Piperidinyl piperidine modified beta-carboline ring-opening compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine preparation, and discloses a piperidyl piperidine modified beta-carboline ring-opening compound as well as a preparation method and application thereof. The beta-carboline ring-opening compound has a structural formula shown in a general formula I: # imgabs0 #, R1 is one of H, C1-C3 alkyl, methoxyl, nitryl, trifluoromethyl, trifluoromethoxyl, monosubstituted halogen group, disubstituted halogen group and trisubstituted methoxyl, and R2 is one of H, C1-C3 alkyl and methoxyl. The beta-carboline ring-opening compound provided by the invention can be used for preparing a medicine for inhibiting the activity of a discoid protein structural domain receptor, or preparing a medicine for treating and / or preventing malignant tumors.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and specifically relates to a piperidinylpiperidine-modified β-carboline ring-opening compound and a preparation method and application thereof. Background Art

[0002] Malignant tumors are major chronic diseases that seriously threaten life and health. In recent years, the treatments for malignant tumors include surgery, chemotherapy and radiotherapy. Among them, chemotherapy is the only method to inhibit the metastasis of cancer cells, but chemotherapy has disadvantages such as easy drug resistance and large toxic side effects. Therefore, scientific research recommends the use of targeted drug therapy, and most of the targeted anti-tumor drugs currently approved on the market use protein kinases as therapeutic targets. Using protein kinases as therapeutic targets can improve anti-cancer activity on the one hand and reduce toxicity on the other hand, so it is of great significance to find new anti-tumor drugs that are highly effective and have few toxic side effects.

[0003] β-Carboline compounds are a large class of naturally occurring indole alkaloids with a planar tricyclic structural skeleton of pyridine [3,4-b] and indole similar to carbazole. Naturally occurring β-carboline compounds are widely distributed and diverse, mainly existing in a variety of terrestrial plants and marine invertebrates. These compounds generally have multiple biological activities such as anti-tumor, anti-viral, and anti-trypanosomal activities, especially in terms of anti-tumor activity, acting on multiple biological targets. These unique biological properties and mechanisms of action have received increasing attention from researchers at home and abroad. However, considering that the ring has limited modifiable sites, the synthesis is complex and costly, in order to enrich the structural diversity of the compounds and reduce the difficulty of synthesis, the present invention has carried out research and development of β-carboline ring-opening derivatives. Summary of the invention

[0004] The purpose of the present invention is to provide a piperidinylpiperidine-modified β-carboline ring-opening compound and a preparation method and application thereof.

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

[0006] In a first aspect of the present invention, there is provided a piperidinylpiperidine-modified β-carboline ring-opening compound, wherein the β-carboline ring-opening compound has a structural formula shown in general formula I:

[0007]

[0008] Wherein, R1 is one of H, C1-C3 alkyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, monosubstituted halogen group, disubstituted halogen group and trisubstituted methoxy group, and R2 is one of H, C1-C3 alkyl and methoxy group.

[0009] In some embodiments, R1 is one of H, methyl, methoxy, nitro, chlorine, trifluoromethyl, trifluoromethoxy, 3,4,5-trimethoxy, bromine, fluorine, 4-chloro-2-fluoro, and 2,6-difluoro.

[0010] In some embodiments, R2 is one of H, methyl, and methoxy.

[0011] The preferred compound codes of the above general structural formula I and their corresponding structures are shown in Table 1:

[0012] Table 1. Codes of some compounds of general formula I and their corresponding structures

[0013]

[0014]

[0015] The second aspect of the present invention provides a method for preparing the compound represented by general formula I, comprising the following steps:

[0016] The chemical reaction formula of the preparation method is shown below:

[0017]

[0018] The preparation method comprises the following steps:

[0019] S1. Using p-nitrobenzyl bromide 1 as the starting material, it reacts with 4-piperidinylpiperidine 2 in acetonitrile solvent conditions of K2CO3 and KI to obtain intermediate 3;

[0020] S2. The intermediate 3 is subjected to palladium carbon, hydrogen or iron powder reduction reaction to obtain 4-([1,4'-bipiperidinyl]-1'-ylmethylphenyl)amine 4;

[0021] S3. reacting 4-([1,4'-bipiperidinyl]-1'-ylmethylphenyl)amine 4 with the hydrolyzed p-bromobenzoic acid 6a-c, and subjecting the reactants to an amidation reaction with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine as condensing agents to obtain an intermediate 7a-c containing an amide bond;

[0022] S4. reacting the intermediate 7a-c containing an amide bond with a substituted aniline via Buckwald coupling to obtain the β-carboline ring-opening compound I;

[0023] Wherein, R1 is selected from one of H, C1-C3 alkyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, monosubstituted halogen group, disubstituted halogen group and trisubstituted methoxy group; R2 is selected from one of H, C1-C3 alkyl and methoxy.

[0024] The third aspect of the present invention provides a pharmaceutical composition, which comprises the above-mentioned β-carboline ring-opening compound or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0025] The fourth aspect of the present invention provides a use of the above-mentioned β-carboline ring-opening compound or a medically acceptable salt thereof as an active ingredient in the preparation of a drug for inhibiting the activity of a discoidin domain receptor.

[0026] In some embodiments, the discoidin domain receptor is DDR1 and / or DDR2.

[0027] The fifth aspect of the present invention also provides a use of the above-mentioned β-carboline ring-opening compound or a medically acceptable salt thereof as an active ingredient in the preparation of a drug for treating and / or preventing malignant tumors.

[0028] In some embodiments, the malignant tumor is one of liver cancer, gastric cancer, breast cancer and colon cancer.

[0029] The compounds of the present invention can be prepared into 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 composition of the present invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations can contain, for example, 0.05% to 90% by weight of active ingredients combined with carriers, more commonly about 15% to 60% by weight of active ingredients. The dosage of the compounds of the present invention can be 0.005 to 5000 mg / kg / day, and the dosage can also exceed this dosage range depending on the severity of the disease or the dosage form.

[0030] The compounds of the present invention can be used in combination with other anti-tumor drugs such as alkylating agents (such as cyclophosphamide or cisplatin), antimetabolites (such as 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (such as camptothecin), mitotic inhibitors (such as paclitaxel or vinblastine), DNA intercalating agents (such as doxorubicin), and can also be used in combination with radiotherapy. These other anti-tumor drugs or radiotherapy can be administered at the same time or at different times with the compounds of the present invention. These combined treatments can produce synergistic effects and thus help improve the therapeutic effect.

[0031] Compared with the prior art, in order to further improve its anti-tumor activity and enrich the structural diversity of compounds, the present invention takes into account the limited substituents that can be modified on the β-carboline aromatic ring, and combines the existing structure-activity relationship of such compounds. The present invention opens the B-ring pyrrole in the β-carboline aromatic ring, performs structural modifications of various groups on the A ring and the C ring, and replaces the C ring pyridine ring with a benzene ring, thereby efficiently constructing β-carboline open-ring derivatives, and studying its anti-tumor activity has a far-reaching impact. At the same time, it is considered that the aromatic amine-substituted benzamide compounds formed after the β-carboline ring is opened can target the DDR kinase activity pocket, and the DDR activity depends on its ATP binding site. By optimizing the structure of the benzamide compound, a molecule that can competitively inhibit ATP binding is formed, thereby inhibiting the activity of DDR. Therefore, the present invention discloses a new type of piperidinyl piperidine-modified β-carboline open-ring derivatives with DDR kinase inhibitory activity, and a preparation method and medical use thereof.

[0032] The present invention opens the B-ring pyrrole in the active β-carboline aromatic tricyclic ring, performs structural modifications of various groups on the benzene ring A ring and the pyridine C ring, and replaces the C ring pyridine ring with a benzene ring, thereby efficiently and innovatively constructing a β-carboline open-ring derivative with strong anti-tumor activity, and studies its inhibitory effect on tumor cells. At present, there is no report on such compounds. A halogen group is introduced at the R1 position of the A ring to enhance its anti-tumor activity, among which the meta-chloro substitution activity is the best; the anti-tumor activity is highest when there is no substitution at the R2 position of the C ring. After testing the activity of various types of cancer cells, it is found that this type of compound selectively has a strong inhibitory effect on the proliferation of various tumor cells (including liver cancer, breast cancer, colon cancer, lung cancer, etc.), while causing less damage to normal cells; at the same time, it shows significant inhibitory activity on the tumor target DDR1 / 2. Therefore, the compounds of the present invention have important prospects for medical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Statistical graph of the inhibitory activity of I5 on normal human gastric mucosal epithelial cells GES-1 and gastric cancer cells HGC27. DETAILED DESCRIPTION

[0034] In order to further illustrate the present invention, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

[0035] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a preferred technical solution.

[0036] Example 1

[0037] Preparation of 1'-(4-nitrobenzyl)-1,4'-dipiperidine (3)

[0038] Dissolve p-nitrobenzyl bromide (2.65 g, 10 mmol) in 20 ml acetonitrile solvent, add K2CO3 (2.76 g, 20 mmol), KI (0.17 g, 1 mmol), and then add 4-piperidinylpiperidine (1.85 g, 11 mmol). After 5 hours, the reaction is complete. Concentrate the reaction solution and spin dry it, add 100 ml H2O, extract with ethyl acetate (150 ml × 3), collect the organic layer, and concentrate to obtain 2.79 g off-white solid, with a yield of 92%.

[0039] Example 2

[0040] 4-([1,4'-Bipiperidinyl]-1'-methylene)aniline (4)

[0041] Dissolve 1'-(4-nitrobenzyl)-1,4'-bipiperidine (3.03 g, 10 mmol) in methanol solvent, add 300 mg Pd / C under nitrogen protection, then introduce H2 to react. The reaction is complete after 6 hours. Filter, collect the filtrate, and concentrate to obtain 2.46 g of off-white solid. The yield is 90%.

[0042] Example 3

[0043] Preparation of 4-bromobenzoic acid (6a)

[0044] Methyl p-bromobenzoate (5a) (2.14 g, 10 mmol) was dissolved in 15 ml methanol, and 2 ml of 2N NaOH aqueous solution was added. The reaction was refluxed at 65°C for 3 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure. The concentrated product was dissolved in an appropriate amount of water, and the pH was adjusted to 4-5 with 1N HCl aqueous solution. The precipitated white solid was filtered, and the filter cake was collected and dried to obtain 1.80 g of white solid. The yield was 90%.

[0045] Example 4

[0046] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a)

[0047] 4-([1,4'-dipiperidinyl]-1'-methylene)aniline (0.27 g, 1 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.38 g, 2 mmol) and 4-dimethylaminopyridine (DMAP) (0.06 g, 0.5 mmol) were added thereto, and then 4-bromobenzoic acid (6a) (0.20 g, 1 mmol) was added thereto. After 6 h, the reaction was completed, and the mixture was concentrated and column chromatography was performed to obtain 0.39 g of a white solid with a yield of 86%. 1 H-NMR (DMSO-d6, 400MHz): δ10.29 (s, 1H, NH), 7.91 (d, 2H, J = 8.5Hz, Ar-H), 7.75 (d, 2H, J = 8.5Hz, Ar-H), 7.70 (d, 2H, J = 8.4Hz, Ar-H), 7.25 (d, 2H, J = 8. 4Hz,Ar-H),3.39(s,2H,CH2),2.83(m,2H,CH2),2.45(s,4H,CH2),2.19(s,1H,CH2),1.88(t,J=11.1Hz,2H,CH2),1.66(m,2H,CH2),1.42(m,8H,CH2).

[0048] Example 5

[0049] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-(m-tolylamino)benzamide (I1)

[0050] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) (0.46 g, 1 mmol) was dissolved in 5 ml of anhydrous toluene. Pd(OAc)2 (0.02 g, 0.05 mmol) and (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (BINAP) (0.06 g, 0.1 mmol) were added under nitrogen protection. Then, Cs2CO3 (0.46 g, 1.4 mmol) and m-toluidine (0.07 g, 1.4 mmol) were added. After reflux at 125°C for 4 h, the reaction was completed. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. A light yellow solid was obtained by column chromatography with a yield of 66%. 1H-NMR (DMSO-d6, 400MHz): δ9.93 (s, 1H, NH), 8.58 (s, 1H, NH), 7.86 (d, 2H, J = 8.8Hz, Ar-H), 7.21 ( d,2H,J=8.4Hz,Ar-H),7.18(d,1H,J=7.6Hz,Ar-H),7.09(d,2H,J=8.4Hz,Ar-H),6.98(d,2H,J=8. 8Hz, Ar-H), 6.77 (d, 1H, J = 7.2Hz, Ar-H), 3.42 (s, 2H, CH2), 2.88 (m, 2H, CH2), 2.67 (m, 4H, CH2), 2. 44(m,1H,CH),2.28(m,3H,CH3),1.91(t,2H,J=10.4Hz,CH2),1.79(m,2H,CH2),1.50(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.1,147.7,142.7,138.9,129.9,129.6,125.1,122.5,120 .6,119.8,116.3,114.8,62.7,61.6,52.3,50.1,27.0,24.6,23.5,21.6.HRMS(ESI):m / z calcd for C 31 H 38 N4O:482.3118; found:483.3125.MS(ESI)m / z=483[M+H] + .

[0051] Example 6

[0052] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-(p-tolylamino)benzamide (I2)

[0053] Referring to the preparation method of compound I1, compound I2 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-toluidine as a pale yellow solid with a yield of 65%. 1H-NMR (DMSO-d6, 400MHz): δ10.29(s,1H,NH),7.94(s,1H,NH),7.90(d,2H,J=8.8Hz,Ar-H),7.72(m,5H,Ar-H),7.56(m,2H,Ar-H),7.2 5(d,3H,J=8.4Hz,Ar-H),3.42(s,2H,CH2),2.97(s,1H,CH2),2.86(s,3H,CH3),1.91(m,4H,CH2),1.73(m,4H,CH2),1.53(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.6,147.6,142.2,138.3,129.9,129.6,125.0,122 .6,119.6,116.1,62.8,61.7,52.3,49.2,26.8,24.6,23.5,21.9.HRMS(ESI):m / z calcd for C 31 H 38 N4O:482.3118; found:483.3122.MS(ESI)m / z=483[M+H] + .

[0054] Example 7

[0055] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-methoxyphenyl)amino)benzamide (I3)

[0056] Referring to the preparation method of compound I1, compound I3 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-methoxyaniline as a pale yellow solid with a yield of 67%. 1 H-NMR (DMSO-d6, 400MHz): δ9.87 (s, 1H, NH), 8.38 (s, 1H, NH), 7.79 (d, 2H, J = 6.0Hz, Ar-H) ,7.69(d,2H,J=6.0Hz,Ar-H),7.21(m,2H,Ar-H),7.13(d,2H,J=6.0Hz,Ar-H),6.92(t,4H, J=8.4Hz, Ar-H),3.75(s,3H,CH3),3.40(s,2H,CH3),2.86(d,2H,J=6.0Hz,CH2),2.51(m, 4H,CH2),2.33(m,1H,CH),1.91(d,2H,J=4.0Hz,CH2),1.70(s,2H,CH2),1.45(m,8H,CH2).13 C-NMR(DMSO-d6,100MHz): δ165.5,149.1,147.0,140.2,132.1,131.5,129.7,127.3,124.3, 124.0,123.1,120.5,113.8,63.0,61.5,60.2,52.0,48.9,25.9,23.6,21.2.HRMS(ESI):m / z calcd forC 31 H 38 N4O2:499.3068; found:499.3061.MS(ESI)m / z=499[M+H] + .

[0057] Example 8

[0058] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-nitrophenyl)amino)benzamide (I4)

[0059] Referring to the preparation method of compound I1, compound I4 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and m-nitroaniline as a pale yellow solid with a yield of 65%. 1 H-NMR (DMSO-d6, 400MHz): δ10.05(s,1H,NH),9.17(s,1H,Ar-H),7.94(d,3H,J= 8.4Hz,Ar-H),7.71(d,3H,J=8.0Hz,Ar-H),7.57(m,2H,Ar-H),7.24(d,3H,J=12 .8Hz,Ar-H),3.40(s,2H,CH2),2.85(d,2H,J=10.8Hz,CH2),2.51(s,4H,CH2),2 .24(s,1H,CH),1.89(m,2H,CH2),1.68(d,2H,J=10.8Hz,CH2),1.43(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ164.6,138.0,134.6,134.1,131.8,130.2,129.5, 125.6,120.7,62.7,61.8,52.9,50.1,27.8,25.9,25.5.HRMS(ESI):m / zcalcd for C 30 H 35 N5O3:514.2813; found:514.2818.MS(ESI)m / z=514[M+H] + .

[0060] Example 9

[0061] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-chlorophenyl)amino)benzamide (I5)

[0062] Referring to the preparation method of compound I1, compound I5 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and m-chloroaniline as a pale yellow solid with a yield of 65%. 1 H-NMR (DMSO-d6, 400MHz): δ10.02 (s, 1H, NH), 8.91 (s, 1H, NH), 7.91 (d, 2H, J = 8.8Hz, Ar-H), 7.71 (d,2H,J=8.4Hz,Ar-H),7.31(d,1H,J=8.0Hz,Ar-H),7.23(d,2H,J=8.0Hz,Ar-H),7.15(m,4H,Ar -H),6.95(d,1H,J=8.0Hz,Ar-H),3.37(s,2H,CH2),2.83(d,2H,J=12.0Hz,CH2),2.42(s,4H,CH2 ),2.14(d,1H,J=11.2Hz,CH2),1.87(m,2H,CH2),1.64(d,2H,J=11.2Hz,CH2),1.41(m,8H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ165.3,146.5,144.3,138.5,134.5,133.5,131.7,129.9,129.2,126 .1,121.2,120.1,117.2,116.6,115.8,63.9,62.7,53.4,50.2,28.3,26.5,25.3.HRMS(ESI):m / z calcd for C 30 H 35 ClN4O:503.2572; found:503.2568.MS(ESI)m / z=503[M+H] + .

[0063] Example 10

[0064] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-(trifluoromethyl)phenyl)amino)benzamide (I6)

[0065] Referring to the preparation method of compound I1, compound I6 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-trifluoromethylaniline as a pale yellow solid with a yield of 69%. 1 H-NMR(DMSO-d6,400MHz): δ10.05(s,1H,NH),9.14(s,1H,NH),7.94(d,2H,J=8 .8Hz, Ar-H), 7.71 (d, 2H, J = 8.4Hz, Ar-H), 7.61 (d, 2H, J = 8.4Hz, Ar-H), 7.26 (m, 6H, Ar-H), 3.39 (s, 2H, CH2), 2.84 (d, 2H, J = 11.2Hz, CH2), 2.45 (s, 4H, CH2), 2. 18(s,1H,CH),1.88(m,2H,CH2),1.66(d,2H,J=10.8Hz,CH2),1.41(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.3,146.6,145.6,138.8,138.0,131.8,130.2,129.8, 127.3,120.7,120.5,117.0,62.7,62.0,53.0,50.1,31.4,27.8,26.2.HRMS(ESI):m / z calcd for C 31 H 35 F3N4O:537.2836; found:537.2842.MS(ESI)m / z=537[M+H] + .

[0066] Embodiment 11

[0067] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-(trifluoromethoxy)phenyl)amino)benzamide (I7)

[0068] Referring to the preparation method of compound I1, compound I7 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-trifluoromethoxyaniline as a pale yellow solid with a yield of 67%. 1H-NMR (DMSO-d6, 400MHz): δ9.99 (s, 1H, NH), 8.85 (s, 1H, NH), 7.90 (d, 2H, J = 8.8Hz, Ar- H),7.70(d,2H,J=8.4Hz,Ar-H),7.26(m,6H,Ar-H),7.14(d,2H,J=8.8Hz,Ar-H),3.38(s ,2H,CH2),2.83(d,2H,J=11.2Hz,Ar-H),2.42(s,4H,CH2),2.15(s,1H,CH),1.87(m,2H, CH2),1.65(d,2H,J=11.2Hz,CH2),1.46(m,5H,CH2),1.41(s,1H,CH),1.36(m,2H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.2,146.6,142.5,141.9,138.8,133.9,129.8,129.4,125.9, 122.7,121.7,120.5,119.5,115.4,72.9,63.5,53.3,50.2,28.1,26.6,25.1.HRMS(ESI):m / z calcd forC 31 H 35 F3N4O2:553.2785; found:553.2781.MS(ESI)m / z=553[M+H] + .

[0069] Example 12

[0070] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3,4,5-trimethoxyphenyl)amino)benzamide (I8)

[0071] Referring to the preparation method of compound I1, compound I8 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and 3,4,5-trimethoxyaniline as a pale yellow solid with a yield of 68%. 1H-NMR (DMSO-d6, 400MHz): δ9.91 (s, 1H, NH), 8.54 (s, 1H, NH), 7.86 (d, 2H, J = 8.4Hz, Ar-H), 7.69(d,2H,J=8.4Hz,Ar-H),7.21(d,2H,J=8.4Hz,Ar-H),7.10(d,2H,J=8.4Hz,Ar-H),6.4 6(s,2H,Ar-H),3.76(s,6H,CH3),3.63(s,3H,CH3),2.83(d,2H,J=11.2Hz,CH2),2.42(s,4 H,CH2),2.15(s,1H,CH),1.87(s,2H,CH2),1.64(d,2H,J=11.2Hz,CH2),1.40(m,8H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ165.3,153.8,147.6,139.1,137.8,133.8,132.5,129.8,129.4,124. 9,120.4,114.6,97.3,62.8,62.1,60.7,56.2,53.3,50.2,27.9,26.6,25.1.HRMS(ESI):m / zcalcd for C 33 H 42 N4O4:559.3279; found:559.3232.MS(ESI)m / z=559[M+H] + .

[0072] Example 13

[0073] Preparation of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chlorophenyl)amino)benzamide (I9)

[0074] Referring to the preparation method of compound I1, compound I9 was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-chloroaniline as a pale yellow solid with a yield of 65%. 1H-NMR (DMSO-d6, 400MHz): δ9.95 (s, 1H, NH), 8.75 (s, 1H, NH), 7.89 (d, 2H, J = 8.4Hz, Ar-H), 7.70(d,2H,J=8.4Hz,Ar-H),7.34(d,2H,J=8.4Hz,Ar-H),7.20(d,4H,J=24.8Hz,Ar-H),7.1 2(d,2H,J=8.4Hz,Ar-H),3.38(s,2H,CH2),2.83(d,2H,J=10.8Hz,CH2),2.44(s,4H,CH2),2 .17(t,1H,J=10.8Hz,CH),1.87(m,2H,CH2),1.65(d,2H,J=11.2Hz,CH2),1.40(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.4,159.0,156.3,148.0,138.6,129.7,124.8,121.7,121 .4,120.6,116.5,116.2,114.2,72.9,63.5,56.4,49.6,30.3,29.5,24.9.HRMS(ESI):m / z calcd forC 30 H 35 ClN4O:503.2572; found:503.2569.MS(ESI)m / z=503[M+H] + .

[0075] Embodiment 14

[0076] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-bromophenyl)amino)benzamide (I 10 )

[0077] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-bromoaniline. 10 , pale yellow solid, yield 66%. 1H-NMR (DMSO-d6, 400MHz): δ9.96 (s, 1H, NH), 8.76 (s, 1H, NH), 7.89 (d, 2H, J = 8.0Hz, A r-H),7.70(d,4H,J=7.6Hz,Ar-H),7.46(d,2H,J=8.0Hz,Ar-H),7.22(d,2H,J=7.6Hz, Ar-H),7.13(d,4H,J=7.6Hz,Ar-H),3.39(s,2H,CH2),2.84(d,2H,J=9.6Hz,CH2),2.4 6(s,4H,CH2),2.20(s,1H,CH),1.88(m,2H,CH2),1.65(s,2H,CH2),1.45(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.0,146.7,142.0,138.6,133.6,132.4,129.8,129.4,126 .8,120.5,115.4,112.4,114.4,67.7,62.6,53.2,50.2,28.0,26.4,24.9.HRMS(ESI):m / z calcd for C 30 H 35 BrN4O:547.2067; found:547.2062.MS(ESI)m / z=547[M+H] + .

[0078] Embodiment 15

[0079] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chloro-2-fluorophenyl)amino)benzamide (I 11 )

[0080] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and 4-chloro-2-fluoroaniline 11 , pale yellow solid, yield 65%. 1H-NMR (DMSO-d6, 400MHz): δ9.95 (s, 1H, NH), 8.52 (s, 1H, NH), 7.87 (d, 2H, J = 8.4Hz, Ar-H), 7. 70(d,2H,J=8.4Hz,Ar-H),7.48(d,1H,J=13.2Hz,Ar-H),7.39(s,1H,Ar-H),7.23(m,3H,Ar-H) ,7.01(d,2H,J=8.4Hz,Ar-H),3.38(s,2H,CH2),2.83(d,2H,J=10.8Hz,CH2),2.43(s,4H,CH2) ,2.14(d,1H,J=17.2Hz,CH),1.87(s,2H,CH2),1.64(d,2H,J=11.2Hz,CH2),1.40(m,8H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ168.7,163.2,147.0,138.7,133.9,129.6,129.4,126.4,126.3,126.0, 125.5,125.4,123.4,120.5,117.3,115.2,62.6,62.2,53.2,50.2,28.0,26.5,25.0.HRMS(ESI):m / z calcd for C 30 H 34 ClFN4O:521.2478; found:521.2481.MS(ESI)m / z=521[M+H] + .

[0081] Example 16

[0082] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-phenyl-1,8-naphthyridin-2-yl)amino)benzamide (I 12 )

[0083] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and 3-phenyl-1,8-naphthyridine-2-amine. 12 , pale yellow solid, yield 65%. 1H-NMR (DMSO-d6, 400MHz): δ10.32(s,1H,NH),10.25(s,1H,NH),7.93(d,J=16.3Hz,3H,Ar-H),7.73(d,J=16.9Hz,7H,Ar-H),7.56(d,J=7.2Hz,4H,Ar-H ),7.25(d,J=8.1Hz,3H,Ar-H),3.41(s,3H,CH2),2.85(m,2H,CH2),2.55(m,4H,CH2),1.89(m,3H,CH2),1.72(d,J=10.6Hz,2H,CH2),1.46(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.8,164.7,138.5,138.2,135.5,134.6,134.2,131.8,130.3,129 .5,128.8,128.2,125.7,120.7,120.6,73.0,62.6,52.9,49.9,27.5,25.8,22.6.HRMS(ESI):m / z calcd for C 38 H 40 N6O:597.3336; found:597.3331.MS(ESI)m / z=597[M+H] + .

[0084] Embodiment 17

[0085] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-fluorophenyl)amino)benzamide (I 13 )

[0086] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and p-fluoroaniline. 13 , pale yellow solid, yield 68%. 1H-NMR (DMSO-d6, 400MHz): δ9.96(s,1H,NH),8.59(s,1H,NH),7.90(d,J=8.4Hz,2H,Ar-H),7.71(d,J=8.4Hz,2H,Ar-H),7.39(d,J=8.4Hz,2H,Ar -H),7.19(m,4H,Ar-H),7.00(d,J=8.4Hz,2H,Ar-H),3.45(s,2H,CH2),2.93(m,3H,CH2),2.18(m,2H,CH2),1.96(m,4H,CH2),1.39(m,10H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ165.1, 147.9, 147.6, 138.6, 135.4, 132.0, 129.9, 128.8, 128.2, 125.0,120.4,116.5,114.2,63.5,61.5,52.2,49.7,31.6,30.3,26.5.HRMS(ESI):m / zcalcd for C 30 H 35 FN4O:487.2868; found:487.2873.MS(ESI)m / z=487[M+H] + .

[0087] Embodiment 18

[0088] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-fluorophenyl)amino)benzamide (I 14 )

[0089] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and m-fluoroaniline 14 , pale yellow solid, yield 66%. 1H-NMR (DMSO-d6, 400MHz): δ10.07 (s, 1H, NH), 8.95 (s, 1H, NH), 7.92 (d, J = 8.5Hz, 2H, Ar-H), 7 .75(d,J=8.1Hz,2H,Ar-H),7.30(d,J=34.9Hz,3H,Ar-H),7.18(d,J=8.5Hz,2H,Ar-H),6.97(d ,J=31.3Hz,2H,Ar-H),6.72(t,J=8.4Hz,1H,Ar-H),3.50(s,2H,CH2),2.18(t,J=7.4Hz,1H,C H),2.00(m,4H,CH2),1.76(s,4H,CH2),1.34(s,1H,CH2),1.30(s,1H,CH2),1.24(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.3,164.5,146.4,144.6,144.8,131.5,131.2,129.8,126.3,120 .7,115.8,114.1,107.7,104.6,104.4,56.7,51.7,49.1,29.5,29.1,25.0.HRMS(ESI):m / zcalcd for C 30 H 35 FN4O:487.2868; found:487.2871.MS(ESI)m / z=487[M+H] + .

[0090] Embodiment 19

[0091] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((2,6-difluorophenyl)amino)benzamide (I 15 )

[0092] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromobenzamide (7a) and 2,6-difluoroaniline 15 , pale yellow solid, yield 65%. 1H-NMR (DMSO-d6, 400MHz): δ9.98 (s, 1H, NH), 8.40 (s, 1H, NH), 7.84 (d, J = 8.2Hz, 2H, Ar-H), 7.74 (d, J = 7.8Hz, 2H ,Ar-H),7.24(m,5H,Ar-H),6.74(d,J=8.0Hz,2H,Ar-H),3.82(s,2H,CH2),3.08(m,9H,CH2),1.40(m,10H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ164.6,138.0,134.2,131.9,130.3,129.5,128.7, 127.9,125.9,120.8,62.7,61.8,52.1,49.8,30.2,29.5,27.2.HRMS(ESI):m / z calcd for C 30 H 34 F2N4O:505.2773; found:505.2779.

[0093] Embodiment 20

[0094] Synthesis of 4-bromo-3-methylbenzoic acid (6b)

[0095] Dissolve methyl 4-bromo-3-methylbenzoate (5b) (2.28 g, 10 mmol) in 15 ml methanol, add 2 ml 2 N NaOH aqueous solution, and reflux at 65°C for 3 h. After the reaction is completed, remove the solvent by distillation under reduced pressure, dissolve the concentrated product in appropriate amount of water, adjust the pH to 4-5 with 1 N HCl aqueous solution, filter the precipitated white solid, collect the filter cake, and dry to obtain 1.97 g of off-white solid. Yield 92%.

[0096] Embodiment 21

[0097] Synthesis of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromo-3-methylbenzamide (7b)

[0098] 4-([1,4'-dipiperidinyl]-1'-methylene)aniline (0.27 g, 1 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.38 g, 2 mmol) and 4-dimethylaminopyridine (DMAP) (0.06 g, 0.5 mmol) were added thereto, and then 4-bromo-3-methylbenzoic acid (6b) (0.21 g, 1 mmol) was added thereto. After 6 h, the reaction was completed, concentrated, and column chromatography was performed to obtain 0.41 g of a light yellow solid with a yield of 88%. 1H-NMR (DMSO-d6, 400MHz): δ10.32 (s, 1H, NH), 7.99 (d, 1H, J = 8.4Hz, Ar-H), 7.92 (s, 1H, Ar-H), 7.74 (d, 2H, J = 8.4Hz, Ar-H), 7.52 (d, 1H, J = 8. 4Hz, Ar-H), 7.29 (d, 2H, J = 7.2Hz, Ar-H), 3.49 (s, 2H, CH2), 3.03 (m, 9H, CH2), 2.51 (s, 3H, CH3), 2.01 (d, 2H, J = 9.2Hz, CH2), 1.65 (m, 8H, CH2).

[0099] Embodiment 22

[0100] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chlorophenyl)amino)-3-methylbenzamide (I 16 ) was synthesized by referring to the preparation method of compound I1, and compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromo-3-methylbenzamide (7b) and p-chloroaniline 16 , pale yellow solid, yield 67%. 1 H-NMR (DMSO-d6, 400MHz): δ9.98 (s, 1H, NH), 7.82 (m, 2H, Ar-H), 7.74 (d, 1H, J = 1.6Hz, NH), 7.71 (d, 2 H,J=8.8Hz,Ar-H),7.30(d,2H,J=8.4Hz,Ar-H),7.22(d,3H,J=13.6Hz,Ar-H),7.09(d,2H,J=8.8Hz, Ar-H),3.39(s,2H,CH2),2.83(d,2H,J=11.2Hz,CH2),2.51(s,2H,CH2),2.42(s,4H,CH2),2.30(s,3 H,CH3),2.15(t,1H,J=11.2Hz,CH),1.87(m,2H,CH2),1.64(d,2H,J=11.2Hz,CH2),1.44(m,6H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.4,145.1,142.7,138.7,133.9,131.0,129.4,127.3,127.2,127 .0,124.3,120.5,120.2,116.3,62.6,62.3,53.2,50.2,28.0,26.5,25.0,18.6.HRMS(ESI):m / z calcd for C 31 H37 ClN4O:517.2729; found:517.2735.MS(ESI)m / z=517[M+H] + .

[0101] Embodiment 23

[0102] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-chlorophenyl)amino)-3-methylbenzamide (I 17 )

[0103] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromo-3-methylbenzoyl (7b) and m-chloroaniline 17 , pale yellow solid, yield 66%. 1 H-NMR(DMSO-d6,400MHz): δ10.03(s,1H,NH),7.94(s,1H,NH),7.85(s,1H,Ar-H),7. 74(d,3H,J=26.8Hz,Ar-H),7.25(d,4H,J=35.6Hz,Ar-H),7.02(m,2H,Ar-H),6.89(d ,1H,J=10.8Hz,Ar-H),3.39(s,2H,CH2),2.84(d,2H,J=10.0Hz,CH2),2.47(s,3H,CH 2),2.30(s,3H,CH),2.22(s,1H,CH2),1.67(d,2H,J=10.8Hz,CH2),1.43(m,8H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ165.5,145.8,144.4,138.6,134.1,133.8,131.2,131.1,129.5,128.3,128.1,12 7.0,120.5,120.1,117.7,117.2,116.2,62.2,56.5,53.1,50.1,27.8,26.3,24.8,19.0,18.8.HRMS(ESI):m / z calcd for C 31 H 37 ClN4O:517.2729; found:517.2725.MS(ESI)m / z=517[M+H] + .

[0104] Embodiment 24

[0105] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chloro-2-fluorophenyl)amino)-3-methylbenzamide (I 18 )

[0106] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-bromo-3-methylbenzoyl (7b) and m-chloroaniline 18 , pale yellow solid, yield 68%. 1 H-NMR (DMSO-d6, 400MHz): δ9.98 (s, 1H, NH), 7.81 (s, 1H, NH), 7.70 (d, 3H, J = 8.0Hz, Ar-H), 7.64(s,1H,Ar-H),7.45(d,1H,J=10.8Hz,Ar-H),7.22(d,3H,J=8.4Hz,Ar-H),7.13(s,1H,A r-H),6.80(d,1H,J=7.2Hz,Ar-H),3.38(s,2H,CH2),2.83(d,2H,J=10.8Hz,CH2),2.50(m, 6H,CH2),2.31(s,3H,CH3),2.17(t,1H,J=11.2Hz,CH),1.65(m,2H,CH2),1.40(m,8H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ165.4,145.3,138.4,133.6,130.8,129.2,127.2,127.3,127.0,126.8,125 .5,124.0,120.4,117.2,116.9,116.1,62.6,62.0,53.2,50.0,28.0,26.8,25.0,18.4.HRMS(ESI):m / z calcd for C 31 H 36 ClFN4O:535.2634; found:535.2631.

[0107] Embodiment 25

[0108] Synthesis of 4-iodo-3-methoxybenzoic acid (6c)

[0109] Dissolve methyl 4-iodo-3-methoxybenzoate (5c) (2.92 g, 10 mmol) in 15 ml methanol, add 2 ml 2N NaOH aqueous solution, reflux at 65°C for 3 h, remove the solvent by distillation under reduced pressure, add appropriate amount of water to the concentrated product, adjust the pH to 4-5 with 1N HCl aqueous solution, filter the precipitated white solid, collect the filter cake, and dry it to obtain 2.63 g white solid. Yield 95%.

[0110] Embodiment 26

[0111] Synthesis of N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-iodo-3-methoxybenzamide (7c)

[0112] 4-([1,4'-dipiperidinyl]-1'-methylene)aniline (0.27 g, 1 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (0.38 g, 2 mmol) and 4-dimethylaminopyridine (DMAP) (0.06 g, 0.5 mmol) were added thereto, and then 6c (0.21 g, 1 mmol) was added thereto. After 6 h, the reaction was completed, concentrated, and column chromatography was performed to obtain 0.46 g of a light yellow solid with a yield of 86%. 1 H-MR(DMSO-d6,400MHz): δ10.41(s,1H,NH),7.75(d,J=8.3Hz,3H,Ar-H),7.66(s,1H,Ar-H),7.53(d,J=1.8Hz,1 H, Ar-H), 7.30 (d, J = 8.3Hz, 2H, Ar-H), 3.97 (s, 3H, CH3), 2.51 (s, 2H, CH2), 2.00 (m, 6H, CH2), 1.73 (m, 13H, CH2).

[0113] Embodiment 27

[0114] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chlorophenyl)amino)-3-methoxybenzamide (I 19 )

[0115] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-iodo-3-methoxybenzamide (7c) and p-chloroaniline. 19 , pale yellow solid, yield 65%. 1H-NMR (DMSO-d6, 400MHz): δ10.00(s,1H,NH),7.97(s,1H,NH),7.73(d,J=8.4Hz,2H,Ar-H),7.59(d,J=8.4Hz,2H,Ar-H),7.30(d,J=7.8Hz,2H,Ar-H),7.2 3(m,5H,Ar-H),3.94(s,3H,CH3),3.38(s,2H,CH2),2.80(s,2H,CH2),2.48( s,5H,CH2),1.86(t,J=11.2Hz,2H,CH2),1.69(m,2H,CH2),1.42(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.3,148.5,141.7,138.7,136.1,133.8,129.4,129.3,126.6,124.7, 121.5,120.7,120.6,113.9,111.2,62.6,62.3,56.2,55.4,53.1,27.8,26.2,24.7.HRMS(ESI):m / z calcd for C 31 H 37 ClN4O2:533.2678; found:533.2670.

[0116] Embodiment 28

[0117] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-chlorophenyl)amino)-3-methoxybenzamide (I 20 )

[0118] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-iodo-3-methoxybenzamide (7c) and m-chloroaniline 20 , pale yellow solid, yield 69%. 1H-NMR (DMSO-d6, 400MHz): δ10.02 (s, 1H, NH), 8.05 (s, 1H, NH), 7.69 (d, J = 8.4Hz, 3H, Ar-H), 7.57 ( d,J=8.8Hz,2H,Ar-H),7.29(m,2H,Ar-H),7.24(d,3H,J=8.4Hz,Ar-H),7.18(s,1H,Ar-H),6.91(d, J=9.2Hz,1H,Ar-H),3.93(s,3H,CH3),3.38(s,2H,CH2),2.83(d,3H,J=11.6Hz,CH2),2.42(s,5H, CH2),2.15(t,J=11.6Hz,1H,CH),1.87(m,3H,CH2),1.64(d,J=11.6Hz,2H,CH2),1.45(m,5H,CH2). 13 C-NMR (DMSO-d6, 100MHz): δ165.0,149.2,138.7,135.6,134.1,134.0,131.0,129.4,127.5,121.3,120 .6,120.3,117.8,116.7,115.4,111.3,62.6,61.9,59.2,53.1,50.2,28.2,26.7,25.0.HRMS(ESI):m / z calcd for C 31 H 37 ClN4O2:533.2678; found:533.2681.

[0119] Embodiment 29

[0120] N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chloro-2-fluorophenyl)amino)-3-methoxybenzamide (I 21 )

[0121] Referring to the preparation method of compound I1, compound I was synthesized from N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-iodo-3-methoxybenzamide (7c) and m-chloroaniline 21 , pale yellow solid, yield 65%. 1H-NMR (DMSO-d6, 400MHz): δ10.33 (s, 1H, NH), 10.00 (s, 1H, NH), 7.73 (d, J = 8.4Hz, 2H, Ar-H), 7.61 (d ,J=8.8Hz,2H,Ar-H),7.47(d,J=8.8Hz,2H,Ar-H),7.28(s,1H,Ar-H),7.23(d,J=8.4Hz,2H,Ar-H),6. 81(d,J=9.2Hz,1H,Ar-H),3.95(s,3H,CH3),3.18(s,2H,CH2),2.83(d,J=11.6Hz,2H,CH2),2.48(s,2 H,CH2),2.24(s,1H,CH),1.86(t,J=11.6Hz,2H,CH2),1.67(d,J=11.6Hz,2H,CH2),1.41(m,8H,CH2). 13 C-NMR(DMSO-d6,100MHz): δ165.2,164.7,148.3,138.6,136.4,133.8,129.4,126.6,125.3,124.8, 121.5,120.6,117.2,116.9,114.8,62.8,62.1,57.0,56.0,53.0,27.7,26.1,24.5.HRMS(ESI):m / z calcd for C 31 H 36 ClFN4O2:551.2584; found:551.2590.

[0122] Test Example 1

[0123] In vitro antitumor activity studies

[0124] The MTT assay was used to detect the 15 The in vitro proliferation inhibitory activity of three human tumor cells, namely human colon cancer cell line HCT116, human liver cancer cell line HepG2 and human gastric cancer cell line HGC27, was tested using the β-carboline derivative HBN8 shown in the following structural formula and the marketed drug sorafenib as positive controls. The experimental results are shown in Table 2.

[0125]

[0126] The test results showed that the half inhibition values ​​(IC 50 ) were all at the single-digit level, significantly lower than the positive control drug sorafenib, and also lower than HBN8 or equivalent to it. 10 ,I 11These five compounds have outstanding activity, and the IC 50 <1μM, especially compound I5 has the best anti-tumor cell proliferation activity, and its IC 50 =0.4μM, which is approximately the positive control drug HBN8 (IC 50 =2.8μM), sorafenib (IC 50 =9.6 μM). IC of chlorine-substituted compound I9 on HepG2 cells 50 =0.8μM, which is significantly better than the positive control drug HBN8. In addition, the cell activity of the electron-donating group substituted compounds I1, I2, I3, I6, I7 and I8 is slightly inferior to that of the halogen substituted compounds. The IC of the electron-withdrawing group nitro substituted compound I4 on HepG2 cells is 50 =3.37μM. After replacing the simple substituent with a larger naphthyridine ring, the in vitro anti-tumor cell proliferation activity was slightly improved, and the IC 50 =1.75μM.

[0127] Table 2. Compound I1-I 15 IC against three human tumor cells 50 value

[0128]

[0129]

[0130] ND: Not detected.

[0131] The present invention selects a halogen with good activity at the R1 position of the A ring to replace, further enriches the substituent at the R2 position of the C ring, and adds a methyl or methoxy group to obtain compound I 16 -I 21 Compound I was detected by MTT method. 16 -I 21 The results of the in vitro proliferation inhibition activity on four human tumor cells, human colon cancer cell line HCT116, human liver cancer cell line HepG2, human breast cancer cell Mcf-7 and human gastric cancer cell line HGC27, are shown in Table 3. The in vitro anti-tumor cell proliferation activity test found that compound I 16 The inhibitory activity on tumor cells is better than other compounds I 17 -I 21 .

[0132] Table 3. Compound I 16 -I 21 IC against four human tumor cells 50 value

[0133]

[0134]

[0135] ND: Not detected.

[0136] Test Example 2

[0137] Study on DDR enzyme inhibitory activity of target compounds

[0138] The effects of the compounds on DDR1 and DDR2 kinases were evaluated using LanthaScreen Eu kinase activity assay (Invitrogen, USA). The β-carboline derivative HBN8 was used as a positive control. The experimental results are shown in Table 4

[0139] Compounds I2, I5, I9, I 10 ,I 11 It has high enzyme inhibitory activity against both DDR1 and DDR2 kinases, especially against DDR1 kinase, with an IC 50 The activities were all lower than <0.9 μM, as shown in Table 4. Among them, the IC of the meta-chloro-substituted compound I5 against DDR1 kinase was 50 The value is as high as 0.15 μM, which is approximately the IC 50 =2.29 μM), which is 15 times more sensitive to DDR1 kinase. IC of bromine-substituted compound 8j on DDR1 kinase 50 The value is 0.12 μM, which is approximately the IC 50 = 9 times of 1.07 μM).

[0140] Table 4. Compounds I2, I5, I9, I 10 ,I 11 In vitro inhibitory activity against DDR1 and DDR2 kinases

[0141]

[0142] Test Example 3

[0143] Study on cell selectivity of the compounds of the present invention

[0144] In order to understand the selectivity of the compound I5 of the present invention for tumor cells and normal cells, the following experiment was designed for research. The drug concentration of I5 was continuously increased to analyze the inhibitory activity of I5 on normal human gastric mucosal epithelial cells GES-1 and gastric cancer cells HGC27. Figure 1 It can be found that when the concentration of I5 is 1 μM, the inhibition rate in HGC27 cells is five times that in GES-1 cells. This shows that I5 can selectively kill tumor cells at a certain concentration and has less toxic side effects on normal cells.

[0145] from Figure 1It can be found that when the concentration of I5 is 1 μM, the inhibition rate in HGC27 cells is five times that in GES-1 cells. This shows that I5 can selectively kill tumor cells at a certain concentration and has less toxic side effects on normal cells.

[0146] Although some embodiments of the present general inventive concept have been shown and described, it will be appreciated by those skilled in the art that changes may be made to these embodiments without departing from the principles and spirit of the present general inventive concept, the scope of which is defined by the claims and their equivalents.

Claims

1. A piperidinylpiperidine-modified β-carboline ring-opening compound, characterized in that: The β-carboline ring-opening compound has a structural formula shown in general formula I: Among them, R1 is one of H, C1-C3 alkyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, monosubstituted halogen group, disubstituted halogen group and trisubstituted methoxy group, and R2 is one of H, C1-C3 alkyl and methoxy.

2. The β-carboline ring-opening compound according to claim 1, characterized in that R1 is one of H, methyl, methoxy, nitro, chlorine, trifluoromethyl, trifluoromethoxy, 3,4,5-trimethoxy, bromine, fluorine, 4-chloro-2-fluoro and 2,6-difluoro, and R2 is one of H, methyl and methoxy.

3. The β-carboline ring-opening compound according to claim 1, characterized in that The β-carboline ring-opening compound is any one of the following compounds: N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-(m-tolylamino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-(p-tolylamino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-methoxyphenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-nitrophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-chlorophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-(trifluoromethyl)phenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-(trifluoromethoxy)phenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3,4,5-trimethoxyphenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chlorophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-bromophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chloro-2-fluorophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-phenyl-1,8-naphthyridin-2-yl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-fluorophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-fluorophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((2,6-difluorophenyl)amino)benzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chlorophenyl)amino)-3-methylbenzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-chlorophenyl)amino)-3-methylbenzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chloro-2-fluorophenyl)amino)-3-methylbenzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chlorophenyl)amino)-3-methoxybenzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((3-chlorophenyl)amino)-3-methoxybenzamide; N-(4-([1,4'-bipiperidinyl]-1'-ylmethyl)phenyl)-4-((4-chloro-2-fluorophenyl)amino)-3-methoxybenzamide.

4. A method for preparing the β-carboline ring-opening compound according to claim 1, characterized in that: The chemical reaction formula of the preparation method is shown below: The preparation method comprises the following steps: S1. Using p-nitrobenzyl bromide 1 as the starting material, it reacts with 4-piperidinylpiperidine 2 in acetonitrile solvent conditions of K2CO3 and KI to obtain intermediate 3; S2. The intermediate 3 is subjected to palladium carbon, hydrogen or iron powder reduction reaction to obtain 4-([1,4'-bipiperidinyl]-1'-ylmethylphenyl)amine 4; S2. reacting 4-([1,4'-bipiperidinyl]-1'-ylmethylphenyl)amine 4 with the hydrolyzed p-bromobenzoic acid 6a-c, and subjecting the reactants to an amidation reaction under the action of condensing agents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine to obtain an intermediate 7a-c containing an amide bond; S3. The intermediate 7a-c containing an amide bond is reacted with a substituted aniline via Buckwald coupling reaction to obtain the β-carboline ring-opening compound I.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the β-carboline ring-opening compound or a medically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier or excipient.

6. Use of the β-carboline ring-opening compound or a medically acceptable salt thereof according to claim 1 as an active ingredient in the preparation of a drug for inhibiting the activity of a discoidin domain receptor.

7. The use according to claim 6, characterized in that: The discoidin domain receptor is DDR1 and / or DDR2.

8. Use of the β-carboline ring-opening compound or a medically acceptable salt thereof according to claim 1 as an active ingredient in the preparation of a medicament for treating and / or preventing malignant tumors.

9. The use according to claim 8, characterized in that: The drug for treating and / or preventing malignant tumors is used to selectively inhibit the proliferation of tumor cells.

10. The use according to claim 9, characterized in that: The malignant tumor is one of liver cancer, stomach cancer, breast cancer and colon cancer.

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