Dibenzodiazepine derivatives and their preparation methods and applications

Abstract

The present invention discloses dibenzodiazepine derivatives, their preparation methods and applications. The dibenzodiazepine derivatives are represented by the general formula (I). The dibenzodiazepine derivatives in the present invention all have certain antimalarial effects, and the IC values ​​of some dibenzodiazepine derivatives for antimalarial activity are as follows: 50 The value can reach below 1 μmol / L, showing excellent antimalarial effects. The preparation method of the dibenzodiazepine derivatives of the present invention uses a one-step condensation cyclization of differently substituted QIKs and differently substituted isatoic anhydrides. The synthesis steps are simple, no amide intermediates and by-products are generated, the raw materials are cheap and readily available, no metal catalyst is required, and the product is green, safe, and efficient. The entire reaction time is short, the post-processing is simple, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and in particular relates to dibenzodiazepine derivatives and preparation methods and applications thereof. Background Art

[0002] Dibenzodiazepines, also known as dibenzodiazepinones in English, are an important class of nitrogen-containing heterocyclic compounds with physiological activities and medicinal value such as sedation, anxiolysis, antidepression, and hypnosis. They are also considered to be histone deacetylase (HDAC) inhibitors and Chk1 kinase inhibitors.

[0003] Currently, the main methods for preparing dibenzodiazepines include multi-step cascade reactions of o-aminobenzoic acid and 2-bromonitrobenzene, condensation and in-situ cyclization reactions of o-phenylenediamine and 2-halogenated benzoic acid, aniline and (2-halo-5-chlorophenyl)amino acids, and o-phenylenediamine and isatoic anhydride, and coupling reactions of 2-aminobenzamide and 1,2-dibromobenzene. These methods all synthesize dibenzodiazepines, but the reactions are complex, generate lactam intermediates, require the use of metal catalysts such as Cu or Pd, cause significant environmental pollution, require noble gas protection, and result in low product recovery rates. Summary of the Invention

[0004] In order to overcome the problems existing in the prior art, one of the objectives of the present invention is to provide a series of dibenzodiazepine derivatives.

[0005] A second object of the present invention is to provide a method for preparing the above-mentioned dibenzodiazepine derivatives.

[0006] A third object of the present invention is to provide a pharmaceutical composition.

[0007] A fourth object of the present invention is to provide the use of the above-mentioned dibenzodiazepine derivatives in the preparation of drugs for treating malaria.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] The first aspect of the present invention is to provide a dibenzodiazepine derivative represented by the general formula (I),

[0010]

[0011] Among them, R 1 Selected from p-toluenesulfonyl, p-chlorobenzenesulfonyl, p-bromobenzenesulfonyl, p-trifluoromethylsulfonyl, p-methoxysulfonyl, 2-thienyl, 2-naphthalenesulfonyl;

[0012] Each R 2 Each is independently selected from hydrogen, halogen, methyl, methoxy;

[0013] R 3 selected from methyl or ethyl;

[0014] Each R 4 Each is independently selected from hydrogen, halogen, methyl, methoxy;

[0015] n is an integer of 1 to 3; m is an integer of 1 to 4.

[0016] Preferably, the halogen is fluorine, chlorine or bromine.

[0017] Preferably, n is 1 or 2; m is 1 or 2.

[0018] Preferably, the dibenzodiazepine derivative is selected from:

[0019] 7-methoxy-10-tosyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0020] 10-((4-chlorophenyl)sulfonyl)-7-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0021] 2,7-dimethoxy-10-((4-(trifluoromethyl)phenyl)sulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one,

[0022] 7-ethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0023] 7-methoxy-10-((4-methoxyphenyl)sulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0024] 10-((4-bromophenyl)sulfonyl)-7-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0025] 2,7-dimethoxy-10-(thiophen-2-ylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one,

[0026] 7-methoxy-10-(phenylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0027] 7-methoxy-10-(naphthalene-2-ylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0028] 9-fluoro-2,7-dimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0029] 7-methoxy-9-methyl-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0030] 7,9-dimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0031] 2-chloro-7-methoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0032] 2-Bromo-7-methoxy-10-toluenesulfonate-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0033] 2-Fluoro-7-methoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0034] 7-methoxy-2-methyl-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0035] 2,3,7-trimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0036] 3-Fluoro-7-methoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0037] 3-chloro-7-methoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0038] 3-bromo-7-methoxy-10-toluenesulfonate-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one,

[0039] 2,7-Dimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one.

[0040] The second aspect of the present invention is to provide a method for preparing the dibenzodiazepine derivative provided in the first aspect of the present invention, comprising the following steps: reacting a compound of formula (II) with a compound of formula (III) under alkaline conditions to obtain the dibenzodiazepine derivative;

[0041]

[0042] Wherein, R in formula (II) 1 、R 2 、R 3 , n is as defined above;

[0043] R in formula (III) 4 , m are as defined above.

[0044] The compounds of formula (II) are variously substituted quinoneimine monoketals (QIKs).

[0045] Preferably, the reaction under alkaline conditions is specifically carried out at a temperature of 90 to 110° C. in the presence of sodium carbonate and sodium acetate.

[0046] Preferably, the molar ratio of the sodium carbonate to the compound of formula (II) is (2.5-3.5):1.

[0047] Preferably, the molar ratio of the sodium acetate to the compound of formula (II) is (0.1-0.3):1.

[0048] Preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(2.5-3.5); further preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(2.5-3); even further preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:3.

[0049] Preferably, the reaction temperature is 95-105°C.

[0050] Preferably, the preparation method further comprises the step of adding a solvent.

[0051] Preferably, the solvent is selected from acetonitrile.

[0052] Preferably, the reaction time is 20 to 30 hours; more preferably, the reaction time is 20 to 25 hours.

[0053] The third aspect of the present invention is to provide a pharmaceutical composition comprising the dibenzodiazepine derivative provided by the first aspect of the present invention.

[0054] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient, and otherwise biologically suitable for use in an organism. Examples of pharmaceutically acceptable excipients include, but are not limited to, conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants in the pharmaceutical composition. If necessary, flavoring agents, preservatives, and sweeteners may also be added to the pharmaceutical composition.

[0055] The fourth aspect of the present invention is to provide use of the dibenzodiazepine derivative provided in the first aspect of the present invention in the preparation of a drug for treating malaria.

[0056] Preferably, the dibenzodiazepine derivatives include 10-((4-chlorophenyl)sulfonyl)-7-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one; 7,9-dimethoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one; 7-methoxy-10-(phenylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one.

[0057] The beneficial effects of the present invention are as follows: the dibenzodiazepine derivatives of the present invention all have certain antimalarial effects, and the IC values ​​of some dibenzodiazepine derivatives for antimalarial activity are 50 The value can reach below 1μmol / L, which has excellent antimalarial effect.

[0058] The preparation method of the dibenzodiazepine derivatives of the present invention involves one-step condensation and cyclization of differently substituted QIKs and differently substituted isatoic anhydrides. The synthesis steps are simple, no amide intermediates and by-products are generated, the raw materials are cheap and readily available, no metal catalyst is required, the method is green, safe and efficient, the entire reaction time is short, the post-processing is simple, and the method is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0059] The specific implementation of the present invention is further described in detail below with reference to the examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that if there are any processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. If the manufacturer of the reagents or instruments used is not indicated, they are deemed to be conventional products that can be purchased commercially.

[0060] The synthesis method of QIKs is:

[0061] Compounds As an example of the preparation method:

[0062]

[0063] Synthesis of quinoneimine monoketals QIKs

[0064] Step 1: At 0°C, dissolve 1.23 g of p-methoxyaniline (10 mmol, 1.0 equiv.) and 0.12 g of p-dimethylaminopyridine (DMAP) (1 mmol, 1.0 equiv.) in 40 mL of DCM. Slowly add 2.1 g of p-toluenesulfonyl chloride (TsCl) (11 mmol, 1.1 equiv.) to the mixture. After the addition, warm the reaction mixture to ambient temperature and continue the reaction for 2 hours. After completion, quench the mixture with saturated ammonium chloride solution. Extract the aqueous layer with DCM (3 x 20 mL). The combined organic layers are then washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product is purified by silica gel column chromatography to obtain the desired N-protected aniline product in a 90% yield.

[0065] Step 2: At 0°C, add 1.4 g of the N-protected aniline product (5 mmol, 1.0 equiv.) to 20 mL of methanol. Simultaneously, slowly add 1.95 g of PhI(OAc)2 (6 mmol, 1.2 equiv.) dropwise to the reaction system over 10 minutes. After the addition is complete, transfer the mixture to room temperature, stir vigorously at room temperature, and monitor by TLC analysis. After completion, quench the reaction with a large amount of saturated NaHCO3, and extract the aqueous layer with DCM (3 × 50 mL). The combined organic layers are then washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography to yield 1.4 g of the target compound in 92% yield. The product is stored at -20°C.

[0066] The QIKs used in the present invention can be prepared by referring to the preparation methods of the above-mentioned compounds. It is only necessary to replace the substituent groups to achieve the preparation of the QIKs in the present invention.

[0067] Example 1

[0068] Preparation of 7-methoxy-10-toluenesulfonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3a)

[0069] The structural formula of compound 3a is: Wherein Ts is p-toluenesulfonyl.

[0070] N-(4,4-Dimethoxycyclohexa-2,5-diene-1-ylidene)-4-methylbenzenesulfonamide (30.7 mg, 0.1 mmol) and 2H-benzo[d][1,3]oxazine-2,4(1H)-dione (also known as isatoic anhydride, purchased from Adamas, 48.9 mg, 0.3 mmol) were placed in a 35 mL sealed tube. Na2CO3 (31.5 mg, 0.3 mmol) and NaOAc (1.6 mg, 20 mol%) were added. Acetonitrile (2 mL) was added to the sealed tube, and the mixture was stirred at 100°C for 24 h. The reaction was monitored by silica gel thin-layer chromatography. After completion of the reaction, the mixture was washed three times with saturated brine (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 3a as a yellow solid (40.5 mg) in a yield of 85%.

[0071] 1 H NMR (600MHz, CDCl3) δ8.09 (d, J=8.0Hz, 2H), 7.89 (dd, J=8.0, 1.6Hz, 1H), 7.30 (d, J=8.0Hz ,3H),6.98-6.91(m,3H),6.83(d,J=8.1Hz,1H),5.80(s,1H),3.75(s,3H),2.40(s,3H)ppm.

[0072] 13 C NMR (150MHz, CDCl3) δ166.8,156.6,150.5,144.8,137.9,136.4,134.2,133.3, 129.5,129.2,127.7,122.0,121.3,121.3,119.3,115.5,113.4,55.8,21.7ppm.

[0073] HRMS (ESI) calculated as [C 21 H 18 N2O4S+H] + 395.0987, and a mass spectrum peak of 395.1068 was detected.

[0074] Example 2

[0075] Preparation of 10-((4-chlorophenyl)sulfonyl)-7-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3b)

[0076] The structural formula of compound 3b is:

[0077] Compound 3b was prepared by referring to the preparation method of compound 3a, with a yield of 30%.

[0078] 1 H NMR (600MHz, CDCl3) δ8.13(d,J=7.1Hz,2H),7.48(d,J=14.5Hz,2H),7.34(d,J=2.9Hz,1H),6.96( d,J=8.7Hz,1H),6.95–6.91(m,2H),6.83–6.77(m,2H),5.60(s,1H),3.76(s,3H),3.72(s,3H)ppm.

[0079] 13 C NMR (150MHz, CDCl3) δ166.8,156.5,154.8,144.67,140.4,138.9,137.8,130.6, 129.2,127.4,123.2,121.5,121.2,120.8,115.6,114.4,113.6,55.8,55.7ppm.

[0080] HRMS (ESI) calculated as [C 20 H 15 ClN2O4S+H] + 415.0441, and a mass spectrum peak of 415.0531 was detected.

[0081] Example 3

[0082] Preparation of 2,7-dimethoxy-10-((4-(trifluoromethyl)phenyl)sulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (3c)

[0083] The structural formula of compound 3c is:

[0084] Compound 3c was prepared by referring to the preparation method of compound 3a with a yield of 20%.

[0085] 1 H NMR (600MHz, CDCl3) δ8.32(d,J=8.2Hz,2H),7.79(d,J=8.3Hz,2H),7.33(d,J=3.0Hz,1H),6.99(d,J=8.7Hz,1H), 6.97–6.94(m,2H),6.85(dd,J=8.7,2.7Hz,1H),6.80(d,J=8.8Hz,1H),5.52(s,1H),3.78(s,3H),3.72(s,3H)ppm.

[0086] 13 C NMR (150MHz, CDCl3) δ166.8,156.6,154.9,144.6,143.0,138.8,135.3,129.6,127 .2,126.1,123.3,121.5,121.2,120.81,115.7,114.4,113.7,55.9,55.7,55.6ppm.

[0087] HRMS (ESI) calculated as [C 22 H 17 F3N2O5S+H] + 479.0810, and a mass spectrum peak of 479.0758 was detected.

[0088] Example 4

[0089] Preparation of 7-ethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3d)

[0090] The structural formula of compound 3d is:

[0091] Compound 3d was prepared by referring to the preparation method of compound 3a, with a yield of 35%.

[0092] 1 H NMR (600MHz, CDCl3) δ8.07(d,J=8.2Hz,2H),7.89(dd,J=8.0,1.6Hz,1H),7.30(t,J=7.0Hz,3H),6.98(d,J=2.7Hz,1H),6 .95–6.92(m,2H),6.84–6.78(m,2H),5.71(s,1H),3.97(dd,J=20.1,7.1Hz,2H),2.40(s,3H),1.38(t,J=7.0Hz,3H)ppm.

[0093] 13 C NMR (150MHz, CDCl3) δ166.8,155.9,150.5,144.7,137.7,136.4,134.1,133.3,129 .5,129.2,127.7,122.0,121.4,121.2,119.2,116.2,114.1,64.2,21.7,14.7ppm.

[0094] HRMS (ESI) calculated as [C 22 H 20 N2O4S+H] +409.1140, and a mass spectrum peak of 409.1251 was detected.

[0095] Example 5

[0096] Preparation of 7-methoxy-10-((4-methoxyphenyl)sulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3e)

[0097] The structural formula of compound 3e is:

[0098] Compound 3e was prepared by referring to the preparation method of compound 3a, with a yield of 37%.

[0099] 1 H NMR (600MHz, CDCl3) δ8.13(d,J=8.9Hz,2H),7.90(dd,J=8.0,1.6Hz,1H),7.30(t,J=8.4Hz,1H),6.99(d,J=2.8Hz,1H),6. 96(dd,J=8.9,6.7Hz,4H),6.83(d,J=8.2Hz,1H),6.80(dd,J=8.8,2.7Hz,1H),5.73(s,1H),3.85(s,3H),3.76(s,3H)ppm.

[0100] 13 C NMR (150MHz, CDCl3) δ166.8,163.7,156.6,150.5,137.9,134.1,133.3,131.5, 130.7,127.9,122.1,121.4,121.2,119.2,115.5,114.0,113.5,55.8,55.6ppm.

[0101] HRMS (ESI) calculated as [C 21 H 18 N2O4S+H] + 411.1019, and a mass spectrum peak of 410.0948 was detected.

[0102] Example 6

[0103] Preparation of 10-((4-bromophenyl)sulfonyl)-7-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3f)

[0104] The structural formula of compound 3f is:

[0105] Compound 3f was prepared by referring to the preparation method of compound 3a with a yield of 33%.

[0106] 1 H NMR (600MHz, CDCl3) δ8.05(d,J=8.7Hz,2H),7.89(d,J=9.7Hz,1H),7.65(d,J=8.6Hz,2H), 7.33(t,J=7.6Hz,1H),6.98–6.93(m,3H),6.85–6.80(m,2H),5.76(s,1H),3.76(s,3H)ppm.

[0107] 13 C NMR (150MHz, CDCl3) δ166.7,156.7,150.4,138.5,137.8,134.4,133.3,132.2,1 30.6,129.0,127.4,125.6,122.2,121.4,121.1,119.4,115.6,113.5,55.8ppm.

[0108] HRMS (ESI) calculated as [C 20 H 15 BrN2O4S+H] + 458.9936, and a mass spectrum peak of 459.0001 was detected.

[0109] Example 7

[0110] Preparation of 2,7-dimethoxy-10-(thiophen-2-ylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (3 g)

[0111] The structural formula of compound 3g is:

[0112] Compound 3g was prepared by referring to the preparation method of compound 3a with a yield of 47%.

[0113] 1 H NMR (600MHz, CDCl3) δ8.05 (s, 1H), 7.72 (d, J = 5.1Hz, 1H), 7.46 (s, 1H), 7.14 (s, 1H), 6.96 (t, J=8.6Hz,2H),6.91(s,1H),6.80(d,J=8.8Hz,2H),5.64(s,1H),3.75(s,3H),3.74(s,3H)ppm.

[0114] 13C NMR (150MHz, CDCl3) δ166.9,156.6,154.6,144.7,140.4,138.6,135.8,134.3, 127.9,127.2,123.5,121.1,121.0,120.8,115.5,114.3,112.8,55.8,55.7ppm.

[0115] HRMS (ESI) calculated as [C 19 H 16 N2O5S2+H] + 417.0501, and a mass spectrum peak of 417.0465 was detected.

[0116] Example 8

[0117] Preparation of 7-methoxy-10-(phenylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3h)

[0118] The structural formula of compound 3h is:

[0119] Compound 3h was prepared according to the preparation method of compound 3a with a yield of 52%.

[0120] 1 H NMR (600MHz, CDCl3) δ8.26–8.23(m,2H),7.93(dd,J=8.0,1.6Hz,1H),7.64–7.60(m,1H),7.56–7.53(m,2H),7.33(ddd,J=8.2 ,7.1,1.6Hz,1H),7.00–6.95(m,3H),6.86(dd,J=8.2,1.1Hz,1H),6.82(dd,J=8.7,2.8Hz,1H),5.86(s,1H),3.77(s,3H)ppm.

[0121] 13 C NMR (150MHz, CDCl3) δ166.8,156.6,150.4,139.5,137.9,134.3,133.7,133. 3,129.1,128.9,127.6,122.0,121.4,121.1,119.4,115.6,113.3,55.8ppm.

[0122] HRMS (ESI) calculated as [C 20 H 16 N2O4S+H] + 381.0831, and a mass spectrum peak of 381.0920 was detected.

[0123] Example 9

[0124] Preparation of 7-methoxy-10-(naphthalene-2-ylsulfonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3i) The structural formula of compound 3i is:

[0125] Compound 3i was prepared by referring to the preparation method of compound 3a with a yield of 46%.

[0126] 1 H NMR (600MHz, CDCl3) δ8.78(s,1H),8.15(dd,J=8.8,1.9Hz,1H),8.00(d,J=8.1Hz,1H),7.94(d,J=8.8Hz,1H),7.89(t,J=7.5Hz,2H),7.65–7.58(m,2H ),7.31(t,J=6.9Hz,1H),7.02(d,J=2.7Hz,1H),6.98(d,J=8.7Hz,1H),6.9 5–6.92(m,1H),6.84(dd,J=8.2,3.5Hz,2H),5.68(s,1H),3.76(s,3H)ppm.

[0127] 13 C NMR (150MHz, CDCl3) δ166.6,156.7,150.4,137.8,136.2,135.3,134.2,133.4,131.9,131.4,129. 6,129.3,129.1,127.9,127.7,127.5,123.4,122.2,121.4,121.2,119.2,115.8,113.6,55.8ppm.

[0128] HRMS (ESI) calculated as [C 24 H 18 N2O4S+H] + 431.0987, and a mass spectrum peak of 431.1063 was detected.

[0129] Example 10

[0130] Preparation of 9-fluoro-2,7-dimethoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3j) The structural formula of compound 3j is:

[0131] Compound 3j was prepared by referring to the preparation method of compound 3a with a yield of 20%.

[0132] 1 H NMR (600MHz, CDCl3) δ8.06(d,J=8.0Hz,2H),7.33(dd,J=9.9,5.5Hz,3H),6.94(dd,J=8.8,3.1Hz,1H),6 .86–6.81(m,2H),6.70(dd,J=11.2,2.7Hz,1H),5.68(s,1H),3.77(s,3H),3.71(s,3H),2.41(s,3H)ppm.

[0133] 13 C NMR (150MHz, CDCl3) δ166.3,155.1,154.8,153.2,145.0,144.1,136.1,129.5,129 .3,127.4,122.7,122.3,121.1,114.9,109.3,102.8,102.6,56.0,55.6,21.7ppm.

[0134] HRMS (ESI) calculated as [C 22 H 19 FN2O5S+H] + 443.0999, and a mass spectrum peak of 443.0985 was detected.

[0135] Example 11

[0136] Preparation of 7-methoxy-9-methyl-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3k) The structural formula of compound 3k is:

[0137] Compound 3k was prepared by referring to the preparation method of compound 3a with a yield of 31%.

[0138] 1 H NMR (600MHz, CDCl3) δ8.09(d,J=8.4Hz,2H),7.88(d,J=8.0Hz,1H),7.28(d,J=6.1Hz,3H),6.93(t,J=7.6Hz,1H),6.86( d,J=8.1Hz,1H),6.83(d,J=2.6Hz,1H),6.71(d,J=2.8Hz,1H),5.80(s,1H),3.73(s,3H),2.38(s,3H),2.30(s,3H)ppm.

[0139] 13C NMR (150MHz, CDCl3) δ166.2,156.8,151.1,145.0,140.2,137.0,136.3,134.6, 129.6,129.1,127.6,122.2,121.7,119.2,115.5,113.0,55.7,29.7,21.7ppm.

[0140] HRMS (ESI) calculated as [C 22 H 20 N2O4S+H] + 409.1144, a mass spectrum peak of 409.1144 was detected.

[0141] Example 12

[0142] Preparation of 7,9-dimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3l)

[0143] The structural formula of compound 31 is:

[0144] Compound 31 was prepared by referring to the preparation method of compound 3a with a yield of 33%.

[0145] 1 H NMR (600MHz, CDCl3) δ8.07(d,J=8.4Hz,2H),7.89(d,J=9.6Hz,1H),7.30(d,J=8.1Hz,3H),6.94–6.87(m,2 H), 6.55 (d, J = 2.5Hz, 1H), 6.47 (d, J = 2.5Hz, 1H), 6.26 (s, 1H), 3.87 (s, 3H), 3.75 (s, 3H), 2.40 (s, 3H) ppm.

[0146] 13 C NMR (150MHz, CDCl3) δ166.7,156.2,150.9,150.8,144.7,136.5,133.9,133.3,12 9.4,129.2,127.9,127.6,121.7,121.3,119.8,103.5,99.4,56.1,55.8,21.6ppm.

[0147] HRMS (ESI) calculated as [C 22 H 20 N2O5S+H] + 425.1093, and a mass spectrum peak of 425.1150 was detected.

[0148] Example 13

[0149] Preparation of 2-chloro-7-methoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3m)

[0150] The structural formula of compound 3m is:

[0151] Compound 3m was prepared by referring to the preparation method of compound 3a with a yield of 30%.

[0152] 1 H NMR (600MHz, CDCl3) δ8.10(d,J=8.0Hz,2H),7.87(s,1H),7.35(d,J=8.0Hz,2H),7.24(dd,J=8.7,2 .5Hz,1H),6.96(d,J=9.0Hz,2H),6.80(d,J=8.7Hz,2H),5.92(s,1H),3.77(s,3H),2.44(s,3H)ppm.

[0153] 13 C NMR (150MHz, CDCl3) δ165.8,156.8,149.0,145.1,137.4,136.2,134.0,132.5, 129.6,129.2,127.6,127.2,122.2,121.4,120.8,115.6,113.3,55.8,21.7ppm.

[0154] HRMS (ESI) calculated as [C 21 H 17 ClN2O4S+H] + 429.0598, and a mass spectrum peak of 429.0689 was detected.

[0155] Example 14

[0156] Preparation of 2-bromo-7-methoxy-10-toluenesulfonate-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3n) The structural formula of compound 3n is:

[0157] Compound 3n was prepared by referring to the preparation method of compound 3a with a yield of 45%.

[0158] 1H NMR (600MHz, CDCl3) δ8.05(d,J=8.4Hz,2H),7.98(d,J=2.3Hz,1H),7.80(d,J=8.4Hz,2H),7.36(dd,J=8.6,2.4Hz,1H),7 .30(s,1H),6.94(s,1H),6.81(dd,J=8.7,2.8Hz,1H),6.73(d,J=8.6Hz,1H),5.79(s,1H),3.75(s,3H),2.41(s,3H)ppm.

[0159] 13 C NMR (150MHz, CDCl3) δ165.6,156.8,149.3,145.0,136.8,135.5,129.7,129.5, 129.2,127.6,126.5,122.7,121.3,121.0,115.7,114.4,113.4,55.8,21.7ppm.

[0160] HRMS (ESI) calculated as [C 21 H 17 BrN2O4S+H] + 473.0092, and a mass spectrum peak of 473.0265 was detected.

[0161] Example 15

[0162] Preparation of 2-fluoro-7-methoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3o)

[0163] The structural formula of compound 3o is:

[0164] Compound 3o was prepared by referring to the preparation method of compound 3a with a yield of 25%.

[0165] 1 H NMR (600MHz, CDCl3) δ8.07(d,J=8.0Hz,2H),7.96–7.91(m,1H),7.32(d,J=8.0Hz,2H),6.98–6.94(m,2H),6.83( dd,J=8.8,2.7Hz,1H),6.66(t,J=8.3Hz,1H),6.55(d,J=9.7Hz,1H),5.83(s,1H),3.76(s,3H),2.42(s,3H)ppm.

[0166] 13C NMR (150MHz, CDCl3) δ165.8,156.9,144.9,136.9,136.4,136.3,129.5,129.2, 127.9,121.3,117.6,115.6,113.4,110.1,110.0,105.7,105.6,55.8,21.7ppm.

[0167] HRMS (ESI) calculated as [C 21 H 17 FN2O4S+H] + 413.0893, and a mass spectrum peak of 413.0913 was detected.

[0168] Example 16

[0169] Preparation of 7-methoxy-2-methyl-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3p)

[0170] The structural formula of compound 3p is:

[0171] Compound 3p was prepared by referring to the preparation method of compound 3a with a yield of 25%.

[0172] 1 H NMR (600MHz, CDCl3) δ8.07(d,J=8.0Hz,2H),7.67(d,J=2.1Hz,1H),7.30(d,J=8.0Hz,2H),7.12(d,J=8.4Hz,1H),6.99(d,J=2.8Hz,1H ), 6.95 (d, J = 8.7Hz, 1H), 6.81 (dd, J = 8.8, 2.8Hz, 1H), 6.74 (d, J = 8.2Hz, 1H), 5.58 (s, 1H), 3.77 (s, 3H), 2.40 (s, 3H), 2.21 (s, 3H) ppm.

[0173] 13 C NMR (150MHz, CDCl3) δ166.9,156.5,148.3,144.7,138.4,136.5,135.2,133.0,131 .7,129.4,129.2,127.8,121.2,121.0,119.2,115.6,113.6,55.8,21.6,20.2ppm.

[0174] HRMS (ESI) calculated as [C 22 H 20 N2O4S+H] +409.1144, and a mass spectrum peak of 409.1369 was detected.

[0175] Example 17

[0176] Preparation of 2,3,7-trimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3q)

[0177] The structural formula of compound 3q is:

[0178] Compound 3q was prepared by referring to the preparation method of compound 3a with a yield of 32%.

[0179] 1 H NMR (600MHz, CDCl3) δ8.13(d,J=7.8Hz,2H),7.35(s,1H),7.34(s,1H),7.33(s,1H),6.92(d,J=8.7Hz,1H),6.84(d,J= 6.3Hz,1H),6.75(d,J=8.7Hz,1H),6.32(s,1H),5.30(s,1H),3.86(s,3H),3.78(s,3H),3.71(s,3H),2.43(s,3H)ppm.

[0180] 13 C NMR (150MHz, CDCl3) δ166.3,156.5,154.6,146.3,144.6,144.5,138.4,137.0,129.6 ,129.0,127.9,121.1,115.3,113.4,112.8,111.9,101.9,56.1,56.1,55.7,21.6ppm.

[0181] HRMS (ESI) calculated as [C 23 H 22 N2O6S+H] + 455.1199, and a mass spectrum peak of 455.1387 was detected.

[0182] Example 18

[0183] Preparation of 3-fluoro-7-methoxy-10-tolyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3r)

[0184] The structural formula of compound 3r is:

[0185] Compound 3r was prepared according to the preparation method of compound 3a with a yield of 43%.

[0186] 1 H NMR (600MHz, CDCl3) δ8.07(d,J=8.0Hz,2H),7.96–7.91(m,1H),7.32(d,J=8.0Hz,2H),6.98–6.94(m,2H),6.83( dd,J=8.8,2.7Hz,1H),6.66(t,J=8.3Hz,1H),6.55(d,J=7.3Hz,1H),5.83(s,1H),3.76(s,3H),2.42(s,3H)ppm.

[0187] 13 C NMR (150MHz, CDCl3) δ165.8,156.9,144.9,136.9,136.4,136.3,129.5,129.2, 127.9,121.3,117.6,115.6,113.4,110.1,110.0,105.7,105.6,55.8,21.7ppm.

[0188] HRMS (ESI) calculated as [C 21 H 17 FN2O4S+H] + 413.0893, and a mass spectrum peak of 413.0913 was detected.

[0189] Example 19

[0190] Preparation of 3-chloro-7-methoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3s)

[0191] The structural formula of compound 3s is:

[0192] Compound 3s was prepared by referring to the preparation method of compound 3a with a yield of 28%.

[0193] 1 H NMR (600MHz, CDCl3) δ8.10(d,J=8.1Hz,2H),7.83(d,J=8.5Hz,1H),7.32(d,J=8.0Hz,2H),6.94(d,J=8 .7Hz,1H),6.89–6.82(m,3H),6.74(dd,J=8.8,2.8Hz,1H),6.18(s,1H),3.72(s,3H),2.41(s,3H)ppm.

[0194] 13C NMR (150MHz, CDCl3) δ166.2,156.8,151.1,145.0,140.2,137.0,136.3,134 .6,129.6,129.1,127.6,122.2,121.7,119.2,115.5,113.0,55.7,21.7ppm.

[0195] HRMS (ESI) calculated as [C 21 H 17 ClN2O4S+H] + 429.0598, and a mass spectrum peak of 429.0776 was detected.

[0196] Example 20

[0197] Preparation of 3-bromo-7-methoxy-10-toluenesulfonate-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3t) The structural formula of compound 3t is:

[0198] Compound 3t was prepared by referring to the preparation method of compound 3a with a yield of 44%.

[0199] 1 H NMR (600MHz, CDCl3) δ8.07(d,J=6.5Hz,2H),7.74(d,J=8.6Hz,1H),7.31(d,J=8.6Hz,2H),7.06-7.00(m,2H),6.9 5(d,J=8.8Hz,1H),6.92(d,J=2.6Hz,1H),6.78(dd,J=8.8,2.6Hz,1H),5.89(s,1H),3.74(s,3H),2.41(s,3H)ppm.

[0200] 13 C NMR (150MHz, CDCl3) δ166.2,156.8,151.0,145.0,136.9,136.2,134.7,129.6, 129.1,128.7,127.7,125.3,122.1,121.5,120.0,115.6,113.2,55.8,21.7ppm.

[0201] HRMS (ESI) calculated as [C 21 H 17 BrN2O4S+H] + 473.0092, and a mass spectrum peak of 473.0265 was detected.

[0202] Example 21

[0203] Preparation of 2,7-dimethoxy-10-methylphenyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one (3u)

[0204] The structural formula of compound 3u is:

[0205] Compound 3u was prepared by referring to the preparation method of compound 3a with a yield of 15%.

[0206] 1 H NMR (600MHz, CDCl3) δ8.09(d,J=7.9Hz,2H),7.34(d,J=3.0Hz,1H),7.30(d,J=7.9Hz,2H),7.26(s,1H),6.95(d,J= 2.9Hz,2H),6.89(d,J=8.7Hz,1H),6.83(d,J=8.7Hz,1H),5.71(s,1H),3.74(s,3H),3.69(s,3H),2.40(s,3H)ppm.

[0207] 13 C NMR (150MHz, CDCl3) δ166.9,156.4,154.7,145.5,139.0,136.5,129.5,129.1,128.5,127 .7,122.9,122.1,121.6,121.2,120.8,115.5,114.8,114.4,113.5,55.8,55.6,21.7ppm.

[0208] HRMS (ESI) calculated as [C 22 H 20 N2O5S+H] + 425.1093, and a mass spectrum peak of 425.1105 was detected.

[0209] Antimalarial activity test

[0210] The antimalarial activity of dibenzodiazepine derivatives, i.e., compounds 3a to 3u, was tested separately. The specific testing method was as follows: (1) Prepare complete culture medium for Plasmodium falciparum containing bovine serum: weigh 12.0 g HEPES (25 mmol / L), 10.0 g albumin, 4.0 g glucose, 4.0 g NaHCO3, 0.4 g L-glutamine, 0.05 g gentamicin, and 0.05 g hypoxanthine in a beaker, add 2 L of autoclaved water, and then add 2 bags of RPMI Medium 1640, mix well, stir for 1-2 hours, autoclave, and store at 4°C. (2) Culture Plasmodium falciparum 3D7 in complete culture medium for Plasmodium falciparum, and add fresh red blood cells to a hematocrit ratio of approximately 2-5%. The culture medium should be changed daily according to the growth of Plasmodium falciparum or synchronization treatment should be performed (blood smears should be made with Giemsa stain to determine the red blood cell infection rate). When the red blood cell infection rate reaches 5-10%, the cultured malarial parasites are cultured in separate dishes to avoid the high level of toxic metabolites in the culture medium causing the parasite to die. Finally, the culture dish is placed in a three-gas incubator (5% CO2, 5% O2, 90% N2, humidity 95%, temperature 37°C) for culture. (3) In vitro culture synchronization: Use 5% D-sorbitol solution (DS) to synchronize the malarial parasites to the ring stage, apply a thin blood film for observation, and perform ring stage synchronization when the parasite infection rate is 5-10% and the ring stage is greater than 60%. The supernatant in the culture dish is discarded, and the remaining red blood cells are transferred to a 15mL centrifuge tube, centrifuged at 1900rpm for 3 minutes at room temperature, the supernatant is discarded, and 5% DS (14 times the volume of red blood cells) is added, mixed, incubated at 37°C for 10 minutes, centrifuged at 1900rpm for 3 minutes at room temperature, and the supernatant is discarded. The remainder was transferred to a culture dish, and about 15 mL of culture medium was added. About 200-300 μL of fresh red blood cells were added to make the hematocrit 5%, and the mixture was placed in a three-gas incubator for constant temperature culture. (4) In vitro inhibition rate test: The 21 synthesized derivatives were prepared into a mother solution with a concentration of 20 mmol / L using DMSO solution, and then diluted to 0.2 mmol / L using MCM culture medium. Then, 1 μL of the drug solution containing each target compound was taken and added to 199 μL of MCM culture medium to obtain a series of 1000 nmol / L target solutions. The SYBR Green I method was used to determine the inhibition of the proliferation of Plasmodium falciparum by different concentrations of the target compound, and the in vitro antimalarial activity of the drug was evaluated by IC50. The specific test results are recorded in Table 1.

[0211] Table 1 Antimalarial activity test results of compounds 3a-3u

[0212]

[0213] As shown in Table 1, compounds 3a to 3u of the present invention all have certain antimalarial activity, among which compounds 3b, 3d, 3f, 3h, 3l, 3o, and 3t all exhibited relatively excellent antimalarial activity.

[0214] While the embodiments of the present invention have been described in detail above, the present invention is not limited to the embodiments described above. Various modifications may be made within the scope of knowledge possessed by a person skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof may be combined with one another unless there is a conflict.

Claims

1. A dibenzodiazepine derivative represented by the general formula (I), The dibenzodiazepine derivatives are 2. The method for preparing the dibenzodiazepine derivative according to claim 1, wherein: The following steps are involved: reacting the compound of formula (II) with the compound of formula (III) under alkaline conditions to obtain the dibenzodiazepine derivative; Wherein, R in formula (II) 1 、R 2 、R 3 , n as defined in claim 1; R in formula (III) 4 , m as defined in claim 1.

3. The method for preparing a dibenzodiazepine derivative according to claim 2, wherein: The reaction under alkaline conditions is specifically a reaction at a temperature of 90-110° C. in the presence of sodium carbonate and sodium acetate.

4. The method for preparing a dibenzodiazepine derivative according to claim 2, wherein: The molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(2.5-3.5).

5. A pharmaceutical composition, characterized in that: The invention comprises the dibenzodiazepine derivative according to claim 1.

6. The pharmaceutical composition according to claim 5, characterized in that: Pharmaceutically acceptable excipients are also included.

7. Use of the dibenzodiazepine derivative according to claim 1 in the preparation of a medicament for treating malaria.

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