Pyridone or pyrimidinone derivatives, their preparation methods and uses

Abstract

The present invention relates to pyridone or pyrimidinone derivatives, a method for preparing the same, and their use in medicine. Specifically, the present invention relates to a pyridone or pyrimidinone derivative represented by the general formula (I), a method for preparing the same, and a pharmaceutically acceptable salt thereof, and their use as therapeutic agents, particularly as inhibitors of coagulation factor XIa (FXIa), wherein the definitions of the respective substituents in the general formula (I) are the same as those defined in the specification.

Description

Technical Field

[0001] The present invention relates to a pyridone or pyrimidinone derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly as a coagulation factor XIa (FXIa) inhibitor. Background Art

[0002] Common cardiovascular diseases such as stroke, thrombosis, myocardial infarction, etc. have become the main causes of death in the world's population. In the world death population statistics in 2017, the population death caused by cardiovascular diseases accounted for about 32% of the total world deaths. The pathological processes of these diseases are often closely related to the formation of thrombus or the onset of stroke or heart disease caused by slow blood flow. Therefore, anticoagulants have been widely used in the treatment of such diseases. Currently, traditional anticoagulants include vitamin K antagonists, fibrinolytic agents, heparin, antiplatelet aggregation drugs, etc. However, due to various factors such as poor compliance of these drugs, large coefficient of variation among individuals, and narrow therapeutic window, non-vitamin K antagonist oral anticoagulants have been continuously developed and marketed in recent years, mainly including direct thrombin inhibitors and coagulation factor antagonists. The safety and effectiveness of currently marketed non-vitamin K antagonist oral anticoagulants have been significantly improved, but there is an adverse reaction of bleeding. To overcome this problem, it is of great significance to develop drugs with low bleeding risk. Research at home and abroad has proved that FXIa inhibitors are potential drugs for the treatment of cardiovascular and cerebrovascular diseases, especially thromboembolic diseases, and also provide a new direction for overcoming the adverse reaction of bleeding. Among them, thromboembolic diseases include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and thromboembolic disorders of the ventricle or peripheral circulation. Thromboembolic diseases also include unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from: medical implants, devices or surgeries, where blood contacts an artificial surface that can promote thrombus formation; at the same time, venous thrombosis also includes deep vein thrombosis.

[0003] FXI is a serine protease zymogen with a molecular weight of approximately 80 kD, composed of two subunits linked by disulfide bonds, and each polypeptide chain has 607 amino acids. Each subunit includes a heavy chain and a light chain region. The heavy chain has 4 AP domains A1 - A4. A1 binds thrombin; A2 binds high molecular weight kininogen; A3 binds factor IX and heparin; A4 binds activated factor XII. Therefore, these 4 AP regions are the sites where FXI interacts with other protein kinases or factors. FXIa is the activated state of FXI and plays an active role in the intrinsic coagulation process. At the initial stage of coagulation, factor XII is activated to form XIIa, and XIIa activates the activity of FXI to FXIa, which then causes a series of cascade reactions to promote coagulation. Therefore, inhibiting FXIa is an effective way to prevent thrombosis or slow blood flow.

[0004] Plasma prekallikrein is a liver - derived precursor of the trypsin - like serine protease plasma kallikrein and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated to plasma kallikrein by activated factor XII or prolyl carboxypeptidase. Plasma kallikrein regulates the activity of multiple proteolytic cascades in the cardiovascular system, such as the intrinsic pathway of coagulation, the kallikrein - kinin system, the fibrinolytic system, the renin - angiotensin system, and the complement pathway. Plasma kallikrein plays a central role in the pathogenesis of thrombosis, inflammation, and blood pressure regulation.

[0005] Currently, the clinical development of FXIa inhibitors is highly competitive both at home and abroad. Among them, the FXIa inhibitor BMS - 986177 developed by BMS has entered phase II clinical trials for the prevention and treatment of major thrombosis and other diseases. Early clinical studies have shown that FXIa inhibitors slow down the formation of thrombi while significantly reducing the risk of bleeding. A series of patent applications for FXIa inhibitors have been published, including WO2017151746A1, WO2017151018A1, and WO2018039094A1, etc. Certain progress has been made in the research and application of FXIa inhibitors, but there is still great room for improvement, and it is still necessary to continue researching and developing new FXIa inhibitors. Summary of the Invention

[0006] The object of the present invention is to provide a pyridone or pyrimidinone derivative represented by the general formula (I), or its stereoisomer, tautomer, or its pharmaceutically acceptable salt:

[0007]

[0008] Wherein:

[0009] X is selected from N or CR 7 ;

[0010] Ring A is selected from aryl or heteroaryl;

[0011] Ring B is selected from heterocyclic group, aryl, heteroaryl or fused ring; wherein the heteroaryl is preferably a 5- to 10-membered heteroaryl;

[0012] R 1 are the same or different and each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -OR 8 or -NR 9 R 10 ;

[0013] R 2 is selected from alkoxy or heteroaryl, wherein the alkoxy or heteroaryl is optionally further substituted by one or more substituents selected from alkyl, cyano or halogen; R 2 is preferably a 5-membered heteroaryl, more preferably a tetrazolyl group;

[0014] R 3 is selected from a hydrogen atom, halogen or alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy or alkoxy;

[0015] R 4 is selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl or -OR 8 , wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxy or R 6 ;

[0016] R 5 are the same or different and each independently selected from a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -NHC(O)R 8 , -NHC(O)OR 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -CH2NHC(O)OR 8 , -CH2NR 9 R 10 or -S(O) r R 8 , wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more substituents selected from alkyl, cycloalkyl, halogen, cyano, =O, -OR8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH2NHC(O)OR 8 、-CH2NR 9 R 10 or -S(O) r R 8 substituted by a substituent;

[0017] The condition is that when X is N or R 7 When it is a halogen, R 5 are the same or different and are independently selected from hydrogen, alkyl, halogen, nitro, cyano, =O, -OR 8 、-C(O)R 8 、-C(O)OR 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-CH2NHC(O)OR 8 、-CH2NR 9 R 10 or -S(O) r R 8 ;

[0018] R 6 is selected from halogen, alkyl, alkoxy, amino, nitro, cyano, hydroxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from one or more R A replaced by;

[0019] R A is selected from halogen, alkyl, hydroxy, alkoxy, amino, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl or -NR 12 C(O)R 13 wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano substituents;

[0020] R 7 Selected from halogen or -ORB ;

[0021] R B is selected from alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy;

[0022] R 8 is selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NR 12 R 13 , -C(O)NR 12 R 13 , -SO2NR 12 R 13 or -NR 12 C(O)R 13 ;

[0023] R 9 and R 10 are each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NR 12 R 13 , -C(O)NR 12 R 13 , -SO2NR 12 R 13 or -NR 12 C(O)R 13 ;

[0024] R 11 , R 12 and R 13Each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylic acid ester group;

[0025] m is 0, 1, 2, 3 or 4;

[0026] n is 0, 1, 2, 3 or 4;

[0027] r is 0, 1 or 2.

[0028] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0029]

[0030] Wherein:

[0031] L is an alkylene group, wherein the alkylene group is optionally further substituted by one or more substituents selected from a halogen or a hydroxyl group;

[0032] Ring B, X, R 1 ~R 3 、R 5 、R 6 、m and n are as defined in general formula (I).

[0033] A preferred embodiment of the present invention is a compound of general formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of general formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

[0034]

[0035] Wherein: Ring B, X, L, R 1 ~R 3 、R 5 、R 6 、m and n are as defined in general formula (II).

[0036] A preferred embodiment of the present invention is a compound of general formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of general formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

[0037]

[0038] Wherein: ring B, X, L, R 1 ~R 3 、R 5 、R 6 、m and n are defined as described in general formula (II).

[0039] A preferred embodiment of the present invention is a compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Selected from:

[0040]

[0041] Wherein: R 5 and m are defined as described in general formula (I).

[0042] A preferred embodiment of the present invention is a compound of general formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of general formula (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

[0043]

[0044] Wherein:

[0045] X 1 ~X 4 are the same or different and each independently selected from a chemical bond, N, NH, C(=O) or C(R 5 )); at least one of X 1 ~X 4 is not selected from N or NH; at most one of X 1 ~X 4 is selected from a chemical bond;

[0046] X, L, R 1 ~R 3 、R 5 、R 6 and n are defined as described in general formula (II).

[0047] A preferred embodiment of the present invention is a compound of general formula (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of general formula (V-A) and (V-B) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

[0048]

[0049] Wherein: X 1 ~X 4 、X, L, R 1 ~R 3 、R6 The definitions of [specific terms] and n are as described in general formula (V).

[0050] A preferred embodiment of the present invention is a compound of general formula (V), (V-A), or (V-B), or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein selected from:

[0051]

[0052] wherein: R 5 and m are defined as in general formula (II).

[0053] A preferred embodiment of the present invention is a compound of general formula (II) or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound of general formula (VI) or its stereoisomer, tautomer, or pharmaceutically acceptable salt,

[0054]

[0055] wherein:

[0056] X 5 ~X 9 are the same or different and each independently selected from a chemical bond, N, NH, C(=O), or C(R 14 )); at least one of X 5 ~X 9 is not selected from N or NH; at most one of X 5 ~X 9 is selected from a chemical bond;

[0057] Y 1 ~Y 2 are the same or different and each independently selected from N or C(R 5 ));

[0058] Each R 14 is the same or different and each independently selected from a hydrogen atom, alkyl, cycloalkyl, halogen, cyano, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -NHC(O)R 8 , -NHC(O)OR 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -CH2NHC(O)OR 8 , -CH2NR 9 R 10 or -S(O) r R 8;

[0059] L, R 1 ~R 3 , R 5 ~R 10 The definitions of r and n are as described in general formula (II).

[0060] A preferred embodiment of the present invention is a compound of general formula (VI) or its stereoisomer, tautomer or pharmaceutically acceptable salt, which is a compound of general formula (VI-A) and (VI-B) or its stereoisomer, tautomer or pharmaceutically acceptable salt,

[0061]

[0062] wherein: X 5 ~X 9 , L, R 1 ~R 3 , R 6 , R 7 , Y 1 ~Y 2 and the definitions of n are as described in general formula (VI).

[0063] A preferred embodiment of the present invention is a compound of general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0064] R 7 is -OR B ;

[0065] R B is selected from C 1- C4 alkyl, wherein the C 1- C4 alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or alkoxy; R B is preferably methyl or ethyl.

[0066] A preferred embodiment of the present invention is a compound of general formula (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B) or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein:

[0067] L is -(CR a R b )s-, where s is 1, 2, 3 or 4;

[0068] R a and R beach independently selected from a hydrogen atom or an alkyl group;

[0069] R 6 is selected from an alkoxy group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the alkoxy group, the phenyl group or the 5- to 10-membered heteroaryl group is optionally further substituted by one or more R A ;

[0070] R A is selected from a halogen atom, an alkyl group, an alkoxy group, a cyano group, an amino group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the alkyl group, the alkoxy group, the phenyl group or the 5- to 10-membered heteroaryl group is optionally further substituted by one or more substituents selected from a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group or a cyano group.

[0071] A preferred embodiment of the present invention is a compound of general formula (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0072] L is selected from -CH2- or -CH2CH2-;

[0073] R 6 is selected from an alkoxy group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the alkoxy group, the phenyl group or the 5- to 10-membered heteroaryl group is optionally further substituted by one or more R A ;

[0074] R A is selected from a halogen atom, an alkyl group, an alkoxy group, a cyano group, an amino group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the alkyl group, the alkoxy group, the phenyl group or the 5- to 10-membered heteroaryl group is optionally further substituted by one or more substituents selected from a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group or a cyano group.

[0075] A preferred embodiment of the present invention is a compound of general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0076] R 7 is -OR B ;

[0077] R 5 are the same or different and each independently selected from a hydrogen atom, an alkyl group, a halogen atom, a cyano group, -OR 8 , -C(O)R 8 , -NHC(O)R 8 , -NR 9 R10 or a pyridyl group;

[0078] The pyridyl group is optionally further substituted by one or more substituents selected from halogen, NR 9 R 10 , and alkyl groups;

[0079] R 8 is selected from a hydrogen atom or a C1-C4 alkyl group, wherein the C1-C4 alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, and cyano groups;

[0080] R 9 and R 10 are each independently selected from a hydrogen atom or a C1-C4 alkyl group, wherein the C1-C4 alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, C1-C4 alkoxy, nitro, or cyano groups.

[0081] Typical compounds of the present invention include, but are not limited to:

[0082]

[0083]

[0084]

[0085] or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0086] Note: If there is a difference between the drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0087] In another aspect, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

[0088] In another aspect, the present invention provides a method for inhibiting factor XIa protease, which comprises administering to a patient a pharmaceutical composition comprising an effective dose of a compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

[0089] In another aspect, the present invention provides the use of a compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of a factor XIa inhibitor or a dual inhibitor of factor XIa and plasma kallikrein.

[0090] Another aspect of the present invention relates to a method for preventing and / or treating a disease mediated by factor XIa, which comprises administering to a patient a therapeutically effective dose of a compound of general formula (I) or a tautomer, meso form, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0091] Another aspect of the present invention relates to a method for preventing and / or treating cardiovascular and cerebrovascular diseases, which comprises administering to a patient a therapeutically effective dose of a compound of general formula (I) or a tautomer, meso form, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0092] Another aspect of the present invention relates to the use of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing a disease mediated by factor XIa, wherein the disease mediated by factor XIa is preferably a cardiovascular and cerebrovascular disease.

[0093] The above-mentioned cardiovascular and cerebrovascular diseases are preferably blood coagulation disorders or thromboembolic diseases; wherein the thromboembolic diseases are selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders and thromboembolic disorders of the ventricle or peripheral circulation; the thromboembolic diseases are preferably selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis resulting from: medical implants, devices or surgeries, wherein blood contacts an artificial surface that can promote thrombosis; wherein the venous thrombosis is preferably deep vein thrombosis.

[0094] Another aspect of the present invention relates to a medicament for inhibiting factor XIa, which comprises a compound of general formula (I) or a tautomer, meso form, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0095] In another aspect, the present invention provides the use of a compound of general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of an anti-coagulation medicament.

[0096] On the other hand, the present invention provides the use of a compound of general formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing thromboembolic diseases; wherein the thromboembolic diseases are selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders and thromboembolic disorders of the ventricular or peripheral circulation; wherein the thromboembolic diseases are preferably selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis resulting from: medical implants, devices or surgery, wherein blood contacts an artificial surface that can promote thrombosis; wherein the venous thrombosis is preferably deep vein thrombosis.

[0097] The pharmaceutical preparations of the present invention can be administered locally, orally, transdermally, rectally, vaginally, parenterally, intranasally, intralungally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly or by inhalation. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing to prepare tablets.

[0098] The preparations of the present invention are suitable to be in unit dosage form, and the preparations can be prepared by any method well known in the pharmaceutical art. The amount of the active ingredient capable of being combined with the carrier substance to produce a single dosage form can vary depending on the host to be treated and the specific mode of administration. The amount of the active ingredient capable of being combined with the carrier substance to produce a single dosage form generally refers to the amount of the compound capable of producing a therapeutic effect.

[0099] The dosage forms for local or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed with a pharmaceutically acceptable carrier under sterile conditions, and it can be mixed with any preservatives, buffers or propellants that may be required.

[0100] When the compounds of the present invention are administered to humans and animals in the form of a medicament, the compounds can be provided alone or in the form of a pharmaceutical composition, which contains an active ingredient combined with a pharmaceutically acceptable carrier, such as 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.

[0101] Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrin, such as a targeting ligand attached to nanoparticles, such as AccurinsTM; and (22) other non-toxic compatible substances for pharmaceutical formulations, such as polymer-based compositions.

[0102] Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (such as capsules, pills, tablets, dragees, powders, granules, and the like) may include one or more pharmaceutically acceptable carriers such as sodium citrate or calcium phosphate, and / or any one of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents; solubilizing agents and emulsifying agents such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

[0103] In addition to the active compound, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0104] In addition to the active compound, ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0105] In addition to the active compound, the powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. The sprays may contain other common propellants such as chlorofluorocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0106] Detailed Description of the Invention

[0107] Unless otherwise stated, some of the terms used in the description and claims of the present invention are defined as follows:

[0108] "Chemical bond" indicates the absence of an indicated substituent, and the two end portions of the substituent are directly bonded.

[0109] "Alkyl", when regarded as a group or part of a group, refers to a straight-chain or branched aliphatic hydrocarbon group including C1-C 20 Preferably C1-C 10 alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl can be substituted or unsubstituted.

[0110] "Alkenyl" refers to an alkyl as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl can be optionally substituted or unsubstituted.

[0111] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. Preferred is C2-C 10 alkynyl, more preferably C2-C6 alkynyl, and most preferably C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl can be substituted or unsubstituted.

[0112] "Alkylene" is a divalent alkyl. Preferably C1-C 10Alkylene, more preferably C1-C6 alkylene, particularly preferably C1-C4 alkylene. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -C(CH3)2-, n-propylene, etc. The alkylene may be substituted or unsubstituted.

[0113] "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused-ring, bridged-ring, and spirocyclic carbocyclic rings. Preferably C3-C 12 Cycloalkyl, more preferably C3-C8 cycloalkyl, most preferably C3-C6 cycloalkyl. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. The cycloalkyl may be optionally substituted or unsubstituted.

[0114] "Spirocycloalkyl" refers to a polycyclic group having 5 to 18 members, two or more cyclic structures, and a single carbon atom (referred to as a spiro atom) shared between the single rings. The ring contains one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system. Preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl is classified into monospiro, dispiro, or polyspirocycloalkyl according to the number of spiro atoms shared between the rings, preferably monospiro and dispirocycloalkyl, preferably 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0115] "Fused-ring cycloalkyl" refers to a fully carbon polycyclic group having 5 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused-ring cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthryl.

[0116] "Bicycloalkyl" refers to a fully carbon polycyclic group having 5 to 18 members, containing two or more cyclic structures, sharing two non-adjacent carbon atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 members, more preferably 7 to 10 members. It can be divided into bicycloalkyl, tricycloalkyl, tetracycloalkyl or polycyclic bicycloalkyl according to the number of constituent rings, preferably bicycloalkyl, tricycloalkyl or tetracycloalkyl, more preferably bicycloalkyl or tricycloalkyl. Non-limiting examples of "bicycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

[0117] "Heterocyclic group", "heterocycle" or "heterocyclic" are used interchangeably in this application, and all refer to non-aromatic heterocyclic groups, in which one or more ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, fused-ring, bridged-ring and spiro-ring. Preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclic group" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclic group can be substituted or unsubstituted.

[0118] "Spiroheterocyclic group" refers to a polycyclic group having 5 to 18 members, two or more cyclic structures, and sharing one atom between monocyclic rings, containing one or more double bonds within the ring, but none of the rings has a completely conjugated π-electron aromatic system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. The spiroalkyl group is divided into monospiroheterocyclic group, bisspiroheterocyclic group or polysspiroheterocyclic group according to the number of shared spiro atoms between rings, preferably monospiroheterocyclic group and bisspiroheterocyclic group. More preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclic group. Non-limiting examples of "spiroheterocyclic group" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0119] "Fused heterocyclic group" refers to a fully carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.

[0120] "Bridged heterocyclic group" refers to a polycyclic group having 5 to 14 members, 5 to 18 members, containing two or more cyclic structures sharing two non-directly connected atoms with each other, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0121] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, where the rings may be connected in a fused manner. The term "aryl" includes monocyclic or bicyclic aryls, such as phenyl, naphthyl, and aromatic groups of tetrahydronaphthyl. Preferred aryls are C6-C 10 aryl, more preferably aryls are phenyl and naphthyl, most preferably naphthyl. Aryl can be substituted or unsubstituted.

[0122] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Preferably it is a bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0123]

[0124] The heteroaryl may be substituted or unsubstituted.

[0125] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other. One or more rings may contain one or more double bonds, but at least one ring has an aromatic system with fully conjugated π electrons, and at the same time, at least one ring does not have an aromatic system with fully conjugated π electrons. The ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen, or S(O) r (where r is selected from 0, 1, or 2), and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring. Among them, the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14-membered, more preferably 8 to 10-membered. Examples of "fused ring" include, but are not limited to:

[0126]

[0127]

[0128] "Alkoxy" refers to a group of (alkyl-O-). Among them, the alkyl is as defined herein. C1-C6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0129] "Halogenated alkyl" refers to a group in which the alkyl is optionally further substituted by one or more halogens, where the alkyl is as defined herein.

[0130] "Hydroxyalkyl" refers to a group in which the alkyl is optionally further substituted by one or more hydroxyl groups, where the alkyl is as defined herein.

[0131] "Halogenated alkoxy" refers to a group in which the alkyl of (alkyl-O-) is optionally further substituted by one or more halogens, where the alkoxy is as defined herein.

[0132] "Hydroxyl" refers to the -OH group.

[0133] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0134] "Amino" refers to -NH2.

[0135] "Cyano" refers to -CN.

[0136] "Nitro" refers to -NO2.

[0137] "Benzyl" refers to -CH2-phenyl.

[0138] "Carboxyl" refers to -C(O)OH.

[0139] "Carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0140] "DMSO" refers to dimethyl sulfoxide.

[0141] "BOC" refers to tert-butoxycarbonyl.

[0142] "Ts" refers to p-toluenesulfonyl.

[0143] "T3P" refers to propylphosphonic anhydride.

[0144] "DPPA" refers to diphenylphosphoryl azide.

[0145] "DEA" refers to diethylamine.

[0146] "THF" refers to tetrahydrofuran.

[0147] "OMS" refers to methanesulfonyloxy.

[0148] "Substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0149] As used in this specification, "substituted" or "substitution", unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, carboxyl, carboxylate group, =O, -OR 8, -C(O)R 8 , -C(O)OR 8 , -NHC(O)R 8 , -NHC(O)OR 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -CH2NHC(O)OR 8 , -CH2NR 9 R 10 or -S(O) r R 8 substituted by a substituent of;

[0150] R 8 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NR 12 R 13 , -C(O)NR 12 R 13 , -SO2NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent of;

[0151] R 9 and R 10 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NR 12 R 13 , -C(O)NR 12 R 13 , -SO2NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent of;

[0152] R 11 、R 12 and R 13 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylic acid ester group;

[0153] r is 0, 1 or 2.

[0154] The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereoisomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0155] Unless otherwise indicated, the structures described in the present invention also include all isomers of this structure (e.g., diastereoisomers, enantiomers and atropisomers and geometric (conformational) isomer forms; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Thus, the individual stereoisomers of the compounds of the present invention as well as mixtures of enantiomers, mixtures of diastereoisomers and mixtures of geometric (conformational) isomers are within the scope of the present invention.

[0156] "Pharmaceutically acceptable salts" refers to certain salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts, amine salts formed with suitable acids.

[0157] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and thus exert biological activity.

[0158] Synthesis Method of the Compounds of the Invention

[0159] To achieve the objectives of the present invention, the following technical solutions are adopted in the present invention:

[0160] A method for preparing a compound represented by general formula (V) of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the following steps:

[0161]

[0162] The compound of general formula (Va) is hydrolyzed to obtain the compound of general formula (Vb); the compound of general formula (Vb) undergoes a condensation reaction with the compound of general formula (Vc) to obtain the compound of general formula (Vd); the compound of general formula (Vd) reacts under acetic acid conditions to obtain the compound of general formula (V);

[0163] Wherein:

[0164] R e is selected from alkyl;

[0165] X 1 ~X 4 , X, L, R 1 ~R 3 , R 6 and n are defined as described in general formula (V).

[0166] A method for preparing the compound of general formula (VI) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof according to the present invention comprises the following steps:

[0167]

[0168]

[0169] The compound of general formula (VIa) reacts with the compound of general formula (VIb) to obtain the compound of general formula (VIc); the compound of general formula (VIc) reacts with ammonium acetate under acetic acid conditions to obtain the compound of general formula (VI);

[0170] Wherein:

[0171] R f is selected from halogen;

[0172] Y 1 is selected from N;

[0173] Y 2 is selected from CH;

[0174] X 5 ~X 9 , L, R 1 ~R 3 , R 6 , R 7 and n are defined as described in general formula (VI). Specific Embodiments

[0175] The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

[0176] Examples

[0177] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It should be noted that the following examples are for illustrating the present invention rather than limiting the present invention. 1 The 1H NMR spectra were measured using a Bruker instrument (400 MHz), and the chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 Presentation method of 1H NMR: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = double doublet, dt = double triplet. When coupling constants are provided, the unit is Hz.

[0178] The mass spectra were obtained using an LC / MS instrument, and the ionization mode can be ESI or APCI.

[0179] The TLC silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) are 0.15 mm - 0.2 mm, and the specifications of the silica gel plates used for separating and purifying products by thin layer chromatography are 0.4 mm - 0.5 mm.

[0180] Column chromatography uses silica gel with 200 - 300 mesh from Yantai Huanghai as the carrier.

[0181] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise specified, commercially available manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH&Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd., etc.

[0182] CD3OD: Deuterated methanol.

[0183] CDCl3: Deuterated chloroform.

[0184] DMSO-d6: Deuterated dimethyl sulfoxide.

[0185] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0186] For purifying the compounds, the eluent systems of column chromatography and thin layer chromatography are used, and the system is selected from: A: Petroleum ether and ethyl acetate system; B: Dichloromethane and methanol system; C: Dichloromethane and ethyl acetate system; D: Dichloromethane and ethanol system. The volume ratio of the solvents varies according to the polarity of the compounds, and a small amount of acidic or basic reagents such as acetic acid or triethylamine can also be added.

[0187] Example 1

[0188] 1-(1-(6-Amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0189]

[0190] The first step

[0191] 4-(5-Chloro-2-nitrophenyl)-2,5-dimethoxypyridine

[0192] 2-Bromo-4-chloro-1-nitrobenzene 1a (50.0 g, 211.46 mmol), 2,5-dimethoxypyridin-4-ylboronic acid 1b (58.0 g, 317.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (7.74 g, 10.57 mmol), and potassium carbonate (87.68 g, 634.38 mmol) were successively added to dioxane (500 mL). Under nitrogen protection, the temperature was raised to 90 °C, and the mixture was stirred for 3 h. 100 mL of ethyl acetate was added, and the insoluble substances were filtered off through diatomaceous earth. The reaction solution was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 4-(5-chloro-2-nitrophenyl)-2,5-dimethoxypyridine 1c (50.0 g, pale yellow solid), with a yield of 80%.

[0193] MS m / z (ESI): 295.0 [M+1] +

[0194] The second step

[0195] 4-(5-Chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one

[0196] 4-(5-Chloro-2-nitrophenyl)-2,5-dimethoxypyridine 1c (50.0 g, 0.17 mol) and pyridine hydrobromide (162.8 g, 1.02 mol) were successively added to N,N-dimethylformamide (200 mL). The mixture was heated to 100 °C and stirred for 3 h. The reaction solution was poured into 2 L of ice water, and the solid was precipitated by stirring. The solid was filtered and dried to obtain 4-(5-chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one 1d (40.0 g, pale yellow solid), with a yield of 84%.

[0197] MS m / z (ESI): 281.0 [M+1] +

[0198] The third step

[0199] Methyl 2-(4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate

[0200] 4-(5-Chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one 1d (10 g, 35.63 mmol), methyl 2-(methanesulfonyloxy)-3-phenylpropionate 1e (synthesis method refers to Tetrahedron Letters 2013, 54(13), 1730) (13.8 g, 53.44 mmol), and potassium carbonate (14.77 g, 106.89 mmol) were successively added to dioxane (200 mL), and the temperature was raised to 90 °C, followed by stirring for 3 h. 300 mL of ethyl acetate was added, and the reaction solution was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain methyl 2-(4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate 1f (8.5 g, light yellow solid), with a yield of 54%. MS m / z (ESI): 443.1 [M+1] +

[0201] The fourth step

[0202] Methyl 2-(4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate

[0203] Methyl 2-(4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate 1f (3 g, 6.76 mmol), iron powder (1.89 g, 33.79 mmol), and ammonium chloride (181 mg, 3.38 mmol) were dissolved in ethanol (20 mL) and water (4 mL), and the temperature was raised to 80 °C, followed by stirring for 2 h. The iron powder was removed by filtration through diatomaceous earth, and then ethanol was removed under reduced pressure. 100 mL of ethyl acetate was added to extract the reaction solution, which was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain methyl 2-(4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate 1g (2.6 g, yellow solid), with a yield of 93%.

[0204] MS m / z (ESI): 413.1 [M+1] +

[0205] The fifth step

[0206] Methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate

[0207] 1 g (2.60 g, 6.30 mmol) of methyl 2-(4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate, trimethyl orthoformate (2.00 g, 18.89 mmol) and trimethylsilyl azide (1.45 g, 12.59 mmol) were successively added to acetic acid (20 mL), and the mixture was continuously stirred at room temperature for 12 h. Ethyl acetate (100 mL) was added to the reaction solution for extraction. The organic phase was washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 1 h (2.5 g, white solid) of methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate, with a yield of 85%.

[0208] MS m / z(ESI): 466.1[M+1] +

[0209] The sixth step

[0210] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionic acid

[0211] 1 h (2.5 g, 5.37 mmol) of methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate and lithium hydroxide monohydrate (643 mg, 26.83 mmol) were dissolved in methanol (20 mL) and water (4 mL), and the mixture was stirred at room temperature for 1 h. The pH value was adjusted to 2 - 3 with 1N hydrochloric acid, methanol was removed under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, the organic layer was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain 1 i (2.3 g, white solid) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionic acid, with a yield of 95%.

[0212] MS m / z(ESI): 452.1[M+1] +

[0213] The seventh step

[0214] N-(2-Amino-4-nitrophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0215] Dissolve the raw materials 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (200 mg, 0.44 mmol), 4-nitrobenzene-1,2-diamine 1j (102 mg, 0.66 mmol) and N,N-diisopropylethylamine (172 mg, 1.33 mmol) in ethyl acetate (20 mL), then add T3P (282 mg, 0.89 mmol, 50% ethyl acetate solution) and react at room temperature for 3 h. Monitor the reaction by TLC until completion. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product N-(2-amino-4-nitrophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 1k (200 mg, yellow solid), with a yield of 76.8%.

[0216] MS m / z (ESI): 587.1 [M+1] +

[0217] The eighth step

[0218] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-nitro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0219] Dissolve the raw material N-(2-amino-4-nitrophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 1k (200 mg, 0.34 mmol) in acetic acid (30 mL), then react at 70 °C for 3 h. Monitor the reaction by TLC until completion. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-nitro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one 1l (150 mg, light yellow solid), with a yield of 77%.

[0220] MS m / z (ESI): 569.2 [M+1]+

[0221] The ninth step

[0222] 1-(1-(6-Amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0223] React 1 l (60 mg, 0.105 mmol) of the raw material 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-nitro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one, ammonium chloride (3 mg, 0.052 mmol), and reduced iron powder (30 mg, 0.527 mmol) in a mixed solvent of ethanol (20 mL) and water (4 mL) at 90 °C for 1 h. Detect the reaction by TLC. After the reaction is complete, filter through diatomaceous earth. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product 1-(1-(6-amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 1 (10 mg), with a yield of 17%.

[0224] MS m / z (ESI): 539.2 [M+1] +

[0225] 1 1H NMR (400 MHz, DMSO-d6) δ 11.99 (br, 1H), 9.59 (s, 1H), 7.80 (s, 2H), 7.67 (s, 1H), 7.36–7.22 (m, 4H), 7.19 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 6.8 Hz, 2H), 6.62 - 6.44 (m, 2H), 6.41 (s, 1H), 6.30 - 6.40 (m, 1H), 4.91 (s, 2H), 3.65–3.53 (m, 1H), 3.50–3.40 (m, 1H), 3.22 (s, 3H).

[0226] Example 2

[0227] N-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazol-6-yl)acetamide

[0228]

[0229] 1-(1-(6-Amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 1 (20 mg, 0.037 mmol), acetic anhydride (4 mg, 0.037 mmol) and 4-dimethylaminopyridine (6 mg, 0.045 mmol) were dissolved in dichloromethane (10 mL), and then reacted at room temperature for 1 h. The reaction was monitored by TLC until completion. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product N-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazol-6-yl)acetamide 2 (10 mg), with a yield of 43.4%.

[0230] MS m / z(ESI): 581.2[M+1] +

[0231] 1 H NMR(400MHz,DMSO-d6)δ12.55-12.42(m,1H),10.00-9.87(m,1H),9.59(s,1H),8.03–7.96(m,1H),7.81(d,J=1.2Hz,2H),7.69-7.66(m,,1H),7.53(d,J=8.4Hz,1H),7.35–7.25(m,3H),7.23–7.13(m,2H),7.11(d,J=7.6Hz,2H),6.45-6.33(m,2H),3.70–3.60(m,1H),3.57–3.47(m,1H),3.21(s,3H),2.07-2.02(m,3H).

[0232] Example 3

[0233] 1-(1-(6-Amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxypyridin-2(1H)-one

[0234]

[0235] The first step

[0236] Methyl 2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate

[0237] The raw material 4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxypyridin-2(1H)-one 3a (synthesis method refers to WO2016146606) (5 g, 16.57 mmol), potassium carbonate (6.87 g, 49.72 mmol), and methyl 2-(methanesulfonyloxy)-3-phenylpropionate 1e (5.57 g, 21.52 mmol) were dissolved in 1,4-dioxane (50 mL), and then reacted at 90 °C for 6 h. TLC was used to detect the completion of the reaction. After completion, it was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system A) gave the product methyl 2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate 3b (5 g, yellow solid), with a yield of 65.0%.

[0238] MS m / z (ESI): 464.2 [M+1] +

[0239] The second step

[0240] 2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid

[0241] The raw material methyl 2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionate 3b (2 g, 4.31 mmol) and lithium hydroxide monohydrate (905 mg, 21.56 mmol) were dissolved in methanol (30 mL) and water (6 mL), and then reacted at room temperature for 12 h. TLC was used to detect the reaction. After completion, the pH was adjusted to ≈5 with dilute hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product 2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3c (1.8 g, yellow solid), with a yield of 92.8%.

[0242] MS m / z (ESI): 450.2 [M+1] +

[0243] The third step

[0244] N-(2-amino-4-nitrophenyl)-2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0245] The raw materials 2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3c (300 mg, 0.67 mmol), 4-nitrobenzene-1,2-diamine 1j (154 mg, 1.0 mmol), and N,N-diisopropylethylamine (259 mg, 2.0 mmol) were dissolved in THF (30 mL), and then T3P (425 mg, 1.33 mmol, 50% ethyl acetate solution) was added. The reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until completion. It was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product N-(2-amino-4-nitrophenyl)-2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 3d (300 mg, yellow solid), with a yield of 76.8%.

[0246] MS m / z(ESI): 585.1[M+1] +

[0247] The fourth step

[0248] 4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-1-(1-(6-nitro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0249] The raw material N-(2-amino-4-nitrophenyl)-2-(4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 3d (300 mg, 0.51 mmol) was dissolved in acetic acid (20 mL), and then the reaction was carried out at 70 °C for 3 h. The reaction was monitored by TLC until completion. It was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product 4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-1-(1-(6-nitro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one 3e (200 mg, light yellow solid), with a yield of 68.8%.

[0250] MS m / z(ESI): 567.1[M+1] +

[0251] The fifth step

[0252] 1-(1-(6-amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxypyridin-2(1H)-one

[0253] The raw material 4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxy-1-(1-(6-nitro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one 3e (200 mg, 0.352 mmol), ammonium chloride (10 mg, 0.179 mmol), and reduced iron powder (100 mg, 1.76 mmol) were reacted in ethanol (20 mL) and water (4 mL) at 90 °C for 1 h. The reaction was monitored by TLC. After completion of the reaction, it was filtered through diatomaceous earth. It was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product 1-(1-(6-amino-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(difluoromethoxy)phenyl)-5-methoxypyridin-2(1H)-one 3 (80 mg), with a yield of 41.2%.

[0254] MS m / z (ESI): 537.2 [M+1] +

[0255] 1 1H NMR (400 MHz, DMSO-d6) δ 12.23 - 11.98 (m, 1H), 7.55 (dd, J = 8.8, 2.8 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J = 2.8 Hz, 1H), 7.34 - 7.15 (m, 7H), 7.09 (s, 1H), 6.57 (s, 1H), 6.51 (dd, J = 8.4, 2.0 Hz, 1H), 6.45 (t, J = 8.0 Hz, 1H), 6.30 (s, 1H), 4.93 (s, 2H), 3.73 - 3.65 (m, 1H), 3.61–3.44 (m, 4H).

[0256] Example 4

[0257] 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0258]

[0259] The first step

[0260] 6-Methylpyridine-2,3-diamine

[0261] 2-Amino-3-nitro-6-methylpyridine 4a (3.0 g, 19.6 mmol) was dissolved in 30 mL of ethanol. Reductive iron powder (5.5 g, 98 mmol), ammonium chloride (0.5 g, 9.8 mmol) and 6 mL of water were added, and the temperature was raised to 80 °C for reaction for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 6-methylpyridine-2,3-diamine 4b (2.0 g, oily liquid), with a yield of 82.9%.

[0262] MS m / z (ESI): 124.1 [M+1] +

[0263] The second step

[0264] N-(3-Amino-6-methylpyridin-2-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0265] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (200 mg, 0.443 mmol) was dissolved in 5 mL of ethyl acetate. 6-Methylpyridine-2,3-diamine 4b (82 mg, 0.664 mmol), T3P (422 mg, 1.330 mmol, 50% ethyl acetate solution) and N,N-diisopropylethylamine (172 mg, 1.330 mmol) were added, and the reaction was carried out at room temperature for 3 hours. Ethyl acetate and water were added to the reaction solution, and extraction and liquid separation were carried out. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent system B) to obtain N-(3-amino-6-methylpyridin-2-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 4c (200 mg, oily liquid), with a yield of 81.1%.

[0266] MS m / z (ESI): 557.2 [M+1] +

[0267] The third step

[0268] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0269] Dissolve N-(3-amino-6-methylpyridin-2-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 4c (200 mg, 0.359 mmol) in 20 mL of acetic acid and react at 120 °C for 12 hours. Cool the reaction solution to room temperature, add ethyl acetate and water, extract and separate the layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is purified by silica gel column chromatography (eluent system B) to obtain 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)pyridin-2(1H)-one 4 (25 mg), with a yield of 12.9%.

[0270] MS m / z (ESI): 539.2 [M+1] +

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.60 (s, 1H), 7.96–7.85 (m, 1H), 7.83 - 7.90 (m, 2H), 7.68 (s, 1H), 7.30 (t, J = 7.3 Hz, 3H), 7.21 (t, J = 7.3 Hz, 1H), 7.15–7.05 (m, 3H), 6.44 (m, 2H), 3.70–3.60 (m, 1H), 3.58–3.48 (m, 1H), 3.21 (s, 3H), 2.53 (s, 3H).

[0272] Example 5

[0273] 1-(1-(6-acetyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0274]

[0275] The first step

[0276] N-(5-acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0277] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (200 mg, 0.443 mmol) was dissolved in 5 mL of ethyl acetate. 1-(3,4-Diaminophenyl)ethanone 5a (100 mg, 0.664 mmol), T3P (422 mg, 1.33 mmol, 50% ethyl acetate solution), and N,N-diisopropylethylamine (172 mg, 1.33 mmol) were added, and the reaction was carried out at room temperature for 3 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted and separated. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent system B) to obtain N-(5-acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 5b (150 mg, oily liquid), with a yield of 58.0%.

[0278] MS m / z(ESI): 584.2[M+1] +

[0279] The second step

[0280] 1-(1-(6-Acetyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0281] N-(5-Acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 5b (150 mg, 0.257 mmol) was dissolved in 20 mL of acetic acid, and the reaction was carried out at 100 °C for 1 hour. The reaction solution was cooled to room temperature, ethyl acetate and water were added, and the mixture was extracted and separated. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent system B) to obtain 1-(1-(6-acetyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 5 (15 mg), with a yield of 10.3%.

[0282] MS m / z(ESI): 566.2[M+1] +

[0283] 11H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.21 (s, 1H), 7.81 (s, 3H), 7.68 - 7.58 (m 1H), 7.36–7.26 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 2H), 6.43 (s, 2H), 3.73–3.60 (m, 2H), 3.20 (s, 3H), 2.62 (s, 3H).

[0284] Example 6

[0285] 2-(1-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-6-carbonitrile

[0286]

[0287] The first step

[0288] N-(2-Amino-4-cyanophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0289] 2-[4-[5-Chloro-2-(1H-tetrazol-1-yl)phenyl]-5-methoxy-2-oxo-1-pyridinyl]-3-phenylpropanoic acid 1i (300 mg, 0.663 mmol), 3,4-diaminobenzonitrile 6a (106 mg, 0.8 mmol), N,N-diisopropylethylamine (257 mg, 1.99 mmol), and T3P (422.3 mg, 1.33 mmol, 50% ethyl acetate solution) were successively added to ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction solution was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain N-(2-amino-4-cyanophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 6b (300 mg, white solid), with a yield of 79.7%.

[0290] MS m / z (ESI): 567.2 [M+1] +

[0291] The second step

[0292] 2-(1-4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-6-carbonitrile

[0293] Dissolve N-(2-amino-4-cyanophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 6b (300 mg, 0.529 mmol) in acetic acid (20 mL), heat to 100 °C and stir for 3 h. Add ethyl acetate (30 mL) to the reaction solution for extraction. The organic phase is washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (eluent system A) to obtain 2-(1-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-benzo[d]imidazole-6-carbonitrile 6 (190 mg), with a yield of 65.4%.

[0294] MS m / z (ESI): 549.2 [M+1] +

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.58 (s, 1H), 8.25 - 7.98 (m, 1H), 7.81 - 7.79 (m, 2H), 7.66 (s, 1H), 7.63 - 7.58 (m, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.25 - 7.18 (m, 2H), 7.13 (d, J = 7.5 Hz, 2H), 6.56 - 6.32 (m, 2H), 3.78 - 3.67 (m, 1H), 3.65 - 3.56 (m, 1H), 3.19 (s, 3H).

[0296] Example 7

[0297] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0298]

[0299] The first step

[0300] N-(2-Amino-4-methoxyphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0301] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1-yl)-3-phenylpropanoic acid 1i (100 mg, 0.221 mmol), 4-methoxybenzene-1,2-diamine 7a (45.87 mg, 0.331 mmol), N,N-diisopropylethylamine (85.65 mg, 0.663 mmol), and T3P (140.8 mg, 0.442 mmol, 50% ethyl acetate solution) were successively added to ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction solution was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain N-(2-amino-4-methoxyphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 7b (70 mg, white solid), with a yield of 55.3%.

[0302] MS m / z (ESI): 572.2 [M+1] +

[0303] The second step

[0304] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0305] N-(2-Amino-4-methoxyphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 7b (70 mg, 0.122 mmol) was dissolved in acetic acid (20 mL), and the mixture was heated to 100 °C and stirred for 3 h. Ethyl acetate (30 mL) was added to the reaction solution for extraction. The organic phase was successively washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one 7 (35 mg), with a yield of 51.6%.

[0306] MS m / z(ESI):554.2[M+1] +

[0307] 1 H NMR(400MHz,DMSO-d6)δ12.52 - 12.42(m,1H),9.60(s,1H),7.82 - 7.78(m,2H),7.68 - 7.65(m,1H),7.55 - 7.48(m,1H),7.34 - 7.26(m,3H),7.23 - 7.16(m,2H),7.14 - 7.07(m,2H),6.86 - 6.77(m,1H),6.47 - 6.37(m,2H),3.77(s,3H),3.68 - 3.58(m,1H),3.54 - 3.43(m,1H),3.22(s,3H).

[0308] Example 8

[0309] 1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8

[0310] (S)-1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (8A)

[0311] (R)-1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one (8B)

[0312]

[0313]

[0314] The first step

[0315] N-(2-Aminopyridin-3-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0316] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (200 mg, 0.443 mmol) was dissolved in 5 mL of ethyl acetate. 2,3-Diaminopyridine 8a (72 mg, 0.664 mmol), T3P (422 mg, 1.33 mmol, 50% ethyl acetate solution), and N,N-diisopropylethylamine (172 mg, 1.33 mmol) were added, and the reaction was carried out at room temperature for 3 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted and separated. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent system B) to obtain N-(2-aminopyridin-3-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 8b (200 mg, oily liquid), with a yield of 83.2%.

[0317] MS m / z (ESI): 543.2 [M+1] +

[0318] The second step

[0319] 1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0320] N-(2-Aminopyridin-3-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 8b (200 mg, 0.368 mmol) was dissolved in 20 mL of acetic acid, and the reaction was carried out at 100 °C for 12 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added, and the mixture was extracted and separated. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent: system B) to obtain 1-(1-(3H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8 (75 mg), with a yield of 38.7%.

[0321] MS m / z (ESI): 525.2 [M+1] +

[0322] 11H NMR (400 MHz, CD3OD) δ 9.30 (s, 1H), 8.38 (m, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.76 - 7.66 (m, 2H), 7.61 - 7.57 (m, 1H), 7.38 - 7.29 (m, 3H), 7.26 - 7.09 (m, 4H), 6.52 (s, 1H), 3.84 - 3.62 (m, 2H), 3.27 (s, 3H).

[0323] The third step

[0324] (S)-1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8A

[0325] (R)-1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8B

[0326] 1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8 (1.95 g) was subjected to SFC chiral resolution (column model: Superchiral S-IC (Chiralway), 2.1 cm I.D. * 25 cm Length, 5 μm; mobile phase: MeOH / DEA = 100 / 0.05 (v / v); flow rate: 20 mL / min; detection wavelength: 254 nm; column temperature: 35 °C), and (S)-1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8A and (R)-1-(1-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 8B were obtained.

[0327] Single configuration compound (shorter retention time):

[0328] MS m / z (ESI): 525.2 [M + 1] +

[0329] 811 mg, retention time: 6.266 min.

[0330] Single-configuration compound (longer retention time):

[0331] MS m / z (ESI): 525.2 [M+1] +

[0332] 799 mg, retention time: 7.605 min.

[0333] Example 9

[0334] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(6-fluoro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one

[0335]

[0336] The first step

[0337] N-(2-Amino-4-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0338] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxo-1-pyridinyl)-3-phenylpropanoic acid 1i (300 mg, 0.663 mmol), 4-fluoro-1,2-diaminobenzene 9a (101 mg, 0.8 mmol), N,N-diisopropylethylamine (257 mg, 1.99 mmol), T3P (422.3 mg, 1.33 mmol, 50% ethyl acetate solution) were successively added to ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction solution was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain N-(2-amino-4-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 9b (293 mg, white solid), with a yield of 79.0%.

[0339] MS m / z (ESI): 560.2 [M+1] +

[0340] The second step

[0341] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(6-fluoro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one

[0342] N-(2-Amino-4-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 9b (290 mg, 0.518 mmol) was dissolved in acetic acid (20 mL), and the mixture was heated to 100 °C and stirred for 3 h. Ethyl acetate (30 mL) was added to the reaction solution for extraction. The organic phase was washed successively with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(6-fluoro-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one 9 (174 mg), with a yield of 62.1%.

[0343] MS m / z (ESI): 542.2 [M+1] +

[0344] 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.59 (s, 1H), 7.83 - 7.79 (m, 2H), 7.68 - 7.65 (m, 1H), 7.49 - 7.43 (m, 1H), 7.34 - 7.25 (m, 4H), 7.23 - 7.18 (m, 1H), 7.15 - 7.05 (m, 3H), 6.51 - 6.34 (m, 2H), 3.71 - 3.62 (m, 1H), 3.59 - 3.51 (m, 1H), 3.21 (s, 3H).

[0345] Example 10

[0346] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(6-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one

[0347]

[0348] The first step

[0349] N-(3-Amino-5-fluoropyridin-2-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0350] 2-[4-[5-Chloro-2-(1H-tetrazol-1-yl)phenyl]-5-methoxy-2-oxo-1-pyridinyl]-3-phenylpropanoic acid 1i (300 mg, 0.663 mmol), 5-fluoro-2,3-diaminopyridine 10a (102 mg, 0.8 mmol), N,N-diisopropylethylamine (257 mg, 1.99 mmol), and T3P (422.3 mg, 1.33 mmol, 50% ethyl acetate solution) were successively added to ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to give N-(3-amino-5-fluoropyridin-2-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 10b (305 mg, white solid) in a yield of 81.9%.

[0351] MS m / z (ESI): 561.2 [M+1] +

[0352] The second step

[0353] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(6-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one

[0354] N-(3-Amino-5-fluoropyridin-2-yl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 10b (290 mg, 0.534 mmol) was dissolved in acetic acid (20 mL), and the mixture was heated to 120 °C and stirred for 12 h. Ethyl acetate (30 mL) was added to the reaction mixture for extraction. The organic phase was successively washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to give 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1-(1-(6-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one 10 (174 mg) in a yield of 65.4%.

[0355] MS m / z (ESI): 543.2 [M+1] +

[0356] 11H NMR (400 MHz, DMSO-d6) δ 13.59 - 12.94 (m, 1H), 9.58 (s, 1H), 8.35 (s, 1H), 7.95 (br, 1H), 7.81 (s, 2H), 7.67 (s, 1H), 7.34 - 7.26 (m, 3H), 7.24 - 7.19 (m, 1H), 7.15 - 7.08 (m, 2H), 6.48 - 6.33 (m, 2H), 3.74 - 3.65 (m, 1H), 3.62 - 3.53 (m, 1H), 3.21 (s, 3H).

[0357] Example 11

[0358] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0359]

[0360] The first step

[0361] N-(2-Amino-4-methylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide

[0362] 2-[4-[5-Chloro-2-(1H-tetrazol-1-yl)phenyl]-5-methoxy-2-oxo-1-pyridinyl]-3-phenylpropanoic acid 1i (300 mg, 0.663 mmol), 3,4-diaminotoluene 11a (97 mg, 0.8 mmol), N,N-diisopropylethylamine (257 mg, 1.99 mmol), and T3P (422.3 mg, 1.33 mmol, 50% ethyl acetate solution) were successively added to ethyl acetate (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain N-(2-amino-4-methylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 11b (290 mg, white solid), with a yield of 78.6%.

[0363] MS m / z (ESI): 556.2 [M + 1] +

[0364] The second step

[0365] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one

[0366] Dissolve N-(2-amino-4-methylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanamide 11b (290 mg, 0.52 mmol) in acetic acid (20 mL), heat to 80 °C and stir for 3 h. Add ethyl acetate (30 mL) to the reaction solution for extraction. The organic phase is washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (eluent system A) to obtain 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyridin-2(1H)-one 11 (180 mg), with a yield of 64.2%.

[0367] MS m / z (ESI): 538.2 [M+1] +

[0368] 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.59 (s, 1H), 7.83 - 7.78 (m, 2H), 7.69 - 7.64 (m, 1H), 7.36 - 7.17 (m, 6H), 7.15 - 7.08 (m, 2H), 7.04 - 6.97 (m, 1H), 6.52 - 6.33 (m, 2H), 3.70 - 3.60 (m, 1H), 3.56 - 3.49 (m, 1H), 3.21 (s, 3H), 2.40 (s, 3H).

[0369] Example 12

[0370] 1-(1-(5-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 12

[0371]

[0372]

[0373] The first step

[0374] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid-(2-(6-(tert-butoxycarbonylamino)-2-fluoropyridin-3-yl)-2-oxoethyl) ester

[0375] Dissolve the raw materials 2-[4-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-5-methoxy-2-oxo-1-pyridinyl]-3-phenylpropanoic acid 1i (2 g, 4.43 mmol) and tert-butyl 5-(2-bromoacetyl)-6-fluoropyridine-2-ylcarbamate 12a (the synthesis method refers to JP2017218449) (2.95 g, 8.85 mmol) and N,N-diisopropylethylamine (1.72 g, 13.28 mmol) in N-methylpyrrolidone (100 mL), and then react at room temperature for 12 h. Detect the reaction by TLC until the reaction is complete. Dilute with ethyl acetate, wash the organic phase with saturated sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the reaction solution under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid-(2-(6-(tert-butoxycarbonylamino)-2-fluoropyridin-3-yl)-2-oxoethyl) ester 12b (3 g, yellow solid), with a yield of 96.3%.

[0376] MS m / z (ESI): 704.2 [M+1] +

[0377] The second step

[0378] tert-Butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)-6-fluoropyridine-2-ylcarbamate

[0379] The raw material 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid-(2-(6-tert-butoxycarbonylamino-2-fluoropyridin-3-yl)-2-oxoethyl) ester 12b (3 g, 4.26 mmol) and ammonium acetate (986 mg, 12.78 mmol) were dissolved in acetic acid (30 mL), and then reacted at 100 °C for 6 h. The reaction was monitored by TLC and was completed. It was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)-6-fluoropyridine-2-carboxylate 12c (1.5 g, yellow solid), with a yield of 51.5%.

[0380] MS m / z(ESI): 684.2[M+1] +

[0381] The third step

[0382] 1-(1-(5-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0383] The raw material tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)-6-fluoropyridine-2-carboxylate 12c (936 mg, 1.37 mmol) was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (10 mL), and then reacted at room temperature for 1 h. The reaction was monitored by TLC and was completed. The solvent was evaporated. It was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product 1-(1-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 12 (330 mg), with a yield of 41.3%.

[0384] MS m / z(ESI): 584.2[M+1] +

[0385] 11H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.62 (s, 1H), 8.07 (dd, J = 10.4, 8.4 Hz, 1H), 7.81 (d, J = 1.2 Hz, 2H), 7.69 (s, 1H), 7.45 (s, 1H), 7.32 - 7.24 (m, 2H), 7.21 - 7.13 (m, 2H), 7.09 (d, J = 7.2 Hz, 2H), 6.58 - 6.34 (m, 3H), 6.31 (s, 2H), 3.53 - 3.44 (m, 1H), 3.41 - 3.32 (m, 1H), 3.25 (s, 3H).

[0386] Example 13

[0387] 1-(1-(5-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0388]

[0389] The starting material 1-(1-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 12 (620 mg, 1.06 mmol), potassium carbonate (176 mg, 1.27 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (451 mg, 1.27 mmol) were dissolved in acetonitrile (20 mL), and then reacted at 0 °C for 0.2 h. The reaction was monitored by TLC until completion. It was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product 1-(1-(5-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 13 (130 mg), with a yield of 20.3%.

[0390] MS m / z (ESI): 600.2 [M+1] +

[0391] 11H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.61 (s, 1H), 7.81 (d, J = 1.6 Hz, 2H), 7.69 (s, 1H), 7.59 - 7.52 (m, 1H), 7.32 - 7.25 (m, 3H), 7.23 - 7.17 (m, 1H), 7.09 (d, J = 7.6 Hz, 2H), 6.58 (s, 2H), 6.44 - 6.36 (m, 2H), 6.34 - 6.24 (m, 1H), 3.46 - 3.37 (m, 1H), 3.34 - 3.29 (m, 1H), 3.26 (s, 3H).

[0392] Example 14

[0393] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(5-(pyridin-4-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one

[0394]

[0395] The first step

[0396] (2-Oxo-2-(pyridin-4-yl)ethyl) 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate

[0397] The starting materials 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (300 mg, 0.66 mmol), 2-bromo-1-(pyridin-4-yl)ethan-1-one hydrobromide 14a (280 mg, 0.99 mmol), and N,N-diisopropylethylamine (258 mg, 1.99 mmol) were dissolved in N-methylpyrrolidone (30 mL), and then reacted at room temperature for 3 h. The reaction was monitored by TLC until completion. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (eluent system B) gave the product (2-oxo-2-(pyridin-4-yl)ethyl) 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate 14b (300 mg, yellow solid) with a yield of 79.1%. MS m / z (ESI): 571.2 [M + 1] +

[0398] The second step

[0399] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(5-(pyridin-4-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one

[0400] Dissolve the raw material 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid (2-oxo-2-(pyridin-4-yl)ethyl) ester 14b (300 mg, 0.53 mmol) and ammonium acetate (122 mg, 1.58 mmol) in acetic acid (30 mL), and then react at 100 °C for 3 h. Monitor the reaction by TLC until completion. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-1-(2-phenyl-1-(5-(pyridin-4-yl)-1H-imidazol-2-yl)ethyl)pyridin-2(1H)-one 14 (32 mg), with a yield of 11%.

[0401] MS m / z (ESI): 551.2 [M+1] +

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.61 (s, 1H), 8.60 - 8.45 (br, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.81 (s, 2H), 7.76 - 7.70 (m, 2H), 7.68 (s, 1H), 7.43 (s, 1H), 7.28 (t, J = 7.2 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 2H), 6.42 (s, 1H), 6.37 - 6.30 (m, 1H), 3.57 - 3.47 (m, 2H), 3.44 - 3.36 (m, 2H), 3.26 (s, 3H).

[0403] Example 15

[0404] 1-(1-(5-(6-Aminopyridin-3-yl)-4-fluoro-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0405]

[0406] The first step

[0407] tert-Butyl 5-acetylpyridin-2-ylcarbamate

[0408] Dissolve 1-(6-aminopyridin-3-yl)ethanone 15a (2 g, 14.69 mmol) and di-tert-butyl dicarbonate (3.85 g, 17.63 mmol) in dichloromethane (100 mL), add N,N-diisopropylethylamine (2.97 g, 29.38 mmol) and 4-dimethylaminopyridine (897 mg, 7.34 mmol), and then react at room temperature for 14 h. Monitor the reaction by TLC until completion. Wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product tert-butyl 5-acetylpyridin-2-ylcarbamate 15b (3.1 g, yellow solid) with a yield of 89.3%.

[0409] MS m / z (ESI): 181.1 [M+1-C4H8] +

[0410] The second step

[0411] tert-Butyl 5-(2-bromoacetyl)pyridin-2-ylcarbamate

[0412] Dissolve tert-butyl 5-acetylpyridin-2-ylcarbamate 15b (3.00 g, 12.70 mmol) and liquid bromine (2.03 g, 12.70 mmol) in THF (100 mL), and then react at room temperature for 12 h. Monitor the reaction by TLC until completion. Quench with saturated sodium thiosulfate solution, extract with ethyl acetate, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system A) to obtain the product tert-butyl 5-(2-bromoacetyl)pyridin-2-ylcarbamate 15c (3 g, yellow solid) with a yield of 75.0%.

[0413] MS m / z (ESI): 259.0 [M+1-C4H8] +

[0414] The third step

[0415] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid (2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-2-oxoethyl) ester

[0416] Dissolve 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (789 mg, 1.75 mmol) and N,N-diisopropylethylamine (677 mg, 5.24 mmol) in N-methylpyrrolidone (30 mL), then dropwise add tert-butyl 5-(2-bromoacetyl)pyridin-2-ylcarbamate 15c (1.1 g, 3.49 mmol) dissolved in N-methylpyrrolidone, and react at room temperature for 4 h. Monitor the reaction by TLC until completion. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product tert-butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate (2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-2-oxoethyl) ester 15d (0.8 g, yellow solid), with a yield of 66.8%.

[0417] MS m / z(ESI): 686.2[M+1] +

[0418] The fourth step

[0419] tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)pyridin-2-ylcarbamate

[0420] Dissolve tert-butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate (2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-2-oxoethyl) ester 15d (1 g, 1.46 mmol) and ammonium acetate (337 mg, 4.37 mmol) in acetic acid (50 mL), then react at 100 °C for 4 h. Monitor the reaction by TLC until completion. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)pyridin-2-ylcarbamate 15e (500 mg, yellow solid), with a yield of 51.5%.

[0421] MS m / z(ESI): 666.2[M+1] +

[0422] The fifth step

[0423] tert-Butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-4-fluoro-1H-imidazol-5-yl)pyridin-2-ylcarbamate

[0424] Dissolve tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)pyridin-2-ylcarbamate 15e (20 mg, 0.03 mmol), potassium carbonate (5 mg, 0.036 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (13 mg, 0.036 mmol) in acetonitrile (5 mL), and then react at room temperature for 0.2 h. Monitor the reaction by TLC until the raw materials are completely reacted. Dilute with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-4-fluoro-1H-imidazol-5-yl)pyridin-2-ylcarbamate 15f (10 mg, white solid), with a yield of 50.0%.

[0425] MS m / z (ESI): 684.2 [M+1] +

[0426] The sixth step

[0427] 1-(1-(5-(6-Aminopyridin-3-yl)-4-fluoro-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0428] Dissolve tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-4-fluoro-1H-imidazol-5-yl)pyridine-2-carboxylate 15f (10 mg, 14.62 μmol) in dichloromethane (8 mL) and trifluoroacetic acid (2 mL), and then react at room temperature for 1 h. Monitor the reaction by TLC until completion, and then evaporate the solvent under reduced pressure. Dissolve the residue in ethyl acetate, wash with saturated sodium bicarbonate solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product 1-(1-(5-(6-aminopyridin-3-yl)-4-fluoro-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 15 (2 mg), with a yield of 23.4%.

[0429] MS m / z (ESI): 584.2 [M+1] +

[0430] 1 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 9.63 (s, 1H), 8.13 (s, 1H), 7.81 (s, 2H), 7.70 (s, 1H), 7.56 - 7.51 (m, 1H), 7.33 - 7.23 (m, 3H), 7.19 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 7.2 Hz, 2H), 6.48 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 6.30 - 6.21 (m, 1H), 6.12 (s, 2H), 3.49 - 3.39 (m, 1H), 3.38 - 3.32 (m, 1H), 3.26 (s, 3H).

[0431] Example 16

[0432] 1-(1-(5-(6-Aminopyridin-3-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0433]

[0434] Dissolve tert-butyl 5-(2-(1-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-2-phenylethyl)-1H-imidazol-5-yl)pyridin-2-ylcarbamate 15e (100 mg, 150.12 μmol) in dichloromethane (50 mL) and trifluoroacetic acid (10 mL), and then react at room temperature for 1 h. Monitor the reaction by TLC until completion, and then evaporate the solvent under reduced pressure. Add saturated sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography (eluent system B) to obtain the product 1-(1-(5-(6-aminopyridin-3-yl)-1H-imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 16 (30 mg), with a yield of 35.3%.

[0435] MS m / z (ESI): 566.2 [M+1] +

[0436] 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 9.62 (s, 1H), 8.33 (s, 1H), 7.80 (d, J = 1.2 Hz, 2H), 7.77 - 7.71 (m, 1H), 7.70 - 7.67 (m, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.27 (t, J = 7.2 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 7.2 Hz, 2H), 6.46 (d, J = 8.8 Hz, 1H), 6.41 (s, 1H), 6.34 - 6.25 (m, 1H), 6.06 - 5.86 (m, 2H), 3.52 - 3.44 (m, 1H), 3.38 - 3.32 (m, 1H), 3.25 (s, 3H).

[0437] Example 17

[0438] 6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-3-(1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyrimidin-4(3H)-one

[0439]

[0440] The first step

[0441] 2-amino-5-chlorophenylboronic acid pinacol ester

[0442] 2-Bromo-4-chloroaniline 17a (20 g, 96.87 mmol), bis(pinacolato)diboron 17b (36.90 g, 145.30 mmol), 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.54 g, 4.84 mmol), and potassium acetate (28.48 g, 290.60 mmol) were successively added to dioxane (200 mL). Under nitrogen protection, the temperature was raised to 90 °C and the mixture was stirred for 3 h. After the reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and insoluble substances were removed by filtration through diatomaceous earth. The reaction solution was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 2-amino-5-chlorophenylboronic acid pinacol ester 17c (21 g, light yellow solid) with a yield of 85.5%.

[0443] MS m / z (ESI): 254.1 [M+1] +

[0444] The second step

[0445] 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline

[0446] 2-Amino-5-chlorophenylboronic acid pinacol ester 17c (21.00 g, 83.33 mmol), 4-chloro-6-methoxypyrimidine 17d (10 g, 69.44 mmol), 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride (5.07 g, 6.94 mmol), and potassium acetate (20.41 g, 208.32 mmol) were successively added to dioxane (200 mL). Under nitrogen protection, the temperature was raised to 90 °C and the mixture was stirred for 3 h. After the reaction solution was cooled to room temperature, ethyl acetate (100 mL) was added, and insoluble substances were removed by filtration through diatomaceous earth. The reaction solution was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline 17e (12 g, white solid) with a yield of 73.6%. MS m / z (ESI): 236.1 [M+1] +

[0447] The third step

[0448] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine

[0449] 4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline 17e (3.7 g, 15.70 mmol), trimethyl orthoformate (8.33 g, 78.50 mmol) and 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (9.03 g, 78.5 mmol) were successively added to acetic acid (50 mL), and the mixture was stirred at room temperature for 6 h. Ethyl acetate (100 mL) was added to the reaction solution for extraction, and the organic phase was washed successively with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine 17f (2.7 g, white solid), with a yield of 59.6%.

[0450] MS m / z(ESI): 289.1[M+1] +

[0451] The fourth step

[0452] 6-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)pyrimidin-4(3H)-one

[0453] 4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine 17f (2.7 g, 9.35 mmol), sodium iodide (12.62 g, 84.17 mmol), and trimethylchlorosilane (15.24 g, 140.29 mmol) were successively added to acetonitrile (30 mL), and the mixture was stirred at room temperature for 8 h. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution, extracted with ethyl acetate (100 mL), and the organic phase was washed successively with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)pyrimidin-4(3H)-one 17g (1.9 g, white solid), with a yield of 74.0%.

[0454] MS m / z(ESI): 275.0[M+1] +

[0455] The fifth step

[0456] Methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropionate

[0457] 17 g (1.9 g, 6.92 mmol) of 6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)pyrimidin-4(3H)-one, 1e (2.68 g, 10.38 mmol) of methyl 2-(methylsulfonyloxy)-3-phenylpropionate and 2.87 g (20.75 mmol) of potassium carbonate were successively added to dioxane (50 mL), and the mixture was heated to 100 °C and stirred for 3 h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate was added, and the mixture was extracted. The organic phase was washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 17h (1.5 g, pale yellow solid) of methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropionate, with a yield of 49.6%.

[0458] MS m / z(ESI): 437.1[M + 1] +

[0459] The sixth step

[0460] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropanoic acid

[0461] 1.5 g (3.23 mmol) of methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropionate and 686 mg (17.17 mmol) of sodium hydroxide were dissolved in methanol (20 mL) and water (2 mL), and the mixture was stirred at room temperature for 30 minutes. The pH was adjusted to 2 - 3 with 1N HCl, methanol was removed under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, the organic layer was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to obtain 17i (1.2 g, pale yellow solid) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropanoic acid, with a yield of 82.7%.

[0462] MS m / z(ESI): 423.1[M + 1] +

[0463] The seventh step

[0464] N-(2-amino-4-methylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropanamide

[0465] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropanoic acid 17i (200 mg, 0.47 mmol), 3,4-diaminotoluene 11b (69 mg, 0.56 mmol), T3P (301 mg, 0.95 mmol, 50% ethyl acetate solution) and N,N-diisopropylethylamine (183 mg, 1.42 mmol) were reacted at room temperature for 1 h. The reaction mixture was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent system A) to give N-(2-amino-4-methylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropanamide 17j (190 mg, white solid), with a yield of 76.2%.

[0466] MS m / z (ESI): 527.2 [M+1] +

[0467] The eighth step

[0468] 6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-3-(1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyrimidin-4(3H)-one

[0469] N-(2-Amino-4-methylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-3-phenylpropanamide 17j (190 mg, 0.36 mmol) was dissolved in 20 mL of acetic acid and reacted at 80 °C for 1 h. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was extracted and separated. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent system A) to give 6-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-3-(1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)pyrimidin-4(3H)-one 17 (110 mg), with a yield of 59.9%.

[0470] MS m / z (ESI): 509.2 [M+1] +

[0471] 11H NMR (400 MHz, DMSO-d6) δ 12.60 - 12.50 (m, 1H), 9.67 (s, 1H), 8.52 (s, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.50 - 7.25 (m, 4H), 7.23 - 7.19 (m, 1H), 7.16 - 7.11 (m, 2H), 7.06 - 6.97 (m, 1H), 6.53 (s, 1H), 6.29 - 6.22 (m, 1H), 3.76 - 3.68 (m, 1H), 3.62 - 3.54 (m, 1H), 2.54 (s, 1H).

[0472] Biological Evaluation

[0473] Test Example 1, Determination of the Activity of the Compounds of the Present Invention against Factor XIa Protease

[0474] The following method is used to determine the inhibitory degree of the compounds of the present invention on the activity of Native human Factor XIa protease under in vitro conditions. This method uses a chromogenic substrate of Factor XIa to test the inhibitory strength on the activity of Factor XIa protease. Native human Factor XIa protein was purchased from Abcam (product number ab62411), and S-2366 was purchased from Chromogenix (product number 82109039).

[0475] The experimental procedure is briefly described as follows: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and then the compound was serially diluted 4-fold with Factor XIa reaction buffer (100 mM Tris-HCl, 200 mM NaCl, 0.02% Tween 20, pH 7.4). The final concentration range of the test compound in the reaction system was 10000 nM - 0.61 nM. The reaction was carried out in a 384-well microplate. First, 2 μL of the test compound at different concentrations diluted with the reaction buffer was added to the wells, and the blank and control wells were replaced with 2 μL of 1% DMSO (the final concentration of DMSO in the reaction system was 0.1%); then 8 μL of the enzyme working solution (the final concentration of Factor XIa was 1.25 μg / uL) was added to each well, and the blank well was replaced with 8 μL of Factor XIa reaction buffer, centrifuged for 30 seconds, and incubated on ice for 5 minutes; finally, 10 μL of the substrate working solution (the final concentration of S-2366 was 1 mM) was added to each well, centrifuged for 30 seconds, and the reaction was initiated. The absorbance at 405 nm was measured after incubation at 37°C for 10 minutes. By comparing with the absorbance of the control group (0.1% DMSO), the percentage inhibition rate of the compound at each concentration was calculated, and a non-linear regression analysis of the logarithm of the compound concentration - inhibition rate was performed using GraphPad Prism 5 software to obtain the IC 50 value, as shown in Table 1.

[0476] Table 1 IC of the compounds of the present invention for inhibiting Factor XIa protease activity 50 Data

[0477]

[0478] As can be seen from Table 1, the compounds of the present invention all have good inhibitory effects on FXIa protease activity.

[0479] Test Example 2: Determination of the in vitro anticoagulant effect of the compounds of the present invention on human or rabbit plasma

[0480] The following method was used to determine the in vitro anticoagulant effect of the compounds of the present invention in human or rabbit plasma. This method was tested using APTT and PT kits from MediRox. The APTT kit was purchased from MediRox (product number MRX930), and the PT kit was purchased from MediRox (product number MR943-10). Both human plasma and rabbit plasma were prepared in-house.

[0481] The preparation of human plasma is briefly described as follows: Human plasma was collected in a citrate-containing blood collection tube, centrifuged at 3000 rpm for 10 min at room temperature, the plasma was collected, aliquoted, and stored at -80°C.

[0482] The APTT and PT test procedures are briefly described as follows: The test compound is first dissolved in DMSO to prepare a 10 mM stock solution, and then the test compound is serially diluted 3-fold with DMSO. The final concentration range of the test compound in the reaction system is 217 μM - 0.03 μM. Take 4 μL of the test compound diluted with DMSO at different concentrations and add it to a centrifuge tube containing 180 μL of plasma. In the blank group, add 4 μL of DMSO, mix well by shaking, and incubate at 37 °C for 5 min for later use. Subsequently, place the APTT / PT reagent on the reagent rack according to the instrument requirements, take the incubated plasma sample, put it into the detection position of the blood coagulation analyzer, measure the coagulation time, and record the coagulation time (s). Using the final concentration of the compound as the abscissa and Ratio (Ratio = Ti / T0, where T0 is the coagulation time of the blank control and Ti is the coagulation time of the test compound) as the ordinate, plot the coagulation dose-effect curve with Graph Pad Prism5, and calculate the compound concentration when the coagulation time is prolonged by 2-fold, that is, the CT2 value, as shown in Table 2.

[0483] Table 2 CT2 data of the compounds of the present invention for in vitro anticoagulant effects on human and rabbit plasma

[0484]

[0485] As can be seen from Table 2, the compounds of the present invention have good in vitro anticoagulant effects in both human and rabbit plasma.

[0486] Note: ND represents not determined

[0487] Test Example 3, Oral Pharmacokinetics Study of the Compounds of the Present Invention in SD Rats

[0488] 1. Experimental Purpose

[0489] Using SD rats as test animals, and determined by LC / MS / MS method. After intragastric administration of the compounds of the present invention, measure the drug concentration in plasma at different times, and study the pharmacokinetic characteristics of the compounds of the present invention in rats.

[0490] 2. Experimental Scheme

[0491] 2.1 Experimental Drugs and Animals

[0492] Compounds 4, 5 and 8 of the present invention;

[0493] 9 healthy adult Sprague Dawley (SD) male rats, purchased from Vital River Laboratory Animal Technology Co., Ltd.

[0494] 2.2 Drug Preparation and Administration

[0495] Oral Gavage Group:

[0496] Weigh an appropriate amount of the sample, and add it to a mixed solution of DMSO, Solutol HS 15, and (20% HP-β-CD in water)

[0497] (V / V / V = 5:10:85), and vortex to mix evenly to prepare a 1 mg / mL solution.

[0498] Nine healthy adult male SD rats were evenly divided into three groups. After fasting overnight, they were given the drug by gavage (the dosage was 10 mg / kg), and they were allowed to eat 4 hours after administration.

[0499] 2.3 Sample collection

[0500] Approximately 0.2 mL of blood was collected from the jugular vein before drug administration and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after drug administration, and anticoagulated with sodium heparin. After the blood samples were collected, they were placed on ice and centrifuged to separate plasma (centrifugation conditions: 2000 g, 5 minutes, 4 °C). The collected plasma was stored at -40 to -20 °C before analysis.

[0501] 2.4 Sample pretreatment

[0502] Add 400 μL of acetonitrile (containing the internal standard working solution, where verapamil is 5 ng / mL and glibenclamide is 50 ng / mL) to 10 μL of the plasma sample, vortex for 10 minutes, centrifuge at 3700 revolutions per minute for 10 minutes, take 70 μL of the supernatant, add 70 μL of water, vortex for 10 minutes, and take 2 μL of the mixture for LC-MS / MS injection analysis.

[0503] 3. Results of pharmacokinetic parameters

[0504] The pharmacokinetic parameters of the compound of the present invention are shown in Table 3 below.

[0505] Table 3

[0506]

[0507] Conclusion: As can be seen from Table 3, the compound of the present invention has good pharmacokinetic properties.

Claims

1. A compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Wherein: X is selected from CR 7 ; Ring B is a 5- to 10-membered heteroaryl; R 1 identical or different and each independently selected from halogen; R 2 selected from 5-membered heteroaryl; R 3 selected from a hydrogen atom; L is selected from -CH2- or -CH2CH2-; R 6 selected from phenyl; R 5 Same or different, each independently selected from a hydrogen atom, C1-C 10 alkyl group, halogen, cyano group, -OR 8 , -C(O)R 8 , -NHC(O)R 8 , -NR 9 R 10 or pyridyl; The pyridyl group is optionally further substituted by one or more substituents selected from halogen, NR 9 R 10 , C1-C 10 alkyl; R 8 selected from a hydrogen atom or a C1-C4 alkyl group; R 9 and R 10 each independently selected from a hydrogen atom or a C1-C4 alkyl group R 7 selected from -OR B ; R B Selected from C1-C 10 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4.

2. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Among them: Ring B, X, L, R 1 ~R 3 , R 5 , R 6 , m and n are defined as described in claim 1.

3. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (IV), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Among them: ring B, X, L, R 1 ~R 3 , R 5 , R 6 , m and n are defined as described in claim 1.

4. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (V), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein: X 1 ~X 4 Same or different, each independently selected from a chemical bond, N, NH or C(R 5 )); X 1 ~X 4 At least one of them is not selected from N or NH; X 1 ~X 4 At most one of them is selected from a chemical bond; X, L, R 1 ~R 3 , R 5 , R 6 and the definitions of n are as described in claim 1.

5. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 4, which is a compound of formula (V-A) and (V-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein: X 1 ~X 4 、X, L, R 1 ~R 3 、R 6 The definitions of and n are as described in claim 4.

6. The compound or its stereoisomer or its pharmaceutically acceptable salt according to claim 4 or 5, wherein the selected from: Wherein: R 5 The definitions of R and m are as described in claim 1.

7. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (VI), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein: X 5 ~X 9 Same or different, each independently selected from N or C(R 14 )); X 5 ~X 9 One of them is selected from N; Y 1 ~Y 2 identical or different, each independently selected from N or C(R 5 ); Each R 14 is the same or different and each independently selected from a hydrogen atom, a halogen, -NR 9 R 10 ; L, R 1 ~R 3 , R 5 , R 6 , R 7 , R 9 , R 10 The definitions of and n are as described in claim 1.

8. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 7, which is a compound of formula (VI-A) and (VI-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein: X 5 ~X 9 , L, R 1 ~R 3 , R 6 , R 7 , Y 1 ~Y 2 The definitions of and n are as described in claim 7.

9. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 7 or 8, wherein: R 7 is - OR B ; R B is methyl or ethyl.

10. A compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, 7 or 8, wherein: R 2 is a tetrazolyl group.

11. The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound is:

12. A pharmaceutical composition comprising an effective dose of the compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

13. Use of the compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 12 in the preparation of a factor XIa inhibitor, or a dual inhibitor of factor XIa and plasma kallikrein.

14. Use of the compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing a disease mediated by factor XIa.

15. The use according to claim 14, wherein the disease mediated by factor XIa is a cardiovascular and cerebrovascular disease.

16. The use according to claim 15, wherein the cardiovascular and cerebrovascular disease is a blood coagulation disorder or a thromboembolic disease.

17. The use according to claim 16, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, an arterial cerebrovascular thromboembolic disorder, a venous cerebrovascular thromboembolic disorder and a thromboembolic disorder of the ventricular or peripheral circulation.

18. The use according to claim 16, wherein the thromboembolic disease is acute coronary syndrome.

19. The use according to claim 16, wherein the thromboembolic disease is unstable angina, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from: medical implants, devices, or surgeries, wherein blood contacts an artificial surface that promotes thrombosis.

20. The use according to claim 19, wherein the venous thrombosis is deep vein thrombosis.

21. Use of a compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the preparation of a drug for treating anticoagulants.

22. Use of a compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the preparation of a drug for treating or preventing thromboembolic diseases.

23. The use according to claim 22, wherein the thromboembolic disease is selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and thromboembolic disorders of the ventricular or peripheral circulation.

24. The use according to claim 22, wherein the thromboembolic disease is acute coronary syndrome.

25. The use according to claim 22, wherein the thromboembolic disease is selected from unstable angina, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from: medical implants, devices, or surgeries, wherein blood contacts an artificial surface that promotes thrombosis.

26. The use according to claim 25, wherein the venous thrombosis is deep vein thrombosis.

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