CN108912095B

CN108912095B - Benzimidazoles compound and its preparation method and application

Info

Publication number: CN108912095B
Application number: CN201810901513.8A
Authority: CN
Inventors: 谢德逊; 李权伟; 薛伟才; 刘辉
Original assignee: Guangzhou Iwahito Medical Technology Co Ltd
Current assignee: Guangzhou Iwahito Medical Technology Co Ltd
Priority date: 2018-08-09
Filing date: 2018-08-09
Publication date: 2019-08-20
Anticipated expiration: 2038-08-09
Also published as: CN108912095A

Abstract

The present invention relates to a kind of benzimidazoles compound and its applications.For the structure of the benzimidazoles compound as shown in I, which shows preferable FAK inhibitory activity as focal adhesion kinase inhibitor.At the same time, with stronger drug effect, better medicine for property and/or toxicological characteristics, such as: good brain/blood plasma than, good bioavilability, good metabolic stability and its reduce the inhibition that acts on mitochondrial respiratory, have preferable potential applicability in clinical practice.

Description

Benzimidazoles compound and its preparation method and application

Technical field

The present invention relates to medicinal chemistry arts, more particularly to benzimidazoles compound and its preparation method and application.

Background technique

The discovery of focal adhesion kinase (FAK) starts from 1992, is a kind of intracytoplasmic non-receptor tyrosine kinase, It is expressed in the cell of various tissues, has and adjust various kinds of cell effect.FAK is the early stage regulator of integrin signal cascade, So that the integrin for responding various stimulations is clustered in generation FAK autophosphorylation on Tyr397, a large amount of downstream signal is activated Access adjusts the biological behaviours such as migration, hyperplasia, the differentiation of cell.In normal cell, FAK adjusts various elementary cell function It can be as bred and growing, prevent apoptosis, adherency and cytochrome oxidase isozymes, invasion and migration.In cancer cell, FAK is that a plurality of signal passes The joint of guiding path.The FAK of excessive unconventionality expression is detected in a large amount of human cancer cell, such as breast cancer, ovum Nest cancer/colon cancer, prostate cancer, colon cancer etc..Important function based on FAK in tumour generation, migration, increment, apoptosis, suppression The activity of FAK processed can block fast breeding and the diffusion of cancer cell, therefore the inhibitor for designing synthesis FAK controls cancer Treatment is of great significance.

In addition, by deeper into research and bucketing in addition to FAK mouse models research shows that: in embryo growth and When growth of cancer cells, FAK is played a key role in the formation of blood vessel.Therefore FAK can be used for treating pathologic vessels, Such as the antiangiogenesis therapy in the diseases such as such as cancer and retinopathy.

Based on the above two o'clock, FAK is one of the antitumor gold target spot currently received significant attention, and FKA inhibitor is in recent years Also to become the hot spot of major pharmaceuticals research.

Summary of the invention

Based on this, the present invention provides a kind of new benzimidazoles compound, which inhibits as focal adhesion kinase Agent shows preferable FAK inhibitory activity.

Specific technical solution is as follows:

Benzimidazoles compound or its pharmaceutically acceptable salt, stereoisomer with structure shown in formula (I), mutually Tautomeric, nitrogen oxides, solvate, metabolin, prodrug or mixture:

Wherein,

R^NSelected from hydrogen, methyl, isopropyl；

R^CSelected from hydrogen, methoxyl group, fluorine.

The R in one of the embodiments,^NSelected from methyl, isopropyl；

R^CSelected from hydrogen, methoxyl group, fluorine.

The benzimidazoles compound has structure shown in formula (II) in one of the embodiments:

Wherein,

R^NSelected from methyl, isopropyl；

R^CSelected from hydrogen, fluorine.

The benzimidazoles compound has structure shown in formula (III) in one of the embodiments:

Wherein,

R^NSelected from methyl；

R^CSelected from methoxyl group, fluorine.

The benzimidazoles compound one of has following structure in one of the embodiments:

The benzimidazoles compound is selected from one of the embodiments:

2- ((2- ((1H- benzo [d] imidazoles -2- base) amino) -5- chloropyridine -4- base) amino)-N- methoxybenzoyl Amine,

2- ((the chloro- 2- of 5- ((1- methyl-1 H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) amino)-N- methoxyl group Benzamide,

2- ((the chloro- 2- of 5- ((6- methoxyl group -1- methyl-1 H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) ammonia Base)-N- methoxy benzamide,

2- ((the chloro- 2- of 5- ((fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- base of 6-) amino) pyridin-4-yl) amino)-N- Methoxy benzamide,

2- ((the chloro- 2- of 5- ((fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- base of 7-) amino) pyridin-4-yl) amino)-N- Methoxy benzamide,

2- ((the chloro- 2- of 5- ((1- isopropyl 1H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) amino)-N- methoxy Yl-benzamide.

The present invention also provides a kind of drugs.

The specific technical proposal is:

A kind of drug includes above-mentioned benzimidazoles compound or its pharmaceutically acceptable salt, stereoisomer, mutually Tautomeric, nitrogen oxides, solvate, metabolin, prodrug or mixture, and pharmaceutically acceptable excipient.

The active constituent of the drug also includes additional therapeutic agent in one of the embodiments,.

The additional therapeutic agent includes one in anticancer agent and treatment pulmonary hypertension medicine in one of the embodiments, Kind is several.

The present invention also provides application of the above compound in the drug that preparation prevents and treats FAK related disease.

The FAK related disease includes: that cancer, pulmonary hypertension or pathologic vessels are raw in one of the embodiments, At.

The present invention provides a kind of new benzimidazoles compound, and the compound is as focal adhesion kinase inhibitor, performance Preferable FAK inhibitory activity out.At the same time, have stronger drug effect, better medicine for property and/or toxicological characteristics, such as: good Good brain/blood plasma than, good bioavilability, good metabolic stability and its can reduce to mitochondrial respiratory effect Inhibit, has preferable potential applicability in clinical practice.

Detailed description of the invention

The description of benzimidazoles compound of the present invention

The present invention provides the benzimidazoles compound with structure shown in formula (I) or its pharmaceutically acceptable salt, stands Body isomers, tautomer, nitrogen oxides, solvate, metabolin, prodrug or mixture:

Wherein,

R^NSelected from hydrogen, methyl, isopropyl；

R^CSelected from hydrogen, methoxyl group, fluorine.

Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the scope of the present invention.

Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition, must Must be suitble to chemistry or toxicology, the mammal with the other components of composition preparation and for treatment is related.

The salt of the compound of the present invention further includes the centre for being used to prepare or purifying benzimidazoles compound shown in formula (I) The salt of the enantiomter of the separation of benzimidazoles compound shown in body or formula (I), but it is not necessarily pharmaceutically acceptable salt.

Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.

Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.

Disclosed compound of present invention can contain asymmetric or chiral centre, therefore can be with different stereoisomer forms In the presence of.It is including but not limited to non-the present invention is directed to all stereoisomer forms of compound shown in formula (I) benzimidazole Enantiomter, enantiomter, atropisomer and geometry (or conformation) isomers and their mixture such as disappear outside Mixture is revolved, component part of the invention is become.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.

The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.

If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..

If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.

Benzimidazoles compound of the present invention and its pharmaceutical composition, preparation and administration

The characteristics of pharmaceutical composition of the invention includes benzimidazoles compound shown in formula (I), listed by the present invention Compound or embodiment compound.The amount of compound can effectively treat or mitigate patient's in composition of the invention The relevant disease of FAK kinases.

As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable tax Shape agent, these are as applied by the present invention, including any solvent, diluent or other liquid excipients, dispersing agent or suspension Agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc. are suitable for peculiar Target formulation.As described in following documents: In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins, Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick And J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, shows different Excipient can be applied to the preparation and their well known preparation methods of pharmaceutically acceptable composition.In addition to any conventional tax The shape agent range incompatible with the compound of the present invention, for example, caused by any undesirable biological effect or with can pharmaceutically connect The interaction that any other component for the composition received generates in harmful manner, their purposes are also that the present invention is considered Range.

Pharmaceutical composition of the invention further comprises i) one or more other Fak inhibitors and/or ii) it is a kind of or more The other types of kinases inhibitor of kind and/or one or more other types of therapeutic agents.One or more of them is other The kinases inhibitor of type include such as PYK2 or src inhibitor, other types of therapeutic agent include other anticancer agents, its He treats pulmonary hypertension medicine etc..

When available for treatment, the benzimidazoles compound of the present invention of therapeutically effective amount, especially formula (I) benzimidazole Class compound and its pharmaceutically acceptable salt can be used as unprocessed chemicals and give, and be alternatively arranged as the work of pharmaceutical composition Property ingredient provide.Therefore, the content of present invention also provides pharmaceutical composition, which includes the book hair of therapeutically effective amount Bright compound, especially formula (I) benzimidazoles compound or its pharmaceutically acceptable salt and one or more pharmaceutically may be used Carrier, diluent or the excipient of receiving.Term as used herein " therapeutically effective amount " refer to be enough to show it is significant The total amount of each active component of patient benefit's (such as viral load reduction).When using separate active ingredients for separate administration, The term only refers to the ingredient.When combining applications, no matter the term then refers to combination, when being sequentially or simultaneously administered, all cause to control The combined amount of the active constituent of therapeutic effect.In the sense of being compatible with the other ingredients of the formulation and harmless to its recipients, Carrier, diluent or excipient must be acceptable.The another aspect of content according to the present invention also provides and is used to prepare drug The method of preparation, this method include by the compounds of this invention, especially formula (I) benzimidazole or its pharmaceutically acceptable salt It is mixed with one or more pharmaceutically acceptable carriers, diluent or excipient.Term used in the present invention " pharmaceutically may be used Receive " refer to such compound, raw material, composition and/or dosage form, they are applicable within the scope of reasonable medical judgment In contacted with patient tissue and without excessive toxicity, irritation, allergy or it is relative to a reasonable benefit/risk ratio other Problem and complication, and effective for given application.

In conjunction with one or more excipient with prepare one-pack type active constituent amount by must be according to the host for the treatment of Change with specific administration routes.For example, it is contemplated that the preparation for being administered orally to people would generally include, such as 0.5mg-2g (suitable 0.5mg-1g active constituent, such as 0.5mg-0.5g are living for compound active constituent with suitable and the amount of convenience excipient Property agent, more suitably 0.5-100mg, such as 1-30mg), the excipient can be total composition about 98% weight of about 5%-. Formula (I) compound is mixed with carrier material will be according to disease to be treated, disease to prepare the amount of the active constituent of single formulation Severity, administration time, administration route, the discharge rate of compound used therefor, treatment time and patient age, gender, body Weight and situation and change.Preferred unit dosage forms are the daily dose containing hereinbefore active constituent or divided dose or its suitable point Several unit dosage forms.It can start to treat with the low dose of already clearly below compound optimal dose.Hereafter, added with lesser increment Large dosage until reaching optimum efficiency in this case.In general, the concentration level for most desirably giving compound is logical Often effective result can be provided without regard to causing any harmful or toxic side effect in anti-tumor aspect.

During being treated or prevented using the compounds of this invention, if it is desired to separated dosage, it will usually be administered So that the daily dose obtained is 0.1mg/kg-75mg/kg.Relatively low-dose will be given when using parenteral route.For example, just For vein or intraperitoneal administration, usually used dosage is 0.1mg/kg-30mg/kg.Equally, it for inhalation, will adopt Dosage is 0.05mg/kg -25mg/kg.Oral administration is also suitably, especially in form of tablets.In general, unit dosage forms Will contain from about 0.5mg-0.5g the compounds of this invention and unit dosage forms can by daily single, it is secondary, three times or four times or if If needing, it is administered with higher frequency.

The pharmaceutical dosage form of the compound of the present invention and combinations thereof can be with quick-release, controlled release, sustained release or target drug release system System form provides.For example, common formulations include solution and suspension, (micro-) lotion, ointment, gel and patch, liposome, piece Agent, dragee, soft shell or hard-shell capsule, suppository, ovule, implantation material, amorphous or crystalline powder, aerosol and freeze-drying system Agent.Depending on the administration route used, it may be necessary to which drug, such as syringe and needle, sucking are applied or given to special device Device, pump, injection pen, medicator or special-purpose bottle (Special flask).Pharmaceutical dosage form is usually by drug, excipient and container/close Envelope system composition.One or more excipient (also known as non-active ingredient) can be added in the compound of the present invention to improve Or promote manufacture, stability, administration and the safety of drug, and can provide the method for obtaining required drug release patterns.Cause This, being added to excipient type in drug can be depending on various factors, such as the physics and chemical characteristic of drug, administration route And preparation step.There is pharmaceutical excipient in this field and including those of listed in various pharmacopeia.(referring to United States Pharmacopeia (U.S.Pharmacopeia, USP), Japanese Pharmacopoeia (Japanese Pharmacopoeia, JP), European Pharmacopoeia (European Pharmacopoeia, EP) and British Pharmacopoeia (British pharmacopoeia, BP)；U.S. Food and Drug Administration (the U.S.Food and Drug Administration, www.fda.gov) drug evaluation and research center (Center For Drug Evaluation and Research, CEDR) publication, such as " inactive ingredients guide " (Inactive Ingredient Guide,1996)；" medicated premix handbook " (Handbook of that Ash and Ash writes Pharmaceutical Additives, 2002, united information resource company (Synapse Information Resources, Inc.,Endicott NY；etc.).

Pharmaceutical composition is suitable for being administered by any suitable approach, for example, by oral (including oral cavity or sublingual), directly Intestines, nose, part (including oral cavity, sublingual or percutaneous), vagina or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, synovial membrane It is interior, breastbone is interior, intrathecal, intralesional, intravenous or intradermal injection or infusion) approach.Can by art of pharmacy it is any Perception method prepares this kind of preparation, such as by mixing active constituent with carrier or excipient.It is preferred that being administered orally or being administered to Medicine.

Pharmaceutical preparation suitable for oral administration is provided by independent unit, such as capsule or tablet；Powder or granule； Solution or suspension in aqueous or non-aqueous liquid；Edible foam formulations or foaming preparations (whip)；Or oil-in-water cream Liquor or water in oil emulsion liquor.

For example, for oral administration in the form of a tablet or capsule, active medicine component can with can pharmaceutically connect The oral, non-toxic inert carrier (such as ethyl alcohol, glycerol, water etc.) received mixes.By the way that compound powder is broken into suitable fine ruler It is very little, and mix with the pharmaceutical carrier (such as the edible carbohydrate such as starch or mannitol) equally crushed to prepare powder.Also Corrigent, preservative, dispersing agent and colorant may be present.

It by preparing pulverulent mixture as described above, and is loaded into the gelatin shell of forming, to prepare capsule.It is filling It fills out before operation, it can be by glidant and lubricant (such as colloidal silicon dioxide, talcum powder, magnesium stearate, calcium stearate or solid-state Polyethylene glycol) it is added in pulverulent mixture.Can also be added when taking capsule by improve drug utilizability disintegrating agent or Solubilizer (such as agar, calcium carbonate or sodium carbonate).

When furthermore needing or is required, suitable adhesive, lubricant, disintegrating agent and colorant can also be mixed mixture In.Suitable adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis Gummy (such as gum arabic, tragacanth or mosanom), carboxymethyl cellulose, polyethylene glycol etc..For these dosage forms Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes but is not limited to starch, methylcellulose, agar, bentonite, xanthan Glue etc..For example, lubricant and disintegrating agent is added by the way that pulverulent mixture, granulation or pre- tabletting is made, and it is tabletted, to make At tablet.By the compound suitably crushed and diluent as described above or base-material, optionally with adhesive, (such as carboxymethyl is fine Tie up element, alginates, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorbsion accelerator (quaternary salt) and/or Absorbent (such as bentonite, kaolin or Dicalcium Phosphate) mixing, to prepare pulverulent mixture.Useful binders (such as syrup, shallow lake Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) wetting after pressurize sieving, by powder Shape granulating mixture.One alternative of granulation is pulverulent mixture can be passed through tablet press machine, the result is that bad by being formed Agglomerate smashes particle is made again.Can be by the way that stearic acid, stearate be added, talcum powder or mineral oil make particle lubrication to prevent from gluing Onto the punch die of tablet press machine.Then the mixture through lubricating is tabletted.The compound of the content of present invention can also be with free flow Dynamic inert carrier mixing, can be tabletted without passing through granulation or pre- tableting step.Can provide it is transparent or opaque by The protectiveness packet of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polish coating of wax) composition Clothing material.Dyestuff can be added in these coating materials and distinguish different unit doses.

Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, so that specified rate contains There is the compound of predetermined amount.Syrup can be prepared by the way that compound to be dissolved in suitably seasoned aqueous solution, and elixir can lead to It crosses using non-toxic vehicle and prepares.Solubilizer and emulsifier (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain can also be added Pears alcohol ether), preservative, flavoring additive (such as peppermint oil or natural sweetener or saccharin or other artificial sweeteners) etc..

If appropriate, the dosage unit preparations microencapsulation that will can be used to be administered orally.Preparation can also be made and be prolonged When or sustained release, such as by being coated or being embedded in the microparticle materials such as polymer, wax.

The compounds of this invention, especially formula (I) benzimidazoles compound and its pharmaceutically acceptable salt can be with rouge Plastid delivery system is given, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be by a variety of phosphatide (such as cholesterol, octadecylamine or phosphatidyl choline) is constituted.

The compounds of this invention, especially formula (I) benzimidazoles compound and its pharmaceutically acceptable salt can also pass through Monoclonal antibody is used to pass medicine as individual carrier (compound molecule is coupled).Compound can also with as medicine can be targeted The soluble polymer of object carrier is coupled.This quasi polymer may include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyl first Base acrylamide phenol, polyhydroxyethylaspart or the polyethylene-oxide polylysine replaced by palmitoyl residues.This Outside, compound can be coupled with a kind of Biodegradable polymeric, for reaching the controlled release of drug, for example poly- cream of this quasi polymer Acid, poly-epsilon-caprolactone, polyhydroxybutyrate, polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel Cross-linked copolymer or amphipathic nature block polymer.

Pharmaceutical preparation suitable for percutaneous dosing can be used as discrete patch (discrete patch) to protect in a long time It holds and recipient's epidermis close contact.For example, active constituent can usually can be found in by passing medicine by electro-ionic osmosis patch Pharmaceutical Research 1986,3(6),318。

Pharmaceutical preparation suitable for local administration can be made into ointment, cream, suspension, lotion, powder, solution, paste Agent, gelling agent, spray, aerosol, oil formulation or transdermal patch.

Pharmaceutical preparation suitable for rectally can be used as suppository or provide as enema.

Pharmaceutical preparation suitable for vagina administration can be with vaginal plug, vagina plug, cream, creme, gelling agent, paste, foam Agent or spray provide.

Pharmaceutical preparation suitable for parenteral includes water-based and non-aqueous sterile injection solution and aqueous and non-aqueous Sterile suspensions, water-based and non-aqueous sterile injection solution can contain antioxidant, buffer, bacteriostatic agent and make the preparation The isotonic solute with receptor's blood waiting, aqueous and non-aqueous sterile suspensions may include suspending agent and thickener.Preparation can be with Unit dose or multi-dose container provide, for example, sealing peace is triumphant and bottle, and can be reserved under the conditions of freeze-drying (freeze-drying), Only sterile liquid carrier, such as water for injection need to be added before use.The injection solution and suspension for facing used time configuration can be by Sterile powder injection, granule and tablet preparation.

It is the coarse powder of 20-500 micron range including partial size suitable for the pharmaceutical preparation (wherein carrier is solid) of nose administration Agent is quickly sucked from the coarse powder agent container close to nose by being administered in a manner of snuffing by nasal passage.Wherein carrier is Liquid, be suitable for nasal mist or nasal drop administration appropriate formulation include active constituent aqueous solution agent or oiliness it is molten Liquor.

Suitable for the pharmaceutical preparation by inhalation, including dry powder, aerosol, suspending agent or liquid composite.

By the dry powder agent composite of inhalation delivery to lung, typically comprise with as thin fine powder one kind or A variety of pharmaceutically acceptable excipient together, formula (I) benzimidazole chemical combination of the present invention as thin fine powder Object or pharmaceutically acceptable salt.Pharmaceutically acceptable excipient particularly suitable for dry powder doses is those skilled in the art It is known that and including lactose, starch, mannitol and mono-, two- and polysaccharide.It can be for example, by micronization (micronisation) it and mills, prepares thin fine powder.In general, (such as micronization) chemical combination that size reduces Object can pass through about 1 to about 10 micron of D50 value (for example, as detected using laser diffractometry) definition.

Patient's dry powder doses can be given via storage cavern Diskus (RDPI), the inhalator has proper storage dry powder dosage form The storage cavern of the drug of the multiple dosing (dosage without metering) of formula.RDPI is typically comprised for measuring each from storage cavern to passing Send the device of the drug dose of position.For example, metering device may include jigger, second can be moved to from first position It sets, in first position, cup can load the drug from storage cavern, and in the second position, preparation can be used for the drug of the metering of patient's sucking Dosage.

Alternatively, dry powder doses can be rendered as more-dose dry powder agent inhalator (MDPI) capsule (such as gelatin or plastics), Cylindrantherae or blister package.MDPI is inhalator, and wherein drug is included in more-dose package, containing (or otherwise take Band) multiple restriction dosage (or part thereof) drug.When dry powder doses are rendered as blister package comprising multiple for accommodating The bubble-cap of the drug of dry powder form.Bubble-cap is typically arranged in regular fashion to be easy to make drug from wherein discharging.For example, It can usually arrange in a circular manner bubble-cap in collar plate shape blister package, or bubble-cap can be elongated and be in, it may for example comprise item or with shape Formula.

It can be by the way that formula (I) benzimidazoles compound of the invention or pharmaceutically acceptable salt be suspended or dissolved in liquid Change in propellant and forms aerosol.Suitable propellant includes halogenated hydrocarbons, hydro carbons and other liquefied gas.Representative propellant packet It includes: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1- Difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, iso-butane and pentane.Typically inhaled via dosing Enter device (MDI) and gives the aerosol comprising polymorph of the present invention or salt to patient.Such device is those skilled in the art Known.

Aerosol can contain additional pharmaceutically acceptable excipient, and the excipient is usually used in company with MDI, such as table Face activating agent, lubricant, cosolvent and other excipient with improve preparation physical stability, improve valve characteristic, improve it is molten Solution property improves taste.

It will be appreciated that preparation further includes related with the preparation type other than the ingredient being particularly mentioned above Other ingredients commonly used in the art, be for example suitable for oral administration this kind of preparation may include corrigent.

The purposes of the compounds of this invention and pharmaceutical composition

The characteristics of pharmaceutical composition of the invention includes the compound of formula (I) benzimidazole, change listed by the present invention Close object or embodiment compound and pharmaceutically acceptable carrier, adjuvant or excipient.Compound in composition of the invention Suitable for the prevention and treatment of FAK related disease, wherein FAK related disease include cancer, pulmonary hypertension, immunity disease, Arthritis, inflammatory bowel disease, pathologic vessels generate related disease, etc..The compounds of this invention and its pharmaceutical composition particularly for Prepare the drug that treating cancer, pulmonary hypertension, pathologic vessels generate related disease.The compound of the present invention or its medicine group With closing object treatability and i) one or more other Fak inhibitors and/or ii) one or more other types of protein kinases Inhibitor and/or one or more other types of therapeutic agents are combined use, can in one dosage type low temperature be administered orally, with point The peroral dosage form (such as successively or non-sequential) opened is administered orally or together or separates (such as successively or non-sequential) injection and apply With.It wherein, include other anticancer agents, other treatment pulmonary hypertension medicine in other types of therapeutic agent.

It is expected that the compounds of this invention or its pharmaceutical composition have (other than other characteristics) antitumor properties, it is described anti-swollen Tumor characteristic is considered as the inhibition to FAK, for example, the compound or its pharmaceutical composition can show antiproliferative and/or Promote apoptosis and/or anti-invasion and/or anti-cell movement and/or anti-angiogenic activity.This compound seems to can be used for treating, Such as the tumour that FAK causes, particular as anticancer agent.

Thus, it is expected that the compounds of this invention or its pharmaceutical composition can be used for treating the disease individually or partially mediated by FAK Disease or medical conditions, i.e., the described compound can be used for generating FAK inhibitory effect in the warm-blooded animal for needing this treatment.Cause This, the compounds of this invention provides the method for the treatment of malignant cell, it is characterized in that inhibiting FAK.Specifically, the compounds of this invention or Its pharmaceutical composition can be used for generating independent or part and be invaded by inhibiting the antiproliferative of FAK function mediation and/or promoting apoptosis and/or resist It attacks and/or anti-cell moves and/or anti-angiogenic activity effect.Specifically, it is contemplated that the compounds of this invention can be used for prevent or Treatment to inhibiting those of sensitive tumour of FAK, the tumour with such as angiogenesis, proliferation is related with signal transduction step, institute It states step and causes the proliferation of these tumour cells, invasion, migration and especially angiogenesis.Therefore, the compounds of this invention is available In treatment hyperproliferation disease, including cancer.Benign or malignant tumour may influence it is any tissue and it is for example white including non-physical knurl Blood disease, Huppert's disease or lymthoma and solid tumor, such as cholangiocarcinoma, osteocarcinoma (including Ewing' s tumor), bladder cancer, the cancer of the brain/ CNS cancer, breast cancer, colorectal cancer, carcinoma of endometrium, gastric cancer, head and neck cancer, liver cancer, lung cancer (including non-small cell lung cancer and small Cell lung cancer), neural cancer (including neuroblastoma), the cancer of the esophagus, oophoroma, cancer of pancreas, prostate cancer, kidney, cutaneum carcinoma, Carcinoma of testis, thyroid cancer, uterine cancer, cervix cancer and carcinoma of vulva and Kaposi sarcoma.It is expected that the compounds of this invention can be used for Treat pathogenic angiogenesis (pathologic vessels generation), for example, for treat the above cancer and generate it is improper or The Other diseases of pathogenic angiogenesis, such as senile macular degeneration (AMD) and cancer relevant to solid tumor.

The compound of the present invention or its pharmaceutical composition can be used for preparing treatment especially suitable for treating cancer, including swollen Tumor, such as cutaneum carcinoma, breast cancer, the cancer of the brain, neck cancer, carcinoma of testis etc..Shifted it is especially suitable for treatment or malignant tumour.It is more special Not, composition and the cancer of method treatment it can include, but are not limited to following tumor type: such as astrocyte through the invention Cancer, breast cancer, neck cancer, colorectal cancer, carcinoma of endometrium, the cancer of the esophagus, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngocarcinoma, lung cancer, mouth Chamber cancer, oophoroma, prostate cancer and thyroid cancer and sarcoma.More particularly, these compounds can be used for treating: cardia Cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, embryonal-cell lipoma), myxoma, rhabdomyoma, fibroma, fat Tumor and teratoma；Lung cancer: bronchiolar carcinoma (pinacocyte, undifferentiated cellule, undifferentiated maxicell, gland cancer), Alveolar (bronchiole) cancer, bronchial adenoma, sarcoma, lymthoma, cartilage hamartoma, celiothelioma；Gastrointestinal tract site cancer: esophagus Cancer (squamous cell carcinoma, gland cancer, leiomyosarcoma, lymthoma), gastric cancer (cancer, lymthoma, leiomyosarcoma), cancer of pancreas (conduit Gland cancer, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasopressin), carcinoma of small intestine (gland cancer, lymthoma, class Carcinoma, Kaposi sarcoma, liomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (gland cancer, tubular gland Tumor, villous adenoma, hamartoma, liomyoma)；Genitourinary tract cancer: kidney (gland cancer, WilmShi tumour (nephroblastoma), Lymthoma, leukaemia), bladder and carcinoma of urethra (squamous cell carcinoma, transitional cell carcinoma, gland cancer), prostate cancer (gland cancer, sarcoma), Carcinoma of testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell cancer, fibroma, fiber Adenoma, adenomatoid tumor, lipoma)；Liver region cancer: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, Adenoma, hemangioma；Bony site associated cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma cell Tumor, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), Huppert's disease, malignant giant born of the same parents chordoma, Osteochondrofibroma (osteochronfroma) (osteocartilaginous exostosis), benign chondromas, chondroblastoma, cartilage are viscous Liquid sample fibroma (chondromyxofibroma), osteoidosteoma and giant-cell tumor；Nervous system cancer: skull cancer (osteoma, blood Tuberculation, granuloma, xanthoma, osteitis deformans), meninx cancer (meningoma, meningeal sarcoma (meningiosarcoma), nerve Glioma), the cancer of the brain (astrocytoma, neuroblastoma, glioma, ependymoma, gonioma (pinealoma), at Spongiocytoma, oligodendroglioma, neurinoma, retinoblastoma, congenital tumor), intraspinal cord neurinomas, Meningoma, glioma, sarcoma)；Gynecological cancer: uterine cancer (carcinoma of endometrium), cervical carcinoma (neck cancer, preneoplastic palace Neck atypical hyperplasia (pre-tumor cervicaldysplasia)), oophoroma (oophoroma (serous cystoma gland cancer, mucus Property tumour gland cancer, non-classified cancer), granulosa egg capsule thecoma (granulosa-thecal cell tumors), Sai-Lay Cytoma, dysgerminoma, malignant teratoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, gland cancer, fibrosarcoma, melanocyte Tumor), carcinoma of vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), salpingioma (cancer)；Blood Liquid cancer: leukemia (myelocytic leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic Leukaemia, myeloproliferative disease, Huppert's disease, myelodysplastic syndrome), Hodgkin's disease, non-Huo Qijin lymph Tumor (malignant lymphoma)；Skin cancer: chromoma, basal-cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, depauperation Mole, lipoma, hemangioma, histiocytoma, cheloid, psoriasis；And adrenal gland cancer, neuroblastoma.Therefore, this The term " cancer cell " that place provides includes the cell with any or relevant illness determined above.

The compound of the present invention or its pharmaceutical composition can be individually alternatively, if desired, with other reactive compound knots It closes and uses.When with following be used together, it is believed that the compound with formula (I) benzimidazole is effective: alkylating agent, blood Pipe formation inhibitor, antibody, metabolic antagonist, antimitotic agent, antiproliferative, antivirotic, aurora kinase inhibitors, Its apoptosis promotor (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitor, the activator of death receptor pathway *, Bcr-Abl kinase inhibitor, BiTE (Bi specific T-cells connector (Engager)) antibody, antibody drug conjugate, biology Reaction modifier, the kinase inhibitor of cyclin dependent, cell cycle inhibitor, cyclooxygenase-2 inhibitor, DVDs, Leukemia viral oncogene homologue (ErbB2) acceptor inhibitor, growth factor receptor inhibitors, heat shock protein (HSP) -90 inhibit Agent, histone deacetylase (HDAC) inhibitor, hormonotherapy are immunized, the inhibitor (IAPs) of apoptosis albumen, It is inserted into antibiotic, kinase inhibitor drives protein inhibitor, and the warm-blooded animal of Jak2 inhibitor, rapamycin inhibitor targets, Microrna, mitogen-activation extracellular signal-regulated kinase inhibitor, multivalent binding proteins, the drug of non-steroidal anti-inflammatory disease (NSAIDs), poly- ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitor, platinum chemotherapy, polo-like kinase (Plk) Inhibitor, PI-3 kinase (PI3K) inhibitor, proteasome inhibitor, purine analogue, pyrimidine analogue, receptor junket ammonia Acid kinase inhibitor, gynergen alkaloid (etinoids)/trigone (deltoids) plant alkaloid, small inhibition Ribonucleic acid (siRNAs), topoisomerase inhibitors, ubiquitinbond enzyme inhibitor, etc. and one or more these medicaments group It closes.

In some embodiments, when administering drug combinations, there are two types of modes: 1) by compound of the present invention or medicine group Close object with can associated with other active medicines individual preparation is respectively prepared, two kinds of dosage forms can be identical or different, and when use can Successively to use, can also use simultaneously；Successively in use, the first drug does not lose it also in body when giving second of drug Interior useful effect；2) by the compounds of this invention or pharmaceutical composition and can associated with other active medicines single formulation is made, It is administered simultaneously.

Formula (I) benzimidazoles compound or its pharmaceutically acceptable salt of the present invention can combine with other therapeutic agents to Medicine, the other therapeutic agents include the therapeutic agent that other can be used for treating pulmonary hypertension (PHA).These therapeutic agents include blood Pipe vasodilator, such as Epoprostenol (Flolan^TM), Tadalafei (Adcirca^TM) or ambrisentan (Volibris^TM), etc..

" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection, Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents.

Specific embodiment

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from Shantou Western Gansu Province chemical plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao is risen Imperial chemical reagent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan is dried to obtain by sodium metal reflux.Anhydrous methylene chloride and chloroform are returned by calcium hydride Stream is dried to obtain.Ethyl acetate, n,N-dimethylacetamide and petroleum ether are used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃Or DMSO-d₆For solvent (report is as unit of ppm), use TMS (0ppm) or chloroform (7.25ppm) as reference standard. When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.

Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered For analyzing, the source ESI is applied to LC-MS spectrometer.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:

Table 1

Time (min)	A(CH₃CN, 0.1%HCOOH)	B(H₂O, 0.1%HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

The use of logogram word below is through the present invention:

Bis- diphenylphosphine -9,9- the xanthphos of XantPhos 4,5-

Cs₂CO₃Cesium carbonate

Pd2(dba)3,Pd₂(dba)₃Tris(dibenzylideneacetone) dipalladium

Pd(OAc)₂Palladium acetate

HCl hydrochloric acid

PE petroleum ether

EA, EtOAc ethyl acetate

DCM methylene chloride

DCE 1,2- dichloroethanes

CDCl₃Deuterated chloroform

CH₃OH, MeOH methanol

CH₃CH₂OH, EtOH ethyl alcohol

DMSO dimethyl sulfoxide

THF tetrahydrofuran

TEA triethylamine

DMF N,N-dimethylformamide

NMP N-Methyl pyrrolidone

DMF-DMA N,N-dimethylformamide dimethylacetal MTBE methyl tertiary butyl ether(MTBE)

DPPA diphenyl phosphate azide

CBZ, Cbz benzyloxycarbonyl group

TFAA trifluoroacetic anhydride

Bis- (the 2- diphenylphosphine phenyl) ethers of DPEphos

DIPEA diisopropylethylamine, n,N-diisopropylethylamine

The t-BuOH tert-butyl alcohol

BnOH benzylalcohol

BH₃The tetrahydrofuran solution of THF solution borine

K₂CO₃Potassium carbonate

Na₂SO₄Sodium sulphate

NaN₃Sodium azide

KNO₃Potassium nitrate

NaOH sodium hydroxide

TsCl benzene sulfonyl chloride

H₂O water

Et₂O ether

CH₃CN acetonitrile

NBS N- bromo-succinimide

Yb(OTf)₃Ytterbiumtriflate

TFAA trifluoroacetic anhydride

MsCl mesyl chloride

Pd/C palladium/carbon

N₂Nitrogen

L liter

ML milliliters

UM, μM micromole/L

L microlitres of uL, μ

G grams

Mg milligrams

Mmol mMs

Mol moles

M mol/L

DEG C degree Celsius

H hours

Min, minute

Equiv. equivalent

TLC thin-layer chromatography

V/V, v/v volume ratio

Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, R^1C、R²、R^2a、 R⁴、M¹、M²、M³、M⁴、M⁵, L have as described in the present invention definition.

The present invention also provides the preparation method of compound shown in formula (I) benzimidazole, following synthetic schemes is described The step of preparing disclosed compound of present invention.Unless otherwise stated, R^N、R^CWith definition as described in the present invention.

Synthetic schemes:

Formula (I) compound represented can be prepared by general synthetic method described in synthetic schemes, specific to walk Suddenly it can refer to embodiment, wherein Hal is halogen, preferably chlorine, bromine.Formula (I-A) compound represented and chemical combination shown in formula (I-B) The salt of compound shown in object or formula (I-B) is in catalysis (catalyst system such as Pd₂(dba)₃/XantPhos/CsCO₃, etc.) effect under, Coupling reaction occurs in solvent appropriate (such as Isosorbide-5-Nitrae-dioxane, n-butanol etc.) and obtains formula (I) compound.

Work as R^CFor hydrogen, R^NWhen selected from hydrogen, methyl or isopropyl, the synthesis of (I-B) compound the following steps are included:

1) adjacent diphenylamines obtains cyclization product (a) with reacting for bromination nitrile in the in the mixed solvent of methanol and water.

2) cyclization product (a) and iodo compound R^NI reacts under the conditions of existing for the potassium hydroxide using acetone as solvent, Obtain the substituted compound (I-B-N) on the position N.

3) compound (I-B-N) obtains target compound by coupling reaction with compound (I-A) again.

Work as R^NFor methyl, R^CWhen for 6 bit substituent, comprising the following steps:

1) compound (b-1) is reacted with methylamine water solution, obtains compound (b-2)；

2) compound (b-2) hydrogenating reduction under the catalysis of palladium carbon obtains compound (b-3)；

3) compound (b-3) obtains cyclization product (I-B- with reacting for bromination nitrile in the in the mixed solvent of methanol and water C₆)

Work as R^NFor methyl, R^CWhen for 7 bit substituent, comprising the following steps:

1) compound (c-1) reacts in tetrahydrofuran with iodomethane under the action of sodium hydrogen, obtains compound (c- 2)；

2) compound (c-2) hydrogenating reduction under the catalysis of palladium carbon obtains compound (c-3)；

3) compound (c-3) obtains cyclization product (I-B- with reacting for bromination nitrile in the in the mixed solvent of methanol and water C₇)

Benzimidazoles compound of the invention is described in further detail below in conjunction with specific embodiment.

Embodiment

Embodiment 1:2- ((2- ((1H- benzo [d] imidazoles -2- base) amino) -5- chloropyridine -4- base) amino)-N- methoxy Yl-benzamide

Step 1:1H- benzo [d] imidazoles -2- amine

2.0g (18mmol) o-phenylenediamine and 10mL methanol solution (VMeOH/VH2O=are added in 50mL single port pear shape bottle 1:1), it is stirred at room temperature, is slowly added to 3.0g (28mmol) bromination nitrile, connect condenser pipe (adding deflated balloon), move to 60 DEG C of oil baths and stir It mixes overnight, mixed liquor color is gradually deepened to brown.Oil bath is removed to be cooled to room temperature, TLC detects fully reacting, and methanol is removed in rotation, It with 1M NaOH solution tune pH=8, is extracted with EA (15mL*3), merges organic phase, anhydrous sodium sulfate is dry, concentrated by rotary evaporation, quickly Silica gel column chromatography (gradient elution polarity: PE:EA=50:1~EA:EtOH=1:1) obtains about 2.4g light yellow solid, yield 97%, Rf=0.3 (DCM/MeOH=10/1).LC-MS [M+H]=134.2.

Step 2:2- ((2- ((1H- benzo [d] imidazoles -2- base) amino) -5- chloropyridine -4- base) amino)-N- methoxyl group Benzamide

(200mg, 0.64mmol) compound 2- [(2,5- dichloropyridine -4- base) ammonia is added in the microwave tube of 20ml Base]-N- methoxy benzamide, 1H- benzo [d] imidazoles -2- amine (110mg, 0.83mmol), cesium carbonate (417mg, 1.28mmol), Isosorbide-5-Nitrae-dioxy six of XantPhos (93mg, 0.16mol), Pd2 (dba) 3 (117mg, 0.128mmol) and 10ml Ring under nitrogen protection, pumps the air in system using oil pump, is replaced into nitrogen, repeatedly for three times, by microwave channel closure, in 150 50min is reacted in DEG C microwave reactor.After TLC detects fully reacting, catalyst, ethyl acetate elution, rotation are filtered off with diatomite Dry solvent, Flash silica column chromatograph (gradient elution polarity: DCM:MeOH=100:1~40:1), collect yellow-brown solid 67mg, Yield 25.6%, Rf=0.3 (DCM/MeOH=5/1).1H NMR(600MHz,DMSO)δ11.97(s,1H),11.76(s, 1H), 10.36 (s, 1H), 9.73 (s, 1H), 8.18 (s, 1H), 7.70 (d, J=7.2Hz, 1H), 7.62 (dd, J=9.2, 7.2Hz, 1H), 7.45 (brs, 1H), 7.31 (brs, 1H), 7.20 (t, J=7.5Hz, 1H), 7.02 (brs, 1H), 3.72 (s, 3H) .HPLC purity: 96.34%.LC-MS [M+H]=409.1.

Embodiment 2:2- ((the chloro- 2- of 5- ((1- methyl-1 H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) amino) - N- methoxy benzamide

Step 1:1H- benzo [d] imidazoles -2- amine

Step 2:1- methyl-1 H- benzo [d] imidazoles -2- amine

In 50mL single port pear shape bottle, 0.55g (4.1mmol) 1H- benzo [d] imidazoles -2- amine is dissolved in 15mL acetone, is added Enter 0.46g (8.2mmol) potassium hydroxide powder, room temperature stirs 10min, moves to ice-water bath, and 0.28mL iodomethane is added dropwise (4.5mmol), stirs 10min, and TLC detects fully reacting.Room temperature is moved to, 15mLH2O is added, solvent is removed in rotation, with EA (10mL* 3) it extracts, merges organic phase, concentration, Flash silica column chromatographs (eluant, eluent: PE:EA=PE~50:1), must fluorescence brown Thick liquid 550mg, yield 90%, Rf=0.25 (DCM/MeOH=5/1).LC-MS [M+H]=148.1.

Step 3:2- ((the chloro- 2- of 5- ((1- methyl-1 H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) amino)-N- Methoxy benzamide

200mg (0.64mmol) compound 2- [(2,5- dichloropyridine -4- base) amino]-is added in the microwave tube of 20ml N- methoxy benzamide, 141mg (0.95mmol) 1- methyl-1 H- benzo [d] imidazoles -2- amine, 417mg (1.28mmol) carbon Sour caesium, Isosorbide-5-Nitrae-dioxane of 93mg (0.16mol) XantPhos, 117mg (0.128mmol) Pd2 (dba) 3 and 10ml, nitrogen Under protection, the air in system is pumped using oil pump, is replaced into nitrogen, repeatedly for three times, by microwave channel closure, in 150 DEG C of microwaves 50min is reacted in reactor.After TLC detects fully reacting, catalyst is filtered off with diatomite, ethyl acetate elution is spin-dried for solvent, Flash silica column chromatographs (gradient elution polarity: PE:EA=100:1~EA) and collects crude product.Sample is dissolved with methylene chloride 2mL Off-white powder, filtering is precipitated in product, and methylene chloride rinses, and obtains net product 95.4mg, yield 35.2%, Rf=0.3 (EA), LC-MS [M+H]=425.2.1H-NMR (400MHz, d4-MeOH) δ 8.13 (s, 1H), 7.76 (d, J=8.2Hz, 1H), 7.60 (dd, J=16.0,8.0Hz, 2H), 7.44-7.34 (m, 2H), 7.31 (d, J=6.8Hz, 1H), 7.19 (p, J=7.2Hz, 3H),3.82(s,3H),3.67(s,3H).HPLC purity: 92.10%.

Embodiment 3:2- ((the chloro- 2- of 5- ((6- methoxyl group -1- methyl-1 H- benzo [d] imidazoles -2- base) amino) pyridine -4- Base) amino)-N- methoxy benzamide

Step 1:5- methoxy-. N-methyl -2- nitroaniline

In 50mL single port pear shape bottle, 40% methylamine water solution (6.0g, 75.96mmol) is slowly added to dropwise under ice bath The fluoro- 4- methoxy nitrobenzene (1g, 5.84mmol) of 2-, K2CO3 (1.62g, 11.69mmol) 6mL DCM solution in, room temperature is stirred It mixes overnight.After TLC detects fully reacting, 10mL water is added, extracts (10mL*3) with DCM, merges organic phase, be concentrated to get bright orange Color solid 1.1g, directly casts single step reaction.Rf=0.27 (PE/EA=10/1), LC-MS [M+H]=183.2.

Step 2:5- methoxyl group-N1- methylbenzene -1,2- diamines

In 50mL single port pear shape bottle, by 5- methoxy-. N-methyl -2- nitroaniline (600mg, 3.29mmol) and 10% Pd/C (105mg, 0.099mmol) is dissolved in 15mL ethyl alcohol, and under hydrogen protection, oil well pump, the air in discharge system uses hydrogen Gas is replaced three times, and hydrogenation ball is stirred overnight at room temperature.TLC detects fully reacting, diatomite filtration catalytic agent, ethyl acetate punching It washes, is spin-dried for solvent, obtain brownish black thick liquid, it is not post-treated directly to cast single step reaction.Rf=0.14 (PE/EA=10/ 1).LC-MS [M+H]=153.3.

Step 3:6- methoxyl group -1- methyl-1 H- benzo [d] imidazoles -2- amine

In 50mL single port eggplant type bottle, by 5- methoxyl group-N1- methylbenzene -1,2- diamines (500mg, 3.28mmol), bromination Cyanogen (521mg, 4.93mmol) is separately added into 10mL methanol aqueous solution (v/v=1:1), in 60 DEG C of stirring 4h.TLC detection reaction Completely, methanol is removed in rotation, with 1M NaOH solution tune pH=8, is extracted with EA (10mL*3).Merging organic phase, concentrated by rotary evaporation, quickly Silica gel column chromatography (gradient elution polarity: DCM:MeOH=100:1~10:1) obtains about 484mg brown solid, yield 83.2%. Rf=0.21 (DCM/MeOH=10/1).LC-MS [M+H]=178.3.1H-NMR (400MHz, CDCl3) δ 7.29 (d, J= 8.6Hz, 1H), 6.74 (dd, J=8.6,2.2Hz, 1H), 6.63 (d, J=2.2Hz, 1H), 3.84 (s, 3H), 3.50 (s, 3H).

Step 4:2- ((the chloro- 2- of 5- ((6- methoxyl group -1- methyl-1 H- benzo [d] imidazoles -2- base) amino) pyridine -4- Base) amino)-N- methoxy benzamide

Compound 2- [(2,5- dichloropyridine -4- base) amino]-N- methoxybenzoyl is added in the microwave tube of 20ml Amine (274mg, 0.88mmol), 6- methoxyl group -1- methyl-1 H- benzo [d] imidazoles -2- amine (120mg, 0.68mmol), cesium carbonate (440mg, 1.35mmol), XantPhos (100mg, 0.17mol), the 1 of Pd2 (dba) 3 (125mg, 0.14mmol) and 10ml, 4- dioxane under nitrogen protection, pumps the air in system using oil pump, is replaced into nitrogen, repeatedly for three times, microwave tube is sealed Mouthful, 50min is reacted in 150 DEG C of microwave reactors.After TLC detects fully reacting, catalyst, ethyl acetate are filtered off with diatomite Elution is spin-dried for solvent, and Flash silica column chromatographs (gradient elution polarity: DCM:MeOH=100:0~50:1), obtains crude product Huang Color powder.With methylene chloride 5mL sample dissolution, crystallization under low temperature filters, is washed with a small amount of DCM, obtain yellow powder 72.5mg, yield 23.6%, Rf=0.25 (DCM/MeOH=10/1).1H-NMR(400MHz,DMSO)δ12.01(s,1H), 9.75 (s, 1H), 9.64 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 7.62 (d, J=6.9Hz, 2H), 7.24 (d, J=8.5Hz, 1H), 7.16 (t, J=7.3Hz, 1H), 6.97 (s, 1H), 6.70 (s, 1H), 4.10 (q, J= 5.2Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.66 (s, 2H), 3.17 (d, J=5.2Hz, 3H)

HPLC purity is 98.73%.LC-MS [M+H]=453.1.

Embodiment 4:2- ((the chloro- 2- of 5- ((fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- base of 6-) amino) pyridin-4-yl) Amino)-N- methoxy benzamide

The fluoro- N- methyl -2- nitroaniline of step 1:5-

In 50mL single port pear shape bottle, 40% methylamine water solution (3.0g, 39mmol) is slowly added to 2 dropwise under ice bath, In 4- difluoro nitrobenzene (2g, 12.6mmol), there are a large amount of yellow solids, continues to stir 1.5h.TLC detects fully reacting, adds Enter 40mL water, yellow solid is precipitated, filter, with 10mL water washing solid, collects solid, be spin-dried for solvent, it is direct to obtain crude product It throws in next step.Rf=0.45 (PE/EA=10/1).

The fluoro- N1- methylbenzene -1,2- diamines of step 2:5-

In 50mL single port pear shape bottle, by the fluoro- N- methyl -2- nitroaniline (2.1g, 12mmol) of 5- and 10%Pd/C (390mg, 0.37mmol) is dissolved in ethyl alcohol (50mL), and under hydrogen protection, oil well pump, the air in discharge system uses hydrogen Three times, hydrogenation ball is stirred overnight at room temperature for displacement.TLC detects fully reacting, diatomite filtration catalytic agent, ethyl acetate punching It washes, is spin-dried for solvent, obtain brownish black thick liquid 1.82g, it is not post-treated directly to cast single step reaction.Rf=0.12 (PE/EA =10/1).

Fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- amine of step 3:6-

In 50mL single port eggplant type bottle, by fluoro- N1- methylbenzene -1, the 2- diamines (500mg, 3.57mmol) of 5-, cyanogen bromide (566mg, 5.35mmol) is separately added into 10mL methanol aqueous solution (v/v=1:1), is stirred overnight in 60 DEG C.TLC detection, instead It should be complete.Methanol is removed in rotation, with 1M NaOH solution tune pH=8, is extracted with EA (10mL*3).Merging organic phase, concentrated by rotary evaporation, fastly Fast silica gel column chromatography (gradient elution polarity: DCM:MeOH=100:1~10:1) obtains about 446.4mg brown solid, yield 75.8%.Rf=0.4 (DCM/MeOH=10/1).LC-MS [M+H]=166.1.1H-NMR(400MHz,CDCl3)δ7.33 (dd, J=8.6,4.7Hz, 1H), 6.86 (m, 2H), 4.64 (s, 2H), 3.55 (s, 3H).

Step 4:2- ((the chloro- 2- of 5- ((fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- base of 6-) amino) pyridin-4-yl) ammonia Base)-N- methoxy benzamide

Compound 2- [(2,5- dichloropyridine -4- base) amino]-N- methoxybenzoyl is added in the microwave tube of 20ml Amine (300mg, 0.84mmol), fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- amine (120mg, 0.73mmol) of 6-, cesium carbonate (470mg, 1.45mmol), XantPhos (105mg, 0.18mol), the 1 of Pd2 (dba) 3 (133mg, 0.15mmol) and 10ml, 4- dioxane under nitrogen protection, pumps the air in system using oil pump, is replaced into nitrogen, repeatedly for three times, microwave tube is sealed Mouthful, 50min is reacted in 150 DEG C of microwave reactors.After TLC detects fully reacting, catalyst, ethyl acetate are filtered off with diatomite Elution is spin-dried for solvent, and Flash silica column chromatographs (gradient elution polarity: DCM:MeOH=100:0~50:1), obtains crude product Huang Color powder.With methylene chloride 5mL sample dissolution, off-white powder, filtering is precipitated, 10mL methylene chloride rinses, and obtains net product 173.3mg, yield 54.1%, Rf=0.45 (DCM/MeOH=10/1).1H-NMR(400MHz,DMSO)δ12.04(s,1H), 9.79 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.66 (d, J=7.6Hz, 2H), 7.41-7.26 (m, 2H), 7.21 (t, J =7.4Hz, 1H), 6.95 (t, J=8.4Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H) .HPLC purity are 96.22%.LC-MS [M+H]=441.2.

Embodiment 5:2- ((the chloro- 2- of 5- ((fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- base of 7-) amino) pyridin-4-yl) Amino)-N- methoxy benzamide

The fluoro- N- methyl -6- nitroaniline of step 1:2-

Under ice bath, in 50mL single port pear shape bottle, the fluoro- 6- nitroaniline of 2- is added in NaH (140mg, 3.52mmol) In the 10mL THF solution of (500mg, 3.20mmol), 10min is stirred, is slowly added to iodomethane (0.2mL, 3.20mmol) dropwise 1.0mL THF solution, stir 30min.Room temperature is moved to, is stirred at room temperature.TLC detects raw material fully reacting, and 10mLH2O is added and quenches It goes out reaction, extracts (8mL*3) with EA, merge organic phase, concentration, silica gel column chromatography (elution polarity: PE:EA=100:1) obtains Rufous liquid 512.8mg, yield 94.1%, Rf=0.9 (PE/EA=10/1).1H-NMR(400MHz,CDCl3)δ7.96 (d, J=8.7Hz, 1H), 7.85 (s, 1H), 7.20 (dd, J=13.8,7.8Hz, 1H), 6.57 (td, J=8.3,4.6Hz, 1H), 3.27 (dd, J=7.4,5.6Hz, 3H) .LC-MS [M+H]=171.1.

The fluoro- N1- methylbenzene -1,2- diamines of step 2:6-

In 50mL single port pear shape bottle, by the fluoro- N- methyl -6- nitroaniline (500mg, 2.94mmol) of 2- and 10%Pd/C (93mg, 0.088mmol) is dissolved in ethyl alcohol (10mL), and under hydrogen protection, oil well pump, the air in discharge system uses hydrogen Three times, hydrogenation ball stirs 2h at room temperature for displacement.TLC detection fully reacting, diatomite filtration catalytic agent, ethyl acetate rinse, It is spin-dried for solvent, obtains brown liquid 372mg, yield 90.4% is not post-treated directly to cast single step reaction.Rf=0.2 (PE/ EA=10/1).LC-MS [M+H]=141.25.

Fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- amine of step 3:7-

In 50mL single port eggplant type bottle, by fluoro- N1- methylbenzene -1, the 2- diamines (370mg, 2.64mmol) of 6-, cyanogen bromide (420mg, 3.96mmol) is separately added into 10mL methanol aqueous solution (v/v=1:1), is stirred overnight in 60 DEG C.TLC detection, instead It should be complete.Methanol is removed in rotation, with 1M NaOH solution tune pH=8, is extracted with EA (10mL*3).Merging organic phase, concentrated by rotary evaporation, fastly Fast silica gel column chromatography (gradient elution polarity: DCM:MeOH=100:1~20:1) obtains 368mg white solid, yield 84.4%. Rf=0.3 (DCM/MeOH=10/1).LC-MS [M+H]=166.1.1H-NMR (400MHz, CDCl3) δ 7.17 (d, J= 7.9Hz, 1H), 7.00 (td, J=8.0,5.2Hz, 1H), 6.76 (dd, J=11.6,8.2Hz, 1H), 4.99 (s, 2H), 3.74 (s,3H).

Step 4:2- ((the chloro- 2- of 5- ((fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- base of 7-) amino) pyridin-4-yl) ammonia Base)-N- methoxy benzamide

Compound 2- [(2,5- dichloropyridine -4- base) amino]-N- methoxybenzoyl is added in the microwave tube of 20ml Amine (294mg, 0.94mmol), fluoro- 1- methyl-1 H- benzo [d] imidazoles -2- amine (120mg, 0.73mmol) of 7-, cesium carbonate (470mg, 1.45mmol), XantPhos (105mg, 0.18mol), the 1 of Pd2 (dba) 3 (133mg, 0.15mmol) and 10ml, 4- dioxane under nitrogen protection, pumps the air in system using oil pump, is replaced into nitrogen, repeatedly for three times, microwave tube is sealed Mouthful, 50min is reacted in 150 DEG C of microwave reactors.After TLC detects fully reacting, catalyst, ethyl acetate are filtered off with diatomite Elution is spin-dried for solvent, and Flash silica column chromatographs (gradient elution polarity: DCM:MeOH=100:0~50:1), obtains crude product Huang Color powder.With methylene chloride 5mL sample dissolution, yellow solid, filtering is precipitated, 10mL methylene chloride rinses, and obtains net product 142mg, yield 44.3%, Rf=0.3 (DCM/MeOH=20/1).1H-NMR(400MHz,DMSO)δ12.00(s,1H),9.83 (d, J=19.9Hz, 2H), 8.39 (s, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.63 (d, J=7.8Hz, 2H), 7.18 (dd, J=11.6,7.7Hz, 2H), 7.11-6.97 (m, 1H), 6.98-6.84 (m, 1H), 3.84 (s, 3H), 3.71 (s, 3H). HPLC purity is 95.66%.LC-MS [M+H]=441.2.

Embodiment 6:2- ((the chloro- 2- of 5- ((1- isopropyl 1H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) ammonia Base)-N- methoxy benzamide

Step 1:1- isopropyl -1H- benzo [d] imidazoles -2- amine

In 50mL single port eggplant type bottle, by 0.55g (4.1mmol) 1H- benzo [d] imidazoles -2- amine

It is dissolved in 15mL acetone, 0.70g (12mmol) potassium hydroxide powder and 1.1g (8.2mmol) potassium carbonate, room temperature is added 10min is stirred, ice-water bath is moved to, 0.45mL (4.5mmol) 2- iodopropane is added dropwise, moves to 65 DEG C of oil bath stirring 3h.TLC detection EA dilute reaction solution is added in reaction, and suction filtration removes solid, and reaction solution rotation removes solvent, 10mL water is added, and with EA extraction, (8mL*3 is closed And organic phase, Na2SO4 is dry, and concentration, Flash silica column chromatographs (gradient elution DCM:MeOH=100:1~30:1), obtains 275mg light yellow solid, yield 38%, Rf=0.25 (DCM/MeOH=5/1).1H-NMR(400MHz,CDCl3)δ7.40(d, J=7.8Hz, 1H), 7.27 (d, J=7.4Hz, 1H), 7.11 (t, J=7.3Hz, 1H), 7.04 (t, J=7.6Hz, 1H), 4.45 (dt, J=13.9,6.9Hz, 1H), 1.59 (d, J=6.9Hz, 7H), 1.29-1.17 (m, 7H).LC-MS [M+H]=176.1.

Step 2:2- ((the chloro- 2- of 5- ((1- isopropyl 1H- benzo [d] imidazoles -2- base) amino) pyridin-4-yl) amino) - N- methoxy benzamide

200mg (0.64mmol) compound 2- [(2,5- dichloropyridine -4- base) amino]-is added in the microwave tube of 20ml N- methoxy benzamide, 168mg (0.96mmol) 1- isopropyl -1H- benzo [d] imidazoles -2- amine, 417mg (1.28mmol) Cesium carbonate, Isosorbide-5-Nitrae-dioxane of 93mg (0.16mol) XantPhos, 117mg (0.128mmol) Pd2 (dba) 3 and 10ml, nitrogen Under gas shielded, the air in system is pumped using oil pump, is replaced into nitrogen, it is repeatedly for three times, micro- in 150 DEG C by microwave channel closure 50min is reacted in wave reactor.After TLC detects fully reacting, catalyst is filtered off with diatomite, ethyl acetate elution is spin-dried for molten Agent, Flash silica column chromatograph (gradient elution polarity: PE:EA=100:1~EA) and collect crude product 109mg, yield 37.7%, Rf =0.4 (EA).It is recrystallized with DCM/PE, obtains 22mg buff powder, LC-MS [M+H]=451.1.1H-NMR(400MHz, CDCl3) δ 9.09 (s, 1H), 8.08 (s, 1H), 7.66 (d, J=7.2Hz, 1H), 7.45-7.50 (m, 2H), 7.26 (s, 2H), 7.00-7.10 (m, 4H), 5.12 (brs, 1H), 3.80 (s, 3H), 1.56 (d, J=5.6Hz, 6H).HPLC purity: 96.15%.

The active biochemical test of FAK:

The external zymetology inhibitory activity of 1 the compounds of this invention of example

It tests the FAK used and purchases Invitrogen purchased from Carna (Cat.No 08-137), Fluorescein-Poly GT (Cat.No.PV3610).Experiment is using Lantha screen method measurement compound to the inhibitory activity of FAK.

Experimental method:

1,1 × kinase buffer liquid is prepared

Preparation (25mM HEPES, PH7.5,0.01mM Triton, the 10mM MgCl of 1 × kinase buffer liquid₂,0.5mM EGTA, 0.01%BRIJ-35,2mM DTT).

2, the compound of kinases test prepares: the serial dilution of compound

(1) using 100% DMSO by untested compound be diluted to highest test concentrations 100 times (test it is most highly concentrated Degree is 10uM, and the compound concentration prepared in this step is 1000uM)；(2) untested compound is transferred in a hole in 96 holes, And by the way that 20uL original solution is added in 60uL 100%DMSO 4 times of gradient dilutions of progress, 10 concentration in total；(3) it takes 100uL 100%DMSO is added separately in two emptying apertures of 96 orifice plate of same, is compareed as experiment without compound and without enzyme, This block plate is labeled as source plate；(4) intermediate plate for preparing 96 holes, takes each concentration compound of 4uL to be transferred to from source plate respectively Between plate, and the kinase buffer liquid of 96uL is added, concussion mixes 10 minutes；(5) preparing experiment plate: respectively from each concentration of intermediate plate 5uL is taken to be transferred in 384 hole experimental plates in hole, two secondary orifices of each concentration.

3, kinase reaction

(1) prepare 2 × kinase solution: preparing the FAK solution (FAK of 2 times of final test concentrations using 1 × kinase buffer liquid Final concentration of 0.4nM), it takes the kinase solution of 5uL to be transferred in each hole of correspondence of experimental plate, in no enzyme control wells, is added 5uL's Kinase buffer liquid shakes plate；(2) prepare 4 × substrate solution: 4 times of final test concentrations are prepared using 1 × kinase buffer liquid Fluorescein-PolyGT and ATP solution (Fluorescein-PolyGT final concentration of 0.2uM, ATP 6uM), takes 2.5uL Substrate solution be transferred in each hole of correspondence of experimental plate, start kinase reaction, shake plate；(3) it kinase reaction: is protected from light incubates at room temperature It educates 30 minutes.

4, kinase assay

Detection solution (the antibody final concentration of 2nM, EDTA of 2 times of final test concentrations are prepared using antibody dilution buffer Final concentration of 10mM), it takes the detection solution of 10uL to be transferred in each hole of correspondence of experimental plate, terminates kinase reaction, centrifugation mixes, It is incubated for 60 minutes, read plate machine testing fluorescence signal.

5. DATA REASONING

Collecting the exciting light on Envision is 340nM, the fluorescence data that transmitting light is 520nM and 495nM.

6. curve matching

(1) RFU data are copied from Envision program；(2) RFU 520nM/RFU 495nM ratio is calculated；(3) will compare Value is converted into percent inhibition: inhibiting rate %=(maximum value-sample value)/(maximum value-minimum value) × 100, wherein maximum value For DMSO control group, minimum value is no enzyme control group；(4) IC50 accounting equation are as follows:

Y=Bottom+ (Top-Bottom)/(1+ (IC₅₀/X)^HillSlope)

Specific IC₅₀Activity data is shown in Table 1.

The external zymetology inhibitory activity of the representation compound of the present invention of table 1

Embodiment	IC₅₀(nM)	Embodiment	IC₅₀(nM)
				Embodiment 1	18	Embodiment 2	2.5
Embodiment 3	1.7	Embodiment 4	1.4
				Embodiment 5	2.6	Embodiment 6	2.2

As shown in Table 1, (1) can tentatively obtain imidazole ring N (i.e. 1) from the external inhibitory activity data of embodiment 1,2,6 Upper introducing substituent group can obviously increase its external FAK zymetology inhibitory activity, and introduce the biggish group of steric hindrance with stronger suppression System activity；

(2) from the external inhibitory activity data of embodiment 2,4,5, can obtain on imidazole ring 6 introducing substituent groups have compared with Strong inhibitory activity；

(3) from the activity data of embodiment 2,3,4, it can show that 6 are replaced by short of electricity subbase group with stronger activity.

To sum up, it can obtain in the compound of the present invention, 1 bit substituent steric hindrance is big, and 6 bit substituent electron deficients are conducive to increase Add it to FAK zymetology inhibitory activity；Meanwhile direction also is provided to the effect research of subsequent structure.

To the inhibitory activity of cell under the conditions of 2 the compounds of this invention of example external 2D, 3D

Experimental method:

Cell experiment condition:

Cell Name	Cell (a)/hole	Brooding time (h)	Complete medium
				BXPC-3	3000	96	RPMI1640+10%FBS
NCI-H1975	4000	96	RPMI1640+10%FBS

1) glue is spread

A. complete medium is prepared, is mixed well.B. matrigel and corresponding cell culture medium are mixed in 1:1 ratio, 96 transparent orifice plate bottoms of bottom are paved with uniformly with the hole 40uL/ after mixing, being subsequently placed in 37 DEG C of incubators makes its solidification, to With.

2) plating cells

A. recovery cell passes or so two generations selection good cell strain of growth conditions.B. by Tissue Culture Dish from incubator The Cell Name marked on bottle, type of culture medium and cell algebra are checked in middle taking-up.C. culture medium is discarded, after PBS rinse, Trypsin digestion cell is added.D. complete medium is added and is transferred in centrifuge tube, 1000rpm is centrifuged 5 minutes.E. centrifugation is discarded Cell supernatant in pipe is added complete medium resuspension cell appropriate and (2D: is resuspended with complete medium；3D: with containing 2% The complete medium of matrigel is resuspended).F. it is counted using cell counter.G. cell suspension is adjusted to suitable concentration.H. will Cell suspension is added in 96 orifice plates (2D: 96 transparent orifice plates of bottom；3D: resulting 96 orifice plate of step 1), the hole 90uL/, label Cell Name, plants plate density, and culture plate is placed in CO by the details such as date₂In incubator overnight.

3) preparation and addition of compound

A. the preparation (dissolving untested compound with DMSO, configure the mother liquor of 10mM) of compound: the used time is with DMSO by chemical combination 3 times of object dilutions, obtain the compound of 9 concentration gradients, the compound after above-mentioned gradient dilution are carried out 20 with complete medium It dilutes again, and is uniformly mixed and obtains the drug working solution of 10 × concentration.B. the addition of compound: taking out tissue culture plate, will The drug working solution of the above-mentioned 10 × concentration in the hole 10uL/ is added in the corresponding aperture of tissue culture plate, is incubated in 37 DEG C of incubators It educates 96 hours.

4) it detects and analyzes

A. after compound is handled 96 hours, cellular morphology is observed under inverted microscope, the cell in DMSO control wells is raw Long status is normal, there are no contamination phenomenon.B. CCK-8 reagent is placed equilibrium at room temperature 30 minutes.C. after cell incubation, to The CCK-8 reagent in the hole 10uL/ is wherein added.D. tissue culture plate is placed in 37 DEG C of incubators and continues to be incubated for 2-4 hours.E. make Optical density (OD) value of each hole 450nm wavelength is read with microplate reader.F. resulting experimental result is recorded and analyzed: using GraphPad 5.0 software of Prism is analyzed and processed data, and the calculation formula of inhibitory rate of cell growth is as follows, IC₅₀It can be in GraphPad It is calculated automatically in Prism 5.0.

Growth inhibition ratio %=(OD_{Negative group}-OD_{Experimental group})/(OD_{Negative group}-OD_{Blank group}) * 100%

The cell in vitro inhibitory activity of the representation compound of the present invention of table 2

As shown in Table 2, the compound of the present invention is stronger to the growth inhibition effect of cell and of the invention under the conditions of 3D The growth inhibition effect of compound on intracellular will be substantially better than GSK2256098.

The pharmacodynamic activity of 3 the compounds of this invention of example

Experimental method:

1, testing compound solution is prepared

Untested compound is configured to solution with DMSO, KolliphorHS15, Saline by a certain percentage, for oral and Intravenous injection administration.

2, zoopery

140-190g male SD rat is taken, is randomly divided into two groups, one group of intravenous injection untested compound, dosage 1.0mg/ Kg, another group oral to give untested compound, dosage 5mg/kg；Temporally put 0.083 after intravenous injection administration, 0.25, 0.5,1,2,4,6,8 and 24 hour tail vein blood；It is temporally put after oral administration 0.25,0.5,1,2,4,6,8 and 24 hour Tail vein blood.The standard curve that OK range is established according to sample concentration, using AB SCIEX API4000 type LC-MS/MS, The concentration of untested compound in plasma sample is measured under MRM mode.According to pharmaceutical concentration-time curve, using WinNonLin The non-compartment model method of 6.3 softwares calculates pharmacokinetic parameters.

3, result

The pharmacodynamic activity of the representation compound of the present invention of table 3

Remarks: "/" expression does not calculate.

As shown in Table 3, the internal metabolism of the compounds of this invention is preferable, there is preferable absorb and higher exposed amount, life Object availability is higher.

Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, all should be considered as described in this specification.

The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims

1. benzimidazoles compound or its pharmaceutically acceptable salt, stereoisomer, interconversion with structure shown in formula (I) Isomers or mixture:

Wherein,

R^NSelected from methyl, isopropyl；

R^CSelected from hydrogen, methoxyl group, fluorine.

2. benzimidazoles compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers or mixture, which is characterized in that the benzimidazoles compound has structure shown in formula (II):

Wherein,

R^NSelected from methyl, isopropyl；

R^CSelected from hydrogen, fluorine.

3. benzimidazoles compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers or mixture, which is characterized in that the benzimidazoles compound has structure shown in formula (III):

Wherein,

R^NSelected from methyl；

R^CSelected from methoxyl group, fluorine.

4. benzimidazoles compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, interconversion Isomers or mixture, which is characterized in that the benzimidazoles compound one of has following structure:

5. a kind of drug, which is characterized in that the drug includes the described in any item benzimidazoles compounds of claim 1-4 Or its pharmaceutically acceptable salt, stereoisomer, tautomer or mixture, and pharmaceutically acceptable figuration Agent.

6. drug according to claim 5, which is characterized in that the active constituent of the drug also includes additional treatment Agent.

7. drug according to claim 6, which is characterized in that the additional therapeutic agent includes anticancer agent.

8. drug according to claim 6, which is characterized in that the additional therapeutic agent includes treatment pulmonary hypertension Medicine.

9. application of the described in any item compounds of claim 1-4 in the drug that preparation prevents and treats FAK related disease.

10. application according to claim 9, which is characterized in that the FAK related disease includes: cancer, pulmonary hypertension Or pathologic vessels generate.