CN104447730B - Oxazolidinone compounds and its application in medicine - Google Patents

Abstract

Application the present invention relates to Yi Lei oxazolidinone compounds and its in the medicine for preparing prevention and treatment thromboembolic disorders.Particularly, the present invention relates to logical formula (I)) shown in compound, wherein or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, each variable is defined as in the description.The invention further relates to lead to the salt of compound its stereoisomer shown in formula (I), geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug as the purposes of medicine, especially as the purposes of the medicine for preventing and treating thromboembolic disorders.

Description

Oxazolidinone compounds and its application in medicine

Technical field

The invention belongs to drug field, and in particular to a kind of Xin oxazolidinone compounds, pharmaceutical composition, and its make To prepare the purposes of medicine, purposes especially as the medicine for preparing factor Xa inhibitor and for treating thromboembolism The purposes of illness.

Background technology

The main practical function of the Xa factor of activation is to produce fibrin ferment by the limited proteolysis to fibrin ferment, Xa factor is in occupation of center in the final general path of blood clotting, and it in connection with inherent and external activation equipment System.Fibrin ferment is the final serine protease in the path for produce fibrin clot.Answered by forming factor Compound (Xa factor, factor Ⅴ, Ca²⁺And phosphatide) amplify generation of the fibrin ferment by its precursor.One Xa factor molecule can be produced Raw 138 prothrombin molecules (Elodi, a., Varadi, K.:Optimization of conditions for the catalytic effect of the factor IXa–factor VIII complex:Probable role of the complex in the amplification of blood coagulation.Thromb.Res.1979,15,617- 629), so suppression Xa factor may be than making thrombin inactivation more effective in the interference in blood coagulation system.

Accordingly, it would be desirable to effectively be used as potential valuable therapeutic agent with special Xa factor inhibitor to treat thrombus Embolism illness.The present invention relates to new Xa factor inhibitor；Preferably there are improved pharmacological characteristics；More preferably have more High Xa factor inhibitory activity and more preferable selectivity；And/or the characteristic for preferably having the advantage that and improving, but do not limit In, pharmacy characteristic (such as solubility, permeability and the adaptability to Sustained-release formulations), volume requirements (such as relatively low dosage and/ Or dosage once a day), reduction characterized with peak valley haemoconcentration factor (such as clearance rate and/or volume of distribution), increase The factor (such as protein binding, volume of distribution) of active agent concentration, the factor of the tendency of reduction clinical medicine interphase interaction are (such as Cytochrome P 450 enzymes suppress or induce), reduction adverse side effect possibility the factor (medicine outside such as serine protease Selectivity of science, possible chemistry or metabolic response and limited CNS permeability) and improvement production cost or feasible Property factor (as synthesis difficulty, the number of chiral centre, chemical stability and the simplicity of operation).

The content of the invention

The present invention provides Yi Zhong oxazolidinone compounds, or its pharmaceutical composition, can effectively treat and inhibiting factor Thrombotic disease related Xa.

On the one hand, the present invention relates to Yi Zhong oxazolidinone compounds, change with the compound as shown in formula (I), or formula (I) The stereoisomer of compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy Upper acceptable salt or prodrug,

Wherein, Q is O or-CH₂-；

R is following minor structure：

Condition be Q be O when, R is not

Wherein each X¹It independently is-CH₂- or-C (=O)-；

Each Y independently is-CH₂- ,-O- or-NR⁴-, wherein R⁴For hydrogen, methyl or ethyl；

Each m independently is 0 or 1；

X is hydrogen, fluorine, chlorine, bromine or iodine；

R²For C_1-3Alkyl or C_1-3Alkoxy；

R³For hydrogen, C_1-3Alkyl or C_1-3Alkoxy；

Each n₁And n₂It independently is 1,2 or 3；With

N is 0,1,2 or 3.

In some embodiments,

R²For methyl, methoxyl group, ethyoxyl or positive propoxy；With

R³For hydrogen, methyl, methoxyl group, ethyoxyl or positive propoxy.

The present invention relates to the compound of one of or its stereoisomer, geometric isomer, dynamic isomer, Nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

On the one hand, present invention also offers a kind of pharmaceutical composition containing compound of the present invention, the drug regimen Thing contains compound of the present invention, and its pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or Combinations thereof.

On the other hand, preparing, preventing, handling or controlling the present invention relates to described compound or described pharmaceutical composition Treat the purposes in the medicine of thrombotic disease.

In certain embodiments, purposes of the present invention, wherein the thrombotic disease is miocardial infarction, heart strand Bitterly, block again and revascularization or aortocoronary bypass after ISR, apoplexy, of short duration ischaemic hair Work, peripheral arterial occlusive disease, pulmonary embolism or Deep vain thrombosis.

In certain embodiments, purposes of the present invention is that described compound or described pharmaceutical composition are used to make The purposes of the medicine of standby treatment disseminated intravascular coagulation (DIC).

In further embodiments, purposes of the present invention is that the compound or described pharmaceutical composition are used to make The purposes of standby inhibiting factor Xa medicine.

Another aspect of the present invention is related to the method for the preparation, separation and purifying for the compound that (I) is included.

Application of the present invention comprising the compounds of this invention and its pharmaceutically acceptable salt, for producing medical product treatment Patient's thrombotic disease, including those diseases described in the invention.The present invention includes pharmaceutical composition, the drug regimen Thing includes the compound and at least one pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium representated by formula (I) Effective therapeutic dose with reference to needed for of thing.The same disease for including effectively suppression osteoporosis of the invention, or it is quick to this illness The method of sense, this method is included is treated using the therapeutically effective amount of compound representated by formula (I) to patient.

Unless otherwise indicated, all stereoisomers of the compound of the present invention, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the model of the present invention Enclose.

Specifically, salt is pharmaceutically acceptable salt.Term is " pharmaceutically acceptable " must including material or composition Must be adapted to chemistry or toxicology, with constituting the other components of preparation and relevant for the mammal for the treatment of.

The salt of the compound of the present invention also includes being used to preparing or purifying the intermediate of compound shown in formula (I) or formula (I) The salt of the enantiomter of shown compound separation, but it is not necessarily pharmaceutically acceptable salt.

If the compound of the present invention is alkaline, conceivable salt can be any suitable by what is provided on document 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, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, Lactic acid citric acid, Oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or combinations thereof.

If the compound of the present invention is acid, conceivable salt can be prepared by suitable method, e.g., Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N⁺(R¹⁴)₄Salt and alkaline earth gold Belong to hydroxide, etc..Suitable salt is included, but is not limited to, the organic salt obtained from amino acid, such as glycine and smart ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N⁺(R¹⁴)₄Salt, such as R¹⁴It is H, C_1-4Alkyl, C_6-10Aryl, C_6-10Aryl C_1-4Alkyl Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium. Also the amine cation of appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions formation, such as halide, hydroxide, carboxylation are included Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of the document combined, patent and similar material Or many it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.

It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As for example also referring to primate (such as the mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and for being somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkane Base can be replaced with individually optional by one or more substituents described in the invention.Some of embodiments are, alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom, other Embodiment is that alkyl group contains 1-3 carbon atom.Alkyl group further example is included, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n-Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), 2- methyl-propyls or isobutyl group (i-Bu ,-CH₂CH(CH₃)₂), 1- methyl-propyls or sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), the tert-butyl group (t-Bu ,-C (CH₃)₃) etc..

Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom； In another embodiment, alkoxy base contains 1-3 carbon atom.The example of alkoxy base is included, but is not limited to, methoxy Base (MeO ,-OCH₃), ethyoxyl (EtO ,-OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), the oxygen of 2- third Base (i-PrO, i- propoxyl group ,-OCH (CH₃)₂) etc..

Term " halogen " or " halogen atom " refer to F, Cl, Br or I.

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

Term " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or is that precursor structure is influenceed through enzymatic conversion in blood or tissue in blood by pro-drug.This hair Bright pro-drug compounds can be ester, in existing invention ester can as pro-drug the phenyl ester class that has, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.One for example in the present invention Compound includes hydroxyl, you can be acylated the compound for obtaining prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.On pro-drug begging for completely By may be referred to documents below：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

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.

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopt and experimentally characterized as stating.Such product can be by, by aoxidizing, being reduced, water to drug compound Solution, amidated, desamido- effect is esterified, degreasing, and enzymatic lysis etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention is fully contacted to the metabolite produced by a period of time with mammal.

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：S.P.Parker,Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley＆Sons, Inc., New York, the compound of 1994. present invention can include asymmetric center or chiral centre, therefore There are different stereoisomers.All stereoisomeric forms in any ratio of compound of the invention, including but not limited to, diastereomeric Body, enantiomter, atropisomer, and their mixture, such as racemic mixture constitute the part of the present invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use To name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, and prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.50：50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may cause do not have stereoselectivity in chemical reaction process or three-dimensional fixed Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.

" stereoisomer " refers to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

Term " dynamic isomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Mutual inversion of phases is built by low energy.Such as proton tautomer (i.e. prototropic dynamic isomer) includes migrating by proton Change, the isomerization of such as keto-enol and imine-enamine.Valence (chemical valence) dynamic isomer includes Recombinate the change of bonding electrons.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, malate, 2- Hydracrylate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, first Hydrochlorate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydrogen Iodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate, the third two Hydrochlorate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfuric acid Salt, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, 11 Hydrochlorate, valerate, etc..The salt obtained by appropriate alkali includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt. The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any included N group is formed.Water-soluble or oil-soluble is scattered Product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically may be used The amine cation of the salt of receiving further comprises appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions formation, such as halide, Hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention are formed Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

When term " blocking group " or " Pg " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected to block with amino group Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description of group typically refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005。

In addition, compound disclosed by the invention including their salt, with their hydrate forms or can also include it The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) inherently or by design forms solvate；Therefore, it is contemplated that including solvation And unsolvated form.

Any structural formula that the present invention is provided is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the formula that there is the compound of isotope enrichment the present invention to provide is described, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there is radio isotope, such as³H,¹⁴C and¹⁸F those compounds, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research (to use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or available in the radiotherapy of patient.¹⁸The compound of F enrichments to PET or It is especially desirable for SPECT researchs.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art Embodiment and preparation process in the routine techniques or the present invention known is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.

In addition, higher isotope particularly deuterium is (i.e.,²H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increase or volume requirements reduction or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is seen as the substituent of formula (I) compound.It can be determined with isotope enrichment factor The concentration of such adopted higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to specified same Ratio between the isotope abundance and natural abundance of position element.If the substituent of the compounds of this invention is designated as deuterium, the change Compound has at least 3500 (52.5% deuterium incorporations at each specified D-atom), at least 4000 for each D-atom specified (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution₂O, acetone-d₆、 DMSO-d₆Those solvates.

The compounds of this invention and pharmaceutical composition, preparation and purposes

Include the compound shown in formula (I) according on the other hand, the characteristics of pharmaceutical composition of the invention, the present invention is listed The compound gone out, or embodiment 1-7 compound, and pharmaceutically acceptable carrier, assistant agent, or excipient.The group of the present invention The amount of compound can effectively treat or mitigate patient's thrombotic disease or as Xa factor inhibitor in compound.

There is free form in the compound of the present invention, or suitably, be used as pharmaceutically acceptable derivates.According to this hair Bright, pharmaceutically acceptable derivates are included, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, or energy Directly or indirectly according to other any adducts or derivative being administered the need for patient, described by other aspects of the present invention Compound, its metabolite or his residue.

As described in the invention, pharmaceutically acceptable composition of the invention is further carried comprising pharmaceutically acceptable Body, assistant agent, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described by documents below：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, show different Carrier can be applied to the preparation and their known preparation methods of pharmaceutically acceptable composition.Except any conventional carrier The incompatible scope of compound of medium and the present invention, such as produced any bad biological effect or with can pharmaceutically connect The interaction that any other component for the composition received is produced in harmful manner, their purposes is also that the present invention is considered Scope.

It can be included, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminium, aluminum stearate, ovum Phosphatide, such as haemocyanin, human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturation vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization Body, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose and its derivative Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Thing, such as propane diols and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colouring agent, releasing agent, coating agents, sweetener, flavor enhancement and perfume (or spice) Material, preservative and antioxidant.

The compounds of this invention can be administered in the form of oral agents, such as tablet, and (each all includes holding capsule Continuous release or the formula of time controlled released), pill, pulvis, granula, elixir, tincture, suspending agent, syrup, and emulsifying agent.It Can also be with intravenous (bolus or transfusion), intraperitoneal, subcutaneous or intramuscular form is applied, all agent used Amount form is all known to the those of ordinary skill of pharmaceutical field.They can be administered alone, but typically will be based on selected Method of application and the pharmacy practice of standard select a kind of pharmaceutical carriers to apply together.

The dosage regimen of the compounds of this invention will with known various factors different, the characteristics of pharmacokinetics of such as particular agent And its pattern and route of administration；The race of recipient, age, sex, health status, medical conditions and body weight；The property of symptom And degree；The species of parallel treatment；The frequency for the treatment of；The approach of dispenser, the kidney and liver function of patient, and wish the effect that reaches Really.One doctor or animal doctor can make decision and output the medicine of effective dose to prevent, offset or prevent thromboembolism Advancing of disease.

According to general guideline, in order to reach the effect specified, the day of each used active component is oral The scope of dosage be about 0.001 arrive 1000mg/kg body weight between, it is preferable that about 0.01 to 100mg/kg body weight it Between.Moreover, most preferably, between about 1.0 to 20mg/kg body weight/days.Applied for intravenous, in conventional rate Most preferred dosage range is about 1 to about 10mg/kg body weight/minute in infusion process.The compounds of this invention can be with every Day once applies, or can be administered with daily in two times for three times or four times.

The compound of the present invention can in intranasal form be applied by local use of suitable nasal carrier, or be passed through Applied using percutaneous drug paste with cutaneous routes.When being applied in the form of transdermal delivery system, applied during whole medication Dosage is continuous rather than interval.

Typically, the compound with the form according to administration and conventional pharmacy practice come the suitable drug dilution of selection Agent, excipient, or carrier (referring to pharmaceutical carriers herein), which are mixed, to be applied, and method of application can be oral tablet, capsule, the wine made of broomcorn millet Agent, syrup etc..

For example, for tablet or capsules per os administration, active medicine component can be with a kind of oral, non-poison Property, pharmaceutically acceptable inert carrier combine, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, Dicalcium Phosphate, calcium sulfate, mannitol, sorbierite etc.；For orally administering in liquid form, oral drug components can with appoint What oral, atoxic, pharmaceutically acceptable inert carrier combination, such as ethanol, glycerine, water etc..Moreover, when needs Or when required, suitable adhesive, lubricant, decomposing agents and colouring agent can also be added in mixture.It is suitable viscous Mixture includes starch, gelatin, natural sugar such as glucose or beta lactose, corn sweetener, natural and synthesis natural gum such as Ah Draw primary glue, tragacanth, or mosanom, carboxymethyl cellulose, polyethylene glycol, wax etc..Applied in these formulations Lubricant includes enuatrol, odium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc..Distintegrant includes, but not It is limited to, starch, methylcellulose, agar, bentonite, xanthans, etc..

The compounds of this invention can also be applied in the form of liposomal delivery system, such as the vesica of small individual layer, big list The vesica and multi-layer vesicles of layer.Liposome can be formed by different phosphatide, such as cholesterol, stearylamine, or phosphatidyl Choline.

The compounds of this invention is also coupled with soluble polymer, the polymer as targeting pharmaceutical carriers.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyl methacrylate amine-phenol, poly- hydroxyethyl asparagus fern Acid amides phenol, or the polyethylene oxide-polylysine replaced with palmitoyl residues.Moreover, the compounds of this invention can be with one Class Biodegradable polymeric is coupled, for completing controllable insoluble drug release, for example, PLA, polyglycolic acid, gather breast The copolymer of acid and polyglycolic acid, poly epsilon caprolactone lactone, poly butyric, poe, polyacetals, poly- dihydropyran, paracyanogen base Acrylate, and hydrogel crosslinking or amphipathic blocking copolymer.

, can be containing about 1mg to about 100mg's suitable for the per unit dosage of the formulation (pharmaceutical composition) of administration Active component.In these pharmaceutical compositions, the about 0.5- of the general gross weight that will account for composition of weight of active component 95%.

Gelatine capsule can contain active component and powder carrier, such as lactose, starch, cellulose derivative, stearic acid Magnesium, stearic acid, etc..Similar diluent can be used to make compressed tablets.Tablet and capsule can be manufactured as sustainable The product of release provides the medicine that continuously discharges within a period of time.The tablet of compression can be thin with sugaring clothing or bag last layer Film covers any offending taste and makes tablet and air exclusion, or plus enteric solubility coating in stomach Optionally decomposed in alimentary canal.

The liquid dosage form orally administered can improve the acceptance of patient containing colouring agent and flavoring.

Generally, water, a kind of suitable oil, salt solution, the dextrose (glucose) of hydration, and related sugar juice and glycol (such as propane diols or polyethylene glycol) is the suitable supporting agent of parenteral solution.The solution applied without enteron aisle preferably comprises work Property composition water soluble salt, suitable stabilizer, and may necessary buffer substances.Antioxidant is suitable stable Agent, such as sodium hydrogensulfite, sodium sulfite, or vitamin C, can also individually can both be applied in combination can also with citric acid and Its salt and EDETATE SODIUM salt.In addition, parenteral solution also contains preservative, such as geramine, methyl-or propyl group-to hydroxyl Yl benzoic acid ester, and chlorobutanol.

Wherein compound of the invention and other anti-freezing agent combinations, for example, for every kg patient body weight, Yi Zhong Dosage can be that 7.5mg the second anti-coagulants is arrived in the compound of about 0.1 to 100mg formula (I) and about 1.For a kind of piece Agent formulation, compound of the invention typically can be that each dosage unit has about 5 to arrive 10mg, and the amount of the second anti-agglutinant It is that each dosage unit has about from 1 to 5mg.Wherein, other anti-freezing reagents are specifically included, but are not limited to, Eliquis, profit Cut down husky class, Yi Dushaban, shellfish Qu Shaban, dabigatran, bemiparin, Enoxaparin Sodium, tinzaparin sodium, Danaparoid sodium, Pentosan sodium, Nadroparin Calcium, Ardeparin Sodium, Parnaparin Sodium etc..

According to general guideline, the compounds of this invention is administered in combination with a kind of antiplatelet reagent, general day agent Amount can be the antiplatelet that per kilogram patient body weight about 0.01 arrives 150mg to the compound of 25mg formula (I) and about 50 Reagent, the compound of preferably approximately 0.1 to 1mg formula (I) and about 1 to 3mg antiplatelet reagent.When formula (I) chemical combination When thing is administered in combination with thrombolytics, general daily dose can be change of the per kilogram patient body weight about 0.1 to 1mg formula (I) Compound, and under conditions of thrombolytics presence, compared with general dosage when thrombolytics is administered alone, when thrombolytics and formula (I) when compound is applied together, the dosage of thrombolytics can reduce about 70-80%.

When two or more foregoing second therapeutic agents are applied together with the compound of formula (I), usually, it is contemplated that Additional or collaboration the effect of therapeutic agent, each group in typical daily dose and typical formulation during combined administration The amount divided, relative to usual dosage when being administered alone, can decline.

Especially, when being provided as a single dosage unit, change between the active component that there is combination Learn the possibility of reaction.Due to this reason, when the compound and second therapeutic agent of formula (I) are in a single dosage unit When being combined, their compound method will make the physical contact between active component minimize (being to reduce), although active component Combination is in a single dosage unit.For example, a kind of active component can be enteric coating peridium.Pass through enteric coating peridium one Kind of active component, it is possible to not only minimize the contact between united active component, and it is also possible to control these into A kind of release in the gastrointestinal tract in point discharges so as to a kind of do not discharge under one's belt of these components in small intestine.Activity Composition it is a kind of can also superscribe its sustained release in the gastrointestinal tract of influence and can also be used for reduce united activity into The material of physical contact between point further, the component of sustained release can also extraly with enteric coating peridium in order to this into Divide and only discharged in enteron aisle.Also another method is related to the formula of joint product, and one of component is held with one kind The polymer peridium of continuous and/or enteric release, and another component is also with for example a kind of hydroxyl of low sticky rank of polymer Propyl methocel (HPMC) or other suitable material coatings known in the field, to reach further separation The purpose of active component.The reaction of polymer peridium pair and other components forms a kind of extra obstruction.

Once understanding present disclosure, the contact between the component of the joint product for making the present invention of these and other is minimum The method of change be for those skilled in the art it will be apparent that no matter they be with single formulation apply or in a separate form Using, but be in the identical time or apply in an identical manner.

Compound of the present invention or its pharmaceutical salts or its hydrate can be effective for preventing, handling, treat or subtract Light patient's thrombotic disease, particularly can effectively treat miocardial infarction, angina pectoris, block again and revascularization or active ISR, apoplexy after arteries and veins coronary bypass-forming operation, of short duration ischaemic breaking-out, peripheral arterial occlusive disease, pulmonary embolism Or Deep vain thrombosis.

The general synthetic method of this compound

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.

Those skilled in the art will realize that：Chemical reaction described in the invention can be for suitably preparing perhaps Other compounds of many present invention, and be considered as preparing other methods of compound of the invention in model of the invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.Separately

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from Shantou Western Gansu Province chemical plant, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao is risen Imperial chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride and chloroform are returned by calcium hydride Stream is dried to obtain.Ethyl acetate, DMA and petroleum ether are that drying is used in advance through anhydrous sodium sulfate.

Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.

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

By being equipped with G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrometer determine, G1329A automatic samplers and G1315B DAD detectors Applied to analysis, ESI sources are applied to LC-MS spectrometers.

Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C) Agilent6120 series LC-MS spectrometer determine, G1329A automatic samplers and G1315D DAD detector applications In analysis, ESI sources are applied to LC-MS spectrometers.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 posts, and specification is 2.1 × 30mm, 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；HPLC peak value 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 evaluated by the series of high efficiency liquid chromatograies (HPLC) of Agilent 1100, wherein UV detections At 210nm and 254nm, Zorbax SB-C18 posts, specification is 2.1 × 30mm, and 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature is maintained at 40 DEG C.

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

CDC13 deuterochloroforms

DMSO dimethyl sulfoxide (DMSO)s

DMSO-d₆Deuterated dimethyl sulfoxide

CuI cuprous iodides

CH₃NH₂Methylamine

EtOH ethanol

G grams

Mg milligrams

Mol moles

Mmol mMs

H hours

ML milliliters

FXa factors Xa

HATU 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester

Mol, mole

MM mMs

μM micromole

Pos.ion cations

Neg.ion anions

ESI electron spray ionisations

M/z mass-charge ratios

PT plasma prothrombin times

The partial thromboplastin time of APTT activation

Synthetic schemes 1：

The method that target product 6a can be described by synthetic schemes 1 is prepared, wherein X, X¹, Y and m there is such as this hair Bright described implication.

Compound 1a and raw material 2a is in cuprous iodide, and part (such as N, N'- dimethyl-ethylenediamine) and alkali (such as potassium carbonate) are deposited Under, coupling reaction is carried out through high temperature in a solvent, intermediate 3a is obtained；Intermediate 3a takes off under methylamine effect in ethanol Protection, generation intermediate 4a；Intermediate 4a and acid 5a carries out condensation reaction and obtains target product 6a.

Synthetic schemes 2：

The method that target product 6b can be described by synthetic schemes 2 is prepared, wherein X, X¹, Y and m there is such as this hair Bright described implication.

Compound 1b and raw material 2a is in cuprous iodide, and part (such as N, N'- dimethyl-ethylenediamine) and alkali (such as potassium carbonate) are deposited Under, coupling reaction is carried out through high temperature in a solvent, intermediate 3b is obtained；Intermediate 3b takes off under methylamine effect in ethanol Protection, generation intermediate 4b；Intermediate 4b and acid 5a carries out condensation reaction and obtains target product 6b.

Embodiment

The following examples can be so that the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright scope.

Embodiment 1：(R) the chloro- N- of -5- ((2- oxos -3- (3- ((2- oxo-piperidine -1- bases) methyl) phenyl) oxazolidines - 5- yls) methyl) thiophene-2-carboxamide derivatives

Step 1:1- (3- bromobenzyls) piperidines -2- ketone

Potassium hydroxide (3.36g, 60mmol) is dissolved in DMSO (10mL), is stirred at room temperature 15 minutes.Add 2- piperazines Pyridine ketone (4.0g, 12mmol), tetrabutylammonium iodide (740mg, 2.0mmol) and 3- bromobenzyls bromine (2.5g, 10mmol), at room temperature Stirring 4 hours.Add water (20mL) and reaction is quenched, extracted with ethyl acetate (30mL × 3).Merge organic phase, saturated aqueous common salt (50mL) is washed, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product is through column chromatography (petrol ether/ethyl acetate (v/ V)=1/1), obtain white solid (2.0g, 75.0%).

MS(ESI,pos.ion)m/z:268.1(M+1)。

Step 2:(S) -2- ((2- oxos -3- (3- ((2- oxo-piperidine -1- bases) methyl) phenyl) oxazolidine -5- bases) first Base) isoindoline -1,3- diketone

Nitrogen protection under, sequentially added into 50mL two mouthfuls of round-bottomed flasks 1- (3- bromobenzyls) piperidines -2- ketone (4.45g, 16.7mmol), (R) -2- ((2- oxooxazolidine -5- bases) methyl) isoindoline -1,3- diketone (4.64g, 20mmol), carbonic acid Potassium (6.91g, 50.1mmol), cuprous iodide (0.636g, 3.34mmol), N¹,N²- dimethyl ethane -1,2- diamines (0.5mL, 3.34mmol) with Isosorbide-5-Nitrae-dioxane (20mL), it is heated to 120 DEG C and stirs 12 hours.It is cooled to room temperature, with ethyl acetate (30mL × 3) extract.Merge organic phase, washed successively with water (20mL × 2), saturated aqueous common salt (40mL), anhydrous sodium sulfate drying.Cross Filter, decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtains white solid (6.2g, 86%).

MS(ESI,pos.ion)m/z:434.2(M+1).

Step 3:(S) -5- (amino methyl) -3- (3- ((2- oxo-piperidine -1- bases) methyl) phenyl) oxazolidine -2- ketone

Methylamine (40% aqueous solution, 8.0mL) is added to (S) -2- ((2- oxos -3- (3- ((2- oxo-piperidine -1- bases) Methyl) phenyl) oxazolidine -5- bases) methyl) and isoindoline -1,3- diketone (430mg, 1.4mmol) ethanol (20mL) solution In, it is heated to return stirring 1.5 hours.Decompression boils off solvent, and crude product directly throws next step.

Step 4:(R) the chloro- N- of -5- ((2- oxos -3- (3- ((2- oxo-piperidine -1- bases) methyl) phenyl) oxazolidines -5- Base) methyl) thiophene-2-carboxamide derivatives

5- chlorothiophene -2- formic acid (0.273g, 1.68mmol), N, N- bis- are sequentially added into 50mL two mouthfuls of round-bottomed flasks Wopropyl ethyl amine (0.52mL, 2.8mmol), dichloromethane (20mL), HATU (0.798g, 2.1mmol) and (S) -5- (amino first Base) -3- (3- ((2- oxo-piperidine -1- bases) methyl) phenyl) oxazolidine -2- ketone (0.424g, 1.4mmol).It is stirred at room temperature 6 hours, extracted with dichloromethane (30mL × 2).Merge organic phase, successively with water (20mL × 2), saturated sodium bicarbonate (30mL) Solution, saturated aqueous common salt (20mL) washing, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product is purified through column chromatography (petrol ether/ethyl acetate (v/v)=1/1), obtains white solid (0.2g, 32%).

MS(ESI,pos.ion)m/z:448.1(M+1).

¹H NMR(600MHz,CDCl₃) δ 7.45 (s, 1H), 7.39-7.33 (m, 2H), 7.31 (t, J=7.8Hz, 1H), 7.02 (d, J=7.4Hz, 1H), 6.88 (d, J=3.9Hz, 2H), 4.87-4.82 (m, 1H), 4.61 (d, J=14.9Hz, 1H), 4.57 (d, J=14.8Hz, 1H), 4.09 (t, J=8.7Hz, 1H), 3.89-3.80 (m, 2H), 3.73-3.68 (m, 1H), 3.24 (t, J=5.4Hz, 2H), 2.55-2.46 (m, 2H), 1.80 (s, 4H)

Embodiment 2：(R) the chloro- N- of -5- ((3- (the fluoro- 5- of 3- ((3- oxo-morpholines) methyl) phenyl) -2- Yang Dai oxazoles Alkane -5- bases) methyl) thiophene-2-carboxamide derivatives

Step 1:(the bromo- 5- fluorophenyls of 3-) methanol

At 0 DEG C, slowly dripped into tetrahydrofuran (20mL) solution of the bromo- 5- fluobenzoic acids (4.38g, 20.0mmol) of 3- Plus 1M borine tetrahydrofuran complex tetrahydrofuran solution (30mL, 30.0mmol).Continue stirring 1.5 hours at 0 DEG C, so After be stirred at room temperature overnight.Methanol is slowly added to thereto at room temperature until being quenched without gas effusion.Decompression boils off solvent, slightly Product purifies (petrol ether/ethyl acetate (v/v)=10/1) through column chromatography, obtains weak yellow liquid (3.9g, 95%).

MS(ESI,pos.ion)m/z:186.90(M-17)

Step 2:1- bromo- 3- (bromomethyl) -5- fluorobenzene

At 0 DEG C, into anhydrous methylene chloride (50mL) solution of (the bromo- 5- fluorophenyls of 3-) methanol (3.9g, 19mmol) Add phosphorus tribromide (3.6mL, 38mmol).It is warmed to room temperature and is stirred overnight.Water (40mL) is added, with dichloromethane (60mL × 3) Extraction.Merge organic phase, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product purifies (petroleum ether/second through column chromatography Acetoacetic ester (v/v)=40/1), obtain colorless oil (4.7g, 92%).

MS(EI)m/z::267.9(M).

Step 3:4- (the bromo- 5- fluorophenyls of 3-) morpholine -3- ketone

At 0 DEG C, to 1- bromo- 3- (bromomethyl) -5- fluorobenzene (4.7g, 18mmol), morpholine -3- ketone (1.8g, 18mmol) With in tetrahydrofuran (50.0mL) solution of tetrabutylammonium iodide (320mg, 0.88mmol) add 60% sodium hydride (1.4g, 35mmol).Continue to stir 1 hour at 0 DEG C, be warmed to room temperature stirring 4 hours.Add water (50mL), with ethyl acetate (60mL × 3) extract, merge organic phase, washed with saturated aqueous common salt (40mL), anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, slightly Product purifies (petrol ether/ethyl acetate (v/v)=4/1) through column chromatography, obtains pale yellow oil (1.50g, 30%).

MS(ESI,pos.ion)m/z:288.00(M+1).

Step 4:(R) -2- ((3- (the fluoro- 5- of 3- ((3- oxo-morpholines) methyl) phenyl) -2- oxooxazolidine -5- bases) Methyl) isoindoline -1,3- diketone

4- (the bromo- 5- fluorophenyls of 3-) morpholine -3- ketone (1.5g, 5.2mmol), (R) -2- ((2- oxygen are sequentially added in tube sealing Dai oxazolidine -5- bases) isoindoline -1,3- diketone (1.3g, 5.2mmol), N, N'- dimethyl-ethylenediamines (180mg, 2.1mmol), cuprous iodide (200mg, 1.05mmol), potassium carbonate (2.2g, 16mmol) and Isosorbide-5-Nitrae-dioxane (20mL), Under nitrogen atmosphere, it is heated to 120 DEG C and stirs 8 hours.Filtering, filtrate decompression boils off solvent, and crude product purifies (dichloro through column chromatography Methane/methanol (v/v)=100/1), obtain white solid (1.08g, 46%).

MS(ESI,pos.ion)m/z:454.10(M+1).

Step 5:(R) -4- (3- (5- (amino methyl) -2- oxooxazolidine -3- bases) -5- fluorophenyls) morpholine -3- ketone

To (R) -2- ((3- (the fluoro- 5- of 3- ((3- oxo-morpholines) methyl) phenyl) -2- oxooxazolidine -5- bases) methyl) The methylamine water solution (3mL) of addition 40% in ethanol (30mL) solution of isoindoline -1,3- diketone (1.08g, 2.38mmol). It is heated to 95 DEG C to stir 1.5 hours, is cooled to room temperature, decompression boils off solvent, and crude product is not directly used in next after further treatment Step reaction.

Step 6:(R) the chloro- N- of -5- ((3- (the fluoro- 5- of 3- ((3- oxo-morpholines) methyl) phenyl) -2- oxooxazolidines - 5- yls) methyl) thiophene-2-carboxamide derivatives

To (R) -4- (3- (5- (amino methyl) -2- oxooxazolidine -3- bases) -5- fluorophenyls) morpholine -3- ketone (769mg, 2.38mmol) and in dichloromethane (40mL) solution of 5- chlorothiophene -2- formic acid (464mg, 2.86mmol) add HATU (1.36g, 3.57mmol) and N, N- diisopropylethylamine (829 μ L, 4.76mmol).It is stirred at room temperature 6 hours.Decompression boils off molten Agent, adds dichloromethane (50mL), and organic phase is washed with saturated sodium bicarbonate solution (30mL) successively, saturated aqueous common salt (30mL) Washing, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, crude product purify through column chromatography (methylene chloride/methanol (v/v)= 10/1) faint yellow solid (290mg, 26%), is obtained.

MS(ESI,pos.ion)m/z:468.05(M+1)；

¹H NMR(400MHz,DMSO-d₆) δ 8.96 (t, J=5.7Hz, 1H), 7.68 (d, J=4.0Hz, 1H), 7.39 (d, J=11.4Hz, 1H), 7.25 (s, 1H), 7.19 (d, J=4.0Hz, 1H), 6.83 (d, J=9.0Hz, 1H), 4.90-4.78 (m, 1H), 4.55 (s, 2H), 4.17 (t, J=9.0Hz, 1H), 4.12 (s, 2H), 3.88-3.79 (m, 3H), 3.60 (t, J= 5.5Hz, 2H), 3.27 (t, J=5.1Hz, 2H)

Embodiment 3：The chloro- N- of 5- ((5- oxos -1- (4- (3- oxo-morpholines) phenyl) pyrrolidin-3-yl) methyl) thiophene Fen -2- formamides

Step 1:4- (methylol) pyrrolidin-2-one

At 0 DEG C, 5- pyrrolidones -3- methyl formates (5g, 34.931mmol) are dissolved in dry isopropanol (80mL) In, sodium borohydride (4.72g, 122.3mmol) is added, after being stirred 2 hours at 0 DEG C, moves to and is stirred overnight at room temperature.Add first Alcohol (20mL), decompression boils off solvent, and crude product purifies (ethyl acetate/methanol (v/v)=10/1) through column chromatography, obtains white solid (4.0g, 99.5%).

MS(ESI,pos.ion)m/z:116.1(M+1).

Step 2:2- ((5- oxo-pyrrolidine -3- bases) methyl) isoindoline -1,3- diketone

Triphenylphosphine (1.914g, 7.30mmol), phthalyl are sequentially added into 100mL two mouthfuls of round-bottomed flasks sub- Amine (1.073g, 7.296mmol), tetrahydrofuran (40mL), 4- (methylol) pyrrolidin-2-one (0.70g, 6.08mmol), it is cold To after 0 DEG C, diisopropyl azodiformate (1.475g, 7.296mmol, 1.437mL) is added, it is small that mixture stirs 1 at 0 DEG C When after move to and be stirred overnight at room temperature.Decompression boils off solvent, and crude product purifies (ethyl acetate) through column chromatography, obtains white solid title Compound (1.16g, 78.1%).

MS(ESI,pos.ion)m/z:245.2(M+1).

Step 3:2- ((5- oxos -1- (4- (3- oxo-morpholines) phenyl) pyrrolidin-3-yl) methyl) isoindoline -1, 3- diketone

Under nitrogen protection, 2- ((5- oxo-pyrrolidine -3- bases) methyl) iso-indoles is sequentially added into 50mL hermetically sealed can Quinoline -1,3- diketone (0.55g, 2.25mmol), 4- (4- iodophenyls) morpholine -3- ketone (1.09g, 3.60mmol), potassium carbonate (0.943g, 6.76mmol), cuprous iodide (0.129g, 0.676mmol), N¹,N²- dimethyl ethane -1,2- diamines (0.07mL, 0.676mmol) with Isosorbide-5-Nitrae-dioxane (20mL), it is heated to 125 DEG C and stirs 12 hours.It is cooled to room temperature, with ethyl acetate (30mL × 3) extract.Merge organic phase, washed successively with water (20mL × 2), saturated aqueous common salt (40mL), anhydrous sodium sulfate drying.Cross Filter, decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtains white solid title Compound (0.7g, 70%).

MS(ESI,pos.ion)m/z:420.1(M+1).

Step 4:4- (4- (4- (amino methyl) -2- oxo-pyrrolidine -1- bases) phenyl) morpholine -3- ketone

Methylamine (40% aqueous solution, 5.0mL) is added to 2- ((5- oxos -1- (4- (3- oxo-morpholines) phenyl) pyrroles Alkane -3- bases) methyl) isoindoline -1,3- diketone (0.7g, 2.0mmol) ethanol (20mL) solution in, be heated to 95 DEG C stirring 1.5 hour.Decompression boils off solvent, and crude product directly throws next step.

Step 5:The chloro- N- of 5- ((5- oxos -1- (4- (3- oxo-morpholines) phenyl) pyrrolidin-3-yl) methyl) thiophene - 2- formamides

2- chlorothiophene -5- formic acid (0.488g, 3.0mmol), N, N- bis- are sequentially added into 100mL two mouthfuls of round-bottomed flasks Wopropyl ethyl amine (0.99mL, 6.0mmol), dichloromethane (50mL), HATU (1.529g, 3.9mmol) and 4- (4- (4- (amino Methyl) -2- oxo-pyrrolidine -1- bases) phenyl) morpholine -3- ketone (0.386g, 1.33mmol).It is stirred at room temperature overnight, with two Chloromethanes (30mL × 2) is extracted.Merge organic phase, successively with water (20mL × 2), saturated sodium bicarbonate (30mL) solution, saturation Saline solution (20mL) is washed, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, crude product purify through column chromatography (petroleum ether/ Ethyl acetate (v/v)=1/1), obtain titled compound as white solid (0.5g, 40%).

MS(ESI,pos.ion)m/z:434.1(M+1).

¹H NMR(600MHz,CDCl₃) δ 7.61 (d, J=8.7Hz, 2H), 7.36 (d, J=3.8Hz, 1H), 7.33 (t, J =5.8Hz, 1H), 7.28 (d, J=8.4Hz, 2H), 6.89 (d, J=3.8Hz, 1H), 4.35 (s, 2H), 4.06 (t, J= 4.9Hz, 2H), 3.88-3.82 (m, 1H), 3.78-3.72 (m, 2H), 3.58 (dd, J=9.7,4.4Hz, 1H), 3.43-3.36 (m, 1H), 3.30 (dt, J=13.7,6.8Hz, 1H), 2.75-2.65 (m, 2H), 2.29 (dd, J=16.2,4.7Hz, 1H)

Embodiment 4：The chloro- N- of (S, Z) -5- ((3- (4- (cyclopenta (methoxyimino) methyl) phenyl) -2- Yang Dai Evil Oxazolidine -5- bases) methyl) thiophene-2-carboxamide derivatives

Step 1:Cyclopenta (4- nitrobenzophenones) methanol

At nitrogen atmosphere and -78 DEG C, to 4- nitrobenzaldehydes (2g, 13.23mmol) anhydrous tetrahydro furan (20mL) 2M cyclopenta magnesium chloride diethyl ether solution (12.4mL, 24.8mmol) is added dropwise in solution.It is warmed to room temperature stirring 3 hours.Then plus Enter saturated ammonium chloride (20mL) to be quenched, aqueous phase is extracted with ethyl acetate (10mL × 3), merge organic phase, use saturated aqueous common salt (20mL) is washed, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product is purified through column chromatography, obtain (640mg, 21.8%).

MS(ESI,pos.ion)m/z:222(M+1).

Step 2:Cyclopenta (4- nitrobenzophenones) ketone

Three are slowly added into the acetone soln for cyclopenta (4- nitrobenzophenones) methanol (640mg, 2.89mmol) being cooled to The water and concentrated sulfuric acid solution of chromium oxide.After being stirred 1 hour at 4 DEG C, water dissolving is added, chromic salts is removed in filtering, and filtrate uses three chloromethanes Alkane is extracted.Decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=2/1) through column chromatography, obtains white solid (538mg, 85%).

MS(ESI,pos.ion)m/z:220(M+1).

Step 3:(4- aminophenyls) (cyclopenta) ketone

Hydrochloric acid (1mL) is slowly added into iron (1g, 17.9mmol) water (5mL) solution, 65 DEG C is heated to and stirs 15 points Clock.Solvent is poured out, methanol (10mL) solution of cyclopenta (4- nitrobenzophenones) ketone (538mg, 2.45mmol) is added thereto, PH 2-3 are acidified to hydrochloric acid, 65 DEG C is heated to and stirs 2 hours.It is cooled to room temperature, adds triethylamine (2mL), filtering, filtrate decompression Boil off solvent.Crude product is purified through column chromatography, obtains yellow solid (260mg, 56.0%).

MS(ESI,pos.ion)m/z:190(M+1).

Step 4:(4- (pentamethylene formoxyl) phenyl) methyl carbamate

It is slow into dichloromethane (10mL) solution of (4- aminophenyls) (cyclopenta) ketone (260mg, 1.36mmol) Add N, N- diisopropylethylamine (500 μ L, 3.1mmol).It is stirred at room temperature after 15 minutes, chloro-carbonic acid is slowly added dropwise thereto Methyl esters (130 μ L, 1.65mmol).After dripping, it is stirred for 1 hour, suction filtration, solid is washed with dichloromethane, crude product warp Column chromatography is purified, and obtains title compound for white solid (270mg, 79.5%)

MS(ESI,pos.ion)m/z:248(M+1).

Step 5:(Z)-(4- (pentamethylene base (methoxyimino) methyl) phenyl) methyl carbamate

Sequentially added into round-bottomed flask (4- (pentamethylene formoxyl) phenyl) methyl carbamate (270mg, 1.09mmol), methoxyl group amine salt hydrochloride (100mg, 1.20mmol), sodium sulphate (200mg, 1.41mmol), pyridine (0.5mL) With methanol (10mL), it is stirred at room temperature complete to TLC monitoring reactions.Decompression boils off solvent, and crude product purifies (oil through column chromatography Ether/ethyl acetate (v/v)=1/1), obtain title (162mg, 53.7%).

MS(ESI,pos.ion)m/z:277(M+1).

Step 6:The chloro- N- of (S, Z) -5- ((3- (4- (cyclopenta (methoxyimino) methyl) phenyl) -2- Yang Dai oxazoles Alkane -5- bases) methyl) thiophene-2-carboxamide derivatives

At nitrogen atmosphere and -78 DEG C, to (Z)-(4- (pentamethylene base (methoxyimino) methyl) phenyl) amino first The n-hexane that 1.6M n-BuLi is added dropwise in anhydrous tetrahydro furan (10mL) solution of sour methyl esters (160mg, 0.579mmol) is molten Liquid (84 μ L, 1.34mmol).Continue at -78 DEG C after stirring 1.5 hours, be added dropwise thereto (R) -5- chloro- N- (oxirane - 2- ylmethyls) thiophene-2-carboxamide derivatives (189mg, 0.868mmol) tetrahydrofuran (5mL) solution.Continue to stir 2 at -78 DEG C After hour, it is warmed to room temperature and is stirred overnight.Add saturated ammonium chloride (20mL) to be quenched, extracted with ethyl acetate (10mL × 3), merged Organic phase, is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (20mL).Filtering, decompression boils off solvent, and crude product is through column chromatography Purify (petrol ether/ethyl acetate (v/v)=1/1), obtain title compound for white solid (16mg, 6.0%).

MS(ESI,pos.ion)m/z:462(M+1)；

¹HNMR(400MHz,CDCl₃) δ 7.66-7.64 (d, J=8Hz, 2H), 7.60-7.58 (d, J=8Hz, 1H), 7.47-7.45 (d, J=8 Hz, 1H), 7.16-7.13 (dd, J=6Hz, 1H), 6.88-6.86 (d, J=8Hz, 1H), 6.22 (m,1H),4.78-4.77(m,1H),4.54-4.51(m,,1H),4.36-4.35(m,,1H),3.94(s,1H)3.92–3.87 (m,1H),3.78(s,1H),3.48-3.43(m,1H),1.64-1.62(m,1H),1.61-1.59(m,8H).

Embodiment 5：(S) the chloro- N- of -5- ((3- (4- (3- methoxyl group oxetanes -3- bases) phenyl) -2- Yang Dai oxazoles Alkane -5- bases) methyl) thiophene-2-carboxamide derivatives

Step 1:3- (4- nitros) oxa- ring butyl- 3- alcohol

At -78 DEG C, add into anhydrous tetrahydro furan (120mL) solution of the iodo- 4- nitrobenzene (10g, 40.16mmol) of 1- Enter the hexane solution (27.6mL, 44.18mmol) of 1.6M n-BuLis, stir 10 minutes.3- oxygen is being slowly added dropwise thereto Anhydrous tetrahydro furan (10mL) solution of heterocycle butanone (2.88g, 40mmol), stirs 10 minutes, is warmed to room temperature.Add water (40mL), aqueous phase is extracted with ethyl acetate (30mL × 3).Merge organic phase, washed with saturated aqueous common salt (40mL), anhydrous slufuric acid Sodium is dried.Filtering, decompression boil off solvent, crude product is purified through column chromatography, obtain title compound for white solid (1.1g, 12.8%)

MS(ESI,pos.ion)m/z:196.0(M+1).

Step 2:3- methoxyl groups -3- (4- nitrobenzophenones) oxetanes

At -5 DEG C, to tetrahydrofuran (20mL) solution of 3- (4- nitros) oxa- ring butyl- 3- alcohol (2g, 10.25mmol) The sodium hydride (740mg, 18.4mmol) of middle addition 60%.At -5 DEG C continue stir 1 hour, add iodomethane (750 μ L, 12.3mmol).It is warmed to room temperature and is stirred overnight.Water (30mL) is added, aqueous phase is extracted with ethyl acetate (20mL × 3).Merge organic Phase, is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (40mL).Filtering, decompression boils off solvent, and crude product is pure through column chromatography Change, obtain white solid (1.75g, 82%).

MS(ESI,pos.ion)m/z:210.0(M+1).

Step 3:4- (3- methoxyl group oxetanes -3- bases) ammonia

Into methanol (30mL) solution of 3- methoxyl groups -3- (4- nitrobenzophenones) oxetanes (1.75g, 8.37mmol) Palladium/carbon (500mg) of addition 10%.In H₂It is stirred overnight under atmosphere.Filtering, filtrate decompression boils off solvent, obtains title compound For white solid (1.3g, 87%)

MS(ESI,pos.ion)m/z:180.0(M+1).

Step 4:(4- (3- methoxyl group oxetanes -3- bases) phenyl) methyl carbamate

Into dichloromethane (10mL) solution of 4- (3- methoxyl group oxetanes -3- bases) ammonia (1.5g, 8.37mmol) It is slowly added to N, N- diisopropylethylamine (1.3g, 10.04mmol).It is stirred at room temperature after 15 minutes, is slowly added dropwise thereto Methylchloroformate (900mg, 10.4mmol).After dripping, it is stirred for 1 hour, suction filtration, solid is washed with dichloromethane, slightly Product is purified through column chromatography, obtains title compound for white solid (1.18g, 56.2%).

Step 5:(R) the chloro- N- of -5- (oxirane -2- ylmethyls) thiophene-2-carboxamide derivatives

The sodium hydride (160mg, 4.0mmol) of addition 60%, DMF (3mL) and 5- into round-bottomed flask Chlorothiophene -2- formamides (400mg, 2.25mmol).It is heated to 60 DEG C of stirrings to produce to without gas, is cooled to room temperature, adds thereto Enter (R) -2- (chloromethyl) oxirane (300 μ L, 3.7mmol).It is stirred at room temperature 12 hours.Add saturated ammonium chloride solution (2mL) is quenched, and adds water (30mL), is extracted with ethyl acetate (20mL × 3).Merge organic phase, use saturated aqueous common salt (40mL) is washed, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product is purified through column chromatography, is obtained title compound and is White solid (82mg, 14%).

¹H NMR(400MHz,CDCl₃)δ7.37-7.36(d,2H),6.90-6.89(d,2H),4.85-4.78(m,1H), 4.09-4.03(m,1H),3.87-3.70(m,3H),1.99(bar,1H)；

MS(ESI,pos.ion)m/z:218.0(M+1).

Step 6:(S) the chloro- N- of -5- ((3- (4- (3- methoxyl group oxetanes -3- bases) phenyl) -2- oxooxazolidines - 5- yls) methyl) thiophene-2-carboxamide derivatives

At nitrogen atmosphere and -78 DEG C, to (4- (3- methoxyl group oxetanes -3- bases) phenyl) methyl carbamate The hexane solution of 1.6M n-BuLi is added dropwise in anhydrous tetrahydro furan (10mL) solution of (80mg, 0.33mmol) (0.42mL,0.66mmol).Continue at -78 DEG C after stirring 1.5 hours, be added dropwise thereto (R) -5- chloro- N- (oxirane - 2- ylmethyls) thiophene-2-carboxamide derivatives (81mg, 0.37mmol) tetrahydrofuran (5mL) solution.Continue stirring 2 at -78 DEG C small Shi Hou, is warmed to room temperature and is stirred overnight.Add saturated ammonium chloride (20mL) to be quenched, extracted, be associated with ethyl acetate (10mL × 3) Machine phase, is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (20mL).Filtering, decompression boils off solvent, and crude product is pure through column chromatography Change (petrol ether/ethyl acetate (v/v)=1/1), obtain titled compound as white solid (15mg, 10.5%).

MS(ESI,pos.ion)m/z:423.1(M+1)；

¹H NMR(400MHz,CDCl₃)δ7.41-7.35(m,5H),6.93(bar,1H)；6.89-6.88(d,2H), 4.96-4.95(m,1H)；4.93-4.91(d,2H),4.81-4.79(d,2H)；4.48-4.44(dd,1H),4.28-4.24 (dd,1H),4.16-4.10(q,1H),3.89-3.83(q,1H),3.10(s,3H).

Embodiment 6：The chloro- N- of (S, E) -5- ((3- (4- (3- (cyanoimino) morpholinyl) phenyl) -2- oxooxazolidines - 5- yls) methyl) thiophene-2-carboxamide derivatives

Step 1:4- (4- iodophenyls) morpholinyl -3- thioketones

Lawesson reagent is added in toluene (300mL) solution of 4- (4- iodophenyls) morpholinyl -3- ketone (9.7g, 32mmol) (6.5g, 16mmol), is heated to 100 DEG C and stirs 3 hours.It is cooled to room temperature, is extracted with ethyl acetate (100mL × 2).Merge organic Phase, is washed, anhydrous sodium sulfate drying with water (50mL × 2), saturated aqueous common salt (50mL) successively.Filtering, decompression boils off solvent, slightly Product purifies (petroleum ether/dichloromethane (v/v)=1/1) through column chromatography, obtains titled compound as white solid (9.1g, 89%).

MS(ESI,pos.ion)m/z:320.0(M+1).

Step 2:4- (4- iodophenyls) -5- (methyl mercapto) -3,6- dihydro -2H-1,4- oxazine -4- iodide

Iodine first is added in acetonitrile (50mL) solution of 4- (4- iodophenyls) morpholinyl -3- thioketones (9.26g, 29.0mmol) Alkane (16.5g, 116mmol).It is stirred at room temperature 2 hours.Decompression boils off solvent, and crude product directly throws next step.

Step 3:(E)-N- (4- (4- iodophenyls) morpholinyl -3- subunits) cyanamide

4- (4- iodophenyls) -5- (methyl mercapto) -3,6- dihydro -2H-1,4- Evil are sequentially added into 250mL hermetically sealed can Piperazine -4- iodide (13.4g, 29.0mmol), acetonitrile (150mL), cyanamide (9.75g, 232mmol) and triethylamine (11.7g, 116mmol).85 DEG C are heated to stir 15 hours.Filtering, filter cake is washed with acetonitrile, and filtrate decompression boils off solvent, and crude product is through post Chromatographic purifying (petrol ether/ethyl acetate (v/v)=1/1), obtains titled compound as white solid (7.2g, 76%).

MS(ESI,pos.ion)m/z:328.0(M+1).

Step 4:(4- (4- (5- (azido-methyl) -2- oxooxazolidine -3- bases) phenyl) morpholinyl -3- is sub- by (R, E)-N- Base) cyanamide

Nitrogen protection under, sequentially added into 50mL hermetically sealed can (R) -5- (azido-methyl) oxazolidine -2- ketone (1.56g, 11.0mmol), (E)-N- (4- (4- iodophenyls) morpholinyl -3- subunits) cyanamide (3.6g, 11.0mmol), potassium carbonate (4.56g, 33.0mmol), cuprous iodide (419mg, 2.2mmol), N¹,N²- dimethyl ethane -1,2- diamines (388mg, 4.4mmol) and 1, 4- dioxane (50mL), is heated to 120 DEG C and stirs 4 hours.It is cooled to room temperature, is extracted with ethyl acetate (50mL × 3).It is associated with Machine phase, is washed, anhydrous sodium sulfate drying with water (50mL × 2), saturated aqueous common salt (40mL) successively.Filtering, decompression boils off solvent, Crude product purifies (petrol ether/ethyl acetate (v/v)=1/6) through column chromatography, obtain titled compound as white solid (0.9g, 20%).

MS(ESI,pos.ion)m/z:342.15(M+1).

Step 5:(S, E)-N- (4- (4- (5- (amino methyl) -2- oxooxazolidine -3- bases) phenyl) morpholine -3- subunits) Cyanamide

By (R, E)-N- (4- (4- (5- (azido-methyl) -2- oxooxazolidine -3- bases) phenyl) morpholinyl -3- subunits) ammonia Nitrile (0.09g, 0.26mmol) and triphenylphosphine (138mg, 0.526mmol) are dissolved in tetrahydrofuran/water (v/v)=10/1 (22mL) Mixed solution in, be stirred at room temperature 10 hours.Extracted with ethyl acetate (30mL × 3).Merge organic phase, water is used successively (20mL × 2), saturated aqueous common salt (40mL) are washed, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product is through post layer Analysis purifying (methylene chloride/methanol (v/v)=10/1), obtains colorless oil title compound (83mg, 100%).

MS(ESI,pos.ion)m/z:316.2(M+1).

Step 6:The chloro- N- of (S, E) -5- ((3- (4- (3- (cyanoimino) morpholinyl) phenyl) -2- oxooxazolidines -5- Base) methyl) thiophene-2-carboxamide derivatives

2- chlorothiophene -5- formic acid (0.496g, 3.05mmol), N, N- bis- are sequentially added into 50mL two mouthfuls of round-bottomed flasks Wopropyl ethyl amine (1.74mL, 10.2mmol), dichloromethane (30mL), HATU (1.45g, 3.81mmol).It is stirred at room temperature 1 (S, E)-N- (4- (4- (5- (amino methyl) -2- oxooxazolidine -3- bases) phenyl) morpholine -3- imino groups) ammonia is added after hour Nitrile (0.803g, 2.55mmol).It is stirred at room temperature 6 hours, is extracted with dichloromethane (30mL × 2).Merge organic phase, successively Washed with water (20mL × 2), saturated aqueous common salt (20mL), anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, crude product warp Column chromatography purifies (methylene chloride/methanol (v/v)=10/1), obtains compound as white solid (0.078g, 6.7%).

MS(ESI,pos.ion)m/z:460.0(M+1)；

¹H NMR(600MHz,DMSO-d₆) δ 8.98 (t, J=5.7Hz, 1H), 7.69 (d, J=4.0Hz, 1H), 7.62 (d, J=8.9Hz, 2H), 7.41 (d, J=8.9Hz, 2H), 7.20 (d, J=4.0Hz, 1H), 4.86 (td, J=11.2,5.8Hz, 1H), 4.73 (s, 2H), 4.21 (t, J=8.9Hz, 1H), 4.04 (t, J=5.0Hz, 2H), 3.87 (dd, J=9.0,6.1Hz, 1H), 3.71 (t, J=4.9Hz, 2H), 3.62 (dd, J=14.4,8.2Hz, 2H)

Embodiment 7：(S) the chloro- N- of -5- ((3- (4- (1,1- dioxothiochromane -6- bases) phenyl) -2- oxazoles Alkane -5- bases) methyl) thiophene-2-carboxamide derivatives

Step 1:(R) -2- (2- hydroxyls -3- ((4- iodophenyls) amino) propyl group) isoindoline -1,3- ketone

Sequentially added into round-bottomed flask (S) -2- (oxirane -2- ylmethyls) isoindoline -1,3- diketone (2.0g, 9.84mmol), 4- Iodoanilines (2.2g, 10.0mmol), ethanol (90mL) and water (10mL), are heated to 100 DEG C and stir 12 hours. Product is settled out from solution.Suction filtration is precipitated, filter cake is washed with ether, be dried in vacuo.Merge mother liquor, decompression boils off solvent, to (S) -2- (oxirane -2- ylmethyls) isoindoline -1,3- diketone (1.0g, 4.92mmol), second are added in residue Alcohol (90mL) and water (10mL), gained mixture are heated to 100 DEG C and stirred 12 hours.Refilter, filter cake is washed with ether, vacuum Dry.Filter cake that is merging and drying is that title compound is white solid (3.6g, 84.9%).

¹H NMR(CDCl₃, 400MHz) δ 7.85-7.88 (m, 2H), 7.38-7.77 (m, 2H), 7.41 (d, J=8.8Hz, 2H), 6.48 (d, J=8.8Hz, 2H), 4.11-4.16 (m, 1H), 3.90 (d, J=5.0Hz, 2H), 3.13-3.27 (m, 2H)

Step 2:(S) -2- ((3- (4- iodophenyls) -2- oxooxazolidine -5- bases) methyl) isoindoline -1,3- diketone

To (R) -2- (2- hydroxyls -3- ((4- iodophenyls) amino) propyl group) isoindoline -1,3- ketone (3.4g, 8.05mmol) Tetrahydrofuran (90mL) solution in add N, N^’The 4- dimethylaminos of-carbonyl dimidazoles (2.6g, 16.0mmol) and catalytic amount Pyridine.It is heated to 60 DEG C to stir 12 hours, adds N, N^’- carbonyl dimidazoles (2.6g, 16.0mmol), in 60 DEG C of stirrings 12 again Hour.Precipitate suction filtration, tetrahydrofuran washing, vacuum drying.Merge mother liquor, decompression boils off solvent, and crude product is purified through column chromatography (petrol ether/ethyl acetate (v/v)=2/1), obtains white solid (3.0g, 83.1%).

¹H NMR(CDCl₃, 400MHz) δ 7.87-7.89 (m, 2H), 7.52-7.77 (m, 2H), 7.66 (d, J=8.8Hz, 2H), 7.30 (d, J=8.8Hz, 2H), 4.96-5.00 (m, 1H), 4.07-4.17 (m, 2H), 3.87-4.00 (m, 2H)

Step 3:(S) -5- (amino methyl) -3- (4- iodophenyl) oxazolidine -2- ketone

To (S) -2- ((3- (4- iodophenyls) -2- oxooxazolidine -5- bases) methyl) isoindoline -1,3- diketone (1.6g, The methylamine water solution (3.5mL) of addition 40% in ethanol (80mL) solution 3.57mmol).It is heated to 95 DEG C to stir 1 hour, subtracts Pressure boils off solvent.Crude product, which is not purified, is directly used in next step reaction.

Step 4:(S) the chloro- N- of -5- ((3- (4- iodophenyls) -2- oxooxazolidine -5- bases) methyl) thiophene-2-carboxamide derivatives

Sequentially added into round-bottomed flask (S) -5- (amino methyl) -3- (4- iodophenyl) oxazolidine -2- ketone (1.10g, 3.46mmol), 5- chlorothiophenes -2- formic acid (800mg, 4.92mmol), HATU (2.9g, 7.63mmol), diisopropylethylamine (1.7mL, 10.3mmol) and N,N-dimethylformamide (15mL).It is stirred at room temperature 3 hours.Water (30mL) is added, acetic acid is used Ethyl ester (30mL × 3) is extracted, and merges organic phase, is washed successively with water (30mL × 2), saturated aqueous common salt (50mL) is washed, anhydrous Sodium sulphate is dried.Filtering, decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, obtained White solid (1.5g, 93.8%).

¹H NMR(CDCl₃, 400MHz) δ 8.02 (s, 1H), 7.66 (d, J=8.8Hz, 2H), 7.30 (d, J=4.0Hz, 1H), 7.28 (d, J=8.8Hz, 2H), 6.90 (d, J=4.0Hz, 1H), 6.60 (t, J=6.0Hz, 1H), 4.82-4.89 (m, 1H), 4.08 (t, J=8.8Hz, 1H), 3.71-3.92 (m, 3H)

Step 5:(S) the chloro- N- of -5- ((3- (4- (1,1- dioxothiochromane -6- bases) phenyl) -2- oxazolidines - 5- yls) methyl) thiophene-2-carboxamide derivatives

The chloro- N- of (S) -5- ((3- (4- iodophenyls) -2- oxooxazolidine -5- bases) methyl) are sequentially added into round-bottomed flask Thiophene-2-carboxamide derivatives (231mg, 0.499mmol), 6- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- bases) dihydrobenzene And thiapyran 1,1- dioxide (192mg, 0.623mmol), sodium carbonate (64mg, 0.604mmol), tetra-triphenylphosphine palladium (116mg, 0.0932mmol), toluene (16mL), ethanol (4mL) and water (1mL), under nitrogen atmosphere, are heated to 100 DEG C of stirrings 16 hours.Water (20mL) is added, with ethyl acetate (20mL × 3).Merge organic phase, washed with saturated aqueous common salt (40mL), nothing Aqueous sodium persulfate is dried.Filtering, decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (v/v)=1/1) through column chromatography, Obtain white solid (26mg, 10.1%).

¹H NMR(400MHz,DMSO-d₆) δ 8.98 (t, J=5.6Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.73- 7.78 (m, 3H), 7.65-7.69 (m, 4H), 7.19 (d, J=4.0Hz, 1H), 4.83-4.90 (m, 1H), 4.23 (t, J= 8.8Hz, 1H), 3.89 (dd, J=6.0,9.2Hz, 1H), 3.49-3.53 (m, 2H), 3.08 (t, J=6.0Hz, 2H), 2.31- 2.37(m,2H)；

MS(ESI,pos.ion)m/z:517.2(M+1).

Active testing example

Test of anticoagulation in vitro

Compound extends the clotting time of rabbit plasma

1. the preparation of each concentration compound

4 each compound working solutions of μ L (100mM) are taken, the working solution of each concentration is diluted to dimethyl sulfoxide liquid.

2. the preparation of plasma sample

Some rabbits are taken, auricular vein injects 3% pentobarbital solution (30mg/kg) anesthesia, with containing 3.8% sodium citrate 0.2mL vacuum test tube abdominal aorta is taken a blood sample to 2mL, collects multitube, is turned upside down mixing for several times, is stood 10min, in 3000rpm centrifuges 10min, draws each pipe blood plasma, all blood plasma are mixed to same centrifuge tube, and often pipe is dispensed 1.6mL, is put rapidly Enter -80 DEG C of refrigerators to save backup.

3. sample-adding and measure clotting time PT and APTT

1.5mL EP pipes are got out, often pipe adds 180 μ L plasma specimens；4 μ L are separately added into each pipe blood specimen corresponding The medicine of concentration, control group adds 4 μ L dimethyl sulfoxide solutions, and concussion is mixed, 37 DEG C of incubation 5min；It is complete with Sysmex CA1500 Automatic blood coagulation instrument determines PT and APTT；Amount effect curve is drawn, curve is fitted, thus calculating clotting time of sening as an envoy to doubles Test compound concentration (CT₂)。

Inhibitory action and anticoagulation effect in vitro of the compound to people FXa activity

A：1.00nM-10nM；B：10.01nM-50nM；C：50.01nM-1.00μM；D：1.01μM-20.00μM

Conclusion：This series compound has preferable factor Xa inhibitory activity, while having the extension clotting time Effect.

The solubility test of compound

Water (10mL) is added into 15mL conical pipes, sample is added in vibration, until sample stops dissolving, 37 DEG C of constant temperature Water-bath shakes 24h, shake speed 40rpm.After shaking terminates, sample is filtered through water system miillpore filter (0.45 μm, Φ 13mm), Primary filtrate is discarded, precision pipettes subsequent filtrate (500 μ L), adds dilution acetonitrile-water (500 μ L, v/v=60/40), and the two is mixed It is even, produce need testing solution.

Need testing solution (40 μ L) is taken, is detected using HPLC, sample concentration is calculated by one point external standard method：

Numbering	Compound solubility (mg/mL)
		Embodiment 1	0.26
Embodiment 2	0.48
		Embodiment 3	0.60
Embodiment 4	0.11

Embodiment 5	0.15
		Embodiment 6	0.32
Embodiment 7	0.16

Conclusion：This series compound has preferable solubility.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means to combine specific features, structure, material or the spy that the embodiment or example are described Point is contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be with office Combined in an appropriate manner in one or more embodiments or example.In addition, in the case of not conflicting, the skill of this area Art personnel can be tied the not be the same as Example or the feature of example and non-be the same as Example or example described in this specification Close and combine.

Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (9)

1. a kind of compound as shown in formula (I), or formula (I) compound pharmaceutically acceptable salt,

Wherein, Q is O；

R is following minor structure：

Wherein, R³For hydrogen, C_1-3Alkyl or C_1-3Alkoxy；

N is 0,1,2 or 3.

2. compound as claimed in claim 1, wherein：

R³For hydrogen, methyl, methoxyl group, ethyoxyl or positive propoxy.

3. the compound according to claim any one of 1-2, comprising the structure of one of or its can pharmaceutically connect The salt received,

4. a kind of pharmaceutical composition, comprising the compound described in claim any one of 1-3, and its it is pharmaceutically acceptable auxiliary Agent.

5. pharmaceutical composition according to claim 4, described assistant agent is excipient, diluent or combinations thereof.

6. the compound described in a kind of any one of claim 1-3 or the pharmaceutical composition described in claim 4 prepare prevention, Purposes in the medicine of processing, treatment or mitigation patient's thrombotic disease.

7. purposes according to claim 6, wherein the thrombotic disease is miocardial infarction, angina pectoris, blocked again With the ISR after revascularization or aortocoronary bypass, apoplexy, of short duration ischaemic breaking-out, peripheral arterial Obliteran, pulmonary embolism or Deep vain thrombosis.

8. purposes according to claim 7, the purposes is that compound or right described in claim any one of 1-3 will The pharmaceutical composition described in 4 is asked to be used for the purposes for preparing the medicine for the treatment of disseminated intravascular coagulation.

9. purposes according to claim 7, the purposes is any one of claim the 1-3 compound or claim Pharmaceutical composition described in 4 is used for the purposes for preparing inhibiting factor Xa medicine.