CN109867660A

CN109867660A - Tetrahydroisoquinoline amide compound and its medicinal usage containing quaternary ammonium ion

Info

Publication number: CN109867660A
Application number: CN201811382408.4A
Authority: CN
Inventors: 吴勇勇; 宋智泉; 蔡家强; 朱加望; 王利春; 王晶翼
Original assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Current assignee: Sichuan Kelun Botai Biological Pharmaceutical Ltd By Share Ltd
Priority date: 2017-12-01
Filing date: 2018-11-20
Publication date: 2019-06-11

Abstract

The present invention relates to the purposes of the preparation method and the compound of tetrahydroisoquinoline amide compound, the compound containing quaternary ammonium ion in the treatment or prevention of thromboembolic disorders.

Description

Tetrahydroisoquinoline amide compound and its medicinal usage containing quaternary ammonium ion

Technical field

The present invention relates to the preparation method of tetrahydroisoquinoline amide compound, the compound containing quaternary ammonium ion and it is somebody's turn to do Purposes of the compound in the treatment or prevention of thromboembolic disorders.

Background technique

The thrombotic diseases such as apoplexy, myocardial infarction and Deep vain thrombosis be disable, lethal major reason.Just Normal blood coagulation is the equilibrium process closely adjusted, needs to keep the state of fluid of the blood under normal physiological conditions, simultaneously Have and form the mechanism of tampon in damage location rapidly, is lost threat to life to prevent Hemostatic Oral Liquid.Coagulation process can be divided into three The approach of interdependence: external (extrinsic), inherent (intrinsic) and common (common) approach.Wherein, blood coagulation Factor XI, plasma thromboplastin antecedent a is located near the source of inherent coagulation pathway, and the beginning of inherent coagulation pathway and the formation of plasma thromboplastin antecedent a (pass through The activation of fibrin ferment or XIIa) it is extremely important to maintenance blood clot integrality.But plasma thromboplastin antecedent a is not to normal haemostasis must It needs.Some researches show that the level for increasing plasma thromboplastin antecedent is associated with the venous thronbosis of male and myocardial infarction, and increases The probability of the cerebrovascular and coronary artery disease is added.Thus deduction inhibition XIa can effectively inhibit thrombosis and will not Lead to significant bleeding.

The inhibitor of a variety of plasma thromboplastin antecedent a is disclosed in the patents such as WO2013/055984.However, despite the presence of known Plasma thromboplastin antecedent a inhibitor, but these inhibitor metabolic stability in vivo, safety etc. still remain deficiency. Therefore, people it is highly desirable develop to selectivity XIa inhibitory effect it is stronger, the properties such as drug metabolism stability are changed Kind, the smaller novel plasma thromboplastin antecedent a inhibitor of toxic side effect.

Summary of the invention

The compound that the purpose of the present invention is to provide a kind of as more potent and safe plasma thromboplastin antecedent a inhibitor, Its pharmaceutically acceptable salt, solvate, isomers or its prodrug, they can be used for treating or preventing thromboembolism venereal disease Disease.In more detail, the present invention provides the substituted tetrahydroisoquinoline amide compound containing quaternary ammonium ion, the compound choosing Selecting property while keeping and improving to the high-affinity of plasma thromboplastin antecedent a, factor Xa and VIIa unrestraint are made With to have the remarkable result for improving blood solubility, improving internal metabolic stability, improving anticoagulant.Due to the present invention Compound is reduced in the volume distribution (Volume Distribution) of human body, limits it in the distribution of other tissues, thus Improve Drug safety.

Specifically, the compound of the present invention be related to it is following:

It is following formula (I) compounds represented or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, more Crystal form object, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug,

In above-mentioned formula (I),

Indicate singly-bound or double bond；

X^-Indicate anion；

M is indicated with flowering structure:

R^5a、R^5bAnd R^5cIt is separately selected from: C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base or R^5a、 R^5bN connected to it⁺3-10 circle heterocyclic ring base is collectively formed；The wherein C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 member Heterocycle is optionally selected from deuterium, halogen, hydroxyl ,-S (O) by one or more_pR^m, cyano, C_1-6Alkyl, C_1-6Alkoxy ,-(O-C_1-4 Alkylidene)_n-OR^h、C_1-6Alkoxy -C_1-6Alkylidene-,-COOR^h、-N(R^g)₂、-NR^gCOR^h、-CON(R^g)₂、C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10The substituent group substitution of aryl, 5-10 unit's heteroaryl；

The R⁶Selected from hydrogen, deuterium, halogen, hydroxyl ,-COOR^h、-N(R^g)₂、-NR^gCOR^h、-CON(R^g)₂、-S(O)_pR^m, cyanogen Base, C_1-6Alkyl, alkoxy；

The L³Selected from key, C_1-6Alkylidene, C_2-6Alkenylene, the alkylidene, alkenylene are optionally selected by one or more From halogen, C_1-6Alkoxy, halogenated C_1-6The substituent group of alkyl replaces；

Part is selected from flowering structure:

R⁰Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-4Alkoxy ,-C_1-3Alkylidene-C_1-4Alkoxy, halogen Substituted alkyl, C_3-6Naphthenic base；

L¹It is selected from: key, C_1-6Alkylidene, C_3-10Cycloalkylidene, 3-10 member sub- heterocycle, C_6-10Arlydene, 5-10 member are sub- miscellaneous Aryl；The sub- heterocycle of 3-10 member contains one or more selected from N, NR⁷, O, P and S (O)_PRing members, 5-10 member is sub- Heteroaryl contains one or more selected from N, NR⁷, O and S (O)_PRing members；The C_1-6Alkylidene, C_3-10Cycloalkylidene, C_6-10 Arlydene, the sub- heterocycle of 3-10 member, 5-10 member inferior heteroaryl are optionally selected from deuterium, halogen, hydroxyl, cyano, C by one or more_1-6 Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Halogenated alkoxy ,-C_1-6Alkylidene-C_1-6Alkoxy ,-C (O) C_1-4Alkyl ,- COOR^h、-N(R^g)₂、C_3-10Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 unit's heteroaryl ,-CON (R^g)₂、-NR^gCO₂R^h Substituent group replace；

R¹It is selected from: H ,-COOR^h、-N(R^g)₂、C_1-6Alkyl, C_3-10Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 member Heteroaryl ,-CON (R^g)₂、-CO-(O-C_1-4Alkylidene)_n-OR^h、-CO-(O-C_1-4Alkylidene)_n-N(R^g)₂、-NR^gCO₂R^h、-C_1-4 Alkylidene-CO₂-C_1-4Alkylidene-O-CO₂-C_1-4Alkyl；The 3-10 circle heterocyclic ring base contains one or more selected from N, NR⁷、O、P With S (O)_PRing members, the 5-10 unit's heteroaryl contains one or more selected from N, NR⁷, O and S (O)_PRing members；It is described C_1-6Alkyl, C_3-10Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 unit's heteroaryl optionally by one or more deuteriums, halogen, Hydroxyl, cyano, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl, C_1-6Halogenated alkoxy ,-C (O) C_1-4Alkyl ,-COOR^h、-N (R^g)₂、-CON(R^g)₂、-NR^gCO₂R^h、C_3-10The substituent group of naphthenic base and 3-10 circle heterocyclic ring base replaces；

R²It is selected from: hydrogen, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-4Alkoxy, C_1-4Haloalkoxy Base ,-CH₂NH₂、-CH₂OH、-CH₂-OC_1-4Alkyl ,-C (O) C_1-4Alkyl ,-CONH₂, 5-7 circle heterocyclic ring base and 5-6 unit's heteroaryl；

R³Selected from hydrogen atom, halogen and C_1-4Alkyl；

L²It is selected from: key, alkenylene, C_3-6Cycloalkylidene, 5-6 member sub- heterocycle, 5-6 member inferior heteroaryl, the 5-6 member are sub- Heterocycle, 5-6 member inferior heteroaryl contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The alkenylene is optionally by alkane Base, halogenated alkyl replace；The C_3-6Cycloalkylidene, the sub- heterocycle of 5-6 member, 5-6 member inferior heteroaryl are optionally selected by one or more From deuterium, hydroxyl, cyano ,=O ,-N (R^g)₂、C_1-6Halogenated alkyl, halogen ,-C_1-4Alkylidene-OH, C_1-3Alkoxy, C_1-3Alkyl halide Oxygroup and-C (O) C_1-4The substituent group of alkyl replaces；

A is selected from: C_3-10Cycloalkylidene, C_6-10Arlydene, 3-10 member sub- heterocycle, 5-10 member inferior heteroaryl；The 3-10 member Sub- heterocycle, 5-10 member inferior heteroaryl contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The C_3-10Cycloalkylidene, C_6-10Arlydene, the sub- heterocycle of 3-10 member, 5-10 member inferior heteroaryl optionally by one or more selected from H, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-4Alkoxy, C_1-6Halogenated alkyl, C_1-4Halogenated alkoxy ,-CH₂N(R^g)₂、-CO(C_1-4Alkyl) ,-CON (R^g)₂、- COOR^h, 5-7 circle heterocyclic ring base and 5-6 unit's heteroaryl substituent group replace；

R⁴Selected from H, C_3-10Naphthenic base, C_6-10Aryl, 3-10 circle heterocyclic ring base, 5-10 unit's heteroaryl；The 3-10 circle heterocyclic ring Base, 5-10 unit's heteroaryl contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The C_3-10Naphthenic base, C_6-10Aryl, 3-10 circle heterocyclic ring base, 5-10 unit's heteroaryl are optionally selected from deuterium, halogen, hydroxyl, cyano, C by one or more_1-6Alkyl, C_1-4Alkane Oxygroup, C_1-6Halogenated alkyl, C_1-4Halogenated alkoxy ,-CH₂N(R^g)₂、-CO(C_1-4Alkyl) ,-CON (R^g)₂With-COOR^hSubstitution Base replaces；

R⁷It is each independently selected from: H, C_1-4Alkyl ,-CO (C_1-4Alkyl) ,-COCF₃、-CO₂(C_1-4Alkyl) ,-CONH₂、-C (O)NH-(C_1-4Alkyl)-CO₂(C_1-4Alkyl) ,-(C_1-4Alkylidene) CO₂(C_1-4Alkyl) ,-C_1-4Alkylidene-R^h、-CO₂R^h、-C (O)NHR^g；

The R^gIt is each independently selected from H, C_1-6Alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base；And multiple R^gEach other It can be identical or different；

The R^hIt is each independently selected from H, C_1-6Alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 member are miscellaneous Aryl；And multiple R^hIt each other can be identical or different；

The R^mSelected from H, C_1-6Alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 unit's heteroaryl；And it is more A R^mIt each other can be identical or different；

N each independently represents 0,1,2,3 or 4；

P each independently represents 0,1 or 2.

Another aspect provides a kind of preparation method of compound, including following manner,

Method one:

In method one, R^LThe C for indicating halogen or being optionally optionally substituted by halogen_1-3Alkyl sulfonic acid ester group (such as trifluoro methylsulphur Perester radical)；PG¹、PG²For protecting group；R^1PFor the R protected by protecting group¹；Y indicates leaving group, it is preferable that the leaving group is selected from H, halogen, the C being optionally optionally substituted by halogen_1-3Alkyl sulfonic acid ester group, boronate, boric acid ester group, substituted silicon substrate or substituted gold Belong to group；M^aIt indicates with flowering structure:Wherein R^5a’With R^5aIdentical or R^5a’In formula (I) R in^5a、R^5bN connected to it⁺It is H when 3-10 circle heterocyclic ring base is collectively formed；M^bWith M^aIdentical or M^bThrough one or more steps Reaction is converted into M^a(for example, working as M^aForWhen, M^bFor)；

Step 1: compound SM-1 is by deprotection reaction and continues to carry out acid amide condensation in the presence of condensing agent instead Compound IM-1 should be generated；

Step 2: compound IM-1 is by deprotection reaction and continues to carry out acid amide condensation in the presence of condensing agent instead Compound IM-2 should be generated；

Step 3: compound IM-2 is by coupling reaction or continues the reactions generation compound such as to be deprotected, be alkylated IM-3；

Step 4: compound IM-3 (such as reacts, the alkylating reagent is excellent by quaternization reaction with alkylating reagent Select iodomethane), deprotection reaction, or continue ion exchange generate formula (I) compound；

Method two:

In method two, R^L、PG¹、PG²、R^1P、Y、R^5a’、M^aAnd M^bAs defined in method one；

Step 1: compound SM-1 is by deprotection reaction and continues to carry out acid amide condensation in the presence of condensing agent instead Compound IM-4 should be generated；

Step 2: compound IM-4 is by deprotection reaction and continues to carry out acid amide condensation in the presence of condensing agent instead Compound IM-2 should be generated；

Step 3: compound IM-2 is by coupling reaction or continues deprotection, alkylated reaction generation compound IM- 3；

Step 4: compound IM-3 (such as reacts, the alkylating reagent is excellent by quaternization reaction with alkylating reagent Select iodomethane), deprotection reaction, or continue ion exchange process generate formula (I) compound；

Method three:

In method three, R^pWithIdentical or R^PC (O)-is the blocking group for the amino that can be removed；R^L、 R^1P、Y、R^5a’、M^aAnd M^bAs defined in method one；

Step 1: compound SM-2 generates compound IM-5 by coupling reaction；

Step 2: compound IM-5, SM-3 and SM-4 carry out Ugi reaction in alcoholic solvent and generate compound IM-6；

Step 3: compound IM-6 is by deprotection reaction and continues to carry out acid amide condensation in the presence of condensing agent instead Compound IM-7 should be generated；Work as R^pWithWhen identical, this step is omitted；

Step 4: compound IM-7 generates compound IM-3 by the reactions such as deprotection and alkylation；Work as M^aAnd M^bIt is identical When, this step is omitted；

Step 5: compound IM-3 (such as reacts, the alkylating reagent is excellent by quaternization reaction with alkylating reagent Select iodomethane), deprotection reaction, or continue ion exchange process generate formula (I) compound,

In the above method one, method two or method three, R¹、R²、R³、R⁴、L²、A、M、W、Q、L¹、X^-As hereinbefore defined.

Another aspect provides a kind of pharmaceutical compositions, contain compound of the present invention, its pharmacy Acceptable salt, ester, solvate, isomers, their any crystal form or racemoid, they metabolite form or they Mixture, preferably further contain pharmaceutically acceptable auxiliary material.

Another aspect provides a kind of pharmaceutical preparation, wherein said preparation include compound of the present invention, Its pharmaceutically acceptable salt, ester, solvate, hydrate, isomers, their any crystal form or racemoid, their metabolism As active constituent, said preparation is solid pharmaceutical preparation, semisolid preparation, liquid preparation or gaseous state for object form or their mixture The form of preparation.

Another aspect provides compounds of the present invention, its pharmaceutically acceptable salt, ester, solvation Object, hydrate, isomers, their any crystal form or racemoid, their metabolite form or their mixture, or Pharmaceutical composition of the present invention or medicament of the present invention are used to treat the inhibition phase with plasma thromboplastin antecedent a in preparation Application in the drug of related disorders.The thromboembolic disorders include arterial cardiovascular thromboembolic disorders, vein painstaking effort The thromboembolic disorders of pipe thromboembolic disorders and heart chamber.

Invention effect

The compound of the present invention changes the electron cloud situation on tetrahydroisoquinoline ring by introducing quaternary ammonium ion significantly, The solubility of blood is significantly improved, the volume for reducing drug in human body is distributed (Volume Distribution).Therefore, The compounds of this invention not only has high-affinity to plasma thromboplastin antecedent a, but also has high choosing to factor Xa and VIIa Selecting property, and there is good internal metabolic stability, improved pharmacokinetic properties and anticoagulant curative effect.

Specifically, the present invention includes but is not limited to following technical proposals.

Specific embodiment

Definition

Unless hereinafter defined otherwise, the meaning of all technical terms and scientific terms used herein is intended to and this Field technical staff is generally understood identical.It refers to that technology used herein is intended to refer to be generally understood in the art Technology, the replacement of variation or equivalence techniques including those technologies that will be apparent to those skilled in the art.While it is believed that with Lower term is for those skilled in the art it is well understood that but still illustrating defined below preferably to explain the present invention.

The terms "include", "comprise", " having ", " containing " or " being related to " and its other variant forms herein are packet Containing the (inclusive) or open of property, and it is not excluded for other unlisted elements or method and step.

Term " quaternary ammonium " (such as quaternary ammonium ion or quaternary ammonium compound) refers to the positively charged structural portion comprising nitrogen-atoms Point, the nitrogen-atoms is by four covalent bonds in conjunction with carbon atom.For example, nitrogen-atoms passes through four singly-bounds and four carbon atom knot It closes, therefore positively charged.Term " quaternized ", which refers to, generates quaternary ammonium ion or quaternary ammonium compound as defined above by chemical reaction Process.

Term " halogenated " or " halogen " group definition be include F, Cl, Br or I.

Term " alkyl " is defined as linear chain or branched chain saturated aliphatic hydrocarbons.In some embodiments, alkyl have 1 to 12 carbon atoms preferably have 1 to 6 carbon atom, more preferably have 1 to 4 carbon atom.For example, as used herein, art Language " C_1-6Alkyl " refers to linear or branching group (such as the methyl, ethyl, n-propyl, isopropyl, positive fourth of 1 to 6 carbon atom Base, isobutyl group, sec-butyl, tert-butyl, n-pentyl or n-hexyl).Term " C_1-4Alkyl " refers to the linear of 1 to 4 carbon atom or branch The aliphatic hydrocarbon chain (i.e. methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or tert-butyl) of change.In this hair In bright, " alkyl " optionally replaces that (group is referred to as at this time by the substituent group such as halogen that 1 or multiple (such as 1 to 3) is suitble to " halogenated alkyl ") (such as-CF₃、-C₂F₅、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂Cl or-CH₂CH₂CF₃Deng).

Term " alkenyl " refers to the alkyl containing at least one carbon-to-carbon double bond.In some embodiments, alkenyl has 2 (" C is expressed as to 12 carbon atoms_2-12Alkenyl "), preferably there are 2 to 6 carbon atoms (to be expressed as " C_2-6Alkenyl ").Alkenyl can be with It is linear chain or branched chain alkenyl.The non-limitative example of alkenyl includes vinyl, acrylic, n-butene base, 3- methyl but-2-ene Base, n-pentene base, octenyl and decene base.Alkenyl can be unsubstituted alkenyl, or by one or more identical or different Substituent group replaces, such as halogen, alkenyl, alkynyl, aryl, naphthenic base, cyano, the substituent groups such as hydroxyl.

Two obtained saturations of hydrogen atom are removed in term " alkylidene " expression from linear or branched saturated hydrocarbon base Bivalent hydrocarbon radical.In some embodiments, alkylidene group contains 1-10 carbon atom and (is expressed as " C_1-10Alkylidene "), in addition In some embodiments, alkylidene group contains 1-6 carbon atom and (is expressed as " C_1-6Alkylidene "), in other embodiments, Alkylidene group contains 1-4 carbon atom and (is expressed as " C_1-4Alkylidene ").Such example includes methylene (- CH₂), sub- second Base (- CH₂CH₂), isopropylidene (- CH (CH3) CH2-) etc., wherein the alkylidene can be independently unsubstituted or by one Replaced a or multiple substituent groups described in the invention.

Term " alkenylene " refers to removes the bivalent group that a hydrogen atom obtains from the alkenyl that the present invention defines.Sub- alkene The non-limiting example of base includes-CH=CH- ,-C (CH₃)=CH- and-CH=CHCH₂-。

Term " alkoxyalkyl " refers to that one or more alkyl defined through the invention are connected to its remaining part of molecule The alkoxy divided.

Term " halogenated alkoxy " refers to that one or more hydrogen in alkoxy defined in the present invention are determined by the present invention The halogen of justice replaces, and the example includes but is not limited to-OCF3 ,-OCH2CCl3 ,-OCH2CH2CF2H and-OCH2CF3.

Term " halogenated alkyl " refers to one or more hydrogen in alkyl defined in the present invention defined in the present invention Halogen replaces, and the example includes but is not limited to-CF3 ,-CH2CCl3 ,-CH2CH2CF2H and-CH2CF3.

Term " naphthenic base " refers to saturated or unsaturated non-aromatic monocyclic (such as cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, suberyl, cyclooctyl, cyclononyl) or polycyclic (including loop coil, condensed or bridging system are (such as bicyclic [1.1.1] amyl, double Ring [2.2.1] heptyl, bicyclic [3.2.1] octyl or bicyclic [5.2.0] nonyl, decahydronaphthalene naphthalene etc.) hydrocarbon ring, optionally by 1 Or the substituent group substitution that multiple (such as 1 to 3) are suitable.In some embodiments, the naphthenic base has 3 to 15 carbon originals Son preferably has 3 to 6 carbon atoms.For example, term " C_3-6Naphthenic base " refers to the saturation or unsaturation of 3 to 6 ring carbons Non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl), optionally by The suitable substituent group of 1 or multiple (such as 1 to 3) replaces, such as methyl substituted cyclopropyl.

Term " heterocycle ", which is included in ring, has carbon atom and at least one hetero atom (such as O, S, N, P) or hetero atom Partially (such as SO₂、CO、CONH、COO、PO、PO₂) the nonaromatic cyclic group optionally replaced.In some embodiments, the heterocycle The ring member nitrogen atoms number of base is 3 to 18, and preferably ring member nitrogen atoms number is 3 to 10, and more preferable ring member nitrogen atoms number is 3 to 6.It is described Heterocycle can be the non-aromatic monocyclic or condensed ring radical of saturation, fractional saturation.The example of heterocycle includes cyclohexylimino, miaow Oxazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, pyridyl group, pyrrolidinyl, thienyl, 4,5- dihydro -1H- imidazoles Base, 1,2,3,6- tetrahydro pyridyls, 3- oxypiperazin, 4H-1,3- oxazines base, 5,6- dihydro -4H-1,3- oxazines base.

Term " aryl " refers to full carbon monocycle or fused rings polycyclic aromatic group with conjugated pi electron system.For example, such as this Used in text, term " C_6-10Aryl " means the aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.Aryl Substituent group (such as halogen ,-OH ,-CN, the C being optionally suitble to by 1 or multiple (such as 1 to 3)_1-6Alkyl etc.) replace.

Term " heteroaryl " refers to monocycle or polycyclic aromatic ring system, and it includes the hetero atoms that at least one can be identical or different (hetero atom is such as oxygen, nitrogen or sulphur), also, in some cases can be in addition benzo-fused.In section Example In, the ring member nitrogen atoms number of the heteroaryl is 3 to 18, and preferably ring member nitrogen atoms number is 5 to 10.Particularly, heteroaryl is selected from Thienyl, furyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazoles base, Triazolyl, thiadiazolyl group etc. and their benzo derivative；Or pyridyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical Deng and their benzo derivative.

Term " alkoxy " includes that alkyl as defined herein is connected on oxygen atom, and by oxygen atom and molecule Rest part is connected, and preferably refers to that carbon atom number is 1~6 alkoxy.Such example include, but is not limited to methoxyl group, Ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyl oxygroup, isoamyl Base oxygroup, neopentyl epoxide, tertiary pentyl oxygroup etc..

Term " protecting group " refers to chemical group with the following characteristics: can i) be formed with corresponding functional group reactions protected Group；Ii) the stable reaction conditions that shielded group will be subjected to；And iii) can remove and discharge from shielded group Functional group.The example of protecting group and its introducing and removal methods may refer to T.W.Greene and P.G.M.Wuts, " Protective Groups in Organic Synthesis ", the third edition, John Wiley&Sons, NewYork, 1999.

Term " anion " indicates negatively charged organic or inorganic ion, can specifically enumerate fluorine ion, chloride ion, bromine Ion, iodide ion, sulfate ion, phosphate ion, nitrate ion, carbonate ions, acetato-, lactic acid ion, winestone acid ion, Benzoate, citrate ions, trifluoroacetic acid ion, methanesulfonate, ethanesulfonic acid ion, methyl sulfate ion, benzene sulfonic acid Ion, p-methyl benzenesulfonic acid ion, isethionic acid ion, adipic acid ion, ethane -1,2- disulfonic acid ion, 1,5- naphthalenedisulfonic acid Ion, naphthalene-2-sulfonic acid ion, apple acid ion, Malaysia acid ion, malonic acid ion, fumaric acid ion, amber acid ion, 1- Hydroxy-2-naphthoic acid ion, O-phthalic acid ion, sorb acid ion, oleic acid ion and glucuronic acid ion etc., wherein excellent Choosing is fluorine ion, chloride ion, bromide ion, iodide ion, trifluoroacetic acid ion, sulfate ion, lactic acid ion, winestone acid ion, benzene Formate ion, citrate ions, methanesulfonate, benzene sulfonic acid ion, p-methyl benzenesulfonic acid ion, adipic acid ion, ethane -1,2- Disulfonic acid ion, 1,5- naphthalenedisulfonic acid ion, naphthalene-2-sulfonic acid ion, apple acid ion, Malaysia acid ion, malonic acid ion, richness Horse acid ion, amber acid ion, 1- hydroxy-2-naphthoic acid ion or glucuronic acid ion.

Usable solid line (-), real wedge shape hereinEmpty wedge shapeDescribe the carbon-carbon bond of the compound of the present invention. It is bonded to the key of asymmetric carbon atom to describe using solid line and indicates, including all possible stereoisomer at the carbon atom (for example, specific enantiomter, racemic mixture etc.).Asymmetric carbon atom is bonded to using real or imaginary wedge shape to describe Key indicate, exist shown in stereoisomer.When being present in racemic mixture, using real and imaginary wedge shape to define phase To spatial chemistry, rather than absolute stereochemistry.Unless otherwise specified, the compound of the present invention can be stereoisomer (it includes cis- and transisomer, optical isomer (such as R and S enantiomter), diastereoisomer, geometrical isomerism Body, rotational isomer, conformer, atropisomer and its mixture) form exist.The compound of the present invention can express The isomerism of more than one types, and be made of its mixture (such as racemic mixture and diastereoisomer to).

The present invention covers all possible crystal form or polymorph of the compounds of this invention, can be single polycrystalline type The mixture of the arbitrary proportion of object or more than one polymorph.

It is also understood that the compound of the present invention can exist in a free form for treating, or where appropriate, pharmaceutically with it Acceptable derivates form exists.In the present invention, pharmaceutically acceptable derivates include but is not limited to that can pharmaceutically connect The salt received, ester, solvate, metabolin, isotope labelling compound or prodrug, by them to needing its patient to be administered Afterwards, the compound of the present invention or its metabolin or residue can be directly or indirectly provided.Therefore, when referenced herein " this When the compound of invention ", it is also intended to the above-mentioned various derivative forms for covering compound.

Term " substitution " refers to that one or more (such as 1,2,3 or 4) hydrogen on specified atom is selected The group selected replaces, and condition is the normal atom valency being less than specified atom in the current situation and the substitution is formed Stable compound.Selected substituting group quantity is just allowed when this combination forms stable compound.

If substituent group is described as " optionally by ... replace ", substituent group can (1) it is unsubstituted or (2) are substituted. If the carbon of substituent group is described as being optionally substituted one or more substitutions in base list, the one or more on carbon The optional substituent group substitution that hydrogen can be independently selected individually and/or together.If the nitrogen of substituent group is described as optionally Be substituted in base list it is one or more replace, then one or more hydrogen on nitrogen can be respectively independently selected optional Substituent group substitution.

If substituent group is described as " independently selected from ", each substituent group can be identical as another (other) substituent group or not Together.

As used herein, term " one or more " means 1 under reasonable terms or more than 1, such as 2 A, 3,4,5 or 10.

Unless indicated, otherwise as used herein, the tie point of substituent group may be from any suitable location of substituent group.

When the key of substituent group is shown as pass through key in ring and not specified position, then such substituent group can be bonded to this can Any ring member nitrogen atoms appropriate in substituted ring.

The invention also includes the compounds of all pharmaceutically acceptable isotope labellings, with the compound of the present invention phase Together, in addition to one or more atoms are by with same atoms ordinal number but atomic mass or mass number are different from being dominant in nature The atomic mass of gesture or the atom substitution of mass number.It is suitble to include that the example of isotope in the compound of the present invention includes (but being not limited to) hydrogen isotope (such as deuterium (D,²H), tritium (T,³H))；Carbon isotope (such as¹¹C、¹³C and¹⁴C)；Chlorine it is same Position element (such as³⁶Cl)；Fluorine isotope (such as¹⁸F)；Iodine isotope (such as¹²³I and¹²⁵I)；Nitrogen isotope (such as¹³N And¹⁵N)；Oxygen isotope (such as¹⁵O、¹⁷O and¹⁸O)；Phosphorus isotope (such as³²P)；And sulphur isotope (such as³⁵S).Certain The compound of the present invention of a little isotope labellings can be used in drug and/or substrate tissue distribution research (such as analysis).This hair Bright pharmaceutically acceptable solvate include wherein recrystallisation solvent those of can be replaced by isotope, for example, D₂O, acetone- d₆Or DMSO-d₆。

In addition to this, here undefined group in accordance with common definition.

The pharmaceutically acceptable salt of the compound of the present invention includes its acid-addition salts and base addition salts.Example includes alkali gold The salt of the formation such as category, alkaline-earth metal, ammonium, alkylammonium, the salt formed with inorganic acid or organic acid.These salt can enumerate sodium salt, Sylvite, calcium salt, ammonium salt, aluminium salt, triethyl ammonium salt, acetate, propionate, butyric acid salt, formates, trifluoroacetate, maleic acid Salt, tartrate, citrate, stearate, succinate, ethylsuccinate, Lactobionate, gluconate, Portugal heptan Sugar lime, benzoate, mesylate, esilate, 2- isethionate, benzene sulfonate, tosilate, lauryl Sulfate, malate, aspartate, glutamate, adipate, trishydroxymethylaminomethane salt and cysteine shape At salt, with n-acetylcysteine formed salt, hydrochloride, hydrobromate, phosphate, sulfate, hydriodate, niacin Salt, oxalates, picrate, rhodanate, undecanoate, the salt formed with acrylate copolymer and carboxy vinyl are poly- Close the salt etc. that object is formed.The summary of suitable salt referring to Stahl and Wermuth " Handbook ofPharmaceutical Salts:Properties,Selection,and Use"(Wiley-VCH,2002).It is for the preparation of the compounds of the present invention The method of pharmaceutically acceptable salt is well known by persons skilled in the art.

The compound of the present invention can exist in the form of solvate (preferably hydrate), wherein the compound of the present invention packet Polar solvent containing the structural element as the compound lattice, especially such as water, methanol or ethyl alcohol.Polar solvent is special The amount for being water can be with stoichiometric ratio or non-stoichiometric presence.

It within the scope of the invention further include the metabolin of the compound of the present invention, i.e., when the compound of the present invention is administered The substance formed in vivo.Such product can be by the oxidation for the compound being for example administered, reduction, hydrolysis, amidation, deamidation Change, esterification, degreasing, enzymatic hydrolysis etc. generate.Therefore, the present invention includes the metabolin of the compound of the present invention, including by making this The compound and mammalian animal of invention are enough to generate compound made from the method for the time of its metabolite.

The present invention further comprises the prodrug of the compound of the present invention within its scope, for that itself can have smaller pharmacology Certain derivatives of activity or the compound of the present invention without pharmacological activity are learned when being administered in body or Shi Ketong thereon It crosses such as hydrolytic rupture and is converted to have and it is expected active the compound of the present invention.Usually such prodrug can be the compound Functional group derivant, be easy to be converted to desired therapeutical active compound in vivo.Other letters used about prodrug Breath can be found in " Pro-drugs as Novel Delivery Systems ", and volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and " Bioreversible Carriers in Drug Design, " Pergamon Press, 1987 (E.B.Roche is edited, American Pharmaceutical Association).Prodrug of the invention can Such as by use it is known to those skilled in the art as " preceding-part (pro-moiety) (such as " Design ofProdrugs ", Described in H.Bundgaard (Elsevier, 1985)) " certain parts substitute appropriate official present in the compound of the present invention It can roll into a ball to prepare.

Present invention also contemplates that the compound of the present invention containing protecting group.In any process of preparation the compound of the present invention In, protection may be necessary and/or desired in any sensitive group in relation on molecule or reactive group, be consequently formed The form of the chemoproection of the compound of invention.This can be realized by conventional protecting group, for example, in Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；And T.W.Greene& P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley&Sons, described in 1991 Those of protecting group, these bibliography by quotes addition herein.Using methods known in the art, in subsequent stages appropriate Section can remove protecting group.

Compound

It is an advantage of the invention to provide following formula (I) compounds represented or its pharmaceutically acceptable salt, Ester, stereoisomer, tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin Or prodrug,

In above-mentioned formula (I),

Indicate singly-bound or double bond；

X^-Indicate anion；

M is indicated with flowering structure:

Part is selected from flowering structure:

R³Selected from hydrogen atom, halogen and C_1-4Alkyl；

N each independently represents 0,1,2,3 or 4；

P each independently represents 0,1 or 2.

In certain embodiments, in above-mentioned Formulas I,

Indicate singly-bound or double bond；

X- indicates anion；

M is indicated with flowering structure:

R^5a、R^5bAnd R^5cIt is separately selected from: C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base or R^5a、 R^5bN connected to it⁺3-10 circle heterocyclic ring base is collectively formed；The wherein C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 member Heterocycle is optionally selected from deuterium, halogen, hydroxyl ,-S (O) by one or more_pR^m, cyano, C_1-6Alkyl ,-(O-C₁- 4 alkylidenes)_n- OR^h、C_1-6Alkoxy -C_1-6Alkylidene-,-COOR^h、-N(R^g)₂、-NR^gCOR^h、-CON(R^g)₂、C_1-6Halogenated alkyl, C_3-6Cycloalkanes Base, 3-10 circle heterocyclic ring base, C_6-10The substituent group substitution of aryl, 5-10 unit's heteroaryl；

Part is selected from flowering structure:

R³Selected from hydrogen atom, halogen and C_1-4Alkyl；

N each independently represents 0,1,2,3 or 4；

P each independently represents 0,1 or 2.

In certain embodiments, shown in the structure of the compounds of this invention such as following formula (II),

Wherein, L²Selected from alkenylene, and the alkenylene is optionally by one or more C_1-4Alkyl, C_1-3Halogenated alkyl takes Generation；

Or L²Selected from following group, wherein position 1 is connect with phenyl, position 2 is connected with carbonyl (C=O):

Wherein, R^aIt is each independently selected from H, hydroxyl, cyano ,=O, NH₂, halogen ,-C_1-4Alkylidene-OH, C_1-3Alkoxy, C_1-3Halogenated alkoxy and-C (O) C_1-3Alkyl；

R^bAnd R^cEach independently optionally from H, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-4Alkoxy, C_1-3Halogenated alkyl, C_1-3Halogenated alkoxy；

M、W、Q、L¹、R¹、R²、R³、R⁴、X^-As hereinbefore defined.

In certain embodiments, the present invention provides a kind of compound or its pharmaceutically acceptable salt, ester, solid are different Structure body, tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, In,

L¹Selected from phenylene and 5-10 member inferior heteroaryl, the 5-10 member inferior heteroaryl contain it is one or more selected from N, NR⁷, O and S (O)_PRing members, wherein R⁷, p it is as hereinbefore defined, the phenylene and 5-10 member inferior heteroaryl are optionally by one Or it is multiple selected from deuterium, Cl, F, hydroxyl, cyano, C_1-4Alkyl, C_1-4Alkoxy, C_1-3Halogenated alkyl, C_1-3Halogenated alkoxy, carboxylic Base ,-COO-C_1-4Alkyl ,-N (C_1-4Alkyl)₂、-NH(C_1-4Alkyl) and-NH₂Substituent group replace；

R¹Selected from H, carboxyl ,-N (C_1-4Alkyl)₂、-NH(C_1-4Alkyl) ,-NH₂、C_1-6Alkyl, C_3-7Naphthenic base, 3-7 member are miscellaneous Ring group, 5-6 unit's heteroaryl ,-CON (C_1-4Alkyl)₂、-CONH(C_1-4Alkyl) ,-CONH₂、-COO-C_1-4Alkyl ,-COO-C_1-4It is sub- Alkyl-O- (C_1-4Alkyl) ,-COO-C_1-4Alkylidene-N- (C_1-4Alkyl)₂、-NHCOO-C_1-4Alkyl ,-C_1-4Alkylidene-COO- C_1-4Alkylidene-O-COO-C_1-4Alkyl；The 3-7 circle heterocyclic ring base, 5-6 unit's heteroaryl optionally by one or more selected from deuterium, Cl, F, hydroxyl, cyano, C_1-4Alkyl, C_1-4Alkoxy, C_1-3Halogenated alkyl, C_1-3Halogenated alkoxy, carboxyl ,-COO-C_1-4Alkyl ,-N (C_1-4Alkyl)₂、-NH(C_1-4Alkyl) and-NH₂Substituent group replace；

Preferably, L¹-R¹Selected from following group:

And/or

L³Selected from key, C_1-4Alkylidene, C_2-4Alkenylene, the C_1-4Alkylidene, C_2-4Alkenylene is optionally one or more Selected from F, Cl, C_1-4Alkoxy, C_1-4The substituent group of halogenated alkyl replaces；Preferably, L³Selected from key, methylene or ethylidene；

And/or

R^5a、R^5b、R^5cIt is separately selected from: C_1-3Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base or R^5a、R^5bConnect with it The N connect⁺3-6 circle heterocyclic ring base, the C is collectively formed_1-3Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base are optionally selected by one or more From halogen, hydroxyl, carboxyl, C_1-4Alkoxy ,-COO-C_1-4Alkyl ,-S (O)_p(C_1-3Alkyl) ,-CON (R^g)₂、-N(R^g)₂Substitution Base replaces；The R^gIt is each independently selected from H or C_1-3Alkyl works as R^gWhen being multiple, multiple R^gIt can be identical or different；The p Selected from 0,1 or 2；

Preferably, R^5a、R^5b、R^5cIt is separately selected from: methyl, ethyl, aziridinyl, azelidinyl, oxa- ring Butyl, oxiranyl ,-(CH₂)_nCON(CH₃)₂、-(CH₂)_nS(O)₂CH₃、-(CH₂)_nOCH₃、-(CH₂)_nOH、-(CH₂)_nCOOH、-(CH₂)_nCOO-C_1-3Alkyl or R^5a、R^5bN connected to it⁺Following group is collectively formed:

Wherein n each independently represents 1,2 or 3.

In certain embodiments, shown in the structure of the compounds of this invention such as formula (III-1),

R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；

Preferably, R^b、R^cIt is separately selected from: H, Cl, F；

It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as formula (III-2),

Wherein, R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；Preferably, R^b、R^cIt is separately selected from: H, Cl, F；It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、R^5c、L³、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as following formula (IV-1),

Wherein,

R⁸It is selected from: H, C_1-3Halogenated alkyl, C_1-4Alkyl, it is preferable that R⁸Selected from H, CH₂F、CHF₂、CF₃、CH₂Cl、CHCl₂、 CCl₃、C_1-4Alkyl；

T is selected from: N, CH, CF, CCl, CC_1-4Alkyl；

R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；Preferably, R^b、R^c It is separately selected from: H, Cl, F；It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as following formula (IV-2),

Wherein,

T is selected from: N, CH, CF, CCl, CC_1-4Alkyl；

R^5a、R^5b、R^5c、L³、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as formula (III-1a),

Wherein, R^5a、R^5b、W、Q、L¹、R¹、R^b、R^c、X^-As hereinbefore defined.

Preferably, R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；

It is highly preferred that R^b、R^cIt is separately selected from: H, Cl, F；

It is further preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as formula (III-2a),

Wherein,

R^5a、R^5b、R^5c、L³、W、Q、L¹、R¹、R^b、R^c、X^-As hereinbefore defined.

It is further preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as following formula (IV-1a),

Wherein,

T is selected from: N, CH, CF, CCl, CC_1-4Alkyl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, shown in the structure of the compounds of this invention such as following formula (IV-2a),

Wherein,

T is selected from: N, CH, CF, CCl, CC_1-4Alkyl；

R^5a、R^5b、R^5c、L³、W、Q、L¹、R¹、X^-As hereinbefore defined.

In certain embodiments, the structure of the compounds of this invention is as follows,

The present invention, which covers, carries out the resulting compound of any combination to each embodiment.

Preparation method

Another object of the present invention is to provide the preparation method of the compound of above-mentioned formula (I), can use comprising as follows State the method preparation of following reaction step documented by the reaction path diagram of method.

Method one:

In method one, R^LThe C for indicating halogen or being optionally optionally substituted by halogen_1-3Alkyl sulfonic acid ester group (such as trifluoro methylsulphur Perester radical)；PG¹、PG²For protecting group；R^1PFor the R protected by protecting group¹；Y indicates H, halogen, the C being optionally optionally substituted by halogen_1-3 Alkyl sulfonic acid ester group, boronate, boric acid ester group, substituted silicon substrate and various substituted metal groups etc.；M^aIt indicates with flowering structure:R^5a’With R^5aIdentical or R^5a’The R in formula (I)^5a、R^5bN connected to it⁺Jointly It is H when forming 3-10 circle heterocyclic ring base；M^bWith M^aIdentical or M^bIt can be anti-by one or more steps well known by persons skilled in the art M should be converted into^a(for example, working as M^aForWhen, M^bFor)

Step 3: compound IM-2 by coupling reaction (such as Suzuki, Buckwald, Stille, Negishi, The cross-coupling methods such as Hiyama and Kumada), or continue the reactions such as deprotection, alkylation and generate compound IM-3；

Step 4: compound IM-3 (such as is tried in solvent appropriate with the alkylations such as iodomethane by quaternization reaction Agent reaction), deprotection reaction, or continue the processes such as ion exchange generate formula (I) in compound.Those skilled in the art's meeting Understand, the sequence (for example, carry out deprotection reaction first and then carry out quaternization reaction) of the above process can be adjusted as needed.

Method two:

In method two, R^L、PG¹、PG²、R^1P、Y、R^5a’、M^aAnd M^bAs defined in method one.

Step 1: compound SM-1 is by deprotection reaction and continues to carry out acid amide condensation in the presence of condensing agent instead Compound IM- should be generated

Method three:

In method three, R^pWithIdentical or R^PC (O)-is the blocking group for the amino that can be removed；R^L、 R^1P、Y、R^5a’、M^aAnd M^bAs defined in method one.

Step 1: compound SM-2 by coupling reaction (such as Suzuki, Buckwald, Stille, Negishi, The cross-coupling methods such as Hiyama and Kumada) generate compound IM-5；

Step 5: compound IM-3 (such as is tried in solvent appropriate with the alkylations such as iodomethane by quaternization reaction Agent reaction), deprotection reaction, or continue the processes such as ion exchange generate formula (I) in compound.Those skilled in the art's meeting Understand, the sequence (for example, carry out deprotection reaction first and then carry out quaternization reaction) of the above process can be adjusted as needed.

In addition, the compound of the present invention can also the preparation of the various ways as known to the technical staff of organic synthesis field. Known synthetic method or ability in method described below and synthetic organic chemistry field can be used in the compound of the present invention Its version that field technique personnel are understood synthesizes.Preferred method includes but is not limited to those described above.Reaction can It is carried out in being suitable for used reagent and material and the solvent or solvent mixture that are adapted for carrying out conversion.Organic synthesis field Technical staff it will be appreciated that functional group present on molecule should be consistent with the conversion proposed.This will need following judgement sometimes: Modify synthesis step sequence or select another ad hoc approach route relative to a kind of method route with obtain it is of the invention needed for Compound.

It will also be appreciated that another major consideration for designing any route of synthesis in this field is correct selection for protecting Protect the blocking group of reactive functional groups present in heretofore described compound.Permitted to trained stakeholder description Authority's explanation of more alternative solutions be Greene et al. (Protective Groups in Organic Synthesis, the 4th Version, Wiley-Interscience (2006)).

Unless otherwise stated, the substituent group of compound is as defined herein in above-mentioned route.Those skilled in the art's meeting Understand, according to the product structure that expectation obtains, one or more steps in the above route can be omitted.Those skilled in the art The sequence of reaction step can be adjusted as suitably desired.

Pharmaceutical composition and pharmaceutical preparation

Another object of the present invention is to provide a kind of pharmaceutical compositions, and it includes prevention or the present invention of therapeutically effective amount Compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolin Or prodrug or their mixture and one or more pharmaceutically acceptable carriers.

" pharmaceutically acceptable carrier " refers to the diluent, adjuvant, excipient being administered together with therapeutic agent in the present invention Or medium, and its tissue that the mankind and/or other animals are adapted for contact in the range of reasonable medical judgment without Excessive toxicity, stimulation, allergic reaction or with reasonable benefit/risk than corresponding other problems or complication.

Workable pharmaceutically acceptable carrier includes but is not limited to sterile liquid in pharmaceutical composition of the invention, Such as water and oil, the oil including those petroleum, animal, plant or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame Oil etc..When described pharmaceutical composition is administered intravenously (IV, water is exemplary carrier.Physiological saline and grape can also be used Sugar and glycerine water solution are especially used for injection as liquid-carrier.Suitable drug excipient include starch, glucose, Lactose, sucrose, gelatin, maltose, chalk, silica gel, odium stearate, glycerin monostearate, talcum, sodium chloride, skimmed milk power, Glycerol, propylene glycol, water, ethyl alcohol etc..The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffering Agent.Oral preparation may include standard vector, such as the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, fiber Element, magnesium carbonate etc..The example of suitable pharmaceutically acceptable carrier is such as in Remington ' s Pharmaceutical Described in Sciences (1990).

Pharmaceutical composition of the invention can be acted on systematically and/or locally be acted on.For this purpose, they can be suitble to Approach administration, such as by injection (as in intravenous, intra-arterial, subcutaneous, peritonaeum, intramuscular injection, including instil) or it is percutaneous Administration；Or oral, buccal, intranasal, it is transmucosal, local, in the form of eye-drops preparations or pass through inhalation.

For these administration routes, pharmaceutical composition of the invention is administered in the dosage form that can be suitble to.The dosage form include but It is not limited to tablet, capsule, pastille, hard candy agent, powder, spray, cream, ointment, suppository, gelling agent, paste, washes Agent, ointment, aqueous suspension, injectable solutions, elixir, syrup etc..

Content or dosage of the compound of the present invention in pharmaceutical composition can be about 0.01mg to about 1000mg, be suitble to Ground is 0.1-500mg, preferably 0.5-300mg, more preferable 1-150mg, particularly preferred 1-50mg, for example, 1.5mg, 2mg, 4mg, 10mg, 25mg etc..

An embodiment according to the present invention, described pharmaceutical composition also may include one or more other therapeutic agents, Such as other therapeutic agents for preventing or treating the relevant disease of inhibition to plasma thromboplastin antecedent a.

Another object of the present invention is to provide a kind of method for preparing pharmaceutical composition of the invention, the method includes The compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent are closed Object, hydrate, metabolin or prodrug or their mixture are combined with one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide a kind of pharmaceutical preparation, it includes the compound of the present invention or its pharmaceutically may be used Salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolin or the prodrug of receiving or theirs is mixed Close object or pharmaceutical composition of the invention.

Treatment method and purposes

Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, ester, alloisomerisms Body, tautomer, polymorph, solvate, metabolin or prodrug or their mixture or drug of the invention Composition is in preparation for preventing or treating the purposes in the relevant drug of inhibition to plasma thromboplastin antecedent a.

Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, ester, alloisomerisms Body, tautomer, polymorph, solvate, metabolin or prodrug or their mixture or drug of the invention Composition, it is used to prevent or treat diseases relevant to the inhibition of plasma thromboplastin antecedent a.

Another object of the present invention is to provide prevention or the treatment method relevant to the inhibition of plasma thromboplastin antecedent a, institutes The method of stating includes to needing its individual that a effective amount of the compound of the present invention or its pharmaceutically acceptable salt, ester, solid is administered Isomers, tautomer, polymorph, solvate, metabolin or prodrug or their mixture, or the present invention Pharmaceutical composition.

An embodiment according to the present invention, usable the compound of the present invention prevented or treat with blood coagulation because The relevant inhibition of sub- XIa includes but is not limited to thromboembolic disorders, and the thromboembolic disorders preferably include the artery heart Vascular thrombosis thromboembolic disorder, the thromboembolic disorders of intravenous cardio thromboembolic disorders and heart chamber.

It is highly preferred that the thromboembolic disorders include unstable angina pectoris, acute coronary syndrome, atrium Fibrillation, for the first time myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, apoplexy, artery Atherosis, periphery occlusive arterial diseases, venous thronbosis, Deep vain thrombosis, thrombophlebitis, arterial embolism Plug, coronary artery thrombosis formed, and cerebral artery thrombosis is formed, cerebral embolism, renal embolism, pulmonary embolism, and due to (a) artificial valve or its Obtained by its implantation material, (b) inlying catheter, (c) bracket, (d) extracorporal circulatory system, (e) haemodialysis, or (f) blood is exposed to easy blood Thrombosis caused by the artificial surfaces that bolt is formed.

Term language " effective quantity " refers to be administered after can alleviate one or more symptoms of treated illness to a certain extent The amount of compound.

Dosage regimen be can adjust to provide optimal required response.For example, single bolus can be administered, can be administered at any time several Divided dose, or dosage can be proportionally reduced or increased as indicated in the urgent need for the treatment of condition.It should be noted that dose value can be with will subtract The type and seriousness of the light patient's condition and change, and may include single or multiple dosage.It further understands, for any specific Individual, specific dosage regimen should be sentenced according to the profession of individual need and administration composition or the personnel for the administration for supervising composition Break to adjust at any time.

The amount of the compound of the present invention being administered can depend on individual treated, the seriousness of illness or the patient's condition, to The rate of medicine, the disposition of compound and the judgement of prescriber.In general, effective dose is in per kg body weight per day about 0.0001 To about 50mg, for example, about 0.01 to about 10mg/kg/ days (single or divided doses).For the people of 70kg, this can be added up to about 0.007mg/ to about 3500mg/, for example, about 0.7mg/ to about 700mg/.In some cases, it is not higher than aforementioned model The dosage level of the lower limit enclosed can be it is enough, and in other cases, still can be in the feelings for not causing any harmful side effect Larger dose is used under condition, condition is that the larger dose is divided into several smaller doses to be administered throughout the day first.

Unless otherwise stated, otherwise as used herein, term " treatment " means to reverse, mitigates, inhibits such art The progress of one or more symptoms of illness or the patient's condition applied by language or such illness or the patient's condition, or prevent such illness Or one or more symptoms of the patient's condition or such illness or the patient's condition.

" individual " includes people or non-human animal as used herein.Exemplary individual human include with disease (such as this Disease described in text) individual human (referred to as patient) or normal individual." non-human animal " includes all vertebrates in the present invention, Such as nonmammalian (such as birds, amphibian, reptile) and mammal, such as non-human primates, domestic animal and/or Domesticated animal (such as sheep, dog, cat, milk cow, pig etc.).

Specific embodiment

Prepare embodiment

In order to keep the purpose of the present invention and technical solution clearer, this hair is further described below in conjunction with specific embodiment It is bright.It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.Also, the following example In unmentioned specific experiment method, according to routine experiment method carry out.

The structure for the compound recorded in embodiment below by nuclear magnetic resonance (¹HNMR) or mass spectrum (MS) determines.

¹HNMR displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).¹The measurement of HNMR is with JEOL Eclipse 400 nuclear magnetic resonance spectrometers, measurement solvent are deuterated methanol (CD₃OD), deuterated chloroform (CDCl₃), hexadeuterated dimethyl sulfoxide (DMSO-d6), It is inside designated as tetramethylsilane (TMS), chemical shift is with 10^-6(ppm) it is provided as unit,

Abbreviation in nuclear magnetic resonance used in embodiment (NMR) map is shown in following:

S: unimodal, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: four doublets, ddd: in pairs two Weight peak, ddt: triplet, dddd in pairs: double doublet, m in pairs: multiplet, br: broad peak (broad), J: coupling constant, Hz: Hertz.

The measurement of MS Agilent (ESI) mass spectrograph, manufacturer: Agilent, model: Agilent 6120B；

It prepares efficient liquid phase and uses Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 × 20mml chromatographic column).

The aluminium sheet (20 × 20cm) that thin-layer chromatography silica gel plate (TLC) uses Merck to produce, thin-layer chromatography isolates and purifies use Specification is that Yantai produces GF254 (0.4~0.5nm).

The monitoring of reaction uses thin-layered chromatography (TLC) or LCMS, and the solvent system used has: methylene chloride and methanol System, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, the volume ratio of solvent according to the polarity of compound not With and be adjusted or be added triethylamine etc. and be adjusted.

Microwave reaction uses BiotageInitiator+ (400W, RT~300 DEG C) microwave reactor.

Column chromatography is generally carrier using 200~300 mesh silica gel of Qingdao Haiyang.The system of eluant, eluent includes: methylene chloride And methanol system, n-hexane and ethyl acetate system, the volume ratio of solvent is different according to the polarity of compound and is adjusted, A small amount of triethylamine can be added to be adjusted.

Without specified otherwise in embodiment, the temperature of reaction is room temperature (20 DEG C~30 DEG C)

Reagent used in the present invention is purchased from Acros Organics, Aldrich Chemical Company, special uncleization Xue Deng company.

In conventional synthetic method and embodiment and intermediate synthesis example, the meaning respectively abridged is as shown below.

Alloc-Cl: allyl chlorocarbonate DMF:N, dinethylformamide

DMA:N, N- dimethyl acetamide DMSO: dimethyl sulfoxide

NMP:N- methyl pyrrolidone DIBAL-H: diisobutyl aluminium hydride

DIPEA:N, N- diisopropylethylamine THF: tetrahydrofuran

Boc: tert-butoxycarbonyl NBS；N- bromine succinimide

Cbz-Cl: benzyl chloroformate m-CPBA: metachloroperbenzoic acid

TFA: trifluoracetic acid Et₂O: Anaesthetie Ether,

EtOH: ethyl alcohol Dioxane:1,4- dioxane

TLC: thin-layer chromatography Me: methyl

HATU:O- (7- azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphate

DCM: methylene chloride EA: ethyl acetate

The chloro- 5,6- dicyan -1,4- benzoquinones MTBE of DDQ:2,3- bis-: methyl tertiary butyl ether(MTBE).

XPhos:2- dicyclohexyl phosphine -2', 4', 6'- tri isopropyl biphenyl PE: petroleum ether

Embodiment A:1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole-formic acid (1-4) preparation

Step 1: the preparation of the chloro- 2- fluorobenzene (1-2) of 1- nitrine -3-

Sodium nitrite (9.7g, 0.14mol) is dissolved in 25mL water, be added to be cooled to -5 DEG C dissolved with the chloro- 2- fluorobenzene of 3- In the trifluoroacetic acid solution (100mL) of amine (20.0g, 0.14mmol), the Sodium azide (9.1g, 0.14mol) for being dissolved in 5mL water is dripped It is added in reaction solution, drop finishes, and reaction solution is quenched with water after stirring 2 hours at 0 DEG C, and ethyl acetate extraction, organic phase is dry, mistake Filter obtains title compound (18.7g) after concentration, is directly used in and reacts in next step.

MS m/z(ESI):172[M+H]⁺

Step 2: the preparation of 1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- Ethyl formate (1-3)

The chloro- 2- fluorobenzene (18.7g, 0.11mol) of compound 1- nitrine -3- is dissolved in DMSO (80mL), sodium carbonate is added afterwards (2.0g), L-PROLINE (2.0g) and ethyl propiolate (21.6g, 0.22mol).Reaction solution is warming up to 75 DEG C and is stirred overnight.Instead Liquid is answered to be quenched with water, ethyl acetate extraction, organic phase dries, filters, and crude product is obtained after concentration, crude product crosses silica gel column purification Obtain title compound (17.3g, yield: 46.6%).

MS m/z(ESI):270[M+H]⁺

Step 3: 1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole-formic acid (1-4) preparation

By compound 1- (the chloro- 2- fluorobenzene of 3-) -1H-1,2,3- triazole -4- Ethyl formates (17.3g, 0.06mol) are dissolved in LiOHH is added in THF (200mL) and water (100mL) afterwards₂O (3.8g, 0.09mol), is stirred overnight at room temperature.LC-MS monitoring reaction After remove THF, water phase is extracted with ethyl acetate, and organic phase dries, filters, after concentration crude product, crude product and petroleum Ether mixing, is filtered, and title compound (15.2g, yield: 98.1%) are obtained after filtration cakes torrefaction.

MS m/z(ESI):242[M+H]⁺

The preparation of embodiment B:5- bromo- 2- (tertbutyloxycarbonyl) -1,2,3,4- tetrahydroisoquinoline -1- formic acid (1-8)

Step 1: the preparation of 2- bromophenylethyl methyl carbamate (1-6)

By compound bromophenyl ethamine (50g, 0.25mol), pyridine (30.4g, 0.38mol) is dissolved in methylene chloride (750mL) is added dropwise methylchloroformate (23.6g, 0.25mol), and 0 DEG C is stirred to react 3.5 hours, and TLC monitors end of reaction, reaction Liquid is quenched with dilute hydrochloric acid, and methylene chloride extraction, organic phase dries, filters, and is concentrated to give title compound (42.2g).

MS m/z(ESI):258[M+H]⁺

Step 2: the preparation of 5- bromo- 2- (methoxycarbonyl group) -1,2,3,4- tetrahydroisoquinoline -1- formic acid (1-7)

By compound 2- bromophenylethyl methyl carbamate (22.9g, 0.09mol) be dissolved in acetic acid/sulfuric acid (3/1, 500mL), ice bath is cooled to 0 DEG C, is slowly added dropwise glyoxylic acid ethyl ester (7.4g, 0.10mol), and drop finishes, and reaction is stirred at room temperature overnight, After being quenched with ice water, potassium carbonate alkalization, ethyl acetate is extracted twice, and after water phase is acidified with dilute hydrochloric acid, ethyl acetate extraction is organic It mutually dries, filters, obtains title compound (14.0g, 50.2%) after concentration.

MS m/z(ESI):313[M+H]⁺

Step 3: the preparation of 5- bromo- 2- (tertbutyloxycarbonyl) -1,2,3,4- tetrahydroisoquinoline -1- formic acid (1-8)

Compound 5- bromo- 2- (methoxycarbonyl group) -1,2,3,4- tetrahydroisoquinoline -1- formic acid (14g, 44.6mmol) is dissolved in Isosorbide-5-Nitrae-dioxane/ethyl alcohol (1/1,250mL) is warming up to 90 DEG C after sodium hydrate aqueous solution (10.0M, 100mL) is added, stirring It is cooled to room temperature, is added sodium hydrate aqueous solution (1.0M, 45mL) two days later, be added dropwise (Boc)₂O (14.6g, 66.9mmol), drop Finish, is stirred at room temperature after reaction 5 hours plus water quenching is gone out, ethyl acetate is extracted twice, and ethyl acetate extracts after water phase is acidified with dilute hydrochloric acid It takes, organic phase is dried, filtered with anhydrous sodium sulfate, obtains title compound (6.0g, 37.7%) after concentration.

MS m/z(ESI):356[M+H]⁺

The preparation of -1 (2H) t-butyl formate (1-10) of embodiment C:4- pinacol borate -5,6- dihydropyridine

By -1 (2H)-t-butyl formate of compound 4- (trifluoro-methanesulfonyl oxy) -5,6- dihydropyridine (10g, 0.03mol), boric acid pinacol ester (8.8g, 1.15eq), KOAc (2.9g, 3.5eq) are dissolved in Isosorbide-5-Nitrae-dioxane (100mL), nitrogen Pd (dppf) Cl is added under compression ring border₂(735mg, 0.03eq), dppf (499mg, 0.03eq), after be warming up to 80 DEG C, it is stirred At night, Isosorbide-5-Nitrae-dioxane is removed, residue crosses silica gel column purification and obtains title compound (7.4g, 79.6%).

MS m/z(ESI):310[M+H]⁺

Embodiment D:(R) 3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- formic acid (1-16) preparation

Step 1: the preparation of the chloro- 2- fluorobenzaldehyde oxime (1-12) of 3-

Compound 3-chlorin -2- fluorobenzaldehyde (50.0g, 0.32mol) and hydroxylamine hydrochloride (22.2g, 0.32mol) are dissolved in Et is added in THF (400mL)₃It is stirred overnight after N (32.3g, 0.32mol), reaction solution is quenched with water, ethyl acetate extraction, organic It is mutually washed twice with saturation NaCl aqueous solution, anhydrous magnesium sulfate dries, filters, and the crude product after concentration crosses silica gel column purification and obtains title Compound (29.1g, 53.2%).

MS m/z(ESI):174[M+H]⁺

Step 2: the preparation of the fluoro- N- hydroxyl benzimide chlorine (1-13) of the chloro- 2- of 3-

Compound 3-chlorin -2- fluorobenzaldehyde oxime (28.0g, 0.16mol) is dissolved in DMF (200mL), addition NCS (25.4g, 0.19mol), after being stirred at room temperature 3 hours plus water quenching is gone out, ethyl acetate extraction, and organic phase washing dries, filters, is concentrated to give title Compound (37.6g) is directly used in and reacts in next step without purifying.

MS m/z(ESI):208[M+H]⁺

Step 3: the preparation of 3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- t-butyl formate (1-14)

By the fluoro- N- hydroxyl benzimide chlorine of compound 3-chlorin -2- (37.6g, crude product) and tert-butyl acrylate (46g, It 0.36mol) is dissolved in methylene chloride (300mL), Et is added₃N (27.3g, 0.27mol), reaction solution is slow to be stirred overnight at room temperature, LC- MS monitors end of reaction, and reaction solution adds water quenching to go out, and removes methylene chloride, and water phase is extracted with ethyl acetate, the anhydrous sulphur of organic phase Sour magnesium dries, filters, and is concentrated to give crude product, and crude product crosses silica gel column purification and obtains title compound (36.7g, two step yields: 75.8%).

MS m/z(ESI):300[M+H]⁺

Step 4: the preparation of (R) -3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- t-butyl formate (1-15)

18g 3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- t-butyl formate is dissolved in 150ml mixed solvent In MeOH/CAN (1/1), chiral HPLC isolates and purifies to obtain title compound (7.2g, yield 40%).

MS m/z(ESI):300[M+H]⁺

Step 5: the preparation of (R) -3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- formic acid (1-16)

By compound (R) -3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- t-butyl formate (5.0g, It 16.68mmol) is dissolved in methylene chloride (10mL), is added trifluoroacetic acid (10mL), is stirred overnight at room temperature, LC-MS monitoring has been reacted Finish, remove solvent, ether (50mL) is added in residue, and filtering, filtration cakes torrefaction obtains title compound (4.0g, yield: 100%).

MS m/z(ESI):244[M+H]⁺

Embodiment E:(E) -3- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- base) phenyl) acrylic acid (1-22) preparation

The preparation method of synthetic method referenced patent WO2008157162 intermediate 7 (105-107 pages).

Embodiment 1:4- (1- ((4- carboxyl phenyl) carbamoyl) -2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- Triazole -4- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2,3,6- tetrahydro -1- trifluoroacetic acid Salt (2)

Step 1: the bromo- 1- of 5- ((4- (tertbutyloxycarbonyl) phenyl) carbamyl) -3,4- dihydro-isoquinoline -2 (1H)-first The preparation of tert-butyl acrylate (2-1)

By the bromo- 2- of compound 5- (tertbutyloxycarbonyl) -1,2,3,4- tetrahydroisoquinoline -1- formic acid (3.0g, 8.42mmol), The 4-aminobenzoic acid tert-butyl ester (1.6g, 8.42mmol) is dissolved in DMF (30mL), and DIPEA (3.3g, 25.3mmol) and HATU is added (3.8g, 10.10mmol), finishes, and is stirred overnight at room temperature, and LC-MS monitors end of reaction, is added to the water, and stirs 30 minutes, mistake It filters, silica gel column purification is crossed after filtration cakes torrefaction and obtains title compound (2.4g, yield 53.6%).

MS m/z(ESI):531[M+H]+

Step 2: 4- (the bromo- 1,2,3,4- tetrahydroisoquinoline -1- formamide of 5-) t-butyl perbenzoate hydrochloride (2-2) Preparation

By the bromo- 1- of compound 5- ((4- (tertbutyloxycarbonyl) phenyl) carbamyl) -3,4- dihydro-isoquinoline 2 (1H)-first Tert-butyl acrylate (2.4g, 4.52mmol) is dissolved in THF (15mL), and ice bath is cooled to 0 DEG C, and hydrochloric acid-Isosorbide-5-Nitrae dioxane solution is added dropwise (4M,10mL).It is stirred at room temperature 1.5 hours, LC-MS monitors end of reaction.Reaction solution is cooled to 0 DEG C, ether, stirring 5 is added It is filtered after minute, filtration cakes torrefaction obtains title compound (1.8g, 85.7%).

MS m/z(ESI):431[M+H]+

Step 3: 4- (the bromo- 2- of 5- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- carbonyl) -1,2,3,4- Tetrahydroisoquinoline -1- formamide) t-butyl perbenzoate (2-3) preparation

By compound 4- (the bromo- 1,2,3,4- tetrahydroisoquinoline -1- formamide of 5-) t-butyl perbenzoate hydrochloride (500mg, 1.07mmol), 1- (the chloro- 2- fluorobenzene of 3-) -1H-1,2,3- triazole -4- formic acid (266mg, 1.07mmol) are dissolved in DMF (15mL) is added DIPEA (414mg, 3.21mmol) and HATU (486mg, 1.28mmol), finishes, and reaction is stirred at room temperature overnight, LC-MS monitors end of reaction, is added to the water, and stirs 10 minutes, filtering, crosses silica gel column purification after filtration cakes torrefaction and obtains title compound (669mg, yield: 95.6%).

MS m/z(ESI):654[M+H]⁺

Step 4: 4- (1- ((4- (tertbutyloxycarbonyl) phenyl) carbamyl) -2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1, 2,3- triazole -4- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (2- 4) preparation

By compound 4- (the bromo- 2- of 5- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- carbonyl) -1,2,3,4- Tetrahydroisoquinoline -1- formamide) t-butyl perbenzoate (400mg, 0.61mmol), -1 (2H)-pyridine of 3,6- dihydro -4- borate T-butyl formate (207mg, 0.67mmol) is dissolved in Isosorbide-5-Nitrae dioxane (10mL), is added sodium carbonate (98mg, 0.92mmol), nitrogen Pd (dppf) Cl is added under compression ring border₂(40mg) reacts 50 minutes for 100 DEG C of microwave afterwards, and LC-MS monitors end of reaction, removes molten Agent, residue cross silica gel column purification and obtain title compound (401mg, yield: 86.6%).

MS m/z(ESI):757[M+H]⁺

Step 5: 4- (2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- carbonyl) -5- (1,2,3,6- tetra- Pyridinium hydroxide -4- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate hydrochloride (2-5) preparation

By compound 4- (1- ((4- (tertbutyloxycarbonyl) phenyl) carbamyl) -2- (1- (the chloro- 2- fluorophenyl of 3-) -1H- 1,2,3- triazole -4- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -5,6- dihydropyridine -1 (2H)-t-butyl formate (200mg, 0.26mmol) is dissolved in THF (5mL), and ice bath is cooled to 0 DEG C, and hydrochloric acid-Isosorbide-5-Nitrae-dioxane solution (4M, 3mL) is added dropwise, Drop finishes, and is stirred at room temperature 2 hours, and LC-MS monitors end of reaction, is added ether (50mL), is cooled to mistake after 0 DEG C of stirring 30 minutes Filter, filtration cakes torrefaction obtain title compound (103mg, yield: 56.3%).

MS m/z(ESI):657[M+H]⁺

Step 6: 4- (2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- carbonyl) -5- (1- methyl-1,2, 3,6- tetrahydropyridine -4- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate (2-6) preparation

By compound 4- (2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- carbonyl) -5- (1,2,3,6- tetra- Pyridinium hydroxide -4- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate hydrochloride (50mg, 0.07mmol) It is dissolved in the methanol buffer (3mL) that pH is 4, sequentially adds formalin (35%, 1mL) and NaBH₃CN(13mg, 0.21mmol), it finishes, is stirred overnight at room temperature, LC-MS monitors end of reaction, boils off solvent, residue HPLC purifies to obtain title Compound (35mg, 68.6%).

MS m/z(ESI):671[M+H]⁺

Step 7: iodate 4- (1- ((4- (tert-butoxycarbonyl) phenyl) carbamoyl) -2- (1- (chloro- 2- fluorobenzene of 3- Base) -1H-1,2,3- triazole -4- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2,3,6- tetrahydro The preparation of (2-7)

By compound 4- (2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- triazole -4- carbonyl) -5- (1- methyl-1, 2,3,6- tetrahydropyridine -4- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate (35mg, It 0.05mmol) is dissolved in DMF (0.5mL), MeI (71mg, 0.5mmol) is added thereto, finishes, room temperature reaction is overnight.LC-MS End of reaction is monitored, decompression boils off solvent, and residue HPLC purifies to obtain title compound (27mg, 79.8%).

MS m/z(ESI):685[M-I^-]⁺

Step 8: 4- (1- ((4- carboxyl phenyl) carbamoyl) -2- (1- (the chloro- 2- fluorophenyl of 3-) -1H-1,2,3- three Azoles -4- carbonyl) -1,2,3-, tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2, the trifluoroacetate of 3,6- tetrahydro -1- (2) preparation

By compound iodate 4- (1- ((4- (tert-butoxycarbonyl) phenyl) carbamoyl) -2- (1- (chloro- 2- fluorobenzene of 3- Base) -1H-1,2,3- triazole -4- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2,3,6- tetrahydro (27mg, 0.04mmol) is dissolved in DCM (0.5mL), and TFA (0.3mL) is added thereto, finishes, and room temperature reaction is overnight.LC-MS End of reaction is monitored, boils off solvent, residue HPLC purifies to obtain title compound (9mg, 35.8%).

MS m/z(ESI):629[M-CF₃COO^-]⁺

Embodiment 2:4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4, 5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -3- oxypiperazin -1- three Fluoroacetate (8)

The preparation method of the first step and second step synthetic operation step reference WO2013056060 intermediate 21 (page 96).

Step 3: the preparation of 3- oxo -4- (1,2,3,4- tetrahydroisoquinoline -5- base) piperazine -1- t-butyl formate (8-4)

Compound 4- (isoquinolin -5- base) -3- oxypiperazin -1- t-butyl formate (549mg, 1.68mmol) is dissolved in second PtO is added in alcohol (10mL)₂(50mg), hydrogen replace 3 times, are passed through hydrogen and are stirred overnight at room temperature, and LC-MS is monitored after completion of the reaction Filtering obtains title compound (528mg, yield 95%) after filtrate concentration.

MS m/z(ESI):332[M+H]⁺

Step 4: the preparation of 4- (3,4- dihydro-isoquinoline -5- base) -3- oxypiperazin -1- t-butyl formate (8-5)

By compound 3- oxo -4- (1,2,3,4- tetrahydroisoquinoline -5- base) piperazine -1- t-butyl formate (528mg, It 1.60mmol) is dissolved in DCM (20mL), activity MnO is added₂(1470mg, 16.90mmol) is finished, and is stirred overnight at room temperature, LC-MS End of reaction is monitored, filtering obtains title compound (492mg, 93.4%) after filtrate concentration.

MS m/z(ESI):330[M+H]⁺

Step 5: 4- ((S) -1- ((4- (tert-butoxycarbonyl) phenyl) carbamoyl) -2- ((R) -3- (chloro- 2- of 3- Fluorophenyl) -4,5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) the tertiary fourth of -3- oxypiperazin -1- formic acid The preparation of ester (8-6)

By compound 4- (3,4- dihydro-isoquinoline -5- base) -3- oxypiperazin -1- t-butyl formate (553mg, 1.68mmol), (R) -3- (the chloro- 2- fluorobenzene of 3-) -4,5- dihydro-isoxazole -5- formic acid (272mg, 1.12mmol) is dissolved in ethyl alcohol (20mL) is added 4- isocyanide t-butyl perbenzoate (255mg, 1.23mmol) after being warming up to 45 DEG C of stirrings 1 hour, is warming up to reflux And be stirred overnight, LC-MS monitors end of reaction, the crude product of title compound is obtained after reaction solution concentration, without further purifying, It is directly used in and reacts in next step.

MS m/z(ESI):776[M+H]⁺

Step 6:

4- ((S) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4,5- dihydro-isoxazole -5- carbonyl) -5- (2- oxypiperazin - 1- yl) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate hydrochloride (8-7) preparation

By 4- ((S) -1- ((4- (tert-butoxycarbonyl) phenyl) carbamoyl) -2- ((R) -3- (chloro- 2- fluorobenzene of 3- Base) -4,5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -3- oxypiperazin -1- t-butyl formate (200mg, 0.26mmol) is dissolved in THF (5mL), and ice bath is cooled to 0 DEG C, and hydrochloric acid-Isosorbide-5-Nitrae-dioxane solution (4M, 3mL) is added dropwise, Drop finishes, and is stirred at room temperature 2 hours, and LC-MS monitors end of reaction, is added ether (50mL), is cooled to mistake after 0 DEG C of stirring 30 minutes Filter, filtration cakes torrefaction obtain title compound (103mg, yield 56.3%).

MS m/z(ESI):676[M+H]⁺

Step 7: 4- ((S) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4,5- dihydro-isoxazole -5- carbonyl) -5- (4- first Base -2- oxypiperazin -1- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate (8-8) preparation

By compound 4- ((S) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4,5- dihydro-isoxazole -5- carbonyl) -5- (2- Oxypiperazin -1- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) t-butyl perbenzoate hydrochloride (50mg, It 0.07mmol) is dissolved in the methanol buffer (3mL) of pH4, sequentially adds formalin (35%, 1mL) and NaBH₃CN(13mg, 0.21mmol), it finishes, is stirred overnight at room temperature, LC-MS monitors end of reaction, boils off solvent, residue HPLC purifies to obtain title Compound (35mg, 68.6%).

MS m/z(ESI):690[M+H]⁺

Step 8: (((3- is chloro- by (R) -3- by -2- by (S) -1- ((4- (tertbutyloxycarbonyl) phenyl) carbamoyl) by iodate 4- 2- fluorophenyl) -4,5- dihydro-isoxazole -5- carbonyl) 1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -3- oxo piperazine The preparation of piperazine -1- (8-9)

By compound tert-butyl group 4- ((S) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4,5- dihydro-isoxazole -5- carbonyl) - 5- (4- methyl -2- oxypiperazin -1- base) -1,2,3,4- tetrahydroisoquinoline -1- formamido) methyl benzoate (34mg, It 0.05mmol) is dissolved in DMF (0.5mL), MeI (71mg, 0.5mmol) is added thereto, finishes, room temperature reaction is overnight.LC-MS End of reaction is monitored, decompression boils off solvent, and residue HPLC purifies to obtain title compound (25mg, 72.4%).

MS m/z(ESI):704[M-I^-]⁺

Step 9: 4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4, 5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -3- oxypiperazin -1- three The preparation of fluoroacetate (8)

By compound iodate 4-, (((3- is chloro- by (R) -3- by -2- by (S) -1- ((4- (tertbutyloxycarbonyl) phenyl) carbamoyl) 2- fluorophenyl) -4,5- dihydro-isoxazole -5- carbonyl) 1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -3- oxo piperazine Piperazine -1- (25mg, 0.04mmol) is dissolved in DCM (0.5mL), and TFA (0.3mL) is added thereto, finishes, reacted at room temperature Night.LC-MS monitors end of reaction, boils off solvent, residue HPLC purifies to obtain title compound (8mg, 33.7%).

MS m/z(ESI):648[M-CF₃COO^-]⁺

Embodiment 3:4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4, 5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2,3,6- tetrahydro -1- Trifluoroacetate (9)

In the present embodiment first step using 1-16 replace 1 third step of embodiment in 1-4, using with 1 third of embodiment The similar approach walked to the 8th step obtains title compound 9.

MS m/z(ESI):631[M-CF₃COO^-]⁺

Embodiment 4:4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4, 5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1- (2- (dimethylamino) -2- oxoethyl) - 1- methyl-1, the trifluoroacetate (10) of 2,3,6- tetrahydro -1-

Step 1: 4- ((S) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4,5- dihydro-isoxazole -5- carbonyl) -5- (1- (2- (dimethylamino) oxoethyl) -1,2,3,6- tetrahydropyridine -4- base) -1,2,3,4- tetrahydroisoquinoline -1- formamide Base) t-butyl perbenzoate (10-1) preparation

Compound 9-3 (49mg, 0.07mmol) is dissolved in DMF (0.5mL), the bromo- N of 2-, N- dimethyl are added thereto Acetamide (58mg, 0.35mmol) and DBU (88mg, 0.35mmol), finish, and room temperature reaction is overnight.LC-MS monitoring has been reacted Finish, decompression boils off solvent, and residue HPLC purifies to obtain title compound (39mg, 74.9%).

MS m/z(ESI):744[M+H]⁺

Second and step 3: 4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (chloro- 2- fluorobenzene of 3- Base) -4,5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1- (2- (dimethylamino) -2- oxo Ethyl) -1- methyl-1, the preparation of the trifluoroacetate (10) of 2,3,6- tetrahydro -1-

The 2-6 in the 7th step of embodiment 1 is replaced using 10-1 in the present embodiment second step, is then used and embodiment 1 The similar approach of 7th to the 8th step obtains title compound.

MS m/z(ESI):702[M-CF₃COO^-]⁺

Embodiment 5:4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4, 5- dihydro-isoxazole-5- carbonyl)-1,2,3,4- tetrahydroisoquinoline-5- base)-1- methyl-1-(oxetanes-3- base)-1,2, The trifluoroacetate (13) of 3,6- tetrahydropyridine -1-

The bromo- N of 2- in 4 first step of embodiment, N- diformazan are replaced using the bromo- propylene oxide of 3- in the present embodiment first step Yl acetamide obtains title compound using method similar to Example 4.

MS m/z(ESI):673[M-CF₃COO^-]⁺

Embodiment 6:(E) -4- (1- ((4- carboxyl phenyl) carbamoyl) -2- (3- (fluoro- 6- (1H-TETRAZOLE-of the chloro- 2- of 3- 1- yl) phenyl) acryloyl group) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2,3,6- tetrahydropyridine -1- Trifluoroacetate (22)

In the present embodiment first step using 1-22 replace 1 third step of embodiment in 1-4, using with 1 third of embodiment The similar approach walked to the 8th step obtains title compound.

MS m/z(ESI):656[M-CF₃COO^-]⁺

Embodiment 7:4- ((S) -1- ((4- carboxyl phenyl) carbamoyl) -2- ((R) -3- (the chloro- 2- fluorophenyl of 3-) -4, 5- dihydro-isoxazole -5- carbonyl) -1,2,3,4- tetrahydroisoquinoline -5- base) -1,1- dimethyl -1,2,3,6- tetrahydropyridine -1- Hydrochloride (54)

By compound iodate 4- ((S) -1- ((4- (tert-butoxycarbonyl) phenyl) carbamoyl) -2- ((R) -3- (3- Chloro- 2- fluorophenyl)-4,5- dihydro-isoxazole-5- carbonyl)-1,2,3,4- tetrahydroisoquinoline-5- base) dimethyl-1,2-1,1-, 3,6- tetrahydropyridine -1- (27mg, 0.04mmol) are dissolved in tetrahydrofuran (0.5mL), and hydrochloric acid-Isosorbide-5-Nitrae dioxy is added thereto Six ring solution (4M, 0.5mL), finish, and 30 DEG C of reactions are overnight.LC-MS monitors end of reaction, and ether (5mL) is added into system, Filtering, gained filter cake is title compound (9mg, 35.8%).

MS m/z(ESI):631[M-Cl^-]⁺

Pharmacological datum

Experimental example one, to the inhibiting effect of plasma thromboplastin antecedent a enzyme

Become factor XI, plasma thromboplastin antecedent a after plasma thromboplastin antecedent activation, further generate more Xa, to amplify fibrin ferment formation Amount.The beginning of inherent coagulation pathway and the formation of plasma thromboplastin antecedent a are considered very important to maintenance blood clot integrality Factor.XIa seems to play the formation for stablizing thrombus key effect, therefore compound makees the inhibition of plasma thromboplastin antecedent a enzyme With being crucial and desired activity.

Reagent:

Enzyme: Ⅺ a of human blood coagulation；Producer: Haemtech company；

Substrate: Boc-Ile-Glu-Gly-Arg-AMCAcetate salt；Producer: Bachem；

Detection method:

By untested compound by various concentration be dissolved in detection buffer (50mM HEPES, 145mM NaCl, 5mM KCl, 0.1%BSA, pH 7.4) in.Plasma thromboplastin antecedent a and untested compound are added in the orifice plate, is incubated at room temperature 10 minutes after mixing. Substrate (Boc-Ile-Glu-Gly-Arg-AMC Acetate salt) starting reaction is added.Under enzyme kinetics mode, selection The a length of 380nm of excitation light wave, wavelength of transmitted light are that 460nm reads fluorescence signal value.It reads 1 time within every 30 seconds, it is continuous to read 20 Circulation.Enzyme activity inhibiting rate under compound various concentration is calculated within the linear response phase.With SigmaPlot or GraphPadPrism The half-inhibitory concentration IC of 5 softwares fitting compound₅₀Value.

Inhibiting effect of 1. compound of table to plasma thromboplastin antecedent a

Compound number	IC₅₀Mean value (nM)
		2	0.56±0.08
8	0.40±0.17
		9	0.12±0.01
10	0.14±0.02
		13	0.16±0.01
22	0.38±0.03

Seen from table 1, the compound of the present invention has apparent inhibitory effect to plasma thromboplastin antecedent a.

Experimental example two, to the selective depression of Novoseven, factor Xa enzyme

Reagent:

Enzyme: human blood coagulation factors VII a；Producer: Haematologic Technologies company；

Substrate: Boc-VPR-AMC；Producer: R&D；

Tissue factor: tissue factor F3；Producer: Sino Biological；

Enzyme: human blood coagulation Xa；Producer: R&D；

Substrate: Mca-RPKPVE-Nval-WRK (Dnp)-NH2；Producer: R&D；

Under normal conditions, low to Factor Ⅶa and Xa inhibitory activity or no activity, then it is generally acknowledged that drug causes bleeding Risk it is smaller, be desired by anticoagulant.

To the selective depression detection method of VII a enzyme of Factor:

Untested compound is dissolved in detection buffer (50mM Hepes, 150mM by 10 μM and 1 μM of final concentration of reaction NaCl,5mM CaCl₂, pH7.4) in.Novoseven and tissue factor equimolar concentration mix, after 37 DEG C are incubated for 15 minutes, It adds untested compound to be incubated at room temperature 10 minutes, substrate (Boc-VPR-AMC) starting reaction is then added.Using enzyme kinetics Mode, a length of 380nm of excitation light wave, wavelength of transmitted light are that 460nm reads fluorescence signal value.It reads 1 time within every 30 seconds, it is continuous to read 20 circulations.Enzyme activity inhibiting rate under compound various concentration is calculated within the linear response phase.It is big according to inhibiting rate under various concentration It is small to judge IC₅₀Range.

To FactorXa enzyme activity selective depression detection method:

By untested compound by 20 μM of final concentration of reaction, 5 μM and 1 μM are dissolved in detection buffer (50mM Tris, 150mM NaCl,10mM CaCl₂, 0.05%Brij35, pH7.5) in.Factor Xa and untested compound are added in the orifice plate, mixes It is incubated at room temperature 10 minutes afterwards.Substrate (Mca-RPKPVE-Nval-WRK (Dnp)-NH is added₂) starting reaction.Using enzyme kinetics Mode, a length of 320nm of selective exitation light wave, wavelength of transmitted light are that 400nm reads fluorescence signal value.Reading in every 30 seconds 1 time, continuously Read 20 circulations.Enzyme activity inhibiting rate under compound various concentration is calculated within the linear response phase.According to inhibiting under various concentration Rate size judges IC₅₀Range.

Inhibiting effect of 2. compound of table to factor Xa and VIIa

Compound number	XaIC₅₀(μM)	VIIaIC₅₀(μM)
			9	>20	>10

As can be seen from Table 2, the compound of the present invention has excellent selection inhibiting effect for Ⅺ a of Factor.

Experimental example three, Compounds in vitro blood coagulation influence

Reagent:

APTT reagent；Sysmex；

PT reagent；Sysmex；

Coagulation pathway includes exogenous cruor pathway and intrinsic coagulation pathway.Parameter relevant to exogenous cruor pathway For prothrombin time, indicated with PT (prothrombin time)；Parameter relevant to intrinsic coagulation pathway is activation portion Divide thromboplastin time, is indicated with aPTT (activated partial thromboplatin time).Since endogenous is solidifying Blood approach and pathologic thrombus form that closely related rather than hemostatic function institute is required, and selective intrinsic coagulation factor inhibitors can To reduce bleeding risk.Therefore, anticoagulant wishes to extend aPTT (activated partial thromboplastin time), and to PT (fibrin ferment The former time) substantially without influence, to reach suitable anticoagulant effect.

APTT (activated partial thromboplastin time) and PT (prothrombin time) detection method:

After different genera (rabbit, dog, monkey, people) blood anticoagulant, upper plasma is collected by centrifugation, and equivalent is divided into more parts, respectively Different untested compounds are added, make final concentration of 10 μM of untested compound, sample, is then put into blood coagulation by 37 DEG C of incubations after mixing The detection of analyzer progress aPTT and PT.Blank plasma (compound is not added) is used as reference, to all samples and blank plasma The ratio of aPTT and PT is analyzed.

Influence (n=3) of 3. compound 9 of table to different genera aPTT and PT

Seen from table 3, compared with the blank plasma that test compound is not added, aPTT after the compound of the present invention 9 is added Be obviously prolonged, show that endogenous anti-thrombotic effect is good, the compound of the present invention is excellent Ⅺ a inhibitor of selectivity, and Ⅺ a with Intrinsic coagulation pathway is related, thus the compound of the present invention by selectively inhibition XIa and reach and keep aPTT value extended Effect.Compared with no blank plasma that test compound is added, the compounds of this invention and exogenous cruor pathway phase joined The PT value of pass has no significant change, and illustrates that the compound of the present invention has the characteristics that exogenous coagulation pathway without influence.

Claims

1. following formula (I) compounds represented or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polycrystalline Type object, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug,

In above-mentioned formula (I),

Indicate singly-bound or double bond；

X- indicates anion；

M is indicated with flowering structure:

R^5a、R^5bAnd R^5cIt is separately selected from: C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base or R^5a、R^5bWith Its N connected⁺3-10 circle heterocyclic ring base is collectively formed；The wherein C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring Base is optionally selected from deuterium, halogen, hydroxyl ,-S (O) by one or more_pR^m, cyano, C_1-6Alkyl, C_1-6Alkoxy ,-(O-C_1-4Alkylene Base)_n-OR^h、C_1-6Alkoxy -C_1-6Alkylidene-,-COOR^h、-N(R^g)₂、-NR^gCOR^h、-CON(R^g)₂、C_1-6Halogenated alkyl, C_3-6 Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl and the substituent group of 5-10 unit's heteroaryl replace；

The R⁶Selected from hydrogen, deuterium, halogen, hydroxyl ,-COOR^h、-N(R^g)₂、-NR^gCOR^h、-CON(R^g)₂、-S(O)_pR^m, cyano, C_1-6 Alkyl, alkoxy；

The L³Selected from key, C_1-6Alkylidene, C_2-6Alkenylene, the C_1-6Alkylidene, C_2-6Alkenylene is optionally selected by one or more From halogen, C_1-6Alkoxy and halogenated C_1-6The substituent group of alkyl replaces；

Part is selected from flowering structure:

R⁰Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-4Alkoxy ,-C_1-3Alkylidene-C_1-4Alkoxy, alkyl halide Base, C_3-6Naphthenic base；

L¹It is selected from: key, C_1-6Alkylidene, C_3-10Cycloalkylidene, 3-10 member sub- heterocycle, C_6-10Arlydene, 5-10 member inferior heteroaryl； The sub- heterocycle of 3-10 member contains one or more selected from N, NR⁷, O, P and S (O)_PRing members, the sub- heteroaryl of 5-10 member Base contains one or more selected from N, NR⁷, O and S (O)_PRing members；The C_1-6Alkylidene, C_3-10Cycloalkylidene, C_6-10Sub- virtue Base, the sub- heterocycle of 3-10 member, 5-10 member inferior heteroaryl are optionally selected from deuterium, halogen, hydroxyl, cyano, C by one or more_1-6Alkane Base, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Halogenated alkoxy ,-C_1-6Alkylidene-C_1-6Alkoxy ,-C (O) C_1-4Alkyl ,- COOR^h、-N(R^g)₂、C_3-10Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 unit's heteroaryl ,-CON (R^g)₂And- NR^gCO₂R^hSubstituent group replace；

R¹It is selected from: H ,-COOR^h、-N(R^g)₂、C_1-6Alkyl, C_3-10Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 member heteroaryl Base ,-CON (R^g)₂、-CO-(O-C_1-4Alkylidene)_n-OR^h、-CO-(O-C_1-4Alkylidene)_n-N(R^g)₂、-NR^gCO₂R^h、-C_1-4Alkylene Base-CO₂-C_1-4Alkylidene-O-CO₂-C_1-4Alkyl；The 3-10 circle heterocyclic ring base contains one or more selected from N, NR⁷, O, P and S (O)_PRing members, the 5-10 unit's heteroaryl contains one or more selected from N, NR⁷, O and S (O)_PRing members；The C_1-6 Alkyl, C_3-10Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 unit's heteroaryl are optionally by one or more deuteriums, halogen, hydroxyl Base, cyano, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl, C_1-6Halogenated alkoxy ,-C (O) C_1-4Alkyl ,-COOR^h、-N (R^g)₂、-CON(R^g)₂、-NR^gCO₂R^hAnd C_3-10The substituent group of naphthenic base and 3-10 circle heterocyclic ring base replaces；

R²It is selected from: hydrogen, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-4Alkoxy, C_1-4Halogenated alkoxy ,- CH₂NH₂、-CH₂OH、-CH₂-OC_1-4Alkyl ,-C (O) C_1-4Alkyl ,-CONH₂, 5-7 circle heterocyclic ring base and 5-6 unit's heteroaryl；

R³Selected from hydrogen atom, halogen and C_1-4Alkyl；

L²It is selected from: key, alkenylene, C_3-6Cycloalkylidene, 5-6 member sub- heterocycle, 5-6 member inferior heteroaryl, the sub- heterocycle of 5-6 member Base, 5-6 member inferior heteroaryl contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The alkenylene is optionally by alkyl, halogen Substituted alkyl replaces；The C_3-6Cycloalkylidene, the sub- heterocycle of 5-6 member, 5-6 member inferior heteroaryl optionally by one or more selected from deuterium, Hydroxyl, cyano ,=O ,-N (R^g)₂、C_1-6Halogenated alkyl, halogen ,-C_1-4Alkylidene-OH, C_1-3Alkoxy, C_1-3Halogenated alkoxy With-C (O) C_1-4The substituent group of alkyl replaces；

A is selected from: C_3-10Cycloalkylidene, C_6-10Arlydene, 3-10 member sub- heterocycle, 5-10 member inferior heteroaryl；The 3-10 member is sub- miscellaneous Ring group, 5-10 member inferior heteroaryl contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The C_3-10Cycloalkylidene, C_6-10 Arlydene, the sub- heterocycle of 3-10 member, 5-10 member inferior heteroaryl are optionally selected from H, halogen, hydroxyl, cyano, C by one or more_1-6 Alkyl, C_1-4Alkoxy, C_1-6Halogenated alkyl, C_1-4Halogenated alkoxy ,-CH₂N(R^g)₂、-CO(C_1-4Alkyl) ,-CON (R^g)₂、- COOR^h, 5-7 circle heterocyclic ring base and 5-6 unit's heteroaryl substituent group replace；

R⁴Selected from H, C_3-10Naphthenic base, C_6-10Aryl, 3-10 circle heterocyclic ring base, 5-10 unit's heteroaryl；The 3-10 circle heterocyclic ring base, 5- 10 unit's heteroaryls contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The C_3-10Naphthenic base, C_6-10Aryl, 3-10 member Heterocycle, 5-10 unit's heteroaryl are optionally selected from deuterium, halogen, hydroxyl, cyano, C by one or more_1-6Alkyl, C_1-4Alkoxy, C_1-6Halogenated alkyl, C_1-4Halogenated alkoxy ,-CH₂N(R^g)₂、-CO(C_1-4Alkyl) ,-CON (R^g)₂With-COOR^hSubstituent group take Generation；

R⁷It is each independently selected from: H, C_1-4Alkyl ,-CO (C_1-4Alkyl) ,-COCF₃、-CO₂(C_1-4Alkyl) ,-CONH₂、-C(O) NH-(C_1-4Alkyl)-CO₂(C_1-4Alkyl) ,-(C_1-4Alkylidene) CO₂(C_1-4Alkyl) ,-C_1-4Alkylidene-R^h、-CO₂R^h、-C(O) NHR^g；

The R^gIt is each independently selected from H, C_1-6Alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base；And multiple R^gIt each other can be with It is identical or different；

The R^hIt is each independently selected from H, C_1-6Alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 member heteroaryl Base；And multiple R^hIt each other can be identical or different；

The R^mSelected from H, C_1-6Alkyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base, C_6-10Aryl, 5-10 unit's heteroaryl；And multiple R^m It each other can be identical or different；

N each independently represents 0,1,2,3 or 4；

P each independently represents 0,1 or 2.

2. compound as described in claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, more Crystal form object, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, which is characterized in that

Indicate singly-bound or double bond；

X- indicates anion；

M is indicated with flowering structure:

R^5a、R^5bAnd R^5cIt is separately selected from: C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring base or R^5a、R^5bWith Its N connected⁺3-10 circle heterocyclic ring base is collectively formed；The wherein C_1-6Alkyl, C_2-6Alkenyl, C_3-6Naphthenic base, 3-10 circle heterocyclic ring Base is optionally selected from deuterium, halogen, hydroxyl ,-S (O) by one or more_pR^m, cyano, C_1-6Alkyl ,-(O-C_1-4Alkylidene)_n-OR^h、 C_1-6Alkoxy -C_1-6Alkylidene-,-COOR^h、-N(R^g)₂、-NR^gCOR^h、-CON(R^g)₂、C_1-6Halogenated alkyl, C_3-6Naphthenic base, 3- 10 circle heterocyclic ring bases, C_6-10Aryl and the substituent group of 5-10 unit's heteroaryl replace；

Part is selected from flowering structure:

R³Selected from hydrogen atom, halogen and C_1-4Alkyl；

A is selected from: C_3-10Cycloalkylidene, C_6-10Arlydene, 3-10 member sub- heterocycle, 5-10 member inferior heteroaryl；The 3-10 member is sub- miscellaneous Ring group, 5-10 member inferior heteroaryl contain 1-4 selected from N, NR⁷, O and S (O)_PIn ring members；The C_3-10Cycloalkylidene, C_6-10 Arlydene, the sub- heterocycle of 3-10 member, 5-10 member inferior heteroaryl are optionally selected from deuterium, halogen, hydroxyl, cyano, C by one or more_1-6 Alkyl, C_1-4Alkoxy, C_1-6Halogenated alkyl, C_1-4Halogenated alkoxy ,-CH₂N(R^g)₂、-CO(C_1-4Alkyl) ,-CON (R^g)₂、- COOR^h, 5-7 circle heterocyclic ring base and 5-6 unit's heteroaryl substituent group replace；

N each independently represents 0,1,2,3 or 4；

P each independently represents 0,1 or 2.

3. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomerism Body, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, which is characterized in that structure As shown in following formula (II),

Wherein, L²Selected from alkenylene, and the alkenylene is optionally by one or more C_1-4Alkyl, C_1-3Halogenated alkyl replaces；

Wherein, R^aIndependently selected from H, hydroxyl, cyano ,=O, NH₂, halogen ,-C_1-4Alkylidene-OH, C_1-3Alkoxy, C_1-3It is halogenated Alkoxy and-C (O) C_1-3Alkyl；

R^bAnd R^cEach independently optionally from H, halogen, hydroxyl, cyano, C_1-6Alkyl, C_1-4Alkoxy, C_1-3Halogenated alkyl, C_1-3Halogen For alkoxy；

M、W、Q、L¹、R¹、R²、R³、R⁴、X^-As claims 1 or 2 defines.

4. compound as described in any one of claims 1 to 3 or its pharmaceutically acceptable salt, ester, stereoisomer, interconversion Isomers, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein

L¹Selected from phenylene and 5-10 member inferior heteroaryl, the 5-10 member inferior heteroaryl contains one or more selected from N, NR⁷, O and S(O)_PRing members, wherein R⁷As defined in claim 1 with p, the phenylene and 5-10 member inferior heteroaryl are optionally by one Or it is multiple selected from deuterium, Cl, F, hydroxyl, cyano, C_1-4Alkyl, C_1-4Alkoxy, C_1-3Halogenated alkyl, C_1-3Halogenated alkoxy, carboxylic Base ,-COO-C_1-4Alkyl ,-N (C_1-4Alkyl)₂、-NH(C_1-4Alkyl) and-NH₂Substituent group replace；

R¹Selected from H, carboxyl ,-N (C_1-4Alkyl)₂、-NH(C_1-4Alkyl) ,-NH₂、C_1-6Alkyl, C_3-7Naphthenic base, 3-7 circle heterocyclic ring base, 5-6 unit's heteroaryl ,-CON (C_1-4Alkyl)₂、-CONH(C_1-4Alkyl) ,-CONH₂、-COO-C_1-4Alkyl ,-COO-C_1-4Alkylidene- O-(C_1-4Alkyl) ,-COO-C_1-4Alkylidene-N- (C_1-4Alkyl)₂、-NHCOO-C_1-4Alkyl ,-C_1-4Alkylidene-COO-C_1-4Alkylene Base-O-COO-C_1-4Alkyl；The 3-7 circle heterocyclic ring base, 5-6 unit's heteroaryl optionally by one or more selected from deuterium, Cl, F, hydroxyl, Cyano, C_1-4Alkyl, C_1-4Alkoxy, C_1-3Halogenated alkyl, C_1-3Halogenated alkoxy, carboxyl ,-COO-C_1-4Alkyl ,-N (C_1-4Alkane Base)₂、-NH(C_1-4Alkyl) and-NH₂Substituent group replace；

Preferably, L¹-R¹Selected from following group:

And/or

L³Selected from key, C_1-4Alkylidene, C_2-4Alkenylene, the C_1-4Alkylidene, C_2-4Alkenylene optionally by one or more selected from F, Cl、C_1-4Alkoxy, C_1-4The substituent group of halogenated alkyl replaces；Preferably, L³Selected from key, methylene or ethylidene；

And/or

R^5a、R^5b、R^5cIt is separately selected from: C_1-3Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base or R^5a、R^5bN connected to it⁺ 3-6 circle heterocyclic ring base, the C is collectively formed_1-3Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base are optionally selected from halogen by one or more Element, hydroxyl, carboxyl, C_1-4Alkoxy ,-COO-C_1-4Alkyl ,-S (O)_p(C_1-3Alkyl) ,-CON (R^g)₂、-N(R^g)₂Substituent group take Generation；The R^gIt is each independently selected from H or C_1-3Alkyl works as R^gWhen being multiple, multiple R^gIt can be identical or different；The p is indicated 0,1 or 2；

Preferably, R^5a、R^5b、R^5cIt is separately selected from: methyl, ethyl, aziridinyl, azelidinyl, oxa- ring fourth Base, oxiranyl ,-(CH₂)_nCON(CH₃)₂、-(CH₂)_nS(O)₂CH₃、-(CH₂)_nOCH₃、-(CH₂)_nOH、-(CH₂)_nCOOH、- (CH₂)_nCOO-C_1-3Alkyl or R^5a、R^5bN connected to it⁺Following group is collectively formed:

Wherein n each independently represents 1,2 or 3.

5. compound or its pharmaceutically acceptable salt, ester, stereoisomer as described in any one of Claims 1-4, Tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, feature It is, shown in the structure of compound such as formula (III-1),

Preferably, R^b、R^cIt is separately selected from: H, Cl, F；

It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As any one in Claims 1-4 defines.

6. compound or its pharmaceutically acceptable salt, ester, stereoisomer as described in any one of Claims 1-4, Tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, feature It is, shown in the structure of compound such as formula (III-2),

Wherein, R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；Preferably, R^b、R^c It is separately selected from: H, Cl, F；It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、R^5c、L³、W、Q、L¹、R¹、X^-As any one in Claims 1-4 defines.

7. compound or its pharmaceutically acceptable salt, ester, stereoisomer as described in any one of Claims 1-4, Tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, feature It is, shown in the structure of compound such as following formula (IV-1),

Wherein,

R⁸It is selected from: H, C_1-3Halogenated alkyl, C_1-4Alkyl, it is preferable that R⁸Selected from H, CH₂F、CHF₂、CF₃、CH₂Cl、CHCl₂、CCl₃、 C_1-4Alkyl；

T is selected from: N, CH, CF, CCl, CC_1-4Alkyl；

R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；Preferably, R^b、R^cIt is only respectively It is on the spot selected from: H, Cl, F；It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；

R^5a、R^5b、W、Q、L¹、R¹、X^-As any one in Claims 1-4 defines.

8. compound or its pharmaceutically acceptable salt, ester, stereoisomer as described in any one of Claims 1-4, Tautomer, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, feature It is, shown in the structure of compound such as following formula (IV-2),

Wherein,

T is selected from: N, CH, CF, CCl, CC_1-4Alkyl；

R^b、R^cIt is separately selected from: H, halogen, C_1-4Alkyl, C_1-3Alkoxy, C_1-3Halogenated alkyl；Preferably, R^b、R^cIt is only respectively It is on the spot selected from: H, Cl, F；It is highly preferred that R^bIt is selected from: H, F and R^cFor Cl；R^5a、R^5b、R^5c、L³、W、Q、L¹、R¹、X^-Such as claim Any one in 1 to 4 is defined.

9. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomerism Body, polymorph, solvate, N- oxide, the compound of isotope labelling, metabolin or prodrug, wherein the compound Structure is as follows,

10. the preparation method of the described in any item compounds of claim 1 to 9, the method is selected from method one into method three Any one:

Method one:

In method one, R^LThe C for indicating halogen or being optionally optionally substituted by halogen_1-3Alkyl sulfonic acid ester group (such as triflate Base)；PG¹、PG²For protecting group；R^1PFor the R protected by protecting group¹；Y indicates leaving group, it is preferable that the leaving group is selected from H, halogen Element, the C being optionally optionally substituted by halogen_1-3Alkyl sulfonic acid ester group, boronate, boric acid ester group, substituted silicon substrate or substituted Metal Substrate Group；M^aIt indicates with flowering structure:Wherein R^5a’With R^5aIdentical or R^5a’In formula (I) R^5a、R^5bN connected to it⁺It is H when 3-10 circle heterocyclic ring base is collectively formed；M^bWith M^aIdentical or M^bTurn through one or more steps reaction Turn to M^a(for example, working as M^aForWhen, M^bFor)；

Step 1: compound SM-1 is by deprotection reaction and continues to carry out acid amide condensation reaction life in the presence of condensing agent At compound IM-1；

Step 2: compound IM-1 is by deprotection reaction and continues to carry out acid amide condensation reaction life in the presence of condensing agent At compound IM-2；

Step 3: compound IM-2 is by coupling reaction or continues the reactions generation compound IM-3 such as to be deprotected, be alkylated；

Step 4: compound IM-3 (such as reacts, the preferred iodine of alkylating reagent by quaternization reaction with alkylating reagent Methane), deprotection reaction, or continue ion exchange generate formula (I) compound；

Method two:

Step 1: compound SM-1 is by deprotection reaction and continues to carry out acid amide condensation reaction life in the presence of condensing agent At compound IM-4；

Step 2: compound IM-4 is by deprotection reaction and continues to carry out acid amide condensation reaction life in the presence of condensing agent At compound IM-2；

Step 3: compound IM-2 is by coupling reaction or continues deprotection, alkylated reaction generation compound IM-3；

Step 4: compound IM-3 (such as reacts, the preferred iodine of alkylating reagent by quaternization reaction with alkylating reagent Methane), deprotection reaction, or continue ion exchange process generate formula (I) compound；

Method three:

In method three, R^pWithIdentical or R^PC (O)-is the blocking group for the amino that can be removed；R^L、R^1P、 Y、R^5a’、M^aAnd M^bAs defined in method one；

Step 1: compound SM-2 generates compound IM-5 by coupling reaction；

Step 3: compound IM-6 is by deprotection reaction and continues to carry out acid amide condensation reaction life in the presence of condensing agent At compound IM-7；Work as R^pWithWhen identical, this step is omitted；

Step 4: compound IM-7 generates compound IM-3 by the reactions such as deprotection and alkylation；Work as M^aAnd M^bWhen identical, this Step is omitted；

Step 5: compound IM-3 (such as reacts, the preferred iodine of alkylating reagent by quaternization reaction with alkylating reagent Methane), deprotection reaction, or continue ion exchange process generate formula (I) compound,

In the above method one, method two or method three, R¹、R²、R³、R⁴、L²、A、M、W、Q、L¹、X^-As in claim 1 to 9 Any one is defined.

11. pharmaceutical composition, contain compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, ester, molten Agent compound, isomers, their any crystal form or racemoid, their metabolite form or their mixture, preferably into one Step contains pharmaceutically acceptable auxiliary material.

12. pharmaceutical composition described in claim 11, wherein further include can with it is according to any one of claims 1 to 9 Compound, its pharmaceutically acceptable salt, ester, solvate, isomers, their any crystal form or racemoid, their metabolism Other active constituents associated with object form or their mixture.

13. a kind of pharmaceutical preparation, wherein said preparation includes compound according to any one of claims 1 to 9, its is pharmaceutically acceptable Salt, ester, solvate, isomers, their any crystal form or racemoid, their metabolite form or their mixing For object as active constituent, said preparation is the form of solid pharmaceutical preparation, semisolid preparation, liquid preparation or gaseous state preparation.

14. compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, ester, solvate, isomers, it Any crystal form or racemoid, their metabolite form or their mixture or claim 11 or 12 it is any one Pharmaceutical preparation described in item described pharmaceutical composition or claim 13 is in preparation for treating and the suppression of plasma thromboplastin antecedent a Application in the drug of related disease processed；

Preferably, the disease relevant to the inhibition of plasma thromboplastin antecedent a is thromboembolic disorders, the thromboembolism venereal disease Disease includes the thromboembolism of arterial cardiovascular thromboembolic disorders, intravenous cardio thromboembolic disorders and heart chamber Venereal disease disease；

It is highly preferred that the thromboembolic disorders include unstable angina pectoris, acute coronary syndrome, human atrial fiber Property trembling, myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, apoplexy, artery are athero- for the first time Hardening, periphery occlusive arterial diseases, venous thronbosis, Deep vain thrombosis, thrombophlebitis, arterial embolism, hat Shape Arterial thrombosis, cerebral artery thrombosis formation, cerebral embolism, renal embolism, pulmonary embolism, and due to (a) artificial valve or other plants Enter object gained, (b) inlying catheter, (c) bracket, (d) extracorporal circulatory system, (e) haemodialysis or (f) blood is exposed to easy thrombus shape At artificial surfaces caused by thrombosis.