CN107311933B - Benzimidazole derivative, preparation method and application thereof - Google Patents
Benzimidazole derivative, preparation method and application thereof Download PDFInfo
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Abstract
The invention discloses benzimidazole derivatives shown as a formula I, pharmaceutically acceptable salts and solvates thereof, a preparation method thereof and application of the benzimidazole derivatives in preparing medicaments for treating tumors, antiviral medicaments, antibacterial medicaments, antiparasitic medicaments, antihypertensive medicaments and the like. The compound has the advantages of remarkable proliferation capacity for inhibiting tumor cells with kras mutation, stable structure, simple and convenient preparation and potential for developing novel antitumor drugs.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to benzimidazole derivatives, a preparation method thereof and application of the benzimidazole derivatives as medicaments for treating tumors, antiviral medicaments, antibacterial medicaments, antiparasitic medicaments, antihypertensive medicaments and the like.
Background
Malignant tumors are serious diseases threatening human life and health. According to the statistics of the world health organization, about 1400 million new cancer cases exist in the world in 2012, compared with 2008, the cancer patients and the mortality rate all have an increasing trend in the world, and the number of new cancer cases is estimated to increase by about 70% in the next twenty years. Cancer is the second leading cause of death in 880 ten thousand people in 2015 as the second leading cause of death in the world, with the highest incidence of lung, liver, colorectal, gastric and breast cancers. Approximately 70% of cancer deaths occur in low and medium income countries, with new cancer cases and deaths occurring in China at the top of the world.
The existing organic small-molecule anticancer drugs easily cause toxic and side effects such as bone marrow suppression, gastrointestinal tract effect, rash, alopecia and the like, and the curative effect also needs to be improved. The activation of protooncogenes and the inactivation of cancer suppressor genes are important reasons for causing tumors, and the research of novel targeted anticancer drugs is a new strategy for finding high-efficiency and low-toxicity antitumor drugs according to the abnormality of protooncogenes and related molecules involved in the process of generating tumors.
Malignant tumor is a multifactorial disease, gene mutation is an important cause of tumor, and more than 100 kinds of tumor-inducing protooncogenes are known, mainly including MYC, Ras, HER2, BRAF, MET, BCR-ABL, PDGFR, KTT, FGFR3, ALK, RET, MITF, CUG2, FAM83, LAPTM4B, PLAG1, etc. Among them, about 1/3 of cancers are associated with Ras gene mutations, which are involved in about 50% of colorectal cancers, 30% of lung cancers and 20% of blood cancer induction.
The 36 genes in the human Ras gene family with tumor associated three characteristic genes are H-Ras, K-Ras and N-Ras, respectively, responsible for encoding H-Ras, K-Ras4A, K-Ras4B and N-Ras four Ras proteins. Among them, K-Ras gene mutation is most closely related to tumors, because of the extremely strong affinity of K-Ras protein and substrate GTP (pmol. L)-1Grade), there is a great challenge to design inhibitors of kras protein, and therefore, there is no effective Ras-targeting therapeutic agent clinically.
Ras protein synthesized by Ras gene translation is a protein precursor, and a biological function needs to be obtained through farnesylation modification. The activated Ras protein is a small GTP hydrolase, is positioned in the cell intima, stimulates a downstream signal path to transmit mitotic signals, and plays an important role in regulating and controlling the growth, proliferation and differentiation of cells and the conduction of other signals. PDE (phosphodiesterase) is a subtype of phosphodiesterase 6, has an isoprene binding pocket in the spatial structure, can selectively recognize farnesylated Ras protein, regulates the intimal localization of the Ras protein, and has the action mechanism mainly comprising the maintenance of the spatial structure of K-Ras, the assistance of the localization of the palmitylated K-Ras to a cell membrane, and the transportation of the K-Ras to a golgi after the K-Ras is subjected to the action and is subjected to the debalmitylation, so that the retentization and the membrane localization are promoted, and the circulation of the K-Ras between a GTP activated state and a GDP inactivated state is fully ensured.
Blocking the interaction of kras and PDE can provide a new treatment strategy for tumors caused by K-Ras mutation.
Disclosure of Invention
According to one aspect of the present invention there is provided a benzimidazole derivative of formula I, a pharmaceutically acceptable salt, solvate thereof:
wherein A is selected from a substituted or unsubstituted five to ten membered heterocyclic group containing 1 to 3 heteroatoms selected from S, N and O, or-NH-R4.
When a is a substituted or unsubstituted five-to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from S, N and O, it is preferably a substituted or unsubstituted five-to seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from S, N and O;
when a is-NH-R4, wherein R4 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C5-C10 aryl, substituted or unsubstituted C6-C12 alkylaryl, substituted or unsubstituted five-to ten-membered heterocyclyl containing 1 to 3 heteroatoms selected from S, N and O, substituted or unsubstituted eight-to ten-membered heterocyclylcyclyl containing 1 to 3 heteroatoms selected from S, N and O;
preferably, R4 is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C5-C8 aryl, substituted or unsubstituted C6-C10 alkylaryl, substituted or unsubstituted five to eight membered heterocyclyl containing 1 to 3 heteroatoms selected from S, N and O, substituted or unsubstituted eight to ten membered fused cyclic containing 1 to 3 heteroatoms selected from S, N and O;
wherein the term "substituted" refers to C1-C6 alkoxy substituted with 1 to 3 same or different substituents selected from the group consisting of hydroxy, amino, halogen, nitro, carboxy, sulfonyl, C1-C6 alkoxy, C5-C7 aryl, C5-C7 aryl.
R2 is selected from hydrogen, C1-C6 alkyl, Ar is selected from C5-10 aromatic ring group, preferably, R2 is selected from hydrogen, C1-C3 alkyl, Ar is selected from C5-C7 aromatic ring group, more preferably, R2 is selected from hydrogen, methyl and ethyl, and Ar is selected from C5-C6 aromatic ring group.
R3 is selected from hydrogen, alkyl of C1-C6, preferably, R2 is selected from hydrogen, alkyl of C1-C3, more preferably, R3 is selected from hydrogen, methyl, ethyl.
The halogen is selected from F, Cl, Br or I, preferably F, Cl or Br.
The benzimidazole derivatives of formula I according to the present invention are more preferably the following compounds:
the pharmaceutically acceptable salt is a conventional non-toxic salt formed by reacting the compound with the general formula (I) and an inorganic acid or an organic acid. For example, the conventional non-toxic salts can be prepared by reacting the compound of formula (I) with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, or organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by the compound of the general formula (I) and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid after forming ester and then forming inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula (I) and organic base; or the compound of the general formula (I) forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid or forms corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
According to another aspect of the present invention, the present invention also provides a method for synthesizing a compound represented by formula I, wherein the reaction scheme is as follows:
step 1) carbomethoxy-substituted o-nitrofluorobenzene and corresponding amine compound
The compound of formula 2 can be obtained by condensation under the specific reaction conditions described in the references (Organic Letters,17(19), 4734-4737);
step 2) the compound of formula 2 is subjected to hydrogenation reduction to obtain the compound of formula 3, and the specific reaction conditions can be referred to in the literature (Organic & Biomolecular Chemistry,7(24), 5173-5183);
step 3) reaction of the compound of formula 3 with a substituted benzaldehyde
Condensation to obtain the compound of formula 4, wherein the specific reaction conditions can be found in literature (Tetrahedron,71(4), 532-538);
step 4) carrying out alkaline hydrolysis on the compound of the formula 4 to obtain a compound of a formula 5, wherein the specific reaction conditions can be referred to documents (ChemMedChem,1(9), 955-958);
step 5) condensing the compound of formula 5 with corresponding amine compound, wherein the specific reaction conditions can be referred to in the literature (Journal of Medicinal Chemistry,47(26),6451-6454), to obtain the target product compound of formula I.
Wherein substituent A, R2、R3And Ar is as defined above.
According to another aspect of the invention, the invention also provides the use of the compound shown in the formula I for preparing medicaments such as tumor treatment medicaments, antiviral medicaments, antibacterial medicaments, antiparasitic medicaments and/or blood pressure lowering medicaments.
Another aspect of the present invention is to provide a pharmaceutical composition comprising a compound represented by formula I, a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The pharmaceutical composition comprises a therapeutically effective amount of the compound shown in the formula I, pharmaceutically acceptable salts or solvates thereof and pharmaceutical excipients. The term "effective amount" can refer to an amount effective at dosages and for periods of time necessary to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or the condition of the disease being treated, the particular target organ being administered, the size of the individual patient, or the severity of the disease or symptoms. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation. The "pharmaceutical excipients" refer to various excipients conventionally used in medicines, such as excipients, controlled release agents, stabilizers, etc., which are within the conventional knowledge of those skilled in the art.
Preferably, the pharmaceutical composition comprising the compound represented by formula I according to the present invention can be used for the treatment of viral related diseases, bacterial related diseases, parasitic related diseases, atherosclerosis related diseases, thrombosis related diseases, hypertension related diseases.
The pharmaceutical composition according to the invention may be in the following dosage form: tablets such as, but not limited to, plain tablets, immediate release tablets, sustained release tablets, controlled release tablets, film coated tablets, sugar coated tablets, buccal tablets, sublingual tablets, bioadhesive tablets and the like; capsules such as, but not limited to, hard capsules, soft capsules, and the like; injections such as, but not limited to, sterile or bacteriostatic aqueous injections, oily injections, lyophilized injections, microspheres for injection, etc.; sprays such as, but not limited to, oral sprays, nasal sprays, topical skin sprays, and the like; aerosols such as, but not limited to, aerosols for pulmonary inhalation, topical skin aerosols, and the like; nasal drops such as, but not limited to, nasal drops gels, and the like; powder aerosols such as, but not limited to, powder aerosols for the cavity, powder aerosols for the nasal cavity, powder aerosols for the topical skin, and the like; suppository, patch, and gel for other body cavities such as vagina, rectum, and ear cavity. The preparation of these formulations is carried out by the person skilled in the art on the basis of the available knowledge or with reference to relevant textbooks or tool books or literature.
Advantageous effects
The kras-based drug research is a research difficulty of tumor treatment drugs, no successful drug is available on the market at present, and the compound provided by the invention has the advantages of remarkable proliferation capacity for inhibiting kras mutant tumor cells, stable structure, simple preparation and potential for developing novel antitumor drugs.
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description is made, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention.
The invention relates to 1-benzyl-2-phenyl benzimidazole derivatives have no literature report, the compounds shown in formula I according to the invention can selectively kill cancer cells with Ras gene mutation or inhibit the proliferation of the cancer cells; the mechanism of action of the agents of formula I includes, but is not limited to, inhibition of the interaction of kras protein with PDE.
The experimental procedures in the following examples are conventional unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 preparation of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-formylmorpholine (ZXY8008-1)
The synthetic route of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-formylmorpholine is shown below.
Step a: preparation of 3-benzylamino-4-nitro-benzoic acid methyl ester
9.9g (0.05mol) of methyl 3-fluoro-4-nitrobenzoate (10) was dissolved in 50ml of DMF, and 8.3g (0.06mol) of potassium carbonate and 6.4g (0.06mol) of benzylamine were added to react at 50 ℃ until the starting material disappeared, the reaction solution was poured into water, and a red-orange solid was obtained by filtration, 13.5g, yield: 94.6 percent.1H-NMR(400MHz,DMSO-d6)(ppm):8.73-8.70(t,1H,J＝5.72Hz),8.19-8.17(d,1H,J＝8.68Hz),7.43-7.43(d,1H,J＝1.68Hz),7.39-7.33(m,4H),7.28-7.24(m,1H),7.14-7.12(dd,1H,J＝8.68,1.68Hz),4.67-4.65(d,2H,J＝5.88Hz),3.81(s,3H)。
Step b: preparation of 3-benzylamino-4-amino-benzoic acid methyl ester
14.3g (0.05mol) of 3-benzylamino-4-nitro-methyl benzoate is placed in a 500ml reaction kettle, 3.6g (wet weight) of catalyst Raney nickel is taken and added into 200ml of methanol, the methanol is poured into the reaction kettle while stirring, hydrogen is introduced to react for 3 to 5 hours at 65 ℃, reaction liquid is filtered (a filter cake is washed by proper amount of methanol, the reaction liquid is decompressed and concentrated to obtain light yellow oily liquid, off-white solid is separated out by ether ultrasonic, and the white solid is filtered, dried and obtained by 11.5g, and the yield is 89.5%.1H-NMR(400MHz,CDCl3)(ppm):7.50-7.48(dd,1H,J＝8.12,1.96Hz),7.43-7.41(m,3H),7.39-7.35(m,2H),7.33-7.31(m,1H),6.72-6.70(d,1H,J＝8.16Hz),4.33(s,2H),3.86(s,3H),3.70(s,2H)。
Step c: preparation of 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester
9.3g (0.04mol) of 3-benzylamino-4-amino-benzoic acid methyl ester are dissolved in 100ml of ethanol, 4.3g (0.04mol) of benzaldehyde are added, the mixture is refluxed until the raw materials disappear, the mixture is concentrated under reduced pressure, and the solid crude product is treated with ethanol: sonication with water 7:3, filtration and drying of the filter cake gave 11.5g of white solid, yield: 92.6 percent. 1H-NMR (400MHz, CDCl)3)(ppm):8.05-8.02(dd,1H,J＝8.44,1.4Hz),8.00-7.99(d,1H,J＝0.84Hz),7.88-7.86(d,1H,J＝8.4Hz),7.70-7.68(m,2H),7.50-7.43(m,3H),7.36-7.30(m,3H),7.09-7.07(dd,2H,J＝8.16,1.68Hz),5.501(s,2H),3.897(s,3H)。
Step d: preparation of 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxylic acid
11.5g (0.03mol) of 1-benzyl-2-phenyl-1H-benzo [ d ] are taken]Dissolving imidazole-6-carboxylic acid methyl ester in 300ml methanol, adding 1mol/L sodium hydroxide solution 65ml, reacting overnight at 65 ℃, acidifying the reaction solution with dilute hydrochloric acid until the pH value is about 4, precipitating a large amount of white solid, filtering,the filter cake was washed with water (25 ml. times.2) and dried to give 10.9g of a white solid, yield: 98.5 percent.1H-NMR(400MHz,DMSO-d6)(ppm):12.92(s,1H),8.09-8.08(d,1H,J＝1.12Hz),7.92-7.90(dd,1H,J＝8.4,1.4Hz),7.83-7.81(d,1H,J＝8.68Hz),7.78-7.76(m,2H),7.59-7.53(m,3H),7.33-7.24(m,3H),7.03-7.02(d,2H,J＝6.72Hz),5.70(s,2H)。
Step e: preparation of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-formylmorpholine
263mg (0.80mmol) of 1-benzyl-2-phenyl-1H-benzo [ d ] are taken]Imidazole-6-carboxylic acid and 77mg (0.88mmol) of morpholine are dissolved in 4ml of DMF and 184mg (0.96mmol) of EDCI, 130mg (0.96mmol) of HOBt, 30mg (0.24mmol) of DMAP are added and reacted at 50 ℃ overnight. The raw material disappears, the heating is stopped, the light brown oily matter is obtained by decompression and concentration, the crude product is separated and purified by column chromatography to obtain white solid, and the yield is as follows: 76.9%, melting point: 149-151 ℃ is adopted. ESI-HRMS (M/z) 398.1864[ M + H]+,1H-NMR(400MHz,CDCl3)(ppm):7.90-7.89(d,1H,J＝1.12Hz),7.70-7.68(m,2H),7.51-7.45(m,3H),7.38-7.31(m,4H),7.27-7.24(d,1H,J＝8.96Hz),7.10-7.08(dd,2H,J＝7.84,1.68Hz),5.48(s,2H),3.73(s,8H),13C-NMR(400MHz,CDCl3)(ppm):170.8,162.6,156.0,144.4,136.0,135.8,130.4,129.8,129.6,129.3,129.3,129.0,128.1,126.1,122.1,120.0,110.6,67.0,48.7。
Example 2 preparation of N- (3- (benzyloxy) -phenyl) 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8008-3)
With reference to the preparation and conditions of example 1, 3-benzyloxyaniline and 1-benzyl-2-phenyl-1H-benzo [ d ] were used]Performing amide condensation with imidazole-6-carboxylic acid as raw material, stopping heating, concentrating under reduced pressure to remove solvent, adding 20ml water into the concentrated oily liquid, ultrasonic treating for 15-20 min, precipitating solid, and drying to obtain white solidSolid, yield: 91.0%, melting point: 168-170 ℃. ESI-HRMS (M/z) 510.2176[ M + H]+,1H-NMR(400MHz,DMSO-d6)(ppm):10.20(s,1H),8.15(s,1H),7.95-7.92(dd,1H,J＝8.68,1.4Hz),7.87-7.85(d,1H,J＝8.4Hz),7.77-7.75(m,2H),7.57-7.52(m,4H),7.47-7.45(m,2H),7.42-7.23(m,8H),7.02-7.01(d,2H,J＝7Hz),6.77-6.75(dd,1H,J＝8.12,2.24Hz),5.69(s,2H),5.10(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):165.6,158.5,155.6,145.0,140.5,137.1,136.8,129.4,129.3,129.1,128.9,128.9,128.5,127.8,127.7,127.6,126.0,122.0,118.9,113.0,111.3,109.9,107.1,69.1,47.6。
EXAMPLE 3 preparation of tert-butyl (2- (1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamido) ethyl) carbamate (ZXY8011-1)
Referring to the experimental conditions and post-treatment method of example 2, N-Boc-ethylenediamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 90.2%, melting point: 179-182 ℃. ESI-HRMS (M/z) 471.2390[ M + H]+,1H-NMR(400MHz,CDCl3)(ppm):7.91(s,1H),7.86-7.84(d,1H,J＝8.4Hz),7.72-7.67(m,3H),7.52-7.44(m,3H),7.33-7.28(m,4H),7.06-7.05(d,2H),5.49(s,2H),5.06(m,1H),3.57-3.53(m,2H),3.40-3.39(m,2H),1.41(s,9H),13C-NMR(400MHz,CDCl3)(ppm):168.0,157.6,156.3,145.5,136.2,136.1,130.4,129.7,129.4,129.3,129.2,129.0,128.0,126.0,121.3,119.7,110.8,80.0,48.5,42.2,40.1,28.5。
EXAMPLE 4 preparation of N- (1H-benzo [ d ] imidazol-2-yl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8011-5)
With reference to the experimental conditions and work-up procedure of example 2, 2-amino-benzimidazole and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid is used as raw material to obtainWhite solid, yield: 87.1%, melting point: 250-253 ℃. ESI-HRMS (M/z) 444.1819[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.22(s,2H),8.43(s,1H),8.13-8.11(d,1H,J＝8.4Hz),7.86-7.84(d,1H,J＝8.4Hz),7.77-7.75(dd,2H,J＝7.56,2.24Hz),7.56-7.55(m,3H),7.46-7.44(dd,2H,J＝5.88,3.36Hz),7.35-7.25(m,3H),7.13-7.11(dd,2H,J＝5.88,3.12Hz),7.07-7.06(d,2H,J＝7Hz),5.67(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):155.8,145.6,136.8,135.8,130.3,129.7,129.1,129.0,128.9,128.4,127.7,126.1,122.9,121.5,119.0,113.4,111.8,47.8。
EXAMPLE 5 preparation of N- (3, 4-Dimethoxyphenethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazolecarboxamide (ZXY8013-1)
With reference to the experimental conditions and work-up procedure of example 2, 3, 4-dimethoxyphenethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to prepare a white solid with a yield: 90.8%, melting point: 164-166 ℃. ESI-HRMS (M/z) 492.2281[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.55-8.52(t,1H,J＝5.6Hz),8.04(s,1H),7.82-7.77(m,2H),7.75-7.72(dd,2H,J＝7.04,1.68Hz),7.55-7.51(m,3H),7.33-7.26(m,3H),7.01-6.99(d,2H,J＝7.04Hz),6.84-6.82(d,2H,J＝8.12Hz),6.74-6.72(dd,1H,J＝8.12,1.68Hz),5.63(s,2H),3.70(s,3H),3.68(s,3H),3.49-3.44(m,2H),2.79-2.76(t,2H,J＝7.28Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.2,155.3,148.6,147.2,144.7,136.8,135.8,132.1,129.1,129.0,128.9,127.6,125.9,121.6,120.5,118.8,112.5,111.8,110.6,55.5,55.3,47.6,41.3,34.8。
EXAMPLE 6 preparation of N- (4-phenoxyphenyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8013-2)
Reference to the implementationExample 2 Experimental conditions and work-up procedure 4-amino-diphenyl ether and 1-benzyl-2-phenyl-1H-benzo [ d ]]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 79.0%, melting point: 216-218 ℃. ESI-HRMS (M/z) 496.2020[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):10.3(s,1H),8.16(d,1H,J＝1.12Hz),7.96-7.94(dd,1H,J＝8.4,1.68Hz),7.87-7.85(d,1H,J＝8.4Hz),7.79-7.45(m,4H),7.56-7.52(m,3H),7.40-7.36(m,2H),7.33-7.23(m,3H),7.13-7.09(m,1H),7.05-6.98(m,6H),5.69(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):165.4,157.3,155.6,152.1,145.0,136.8,130.0,129.1,128.9,128.9,127.6,126.0,123.0,122.2,122.0,119.3,118.9,118.0,111.2,47.6。
Example 7 preparation of N- (4-fluorobenzyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8013-3)
With reference to the experimental conditions and the work-up procedure of example 2, p-fluorobenzylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 80.5%, melting point: 139 to 141 ℃. ESI-HRMS (M/z) 436.1820[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):9.07-9.04(t,1H,J＝5.6Hz),8.10(s,1H),7.88-7.86(d,1H,J＝8.4Hz),7.81-7.79(d,1H,J＝8.4Hz),7.74-7.72(m,2H),7.57-7.51(m,3H),7.37-7.23(m,5H),7.17-7.12(m,2H),7.01-6.99(d,2H,J＝7.28Hz),5.64(s,2H),4.47-4.46(d,2H,J＝5.6Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.2,162.64,155.4,144.8,136.8,136.0,135.9,130.2,129.8,129.3,129.202,129.1,128.9,128.9,128.8,127.6,125.9,121.6,118.8,115.1,114.9,110.8,47.6,42.1。
EXAMPLE 8 preparation of (S) -N- (1-phenylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-1)
Referring to the experimental conditions and post-treatment method of example 2, R (+) -alpha-phenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 92.5%, melting point: 177-178 ℃. ESI-HRMS (M/z) 432.2070[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.792-8.772(d,1H,J＝7.84Hz),8.079(s,1H),7.91-7.89(d,1H,J＝8.4Hz),7.80-7.78(d,1H,J＝8.4Hz),7.75-7.73(d,2H,J＝5.6Hz),7.59-7.52(m,3H),7.40-7.38(m,2H),7.33-7.19(m,6H),7.00-6.99(d,2H,J＝7.32Hz),5.65(s,2H),5.23-5.17(m,1H),1.50-1.48(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):165.5,155.3,145.1,144.8,136.8,135.9,130.2,129.8,129.1,128.9,128.9,128.3,127.6,126.6,126.1,126.0,121.8,118.7,110.9,48.6,47.6,22.3。
EXAMPLE 9 preparation of (R) -N- (1-phenylpropyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-2)
Referring to the experimental conditions and post-treatment method of example 2, R (+) -1-amphetamine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 92.1%, melting point: 178-181 ℃. ESI-HRMS (M/z) 446.2227[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.72-8.70(d,2H,J＝8.4Hz),8.05(s,1H),7.904-7.88(dd,1H,J＝8.4,1.4Hz),7.80-7.78(d,1H,J＝8.4Hz),7.75-7.73(m,2H),7.55-7.51(m,3H),7.40-7.38(d,2H,J＝7.28Hz),7.33-7.19(m,6H),7.01-6.99(d,2H,J＝7Hz),5.64(s,2H)4.96-4.92(m,1H),1.90-1.78(m,2H),0.92-0.88(t,3H,J＝7.28Hz),13C-NMR(400MHz,DMSO-d6)(ppm):165.93,155.3,144.7,144.2,136.8,135.8,130.2,129.8,129.1,129.1,128.9,128.2,127.6,126.6,126.0,121.7,118.7,111.0,55.0,47.6,29.0,11.5。
EXAMPLE 10 preparation of (R) -N- (1-phenylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-3)
Referring to the experimental conditions and post-treatment method of example 2, S (-) -alpha-phenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d-]Imidazole-6-carboxylic acid is used as a raw material to obtain a light yellow solid, and the yield is as follows: 95.9%, melting point: 191-193 ℃. ESI-HRMS (M/z) 432.2071[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.81-8.79(d,1H,J＝7.56Hz),8.09(s,1H),7.92-7.90(d,1H,J＝8.4Hz),7.81-7.79(d,1H,J＝8.4Hz),7.75-735(d,2H,J＝5.0Hz),7.53(s,3H),7.40-7.38(d,2H,J＝7Hz),7.33-7.21(m,6H),7.01-6.99(d,2H,J＝6.72Hz),5.65(s,2H),5.22-5.18(m,1H),1.50-1.48(d,3H,J＝6.44Hz),13C-NMR(400MHz,CDCl3)(ppm):166.7,156.4,143.4,136.3,136.0,130.5,129.6,129.4,129.3,129.2,129.0,128.8,128.0,127.5,126.4,126.0,120.9,119.6,111.1,49.5,48.5,21.9。
EXAMPLE 11 preparation of (R) -N- (1- (1H-benzo [ d ] imidazol-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-4)
With reference to the experimental conditions and the work-up procedure of example 2, the (R) - (+) -2- (. alpha. -methylamine) -1H-benzo [ d ] compound was prepared]Imidazole and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 85.7%, melting point: 290-292 deg.C. ESI-HRMS (M/z) 472.2132[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.28(s,1H),8.98-8.96(d,1H,J＝7.84Hz),8.19(s,1H),7.99-7.96(dd,1H,J＝8.44,1.12Hz),7.83-7.81(d,1H,J＝8.68Hz),7.75-7.73(m,2H),7.54-7.50(m,5H),7.32-7.22(m,3H),7.15-7.12(dd,2H,J＝5.88,3.08Hz),7.00-6.98(d,2H,J＝7.28Hz),5.66(s,2H),5.49-5.41(m,1H),1.66-1.65(d,3H,J＝7Hz)。
EXAMPLE 12 preparation of N- (2-bromophenylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-5)
With reference to the experimental conditions and work-up procedure of example 2, o-bromophenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 91.7%, melting point: 147-149 ℃. ESI-HRMS (M/z) 512.1161[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.84-7.82(d,1H,J＝8.4Hz),7.81-7.81(d,1H,J＝1.12Hz),7.69-7.67(dd,2H,J＝8.4,1.12Hz),7.60-7.57(dd,1H,J＝8.4,1.4Hz),7.54-7.52(dd,1H,J＝8.12,1.12Hz),7.50-7.43(m,3H),7.35-7.29(m,3H),7.26-7.18(m,2H),7.10-7.05(m,3H),6.35-6.32(m,1H),5.49(s,2H),3.75-3.70(m,2H),3.10-3.07(t,2H,J＝6.72Hz),13C-NMR(400MHz,CDCl3)(ppm):167.8,156.3,138.5,133.0,131.1,130.4,129.5,129.3,129.2,128.9,128.4,128.0,127.7,125.9,121.1,119.6,110.7,48.4,40.1,35.7。
Example 13 preparation of N- (3H-1,2, 4-Triazol-3-yl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8020-2)
To 263mg (0.80mmol) of 1-benzyl-2-phenyl-1H-benzo [ d]Adding 5ml of toluene and 0.5ml of thionyl chloride into imidazole-6-carboxylic acid, reacting for 2-3 hours at 80 ℃, concentrating under reduced pressure to remove the thionyl chloride, dissolving 75mg (0.88mmol) of 3-amino-1, 2,4 triazole in 5ml of dichloromethane, adding 0.5ml of pyridine, diluting the newly prepared acyl chloride with dichloromethane at 0 ℃, and slowly dropping the diluted acyl chloride into an amine solution. After the reaction, the reaction solution was transferred to a separatory funnel, the organic phase (15ml × 2) was washed with water, the aqueous phases were combined and extracted with 10ml dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid, yield: 74.8%, melting point: 200-203 ℃. ESI-HRMS (M/z) 395.1615[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.318(s,1H),8.06-8.02(dd,1H,J＝8.68,1.4Hz),7.86-7.56(m,9H),7.32-7.25(m,3H),7.05-7.03(d,2H,J＝7Hz),5.66(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):167.7,158.4,156.5,151.2,146.0,136.4,135.1,130.4,129.5,129.2,128.9,127.7,126.3,125.8,125.3,118.5,115.2,47.8。
Example 14 preparation of (R) -N- (1- (3H-imidazo [4,5-c ] pyridin-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8022)
With reference to the experimental conditions and the work-up procedure of example 2, the reaction mixture was prepared with (R) - (+) -2- (. alpha. -methylamine) -1H-pyridoimidazole and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 70.0%, melting point: 270-273 ℃. ESI-HRMS (M/z) 473.2082[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.68(s,1H),9.01-8.99(d,1H,J＝7.56Hz),8.85(s,1H),8.27-8.26(d,1H,J＝3.92Hz),8.17(s,1H),7.98-7.96(d,1H,J＝8.12Hz),7.83-7.81(d,1H,J＝8.68Hz),7.75-7.73(d,2H,J＝5.36Hz),7.54(s,3H),7.47(s,1H),7.30-7.24(m,3H),7.00-6.98(d,2H,J＝6.72Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.0,155.4,144.9,136.8,135.8,130.2,129.7,129.0,128.9,128.8,128.4,127.6,125.9,122.1,118.7,111.0,47.5,44.1,19.3。
Example 15 preparation of N- (4- (methylsulfonyl) phenyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8024)
With reference to the experimental conditions and working up procedure of example 13, 4-methanesulfonylaniline and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 77.8%, melting point: 287-289 deg.C. ESI-HRMS (M/z) 482.1533[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):10.63(s,1H),8.20-8.19(d,1H,J＝1.28Hz),8.06-8.04(m,2H),7.99-7.96(dd,1H,J＝8.72,1.68Hz),7.92-7.88(m,3H),7.78-7.76(m,2H),7.57-7.53(m,3H),7.33-7.25(m,3H),7.03-7.01(d,2H,J＝7Hz),5.71(s,2H),3.19(s,3H),13C-NMR(400MHz,DMSO-d6)(ppm):166.1,155.8,145.3,143.9,136.7,135.9,134.9,130.3,129.6,129.1,128.9,128.7,128.1,127.6,126.0,122.2,120.1,119.0,111.6,47.6,43.8。
Example 16 preparation of N- (2- (dimethylamino) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8026-3)
With reference to the experimental conditions and working up procedure of example 13, 2-aminoimidazole and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 91.7%, melting point: 125-128 ℃. ESI-HRMS (M/z) 399.2179[ M + H]+,1H-NMR(400MHz,DMSO-d6)(ppm):8.42-8.39(t,1H,J＝5.6Hz),8.04(m,1H),7.83-7.72(m,4H),7.55-7.50(m,3H),7.33-7.23(m,3H),7.01-6.99(d,2H,J＝7.04Hz),5.64(s,2H),3.39-3.34(m,2H),2.43-2.39(t,2H,J＝7Hz),2.18(s,6H),13C-NMR(400MHz,DMSO-d6)(ppm):166.1,155.3,144.7,136.8,135.8,130.2,129.8,129.1,129.0,128.9,127.6,125.9,121.5,118.7,110.7,58.3,47.5,45.3,37.5。
Example 17 preparation of (1-benzyl-2-phenyl-1H-benzo [ d ] imidazol-6-yl) (4-ethylpiperazin-1-yl) methanone (ZXY8026-4)
With reference to the experimental conditions and working up procedure of example 13, 4-amino-6-chloropyrimidine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 93.3%, melting point: 126-128 ℃. ESI-HRMS (M/z) 425.2336[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):7.78-7.74(m,3H),7.56-7.54(m,3H),7.51(s,1H),7.30-7.22(m,4H),7.01-6.99(d,2H,J＝7.28Hz),5.63(s,2H),3.58-3.27(m,5H),2.35-2.30(m,6H),1.01-0.97(t,3H,J＝7.28Hz)。
EXAMPLE 18 preparation of N- (1-methylpiperidin-4-yl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY5049-1)
With reference to the experimental conditions and work-up procedure of example 13, 4-amino-1-methylpiperidine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 79.9%, melting point: 222-224 ℃. ESI-HRMS (M/z) 425.2336[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.86-7.83(m,2H),7.69-7.67(m,2H),7.63-7.61(d,1H,J＝8.44Hz),7.51-7.44(m,3H),7.32-7.28(m,3H),7.06-7.04(d,2H,J＝6.44Hz),6.18-6.16(d,1H,J＝7Hz),5.49-5.48(m,2H),3.99-3.97(m,1H),2.83-2.80(d,2H),2.30-2.30(s,3H),2.17-2.12(m,2H),2.04-2.01(m,2H),1.62-1.54(m,2H),13C-NMR(400MHz,CDCl3)(ppm):167.0,156.2,145.4,136.1,136.0,130.3,129.6,129.2,129.1,128.8,127.9,125.9,120.9,119.5,110.8,54.6,48.3,46.8,46.3,32.3。
EXAMPLE 19 preparation of N- (3-fluorophenethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY5049-2)
With reference to the experimental conditions and working up procedure of example 13, 3-fluorophenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] amine]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 83.8%, melting point: 176-178 ℃. ESI-HRMS (M/z) 450.1975[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.83-7.80(m,2H),7.69-7.67(m,2H),7.56-7.53(dd,1H,J＝8.4,1.4Hz),7.54-7.43(m,3H),7.34-7.21(m,4H),7.06-7.04(dd,2H,J＝7.84,1.96Hz),6.99-6.98(d,1H,J＝7.56Hz),6.94-6.90(m,2H),6.35-6.32(t,1H,J＝5.6Hz),5.48(s,2H),3.71-3.66(m,2H),2.93-2.90(t,2H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):167.7,164.2,161.7,156.3,130.4,129.4,129.2,129.2,128.9,128.0,125.9,124.5,121.0,119.6,115.8,115.5,110.7,48.4,41.1,35.5。
EXAMPLE 20 preparation of N- (2-morpholinylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY5049-3)
With reference to the experimental conditions and working up procedure of example 13, N- (2-aminoethyl) morpholine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 83.8%, melting point: 169-171 ℃. ESI-HRMS (M/z) 441.2286[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.89-7.87(d,1H,J＝8.44Hz),7.86-7.85(d,1H,J＝1.12Hz),7.71-7.69(m,2H),7.66-7.64(dd,1H,J＝8.68,1.68Hz),7.53-7.44(m,3H),7.35-7.29(m,3H),7.09-7.07(dd,2H,J＝8.12,1.96Hz),6.90(s,1H),5.51(s,2H),3.71-3.69(t,4H,J＝4.48Hz),3.57-5.33(m,2H),2.62-2.5(t,4H,J＝5.88Hz),2.50(s,4H),13C-NMR(400MHz,CDCl3)(ppm):167.5,156.4,145.5,136.2,136.0,130.4,129.6,129.5,129.3,129.2,129.0,128.0,125.9,120.9,119.7,110.8,67.1,56.9,53.3,48.5,36.2。
Example 21 preparation of N- (2- ((7-nitrobenzo [ c ] [1,2,5] oxadiazole) -4-amino) ethyl) 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8027)
400mg of (2- (1-benzyl-2-phenyl-1H-benzo [ d ] are taken]Imidazole-6-formamido) ethyl) carbamic acid tert-butyl ester is added with 5ml of 4mol/L hydrochloric acid and 5ml of dichloromethane, stirred overnight at room temperature, the next day, adjusted pH to 7-8 by 1mol/L sodium hydroxide, the water layer is extracted by dichloromethane (15ml multiplied by 2), the organic phases are combined, washed by saturated sodium chloride, dried by the organic phase, filtered and concentrated under reduced pressure to obtain white solid. 223mg (0.6mmol) and 120mg (0.6mmol) of 4-chloro-7-nitrobenzene are weighed out from the mixtureAnd 2-oxa-1, 3-diazole was dissolved in 10ml of dichloromethane, 0.5ml of triethylamine was added thereto, and the reaction was carried out at room temperature for 3 hours. Transferring the reaction solution to a separating funnel, washing twice (10ml multiplied by 2), extracting the water phase with 10ml dichloromethane, combining the organic phases, washing with saturated sodium chloride, drying the organic phases, filtering, concentrating the organic phases under reduced pressure, and separating and purifying the crude product by column chromatography to obtain a dark brown solid 91mg, yield: 48.8 percent. ESI-HRMS (M/z) 534.1885[ M + H]+,1H-NMR(400MHz,DMSO-d6)(ppm):9.56(s,1H),8.74-8.72(m,1H),8.52-8.50(d,1H,J＝8.96Hz),8.011(s,1H),7.79(s,2H),7.74-7.72(m,2H),7.56-7.51(m,3H),7.32-7.23(m,3H),6.99-6.97(d,2H,J＝6.72Hz),6.52-6.49(d,1H,J＝8.96Hz),5.63(s,2H),3.68-3,58(m,4H)。
EXAMPLE 22 preparation of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-5-formylmorpholine
Using 1-benzyl-2-phenyl-1H-benzo [ d ]]Imidazole-5-carboxylic acid was synthesized using an amide condensation method analogous to step e of the synthetic method in example 1, with morpholine and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-5-carboxylic acid is used as a raw material to prepare a target compound, and the target compound is separated and purified by column chromatography to obtain a white solid, wherein the yield is as follows: 77.9%, melting point: 147-150 ℃. ESI-HRMS (M/z) 398.1863[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):7.78(s,1H),7.75-7.73(m,2H),7.56-7.52(m,4H),7.32-7.24(m,4H),7.02-7.00(d,2H,J＝8.12Hz),5.62(s,2H),3.61(s,8H),13C-NMR(400MHz,DMSO-d6)(ppm):169.6,154.6,142.0,136.7,136.6,130.1,129.8,129.7,129.1,128.8,127.6,126.2,122.1,118.3,111.2,66.1,47.6。
EXAMPLE 23 preparation of (S) -N- (1- (1H-benzo [ d ] imidazol-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-5-carboxamide
Preparation of 1-benzyl-2-phenyl Using the above method-1H-benzo [ d]Imidazole-5-carboxylic acid with (R) - (+) -2- (. alpha. -methylamine) -1H-benzimidazole and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-5-carboxylic acid was used as starting material to prepare the title compound in a similar manner to example 11, giving a white solid in yield: 85.1%, melting point: 250-252 ℃. ESI-HRMS (M/z) 472.2132[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.26(s,1H),9.01-8.99(d,1H,J＝7.84Hz),8.43(s,1H),7.91-7.88(dd,1H,J＝8.4,1.12Hz),7.76-7.74(dd,2H,J＝7.56,3.92Hz),7.60-7.52(m,6H),7.30-7.23(m,3H),7.15-7.13(m,2H),6.98-6.96(d,2H,J＝7Hz),5.65(s,2H),5.50-5.43(m,1H),1.68-1.66(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.4,156.3,154.8,138.0,136.7,130.1,129.1,128.9,128.8,128.6,127.6,126.6,122.7,121.4,119.2,110.7,47.6,44.1,19.7。
EXAMPLE 24 preparation of (S) -N- (1- (3H-imidazo [4,5-c ] pyridin-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-5-carboxamide
With (R) - (+) -2- (. alpha. -methylamine) -1H-pyridoimidazole (24) and 1-benzyl-2-phenyl-1H-benzo [ d ]]Imidazole-5-carboxylic acid was used as starting material and the title compound was prepared in analogy to example 14, giving a white solid in yield: 77.3%, melting point: 155-157 ℃. ESI-HRMS (M/z) 473.2084[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.71(s,1H),9.07～9.05(d,1H,J＝7.6Hz),8.86(s,1H),8.43～8.43(d,1H,J＝1.12Hz),8.28～8.26(d,1H,J＝5.6Hz),7.9～7.87(dd,1H,J＝8.4,1.4Hz),7.76～7.73(m,2H),7.60～7.58(d,1H,J＝8.4Hz),7.57～7.49(m,3H),7.30～7.23(m,3H),6.98～6.96(d,2H,J＝8.4Hz),5.65(s,2H),5.51～5.44(m,1H),1.70～1.68(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.5,154.9,138.1,136.8,129.8,129.1,128.9,128.9,128.5,127.6,126.1,122.8,119.2,110.8,47.7,44.2,19.4。
Test example 1: antitumor Activity test
The Kras gene mutation leads to the enhancement of the function of Kras protease, and further leads to the uncontrolled proliferation and differentiation of cells, so that tumor cell strains positive to Kras mutation are more sensitive to the cytotoxicity of the Kras inhibitor. Based on this, we performed biological activity tests, and selected Panc-tu-1 positive for kras mutation and Panc-1 negative for kras mutation for comparative study to determine cytotoxicity. The results are given in table 1 below.
Table 1 partial compound cytotoxicity test results
Test example 2: test for antitumor Activity of Compound
The tested cells comprise MDA-MB-231 and LM 3; the cell culture and experiment method comprises inoculating cells into DMEM cell culture solution containing 10% fetal calf serum (supplemented with streptomycin stock solution 5ml/500ml), and placing at 37 deg.C and containing 5% CO2In the cell culture chamber, the medium was changed every 1 to 2 days, digested with 0.25% trypsin, passaged and collected. Cells in logarithmic growth phase are prepared into cell suspension with proper concentration by DMEM cell culture solution containing 10% fetal calf serum, 2500-4000 cells (100 mu l) per well are added into a 96-well cell culture plate, after overnight culture, 100 mu l of culture medium containing different concentrations of test substances is added into each well, and 4 parallel wells are arranged for each concentration. And (3) adding the cell into the culture medium for culturing for 72 hours, then discarding the supernatant, adding 100 mu l of newly-configured serum-free culture solution of 0.5-0.55mg/ml tetrazolium blue (MTT) into each hole, culturing for 4 hours at 37 ℃, then discarding the supernatant, adding 200 mu l of DMSO-soluble formazan into each hole, and measuring the absorbance value by an enzyme-labeling instrument at the wavelength of 570 nm. Preparing the medicine: taking the guiding of the guiding principle discussion draft of antitumor drug efficacy and the guiding principle of non-clinical research technology of cytotoxic antitumor compounds as guidance, diluting a tested compound to 20mg/ml by using a cosolvent DMSO according to the result of a preliminary test, taking 10 mul of diluent, then adding 990 mul of culture medium for preliminary dilution, further diluting the diluent to different concentrations of the tested compound by using the culture medium according to the required concentration, and additionally arranging a blank control group. Data processing, wherein the data is expressed by +/-S; inhibition rate (control group OD value-administration group OD value)/control group OD value × 100%; index of Effect of CompoundThe half concentration (IC50) was used to represent the measured maximum inhibition ratio (Imax). The half-effect concentration (IC50, μ g/ml) was determined by plotting using Origin software and fitting a four parameter Logistic program in the software to the tumor cell growth curve. The results are shown in Table 2 below.
TABLE 2 Experimental results of the inhibition of tumor cell proliferation by the compounds
On the basis of primary screening, the representative compound is tested in tumor cell strains MDA-MB-231 and LM3 with high malignancy degree, the IC50 for inhibiting cell proliferation is nM grade, the capability of inhibiting tumor cell proliferation is very strong, and good development potential of antitumor drugs is shown.
Claims (5)
1. A benzimidazole derivative represented by formula I, pharmaceutically acceptable salts thereof:
wherein A is-NH-R4;
wherein R4 is selected from the group consisting of substituted or unsubstituted C5-C8 aryl, substituted or unsubstituted C6-C10 alkylaryl, substituted or unsubstituted eight to ten membered fused ring group containing 1 to 3 heteroatoms selected from S, N and O;
r2 is selected from hydrogen, Ar is phenyl,
r3 is selected from the group consisting of hydrogen,
wherein "substituted" means substituted with 1 to 3 substituents which may be the same or different, selected from the group consisting of amino, halogen, nitro, sulfonyl, C1-C6 alkoxy, C5-C7 aryl-substituted C1-C6 alkoxy, C5-C7 aryl;
the halogen is selected from F, Cl or Br.
2. Benzimidazole derivatives and pharmaceutically acceptable salts thereof, wherein the benzimidazole derivatives are selected from the following compounds:
3. a method for synthesizing benzimidazole derivatives represented by formula I and pharmaceutically acceptable salts thereof according to claim 1, wherein the reaction scheme is as follows:
step 1) condensing methyl formate substituted o-nitrofluorobenzene and a corresponding amine compound to obtain a compound shown in a formula 2;
step 2) carrying out hydrogenation reduction on the compound of the formula 2 to obtain a compound of a formula 3;
step 3) condensing the compound of the formula 3 with substituted benzaldehyde to form a ring to obtain a compound of a formula 4;
step 4), carrying out alkaline hydrolysis on the compound of the formula 4 to obtain a compound of a formula 5;
step 5) condensing the compound of the formula 5 with a corresponding amine compound to obtain a target product, namely a compound of a formula I;
wherein substituent A, R2、R3And Ar is as defined in claim 1.
4. Use of a benzimidazole derivative of formula I or 2 according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of tumors.
5. A pharmaceutical composition comprising a therapeutically effective amount of a benzimidazole derivative of formula I or of claim 2, or a pharmaceutically acceptable salt thereof, according to claim 1, and a pharmaceutical adjuvant.
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