CN104311556B - Pyrazoles containing epoxy alkyl substituting group piperidone compounds and composition thereof and purposes - Google Patents

Abstract

The present invention relates to pyrazolopiperidone compound and its pharmaceutically acceptable composition and its use in the preparation of medicines for treating diseases related to factor Xa. In particular, the present invention relates to a novel pyrazolopiperidone compound containing epoxyalkyl substituents, pharmaceutical compositions containing these compounds and the use of these compounds in the preparation of drugs for the treatment of diseases related to factor Xa use.

Description

Pyrazolopiperidone compounds containing epoxyalkyl substituents, compositions and uses thereof

technical field

The present invention relates to pyrazolopiperidone compound and its pharmaceutically acceptable composition and its use in the preparation of medicines for treating diseases related to factor Xa. In particular, the present invention relates to a novel pyrazolopiperidone compound containing epoxyalkyl substituents, pharmaceutical compositions containing these compounds and the use of these compounds in the preparation of drugs for the treatment of diseases related to factor Xa use.

Background of the invention

The main practical role of activated factor Xa is the generation of thrombin by limited proteolysis of thrombin. Factor Xa occupies a central position in the final general pathway of blood coagulation, linking intrinsic and extrinsic activation mechanisms. Thrombin is the final serine protease in the pathway to produce a fibrin clot. The generation of thrombin from its precursors is amplified by the formation of the prothrombin complex (factor Xa, factor V, Ca ²⁺ and phospholipids). One factor Xa molecule can produce 138 thrombin molecules (Elodi, a., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa–factor VIII complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), so Xa is inhibited in the interference of the coagulation system factor may be more effective than inactivating thrombin.

Therefore, there is a need for potent and specific factor Xa inhibitors as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. The present invention relates to novel factor Xa inhibitors; preferably with improved pharmacological properties; more preferably with higher factor Xa inhibitory activity and better selectivity; and/or preferably with the following advantages and improved properties, But not limited to, pharmaceutical properties (such as solubility, permeability, and suitability for sustained-release formulations), dosing requirements (such as lower doses and/or once-daily doses), factors that reduce blood concentrations characterized by peak and trough ( factors that increase active drug concentration (eg, protein binding, volume of distribution), factors that reduce the propensity for clinical drug-drug interactions (eg, inhibition or induction of cytochrome P450 enzymes), factors that reduce adverse side effects Factors of possibility (e.g., pharmacological selectivity other than serine proteases, possible chemical or metabolic reactivity, and limited CNS permeability) and factors that improve manufacturing cost or feasibility (e.g., difficulty of synthesis, proximity of chiral centers number, chemical stability, and ease of handling).

Summary of the invention

The invention provides a compound or its pharmaceutical composition, which can effectively inhibit factor Xa and treat related diseases.

In one aspect, the present invention relates to a compound represented by formula (I) or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R ¹ is C _1-6 alkyl, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-OC(=O)- or amino-C(=O)-;

R ² is C _1-6 alkoxy, C _1-6 alkanoylamino, C _2-9 heterocycloalkyl, C _1-6 alkylamino, CH≡CC _1-6 alkoxy or CH ₂ =CH- C _1-6 alkoxy;

Each R ³ is independently hydrogen, oxo, halogen, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylamino;

X ¹ is -(CH ₂ ) _n -;

X ² is -(CH ₂ ) _m -;

n and m are each independently 0, 1, 2 or 3; when n and m are both 0, X ¹ , X ² and O together form =O; and

r is 0, 1, 2 or 3.

In some embodiments, the present invention relates to a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, Hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

In other embodiments, R ¹ is C _1-4 alkyl, C _1-4 alkyl-C(=O)-, C _1-4 alkyl-OC(=O)- or amino-C(= O)-;

R ² is C _1-4 alkoxy, C _1-4 alkanoylamino, C _2-6 heterocycloalkyl, C _1-4 alkylamino, CH≡CC _1-4 alkoxy or CH ₂ =CH- C _1-4 alkoxy; and

Each R ³ is independently hydrogen, oxo, halogen, C _1-4 alkyl, C _1-4 alkoxy, or C _1-4 alkylamino.

^In other embodiments, R is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, methyl-C(=O)-, ethyl-C(= O)-, Propyl-C(=O)-, Isopropyl-C(=O)-, Butyl-C(=O)-, Methyl-OC(=O)-, Ethyl-OC( =O)-, propyl-OC(=O)-, isopropyl-OC(=O)-, butyl-OC(=O)- or amino-C(=O)-;

R2 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert ^- butoxy, isobutoxy, formamido, acetylamino, propionylamino, butyrylamino, pyrrole Alkyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butyl Amino, isobutylamino, CH≡C-CH ₂ -O-, CH≡C-CH ₂ -CH ₂ -O-, CH ₂ ＝CH-CH ₂ -O- or CH ₂ ＝CH-CH ₂ -CH ₂ -O-; and

Each ^R is independently hydrogen, oxo, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, methoxy, ethoxy, propyl oxy, isopropoxy, butoxy, tert-butoxy or isobutoxy.

In other embodiments, the present invention comprises one of the following structures:

or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.

In another aspect, the present invention provides a pharmaceutical composition comprising any one of the compounds described herein.

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

In some other embodiments, the pharmaceutical composition further comprises non-Xa-inhibiting anticoagulant, antiplatelet agent, thrombin inhibitor, thrombolytic agent, fibrinolytic agent or a combination thereof.

In other embodiments, the pharmaceutical composition further comprises a second factor Xa inhibitor.

On the other hand, the compound of the present invention and the pharmaceutical composition are used for preventing, treating, alleviating or delaying glucose unstable angina, acute coronary syndrome, initial myocardial infarction, recurrent myocardial infarction, Sudden hemorrhagic death, transient ischemic attack, stroke, arteriosclerosis, peripheral obstructive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral Embolism, renal embolism, pulmonary embolism, and complications resulting from (a) artificial valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) blood Use in medicines for thrombosis resulting from exposure to other processes on artificial surfaces that promote thrombosis.

Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (II).

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described in more detail and more fully below.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

As used herein, the articles "a" and "an" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms McGraw-Hill Book Company, New York, 1984; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and processes, the compounds of the invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis ( ^2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford , UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolution sp. 268 (EL Liel, Ed., Univ. of Notre Dame Press, Notre Dame, IN1972); Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers, also known as prototropic tautomers, include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. structured. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents described therein can be, but are not limited to, hydrogen, deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, mercapto, amino, arylamino, aminoalkyl, alkyl, alkane thiol, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions of "each...independently" and "...independently" and "...independently" used in the present invention can be used interchangeably. Both should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or it can mean that in the same group, the options expressed by the same symbols do not affect each other. The specific options do not affect each other. example structure and structure, the specific options of R ³ in the two are not affected by each other, and at the same time, if multiple R ³ appear in the same structure, the specific options of multiple R ³ do not affect each other, that is, the specific options of R ³ can be the same , can also be different.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C _1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.

When the group of the present invention is used alone or in connection with other groups, the group has the definition described in the present invention. For example, the definition of alkyl used alone is the same as the definition of alkyl mentioned in alkyl-C(=O)-, alkyl-O-C(=O)- or alkylalkoxy, all of which have the definition described in the present invention .

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 - 4 carbon atoms; in still some embodiments, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-methyl Base-1-butyl, 3-hexyl, n-heptyl, n-octyl, etc.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

The term "alkylamino" denotes an alkyl group attached to the rest of the molecule through a nitrogen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkylamino groups contain 1-12 carbon atoms. In one embodiment, the alkylamino group contains 1-6 carbon atoms; in another embodiment, the alkylamino group contains 1-4 carbon atoms; in yet another embodiment, the alkylamino group contains 1 - 3 carbon atoms. The alkylamino group may be optionally substituted with one or more substituents described herein.

The term "alkanoylamino" means that an alkyl group is attached to the rest of the molecule through an amide group, which is represented by alkyl-C(=O)-NH-.

The term "heterocycloalkyl" means a monovalent saturated carbocyclic ring containing one or more heteroatoms selected from S, O, N. The heterocycloalkyl group may be connected to the rest of the molecule through a carbon atom, or may be connected to the rest of the molecule through a nitrogen atom. Examples of heterocycloalkyl groups are, but not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, and the like.

The term "oxo" means that oxygen is double bonded to the atom at the substitution site, ie =O, such as carbon oxo is -(C=O)-.

The term "amino" is represented by _-NH2 .

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, refer to: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) or formula (II) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. CSS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Designs and Clinical Applic Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "treating" any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, "treating" refers to preventing or delaying the onset, development or worsening of a disease or condition.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/ Carbonate, Bisulfate/Sulfate, Camphorsulfonate, Chloride/HCl, Chlorophylline Salt, Citrate, Ethionate, Fumarate, Glucoheptonate, Glucose Sugarate, Glucuronate, Hippurate, Hydroiodide/Iodide, Isethionate, Lactate, Lactobionate, Lauryl Sulfate, Malate, Malate salt, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate Salt, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate , tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethansulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile will be required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahland Wermuth (Wiley- Additional lists of suitable salts can be found in VCH, Weinheim, Germany, 2002).

In addition, the compounds disclosed in the present invention, including their salts, are also available in the form of their hydrates or in the form of solvents containing them (such as ethanol, dimethyl sulfoxide (DMSO), etc.) for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.

As described in the present invention, the substituent draws a bond to form a ring system (as shown in formula (a)) on the central ring, which means that the substituent R ⁵ can be substituted at any substitutable position on the ring. For example, formula (a) represents that any possible substituted position on W1 ring or W2 ring can be substituted.

Composition, Formulation and Administration of the Compounds of the Invention

The invention provides pharmaceutical compositions comprising one or more compounds of the invention suitable for pharmaceutical use. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. The pharmaceutical composition can be used to prevent, treat, alleviate or delay unstable angina, acute coronary syndrome, initial myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, arterial sclerosis, peripheral obstructive arterial disease, venous thrombosis, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and by (a) Resulting from artificial valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures that expose blood to artificial surfaces that promote thrombosis Thrombus, in particular, has a good inhibitory effect on factor Xa.

Compounds of the invention may be administered alone or in combination with one or more other therapeutic agents. The pharmaceutical composition further comprises a second factor Xa inhibitor and/or non-factor Xa inhibiting anticoagulant, antiplatelet agent, thrombin inhibitor, thrombolytic agent, fibrinolytic agent.

When available for treatment, a therapeutically effective amount of a compound of the present invention, especially a compound of formula (I) or formula (II) and a pharmaceutically acceptable salt thereof, may be administered as a raw chemical or as part of a pharmaceutical composition. Active ingredients provided. Therefore, the pharmaceutical composition provided by the present invention includes a therapeutically effective amount of the compound of the present invention, especially a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier, diluent or excipient. As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit meaningful patient benefit. When a separate active ingredient is administered alone, the term refers to that ingredient alone. When used in combination, the term then refers to combined amounts of the active ingredients that result in a therapeutic effect, whether administered in combination, sequentially or simultaneously. The compounds of the present invention, especially the compounds of formula (I) or formula (II) and pharmaceutically acceptable salts thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the content of the present invention, there is also provided a method for preparing a pharmaceutical preparation, the method comprising combining a compound of the present invention, especially a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, with a or multiple pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" used in the present invention refers to such compounds, raw materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, etc., within the scope of sound medical judgment. , allergic reactions or other problems and complications commensurate with a reasonable benefit/risk ratio and effective for the intended purpose.

When a composition of the present invention comprises a combination of a compound of the present invention and one or more other therapeutic or prophylactic agents, the dosage levels of the compound and the additional drug are generally 50% of the normal administered dose in a monotherapy regimen. About 10-150%, more preferably about 10-80% of the normally administered dose. The pharmaceutical formulations are suitable for administration by any suitable route, for example, orally (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal , intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.

Pharmaceutical compositions for the use of the compounds of the invention may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. In pharmaceutical compositions, the active compound of interest is included in an amount sufficient to produce the desired effect on the disease process or condition.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, lozenges, sugars, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or syrups or elixirs. Compositions intended for oral use may be prepared according to any of the methods well known in the art of manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preservatives, in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granules and disintegrants such as cornstarch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricants, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer sustained action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in US Pat. Nos. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with water or, for example, peanut oil. , liquid paraffin or olive oil in an oily medium.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth and acacia; dispersing agents or The humectant may be a naturally occurring phospholipid such as lecithin, or the condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or ethylene oxide with a long chain fatty alcohol such as heptadecenyloxycetyl alcohol Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate, or ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides Condensation products such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives (such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavor enhancers and One or more sweetening agents (such as sucrose or saccharin).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above as well as flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil or a mineral oil such as liquid paraffin or a mixture of these. Suitable emulsifiers may be naturally occurring gums such as acacia or tragacanth; naturally occurring phospholipids such as soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate esters; and condensation products of said partial esters with ethylene oxide, such as polyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are traditionally employed as a solvent or suspending medium. Thus, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable medicaments.

The pharmaceutical composition may also be used in the form of suppositories or enemas for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches containing a compound of this invention are employed. Topical application as used herein is also intended to include the use of mouthwashes and mouthwashes.

As a general guideline, the daily oral dose of each active ingredient used in order to achieve the indicated effect is in the range of about 0.001 to 1000 mg/kg body weight, preferably, between about 0.01 to 100 mg/kg body weight . And, most preferably, between about 1.0 to 20 mg/kg body weight per day. For intravenous administration, the most preferred dosage range is about 1 to about 10 mg/kg body weight per minute during a conventional rate infusion. The compounds of the present invention may be administered once daily, or may be administered in two, three or four divided times daily.

It is to be understood, however, that the specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound being used, the metabolic stability and duration of action of the compound, age, body weight, General health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the particular condition and the host being treated.

The compounds of the present invention may be used with a second therapeutic agent useful in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds of the present invention are useful, including unstable angina, acute coronary syndrome, primary Myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, arteriosclerosis, peripheral obstructive arterial disease, venous thrombosis, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary Arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and resulting from (a) artificial valve or other implant, (b) indwelling catheter, (c) stent, (d) cardiopulmonary bypass, ( e) Thrombosis resulting from hemodialysis or (f) other procedures that expose blood to artificial surfaces that promote thrombus formation. Such second therapeutic agents may be administered by commonly used routes and in commonly used amounts thereby simultaneously, sequentially or separately from the compounds of the present invention. When a compound of the invention is used contemporaneously with one or more other drugs, such a second therapeutic agent is preferably included in addition to the compound of the invention. Accordingly, the pharmaceutical compositions of the present invention include, in addition to the compounds of the present invention, one or more second therapeutic agents.

The second therapeutic agent includes, but is not limited to, a second Factor Xa inhibitor and a non-Factor Xa inhibiting anticoagulant, antiplatelet agent, thrombin inhibitor, thrombolytic agent, fibrinolytic agent, or combinations thereof.

Where the compound of the present invention is combined with other anticoagulant agents, for example, a daily dose may be about 0.1 to 100 mg of a compound of formula (I) or (II) and about 1 to 7.5 mg of Secondary anticoagulant. For a tablet dosage form, the compound of the invention may generally be from about 5 to 10 mg per dosage unit, and the amount of the second anticoagulant agent is from about 1 to 5 mg per dosage unit. Among them, other anticoagulant agents specifically include, but are not limited to, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran, bemiparin, enoxaparin sodium, tinza Heparin Sodium, Danaparin Sodium, Pentosan Sodium, Nadroparin Calcium, Adeparin Sodium, Parparin Sodium, etc.

According to general guidelines, the compound of the present invention is administered in combination with an antiplatelet agent, and a typical daily dose may be about 0.01 to 25 mg of the compound of formula (I) or (II) and about 50 to 150 mg of the antiplatelet agent per kg of patient body weight. Platelet agents, preferably about 0.1 to 1 mg of a compound of formula (I) or (II) and about 1 to 3 mg of an antiplatelet agent.

When the compound of the present invention is administered in combination with a thrombolytic agent, the general daily dose can be about 0.1 to 1 mg of the compound of formula (I) or (II) per kilogram of patient body weight, and the dosage of the thrombolytic agent can be reduced by about 70-80%. .

When two or more aforementioned second therapeutic agents are administered together with the compound of formula (I) or (II), generally, in consideration of the additive or synergistic effects of the therapeutic agents during combined administration, the typical daily dose The amount of each component in a typical dosage form may be reduced relative to the usual dosage when administered alone.

In particular, when presented as a single dosage unit, there exists the possibility of chemical reactions between the active ingredients in combination. For this reason, when a compound of formula (I) or (II) and a second therapeutic agent are combined in a single dosage unit, they are formulated in a manner that minimizes physical contact between the active ingredients (i.e., reduction), although the active ingredients are combined in a single dosage unit. For example, an active ingredient may be enteric coated. By coating an active ingredient with an enteric coating, it is possible not only to minimize contact between the combined active ingredients, but also to control the release of one of these ingredients in the gastrointestinal tract so that one of the ingredients does not Released not in the stomach but in the small intestine. One of the active ingredients can also be coated with materials that affect its sustained release in the gastrointestinal tract and can also be used to reduce physical contact between the combined active ingredients. Further, the sustained release component can additionally be coated with an enteric coating in order to Release of this ingredient occurs only in the intestinal tract. Still another approach involves the formulation of combination products in which one component is coated with a sustained and/or enteric release polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxyl Propyl methylcellulose (HPMC) or other suitable materials known in the art are coated to achieve the purpose of further separating the active ingredients. The polymer coating creates an additional barrier to reaction with other components.

These and other methods of minimizing contact between the components of the combination products of the invention will be apparent to those skilled in the art once apprised of the present disclosure, whether administered in a single dosage form or in separate forms, But at the same time or in the same way.

The weight ratio of the compound of the invention to the second active ingredient may vary and will depend on the effective dosage of each ingredient. Generally, an effective dose of each will be used. Combinations of the compounds of the invention with other active ingredients will generally also be within the aforementioned ranges, but in each case an effective dose of each active ingredient should be used.

Uses of the compounds and pharmaceutical compositions of the present invention

The present invention provides the use of the compound or the pharmaceutical composition of the present invention in the preparation of medicaments, and the medicaments can be used to inhibit factor Xa. The medicament can be used to prevent, treat, alleviate or delay unstable angina, acute coronary syndrome, initial myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, arteriosclerosis , peripheral obstructive arterial disease, venous thrombosis, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and by (a) prosthetic valve or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures that expose blood to artificial surfaces that promote thrombosis.

The method of treatment comprising the administration of the compound of the present invention or the pharmaceutical composition further comprises administering to the patient a second factor Xa inhibitor, non-factor Xa inhibited anticoagulant, antiplatelet agent, thrombin inhibitor, thrombolytic agent, fiber Proteolytic agents or combinations thereof.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or lessening the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.

The compounds of the present invention (herein, the expression "compound of formula (I) or formula (II) and its stereoisomers, geometric isomers, tautomers, mesomers, racemates, Enantiomers, diastereomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts and prodrugs" can be collectively referred to as "compounds of the present invention"), which can be used for Production of pharmaceutical products for the prevention, treatment, alleviation or delay of unstable angina, acute coronary syndrome, initial myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, arteriosclerosis, Peripheral obstructive arterial disease, venous thrombosis, deep venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and Thrombosis resulting from other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures that expose blood to artificial surfaces that promote thrombosis, including those described herein. Furthermore, the compounds of the present invention can be used to inhibit factor Xa. Therefore, the compound of the present invention can be used for the production of a medicine for alleviating, preventing, controlling or treating the disease mediated by factor Xa. Therefore, the compound of the present invention can be used as an active ingredient of a pharmaceutical composition, which can include a compound represented by formula (I) or formula (II), and can further include at least one pharmaceutically acceptable carrier , Excipients, Diluents, Adjuvants and Vehicles.

General Synthesis Process

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I) or formula (II). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company, and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by reflux drying with sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed using CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, two doublets), dt (doubletoftriplets, double triplet). Coupling constants J are in hertz (Hz).

Low-resolution mass spectrometry (MS) data was determined by an Agilent6320 series LC-MS spectrometer equipped with G1312A binary pump and aG1316ATCC (column temperature maintained at 30°C), G1329A automatic sampler and G1315BDAD detector were used for analysis, ESI source Applied to LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data was measured by an Agilent6120 series LC-MS spectrometer equipped with G1311A quaternary pump and G1316ATCC (column temperature maintained at 30°C), G1329A automatic sampler and G1315DDAD detector were used for analysis, ESI source Applied to LC-MS spectrometer.

The above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1×30mm, 5μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in Table 1:

Table 1

time (min) A( _CH3CN ,0.1%HCOOH) B(H ₂ O,0.1%HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

Compound purification is evaluated by Agilent1100 series high-performance liquid chromatography (HPLC), wherein UV detection is at 210nm and 254nm, ZorbaxSB-C18 column, specification is 2.1 * 30mm, 4 μ m, 10 minutes, flow rate is 0.6mL/min, 5 -95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), the column temperature was kept at 40°C.

The following abbreviations are used throughout this disclosure:

Reaction Scheme 1

Compound 7 can be prepared by the method described in Reaction Scheme 1. Wherein, R ² , R ³ , r and n are as defined in the present invention.

Compound 1 reacts with n-butyllithium to generate compound 2. Compound 2 reacts with compound 3 to form compound 4. Compound 4 reacts with thionyl chloride to generate compound 5. Compound 5 reacts with compound 6 under basic conditions to generate compound 7.

Reaction Scheme 2

Compound 7 can be prepared by the method described in Reaction Scheme 2. wherein R ² is -OL; X is Cl, Br or I; R ³ , r and n are as defined in the present invention.

Compound 4 reacted with compound 11 under basic conditions to generate compound 7.

Reaction scheme 3

Compound 7 can be prepared by the method described in Reaction Scheme 3. Wherein, R ² represents acetamido; R ³ , r and n are as defined in the present invention.

Compound 4 was reacted with sulfuric acid and acetonitrile to generate compound 7.

Reaction Scheme 4

Compound 10 can be prepared by the method described in Reaction Scheme 4. Wherein, R ² , R ³ , r and n are as defined in the present invention.

Compound 7 and compound 8 are heated in a solvent (such as dimethyl sulfoxide) in the presence of a base (such as cesium carbonate, potassium carbonate), a ketone salt (such as cuprous iodide) and a ligand (such as 8-hydroxyquinoline) Compound 9 was obtained. Compound 9 was aminolyzed to give compound 10.

intermediate

1-(4-Methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Step 1) 3,3-Dichloropiperidin-2-one

At -5°C, 2-azidine (30g, 303mmol) was dissolved in chloroform (500mL), phosphorus pentachloride (150g, 757.5mmol) was added, stirred at -5°C for 10 minutes and then heated to reflux for 2 Hour. Cool to room temperature, add ice water (300 mL), and stir at room temperature for 12 hours. Dichloromethane (100 mL×2) was added for extraction, the organic phases were combined, washed with water (50 mL×2) and saturated brine (50 mL) successively, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a light yellow solid (22 g, 43.4%).

MS(ESI,pos.ion)m/z:168.0(M+1).

Step 2) 3-Morpholinyl-5,6-dihydropyridin-2(1H)-one

3,3-Dichloropiperidin-2-one (22.0 g, 131.7 mmol) was dissolved in morpholine (80 mL). Then heated to 140°C and stirred for 12 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain a white solid (13 g, 55%).

MS(ESI,pos.ion)m/z:182.2(M+1).

Step 3) (E)-Ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazino)acetate

After dissolving sodium nitrite (12.2g, 176.8mmol) in water (60mL) below -5°C, add p-methoxyaniline (20g, 162.4mmol) and concentrated hydrochloric acid (41.4mL) in ethanol dropwise (41.4mL) solution. After stirring at -5°C for 20 minutes, sodium acetate (36.42 g, 444 mmol) was added, followed by dropwise addition of ethyl 2-chloroacetoacetate (30 mL) dissolved in (ethanol/water (v/v)=9/1) ( 450mL) of the mixed solution. After the dropwise addition was completed, it was stirred at -5°C for 20 minutes. Filter and wash the filter cake with water. Recrystallized from ethanol/water (v/v)=9/1 mixed solution to obtain a white solid (25 g, 65%).

MS(ESI,pos.ion)m/z:257.0(M+1).

Step 4) 1-(4-Methoxyphenyl)-7a-morpholino-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4 -c] Ethyl pyridine-3-carboxylate

Dissolve ethyl (E)-2-chloro-2-(2-(4-methoxyphenyl)hydrazino)acetate (10.1g, 39.5mmol) in ethyl acetate (80mL) and cool to 5°C , 3-morpholinyl-5,6-dihydropyridin-2(1H)-one (6.0 g, 33 mmol) was added. A solution of triethylamine (18.5 mL, 132 mmol) in ethyl acetate (30 mL) was added slowly. After rising to room temperature and stirring for 0.5 hours, the mixture was heated under reflux and stirred for 12 hours. After cooling to room temperature, ice water (50 mL) was added. Extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain a yellow solid (6.55 g, 55%).

MS(ESI,pos.ion)m/z:403.1(M+1).

Step 5) Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

1-(4-methoxyphenyl)-7a-morpholino-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c ] Pyridine-3-ethyl acetate (6.4 g, 16 mmol) was dissolved in ethyl acetate (100 mL), cooled to 5°C. Dilute hydrochloric acid (30 mL, 4M) was added dropwise, and stirred at 5° C. for 4 hours after the addition was complete. The solvent was evaporated under reduced pressure, and extracted with dichloromethane (50 mL×4). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a white solid (5.1 g, 95.0%).

MS (ESI, pos. ion) m/z: 316.1 (M+1).

Example 1

6-(4-(3-methoxyoxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetra Hydrogen-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1) (4-iodophenyl)lithium

At -78°C, n-butyllithium (2.5M, 8.8mL, 22mmol) was added to a solution of 1,4-diiodobenzene (6.6g, 20mmol) in tetrahydrofuran (20mL), stirred at -78°C for 10 minutes, used directly in the next step.

Step 2) 3-(4-iodophenyl)oxetan-3-ol

At -78°C, a solution of (4-iodophenyl) lithium (10.50 g, 50.01 mmol) was added dropwise to a solution of 3-oxetanone (3.60 g, 50.0 mmol) in tetrahydrofuran (40 mL). Stir at -78°C for 10 minutes, add water (20 mL), extract with ethyl acetate (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain a white solid (8.0 g, 70%).

MS(ESI,pos.ion)m/z:277.0(M+1).

Step 3) 3-(4-iodophenyl)-3-methoxyoxetane

To a solution of 3-(4-iodophenyl)oxetan-3-ol (0.827 g, 3.0 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (0.48 g, 12.0 mmol) at 0°C. Stir at 0°C for 30 minutes, add iodomethane (1.28 g, 9.00 mmol), and stir at room temperature for 3 hours. Extracted with ethyl acetate (50 mL×2), combined the organic phases, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=1/10) to obtain a pale yellow solid (0.83g, 95%).

MS(ESI,pos.ion)m/z:290.9(M+1).

Step 4) 6-(4-(3-methoxyoxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6, 7-Tetrahydro-1H-pyrrolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] ethyl pyridine-3-carboxylate (0.272g, 0.864mmol), 3-(4-iodophenyl)-3-methoxyxetane (0.210g, 0.720mmol), 8-hydroxy Quinoline (31.0mg, 0.216mmol), potassium carbonate (0.40g, 2.88mmol), cuprous iodide (41.0mg, 0.216mmol) and dimethylsulfoxide (15mL), heated to 140°C and stirred for 7 hours. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a white solid (0.17 g, 41%).

MS(ESI,pos.ion)m/z:478.2(M+1).

Step 5) 6-(4-(3-methoxyxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6, 7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Add 6-(4-(3-methoxyoxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4 , ethyl 5,6,7-tetrahydro-1H-pyrrolo[3,4-c]pyridine-3-carboxylate (63.0mg, 0.13mmol), methanol (2mL), ammonia water (25%, 1.0mL, 13.28 mmol), heated to 70°C and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/4) to obtain a white solid (25 mg, 43.0%).

MS(ESI,pos.ion)m/z:449.2(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 3.12 (s, 3H), 3.40 (t, 2H), 3.81 (s, 3H), 4.10 (m, 2H), 4.78 (t, 2H), 4.90 ( t,2H),5.60(s,1H),6.86(s,1H),6.94(d,2H),7.36(d,2H),7.45-7.53(m,4H).

Example 2

6-(4-(3-Acetamidooxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro -1H-pyrazol[3,4-c]pyridine-3-carboxamide

Step 1) N-(3-(4-iodophenyl)oxetan-3-yl)acetamide

To a solution of 3-(4-iodophenyl)oxetan-3-ol (0.552 g, 2.0 mmol) in acetonitrile (20 mL) was added concentrated sulfuric acid (2 mL) dropwise at 0°C. Stir at 0°C for 10 minutes, add iodomethane (1.28 g, 9 mmol), and stir at room temperature for 3 hours. Add saturated sodium bicarbonate (20 mL) solution, extract with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=2/1) to obtain a white solid (0.39 g, 61%).

MS(ESI,pos.ion)m/z:318.1(M+1).

Step 2) 6-(4-(3-Acetamidooxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7 -Ethyl tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] Ethyl pyridine-3-carboxylate (0.132g, 0.42mmol), N-(3-(4-iodophenyl)oxetan-3-yl)acetamide (0.091g, 0.28mmol), 8-Hydroxyquinoline (20.0mg, 0.136mmol), potassium carbonate (0.40g, 2.88mmol), cuprous iodide (26.0mg, 0.136mmol) and dimethyl sulfoxide (15mL), heated to 140°C and stirred for 4 Hour. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (methanol/dichloromethane (v/v)=1/10) to obtain a white solid (33 mg, 15.6%).

MS(ESI,pos.ion)m/z:505.2(M+1).

Step 3) 6-(4-(3-Acetamidooxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7 -Tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxamide

Add 6-(4-(3-acetylaminooxetan-3-yl)phenyl)-1-(4-methoxyphenyl)-7-oxo-4 sequentially into a 10mL sealed jar, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (33.0mg, 0.065mmol), methanol (2mL), ammonia water (25%, 1.0mL, 13.28 mmol), heated to 70°C and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/4) to obtain a white solid (10 mg, 36.0%).

MS(ESI,pos.ion)m/z:494.1(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 1.93 (s, 3H), 3.34-3.70 (m, 4H), 3.81 (s, 3H), 4.10 (m, 2H), 5.65 (s, 1H), 6.01(s,1H),6.86(s,1H),6.94(d,2H),7.32(d,2H),7.45-7.53(m,4H).

Example 3

1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(pyrrolidin-1-yl)oxetan-3-yl)phenyl)-4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1) 3-Chloro-3-(4-iodophenyl)oxetane

To a solution of 3-(4-iodophenyl)oxetan-3-ol (2.78 g, 10 mmol) in dichloromethane (25 mL) was added thionyl chloride (10 mL) dropwise. Stir at 40°C for 3 hours. Extracted with ethyl acetate (50 mL×2), combined the organic phases, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=1/3) to obtain a transparent oil (2.9 g, 98%).

MS(ESI,pos.ion)m/z:294.9(M+1).

Step 2) 1-(3-(4-iodophenyl)oxetan-3-yl)pyrrolidine

3-Chloro-3-(4-iodophenyl)oxetane (0.59 g, 2.00 mmol) was dissolved in tetrahydropyrrole (5 mL). Heat to 90°C and stir for 6 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=2/1) to obtain a colorless oil (0.34 g, 41%).

MS(ESI,pos.ion)m/z:330.0(M+1).

Step 3) 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(pyrrolidin-1-yl)oxetan-3-yl)phenyl)-4 ,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] ethyl pyridine-3-carboxylate (0.30g, 0.96mmol), 1-(3-(4-iodophenyl)oxetan-3-yl)pyrrolidine (0.21g, 0.64mmol), 8-Hydroxyquinoline (29.0mg, 0.20mmol), potassium carbonate (0.414g, 3.0mmol), cuprous iodide (38.0mg, 0.20mmol) and dimethyl sulfoxide (15mL), heated to 140°C and stirred for 4 Hour. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a yellow solid (46 mg) which was directly used in the next step.

Step 4) 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(pyrrolidin-1-yl)oxetan-3-yl)phenyl)-4 ,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Add 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(pyrrolidin-1-yl)oxetan-3-yl) successively to a 10 mL sealed jar Phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.046g, 0.071mmol), methanol (2mL), ammonia water (25 %, 1 mL, 13.28 mmol), heated to 70°C and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/4) to obtain a white solid (14.0 mg, 31.0%).

MS(ESI,pos.ion)m/z:506.2(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 1.80-1.90 (m, 4H), 2.90-2.99 (m, 5H), 3.37 (t, 3H), 3.60-3.70 (m, 2H), 3.82 (m ,4H),4.10(t,2H),5.57(s,1H),6.86(s,1H),6.94(d,2H),7.32(d,2H),7.45-7.47(m,4H).

Example 4

1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(piperidin-1-yl)oxetan-3-yl)phenyl)-4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1) 1-(3-(4-iodophenyl)oxetan-3-yl)piperidine

3-Chloro-3-(4-iodophenyl)oxetane (0.59 g, 2 mmol) was dissolved in piperidine (5 mL). Heat to 90°C and stir for 6 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=2/1) to obtain a colorless oil (0.34 g, 41%).

MS(ESI,pos.ion)m/z:344.0(M+1).

Step 2) 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(piperidin-1-yl)oxetan-3-yl)phenyl)-4 ,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] ethyl pyridine-3-carboxylate (0.315g, 1.0mmol), 1-(3-(4-iodophenyl)oxetan-3-yl)piperidine (0.285g, 0.83mmol), 8-Hydroxyquinoline (29.0mg, 0.2mmol), potassium carbonate (0.414g, 3.0mmol), cuprous iodide (38.0mg, 0.2mmol) and dimethyl sulfoxide (15mL), heated to 140°C and stirred for 4 Hour. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a yellow solid (35 mg) which was directly used in the next step.

Step 3) 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(piperidin-1-yl)oxetan-3-yl)phenyl)-4 ,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Add 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(piperidin-1-yl)oxetan-3-yl) Phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.035g, 0.061mmol), methanol (2mL), ammonia water (25 %, 1 mL, 3.28 mmol), heated to 70°C and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/4) to obtain a white solid (0.14 g, 32.8%).

MS(ESI,pos.ion)m/z:520.3(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 1.60-1.70 (m, 5H), 2.60-2.80 (m, 5H), 2.90 (m, 1H), 3.35-3.40 (m, 3H), 3.44-3.48 (m,3H),3.56-3.66(m,3H),3.82(s,3H),4.10(t,2H),5.56(s,1H),6.84(s,1H),6.93(d,2H), 7.32(d,2H),7.45-7.47(m,4H).

Example 5

1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(prop-2-yn-1-yloxy)oxetan-3-yl)phenyl) -4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1) 3-(4-iodophenyl)-3-(prop-2-yn-1-yloxy)oxetane

To a solution of 3-(4-iodophenyl)oxetan-3-ol (0.552 g, 2.0 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (0.32 g, 8.0 mmol) at 0°C. Add 3-bromopropyne (0.714g, 6.0mmol) and stir at room temperature for 3 hours. Extracted with ethyl acetate (50 mL×2), combined the organic phases, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=1/10) to obtain a white solid (0.83g, 95%).

MS(ESI,pos.ion)m/z:315.0(M+1).

Step 2) 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(prop-2-yn-1-yloxy)oxetan-3-yl) Phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] ethyl pyridine-3-carboxylate (0.315g, 1mmol), 3-(4-iodophenyl)-3-(prop-2-yn-1-yloxy)oxetane (0.471 g, 1.0mmol), 8-hydroxyquinoline (43.5mg, 0.3mmol), potassium carbonate (0.552g, 4.0mmol), cuprous iodide (57.0mg, 0.30mmol) and dimethylsulfoxide (15mL), Heat to 140°C and stir for 4 hours. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a yellow solid (58 mg) which was directly used in the next step.

Step 3) 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(prop-2-yn-1-yloxy)oxetan-3-yl) Phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Add 1-(4-methoxyphenyl)-7-oxo-6-(4-(3-(prop-2-yn-1-yloxy)oxetane successively to a 10 mL sealed jar -3-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.046g, 0.091mmol), methanol (2mL ), ammonia water (25%, 1mL, 13.28mmol), heated to 70°C and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain a white solid (15 mg, 41%).

MS(ESI,pos.ion)m/z:473.2(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 2.43 (s, 2H), 3.40 (t, 2H), 3.82 (s, 3H), 3.88 (m, 2H), 4.10-4.15 (m, 2H), 4.80-4.85(m,2H),5.05-5.15(m,2H),5.53(s,1H),6.86(s,1H),6.94(d,2H),7.32(d,2H),7.45-7.53(m ,6H).

Example 6

1-(4-methoxyphenyl)-6-(4-(3-(4-methylpiperazin-1-yl)oxetan-3-yl)phenyl)-7-oxo- 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1) 1-(3-(4-iodophenyl)oxetan-3-yl)-4-methylpiperazine

3-Chloro-3-(4-iodophenyl)oxetane (0.65 g, 2.2 mmol) was dissolved in 1-methylpiperazine (5 mL). Heat to 90°C and stir for 6 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=2/1) to obtain a colorless oil (0.44 g, 56%).

MS(ESI,pos.ion)m/z:359.0(M+1).

Step 2) 1-(4-methoxyphenyl)-6-(4-(3-(4-methylpiperazin-1-yl)oxetan-3-yl)phenyl)-7- Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] ethyl pyridine-3-carboxylate (0.315g, 1.0mmol), 1-(3-(4-iodophenyl)oxetan-3-yl)-4-methylpiperazine (0.358g , 0.83mmol), 8-hydroxyquinoline (29.0mg, 0.2mmol), potassium carbonate (0.414g, 3mmol), cuprous iodide (38.0mg, 0.2mmol) and dimethyl sulfoxide (15mL), heated to Stir at 140°C for 4 hours. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a yellow solid (35 mg) which was directly used in the next step.

Step 3) 1-(4-methoxyphenyl)-6-(4-(3-(4-methylpiperazin-1-yl)oxetan-3-yl)phenyl)-7- Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Add 1-(4-methoxyphenyl)-6-(4-(3-(4-methylpiperazin-1-yl)oxetan-3-yl)benzene successively to a 10mL sealed jar Base)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.035g, 0.061mmol), methanol (2mL) 1. Aqueous ammonia (25%, 1 mL, 13.28 mmol), heated to 70° C. and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/4) to obtain a white solid (14 mg, 31.8%).

MS(ESI,pos.ion)m/z:535.3(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 2.4-2.6 (m, 8H), 2.80 (m, 2H), 3.07 (m, 1H), 3.37 (t, 2H), 3.44-3.48 (m, 3H ),3.56-3.66(m,2H),3.82(s,3H),4.10(t,2H),5.53(s,1H),6.86(s,1H),6.95(m,2H),7.30(m, 2H),7.45(m,4H).

Example 7

1-(4-methoxyphenyl)-6-(4-(3-morpholinyloxetan-3-yl)phenyl)-7-oxo-4,5,6,7-tetra Hydrogen-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Step 1) 4-(3-(4-iodophenyl)oxetan-3-yl)morpholine

3-Chloro-3-(4-iodophenyl)oxetane (0.65 g, 2.2 mmol) was dissolved in morpholine (5 mL). Heat to 90°C and stir for 6 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/petroleum ether (v/v)=1/1) to obtain a colorless oil (0.46 g, 58%).

MS(ESI,pos.ion)m/z:346.0(M+1).

Step 2) 1-(4-methoxyphenyl)-6-(4-(3-morpholinyloxetan-3-yl)phenyl)-7-oxo-4,5,6, 7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Under nitrogen protection, 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c] ethyl pyridine-3-carboxylate (0.378g, 1.2mmol), 4-(3-(4-iodophenyl)oxetan-3-yl)morpholine (0.276g, 1.0mmol), 8-Hydroxyquinoline (29.0mg, 0.2mmol), potassium carbonate (0.552g, 4.0mmol), cuprous iodide (39.0mg, 0.2mmol) and dimethyl sulfoxide (15mL), heated to 140°C and stirred for 4 Hour. Cool to 25°C, add water (30 mL), extract with dichloromethane (20 mL×2), combine organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain a yellow solid (35 mg) which was directly used in the next step.

Step 3) 1-(4-methoxyphenyl)-6-(4-(3-morpholinyloxetan-3-yl)phenyl)-7-oxo-4,5,6, 7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

Add 1-(4-methoxyphenyl)-6-(4-(3-morpholinyloxetan-3-yl)phenyl)-7-oxo-4 , ethyl 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.035g, 0.061mmol), methanol (2mL), ammonia water (25%, 1mL, 13.28 mmol), heated to 70°C and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain a white solid (14.0 mg, 31.8%).

MS(ESI,pos.ion)m/z:521.2(M+1);

¹ HNMR (400MHz, CDCl ₃ ): δ (ppm) 2.40-2.44 (m, 2H), 2.49-2.54 (m, 2H), 2.80 (d, 1H), 3.08 (d, 2H), 3.37 (t, 3H ),3.45-3.51(m,1H),3.55-3.65(m,5H),3.82(s,3H),4.10(d,2H),5.85(s,1H),6.90(s,1H),6, 93(d,2H),7.30(d,2H),7.46(m,4H).

Biological activity test

Human FXa enzyme inhibition assay

The enzymatic activity of human coagulation factor Xa (FXa) is determined by conversion of a chromogenic substrate specific for FXa. For this, Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The assay was performed on a microtiter plate as described below.

Dissolve the test substance in 10% dimethyl sulfoxide at different concentrations, mix 5 μL of the compound with 10 μL of human FXa (10 nM dissolved in 50 mM Tris, 150 mM NaCl, pH=8.3), and incubate for 15 min in a constant temperature incubator at 25 ° C. After incubation, 5 μL of FXa chromogenic substrate (800 μM, sigma) was added, and the absorbance value was measured kinetically at 25° C. at 405 nm. The test mixtures containing the test substances are compared with the control mixtures without the test substances and the _IC50 values are calculated from these data.

In vitro anticoagulation test

Compound prolongs clotting time in rabbit plasma

1. Preparation of compounds at various concentrations

Take 4 μL of the working solution (10 mM) of each compound and dilute it with dimethyl sulfoxide solution to form working solutions of various concentrations.

2. Preparation of Plasma Samples

Take several rabbits, inject 3% pentobarbital solution (30mg/kg) into the ear vein for anesthesia, use a vacuum blood collection tube containing 0.2mL of 3.8% sodium citrate to collect blood from the abdominal aorta to 2mL, collect multiple tubes, and turn them upside down Mix several times, let stand for 10 minutes, centrifuge at 3000rpm for 10 minutes, absorb the plasma from each tube, mix all the plasma into the same centrifuge tube, aliquot 1.6mL in each tube, and quickly store in a -80°C refrigerator for later use.

3. Adding samples and measuring coagulation time PT and APTT

Prepare 1.5 mLEP tubes and add 180 μL plasma samples to each tube; add 4 μL of corresponding concentration of drugs to each tube of blood samples, add 4 μL dimethyl sulfoxide solution to the control group, shake and mix, and incubate at 37 ° C for 5 minutes; use Sysmex CA1500 to automatically Measure PT and APTT with a coagulation meter; draw a dose-effect curve and fit the curve to calculate the concentration of the test compound (CT2) that doubles the coagulation time.

Inhibitory Effect of Compounds on Human FXa Activity and Anticoagulant Effect in Vitro

A: 1.00nM-50.00nM; B: 50.01nM-100.00nM; C: 100.01nM-1.00μM; D: 1.01μM-10.00μM; E: 10.01μM-50.00μM;

Conclusion: This series of compounds has good inhibitory activity of blood coagulation factor Xa, and also has the effect of prolonging blood coagulation time.

Solubility testing of compounds

Add water (10 mL) into a 15 mL conical tube, add the sample while shaking until the sample stops dissolving, shake in a constant temperature water bath at 37°C for 24 hours, and shake at a speed of 40 rpm. After shaking, filter the sample through a water-based microporous membrane (0.45 μm, Φ13 mm), discard the initial filtrate, and accurately pipette the subsequent filtrate (500 μL), add diluent acetonitrile-water (500 μL, v/v=60/ 40), the two are mixed to obtain the test solution.

Take the test solution (40 μL), use HPLC to detect, and calculate the sample concentration by the external standard one-point method:

Numbering Compound solubility (mg/mL) Example 1 0.33 Example 2 0.52 Example 3 0.33

Example 4 0.60 Example 5 0.51 Example 6 0.56 Example 7 0.38

Conclusion: This series of compounds has good solubility.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (9)

1. A compound, such as a compound shown in formula (II), or a stereoisomer or a pharmaceutically acceptable salt of a compound shown in formula (II), Wherein, R ¹ is amino-C(=O)-; R ² is C _1-6 alkoxy, C _1-6 alkanoylamino, C _2-9 heterocycloalkyl, C _1-6 alkylamino, CH≡CC _1-6 alkoxy or CH ₂ =CH- C _1-6 alkoxy; each ^R3 is independently hydrogen; and n is 1. 2. The compound according to claim 1, wherein, R ¹ is amino-C(=O)-; R ² is C _1-4 alkoxy, C _1-4 alkanoylamino, C _2-6 heterocycloalkyl, C _1-4 alkylamino, CH≡CC _1-4 alkoxy or CH ₂ =CH- C _1-4 alkoxy; and Each ^R3 is independently hydrogen. 3. The compound according to claim 1, wherein, R ¹ is amino-C(=O)-; R2 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert ^- butoxy, isobutoxy, formamido, acetylamino, propionylamino, butyrylamino, pyrrole Alkyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, CH≡ C- _CH2 -O-, CH≡C- _CH2 - _CH2 -O-, _CH2 =CH- _CH2 -O- or _CH2 =CH- _CH2 - _CH2 -O-; and Each ^R3 is independently hydrogen. 4. A compound comprising one of the following structures: or a stereoisomer or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition comprising the compound of any one of claims 1-4. 6. The pharmaceutical composition according to claim 5, further comprising a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof. 7. The pharmaceutical composition according to claim 6, which further comprises non-Xa-inhibiting anticoagulants, antiplatelet agents, thrombin inhibitors, thrombolytic agents, fibrinolytic agents or combinations thereof. 8. The pharmaceutical composition according to any one of claims 5-7, which further comprises a second factor Xa inhibitor. 9. A compound according to any one of claims 1-4 or a pharmaceutical composition according to any one of claims 5-8 is used for preventing, treating, alleviating or delaying unstable angina pectoris, acute Coronary artery syndrome, initial myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral obstructive arterial disease, venous thrombosis, deep venous thrombosis, thrombotic Phlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and resulting from (a) artificial valves or other implants, (b) indwelling catheters, (c) stents, ( d) Use in medicines for thrombosis resulting from cardiopulmonary bypass, (e) hemodialysis or (f) other procedures that expose blood to artificial surfaces that promote thrombosis.