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CN107311933A - One class benzimidizole derivatives, and its production and use - Google Patents

One class benzimidizole derivatives, and its production and use Download PDF

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Publication number
CN107311933A
CN107311933A CN201710508016.7A CN201710508016A CN107311933A CN 107311933 A CN107311933 A CN 107311933A CN 201710508016 A CN201710508016 A CN 201710508016A CN 107311933 A CN107311933 A CN 107311933A
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substitution
compound
unsubstituted
formulas
yuan
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CN107311933B (en
Inventor
何新华
袁守军
李琳娜
战晓宇
张宪伟
郭东勇
杨德宣
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • 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
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • 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
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the benzimidizole derivatives shown in a class Formulas I, its pharmaceutically acceptable salt, solvate, and preparation method thereof and for preparing the purposes of the medicines such as anti-tumor medicine, antiviral agent, antimicrobial, antiparasitic agent and/or hypotensor.According to the compound of the present invention with the significant multiplication capacity for suppressing the tumour cell that kras is mutated, Stability Analysis of Structures prepares simplicity, with potentiality of the exploitation for new type antineoplastic medicine.

Description

One class benzimidizole derivatives, and its production and use
Technical field
The invention belongs to pharmaceutical field, and in particular to a class benzimidizole derivatives, and preparation method thereof and be used as tumour The purposes of the medicines such as medicine, antiviral agent, antimicrobial, antiparasitic agent and/or hypotensor.
Background technology
Malignant tumour is the major disease for threatening human life and health.Counted according to the World Health Organization, the whole world in 2012 14,000,000 new cancer cases are there are about, were compared compared with 2008, global cancer patient and the death rate are in rising trend, it is contemplated that from now on 20 years neopathy number of cases will increase about 70%.Cancer causes 8,800,000 people dead in 2015 as world's second largest mankind's cause of the death Die, wherein with lung cancer, liver cancer, colorectal cancer, stomach cancer and breast cancer incidence highest.About 70% cancer mortality occurs low Income and middle income country, the newly-increased cases of cancer of China and death toll occupy first place in the world.
Existing organic molecule cancer therapy drug easily causes the poison such as bone marrow suppression, intestines and stomach effect, fash and alopecia secondary Reaction, curative effect is also required to improve.The activation of proto-oncogene and the inactivation of tumor suppressor gene are the major reasons for causing tumour, according to swollen The proto-oncogene and the exception of correlation molecule being related in knurl generating process, it is to find that the new anticancer drug of research targeting, which has, The new strategy of the antineoplastic of high-efficiency low-toxicity.
Malignant tumour be one kind by multi-factor disease, gene mutation is to lead oncogenic major reason, existing known to induce The proto-oncogene of tumour is up to kind more than 100, mainly including MYC, Ras, HER2, BRAF, MET, BCR-ABL, PDGFR, KTT, FGFR3, ALK, RET, MITF, CUG2, FAM83, LAPTM4B, PLAG1 etc..Wherein, about 1/3 cancer has with Ras gene mutations Close, Ras gene mutations are related to about 50% colorectal cancer, 30% lung cancer and 20% leukemia and induced.
The three kind characteristic genes related to tumour are H-Ras, K- respectively in 36 genes of mankind's Ras gene families Ras and N-Ras, is each responsible for encoding tetra- kinds of Ras protein of H-Ras, K-Ras4A, K-Ras4B and N-Ras.Wherein K-Ras bases It is the closest with relation between tumor because being mutated, due to K-Ras albumen and the substrate GTP extremely strong (pmolL of affinity-1Level), design There is huge challenge in the inhibitor of kras albumen, therefore, clinically there is no efficient targeting Ras medicines.
The Ras albumen of Ras gene translations synthesis is amyloid protein precursor, it is necessary to obtain biology work(by farnesylation Energy.Ras albumen after activation is a kind of small GTP hydrolases, is positioned at intercellular membrane, and stimulating downstream signaling pathway to transmit has silk point The signal split, plays a significant role in the growth of regulating cell, propagation, differentiation and the conduction of other signals.PDEδ (phosphodiesterase δ) is that there is an isoprene to combine in a hypotype of phosphodiesterase 6, its space structure Pocket, the Ras albumen of identification farnesylation that can be selective, the inner membrance positioning of regulation Ras albumen, its mechanism of action is mainly wrapped The space structure for maintaining K-Ras is included, assists the K-Ras of palmization to navigate to cell membrane and gone palm fibre when K-Ras plays a role After palmitic acidization, PDE δ are transported to golgiosome, are promoted its palmization and film positioning again, are fully ensured that K-Ras lives in GTP Change the circulation between state and GDP inactivation states.
Kras and PDE δ interaction is blocked, the tumour caused by being mutated for K-Ras provides new therapeutic strategy.
The content of the invention
There is provided the benzimidizole derivatives shown in Formulas I, its pharmaceutically acceptable according to an aspect of the present invention Salt, solvate：
Wherein, A selected from substitution or it is unsubstituted containing in S, N and O 1 to 3 heteroatomic five yuan to ten yuan it is miscellaneous Ring group or-NH-R4.
When A for substitution or it is unsubstituted containing in S, N and O 1 to 3 heteroatomic five yuan to ten circle heterocycles bases When, preferably substitution or it is unsubstituted containing in S, N and O 1 to 3 heteroatomic five yuan to seven membered heterocyclic base；
When A is-NH-R4, wherein R4 is selected from substitution or unsubstituted C1-C6 alkyl, substitution or unsubstituted C5- C10 aryl, substitution or unsubstituted C6-C12 alkylaryls, substitution or unsubstituted containing 1 to 3 in S, N and O Heteroatomic five yuan to ten circle heterocycles bases, substitution or unsubstituted containing 1 to 3 heteroatomic eight yuan extremely in S, N and O Ten yuan of miscellaneous and ring groups；
Preferably, R4 is selected from substitution or unsubstituted C1-C4 alkyl, substitution or unsubstituted C5-C8 aryl, substitution Or unsubstituted C6-C10 alkylaryls, substitution or unsubstituted contain 1 to 3 heteroatomic five yuan in S, N and O To eight circle heterocycles bases, substitution or unsubstituted contain 1 to 3 heteroatomic eight yuan to ten yuan and ring group in S, N and O；
Wherein term " substituted " refers to be replaced by 1 to 3 identical or different substituent, and the substituent is selected from hydroxyl Base, amino, halogen, nitro, carboxyl, sulfonyl, C1-C6 alkoxies, the C1-C6 alkoxies of C5-C7 aryl substitution, C5-C7 virtues Base.
R2 is selected from hydrogen, C1-C6 alkyl, and Ar is selected from C5-10 aromatic ring yl, it is preferable that R2 is selected from hydrogen, C1-C3 alkyl, Ar is selected from C5-C7 aromatic ring yl, it is highly preferred that R2 is selected from hydrogen, methyl, ethyl, Ar is selected from C5-C6 aromatic ring yl.
R3 is selected from hydrogen, C1-C6 alkyl, it is preferable that R2 is selected from hydrogen, C1-C3 alkyl, it is highly preferred that R3 is selected from hydrogen, first Base, ethyl.
The halogen is selected from F, Cl, Br or I, preferably F, Cl or Br.
The more preferably following compound of benzimidizole derivatives according to the Formulas I of the present invention：
It is conventional with inorganic acid or organic acid reaction formation that " pharmaceutically acceptable salt " is logical formula (I) compound Nontoxic salts.For example, the conventional nontoxic salts can be made by logical formula (I) compound with inorganic acid or organic acid reaction, it is described Inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and the organic acid includes citric acid, wine Stone acid, lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, ethyl sulfonic acid, naphthalenedisulfonic acid, maleic acid, Malic acid, malonic acid, fumaric acid, butanedioic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutter acid, hydroxymaleic acid, phenylacetic acid, Benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin and isethionic acid etc.；Or Logical formula (I) compound and propionic acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, lemon Sodium salt, sylvite, calcium salt, aluminium salt or ammonium salt after acid, aspartic acid or glutamic acid formation ester again with inorganic base formation；Or formula (I) compound and methylamine salt, ethylamine salt or the ethanolamine salt of organic base formation；Or logical formula (I) compound and lysine, smart ammonia Acid, ornithine formation ester after again with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid formation corresponding inorganic acid salt or With the corresponding acylate of formic acid, acetic acid, picric acid, methanesulfonic acid and ethyl sulfonic acid formation.
According to another aspect of the present invention, the present invention also provides the synthetic method of compound shown in Formulas I, and reaction process is such as Under：
Step 1) methyl formate base substitution adjacent nitro fluorobenzene and corresponding aminesIt is condensed to yield formula 2 Compound, specific reaction condition may be referred to document (Organic Letters, 17 (19), 4734-4737) record side Method；
Step 2) compound of formula 2 obtains the compound of formula 3 by hydro-reduction, and specific reaction condition may be referred to document (Organic&Biomolecular Chemistry,7(24),5173-5183)；
Step 3) formula 3 compound again with substituted benzaldehydeCondensation cyclization obtains the compound of formula 4, Specific reaction condition may be referred to document (Tetrahedron, 71 (4), 532-538)；
Step 4) compound of formula 4 obtains the compound of formula 5 by basic hydrolysis, and specific reaction condition may be referred to document (ChemMedChem,1(9),955-958)；
Step 5) compound of formula 5 is condensed with corresponding aminated compounds again, and specific reaction condition may be referred to document (Journal of Medicinal Chemistry, 47 (26), 6451-6454), obtains the compound of target product Formulas I.
Wherein substituent A, R2、R3It is as defined above with Ar.
According to another aspect of the present invention, the present invention also provide Formulas I shown in compound be used for prepare anti-tumor medicine, The purposes of the medicines such as antiviral agent, antimicrobial, antiparasitic agent and/or hypotensor.
Another aspect of the present invention is to provide closes containing compound shown in Formulas I, its pharmaceutically acceptable salt or solvent Thing as active component pharmaceutical composition.According to the pharmaceutical composition of the present invention, it is effective that described pharmaceutical composition includes treatment Compound shown in the Formulas I of amount, its pharmaceutically acceptable salt or solvate and excipient substance.Term " effective dose ", which can refer to, is Realize the dosage and the effective amount of period needed for expected effect.This effective dose may produce different changes because of some factors Change, the illness of disease when the species of such as disease or treatment, the construction for the specific target organ being administered, individual patient size or The seriousness of disease or symptom.One skilled in the art does not need excessively experiment to determine specific compound by rule of thumb Effective dose." excipient substance " refers to the various auxiliary materials routinely used in medicine, such as excipient, controlled release agent, stabilizer Deng this belongs to those skilled in the art's Conventional wisdom scope.
Preferably, the pharmaceutical composition of the compound comprising according to I formulas of the present invention can be used for treatment and disease Malicious related disease, the disease related to bacterium, the disease related with parasite, the disease with atherosclerosis correlation and The related disease of thrombus, the disease related to hypertension.
Pharmaceutical composition according to the present invention can be following formulation：Tablet is such as, but not limited to conventional tablet, speed Release piece, sustained release tablets, controlled release tablet, Film coated tablets, sugar coated tablet, buccal tablet, sublingual tablet, biological adhesive tablet etc.；Capsule is for example but not It is limited to hard shell capsules, soft capsule etc.；Injection is such as, but not limited to sterile or bacteriostatic agent aqueous injections, oily injection Agent, freezing dry powder injection, microsphere for injection etc.；Spray is such as, but not limited to oral spray, nasal mist, local skin Spray etc.；Aerosol is such as, but not limited to lung inhalation aerosol, local skin aerosol etc.；Nasal drop is such as, but not limited to Collunarium solution, drop nasal gel etc.；Powder spray is such as, but not limited to cavity powder spray, nasal cavity powder spray, local skin With powder spray etc.；Other cavities of the human body such as suppository of vagina, rectum, ear chamber etc., patch, gel.The preparation of these preparations Technique is that those skilled in the art can prepare according to existing knowledge or with reference to pertinent texts or reference book or document 's.
Beneficial effect
Drug research based on kras is the Research Challenges of anti-tumor medicine, not yet has successful medicine to list at present, The compound that the present invention is provided has the multiplication capacity of the significant tumour cell for suppressing kras mutation, and Stability Analysis of Structures prepares letter Just, with potentiality of the exploitation for new type antineoplastic medicine.
Embodiment
Hereinafter, it will be described in detail the present invention.Before doing so, it should be appreciated that in this specification and appended Claims in the term that uses should not be construed as being limited to general sense and dictionary meanings, and inventor should allowed On the basis of the appropriate principle for defining term to carry out best interpretations, according to implication corresponding with the technical elements of the present invention and generally Thought is explained.Therefore, description presented herein is not intended to limitation originally merely for the sake of the preferred embodiment for illustrating purpose The scope of invention, it will thus be appreciated that without departing from the spirit and scope of the present invention, it can be obtained by it His equivalents or improved procedure.
1- benzyls -2-Phenylbenzimidazole analog derivative of the present invention does not have document report, according to the Formulas I of the present invention Shown compound can selectively kill the cancer cell of Ras gene mutations or suppress its propagation；Pharmaceutically-active machine shown in Formulas I System includes but is not limited to the interaction for suppressing kras albumen and PDE δ.
Experimental method in following embodiments, is conventional method unless otherwise specified.
Material, reagent used etc., unless otherwise specified, are commercially obtained in following embodiments.
The preparation (ZXY8008-1) of embodiment 1, N-1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- N-formyl morpholine Ns
The synthetic route of N-1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- N-formyl morpholine Ns is as follows.
Step a：The preparation of 3- benzamido group -4- nitro-benzoic acid methyl esters
The fluoro- 4- nitrobenzene methyls (10) of 9.9g (0.05mol) 3- are dissolved in 50ml DMF, add 8.3g (0.06mol) potassium carbonate, 6.4g (0.06mol) benzylamine, 50 DEG C of reactions to raw material are disappeared, and reaction solution is poured into water, filtered Orange red solid, 13.5g, yield：94.6%.1H-NMR(400MHz,DMSO-d6)δ(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：The preparation of 3- benzamido group -4- amino-benzoic acid methyl esters
14.3g (0.05mol) 3- benzamido group -4- nitro-benzoic acid methyl esters are placed in 500ml reactors, take catalyst thunder Buddhist nun's nickel 3.6g (weight in wet base) is added into 200ml methanol, is while stirring poured into methanol in reactor, is passed through hydrogen anti-in 65 DEG C Answer 3-5 hours, reacting liquid filtering (, proper amount of methanol filter wash cake.Reaction solution is concentrated under reduced pressure to give pale yellow oily liquid, and ether surpasses Sound separates out pale solid, and suction filtration is dried, obtains white solid 11.5g, yield：89.5%.1H-NMR(400MHz,CDCl3)δ (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：The preparation of 1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- carboxylate methyl esters
9.3g (0.04mol) 3- benzamido group -4- amino-benzoic acid methyl esters are dissolved in 100ml ethanol, add benzaldehyde 4.3g (0.04mol), back flow reaction to raw material disappears, and is concentrated under reduced pressure, solid crude product ethanol：Water=7:3 ultrasounds, filtering, filter cake is done It is dry, obtain white solid 11.5g, yield：92.6%.1H-NMR(400MHz,CDCl3)δ(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：The preparation of 1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids
11.5g (0.03mol) 1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- carboxylate methyl esters are taken to be dissolved in 300ml methanol, 1mol/L sodium hydroxide solutions 65ml is added, 65 DEG C of reactions are stayed overnight, watery hydrochloric acid acidification reaction liquid to pH 4 or so, separated out a large amount of white Color solid, suction filtration, washing filter cake (25ml × 2) is dried, obtains white solid 10.9g, yield：98.5%.1H-NMR(400MHz, DMSO-d6)δ(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：The preparation of N-1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- N-formyl morpholine Ns
Take 263mg (0.80mmol) 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids and 77mg (0.88mmol) Morpholine is dissolved in 4ml DMF, adds 184mg (0.96mmol) EDCI, 130mg (0.96mmol) HOBt, 30mg (0.24mmol) 50 DEG C of reactions of DMAP are stayed overnight.Raw material disappears, and stops heating, be concentrated under reduced pressure to obtain light brown grease, and crude product column chromatography for separation is pure Change, obtain white solid, yield：76.9%, fusing point：149-151℃.ESI-HRMS(m/z):398.1864[M+H]+,1H-NMR (400MHz,CDCl3)δ(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)δ(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。
The system of embodiment 2, N- (3- (benzyloxy)-phenyl) 1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formamides Standby (ZXY8008-3)
With reference to the preparation method of embodiment 1 and condition, with 3- benzyloxy-anilines and 1- benzyls -2- phenyl -1H- benzos [d] miaow Azoles -6- carboxylic acids are that raw material progress is amide condensed, and raw material disappears, and stops heating, be concentrated under reduced pressure removing solvent, to the oily after concentration 20ml water is added in liquid, ultrasonic 15-20 minute, precipitation solid, dry white solid, yield：91.0%, fusing point：168- 170℃。ESI-HRMS(m/z):510.2176[M+H]+,1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
Embodiment 3, (2- (1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamidos) ethyl) tertiary fourth of carbamic acid The preparation (ZXY8011-1) of ester
With reference to the experiment condition of embodiment 2 and post-processing approach, with N-Boc- ethylenediamines and 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：90.2%, fusing point：179-182℃.ESI-HRMS(m/z): 471.2390[M+H]+,1H-NMR(400MHz,CDCl3)δ(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)δ (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。
Embodiment 4, N- (1H- benzos [d] imidazoles -2- bases) -1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formamides Preparation (ZXY8011-5)
With reference to the experiment condition of embodiment 2 and post-processing approach, with 2- amino-benzimidazoles and 1- benzyl -2- phenyl -1H- Benzo [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：87.1%, fusing point：250-253℃.ESI-HRMS(m/z): 444.1819[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ (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。
The system of embodiment 5, N- (3,4- Dimethoxyphenethyls) -1- benzyl -2- phenyl -1H- benzos [d] Imidazole carboxamide Standby (ZXY8013-1)
With reference to the experiment condition of embodiment 2 and post-processing approach, with 3,4- dimethoxy-phenylethylamines and 1- benzyl -2- phenyl - 1H- benzos [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made：90.8%, fusing point：164-166℃.ESI-HRMS (m/z):492.2281[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
The preparation of embodiment 6, N- (4- Phenoxyphenyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides (ZXY8013-2)
With reference to the experiment condition of embodiment 2 and post-processing approach, with 4- amino-diphenyl ether and 1- benzyl -2- phenyl -1H- benzene And [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：79.0%, fusing point：216-218℃.ESI-HRMS(m/z): 496.2020[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
The preparation of embodiment 7, N- (4- luorobenzyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides (ZXY8013-3)
With reference to the experiment condition of embodiment 2 and post-processing approach, with 4-Fluorobenzylamine and 1- benzyl -2- phenyl -1H- benzos [d] Imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：80.5%, fusing point：139-141℃.ESI-HRMS(m/z): 436.1820[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
The system of embodiment 8, (S)-N- (1- phenylethyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides Standby (ZXY8015-1)
With reference to the experiment condition of embodiment 2 and post-processing approach, with R (+)-α-phenylethylamine and 1- benzyl -2- phenyl -1H- benzene And [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：92.5%, fusing point：177-178℃.ESI-HRMS(m/z): 432.2070[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
The system of embodiment 9, (R)-N- (1- phenyl propyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides Standby (ZXY8015-2)
With reference to the experiment condition of embodiment 2 and post-processing approach, with R (+) -1- amphetamines and 1- benzyl -2- phenyl -1H- benzene And [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：92.1%, fusing point：178-181℃.ESI-HRMS(m/z): 446.2227[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
The system of embodiment 10, (R)-N- (1- phenylethyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides Standby (ZXY8015-3)
With reference to the experiment condition of embodiment 2 and post-processing approach, with S (-)-α-phenylethylamine and 1- benzyl -2- phenyl -1H- benzene And [d] imidazoles -6- carboxylic acids are raw material, obtain light yellow solid, yield：95.9%, fusing point：191-193℃.ESI-HRMS(m/z): 432.2071[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
Embodiment 11, (R)-N- (1- (1H- benzos [d] imidazoles -2- bases) ethyl) -1- benzyl -2- phenyl -1H- benzos [d] The preparation (ZXY8015-4) of imidazoles -6- formamides
With reference to the experiment condition of embodiment 2 and post-processing approach, with (R)-(+) -2- (α-methylamine) -1H- benzos [d] imidazoles and 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：85.7%, fusing point：290-292 ℃。ESI-HRMS(m/z):472.2132[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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).
The preparation of embodiment 12, N- (2- bromophenylethyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides (ZXY8015-5)
With reference to the experiment condition of embodiment 2 and post-processing approach, with bromophenyl ethamine and 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：91.7%, fusing point：147-149℃.ESI-HRMS(m/z): 512.1161[M+H]+；1H-NMR(400MHz,CDCl3)δ(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)δ(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。
Embodiment 13, N- (3H-1,2,4- triazole -3- bases) -1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formyls The preparation (ZXY8020-2) of amine
Into 263mg (0.80mmol) 1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids add 5ml toluene and 0.5ml thionyl chlorides, 80 DEG C are reacted 2-3 hours, and be concentrated under reduced pressure removing thionyl chloride, 3- amino -1,2,4 triazole 75mg (0.88mmol) is added under the conditions of 0.5ml pyridines, 0 DEG C, by freshly prepd acyl chlorides dichloromethane with dichloromethane 5ml dissolvings Dilute and slowly drop in amine aqueous solution.After completion of the reaction, reaction solution is transferred in separatory funnel, washing organic phase (15ml × 2), Aqueous phase is extracted with 10ml dichloromethane again after merging, and is merged organic phase, saturated sodium-chloride is washed, is dried, filtering, and be concentrated under reduced pressure rear pillar Chromatography is purified, and obtains white solid, yield：74.8%, fusing point：200-203℃.ESI-HRMS(m/z):395.1615[M+ H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
Embodiment 14, (R)-N- (1- (3H- imidazos [4,5-c] pyridine -2- bases) ethyl) -1- benzyl -2- phenyl -1H- The preparation (ZXY8022) of benzo [d] imidazoles -6- formamides
With reference to the experiment condition of embodiment 2 and post-processing approach, with (R)-(+) -2- (α-methylamine) -1H- pyridine-imidazoles and 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids are raw material, obtain white solid, yield：70.0%, fusing point：270-273 ℃。ESI-HRMS(m/z):473.2082[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
Embodiment 15, N- (4- (methyl sulphonyl) phenyl) -1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formamides Preparation (ZXY8024)
With reference to the experiment condition of embodiment 13 and post-processing approach, with 4- methanesulfonylanilines and 1- benzyl -2- phenyl -1H- Benzo [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made by chloride method：77.8%, fusing point：287-289℃. ESI-HRMS(m/z):482.1533[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
Embodiment 16, N- (2- (dimethylamino) ethyl) -1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formamides Preparation (ZXY8026-3)
With reference to the experiment condition of embodiment 13 and post-processing approach, with 2- aminooimidazoles and 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made by chloride method：91.7%, fusing point：125-128℃.ESI- HRMS(m/z):399.2179[M+H]+,1H-NMR(400MHz,DMSO-d6)δ(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)δ(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。
The system of embodiment 17, (1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- bases) (4- ethyl piperazidine -1- bases) ketone Standby (ZXY8026-4)
With reference to the experiment condition of embodiment 13 and post-processing approach, with 4- amino -6- chlorine pyrimidine and 1- benzyl -2- phenyl -1H- Benzo [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made by chloride method：93.3%, fusing point：126-128℃. ESI-HRMS(m/z):425.2336[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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).
Embodiment 18, N- (1- methyl piperidine -4- bases) -1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formamides Prepare (ZXY5049-1)
With reference to the experiment condition of embodiment 13 and post-processing approach, with 4- amino -1- methyl piperidines and 1- benzyl -2- phenyl - 1H- benzos [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made by chloride method：79.9%, fusing point：222-224 ℃。ESI-HRMS(m/z):425.2336[M+H]+；1H-NMR(400MHz,CDCl3)δ(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)δ(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。
The preparation of embodiment 19, N- (3- fluorobenzene ethyl) -1- benzyls -2- phenyl -1H- benzos [d] imidazoles -6- formamides (ZXY5049-2)
With reference to the experiment condition of embodiment 13 and post-processing approach, with 3- fluorophenethylamines and 1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made by chloride method：83.8%, fusing point：176-178℃.ESI- HRMS(m/z):450.1975[M+H]+；1H-NMR(400MHz,CDCl3)δ(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)δ(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。
The preparation of embodiment 20, N- (2- morpholinyl ethyls) -1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamides (ZXY5049-3)
With reference to the experiment condition of embodiment 13 and post-processing approach, with N- (2- amino-ethyls) morpholines and 1- benzyl -2- phenyl - 1H- benzos [d] imidazoles -6- carboxylic acids are raw material, and white solid, yield is made by chloride method：83.8%, fusing point：169-171 ℃。ESI-HRMS(m/z):441.2286[M+H]+；1H-NMR(400MHz,CDCl3)δ(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)δ(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。
Embodiment 21, N- (2- ((7- nitros benzo [c] [1,2,5] oxadiazoles) -4- amino) ethyl) 1- benzyl -2- benzene The preparation (ZXY8027) of base -1H- benzos [d] imidazoles -6- formamides
Take 400mg (2- (1- benzyl -2- phenyl -1H- benzos [d] imidazoles -6- formamidos) ethyl) tertiary fourth of carbamic acid Ester adds 4mol/L hydrochloric acid 5ml and dichloromethane 5ml, is stirred overnight at room temperature, next day, adjusts pH 7-8 left with 1mol/L sodium hydroxides The right side, water layer is extracted (15ml × 2) with dichloromethane, merges organic phase, and saturated sodium-chloride is washed, and organic phase is dried, and filtering is depressurized dense Contracting, obtains white solid.223mg (0.6mmol) and chloro- 7- nitros benzo -2- oxa- -1 of 120mg (0.6mmol) 4- are therefrom weighed, 3 diazole are dissolved in 10ml dichloromethane, add 0.5ml triethylamines, react at room temperature 3 hours.Reaction solution is transferred in separatory funnel, water Wash (10ml × 2) twice, aqueous phase is extracted with 10ml dichloromethane again, merges organic phase, and saturated sodium-chloride is washed, and dries organic phase, Filtering, organic phase is concentrated under reduced pressure, and crude product column chromatographic isolation and purification obtains dark brown solid 91mg, yield：48.8%.ESI- HRMS(m/z):534.1885[M+H]+,1H-NMR(400MHz,DMSO-d6)δ(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)。
The preparation of embodiment 22, N-1- benzyls -2- phenyl -1H- benzos [d] imidazoles -5- N-formyl morpholine Ns
Using 1- benzyls -2- phenyl -1H- benzos [d] imidazole-5-carboxylic acid, walked using similar in the synthetic method of embodiment 1 Rapid e amide condensed method, using morpholine and 1- benzyl -2- phenyl -1H- benzo [d] imidazole-5-carboxylic acids as raw material, prepares targeted Compound, white solid, yield are obtained through column chromatographic isolation and purification：77.9%, fusing 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)δ(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。
Embodiment 23, (S)-N- (1- (1H- benzos [d] imidazoles -2- bases) ethyl) -1- benzyl -2- phenyl -1H- benzos [d] The preparation of imidazoles -5- formamides
1- benzyls -2- phenyl -1H- benzos [d] imidazole-5-carboxylic acid is prepared using the above method, with (R)-(+) -2- (α-first Amine) -1H- benzimidazoles and 1- benzyls -2- phenyl -1H- benzos [d] imidazole-5-carboxylic acid be raw material, using similar to embodiment 11 Method prepare target compound, obtain white solid, yield：85.1%, fusing point：250-252℃.ESI-HRMS(m/z): 472.2132[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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) δ(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。
Embodiment 24, (S)-N- (1- (3H- imidazos [4,5-c] pyridine -2- bases) ethyl) -1- benzyl -2- phenyl -1H- The preparation of benzo [d] imidazoles -5- formamides
With (R)-(+) -2- (α-methylamine) -1H- pyridine-imidazoles (24) and 1- benzyls -2- phenyl -1H- benzos [d] imidazoles - 5- carboxylic acids are raw material, prepare target compound using the method similar to embodiment 14, obtain white solid, yield：77.3%, melt Point：155-157℃.ESI-HRMS(m/z):473.2084[M+H]+；1H-NMR(400MHz,DMSO-d6)δ(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)δ (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 is tested
Kras gene mutations cause the function of its kras protease to strengthen, and then cause cell proliferation and differentiation out of control therefore, The positive tumor cell line of kras mutation is more sensitive to the cytotoxicity of the kras inhibitor of the present invention.Based on this, we are carried out Biological activity test, chooses kras mutation positive Panc-tu-1 and the negative PANC-1 of kras and carries out comparative study, determine Cytotoxicity.As a result such as table 1 below.
The part of compounds cytotoxicity experiment result of table 1
Test example 2：Antitumor activity of compound is tested
Subject cell:MDA-MB-231、LM3；Cell culture and experimental method:Inoculating cell is in containing 10% hyclone In DMEM cell culture fluids (supplement mycillin stoste 5ml/500ml), it is placed in 37 DEG C and contains 5%CO2Cell culture incubator in, often Change within 1-2 days liquid once, 0.25% Trypsin Induced passes on and collected cell.By exponential phase cell, with containing 10% tire ox The DMEM cell culture fluids of serum are configured to the cell suspension of suitable concentration, are added by every 2500-4000 cell in hole (100 μ l) Into 96 porocyte culture plates, after overnight incubation, culture medium 100 μ l, Mei Genong containing various concentrations tested material are added per hole Degree sets 4 parallel holes.Cell dosing culture abandons supernatant after 72 hours, and the 0.5-0.55mg/ml tetra- that 100 μ l are newly configured is added per hole Supernatant is abandoned after the serum-free medium of nitrogen azoles indigo plant (MTT), 37 DEG C of culture 4h, 200 μ l DMSO Rong Xie formazans, enzyme mark are added per hole Instrument determines absorbance under 570nm wavelength.Medicine is prepared：With《Antitumor pharmacodynamics guideline exposure draft》With《Cell toxicant Anti-tumor compounds non-clinical study technological guidance's principle》, will with cosolvent DMSO according to the result of pilot study to instruct Test-compound is diluted to 20mg/ml, takes and 990 μ l culture mediums progress preliminarily diluted is added after 10 μ l diluents, by required dense Degree is further diluted to different Test compound concentrations with culture medium, separately sets blank control group.Data processing:Data use ± S Represent；Inhibiting rate=(control group OD values-administration group OD values)/control group OD value × 100%；Compound effect index half Concentration (IC50) is represented, and lists actual measurement maximal percentage inhibition (Imax).Mapped with Origin softwares, and four parameters in the software Logistic programs are fitted growth of tumour cell curve, obtain half effect concentration (IC50, μ g/ml).As a result 2 be see the table below.
The compound of table 2. suppresses tumor cell proliferation experimental result
On the basis of primary dcreening operation, according to the representative compound of the present invention in the high tumor cell line MDA- of grade malignancy MB-231 and LM3 are tested, and its IC50 for suppressing cell propagation is nM grades, it is shown that very strong suppression tumor cell proliferation Ability, illustrate good antineoplastic potentiality to be exploited.

Claims (7)

1. benzimidizole derivatives shown in a class Formulas I, its pharmaceutically acceptable salt, solvate：
Wherein, A selected from substitution or it is unsubstituted containing in S, N and O 1 to 3 heteroatomic five yuan to ten circle heterocycles bases Or-NH-R4；
When A for substitution or it is unsubstituted containing in S, N and O 1 to 3 heteroatomic five yuan to ten circle heterocycles bases when, it is excellent Elect as substitution or it is unsubstituted containing in S, N and O 1 to 3 heteroatomic five yuan to seven membered heterocyclic base；
When A is-NH-R4, wherein R4 is selected from substitution or unsubstituted C1-C6 alkyl, substitution or unsubstituted C5-C10 Aryl, substitution or unsubstituted C6-C12 alkylaryls, substitution or it is unsubstituted containing in S, N and O 1 to 3 it is miscellaneous Five yuan of atom are to ten circle heterocycles bases, substitution or unsubstituted contain 1 to 3 heteroatomic eight yuan to ten in S, N and O First miscellaneous and ring group；
R2 is selected from hydrogen, C1-C6 alkyl, and Ar is selected from C5-10 aromatic ring yl,
R3 is selected from hydrogen, C1-C6 alkyl,
Wherein " substituted " refers to be replaced by 1 to 3 identical or different substituent, and the substituent is selected from hydroxyl, amino, halogen Element, nitro, carboxyl, sulfonyl, C1-C6 alkoxies, the C1-C6 alkoxies of C5-C7 aryl substitution, C5-C7 aryl；
The halogen is selected from F, Cl, Br or I, preferably F, Cl or Br.
2. benzimidizole derivatives shown in Formulas I according to claim 1, its pharmaceutically acceptable salt, solvent are closed Thing, it is characterised in that R4 is selected from substitution or unsubstituted C1-C4 alkyl, substitution or unsubstituted C5-C8 aryl, substitution Or unsubstituted C6-C10 alkylaryls, substitution or unsubstituted contain 1 to 3 heteroatomic five yuan in S, N and O To eight circle heterocycles bases, substitution or unsubstituted contain 1 to 3 heteroatomic eight yuan to ten yuan and ring group in S, N and O；
R2 is selected from hydrogen, C1-C3 alkyl, and Ar is selected from C5-C7 aromatic ring yl；
R3 is selected from hydrogen, C1-C3 alkyl.
3. benzimidizole derivatives shown in Formulas I according to claim 1, its pharmaceutically acceptable salt, solvent are closed Thing, it is characterised in that R2 is selected from hydrogen, methyl, ethyl, Ar is selected from C5-C6 aromatic ring yl；R3 is selected from hydrogen, methyl, ethyl.
4. benzimidizole derivatives shown in Formulas I according to claim 1, its pharmaceutically acceptable salt, solvent are closed Thing, it is characterised in that the benzimidizole derivatives shown in the Formulas I are selected from following compound：
5. a kind of benzimidizole derivatives shown in Formulas I according to claim 1, its pharmaceutically acceptable salt, molten The synthetic method of agent compound, reaction process is as follows：
Step 1) methyl formate base substitution adjacent nitro fluorobenzene and corresponding aminesIt is condensed to yield the change of formula 2 Compound；
Step 2) compound of formula 2 obtains the compound of formula 3 by hydro-reduction；
Step 3) formula 3 compound again with substituted benzaldehydeCondensation cyclization obtains the compound of formula 4；
Step 4) compound of formula 4 obtains the compound of formula 5 by basic hydrolysis；
Step 5) formula 5 compound again with corresponding aminated compounds be condensed, obtain the compound of target product Formulas I；
Wherein substituent A, R2、R3Definition with Ar is as described in the appended claim 1.
6. benzimidizole derivatives shown in Formulas I according to claim 1, its pharmaceutically acceptable salt, solvent are closed Thing is used for the purposes for preparing anti-tumor medicine, antiviral agent, antimicrobial, antiparasitic agent and/or hypotensor.
7. a kind of pharmaceutical composition, described pharmaceutical composition includes compound shown in the Formulas I of therapeutically effective amount, it can pharmaceutically connect The salt or solvate and excipient substance received.
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