CN104478869B - Oxazolidinone compound and application thereof to drugs - Google Patents

Abstract

The invention relates to an oxazolidinone compound and an application thereof to preparation of drugs for preventing and treating thromboembolic diseases and in particular relates to a compound shown in a general formula (I) in the specification or stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound. All the variables are defined in the specification. The invention also relates to an application of the compound shown in the general formula (I) or the stereoisomers, geometrical isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of the compound as drugs and in particular relates to an application of the substances as drugs for preventing and treating thromboembolic diseases.

Description

Oxazolidinone compounds and its application in medicine

Technical field

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

Background technology

The main practical function of the Xa factor of activation is to produce thrombin by the limited proteolysises to thrombin, In occupation of center in the final general path of blood coagulation, it in connection with inherent and external activation equipment to Xa factor System.Thrombin is the final serine protease in the path for produce fibrin clot.Answered by forming thrombinogen Compound (Xa factor, factor Ⅴ, Ca²⁺And phospholipid) amplifying generation of the thrombin 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 more more effective than making thrombin inactivation 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 thrombosis Thromboembolism disease.The present invention relates to new Xa factor inhibitor；Preferably there are the pharmacological characteristics for improving；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 dissolubility, permeability and the adaptability to Sustained-release formulations), volume requirements (as relatively low dosage and/ Or dosage once a day), reduce with peak valley characterize 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), reduce adverse side effect probability factor (such as the medicine outside serine protease Selectivity of science, possible chemistry or metabolic response and limited CNS permeabilitys) and improve production cost or feasible Property factor (difficulty, the number of chiral centre, the simplicity of chemical stability and operation such as synthesis).

The content of the invention

The present invention provides a kind of compound, or its pharmaceutical composition, can be with the effectively treatment blood related to inhibitive factor Xa Bolt embolism class diseases.

On the one hand, the present invention relates to a kind of compound, it is the compound as shown in formula (I), or formula (I) compound is vertical It is body isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or prodrug,

Wherein, X is F, Cl, Br or I；

R¹For hydrogen or deuterium；

R²For hydrogen or deuterium；With

R for saturation or part undersaturated 5 yuan or 6 circle heterocycles bases, it contains one or more independently selected from O, N, S Hetero atom, wherein the saturation or part undersaturated 5 yuan or 6 circle heterocycles bases separately by one or more oxos The substituent group of (=O) is replaced.

In some embodiments,

R is

The present invention relates to the compound of one of or its stereoisomer, geometric isomer, tautomer, 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, adjuvant, vehicle or Combinations thereof.

On the other hand, the present invention relates to described compound or described pharmaceutical composition are being prepared, prevent, process or controlled Treat the purposes in the medicine of thrombotic disease.

In certain embodiments, purposes of the present invention, wherein the thrombotic disease is myocardial infarction, heart strand Bitterly, block again and revascularization or the restenosiss after aorta Coronary artery bypass, apoplexy, of short duration ischemia Work, peripheral arterial occlusive disease, pulmonary infarction or venous 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 inravascular 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 the medicine of standby inhibitive factor Xa.

Another aspect of the present invention is related to the method for the preparation, separation and purification of the compound that formula (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, adjuvant, medium representated by formula (I) Effectively treatment amount needed for the combination of thing.The same disease comprising effectively suppression osteoporosis of the invention, or it is quick to this disease The method of sense, the method is included patient is treated using the therapeutically effective amount of compound representated by formula (I).

Unless other aspects show, and all of stereoisomer of 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 " to include that material or compositionss must Must be adapted to chemistry or toxicology, the mammal with the other components of composition preparation and for treating is relevant.

The salt of the compound of the present invention is also included for preparation or the intermediate of compound shown in purification formula (I) or formula (I) The salt of the detached enantiomer of shown compound, 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 mineral acid, such as hydrochloric acid, hydrobromic acid, sulphuric 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, acetone 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；Aminoacid, such as aspartic acid 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., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N⁺(R¹⁴)₄Salt and alkaline earth gold Category hydroxide, etc..Suitable salt is included, but is not limited to, from the organic salt that aminoacid is obtained, 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 salt from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium. Also appropriate, nontoxic ammonium, the such as amine cation that quaternary ammonium salt and gegenions are formed, halogenide, 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

Certain embodiments of the present invention are will now be described in more detail, the example is by the structural formula and chemical formula explanation enclosed.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in such as the present invention of claim definition 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, patent and similar material for being combined Or many it is different from the application or conflicting in the case of 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, carry 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 according to the present invention and public publication are integrally incorporated by reference this 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 versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, 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.

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), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described to receive Examination pair as if people.

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

As described in the invention, the compound of the present invention optionally can be replaced by one or more substituent groups, such as General formula compound above, or as the special example in embodiment the inside, subclass, and the class compound that the present invention is included. In general, term " substituted ", represent replaced by concrete substituent group to one or more hydrogen atoms in structure.Unless Other aspects show that an optional substituted radical can have a substituent group, and each commutable position is taken in group Generation.When more than one position can be selected from one or more substituent groups of concrete group and be replaced in given structural formula, that Substituent group can be replaced with identical or different in each position.

" optional " either " optionally " means that event described later or environment may or may not occur, the explanation Including the thing occasion that either environment occurs or do not occur.For example, mean " optionally by alkyl-substituted heterocyclic group " Alkyl can with but necessarily exist, the explanation is not replaced by alkyl-substituted scene and heterocyclic group including heterocyclic group by alkyl Scene.

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.For example, if the structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then represent 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 substituent groups described in the invention.Some of them embodiment is, 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-pro-pyl (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 " heterocycle ", " heterocyclic radical ", " miscellaneous alicyclic " or " heterocycle " is used interchangeably herein, all referring to monocyclic, Bicyclic or three-ring system, one or more atoms can be replaced with individually optional by hetero atom on its medium ring, and ring can be Full saturation or comprising one or more degrees of unsaturation, but be definitely not the fragrant same clan, only one of which junction point is connected to other points Son gets on.One or more ring hydrogen atoms are taken by one or more substituent groups described in the invention individually optionally Generation.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", and " miscellaneous alicyclic " or " heterocycle " group are the monocyclic of 3-7 yuan of rings (1-6 carbon atom and selected from N, 1,2 or 3 hetero atom of O, P, S, in this S or P optionally by one or more oxygen atom institutes Replacement is obtained as SO, SO₂, PO, PO₂Group, when described ring is three-membered ring, only one of which hetero atom), or 7-10 Bicyclic (the 4-9 carbon atom and selected from N, 1,2 or 3 hetero atom of O, P, S, in this S or P optionally by one or more of unit Oxygen atom replaces and obtains as SO, SO₂, PO, PO₂Group).Heterocyclic radical can be carbon-based or nitrilo, and-CH₂- group can be with Optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optional Be oxidized to N- oxygen compounds.

Heterocyclic radical can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group with saturation or part insatiable hunger With ring or heterocyclic fused formed group.In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, is referred to Saturation comprising 4-7 annular atom or part are undersaturated monocyclic, and wherein at least one annular atom is selected from nitrogen, sulfur and oxygen atom. Unless otherwise indicated, 4-7 former molecular heterocyclic radicals can be carbon-based or nitrilo, and-CH₂- group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The example of heterocycle is included, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, Tetramethylene sulfide Base, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl ， thioxane bases, piperazinyl, Homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- ring Heptyl, thia suberyl, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, 2- pyrrolinyls, 3- pyrrolinyls, dihydro Yin Diindyl base, 2H- pyranoses, 4H- pyranoses, dioxacyclohexyl, 1,3- dioxy amyl group, pyrazolinyl, dithiane base, dithiolane Base, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyl, 3- azabicyclos [3.1.0] hexyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H- indyls quinolizinyl and N- pyridines Base carbamide.The example of heterocyclic group also includes that two carbon atoms are by oxygen atom institute on 1,1- dioxidothiomorpholinyl, and its medium ring Replace such as hybar X base.And-the CH in the heterocyclic radical₂- group can optionally by-C (=O)-replacement.

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

Unless other aspects show, structural formula described in the invention includes all of isomeric forms (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) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the invention or its is right Reflect isomer, diastereomer, or the mixture of geometric isomer (or conformer) and 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. It is such conversion by prodrug hydrolyze in blood or in blood or tissue Jing enzymatic conversions are affected for precursor structure.This Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that have of prodrug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamatess 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 ester, such as these phosphate compounds are that the di on Jing parents is obtained.Beg for regard to prodrug is complete 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 other aspects show that all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless showing in terms of other, 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 pass through the present invention such as and retouch by technology known to art Adopt as stating and experimentally characterized.Such product can be by the way that compound is administered through oxidation, reduction, water Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysises etc. method is obtained.Correspondingly, the present invention includes compound Metabolite, including the metabolite being fully contacted compound and the mammal of the present invention produced by a period of time.

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.The all of stereoisomeric forms in any ratio of compound of the present invention, including but not limited to, diastereomeric Body, enantiomer, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention. Many organic compound are all with optical active forms presence, the i.e. plane of their capable Plane of rotation polarized light.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 Come the symbol for naming compound linearly polarized light to rotate, (-) 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 isomer can be enantiomer, and the mixture of isomer is commonly referred to enantiomeric mixture.50：50 enantiomer mixing Thing is referred to as racemic mixture or racemic modification, and this may cause in chemical reaction process without stereo selectivity or three-dimensional fixed Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack light Learn activity.

" stereoisomer " is referred to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..

Term " tautomer " or " tautomeric form " refer to that the isomerss of the structure of different-energy can be with Mutual inversion of phases is built by mental retardation.Such as proton tautomer (i.e. prototropic tautomer) includes being migrated by proton Change, the such as isomerization of keto-enol and imine-enamine.Atomicity (quantivalence) tautomer includes The change of restructuring bonding electronss.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salt 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 hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange is obtaining these salt.Other pharmaceutically acceptable salts include adipate, malate, 2- Hydracrylate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, fourth Hydrochlorate, Camphora 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 group comprising N is formed.Water solublity or oil-soluble or dispersion Product can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically may be used The salt of acceptance is further included appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, 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 one or more solvent molecules are formed with the compound of the present invention 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 complex that water is formed.

When term " blocking group " or " Pg " refer to a substituent group with other reacted with functional groups, resistance is commonly used to Break or protect special feature.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or protection compound in amino feature, suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl Base is used for blocking or protect the feature of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl-protecting group Group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group 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, it is also possible to their hydrate forms or comprising 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) is inherently or by design forming solvate；Therefore, it is contemplated that including solvation And unsolvated form.

Any structural formula that the present invention is given is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The compound of isotope enrichment has the structure that the formula that the present invention is provided 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 in the compounds of this invention Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, 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 the defined compound of the present invention of isotope enrichment, for example, its In there is radiosiotope, such as³H,¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research and (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 SPECT (single photon emission computed tomography) (SPECT), or can be used 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 techniquess known or the present invention is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.

Additionally, higher isotope is particularly deuterium (i.e.,²H or D) replacement some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements are reduced or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I) compound.Can be determined with isotope enrichment factor Adopted such higher isotope is particularly the concentration of 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 group of the compounds of this invention is designated as deuterium, the change Compound have for each D-atom specified at least 3500 (at each specified D-atoms 52.5% deuterium mix), at least 4000 (60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500 (82.5% deuterium mix), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7 The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be that isotope replaces₂O, acetone-d₆、 DMSO-d₆Those solvates.

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

Include the compound shown in formula (I) according to the characteristics of another aspect, the pharmaceutical composition of the present invention, the present invention is listed The compound for going out, or the compound of embodiment 1-5, and pharmaceutically acceptable carrier, adjuvant, 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, as pharmaceutically acceptable derivates.According to this 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 for needing to be administered or derivant of patient, described by other aspects of the invention Compound, its metabolite or his residue.

As described in the invention, pharmaceutically acceptable compositionss of the invention further include pharmaceutically acceptable load Body, adjuvant, 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, thickening agent, 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 applicable to the preparation of pharmaceutically acceptable compositionss and their known preparation methoies.Except any conventional carrier The incompatible scope of compound of medium and the present invention, such as produced any bad biological effect or with pharmaceutically can connect What any other component for the compositionss received was produced in harmful manner interacts, and their purposes is also that the present invention is considered Scope.

Can include, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminum, aluminium stearate, ovum Phospholipid, such as serum albumin, 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, lanoline, such as sugar, Lactose, dextrose and saccharose；Starch such as corn starch and potato starch；Cellulose and its derivant Such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Gum powder；Fructus Hordei Germinatus；Gelatin；Pulvis Talci；Adjuvant such as cacao bean Fat and suppository wax；Oil such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines；Glycolss chemical combination Thing, such as Propylene Glycol and Polyethylene Glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer agent 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, coloring agent, releasing agent, coating agents, sweeting agent, flavoring agent and perfume (or spice) Material, preservative and antioxidant.

The compounds of this invention can be applied 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, powder, granule, elixir, tincture, suspending agent, syrup, and emulsifying agent.It Can also be with intravenouss (bolus or transfusion), intraperitoneal, subcutaneous or intramuscular form is applied, all agent for using 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 be different with known various factors, such as the characteristics of pharmacokinetics of particular agent And its pattern and route of administration；The race of receiver, 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 for reaching Really.Either veterinary can make decision and output the medicine of effective dose preventing, offset or prevent thromboembolism for one doctor Advancing of disease.

According to general guideline, in order to reach the effect specified, the day of each active component for being used is oral The scope of dosage is of about 0.001 between 1000mg/kg body weight, it is preferable that between about 0.01 to 100mg/kg body weight. And, most preferably, between about 1.0 to 20mg/kg body weight/days.For intravenous administration, in the transfusion of conventional rate During most preferably dosage range be of about 1 to about 10mg/kg body weight/minute.The compounds of this invention can be with daily one It is secondary applying, or can be administered for three times or four times with daily at twice.

The compound of the present invention through the local of suitable nasal carrier using applying in intranasal form, or can pass through Using percutaneous plaster with cutaneous routes administration.When being applied in the form of transdermal delivery system, apply during whole medication Dosage is continuous rather than interval.Typically, the compound is selected with the pharmacy practice according to the form and routine applied The suitable pharmaceutical diluents selected, excipient, or carrier (here refers to pharmaceutical carriers) are mixed to be applied, and method of application can be Oral tablet, capsule, elixir, syrup etc..

For example, for being applied with tablet or capsules per os, 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, Sorbitol etc.；For Orally administered in liquid form, oral drug components can with appoint What oral, atoxic, pharmaceutically combination of acceptable inert carrier, such as ethanol, glycerol, water etc..And, work as needs Or when required, suitable binding agent, lubricant, decomposing agents and coloring 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 sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax etc..Apply in these dosage forms Lubricant includes enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, Sodium Chloride etc..Distintegrant includes, but not It is limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc..

The compounds of this invention can also be applied in the form of liposomal delivery system, such as the vesicle of little monolayer, big list The vesicle and multilamellar vesicle of layer.Liposome can be formed by different phospholipid, such as cholesterol, stearylamine, or phosphatidyl Choline.

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

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

Gelatine capsule can be containing 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 is providing the medicine of the continuous release within a period of time.The tablet of compression can add sugar-coat or bag last layer thin Film covering any offending taste and make tablet and air exclusion, or plus enteric solubility coating in the intestines and stomach Optionally decompose in digestive tract.

Orally administered liquid dosage form can be containing coloring agent and flavouring agent improving the acceptance of patient.

Generally, water, a kind of suitable oil, saline, the dextrose (glucose) of hydration, and the sugar juice and glycol of correlation (such as Propylene Glycol or Polyethylene Glycol) is the Suitable carriers of parenteral solution.The solution applied without intestinal preferably comprises work Property composition water soluble salt, suitable stabilizer, and may necessary buffer substances.Antioxidant is suitable stable Agent, such as sodium sulfite, sodium sulfite, or vitamin C, both individually can also can be applied in combination can also with citric acid and Its salt and EDETATE SODIUM salt.Additionally, parenteral solution also contains preservative, such as geramine, methyl-or propyl group-to hydroxyl Yl benzoic acid ester, and chlorobutanol.

Compound wherein of the invention and other anti-freezing agent combinations, for example, for every kg patient body weight, Yi Zhong Dosage can be the compound of about 0.1 to 100mg formula (I) and about 1 to 7.5mg the second anticoagulant.For a kind of piece Agent dosage form, the compound of the present invention typically can be that each dosage unit has about 5 to 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 compound and about 50 to 150mg antiplatelet of the per kilogram patient body weight about 0.01 to the formula (I) of 25mg Reagent, the compound of preferably approximately 0.1 to 1mg formula (I) and about 1 to 3mg antiplatelet reagent.When the chemical combination of formula (I) 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 the formula (I) of 1mg Compound, and under conditions of thrombolytics are present, compared with general dosage when thrombolytics are 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 aforesaid 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 dosage form during combined administration The amount divided, relative to usual dosage when being administered alone, can decline.

Especially, when providing as a single dosage unit, change between the active component that there is combination Learn the probability of reaction.Due to this reason, when the compound and second therapeutic agent of formula (I) is 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 coating.One is coated with by enteric coating 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 that one kind of these components does not discharge under one's belt in small intestinal.Activity Composition it is a kind of can also superscribe affect its sustained release in the gastrointestinal tract and can also be used for reduce united activity into The material of the physical contact between point further, the component of sustained release can also extraly with enteric coating coating in order to this into Divide and only discharge in intestinal.Also another method is related to the formula of joint product, and one of component is held with one kind The polymer coating of continuous and/or enteric release, and another component is also with for example a kind of hydroxyl of low viscosity rank of polymer Propyl methocel (HPMC) or other suitable material coatings known in the field, to reach further separation The purpose of active component.Polymer coating pair defines a kind of extra obstruction with the reaction of other components.

Once understand present disclosure, the contact minimum made between the component for combining product of the invention of these and other The method of change is it will be apparent that no matter they are applied with single formulation or in detached form for those skilled in the art Apply, but be in the identical time or apply in an identical manner.

Compound according to the present invention or its pharmaceutical salts or its hydrate can be effective for preventing, processing, treat or subtract Light patient's thrombotic disease, particularly can effectively treatment myocardial infarction, angina pectoriss, block again and revascularization or active Restenosiss, apoplexy after arteries and veins Coronary artery bypass, of short duration ischemia outbreak, peripheral arterial occlusive disease, pulmonary infarction Or venous 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 group such as formula (I).Following reaction scheme and embodiment is used to that this to be further illustrated 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 of many present invention, and other methods for preparing the compound of the present invention are considered as the model in the present invention Within enclosing.For example, can 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 reagents except 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 applied to the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Ling Kai is medical, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not through 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 company limited, and Haiyang Chemical Plant, Qingdao is commercially available.

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

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

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with CDC1₃Or DMSO-d₆(report in units of ppm) for solvent, with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When there is multiplet, by using following abbreviation：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 outfit G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) Agilent6320 series LC-MS spectrogrph determining, G1329A automatic samplers and G1315B DAD detectors Analysis is applied to, ESI sources are applied to LC-MS spectrogrphs.

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

Both the above spectrogrph 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；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength is recording 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 purification is evaluated by the series of high efficiency liquid chromatograph (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 (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

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

CDC1₃Deuterochloroform

DMSO dimethyl sulfoxide

G gram

Mg milligrams

Deuterated ethanol-the D1 of ethanol-D1

Mol mole

Mmol mM

μ L microlitre

DMSO-d₆Deuterated dimethyl sulfoxide

NaBH₄Sodium borohydride

NaBD₄Boron deuterate sodium

H hours

ML milliliters

FXa factors Xa

HATU 2- (7- azo BTAs)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester

Synthetic schemes

Synthetic schemes 1：

The method that target product 9a can be described by synthetic schemes 1 is prepared, wherein X₁For Cl, Br, I or other are easy Leaving group, also, R, R₁、R₂There is implication as described in the present invention with X.

Raw material 1a is in go back original reagent (such as NaBH₄Or NaBD₄) in the presence of generate intermediate 2a；Intermediate 2a is replacing examination Intermediate 3a is generated in the presence of agent (such as phosphorus tribromide, methyl sulphonyl or p-toluenesulfonyl)；Intermediate 3a and R-H is in alkali Effect generate intermediate 4a；Intermediate 4a and raw material 5a is in Hydro-Giene (Water Science)., part (such as N, N'- dimethyl-ethylenediamines) and alkali In the presence of (such as potassium carbonate), in a solvent Jing high temperature carries out coupling reaction, obtains intermediate 6a；Intermediate 6a is acted in methylamine Under, the deprotection in ethanol generates intermediate 7a；Intermediate 7a and acid 8a carries out condensation reaction and obtains target product 9a.

Specific 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 The restriction of bright scope.

Embodiment 1:The chloro- N- of 5- [[(5S) -3- [4- [two deuterated-(3- oxomorpholin -4- bases) methyl] thiazol-2-yl] - Oxazolidine -5- the bases of 2- oxos -] methyl] thiophene-2-carboxamide derivatives

Step 1:The bromo- 4- of 2- [two deuterated (deuteroxyl) methyl] thiazole

At 0 DEG C, in the ethanol-D1 (30mL) of 2- bromo thiazoles -4- Ethyl formates (2.8g, 12mmol) on a small quantity in multiple times Boron deuterate sodium (990mg, 24mmol) is added, stirring 0.5 hour is continued at 0 DEG C after adding, be warmed to room temperature stirring 3 hours, It is heated to 70 DEG C to stir 4 hours.Decompression boils off solvent, and water (30mL) is slowly added to thereto, is extracted with ethyl acetate (50mL × 3) Take.Merge organic faciess, washed with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=5/1), obtain pale yellow oil (1.3g, 56%).

MS(ESI,pos.ion)m/z:198.90(M+1)

Step 2:The bromo- 4- of 2- [bromine (two is deuterated) methyl] thiazole

At 0 DEG C, to the dichloromethane of the bromo- 4- of 2- [two deuterated (deuteroxyl) methyl] thiazole (3.3g, 17mmol) (40mL) tribromo oxygen phosphorus (3.2mL, 33mmol) is added in solution.It is warmed to room temperature and is stirred overnight.Water (40mL) is added thereto to, is used Dichloromethane (60mL × 3) is extracted, and merges organic faciess, is washed with saturated aqueous common salt (80mL), anhydrous sodium sulfate drying.Filter, Decompression boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=20/1), obtain white solid (2.2g, 51%).

MS(ESI,pos.ion)m/z:258.85(M+1)。

Step 3:4- [(2- bromo thiazole -4- bases)-two deuterated-methyl] morpholine -3- ketone

At 0 DEG C, to the bromo- 4- of 2- [bromine (two is deuterated) methyl] thiazole (3.8g, 15mmol), morpholine -3- ketone (1.5g, 15mmol) and in tetrahydrofuran (50mL) solution of tetrabutylammonium iodide (270mg, 0.73mmol) add 60% sodium hydride (1.2g, 29mmol), continues to be stirred 1 hour at 0 DEG C.It is warmed to room temperature stirring 4 hours.It is added thereto to water (50mL) and uses second Acetoacetic ester (100mL × 3) is extracted, and merges organic faciess, is washed with saturated aqueous common salt (40mL), anhydrous sodium sulfate drying.Filter, subtract Pressure boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/2), obtain pale yellow oil (1.7g, 42%).

MS(ESI,pos.ion)m/z:280.95(M+1).

Step 4:2- [[(5S) -3- [4- [two deuterated-(3- oxomorpholin -4- bases) methyl] thiazol-2-yl] -2- oxos - Oxazolidine -5- bases] methyl] isoindoline -1,3- diketone

Sequentially add in tube sealing 4- [(2- bromo thiazole -4- bases)-two deuterated-methyl] morpholine -3- ketone (1.7g, 6.1mmol), (R) -2- ((2- Yang Dai oxazolidine -5- bases) isoindoline -1,3- diketone (1.5g, 6.1mmol), N, N'- diformazans Base ethylenediamine (210mg, 2.4mmol), Hydro-Giene (Water Science). (230mg, 1.2mmol), potassium carbonate (2.5g, 18mmol) and 1,4- dioxies Six rings (20mL), under nitrogen atmosphere, are heated to 120 DEG C and stir 8 hours.It is cooled to room temperature, filters, filtrate decompression boils off solvent, Crude product Jing column chromatography purification (methylene chloride/methanol (v/v)=30/1), obtain white solid (1.4g, 52%).

MS(ESI,pos.ion)m/z:445.10(M+1)。

Step 5:4- [[2- [(5S) oxazolidine -3- bases of -5- (amino methyl) -2- oxos -] thiazole-4-yl]-two be deuterated - Methyl] morpholine -3- ketone

To 2- [[(5S) -3- [4- [two deuterated-(3- oxomorpholin -4- bases) methyl] thiazol-2-yl] oxazoles of -2- oxos - Alkane -5- bases] methyl] isoindoline -1,3- diketone (1.4g, 3.1mmol) ethanol (30mL) suspension in add 40% first Amine aqueous solution (3mL).It is heated to 95 DEG C to stir 1.5 hours, decompression boils off solvent.Crude product is not purified be directly used in it is next Step.

Step 6:The chloro- N- of 5- [[(5S) -3- [4- [two deuterated-(3- oxomorpholin -4- bases) methyl] thiazol-2-yl] -2- Oxazolidine -5- the bases of oxo -] methyl] thiophene-2-carboxamide derivatives

To 4- [[2- [(5S) oxazolidine -3- bases of -5- (amino methyl) -2- oxos -] thiazole-4-yl]-two deuterated-methyl] Dichloromethane (40mL) solution of morpholine -3- ketone (940mg, 3.0mmol) and 5- chlorothiophenes -2- formic acid (590mg, 3.6mmol) In sequentially add HATU (1.7g, 4.5mmol), N, N- diisopropylethylamine (780mg, 6.0mmol).It is stirred at room temperature 6 little When.Decompression boils off solvent, adds dichloromethane (35mL), and organic faciess are washed successively with saturated sodium bicarbonate (20mL), saturation food Saline (30mL) is washed, anhydrous sodium sulfate drying.Filter, reduce pressure and boil off solvent, crude product Jing column chromatography purification (dichloromethane/ Methanol (v/v)=40/1), obtain white solid (200mg, 14.6%).

¹H NMR(400MHz,DMSO-d₆) δ 8.95 (t, J=5.8Hz, 1H), 7.68 (d, J=4.1Hz, 1H), 7.19 (d, J=4.0Hz, 1H), 7.09 (s, 1H), 4.96 (td, J=11.7,5.6Hz, 1H), 4.28 (t, J=9.4Hz, 1H), 4.07 (s, 2H), 3.98 (dd, J=9.9,6.5Hz, 1H), 3.84 (t, J=5.1Hz, 2H), 3.65 (t, J=5.6Hz, 2H), 3.40- 3.37(m,2H)；

MS(ESI,pos.ion)m/z:459.10(M+1)。

Embodiment 2:(S) the chloro- N- of -5- ((2- oxo -3- (4- ((2- oxo-piperidine -1- bases) methyl) thiazol-2-yl) Evil Oxazolidine -5- bases) methyl) thiophene-2-carboxamide derivatives

Step 1:(2- bromo thiazole -4- bases) methanol

At 0 DEG C, divide in ethanol (150mL) solution of 2- bromo thiazoles -4- Ethyl formates (13.30g, 56.33mmol) Criticize and add sodium borohydride (4.263g, 112.7mmol), continue to be stirred 0.5 hour at 0 DEG C, be warmed to room temperature stirring 3 hours, then It is heated to 70 DEG C to stir 4 hours.Decompression boils off solvent, is slowly added to water (100mL), is extracted with ethyl acetate (100mL × 3). Merge organic faciess, washed with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing post Chromatography purification (petrol ether/ethyl acetate (v/v)=5/1), obtain colorless oil (9.5g, 87%).

MS(ESI,pos.ion)m/z:196.10(M+1)。

Step 2:2- bromo- 4- (bromomethyl) thiazoles

At 0 DEG C, add in dichloromethane (40mL) solution of (2- bromo thiazole -4- bases) methanol (3.88g, 20.0mmol) Enter phosphorus tribromide (3.8mL, 40.0mmol), be warmed to room temperature and be stirred overnight.Water (40mL) is added, with dichloromethane (60mL × 3) Extraction, merges organic faciess, is washed with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying.Filter, decompression boils off solvent, it is thick to produce Product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=20/1), obtain white solid (3.1g, 60%).

MS(ESI,pos.ion)m/z:256.9(M)。

Step 3:1- ((2- bromo thiazole -4- bases) methyl) piperidines -2- ketone

At 0 DEG C, to 2- bromo- 4- (bromomethyl) thiazoles (900mg, 3.5mmol), piperidines -2- ketone (350mg, 3.5mmol) With in tetrahydrofuran (20mL) solution of tetrabutylammonium iodide (65mg, 0.18mmol) add 60% sodium hydride (270mg, 6.7mmol), continue to be stirred 1 hour at 0 DEG C, be warmed to room temperature stirring 4 hours.Decompression boils off solvent, is slowly added to water (30mL), extracted with ethyl acetate (50mL × 3).Merge organic faciess, washed with saturated aqueous common salt (40mL), anhydrous sodium sulfate is done It is dry.Filter, decompression boils off solvent, and crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1) obtains faint yellow oil Shape thing (700mg, 73%).

MS(ESI,pos.ion)m/z:275.05(M+1)。

Step 4:(S) -2- ((2- oxo -3- (4- ((2- oxo-piperidine -1- bases) methyl) thiazol-2-yl) oxazolidine -5- Base) methyl) isoindoline quinoline -1,3- diketone

Sequentially add in tube sealing 1- ((2- bromo thiazole -4- bases) methyl) piperidines -2- ketone (700mg, 2.54mmol), (R) - 2- ((2- Yang Dai oxazolidine -5- bases) isoindoline -1,3- diketone (626g, 2.54mmol), N, N'- dimethyl-ethylenediamines (89.7mg, 1.02mmol), Hydro-Giene (Water Science). (96.9mg, 0.509mmol), potassium carbonate (1.05g, 7.63mmol) and 1,4- dioxies Six rings (20mL), under nitrogen atmosphere, are heated to 120 DEG C and stir 8 hours.It is cooled to room temperature, adds water (30mL), uses ethyl acetate (60mL × 3) extract.Merge organic faciess, washed with saturated aqueous common salt (40mL × 3), anhydrous sodium sulfate drying.Filter, decompression is steamed Remove solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/4), obtain white solid (655mg, 58.4%).

MS(ESI,pos.ion)m/z:441.10(M+1)。

Step 5:(S) -5- (amino methyl) -3- (4- ((2- oxo-piperidine -1- bases) methyl) thiazol-2-yl) oxazolidines - 2- ketone

To (S) -2- ((2- oxo -3- (4- ((2- oxo-piperidine -1- bases) methyl) thiazol-2-yl) oxazolidine -5- bases) first Base) isoindoline quinoline -1,3- diketone (655mg, 1.49mmol) ethanol (20mL) suspension in add 40% methylamine it is water-soluble Liquid (2.0mL).It is heated to 95 DEG C to stir 1.5 hours, decompression boils off solvent.Crude product is not purified to be directly used in next step.

Step 6:(S) the chloro- N- of -5- ((2- oxo -3- (4- ((2- oxo-piperidine -1- bases) methyl) thiazol-2-yl) oxazoles Alkane -5- bases) methyl) thiophene-2-carboxamide derivatives

To 5- chlorothiophenes -2- formic acid (291mg, 1.79mmol) and N, N- diisopropylethylamine (519 μ L, 2.98mmol) HATU (850mg, 2.24mmol) and (S) -5- (amino methyl) -3- (4- are added in N,N-dimethylformamide (10mL) solution ((2- oxo-piperidine -1- bases) methyl) thiazol-2-yl) oxazolidines -2- ketone (462mg, 1.49mmol).It is stirred at room temperature 6 little When.It is added thereto to water (20mL), ethyl acetate (50mL × 3) extraction.Merge organic faciess, with saturated aqueous common salt (30mL × 3) Washing and anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/ V)=1/6), obtain white solid (230mg, 33.9%).

¹H NMR(600MHz,DMSO-d₆) δ 8.95 (t, J=5.8Hz, 1H), 7.68 (d, J=4.1Hz, 1H), 7.19 (d, J=4.0Hz, 1H), 6.97 (s, 1H), 4.99-4.93 (m, 1H), 4.45 (s, 2H), 4.27 (t, J=9.4Hz, 1H), 3.97 (dd, J=9.9,6.5Hz, 1H), 3.67-3.60 (m, 2H), 3.30 (t, J=5.7Hz, 2H), 2.26 (t, J=6.2Hz, 2H), 1.75–1.69(m,4H)；

MS(ESI,pos.ion)m/z:454.95(M+1)。

Embodiment 3:(S) the chloro- N- of -5- ((2- oxo -3- (4- ((3- oxomorpholins) methyl) thiazol-2-yl) oxazolidines - 5- yls) methyl) thiophene-2-carboxamide derivatives

Step 1:4- ((2- bromo thiazole -4- bases) methyl) morpholine -3- ketone

At 0 DEG C, to 2- bromo- 4- (bromomethyl) thiazoles (1.1g, 4.2mmol), morpholine -3- ketone (400mg, 4.0mmol) With in tetrahydrofuran (30mL) solution of tetrabutylammonium iodide (74mg, 0.20mmol) add 60% sodium hydride (300mg, 7.6mmol), mixture continues stirring 1 hour at 0 DEG C, is then warmed to room temperature stirring 4 hours.After having reacted, water is added (30mL), gained mixture is extracted with ethyl acetate (50mL × 3), merges organic faciess, is washed with saturated aqueous common salt (40mL), nothing Aqueous sodium persulfate is dried.Filter, reduce pressure and boil off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/1), Pale yellow oil (980mg, 88%).

MS(ESI,pos.ion)m/z:278.90(M+1)。

Step 2:(S) -2- ((2- oxo -3- (4- ((3- oxomorpholins) methyl) thiazol-2-yl) oxazolidine -5- bases) first Base) isoindoline -1,3- diketone

Sequentially add in tube sealing 4- ((2- bromo thiazole -4- bases) methyl) morpholine -3- ketone (980mg, 3.5mmol), (R) - 2- ((2- Yang Dai oxazolidine -5- bases) isoindoline -1,3- diketone (870mg, 3.5mmol), N, N'- dimethyl-ethylenediamines (120mg, 1.4mmol), Hydro-Giene (Water Science). (130mg, 0.71mmol), potassium carbonate (1.5g, 11mmol) and 1,4- dioxane (20mL), under nitrogen atmosphere, it is heated to 120 DEG C to stir 8 hours.It is cooled to room temperature, adds water (30mL), uses ethyl acetate (50mL × 3) extract.Merge organic faciess, washed with saturated aqueous common salt (40mL × 3), anhydrous sodium sulfate drying.Filter, decompression is steamed Remove solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/4), obtain white solid (770mg, 49%).

MS(ESI,pos.ion)m/z:442.90(M+1)。

Step 3:(S) -4- ((2- (5- (amino methyl) -2- Yang Dai oxazolidine -3- bases) thiazole-4-yl) methyl) morpholine - 3- ketone

To (S) -2-, ((2- oxo -3- (4- ((3- oxomorpholins) methyl) thiazol-2-yl) oxazolidine -5- bases) methyl) is different 40% methylamine water solution is added in ethanol (20mL) suspension of indoline -1,3- diketone (750mg, 1.7mmol) (2.0mL).It is heated to 95 DEG C to stir 1.5 hours, decompression boils off solvent.Crude product is not purified to be directly used in next step.

Step 4:(S) the chloro- N- of -5- ((2- oxo -3- (4- ((3- oxomorpholins) methyl) thiazol-2-yl) oxazolidine -5- Base) methyl) thiophene-2-carboxamide derivatives

To 5- chlorothiophenes -2- formic acid (330mg, 2.0mmol) and the N of N, N- diisopropylethylamine (590 μ L, 3.4mmol), HATU (970mg, 2.6mmol) and (S) -4- ((2- (5- (amino methyl) -2- are added in dinethylformamide (15mL) solution Yang Dai oxazolidine -3- bases) thiazole-4-yl) methyl) morpholine -3- ketone (530mg, 1.7mmol).It is stirred at room temperature 6 hours.To Wherein add water (20mL), ethyl acetate (50mL × 3) extraction.Merge organic faciess, wash with saturated aqueous common salt (30mL × 3) with Anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/ 4), obtain white solid (210mg, 27%).

¹H NMR(600MHz,DMSO-d₆) δ 8.95 (t, J=5.8Hz, 1H), 7.68 (d, J=4.0Hz, 1H), 7.19 (d, J=4.0Hz, 1H), 7.08 (s, 1H), 4.96 (dt, J=14.5,5.9Hz, 1H), 4.51 (s, 2H), 4.28 (t, J=9.3Hz, 1H), 4.08 (s, 2H), 3.97 (dd, J=9.8,6.5Hz, 1H), 3.84 (t, J=5.1Hz, 2H), 3.68-3.61 (m, 2H), 3.40–3.37(m,2H)；

MS(ESI,pos.ion)m/z:457.00(M+1)。

Embodiment 4:The chloro- N- of 5- [[(5S) -3- [4- [two deuterated-(2- oxo -1- pyridine radicals) methyl] thiazol-2-yl] - Oxazolidine -5- the bases of 2- oxos -] methyl] thiophene-2-carboxamide derivatives

Step 1:1- [(2- bromo thiazole -4- bases)-two deuterated-methyl] pyridin-2-ones

To in methanol (20mL) solution of pyridine -2 (1H) -one (800mg, 8.4mmol) add potassium carbonate (2.24g, 16.2mmol) with the bromo- 4- of 2- [bromine (two is deuterated) methyl] thiazole (2.1g, 8.1mmol).It is heated to 85 DEG C to stir 3 hours, mistake Filter, filtrate decompression boils off solvent.Water (30mL) is added, with ethyl acetate (40mL × 3).Merge organic faciess, use saturated aqueous common salt (50mL) wash, anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (dichloromethane/acetic acid Ethyl ester (v/v)=2/1), obtain yellow solid (1.57g, 71%).

MS(ESI,pos.ion)m/z:272.9(M+1)。

Step 2:2- [[(5S) -3- [4- [two deuterated-(2- oxo -1- pyridine radicals) methyl] thiazol-2-yl] -2- oxos - Oxazolidine -5- bases] methyl] isoindoline -1,3- diketone

Sequentially add in tube sealing 1- [(2- bromo thiazole -4- bases)-two deuterated-methyl] pyridin-2-ones (1.57g, 5.75mmol), (R) -2- ((2- Yang Dai oxazolidine -5- bases) isoindoline -1,3- diketone (1.42g, 5.77mmol), N, N'- bis- Methyl ethylenediamine (202mg, 2.30mmol), Hydro-Giene (Water Science). (220mg, 1.2mmol), potassium carbonate (2.38g, 17.2mmol) and 1, 4- dioxane (25mL), under nitrogen atmosphere, is heated to 120 DEG C and stirs 10 hours.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=2/3), obtain white solid (840mg, 33%).

MS(ESI,pos.ion)m/z:438.90(M+1)。

Step 3:(5S) -5- (amino methyl) -3- [4- [two deuterated-(2- oxo -1- pyridine radicals) methyl] thiazol-2-yl] Oxazolidine -2- ketone

To 2- [[(5S) -3- [4- [two deuterated-(2- oxo -1- pyridine radicals) methyl] thiazol-2-yl] oxazoles of -2- oxos - Alkane -5- bases] methyl] isoindoline -1,3- diketone (840mg, 1.9mmol) ethanol (20mL) solution in add 40% methylamine Aqueous solution (2.0mL).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 without further place Reason is directly used in next step reaction.

Step 4:The chloro- N- of 5- [[(5S) -3- [4- [two deuterated-(2- oxo -1- pyridine radicals) methyl] thiazol-2-yl] -2- Oxazolidine -5- the bases of oxo -] methyl] thiophene-2-carboxamide derivatives

To (5S) -5- (amino methyl) -3- [4- [two deuterated-(2- oxo -1- pyridine radicals) methyl] thiazol-2-yl] oxazoles Dichloromethane (20mL) solution of alkane -2- ketone (590mg, 1.9mmol) and N, N- diisopropylethylamine (985mg, 7.62mmol) Middle addition HATU (1.09g, 2.87mmol) and 5- chlorothiophenes -2- formic acid (373mg, 2.29mmol).It is stirred at room temperature 6 hours. Decompression boils off solvent, dichloromethane (50mL) is added thereto to, successively with saturated sodium bicarbonate aqueous solution (30mL) and saline solution (30mL) wash, anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petroleum ether/acetic acid second Ester (v/v)=1/2), obtain white solid (100mg, 12%).

¹H NMR(600MHz,DMSO-d₆) δ 8.96 (t, J=5.8Hz, 1H), 7.71 (dd, J=6.8,1.8Hz, 1H), 7.68 (d, J=4.1Hz, 1H), 7.43 (ddd, J=8.9,6.6,2.1Hz, 1H), 7.19 (d, J=4.0Hz, 1H), 6.98 (s, 1H), 6.41 (d, J=9.0Hz, 1H), 6.25 (td, J=6.7,1.2Hz, 1H), 5.00-4.91 (m, J=12.1,5.6Hz, 1H), 4.26 (t, J=9.4Hz, 1H), 3.94 (dd, J=9.8,6.6Hz, 1H), 3.69-3.60 (m, 2H)；

MS(ESI,pos.ion)m/z:452.9(M+1)。

Embodiment 5:(S) the chloro- N- of -5- ((2- oxo -3- (4- ((2- oxo pyridines -1 (2H)-yl) methyl) thiazole -2- Base) oxazolidine -5- bases) methyl) thiophene-2-carboxamide derivatives

Step 1:1- ((2- bromo thiazole -4- bases) methyl) pyridine -2 (1H) -one

To in methanol (30mL) solution of pyridine -2 (1H) -one (951mg, 10.0mmol) add potassium carbonate (2.76g, 20.0mmol) with 2- bromo- 4- (bromomethyl) thiazoles (2.57g, 10.0mmol), it is heated to 70 DEG C and stirs 3 hours.Sucking filtration, decompression Solvent is boiled off, water (40mL) is slowly added to, is extracted with ethyl acetate (50mL × 3).Merge organic faciess, use saturated aqueous common salt (50mL) wash, anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petroleum ether/acetic acid second Ester (v/v)=1/1), obtain yellow oil (1.8g, 66%).

MS(ESI,pos.ion)m/z:272.90(M+1)。

Step 2:(S) -2- ((2- oxo -3- (4- ((2- oxo pyridines -1 (2H)-yl) methyl) thiazol-2-yl) oxazoles Alkane -5- bases) methyl) isoindoline quinoline -1,3- diketone

Sequentially add in tube sealing 1- ((2- bromo thiazole -4- bases) methyl) pyridine -2 (1H) -one (1.80g, 6.64mmol), (R) -2- ((2- Yang Dai oxazolidine -5- bases) isoindoline -1,3- diketone (1.63g, 6.64mmol), N, N'- dimethyl-ethylenediamines (234mg, 2.66mmol), Hydro-Giene (Water Science). (253mg, 1.33mmol), potassium carbonate (2.75g, 19.9mmol) and 1,4- dioxies six Ring (20mL), under nitrogen atmosphere, is heated to 120 DEG C and stirs 10 hours.It is cooled to room temperature, adds water (30mL), uses ethyl acetate (60mL × 3) extract.Merge organic faciess, washed with saturated aqueous common salt (40mL × 3), anhydrous sodium sulfate drying.Filter, decompression is steamed Remove solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/5), obtain white solid (760mg, 26.2%).

MS(ESI,pos.ion)m/z:437.15(M+1)。

Step 3:(S) -5- (amino methyl) -3- (4- ((2- oxo pyridines -1 (2H)-yl) methyl) thiazol-2-yl) oxazoles Alkane -2- ketone

To (S) -2- ((2- oxo -3- (4- ((2- oxo pyridines -1 (2H)-yl) methyl) thiazol-2-yl) oxazolidine -5- Base) methyl) isoindoline quinoline -1,3- diketone (759mg, 1.74mmol) ethanol (20mL) suspension in add 40% methylamine Aqueous solution (2.0mL).It is heated to 95 DEG C to stir 1.5 hours, decompression boils off solvent.Crude product is not purified be directly used in it is next Step.

Step 4:(S) the chloro- N- of -5- ((2- oxo -3- (4- ((2- oxo pyridines -1 (2H)-yl) methyl) thiazol-2-yl) Oxazolidine -5- bases) methyl) thiophene-2-carboxamide derivatives

To 5- chlorothiophenes -2- formic acid (339mg, 2.09mmol) and N, N- diisopropylethylamine (606 μ L, 3.48mmol) HATU (992mg, 2.61mmol) and (S) -5- (amino methyl) -3- (4- are added in N,N-dimethylformamide (10mL) solution ((2- oxo pyridines -1 (2H)-yl) methyl) thiazol-2-yl) oxazolidines -2- ketone (533mg, 1.74mmol).It is stirred at room temperature 6 hours.It is added thereto to water (20mL), ethyl acetate (50mL × 3) extraction.Merge organic faciess, with saturated aqueous common salt (30mL × 3) washing and anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product Jing column chromatography purification (petrol ether/ethyl acetate (v/v)=1/7), obtain white solid (520mg, 66%).

¹H NMR(600MHz,DMSO-d₆) δ 8.95 (t, J=5.7Hz, 1H), 7.70 (dd, J=6.7,1.4Hz, 1H), 7.68 (d, J=4.0Hz, 1H), 7.48-7.37 (m, 1H), 7.19 (d, J=4.0Hz, 1H), 6.96 (s, 1H), 6.40 (d, J= 9.1Hz, 1H), 6.24 (t, J=6.3Hz, 1H), 5.06 (s, 2H), 5.00-4.90 (m, 1H), 4.25 (t, J=9.3Hz, 1H), 3.98-3.90 (m, 1H), 3.64 (t, J=5.5Hz, 2H)；

MS(ESI,pos.ion)m/z:451.00(M+1)。

Biological activity test

Mankind FXa enzyme levels are tested

The transformation assay that the enzymatic activity of mankind's factor Xa (FXa) passes through the chromogenic substrate for FXa specificitys.It is right This, factor Xa is cracked from chromogenic substrate falls p-Nitraniline..This is determined as follows to state and carries out on microwell plate.

Tester is dissolved in 10% dimethyl sulfoxide by variable concentrations, (10nM is dissolved in take the μ L of compound 5 and mankind FXa 50mMTris, 150mMNaCl, pH=8.3) 10 μ L mixing, 15min is incubated in 25 DEG C of constant incubators, FXa is added after incubation The μ L of chromophoric substrate (800 μM, sigma) 5, the kinetic test absorbance at 25 DEG C of 405nm.By the test containing test substances Mixture and the control mixture without test substances compare and are calculated IC by these data₅₀Value.

Anticoagulation effect in vitro is tested

Compound extends the clotting time of rabbit plasma

1. the preparation of each concentration compound

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

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 The vacuum test tube abdominal aorta of 0.2mL is taken a blood sample to 2mL, collects multitube, turns upside down mixing for several times, stands 10min, in 3000rpm is centrifuged 10min, draws each pipe blood plasma, and all blood plasma are mixed to same centrifuge tube, the every pipe subpackages of 1.6mL, puts rapidly Enter -80 DEG C of Refrigerator stores standby.

3. it is loaded and determines clotting time PT and APTT

1.5mL EP pipes are got out, often pipe adds 180 μ L plasma specimens；It is corresponding 4 μ L to be separately added into in each pipe blood specimen The medicine of concentration, matched group adds 4 μ L dimethyl sulfoxide solutions, concussion to mix, 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 calculated clotting time of sening as an envoy to and double 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：1.01 μM of -10.00 μM of conclusions：This Series compound has preferable factor Xa inhibitory activity, while with the effect for extending clotting time.

The solubility test of compound

Water (10mL) is added toward 15mL conical pipes, in vibration sample is added, until sample stops dissolving, 37 DEG C of constant temperature Water-bath shakes 24h, shake speed 40rpm.After shaking terminates, by (0.45 μm, the Φ 13mm) filtration of sample Jing water system miillpore filters, Just filtrate is discarded, precision pipettes subsequent filtrate (500 μ L), adds diluent acetonitrile-water (500 μ L, v/v=60/40), and the two is mixed It is even, obtain final product 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	0.13
Embodiment 2	0.10
		Embodiment 3	0.15
Embodiment 4	0.08
		Embodiment 5	0.08

Conclusion：This series compound has preferable dissolubility.

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 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.And, the specific features of description, structure, material or feature can be with office Combine in an appropriate manner in one or more embodiments or example.Additionally, in the case of not conflicting, the skill of this area Art personnel can be tied the feature of the different embodiments or example described in this specification and different embodiments or example 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, changes, replacing and modification.

Claims (8)

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

Wherein, X is F, Cl, Br or I；

R¹For hydrogen or deuterium；

R²For hydrogen or deuterium；With

R is

2. compound according to claim 1, selected from the structure or its pharmaceutically acceptable salt of one of,

3. a kind of pharmaceutical composition, it is comprising the compound described in any one of claim 1-2 and its pharmaceutically acceptable auxiliary Agent.

4. pharmaceutical composition according to claim 3, wherein the adjuvant includes excipient and diluent.

5. the compound or the pharmaceutical composition described in claim 3 described in a kind of any one of claim 1-2 prepare prevention, Purposes in the medicine process, treated or mitigate patient's thrombotic disease.

6. purposes according to claim 5, wherein the thrombotic disease is myocardial infarction, angina pectoriss, blocks again With the restenosiss after revascularization or aortocoronary bypass, apoplexy, of short duration ischemia outbreak, peripheral arterial Occlusive disease, pulmonary infarction or venous thrombosis.

7. the pharmaceutical composition described in the compound or claim 3 described in any one of claim 1-2 is used to prepare treatment more The purposes of the medicine of scattered property intravascular coagulation.

8. compound described in any one of claim 1-2 or the pharmaceutical composition described in claim 3 are used to prepare inhibitive factor The purposes of the medicine of Xa.