, 3H, ArH), 8.10 (d, J=7.2Hz, 2H, ArH), 7.58 (d, J=8.8Hz, 2H, ArH), 7.29 (d, J=4.6Hz, 2H, ArH), 6.94 (d, J=8.8Hz, 2H, ArH), 6.67 (dd, J=7.2, 5.0 Hz, 1H, -NH-), 4.68 (d, J=5.7Hz, 2H, -NHC H ₂ -), 3.74 (s, 4H, -OCH ₂ -), 3.15 (s, 4H, -NCH ₂ -) ; ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 166.06, 156.93, 150.91, 149.77, 149.37, 147.67, 136.90, 130.79, 121.94, 115.11, 111.17, 66.05, 48.75, 42.83; ESI-MS m/z [M ₊ H] ⁺ ; _{Anal.calcd.For C22H23N5O2} : C, _67.85 ; H, 5.95; N, 17.98; Found: C, 67.91; H, 6.02; N, 17.76.

Example 10

Preparation of N-(4-(4-methylpiperazin-1-yl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-9)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6 mmol) and 4-(4-methylpiperazin-1-yl) aniline (5 mmol) to obtain compound I-9 to obtain 1.45 g of a light yellow solid, Yield 72%, melting point: 220-222°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.11(s, 1H, -CONH-), 8.69-8.29(m, 3H, ArH), 8.17-7.95(m, 2H, ArH), 7.55(d, J=8.9Hz, 2H, ArH), 7.28(d, J=5.7Hz, 2H, ArH), 6.92(d, J=8.9Hz, 2H, ArH), 6.66(dd, J=7.6, 4.9Hz, 1H , -NH-), 4.67 (d, J=5.9Hz, 2H, -NHC H ₂ -), 3.24-2.98 (m, 4H, ArNCH ₂ -), 2.47-2.32 (m, 4H, -NCH ₂ -) , 2.20 (s, 3H, -NCH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.46, 149.05, 147.22, 134.99, 129.23, 122.79, 118.56, 110.71, 109.65, , 50.29, 46.06, 43.72; ESI-MSm/z: 403.3[M+H] ⁺ ; Anal.calcd.For C ₂₃ H ₂₆ N ₆ O: C, 68.63; H, 6.51; N, 20.88; Found: C, 68.77; H, 6.45; N, 20.76.

Example 11

Preparation of N-(naphthalene-1-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-10)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6 mmol) and naphthylamine (5 mmol) to obtain compound I-10 to obtain 1.26 g of a yellow solid with a yield of 71% and a melting point of 197-199°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.49(s, 1H, -CONH-), 8.71(s, 1H, ArH), 8.56-8.31(m, 3H, ArH), 8.22(s, 1H, ArH), 8.08-7.80 (m, 3H, ArH), 7.58 (d, J=4.1Hz, 4H, ArH), 7.30 (s, 2H, ArH), 6.75 (s, 1H, -NH-), 4.70 ( s, 2H, -NHC H ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 161.63, 158.75, 151.41, 150.46, 149.05, 135.45, 134.99, 134.48, 128.65, 127.86, 126.45, 126.13, 125. 123.19, 122.79, 120.36, 110.71, 109.81, 43.55; ESI-MS m/z: 355.2[M ₊ H] ⁺ ; _{Anal.calcd.For C22H18N4O} : C, 74.56; H, 5.12; N, 15.81; Found: C, 74.47; H, 5.09; N, 15.92.

Example 12

Preparation of 2-((pyridine-4-methylene)amino)-N-(1,2,3,4-tetrahydronaphthalene-1-yl)nicotinamide (I-11)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6 mmol) and 1,2,3,4-tetrahydronaphthalene-1-amine (5 mmol) to obtain compound I-11 to obtain 1.15 g of a white solid. The yield is 64%, melting point: 144-146°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 8.87-8.54 (m, 4H, ArH), 8.11-8.03 (m, 2H, ArH), 7.33 (s, 2H, ArH), 7.33-7.16 (m, 4H, ArH), 6.59 (s, 1H, -NH-), 5.26 (s, 1H, -NHC H -), 4.71 (s, 2H, -NHC H ₂ -), 2.78 (s, 2H, -CH ₂ Ar), 1.98(s, 2H, -CH ₂ -), 1.82(s, 2H, -CH ₂ -); C ¹³ NMR (75MHz, DMSO-d ₆ ) δppm: 163.54, 159.01, 151.73, 150.46, 149.05, 139.10, 138.43, 135.30, 129.38, 127.18, 126.55, 122.79, 112.15, 108.92, 52.97, 43.57, 30.59, 20.98; ESI-MS m/z: 359.3[M+H] ⁺ ; _{Anal.calcd.For C22H22} N ₄ O: C, 73.72; H, 6.19; N, 15.63; Found: C, 73.67; H, 6.23; N, 15.61.

Example 13

Preparation of N-(1H-benzimidazol-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-12)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 1H-benzimidazol-2-amine (5mmol) to obtain compound I-12 to obtain 1.41g of white solid with a yield of 82% and melting point: 239-241°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 12.46 (s, 1H, ArNH), 9.75 (s, 1H, -CONH-), 8.75-8.26 (m, 3H), 8.33-7.99 (m, 2H, ArH), 7.42(d, J=2.6Hz, 4H, ArH), 7.23-6.94(m, 2H, ArH), 6.72-6.45(m, 1H, -NH-), 4.77(d, J=5.1Hz, 2H, -NHC H ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 171.30, 158.75, 151.41, 150.53, 149.05, 136.92, 135.12, 122.79, 121.76, 121.04, 113.30, 112.06, 110.81, 43.69; ESI-MSm/z: 345.2[M+H] ⁺ ; _{Anal.calcd.For C19H16N6O} : C, _66.27 ; H, 4.68; N, 24.40; Found: C, 66.41; H, 4.53 ; N, 24.49.

Example 14

Preparation of N-(pyridine-4-methylene)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate (I-13)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and N-pyridine-4-methyleneamine (5mmol) to obtain compound I-13 to obtain 1.14g of a white solid with a yield of 71%, melting point: 101-103°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 9.69 (d, J=1.8Hz, 1H, -CONH-), 9.26 (s, 1H, ArH), 8.91-8.84 (m, 4H, ArH), 8.35 (d, J=7.2Hz, 1H, ArH), 8.08-7.96(m, 5H, ArH), 6.87(d, J=3.1Hz, 1H, -NH- ₎ , 4.95(s, 2H, -NHC H2 -), 4.78 (s, 2H, -NHC H ₂ -), 2.42 (s, 9H, -SO ₃ CH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 168.60, 159.23.152.05, 150.46, 149.05, 135.63, 122.79, 113.69, 108.16, 44.99, 43.54, 37.85; ESI-MS m/z: 320.2[M+H] ⁺ ; Anal.calcd.For C ₂₁ H ₂₅ N ₅ O ₁₀ S ₃ : C, 41.79 ; H, 4.17; N, 11.60; S, 15.93; Found: C, 41.72; H, 4.33; N, 11.58; S, 15.82.

Example 15

Preparation of N-(3,4-(dimethoxy)phenethyl)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate (I-14)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and N-(3,4-dimethoxy)phenethylamine (5mmol) to obtain compound I-14 to obtain 1.47g of a white solid. The yield is 75%, melting point: 185-187°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 9.80(s, 1H, -CONH-), 9.07(t, J=5.0Hz, 1H, ArH), 8.88(d, J=6.4Hz, 2H, ArH ), 8.30 (d, J=6.7Hz, 1H, ArH), 8.14-8.03 (m, 1H, ArH), 7.99 (d, J=6.4Hz, 2H, ArH), 6.95 (dd, J=7.3, 6.0 Hz, 1H, -NH-), 6.86(t, J=5.7Hz, 2H, ArH), 6.76(dd, J=8.1, 1.5Hz, 1H, ArH), 5.03(s, 2H, -NHC H ₂ - ), 3.71 (d, J=4.6Hz, 6H, -OCH ₃ ), 3.50 (dd, J=12.9, 6.7Hz, 2H, -NHC H ₂ -), 2.81 (t, J=7.3Hz, 2H, ArCH ₂ -), 2.41 (s, 9H, -SO ₃ CH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 166.35, 159.23, 152.05, 150.37, 149.05, 147.86, 135.63, 132.91, 122.79, 122.42, _113.35 , _108.16 , _56.83 , 43.56, 43.35, 37.85, 35.88; ESI-MS m/z: 393.3[ _{M +} H] ⁺ ; , 4.77; N, 8.28; S, 14.21; Found: C, 44.28; H, 4.82; N, 8.31; S, 14.19.

Example 16

Preparation of 2-((pyridine-4-methylene)amino)-N-(2-(thien-2-yl)ethyl)nicotinamide (I-15)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and N-(2-(thiophen-2-yl)ethylamine (5mmol) to obtain compound I-15 to obtain 1.26g of a yellow solid with a yield of 74%, melting point: 130-132°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 8.92-8.62 (m, 2H, ArH, -CONH-), 8.47 (d, J = 5.6Hz, 2H, ArH), 8.10 (dd, J = 4.7, 1.5Hz, 1H, ArH), 7.93(dd, J=7.6, 1.5Hz, 1H, ArH), 7.49-7.14(m, 3H, ArH), 7.05-6.80(m, 2H, ArH), 6.62(dd, J=7.6, 4.9Hz, 1H, -NH-), 4.67(d, J=5.9Hz, 2H, -NHC H ₂ -), 3.66-3.40(m, 2H, -NHC H ₂ -), 3.08(t , J=6.9Hz, 2H, ArCH ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 166.35, 159.23, 152.05, 150.46, 149.05, 137.22, 135.63, 125.95, 125.50, 124.70, 122.79, 113.69, 108.16, 43.60, 40.44, 32.51; ESI-MS m/z: 339.2[M+H] ⁺ .Anal.calcd. For C ₁₈ H ₁₈ N ₄ OS: C, 63.88; H, 5.36; N, 16.56; Found: C, 63.75; H, 5.39; N, 16.61.

Example 17

Preparation of N,N-dibenzyl-2-((pyridine-4-methylene)amino)nicotinamide (I-16)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and N,N-dibenzylamine (5mmol) to obtain compound I-16 to obtain white solid 1.39g, yield 68%, melting point: 197 -199°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 8.42 (s, 2H, ArH), 8.00 (d, J=4.2Hz, 1H, ArH), 7.50 (d, J=6.9Hz, 1H, ArH), 7.42-7.06 (m, 12H, ArH), 6.90 (s, 1H, ArH), 6.63-6.49 (m, 1H, -NH-), 4.59 (d, J=5.5Hz, 6H, -NHC H ₂ -) ; ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 175.92, 157.02, 150.74, 150.46, 149.05, 137.34, 135.40, 128.60, 127.89, 122.79, 115.39, 108.71, 50.13, 43.69; ESI-MS9 m/z [M+H] ⁺ ; _{Anal.calcd.For C26H24N4O} : C, _76.45 ; H, 5.92; N, 13.72; Found: C, 76.51; H, 5.87; N, 13.65.

Example 18

Preparation of N-(4-(morpholinoethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-17)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 4-(2-morpholinoethyl)aniline (5mmol) to obtain compound I-17 to obtain 1.49g of white solid with a yield of 71.4% , melting point: 183-185°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.23 (s, 1H, -CONH-), 8.47 (dd, J=9.2, 4.9Hz, 3H, ArH), 8.11 (ddd, J=9.2, 6.2, 1.5Hz, 2H, ArH), 7.61(d, J=8.4Hz, 2H, ArH), 7.24(dd, J=15.3, 7.0Hz, 4H, ArH), 6.68(dd, J=7.6, 4.9Hz, 1H , -NH-), 4.68 (d, J=5.9Hz, 2H, -NHC H ₂ -), 3.63-3.50 (m, 4H, -OCH ₂ -), 2.79-2.59 (m, 2H, ArCH ₂ -) , 2.49-2.27 (m, 6H, -NCH ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.46, 149.05, 138.07, 135.10, 128.59, 122.79, 121.26, 110.71, _109.81 , 67.08, 56.15, 53.07, 43.63, 33.42; ESI _- MS m/z: 418.3 [ _{M +} H] ⁺ ; , 16.77; Found: C, 68.89; H, 6.60; N, 16.72.

Example 19

Preparation of N-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-18)

Compound I-1 in Preparation Method Example 2 was prepared from Compound c (6mmol) and 4-(2-(4-methylpiperazin-1-yl)ethyl)aniline (5mmol) to obtain Compound I-18, to obtain White solid 1.35g, yield 63%, melting point: 157-161°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.22 (s, 1H, -CONH-), 8.47 (s, 3H, ArH), 8.11 (dd, J=17.6, 5.5Hz, 2H, ArH), 7.61 (d, J=7.9Hz, 2H, ArH), 7.24(dd, J=17.6, 6.1Hz, 4H, ArH), 6.80-6.58(m, 1H, -NH-), 4.68(d, J=5.5Hz , 2H, -NHC H ₂ -), 2.68 (d, J=7.9Hz, 2H, ArCH ₂ -), 2.43 (m, 10H, -NCH ₂ -), 2.14 (s, 3H, -NCH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.46, 149.05, 138.07, 135.10, 128.59, 122.79, 121.26, 110.71, 109.81, 56.15, 54.39, 53.95, 436.06; ES MS m/z: 431.3[M+H] ⁺ ; _{Anal.calcd.For C25H30N6O} : C, _69.74 ; H, 7.02; N, 19.52; Found: C, 69.68; 19.34.

Example 20

Preparation of N-(4-(2-(piperidin-1-yl)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-19)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6 mmol) and 4-(2-(piperidin-1 base) ethyl) aniline (5 mmol) to obtain compound I-19 to obtain 1.41 g of a white solid, Yield 67%, melting point: 167-170°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.24 (s, 1H, -CONH-), 8.46 (s, 3H, ArH), 8.11 (d, J=16.2, 5.4Hz, 2H, ArH), 7.61 (d, J=8.0Hz, 2H, ArH), 7.25(dd, J=18.6, 6.1Hz, 4H, ArH), 6.78-6.48(m, 1H, -NH-), 4.68(d, J=5.3Hz , 2H, -NHC H ₂ -), 2.68 (d, J=7.6Hz, 2H, ArCH ₂ -), 2.36 (m, 6H, -NCH ₂ -), 2.18 (m, 4H, -NCH ₂ CH ₂ -), 1.37 (m, 2H, -CH ₂ -); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.46, 149.05, 138.07, 135.10, 128.59, 122.79, 121.26, 110.71, 109.81, 56.15, 54.39, 53.95, 46.06, 43.63, 33.42; ESI _- MS m/z: 416.3[M+H] ⁺ ; _{Anal.calcd.For C25H29N5O} : C, 72.26; H, 7.03; N, 16.85; Found: C, 72.18; H, 7.99; N, 16.77.

Example 21

N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2-((pyridine-4- Preparation of methylene) amino) nicotinamide (I-20)

Compound I-1 in the preparation method class example 2, by compound c (6mmol) and 4-(2-(6,7-dimethoxy-dihydroisoquinolin-2 (1H) base) ethyl) aniline ( 5 mmol) to prepare compound I-20, and obtain 1.59 g of white solid, yield 60.7%, melting point: 188-190°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.24 (s, 1H, -CONH-), 8.47 (d, J=5.0Hz, 3H, ArH), 8.25-7.93 (m, 2H, ArH), 7.63 (d, J=8.4Hz, 2H, ArH), 7.26 (dd, J=15.1, 6.7Hz, 4H, ArH), 6.75-6.50 (m, 3H, -NH-,), 4.68 (d, J=5.8 Hz, 2H, -NHC H ₂ -), 3.70 (s, 6H, -OCH ₃ ), 3.54 (s, 2H, ArCH ₂ N-), 2.98-2.55 (m, 8H , -CH ₂ -); ¹³ C NMR(75MHz，DMSO-d ₆ )δppm：162.25，158.75，151.41，150.46，149.41，149.05，148.19，138.07，135.10，128.59，128.14，126.93，122.79，121.26，112.58，111.35，110.71，109.81，56.73， 54.70, 51.36, 43.63, 33.42, 28.76; ESI-MS m/z: _524.3 [ _M +H] ⁺ ; _Anal.calcd . For _C31H33N5O3 : C, 71.11; H, 6.35; N, 13.37 ;Found: C, 71.06; H, 6.52; N, 14.01.

Example 22

Preparation of N-(3,4-dimethoxybenzyl)-N-methyl-2-((pyridine-4-methylene)amino)nicotinamide (I-21)

Compound I-1 in Preparation Method Example 2, compound I-21 was prepared from compound c (6mmol) and 1-(3,4-dimethoxybenzyl)-N methylmethylamine (5mmol) to obtain white Solid 1.27g, yield 65%, melting point: 201-203°C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δppm: 9.09 (m, 1H, -CONH-), 8.86 (d, J=6.4Hz, 2H, ArH), 8.30 (d, J=6.7Hz, 1H, ArH ), 8.12-8.04 (m, 1H, ArH), 7.99 (d, J=6.4Hz, 2H, ArH), 6.95 (dd, J=7.3, 6.0Hz, 1H, -NH-), 6.88 (t, J =5.7Hz, 2H, ArH), 6.72(dd, J=8.1, 1.5Hz, 1H, ArH), 5.05(s, 2H, -NHC H ₂ -), 4.52(dd, J=12.9, 6.6Hz, 2H , -NCH ₂ Ar), 3.70 (d, J=4.6Hz, 6H, -OCH ₃ ), 3.16 (s, 3H, -NCH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 174.92, 157.41 , 151.02, 150.41, 149.05, 148.71, 135.67, 129.36, 122.79, 121.65, 116.83, 113.92, 112.97, 107.92, 56.83, 52.33, 43.63, 35.13; ESI-MS m/z: 493.2 [M ⁺ H. calcd _. For _C22H24N4O3 : C, 67.33 _; H, 6.16; N, 14.28; Found: C, _67.36 ; H, 6.14; N, 14.34.

Example 23

N-(4-(2-((3,4-dimethoxybenzyl)(methyl)amino)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide Preparation of (I-22)

Compound I-1 in Preparation Method Example 2 is prepared from compound c (6mmol) and 4-(2-((3,4-dimethoxybenzyl)(methyl)amino)ethyl)aniline (5mmol) Compound 1-22 was obtained as 1.48 g of white solid, yield 58%, melting point: 167-169°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.22 (s, 1H, -CONH-), 8.57 (d, J=5.0Hz, 4H, ArH), 8.25-7.93 (m, 2H, ArH), 7.63 (d, J = 8.4Hz, 4H, ArH), 7.26 (dd, J = 15.1, 6.7Hz, 4H, ArH), 6.78-6.70 (m, 1H, -NH-), 4.88 (d, J = 5.8Hz , 2H, -NHC H ₂ -), 3.68 (s, 6H, -OCH ₃ ), 3.54 (s, 2H, -NCH ₂ Ar), 2.68 (d, J=7.6Hz, 2H, -NCH ₂ -), 2.14-2.08 (m, 5H, -CH ₂ -, -NCH ₃ ); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 162.25, 158.75, 151.41, 150.35, 148.94, 138.07, 135.10, 130.17, 128.59, 122.79 , 121.31, 113.68, 112.88, 110.71, 109.81, 63.66, 57.57, 56.83, 43.63, 43.02, 32.37; ESI-MS m/z: 355.2[M+H] ⁺ ; Anal.calcd.For C ₃₀ H ₃₃ N ₅ O ₃ : C, 70.43; H, 6.50; N, 13.69; Found: C, 70.48; H, 6.50; N, 14.01.

Example 24

Preparation of N,N-bis(3,4-dimethoxybenzyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-23)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6 mmol) and 2-(3,4-dimethoxybenzyl) amine (5 mmol) to obtain compound I-23 to obtain 1.25 g of a white solid. The rate is 45%, melting point: 167-170°C.

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 9.12 (m, 1H, ArH), 8.89 (d, J=6.4Hz, 2H, ArH), 8.28 (d, J=7.3Hz, 1H, ArH), 8.14-8.03(m, 1H, ArH), 7.99(d, J=6.4Hz, 2H, ArH), 6.93(dd, J=7.3, 6.0Hz, 2H, ArH), 6.82(d, J=6.4Hz, 4H, ArH), 6.72 (s, 1H, -NH-), 5.03 (s, 2H, -NHC H ₂ -), 3.68 (d, J=4.6Hz, 12H, -OCH ₃ ), 3.45 (m, 4H , -NCH ₂ -), 2.81 (m, 4H, -CH ₂ Ar); ¹³ C NMR (75MHz, DMSO-d ₆ ) δppm: 172.80, 157.02, 150.94, 150.26, 149.05, 147.93, 135.40, 132.48, 122.79, 122.39, 115.39, 114.25, 113.75, 108.71, 56.83, 45.88, 43.63, 33.64; ESI-MS m/z: 557.3[M+H] ⁺ ; Anal. calcd. For C ₃₂ H ₃₆ N ₄ O ₅ : C, 69.05 ; H, 6.52; N, 10.06; Found: C, 69.03; H, 6.49; N, 10.02.

Example 25

Preparation of N-(9H-fluoren-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide (I-24)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 9H-fluoren-2-amine (5mmol) to obtain compound 13 to obtain 1.19g of white solid, yield 61%, melting point: 189-192°C .

¹ H NMR (300MHz, DMSO-d ₆ ) δppm: 10.38(s, 1H, -CONH-), 8.53(s, 3H, ArH), 8.16(s, 3H, ArH), 7.94-7.51(m, 4H, ₁₃ ^C _NMR (75MHz，DMSO-d ₆ )δppm：162.25，158.75，151.41，150.46，149.05，142.40，141.89，140.13，138.87，136.28，134.99，125.84，124.88，122.79，119.82，119.06，118.54，117.99，110.71，109.81， 43.63, 38.34; ESI-MS m/z: 393.2[M+H] ⁺ ; Anal. calcd. For C ₂₅ H ₂₀ N ₄ O: C, 76.51; H, 5.14; N, 14.28; Found: C, 76.22; H, 5.32; N, 14.29.

Example 26

Preparation of N-(2-benzoylphenyl)-2-((pyridine-4-methylene)amino)nicotinamide (I-25)

Compound I-1 in Preparation Method Example 2 was prepared from compound c (6mmol) and 2-(aminophenyl)(phenyl)methanone (5mmol) to obtain compound 13 to obtain 1.37g of white solid with a yield of 67%. Melting point: 177-179°C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δppm: 10.59 (s, 1H, -CONH-), 8.45 (s, 2H, ArH), 8.26 (s, 1H, ArH), 8.09 (s, 1H, ArH) , 7.64(d, J=15.3Hz, 6H, ArH), 7.58-7.50(m, 2H, ArH), 7.47(d, J=7.3Hz, 2H, ArH), 7.38(d, J=7.1Hz, 1H , ArH), 7.21 (s, 1H, ArH), 6.57 (d, J=4.9Hz, 1H, -NH-), 4.61 (d, J=5.4Hz, 2H, -NHC H ₂ -); ¹³ C NMR (75MHz，DMSO-d ₆ )δppm：196.06，162.50，158.75，151.41，150.46，149.05，141.29，136.25，134.99，132.50，131.68，129.97，129.24，128.60，124.88，124.35，122.79，110.71，109.81，43.63； ESI-MS m/z: 409.2[ _{M +} H] ⁺ ; _{Anal.calcd.For C25H20N4O2} : C, 73.51; H, 4.94; N, 13.72; Found: C, 73.44; H, 4.96 ; N, 13.85.

Example 27

Tablets containing active agent I-11:

The raw and auxiliary materials are mixed, granulated, dried and pressed into tablets according to conventional methods.

Claims (6)

1. The compound described in the general structural formula (I) or its pharmaceutically acceptable salt: Wherein A ring is selected from: substituted or unsubstituted aromatic group, aromatic heterocyclic group; Among them, n represents an integer from 0 to 2; Wherein R ₁ is H, halogen, haloalkyl, haloalkoxy, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted aryl, aromatic heterocycle base, aliphatic heterocyclic group, cycloalkyl group; Wherein R ₂ is H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted aryl, aromatic heterocyclic group. 2. The compound of the general structural formula (I) defined in claim 1 or a pharmaceutically acceptable salt thereof: Wherein A ring is selected from: substituted or unsubstituted phenyl, naphthyl, aromatic condensed ring, aromatic heterocyclic group, and the substituent is selected from: halogen, haloalkyl, substituted or unsubstituted C ₁ -C ₅ alkyl, Substituted or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted C ₁ -C ₅ alkyl alkoxy; aromatic ring includes an aromatic ring fused with an aliphatic ring, such as a saturated or partially saturated ring, such as Tetrahydronaphthalene ring; Among them, n represents an integer from 0 to 2; Wherein R ₁ is H, F, Cl, -OCF ₃ , substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted aryl, aromatic heterocyclic group , aliphatic heterocyclic group, cycloalkyl group; Wherein R ₂ is H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted aryl, aromatic heterocyclic group. 3. The compound of general structural formula (I) or its pharmaceutically acceptable salt as defined in claim 1 or 2: Wherein A ring is selected from: unsubstituted or up to three substituted benzene rings, naphthalene, pyrrolidine, pyrrolidone, piperidine, piperidone, piperazine, morpholine, imidazolidine, pyrazolidine, pyrrole, indole, pyrazolidine Azole, indazole, triazole, benzotriazole, imidazole, benzimidazole, thiazole, benzothiazole, furan, benzofuran, oxazole, benzoxazole, isoxazole, tetrazole, pyridine, pyrimidine , tridine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, fluorene; Among them, n represents an integer from 0 to 2; Wherein R ₁ is selected from: H, F, Cl, -OCF ₃ , substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₅ alkoxy, substituted or unsubstituted aryl, aromatic hetero Cyclic group, aliphatic heterocyclic group, cycloalkyl group; Wherein R ₂ is H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted aryl. 4. according to the compound of the general structural formula (I) defined in any one of claim 1-3 or its pharmaceutically acceptable salt, be selected from: N-(3-(methoxy)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide; 2-((pyridine-4-methylene)amino)-N-(3,4,5-(trimethoxy)phenyl)nicotinamide methanesulfonate; 2-((pyridine-4-methylene)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide; N-(4-(tert-butyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate; N-([1,1'-biphenyl]-4-yl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(5-(3-(methoxy)phenyl)-1,3,4-thiadiazol-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(piperidin-1-yl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-morpholinephenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(4-methylpiperazin-1-yl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(naphthalene-1-yl)-2-((pyridine-4-methylene)amino)nicotinamide; 2-((pyridine-4-methylene)amino)-N-(1,2,3,4-tetrahydronaphthalene-1-yl)nicotinamide; N-(1H-benzimidazol-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(pyridine-4-methylene)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate; N-(3,4-(dimethoxy)phenethyl)-2-((pyridine-4-methylene)amino)nicotinamide methanesulfonate; 2-((pyridine-4-methylene)amino)-N-(2-(thien-2-yl)ethyl)nicotinamide; N,N-dibenzyl-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(morpholinoethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(2-(piperidin-1-yl)ethyl)phenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2-((pyridine-4- Methylene) amino) nicotinamide; N-(3,4-dimethoxybenzyl)-N-methyl-2-((pyridine-4-methylene)amino)nicotinamide; N-(4-(2-((3,4-dimethoxybenzyl)(methyl)amino)ethylphenyl)-2-((pyridine-4-methylene)amino)nicotinamide; N,N-bis(3,4-dimethoxybenzyl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(9H-fluoren-2-yl)-2-((pyridine-4-methylene)amino)nicotinamide; N-(2-Benzoylphenyl)-2-((pyridine-4-methylene)amino)nicotinamide. 5. The use of the compound of general formula (I) defined in claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumor multidrug resistance. 6. A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of the compound according to any one of claims 1-4 and pharmaceutically acceptable auxiliary materials.