Amide phosphine oxide derivatives and preparation method and use thereof

Abstract

The present invention relates to amide phosphine oxide derivatives, preparation methods thereof and their use in medicine. Specifically, the present invention relates to an amide phosphine oxide derivative represented by general formula (I), preparation methods thereof and pharmaceutically acceptable salts thereof, and their use as therapeutic agents, especially as inhibitors of coagulation factor XIa (FXIa), wherein the definitions of the substituents in the general formula (I) are the same as those in the specification.

Description

Technical Field

[0001] The present invention relates to an amide phosphine oxide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the derivative as a therapeutic agent, in particular as a coagulation factor XIa (FXIa) inhibitor. Background Art

[0002] Common cardiovascular diseases such as stroke, thrombosis, and myocardial infarction have become the main causes of death in the world. In the world death population statistics in 2017, deaths caused by cardiovascular diseases accounted for about 32% of the world's total deaths. The pathological process of these diseases is 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. At present, traditional anticoagulants include vitamin K antagonists, fibrinolytic agents, heparin, antiplatelet aggregation and other drugs. However, due to the limitations of various factors such as poor compliance of such drugs, large coefficient of variation between individuals, and narrow treatment window, non-vitamin K antagonist oral anticoagulants have been continuously developed and marketed in recent years, mainly including antagonists that directly inhibit thrombin and antagonists that act on coagulation factors. 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. In order to overcome this problem, it is of great significance to develop drugs with low bleeding risk. Domestic and foreign studies have shown 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 hemorrhage. Among them, thromboembolic diseases include arterial cardiovascular thromboembolic diseases, venous cardiovascular thromboembolic diseases, arterial cerebrovascular thromboembolic diseases, venous cerebrovascular thromboembolic diseases and ventricular or peripheral circulation thromboembolic diseases. 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 caused by the following: medical implants, devices or surgeries that come into contact with blood and promote thrombosis, and venous thrombosis also includes deep vein thrombosis.

[0003] FXI is a serine protease with a molecular weight of about 80kD. It is composed of two subunits connected 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 four AP domains A1-A4. A1 binds thrombin; A2 binds high molecular weight kininogen; A3 binds coagulation factor IX and heparin; A4 binds activated coagulation factor XII. Therefore, these four 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 beginning of coagulation, coagulation factor XII is activated to form XIIa, and XIIa activates FXI activity to FXIa, which in turn 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 the liver-derived precursor of the trypsin-like serine protease plasma kallikrein and circulates in plasma bound to high molecular weight kininogens. Plasma prekallikrein is activated to plasma kallikrein by activated coagulation 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] At present, there is fierce competition for the clinical development of FXIa inhibitors at home and abroad. Among them, the FXIa inhibitor BMS-986177 developed by BMS has entered the second phase of clinical trials for the prevention and treatment of major thrombosis and other diseases. Early clinical studies have shown that FXIa inhibitors slow the formation of blood clots and significantly reduce the risk of bleeding. A series of patent applications for FXIa inhibitors have been published, including WO2017151746A1, WO2017151018A1 and WO2018039094A1. The research and application of FXIa inhibitors have made certain progress, but there is still huge room for improvement. It is still necessary to continue to research and develop new FXIa inhibitors. Summary of the invention

[0006] The object of the present invention is to provide an amide phosphine oxide derivative represented by general formula (I), or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] Ring A is selected from aryl groups; wherein the aryl group is preferably phenyl;

[0010] Ring B is selected from 5-6 membered heterocyclyl, 5-6 membered aryl, 5-6 membered heteroaryl;

[0011] Ring C is selected from an aryl group, a heteroaryl group or a condensed ring; wherein the heteroaryl group is preferably a 5- to 10-membered heteroaryl group;

[0012] Q is selected from a single bond or -C(O)-NH-;

[0013] R 1 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 、-NR 9 R 10 or -C(O)R 8 ;

[0014] R 2 Selected from heteroaryl or -C(O)R 8 wherein the heteroaryl group is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, cyano or halogen;

[0015] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, =0, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0016] R 4 is selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or -OR 8 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from halogen, hydroxyl or R 8 substituted by a substituent;

[0017] R 5 are the same or different and are independently selected from hydrogen, alkyl, haloalkoxy, halogen, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR 8 、-C(O)R 8 、-NHC(O)R 8 、-NHC(O)OR 8 、-NR 9 R 10 、-C(O)NR 9 R 10 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from alkyl, cycloalkyl, halogen, cyano, =O, -OR 8 、-C(O)R 8、-NR 9 R 10 substituted by a substituent;

[0018] R 6 and R 7 the same or different, each independently selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, -NR 9 R 10 , haloalkyl, alkoxy, haloalkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0019] Or, R 5 and R 6 Together with the atoms to which they are attached, they form a 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heterocyclic ring contains one or more N, O or P(═O), and the 5- to 10-membered heterocyclic ring is optionally further substituted with one or more substituents selected from alkyl, alkoxy, halogen or hydroxy;

[0020] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heterocyclic ring contains one or more N, O or P(═O), and the 5- to 10-membered heterocyclic ring is optionally further substituted with one or more substituents selected from alkyl, alkoxy, halogen or hydroxy;

[0021] R 8 is selected from hydrogen atom, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, =O, -C(O)R 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent;

[0022] R 9 and R 10are the same or different and 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, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are optionally further substituted by one or more 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 、-SO 2 NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent;

[0023] Or, R 9 and R 10 Together with the connected nitrogen atom, it forms a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic ring contains one or more N, O, S or SO 2 , and the 4- to 10-membered heterocyclic ring is optionally further substituted with one or more R 11 replaced by;

[0024] R 11 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 substituted by one or more R A replaced by;

[0025] 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 by one or more substituents selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano;

[0026] R 12 and R 13 are the same or different and 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, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, 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 carboxylate group;

[0027] m is 0, 1, 2, 3 or 4;

[0028] n is 0, 1, 2, 3 or 4.

[0029] The present invention provides a compound represented by the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound represented by the general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0030]

[0031] in:

[0032] L is an alkylene group, wherein the alkylene group is optionally further substituted by one or more substituents selected from halogen or hydroxy;

[0033] R L is selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0034] Ring B, Ring C, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (I).

[0035] The present invention provides a compound represented by the general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound represented by the general formula (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0036]

[0037] Among them: Ring B, Ring C, L, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (II).

[0038] The present invention provides a compound represented by the general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, which is a compound represented by the general formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0039]

[0040] Among them: Ring B, Ring C, L, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (II).

[0041] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein ring B is selected from:

[0042]

[0043] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Selected from:

[0044]

[0045] Where: R 5 and r are as defined in the general formula (I).

[0046] In a preferred embodiment of the present invention, the compound represented by the general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound represented by the general formula (V) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

[0047]

[0048] in:

[0049] X is selected from C or N;

[0050] Ring C, L, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (II).

[0051] In a preferred embodiment of the present invention, the compound represented by the general formula (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof are compounds represented by the general formulas (VA) and (VB) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0052]

[0053] Among them: Ring C, X, L, R 1 ~R3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (V).

[0054] In a preferred embodiment of the present invention, the compound represented by general formula (V) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound represented by general formula (VI) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

[0055]

[0056] Where: X, L, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (V).

[0057] In a preferred embodiment of the present invention, the compound represented by the general formula (VI) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VI-A) or (VI-B) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0058]

[0059] Where: X, L, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r are as described in the general formula (VI).

[0060] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0061] R 2 is selected from 5-membered heteroaryl; wherein the 5-membered heteroaryl is optionally further substituted by one or more substituents selected from alkyl or halogen; preferably, R 2 is selected from triazolyl or tetrazolyl; wherein the triazolyl is optionally further substituted by halogen; wherein the halogen is preferably Cl.

[0062] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0063] L is -(CR a R b )s-, where s is 1, 2, 3 or 4;

[0064] R a and R b are each independently selected from a hydrogen atom or an alkyl group;

[0065] R L Selected from hydrogen atom, alkyl, alkoxy, aryl or heteroaryl, wherein the alkoxy, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy.

[0066] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0067] L is selected from -CH 2 -or-CH 2 CH 2 -;

[0068] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0069] R 5 The same or different, each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a halogen, a cyano group or a cycloalkyl group, preferably a hydrogen atom, a methyl group, a fluorine group, a chlorine group, a difluoromethyl group or a trifluoromethyl group.

[0070] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

[0071] R 6 and R 7 The same or different, each independently selected from C1-4 Alkyl or 4-6 membered cycloalkyl, wherein the C 1-4 The alkyl group is preferably a methyl group or an ethyl group.

[0072] In a preferred embodiment of the present invention, the compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt is a compound represented by general formula (VII) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

[0073]

[0074] in:

[0075] Ring B is selected from 5-6 membered heterocyclyl, 5-6 membered aryl, 5-6 membered heteroaryl;

[0076] Ring C is selected from phenyl, 5- to 10-membered heteroaryl or 8- to 10-membered fused ring;

[0077] Q is selected from a single bond or -C(O)-NH-;

[0078] L is -(CR a R b )s-;

[0079] R a and R b are each independently selected from a hydrogen atom or an alkyl group;

[0080] R 1 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group or a haloalkyl group;

[0081] R 2 Selected from 5-membered heteroaryl or -C(O)R 8 ; wherein the 5-membered heteroaryl group is optionally further substituted by one or more substituents selected from alkyl or halogen;

[0082] R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or =O;

[0083] R 5 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group or a cycloalkyl group;

[0084] R 6 and R 7 The same or different, each independently selected from C 1-4 alkyl;

[0085] R L , R 8Selected from hydrogen atom, alkyl, alkoxy, aryl or heteroaryl, wherein the alkoxy, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy.

[0086] m is selected from 1 or 2;

[0087] n is selected from 1 or 2;

[0088] r is selected from 0, 1 or 2;

[0089] s is selected from 1, 2, 3 or 4.

[0090] Typical compounds of the present invention include, but are not limited to:

[0091]

[0092]

[0093]

[0094]

[0095] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0096] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0097] In another aspect, the present invention provides a pharmaceutical composition comprising an effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0098] In another aspect, the present invention provides a method for inhibiting coagulation factor XIa protease, wherein the method comprises administering to a patient a pharmaceutical composition comprising an effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0099] On the other hand, the present invention provides a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or its pharmaceutical composition (including the pharmaceutical composition provided by the present invention, the same below) for use in the preparation of a coagulation factor XIa inhibitor, or a dual inhibitor of coagulation factor XIa and plasma kallikrein.

[0100] Another aspect of the present invention relates to a method for preventing and / or treating diseases mediated by coagulation factor XIa, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof.

[0101] 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 represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same.

[0102] Another aspect of the present invention relates to an anti-blood coagulation method, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable salts thereof or prodrugs thereof or pharmaceutical compositions containing the same.

[0103] Another aspect of the present invention relates to a method for preventing and / or treating thromboembolic diseases, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, its pharmaceutically acceptable salts or prodrugs or pharmaceutical compositions comprising the same. Another aspect of the present invention relates to the use of a compound of formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical compositions in the preparation of a medicament for treating or preventing a disease mediated by coagulation factor XIa.

[0104] In the present invention, the disease mediated by coagulation factor XIa is preferably a cardiovascular and cerebrovascular disease;

[0105] The cardiovascular and cerebrovascular diseases are preferably blood coagulation disorders or thromboembolic diseases; wherein the thromboembolic diseases are selected from arterial cardiovascular thromboembolic diseases, venous cardiovascular thromboembolic diseases, arterial cerebrovascular thromboembolic diseases, venous cerebrovascular thromboembolic diseases and ventricular or peripheral circulation thromboembolic diseases; 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 artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis caused by the following: medical implants, devices or surgeries that come into contact with blood and can promote thrombosis, etc., artificial blood contacts; wherein the venous thrombosis is preferably deep vein thrombosis.

[0106] Another aspect of the present invention relates to a drug for inhibiting coagulation factor XIa, which includes a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.

[0107] On the other hand, the present invention provides a compound represented by the general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof for use in the preparation of an anti-blood coagulation drug.

[0108] In another aspect, the present invention provides a compound represented by the general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing thromboembolic diseases.

[0109] In the present invention, the thromboembolic disease is selected from arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, arterial cerebrovascular thromboembolic disease, venous cerebrovascular thromboembolic disease and ventricular or peripheral circulation thromboembolic disease;

[0110] The thromboembolic disease is 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 caused by the following: medical implants, devices or surgeries that come into contact with blood and promote thrombosis. The venous thrombosis is preferably deep vein thrombosis. The pharmaceutical preparation of the present invention can be administered topically, orally, percutaneously, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcutaneously or by inhalation. The pharmaceutical composition containing the active ingredient may 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 preparing tablets in admixture.

[0111] The formulations of the present invention are suitable for being present in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can vary depending on the host to be treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that can produce a therapeutic effect.

[0112] Dosage forms for topical or transdermal administration of the compounds of the invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier under sterile conditions, and it may be mixed with any preservatives, buffers or propellants that may be required.

[0113] When the compounds of the present invention are administered to humans and animals in the form of medicines, the compounds can be provided alone or in the form of a pharmaceutical composition containing an active ingredient combined with a pharmaceutically acceptable carrier, for example 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

[0114] 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 carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (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) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution solution); (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrins, such as targeting ligands attached to nanoparticles, such as AccurinsTM; and (22) other non-toxic compatible substances used in drug formulations, such as polymer-based compositions.

[0115] 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 chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any 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 Such as glycerol; (4) disintegrating agents, 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 glyceryl 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, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0116] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum oxide hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0117] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0118] In addition to the active compound, powders and sprays may 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 conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0119] Detailed description of the invention

[0120] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0121] "Alkyl" as a group or part of a group refers to a group comprising C 1 -C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 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. Alkyl groups may be substituted or unsubstituted.

[0122] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl, etc. Alkenyl can be optionally substituted or unsubstituted.

[0123] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight chain or branched. 2 -C 10 Alkynyl, more preferably C 2 -C 6 Alkynyl, most preferably C 2 -C 4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. Alkynyl groups can be substituted or unsubstituted.

[0124] "Alkylene" is a divalent alkyl group. Preferably, C 1 -C10 Alkylene, more preferably C 1 -C 6 Alkylene, particularly preferably C 1 -C 4 Examples of alkylene groups include, but are not limited to, methylene, ethylene, -C(CH 3 ) 2 -, n-propylene, etc. The alkylene group may be substituted or unsubstituted.

[0125] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl may be optionally substituted or unsubstituted.

[0126] "Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. 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.

[0127] "Fused cycloalkyl" refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring 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 a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused 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.

[0128] "Bridged cycloalkyl" refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6-12 members, more preferably 7-10 members. Preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" 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.

[0129] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring is a heteroatom, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged and spirocyclic rings. Preferably, it has a 5-7-membered monocyclic ring or a 7-10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" 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 heterocyclyl group may be substituted or unsubstituted.

[0130] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, containing one or more double bonds in the ring, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral cycloalkyl is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan single spiral heterocyclic group. Non-limiting examples of "spiro heterocyclic 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.

[0131] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. 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.

[0132] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein 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. 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 groups" 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.

[0133] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be fused together. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C 6 -C 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. Aryl may be substituted or unsubstituted.

[0134] "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. Examples of "heteroaryl" include, but are not limited to, furanyl, 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,

[0135]

[0136] A heteroaryl group can be substituted or unsubstituted.

[0137] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, one or more rings may contain one or more double bonds, but at least one ring has a completely conjugated π-electron aromatic system, and at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, one or more selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl. Preferably, it is 7 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include, but are not limited to:

[0138]

[0139]

[0140] The fused rings may be substituted or unsubstituted.

[0141] "Alkoxy" refers to a group of (alkyl-O-) wherein alkyl is as defined herein. 1 -C 6 Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0142] "Haloalkyl" refers to an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.

[0143] "Hydroxyalkyl" refers to an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0144] "Haloalkoxy" refers to an alkyl group (alkyl-O-) optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.

[0145] "Hydroxy" refers to an -OH group.

[0146] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0147] "Amino" refers to -NH 2 .

[0148] "Cyano" refers to -CN.

[0149] "Nitro" refers to -NO 2 .

[0150] "Benzyl" refers to -CH 2 -phenyl.

[0151] "Carboxy" refers to -C(O)OH.

[0152] "Carboxylate" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0153] "DMSO" refers to dimethyl sulfoxide.

[0154] "BOC" refers to tert-butoxycarbonyl.

[0155] "Ts" refers to p-toluenesulfonyl.

[0156] "T3P" refers to propylphosphonic anhydride.

[0157] "DPPA" refers to diphenylphosphoryl azide.

[0158] "DEA" refers to diethylamine.

[0159] "THF" refers to tetrahydrofuran.

[0160] "OMS" means methylenesulfonyloxy.

[0161] "TMS" refers to trimethylsilane.

[0162] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0163] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, carboxyl, carboxylate, =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 substituted by a substituent.

[0164] R 8 is selected from hydrogen atom, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, =O, -C(O)R 11 、-OC(O)R 11 、-NR 12 R 13 、-C(O)NR 12 R 13 、-SO 2 NR 12 R 13 or -NR 12 C(O)R 13 substituted by a substituent.

[0165] R 9 and R 10 are the same or different and 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, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are optionally further substituted by one or more 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 、-SO 2 NR 12 R13 or -NR 12 C(O)R 13 wherein R 9 and R 10 It can form a 4-10 membered heterocyclic ring, which can be further replaced by one or more R 11 replace.

[0166] R 11 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.

[0167] 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.

[0168] R 12 and R 13 the same or different, 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, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, 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 carboxylate group.

[0169] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0170] Unless otherwise indicated, structures depicted herein also encompass all isomeric (e.g., diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.

[0171] "Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) can be metal salts or amine salts formed with suitable acids.

[0172] "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 a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0173] Synthesis method of the compound of the present invention

[0174] In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme:

[0175] The method for preparing the compound represented by the general formula (VI) of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof comprises the following steps:

[0176]

[0177] The compound represented by the general formula (VIa) is hydrolyzed to obtain the compound represented by the general formula (VIb); the compound represented by the general formula (VIb) is subjected to a condensation reaction with the compound represented by the general formula (VIc) to obtain the compound represented by the general formula (VI);

[0178] in:

[0179] R c Selected from alkyl;

[0180] X, L, R 1 ~R 3 , R 5 ~R 8 , m, n and r are as defined in the general formula (VI). DETAILED DESCRIPTION

[0181] The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0182] Example

[0183] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0184] The mass spectrum is obtained by LC / MS, and the ionization method can be ESI or APCI.

[0185] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0186] Column chromatography used Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0187] In the following examples, unless otherwise specified, all temperatures are degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, commercial manufacturers include but are not limited to Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Haohong Biotechnology Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., San Chemical Technology Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd.

[0188] CD 3 OD: deuterated methanol.

[0189] CDCl 3 : Deuterated chloroform.

[0190] DMSO-d 6 : Deuterated dimethyl sulfoxide.

[0191] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0192] The compound is purified using an eluent system for column chromatography and thin layer chromatography, wherein 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, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added.

[0193] Room temperature: 20℃~30℃.

[0194] Example 1

[0195] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphonyl)phenyl)-3-phenylpropanamide

[0196]

[0197] first step

[0198] 4-(5-Chloro-2-nitrophenyl)-2,5-dimethoxypyridine

[0199] 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]palladium dichloride (7.74 g, 10.57 mmol) and potassium carbonate (87.68 g, 634.38 mmol) were added to 1,4-dioxane (500 mL) in sequence, nitrogen was introduced for protection, the temperature was raised to 90°C, and the reaction was stirred for 3 hours. After the reaction, ethyl acetate (100 mL) was added, and the insoluble matter was filtered off with diatomaceous earth. The reaction solution 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 obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 4-(5-chloro-2-nitrophenyl)-2,5-dimethoxypyridine 1c (50.0 g), with a yield of 80%. MS m / z (ESI): 295.0 [M+1] +

[0200] Step 2

[0201] 4-(5-Chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one

[0202] 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 added to N,N-dimethylformamide (200 mL) in sequence, heated to 100°C and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into 2L ice water, stirred to precipitate solid, filtered, and dried to obtain 4-(5-chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one 1d (40.0 g), with a yield of 84%.

[0203] MS m / z(ESI):281.0[M+1] +

[0204] Step 3

[0205] 2-(4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid methyl ester

[0206] 4-(5-chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one 1d (10 g, 35.63 mmol), methyl 2-(methylsulfonyloxy)-3-phenylpropanoate 1e (13.8 g, 53.44 mmol, synthesized according to Tetrahedron Letters 2013, 54(13), 1730) and potassium carbonate (14.77 g, 106.89 mmol) were added to 1,4-dioxane (200 mL) in sequence, the temperature was raised to 90°C, and the reaction was stirred for 3 hours. After the reaction, 300 mL of ethyl acetate was added, 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 was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-3-phenylpropanoate 1f (8.5 g), with a yield of 54%.

[0207] MS m / z(ESI):443.1[M+1] +

[0208] Step 4

[0209] 2-(4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid methyl ester

[0210] 2-(4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionic acid methyl ester 1f (3g, 6.76mmol), iron powder (1.89g, 33.79mmol) and ammonium chloride (181mg, 3.38mmol) were dissolved in 24mL of a mixed solvent (ethanol: water = 5:1), heated to 80°C and stirred for 2 hours. After the reaction was completed, the iron powder was removed by filtration with diatomaceous earth, and then the ethanol was removed by concentration under reduced pressure. 100mL of ethyl acetate was added to extract the reaction solution, washed with a saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain 2-(4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropionic acid methyl ester 1g (2.6g), with a yield of 93%.

[0211] MS m / z(ESI):413.1[M+1] +

[0212] Step 5

[0213] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid methyl ester

[0214] 1 g (2.60 g, 6.30 mmol) of methyl 2-(4-(2-amino-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate, trimethyl orthoformate (2.00 g, 18.89 mmol) and trimethylsilyl azide (1.45 g, 12.59 mmol) were added to acetic acid (20 mL) in sequence and stirred at room temperature for 12 hours. After the reaction, ethyl acetate (100 mL) was added to the reaction solution for extraction. The organic phase was washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate 1h (2.5 g). Yield: 85%. MS m / z (ESI): 466.1 [M+1] +

[0215] Step 6

[0216] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid

[0217] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid methyl ester 1h (2.5 g, 5.37 mmol) and lithium hydroxide monohydrate (643 mg, 26.83 mmol) were dissolved in 24 mL of a mixed solution (ethanol: water = 5:1), and stirred at room temperature for 1 hour. After the reaction, the pH value was adjusted to 2-3 with 1M dilute hydrochloric acid, and the methanol was removed by concentration under reduced pressure. The residual liquid was dissolved with 100 mL of ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (2.3 g), with a yield of 95%.

[0218] MS m / z(ESI):452.1[M+1] +

[0219] Step 7

[0220] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphonyl)phenyl)-3-phenylpropanamide

[0221] The raw materials 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-3-phenylpropanoic acid 1i (100 mg, 221.31 μmol), (4-(dimethylamino)phenyl)dimethylphosphine oxide 1j (37.4 mg, 221.31 μmol, synthesized according to patent WO 2014033446) and propylphosphonic anhydride (140.8 mg, 442.61 μmol) were dissolved in ethyl acetate (20 mL), and then N,N-diisopropylethylamine (85.7 mg, 663.92 μmol) was added and reacted at room temperature for 1 hour. After the reaction is completed, ethyl acetate is added to dilute, the mixture is washed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 1 (20 mg), yield: 15%.

[0222] MS m / z(ESI):603.2[M+1] +

[0223] 1H NMR (400MHz, DMSO-d 6 )δ10.77(s,1H),9.58(s,1H),7.68-7.81(m,7H),7.28-7.34(m,3H),7.15-7.23(m,3H) ,6.41(s,1H),5.90-5.99(m,1H),3.41-3.51(m,2H),3.28(s,3H),1.63(s,J=13.2,6H).

[0224] Example 2

[0225] 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0226]

[0227] first step

[0228] 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0229] 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 2a (503.5 mg, 1.18 mmol, synthesized according to the first step on page 66 of patent WO2018041122), (4-(dimethylamino)phenyl)dimethylphosphine oxide 1j and propylphosphonic anhydride (1.13 g, 3.55 mmol) were dissolved in ethyl acetate (50 mL), and then N,N-diisopropylethylamine (457.5 mg, 3.55 mmol) was added and reacted at room temperature for 1 hour. After the reaction is completed, ethyl acetate is added to dilute, the mixture is washed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(2-acetyl-5-chlorophenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 2 (500 mg), yield: 70.3%.

[0230] MS m / z(ESI):577.2[M+1] +

[0231] 1 H NMR (400 MHz, DMSO-d 6 )δ10.78(s,1H),7.70-7.85(m,5H),7.60(dd,J=8.0,2.0Hz,1H),7.43(s,1H),7.37(s,1H),7.24-7.32(m,4H),7.16 -7.22(m,1H),6.31(s,1H),6.00-6.06(m,1H),3.54(s,3H),3.41-3.51(m,2H),2.38(s,3H),1.62(d,J=13.2Hz,6H).

[0232] Example 3

[0233] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0234]

[0235]

[0236] first step

[0237] 1-Dimethylphosphoryl-3-nitrobenzene

[0238] 1-iodo-3-nitrobenzene 3a (5.00 g, 20.08 mmol), dimethylphosphine oxide (2.35 g, 30.12 mmol), cesium carbonate (13.08 g, 40.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.16 g, 2.01 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (1.49 g, 2.01 mmol) were added to 1,4-dioxane (80 mL) in sequence, nitrogen was introduced, the temperature was raised to 90°C and stirred, and the reaction was continued for 3 hours. After the reaction was completed, the insoluble matter was removed by diatomaceous earth filtration, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-dimethylphosphino-3-nitrobenzene 3b (1.1 g), with a yield of 28%.

[0239] MS m / z(ESI):200.1[M+1] +

[0240] Step 2

[0241] 3-(Dimethylphosphoryl)aniline

[0242] 1-Dimethylphosphoryl-3-nitrobenzene 3b (1.1 g, 5.2 mmol) and palladium on carbon (110 mg) were added to methanol (20 mL) in sequence, and the air was replaced with hydrogen three times. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the insoluble matter was removed by filtration through diatomaceous earth, and the reaction solution was concentrated under reduced pressure to obtain 3-(dimethylphosphoryl)aniline 3c (810 mg) with a yield of 87%.

[0243] MS m / z(ESI):170.1[M+1] +

[0244] Step 3

[0245] 1-Azido-2-bromo-4-chlorobenzene

[0246] 2-Bromo-4-chloroaniline 3d (29 g, 140.46 mmol) and isoamyl nitrite (33.19 g, 280.92 mmol) were added to acetonitrile (300 mL) in sequence, cooled in an ice bath, and trimethylsilyl azido (32.36 g, 280.92 mmol) was slowly added, and the temperature was slowly raised to room temperature and reacted for 3 hours. After the reaction was completed, 300 mL of ethyl acetate was added, and the reaction solution was washed with a saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain 1-azido-2-bromo-4-chlorobenzene 3e (30 g), with a yield of 91%.

[0247] MS m / z(ESI):231.9[M+1] +

[0248] Step 4

[0249] 1-(2-Bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole

[0250] 1-Azido-2-bromo-4-chlorobenzene 3e (15 g, 64.25 mmol) and trimethylethynylsilane (25.24 g, 256.99 mmol) were dissolved in toluene (200 mL), heated to 110°C, and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added to the reaction solution for extraction, the organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(2-bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 3f (16 g) with a yield of 75%.

[0251] MS m / z(ESI):329.9[M+1] +

[0252] Step 5

[0253] 1-(2-Bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazole

[0254] 1-(2-bromo-4-chlorophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 3f (15 g, 45.36 mmol), N-chlorosuccinimide (36.34 g, 272.16 mmol) and potassium fluoride (15.81 g, 272.16 mmol) were dissolved in acetonitrile (200 mL), heated to 90°C, and reacted for 24 hours. After the reaction was completed, it was concentrated under reduced pressure, ethyl acetate (200 mL) was added to the reaction solution for extraction, the organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(2-bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazole 3g (11 g), with a yield of 83%.

[0255] MS m / z(ESI):291.9[M+1] +

[0256] Step 6

[0257] 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dimethoxypyridine

[0258] 1-(2-bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazole 3g (2g, 6.83mmol), 2,5-dimethoxypyridin-4-ylboronic acid 1b (2.50g, 13.65mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (998.13mg, 1.37mmol), and cesium carbonate (6.68g, 20.48mmol) were added to 1,4-dioxane (20mL) in sequence, protected by nitrogen, heated to 100°C, and reacted for 2 hours. After the reaction, 100 mL of ethyl acetate was added, and the insoluble matter was filtered out through diatomaceous earth. 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 was purified by silica gel column chromatography (eluent: System A) to obtain 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dimethoxypyridine 3h (2.0 g), with a yield of 83%.

[0259] MS m / z(ESI):351.0[M+1] +

[0260] Step 7

[0261] 4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one

[0262] 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dimethoxypyridine 3h (4.1 g, 11.67 mmol) and pyridine hydrobromide (11.21 g, 70.05 mmol) were added to N,N-dimethylformamide (40 mL) in sequence, heated to 100°C, and reacted for 6 hours. After the reaction was completed, ethyl acetate (200 mL) was added to the reaction solution for extraction, and the organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 3i (3.5 g) with a yield of 89%.

[0263] MS m / z(ESI):337.0[M+1] +

[0264] Step 8

[0265] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid methyl ester

[0266] 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 3i (3.5 g, 10.38 mmol), methyl 2-(methylsulfonyloxy)-3-phenylpropanoate 1e (5.36 g, 20.76 mmol) and potassium carbonate (4.30 g, 31.14 mmol) were added to 1,4-dioxane (50 mL) in sequence, heated to 100 ° C, and reacted for 4 hours. After the reaction was completed, ethyl acetate (100 mL) was added to the reaction solution for extraction. The organic phase 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 was purified by silica gel column chromatography (eluent: System A) to obtain methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-3-phenylpropanoate 3j (3.1 g) in a yield of 60%.

[0267] MS m / z(ESI):499.1[M+1] +

[0268] Step 9

[0269] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid

[0270] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate 3j (800 mg, 1.6 mmol) and lithium hydroxide monohydrate (336 mg, 9.0 mmol) were dissolved in 6 mL of a mixed solution (methanol: water = 5:1) and reacted at room temperature for 1 hour. After the reaction, the pH value was adjusted to 2-3 with 1 M dilute hydrochloric acid, methanol was removed under reduced pressure, the residual liquid was dissolved with 50 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 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-3-phenylpropanoic acid 3k (600 mg), with a yield of 77%.

[0271] MS m / z(ESI):485.1[M+1] +

[0272] Step 10

[0273] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0274] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (100 mg, 0.21 mmol), 3-(dimethylphosphoryl)aniline 3c (52 mg, 0.31 mmol) and N,N-diisopropylethylamine (80 mg, 0.62 mmol) were dissolved in ethyl acetate (10 mL), and then propylphosphonic anhydride (65 mg, 0.21 mmol) was added and reacted at room temperature for 1 hour. After the reaction is completed, ethyl acetate is added to dilute, the mixture is washed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(3-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 3 (82 mg), yield: 62%.

[0275] MS m / z(ESI):636.1[M+1] +

[0276] 1 H NMR (400 MHz, DMSO-d 6 )δ10.72(s,1H),8.58(s,1H),8.03(d,J=12.6Hz,1H),7.70-7.85(m,3H),7.62-7.66(m,1H),7.43-7.51(m,2H),7.26-7 .34(m,3H),7.17-7.23(m,3H),6.35(s,1H),5.89-6.00(m,1H),3.39-3.51(m,2H),3.31(s,3H),1.64(d,J=13.3Hz,6H).

[0277] Example 4

[0278] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0279]

[0280] first step

[0281] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0282] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (300 mg, 618.15 μmol), (4-(dimethylamino)phenyl)dimethylphosphine oxide 1j (125.5 mg, 741.78 μmol) and propylphosphonic anhydride (393.4 mg, 1.24 mmol) were dissolved in ethyl acetate (30 mL), and then N,N-diisopropylethylamine (239.2 mg, 1.85 mmol) was added and reacted at room temperature for 1 hour. After the reaction is completed, ethyl acetate is added to dilute, the mixture is washed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 4 (100 mg), yield: 25.4%.

[0283] MS m / z(ESI):636.2[M+1] +

[0284] 1 H NMR (400 MHz, DMSO-d 6 )δ10.73(s,1H),8.58(s,1H),7.69-7.81(m,6H),7.64(d,J=2.0Hz,1H),7.26-7.36(m,3H),7.16-7 .24(m,3H),6.36(s,1H),5.90-6.00(m,1H),3.37-3.51(m,2H),3.31(s,3H),1.62(s,J=13.6,6H).

[0285] Example 5

[0286] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0287]

[0288]

[0289] first step

[0290] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0291] 2-(4-(5-chloro-2-(41H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 1i (100 mg, 0.22 mmol), 3-(dimethylphosphoryl)aniline 3c (56 mg, 0.33 mmol) and N,N-diisopropylethylamine (86 mg, 0.66 mmol) were dissolved in ethyl acetate (10 mL), and then propylphosphonic anhydride (70 mg, 0.22 mmol) was added and reacted at room temperature for 1 hour. After the reaction, ethyl acetate was added to dilute the mixture, and the mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(3-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 5 (90 mg) with a yield of 67%.

[0292] MS m / z(ESI):603.2[M+1] +

[0293] 1 H NMR (400 MHz, DMSO-d 6 )δ10.71(s,1H),9.56(s,1H),8.02(d,J=12.4Hz,1H),7.79-7.84(m,3H),7.68(s,1H),7.45-7.51(m,2H),7.28-7.33 (m,3H),7.14-7.23(m,3H),6.40(s,1H),5.87-5.97(m,1H),3.38-3.45(m,2H),3.27(s,3H),1.64(d,J=13.3Hz,6H).

[0294] Example 6

[0295] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-4-methoxybutyramide

[0296]

[0297] first step

[0298] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutyric acid methyl ester

[0299] 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one 3i (0.50 g, 1.65 mmol), methyl 2-bromo-4-methoxybutyrate 6a (0.52 mg, 2.47 mmol, synthesized according to patent CN107793396) and cesium carbonate (1.61 g, 4.94 mmol) were dissolved in 1,4-dioxane (10 mL), heated to 100 ° C, and reacted for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the reaction solution for extraction. The organic phase was washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanoic acid methyl ester 6b (0.41 g) with a yield of 58.8%.

[0300] MS m / z(ESI):467.1[M+1] +

[0301] Step 2

[0302] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxy

[0303] Butyric acid

[0304] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyr-1(2H)-yl)-4-methoxybutanoate 6b (0.41 g, 0.9 mmol) and lithium hydroxide monohydrate (0.40 g, 9.5 mmol) were dissolved in 6 mL of a mixed solution (methanol: water = 5:1) and reacted at room temperature for 1 hour. After the reaction, the pH value was adjusted to 2-3 with 1M dilute hydrochloric acid, and the mixture was concentrated under reduced pressure. The residual liquid was dissolved with 50 mL of ethyl acetate, and the organic layer was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered. The reaction solution was concentrated under reduced pressure to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl))-4-methoxybutanoic acid 6c (0.30 g) with a yield of 75.6%.

[0305] MS m / z(ESI):453.1[M+1] +

[0306] Step 3

[0307] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-4-methoxybutyramide

[0308] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanoic acid 6c (0.2 g, 0.44 mmol), (4-(dimethylamino)phenyl)dimethylphosphine oxide 1j (0.09 g, 0.53 mmol) and N,N-diisopropylethylamine (0.17 g, 1.32 mmol) were dissolved in ethyl acetate (10 mL), and then propylphosphonic anhydride (0.42 g, 1.32 mmol) was added and reacted at room temperature for 1 hour. After the reaction is completed, ethyl acetate is added to dilute, the mixture is washed with saturated brine, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-4-methoxybutyramide 6 (82 mg), yield: 31.9%.

[0309] MS m / z(ESI):604.1[M+1] +

[0310] 1 H NMR (400 MHz, DMSO-d 6 )δ10.58(s,1H),8.64(s,1H),7.66-7.82(m,7H),7.20(s,1H),6.46(s,1H),5.67(s,1H),3 .28-3.32(m,4H),3.20(s,3H),3.11-3.17(m,1H),2.28-2.37(m,2H),1.61(d,J=13.3,6H).

[0311] Example 7

[0312] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0313]

[0314] first step

[0315] 1-(4-Chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole

[0316] 4-Chloro-2-nitroaniline 7a (5 g, 28.97 mmol) was dissolved in acetonitrile (300 mL), and stirred under ice bath for 20 minutes. Isoamyl nitrite (5.09 g, 43.46 mmol, 5.84 mL) and trimethylsilyl azido (5.01 g, 43.46 mmol, 5.72 mL) were added in sequence. After stirring under ice bath for 20 minutes, the ice bath was removed. After reacting at room temperature for 2 hours, cuprous oxide (4.15 g, 28.97 mmol) and trimethylethynylsilane (8.54 g, 86.92 mmol, 12.28 mL) were added in sequence. The reaction was continued at room temperature with stirring for 4 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 1-(4-chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 7b (5 g) with a yield of 58%.

[0317] MS m / z(ESI):297.0[M+1] +

[0318] Step 2

[0319] 4-Chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole

[0320] 1-(4-chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 7b (5 g, 16.85 mmol) was dissolved in acetonitrile (93 mL), silica gel (20.87 g, 16.85 mmol) was added, and the mixture was stirred at room temperature for 10 minutes, and N-chlorosuccinimide (11.25 g, 84.24 mmol) was added, and the mixture was reacted at 80°C for 1 hour. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole 7c (1.65 g), with a yield of 38%.

[0321] MS m / z(ESI):259.0[M+1] +

[0322] Step 3

[0323] 5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline

[0324] 4-Chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole 7c (1.75 g, 6.76 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (5 mL), and ammonium chloride (722.72 mg, 13.51 mmol) and iron powder (3.77 g, 67.55 mmol) were added, and the mixture was reacted at 80°C overnight. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline 7d (1.3 g), with a yield of 84%. MS m / z (ESI): 228.9 [M+1] +

[0325] Step 4

[0326] 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide

[0327] Dissolve 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline 7d (1.3 g, 5.68 mmol) in dichloromethane (20 mL), add triethylamine (3.45 g, 34.05 mmol, 4.73 mL), slowly add 2-chloroacetyl chloride (769.17 mg, 6.81 mmol, 541.67 μL) dropwise at 0°C, react at 0°C for 1 hour, add 30 mL of water, The reaction was quenched, the layers were separated, the aqueous phase was extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 7e (1 g), yield: 58%.

[0328] MS m / z(ESI):304.8[M+1] +

[0329] Step 5

[0330] (2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl ester

[0331] 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 7e (1 g, 3.27 mmol) and L-phenylalanine tert-butyl ester hydrochloride 7f (1.09 g, 4.91 mmol) were dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (2.11 g, 16.36 mmol, 2.70 mL) was added and reacted at 80°C for 8 hours. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL×3) and a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain 7 g (1.3 g) of (2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl ester, with a yield of 81%.

[0332] MS m / z(ESI):489.9[M+1] +

[0333] Step 6

[0334] N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl ester

[0335] Dissolve 7 g (1.3 g, 2.65 mmol) of (2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl ester in dichloromethane (25 mL), add triethylamine (1.61 g, 15.91 mmol, 2.21 mL), slowly add 2-chloroacetyl chloride (359.29 mg, 3.18 mmol, 253.02 μL) dropwise at 0°C, and react at 0°C for 1 hour. 30 mL of water was added to quench the reaction, and the liquids were separated. The aqueous phase was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl ester 7h (1.1 g), yield: 73%.

[0336] MS m / z(ESI):509.8[M+1-56] +

[0337] Step 7

[0338] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate

[0339] N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl ester 7h (1.1 g, 1.94 mmol) was dissolved in methanol (15 mL), and sodium methoxide solution (5.4 M, 395.29 μL) was slowly added dropwise at 0°C, and the mixture was reacted at 0°C for 1 hour. After the reaction, the pH was adjusted to about 6 with 2N dilute hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate 7i (916 mg), with a yield of 89%.

[0340] MS m / z(ESI):529.8[M+1] +

[0341] Step 8

[0342] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid

[0343] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate 7i (916 mg, 1.73 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (196.91 mg, 1.73 mmol, 3 mL) was slowly added dropwise, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 7j (764 mg), with a yield of 93%.

[0344] MS m / z(ESI):473.8[M+1] +

[0345] Step 9

[0346] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0347] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 7j (100 mg, 210.84 μmol) and (4-(dimethylamino)phenyl)dimethylphosphine oxide 1j (53.50 mg, 316.26 μmol) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (81.75 mg, 632.52 μmol) and propylphosphonic anhydride (402.51 mg, 632.52 μmol, 50% ethyl acetate solution) were added, and the mixture was heated at 60°C for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 7 (25 mg) with a yield of 19%.

[0348] MS m / z(ESI):624.8[M+1] +

[0349] 1 H NMR (400 MHz, DMSO-d 6 )δ10.42(s,1H),8.63(s,1H),7.63-7.88(m,7H),7.16-7.39(m,5H),5.36(s,1H),3 .85-4.44(m,4H),3.19-3.32(m,1H),3.02-3.16(m,1H),1.64(s,3H),1.60(s,3H).

[0350] Example 8

[0351] 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-1-(1-(6-(dimethylphosphoryl)-1H-benzo[d]imidazol-2-yl)-2-

[0352] (phenethyl)-5-methoxypyridin-2(1H)-one

[0353]

[0354]

[0355] first step

[0356] (4-Amino-3-nitrophenyl)dimethylphosphine oxide

[0357] 4-iodo-2-nitroaniline 8a (5 g, 18.94 mmol), dimethylphosphine oxide (1.48 g, 18.94 mmol), cesium carbonate (6.17 g, 18.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (14.05 g, 18.94 mmol) were added to 1,4-dioxane (100 mL) in sequence, and the mixture was heated to 100°C and stirred for 3 hours under nitrogen protection. The insoluble matter was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to obtain (4-amino-3-nitrophenyl) dimethylphosphine oxide 8b (2.5 g) with a yield of 62%.

[0358] MS m / z(ESI):215.1[M+1] +

[0359] Step 2

[0360] (3,4-Diaminophenyl)dimethylphosphine oxide

[0361] (4-amino-3-nitrophenyl) dimethylphosphine oxide 8b (2.5 g, 11.67 mmol) was dissolved in ethanol (3 mL), and raw iron powder (3.285 g, 58.35 mmol) and ammonium chloride (312.11 mg, 5.84 mmol) were added, and the temperature was raised to 80°C and stirred for 1 hour. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to obtain (3,4-diaminophenyl) dimethylphosphine oxide 8c (2 g) with a yield of 93%.

[0362] MS m / z(ESI):185.1[M+1] +

[0363] Step 3

[0364] N-(2-amino-4-(dimethylphosphoryl)phenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-

[0365] Oxypyrimidin-1(2H)-yl)-3-phenylpropanamide

[0366] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (100 mg, 206.05 μmol) and (3,4-diaminophenyl)dimethylphosphine oxide 8c (56.92 mg, 309.08 μmol) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (79.74 mg, 618.15 μmol) and propylphosphonic anhydride (196.68 mg, 618.15 μmol, 50% ethyl acetate solution) were added in sequence, and the reaction was carried out at room temperature for 16 hours. After the reaction was complete, ethyl acetate (10 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with water (50 mL×3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product N-(2-amino-4-(dimethylphosphoryl)phenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyrimidin-1(2H)-yl)-3-phenylpropanamide 8d, which was directly used for the next step without purification.

[0367] MS m / z(ESI):651.0[M+1] +

[0368] Step 4

[0369] 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-1-(1-(6-(dimethylphosphoryl)-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one

[0370] N-(2-amino-4-(dimethylphosphoryl)phenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyrimidin-1(2H)-yl)-3-phenylpropanamide 8d (100 mg, 153.50 μmol) was dissolved in acetic acid (30 mL), heated to 100 °C and reacted for 1 hour. After the reaction was complete, ethyl acetate (10 mL) and water (10 mL) were added, and then extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with water (50 mL×3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-1-(1-(6-(dimethylphosphoryl)-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-5-methoxypyridin-2(1H)-one 8 (30 mg), yield: 31%

[0371] MS m / z(ESI):633.1[M+1] +

[0372] 1 H NMR (400 MHz, DMSO-d 6 )δ12.89(d,J=12.6Hz,1H),8.59(s,1H),7.82-8.11(m,1H),7.48-7.72(m,5H),7.24-7.36(m,3H),7.13-7.24(m ,3H),6.48(brs,1H),6.40(s,1H),3.78-3.65(m,1H),3.52-3.64(m,1H),2.50(s,3H),1.68(s,3H),1.65(s,3H).

[0373] Example 9

[0374] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)-3-fluorophenyl)-3-phenylpropanamide

[0375]

[0376] first step

[0377] (4-Amino-2-fluorophenyl)dimethylphosphine oxide

[0378] 3-Fluoro-4-iodoaniline 9a (1 g, 4.22 mmol), dimethylphosphine oxide (658.61 mg, 8.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (308.42 mg, 421.92 μmol), cesium carbonate (4.13 g, 12.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (222.77 mg, 421.92 μmol) were added to N,N-dimethylformamide (20 mL) in sequence, and the temperature was raised to 120°C under nitrogen protection, and the reaction was stirred for 3 hours. After concentration under reduced pressure, ethyl acetate (100 mL) was added to dilute and filtered through celite. The filtrate was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and filtered. The residue was further separated and purified by silica gel column chromatography (eluent: system B) to give (4-amino-2-fluorophenyl)dimethylphosphine oxide 9b (50 mg) in a yield of 6%.

[0379] MS m / z(ESI):188.1[M+1] +

[0380] Step 2

[0381] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)-3-fluorophenyl)-3-phenylpropanamide

[0382] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (50 mg, 103.03 μmol) and (4-amino-2-fluorophenyl)dimethylphosphine oxide 9b (23.14 mg, 123.63 μmol) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (39.87 mg, 309.08 μmol) and propylphosphonic anhydride (131.12 mg, 206.05 μmol, 50% ethyl acetate solution) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)-3-fluorophenyl)-3-phenylpropanamide 9 (35 mg) with a yield of 52%.

[0383] MS m / z(ESI):654.2[M+1] +

[0384] 1 H NMR (400MHz, CD 3 OD)δ8.22(s,1H),7.66-7.80(m,3H),7.63(d,J=8.5Hz,1H),7.55(d,J=2.2Hz,1H),7.43(d,J=8.4Hz,1H),7.16-7.3 4(m,7H),6.48(s,1H),5.87(brs,1H),3.49-3.58(m,1H),3.34-3.43(m,1H),3.38(s,3H),1.83(s,3H),1.80(s,3H).

[0385] Example 10

[0386] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)-3-methylphenyl)-3-phenylpropanamide

[0387]

[0388] first step

[0389] (4-Amino-2-methylphenyl)dimethylphosphine oxide

[0390] 4-iodo-3-methylaniline 10a (5 g, 21.45 mmol), dimethylphosphine oxide (2.51 g, 32.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.57 g, 2.15 mmol), cesium carbonate (20.98 g, 64.36 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.24 g, 2.15 mmol) were added to N,N-dimethylformamide (30 mL) in sequence, and the temperature was raised to 120°C under nitrogen protection, and the reaction was stirred for 3 hours. After concentration under reduced pressure, ethyl acetate (100 mL) was added to dilute and filtered through celite. The filtrate was washed with saturated sodium chloride solution (60 mL×2), dried over anhydrous sodium sulfate, and filtered. The residue was further separated and purified by silica gel column chromatography (eluent: system B) to give (4-amino-2-methylphenyl)dimethylphosphine oxide 10b (400 mg) in a yield of 10%.

[0391] MS m / z(ESI):184.1[M+1] +

[0392] Step 2

[0393] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)-3-methylphenyl)-3-phenylpropanamide

[0394] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (100 mg, 206.05) and (4-amino-2-methylphenyl)dimethylphosphine oxide 10b (45.29 mg, 247.26 μmol) were dissolved in ethyl acetate (50 mL), and N,N-diisopropylethylamine (79.74 mg, 618.15 μmol) and propylphosphonic anhydride (262.24 mg, 412.10 μmol, 50% ethyl acetate solution) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to obtain 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)-3-methylphenyl)-3-phenylpropanamide 10 (80 mg) with a yield of 60%.

[0395] MS m / z(ESI):650.2[M+1] +

[0396] 1 H NMR (400MHz, CD 3 OD)δ8.22(s,1H),7.48-7.74(m,6H),7.13-7.39(m,7H),6.47(s,1H),5.91(brs,1H),3. 46-3.58(m,1H),3.34-3.43(m,1H),3.38(s,3H),2.62(s,3H),1.85(s,3H),1.81(s,3H).

[0397] Examples 11 and 12

[0398] (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphinoyl)

[0399] (R)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)

[0400] Phenyl)-3-phenylpropanamide

[0401]

[0402] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 1 (0.7 g, 1.16 mmol) was chirally separated by HPLC (column model: Superchiral S-IG (Chiralway), 250×21 mm ID, 5 μm; mobile phase: ACN / MeOH / DEA=50 / 50 / 0.05 (v / v); flow rate: 20 mL / min; detection wavelength: 254 nm; column temperature: 35 °C) after purification, (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 11 was obtained (retention time (T R ): 3.454mim, 0.2583g) and (R)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxy-2-oxopyridine

[0403] -1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 12 (retention time (T R ):4.900min, 0.2618g).

[0404] 11MS m / z(ESI):603.2[M+1] +

[0405] 11 1 H NMR (400 MHz, DMSO-d 6 )δ9.57(s,1H),7.80(s,2H),7.66-7.78(m,5H),7.11-7.40(m,7H),6.41(s,1H) ,5.89-5.99(m,1H),3.38-3.49(m,2H),3.27(s,3H),1.64(s,3H),1.60(s,3H).

[0406] 12MS m / z(ESI):603.2[M+1] +

[0407] 12 1 H NMR (400 MHz, DMSO-d 6)δ9.57(s,1H),7.83(s,2H),7.66-7.77(m,5H),7.10-7.37(m,7H),6.40(s,1H) ,5.88-5.99(m,1H),3.38-3.46(m,2H),3.27(s,3H),1.64(s,3H),1.60(s,3H).

[0408] Examples 13 and 14

[0409] (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0410] (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0411]

[0412] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 4 (1.57 g, 2.467 mmol) was chirally separated by HPLC (column model: Superchiral S-IG (Chiralway), 250×21 mm ID, 5 μm; mobile phase: ACN / MeOH / DEA=50 / 50 / 0.05 (v / v); flow rate: 20 mL / min; detection wavelength: 254 nm; column temperature: 35 °C) after purification, (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 13 was obtained (retention time (T R ): 3.447 min, 0.7812 g) and (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 14 (retention time (T R ):5.676min, 0.8247g).

[0413] 13MS m / z(ESI):636.2[M+1]+

[0414] 13 1 H NMR (400 MHz, DMSO-d 6 )δ8.58(s,1H),7.67-7.80(m,6H),7.61-7.66(m,1H),7.25-7.36(m,4H),7.15-7.24(m,3H),6.36 (s,1H),5.95(dd,J=10.7,5.3Hz,1H),3.39-3.50(m,2H),3.31(s,3H),1.64(s,3H),1.60(s,3H).

[0415] 14MS m / z(ESI):636.2[M+1] +

[0416] 14 1 H NMR (400 MHz, DMSO-d 6 )δ8.58(s,1H),7.67-7.80(m,6H),7.62-7.66(m,1H),7.25-7.35(m,4H),7.15-7.24(m,3H),6.36 (s,1H),5.95(dd,J=10.7,5.3Hz,1H),3.39-3.51(m,2H),3.31(s,3H),1.64(s,3H),1.60(s,3H).

[0417] Embodiment 15

[0418] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(dimethylphosphoryl)-4-fluorophenyl)-3-phenylpropanamide

[0419]

[0420] first step

[0421] (5-Amino-2-fluorophenyl)dimethylphosphine oxide

[0422] 3-Bromo-4-fluoroaniline 15a (5 g, 26.31 mmol), dimethylphosphine oxide (4.11 g, 52.63 mmol), palladium acetate (590.78 mg, 2.63 mmol), potassium phosphate (11.17 g, 52.63 mmol) were added to N,N-dimethylformamide (20 mL) in sequence, and the temperature was raised to 100°C under nitrogen protection, and the reaction was stirred for 2 hours. After concentration under reduced pressure, ethyl acetate (100 mL) was added for dilution, and the filtrate was washed with saturated sodium chloride solution (30 mL × 2) after filtration through diatomaceous earth, and the filtrate was further separated and purified by silica gel column chromatography (eluent: B system) to obtain (5-amino-2-fluorophenyl) dimethylphosphine oxide 15b (1.2 g), with a yield of 24%.

[0423] MS m / z(ESI):188.2[M+1] +

[0424] Step 2

[0425] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(dimethylphosphoryl)-4-fluorophenyl)-3-phenylpropanamide

[0426] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (200 mg, 412.10 μmol) and (5-amino-2-fluorophenyl)dimethylphosphine oxide 15b (115.69 mg, 618.15 μmol) were dissolved in ethyl acetate (50 mL), and N,N-diisopropylethylamine (159.48 mg, 1.24 μmol) and propylphosphonic anhydride (262.24 mg, 412.10 μmol, 50% ethyl acetate solution) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(3-(dimethylphosphoryl)-4-fluorophenyl)-3-phenylpropanamide 15 (82 mg) with a yield of 30%.

[0427] MS m / z(ESI):654.2[M+1] +

[0428] 1 H NMR (400 MHz, DMSO-d 6)δ10.75(s,1H),8.58(s,1H),8.02(ddd,J=13.0,5.8,2.8Hz,1H),7.87-7.95(m,1H),7.69-7.82(m,2H),7.64(d,J=2.2Hz,1H),7.41- 7.53(m,1H),7.13-7.36(m,6H),6.35(s,1H),5.89(dd,J=10.1,5.7Hz,1H),3.38-3.48(m,2H),3.30(s,3H),1.72(s,3H),1.68(s,3H).

[0429] Example 16

[0430] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(diethylphosphoryl)phenyl)-3-phenylpropanamide

[0431]

[0432] first step

[0433] (4-Nitrophenyl)diethylphosphine oxide

[0434] 1-Iodo-4-nitrobenzene 16a (2 g, 8.03 mmol), diethylphosphine oxide (1.28 g, 12.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (464.74 mg, 803.20 μmol), cesium carbonate (5.23 g, 16.06 mmol) and tris(dibenzylideneacetone)dipalladium (464.74 mg, 803.20) were added to 1,4-dioxane (30 mL) in sequence. Under nitrogen protection, the temperature was raised to 100 °C and the reaction was stirred for 3 hours. After concentration under reduced pressure, ethyl acetate (100 mL) was added to dilute, and after filtration through celite, the filtrate was washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The residue was further separated and purified by silica gel column chromatography (eluent: B system) to obtain (4-nitrophenyl) diethylphosphine oxide 16b (1.2 g), with a yield of 66%. MS m / z (ESI): 228.1 [M+1] +

[0435] Step 2

[0436] (4-Aminophenyl)diethylphosphine oxide

[0437] (4-nitrophenyl) diethylphosphine oxide 16b (1.2 g, 5.28 mmol) was dissolved in ethanol (20 mL) and water (4 mL), iron powder (1.47 g, 26.41 mmol) and ammonium chloride (310.67 mg, 5.84 mmol) were added, and the temperature was raised to 80°C and stirred for 1 hour. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to obtain (4-aminophenyl) diethylphosphine oxide 16c (2 g) with a yield of 93%.

[0438] MS m / z(ESI):198.0[M+1] +

[0439] Step 3

[0440] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(4-(diethylphosphoryl)phenyl)-3-phenylpropanamide

[0441] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (100 mg, 206.05 μmol) and (4-aminophenyl)diethylphosphine oxide 16c (60.95 mg, 309.08 μmol) were dissolved in ethyl acetate (50 mL), and N,N-diisopropylethylamine (79.74 mg, 618.15 μmol) and propylphosphonic anhydride (262.24 mg, 412.10 μmol, 50% ethyl acetate solution) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(4-(diethylphosphoryl)phenyl)-3-phenylpropanamide 16 (100 mg) with a yield of 73%.

[0442] MS m / z(ESI):664.2[M+1] +

[0443] 1 H NMR (400 MHz, DMSO-d 6)δ10.72(s,1H),8.58(s,1H),7.54-7.88(m,7H),7.10-7.41(m,6H),6.36(s,1H),5.94(dd, J=10.4,5.4Hz,1H),3.36-3.49(m,2H),3.31(s,3H),1.76-2.01(m,4H),0.86-0.99(m,6H).

[0444] Embodiment 17

[0445] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0446]

[0447] first step

[0448] 1-Bromo-2-(difluoromethyl)-4-nitrobenzene

[0449] 2-Bromo-5-nitrobenzaldehyde 17a (5 g, 21.74 mmol) was dissolved in dichloromethane (50 mL), cooled in an ice bath, and diethylaminosulfur trifluoride (5.25 g, 32.6 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was washed with saturated sodium bicarbonate water (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The residue was further separated and purified by silica gel column chromatography (eluent: A system) to obtain 1-bromo-2-(difluoromethyl)-4-nitrobenzene 17b (3.7 g), with a yield of 68%.

[0450] Step 2

[0451] (2-(Difluoromethyl)-4-nitrophenyl)dimethylphosphine oxide

[0452] 1-Bromo-2-(difluoromethyl)-4-nitrobenzene 17b (1 g, 3.97 mmol), dimethylphosphine oxide (464.56 mg, 5.95 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (229.60 mg, 396.81 μmol), cesium carbonate (2.59 g, 7.94 mmol) and tris(dibenzylideneacetone)dipalladium (181.68 mg, 198.40 μmol) were added to 1,4-dioxane (30 mL) in sequence. Under nitrogen protection, the temperature was raised to 100 °C and the reaction was stirred for 3 hours. After concentration under reduced pressure, ethyl acetate (100 mL) was added to dilute the mixture. After diatomaceous earth filtration, the filtrate was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered. The residue was further separated and purified by silica gel column chromatography (eluent: System B) to obtain (2-(difluoromethyl)-4-nitrophenyl)dimethylphosphine oxide 17c (600 mg). Yield: 61%.

[0453] MS m / z(ESI):250.0[M+1] +

[0454] Step 3

[0455] (4-Amino-2-(difluoromethyl)phenyl)dimethylphosphine oxide

[0456] (2-(Difluoromethyl)-4-nitrophenyl)dimethylphosphine oxide 17c (500 mg, 2.01 mmol) was dissolved in ethanol (20 mL) and water (4 mL), iron powder (560.40 mg, 10.03 mmol) and ammonium chloride (129.02 mg, 2.412 mmol) were added, the temperature was raised to 90°C, and the reaction was continued for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain (4-amino-2-(difluoromethyl)phenyl)dimethylphosphine oxide 17d (400 mg), yield: 91%. MS m / z (ESI): 220.1 [M+1] +

[0457] Step 4

[0458] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide

[0459] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-3-phenylpropanoic acid 3k (100 mg, 206.05 μmol) and (4-amino-2-(difluoromethyl)phenyl)dimethylphosphine oxide 17d (67.74 mg, 309.08 μmol) were dissolved in ethyl acetate (50 mL), and N,N-diisopropylethylamine (79.74 mg, 618.15 μmol) and propylphosphonic anhydride (262.24 mg, 412.10 μmol, 50% ethyl acetate solution) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(3-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)-3-phenylpropanamide 17 (100 mg) with a yield of 71%.

[0460] MS m / z(ESI):686.1[M+1] +

[0461] 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),8.57(s,1H),8.14(s,1H),8.02(t,J=55.4Hz,1H),7.83-7.90(m,1H),7.69-7.80(m,3H),7.64(s,1H),7.25 -7.37(m,3H),7.15-7.25(m,3H),6.37(s,1H),5.85-5.94(m,1H),3.38-3.51(m,2H),3.30(s,3H),1.75(s,3H),1.72(s,3H).

[0462] Embodiment 18

[0463] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)-4-methoxybutyramide

[0464]

[0465]

[0466] first step

[0467] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-N-(3-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)-4-methoxybutyramide

[0468] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridin-1(2H)-yl)-4-methoxybutanoic acid 6c (150 mg, 330.92 μmol) and (4-amino-2-(difluoromethyl)phenyl)dimethylphosphine oxide 17d (108.79 mg, 496.39 μmol) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (128.07 mg, 992.77 μmol) and propylphosphonic anhydride (635.90 mg, 992.77 μmol, 50% ethyl acetate solution) were added, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methoxy-2-oxopyridine-1(2H)-yl)-N-(3-(difluoromethyl)-4-(dimethylphosphoryl)phenyl)-4-methoxybutyramide 18 (50 mg) with a yield of 22%.

[0469] MS m / z(ESI):654.2[M+1] +

[0470] 1 H NMR (400 MHz, DMSO-d 6 )δ10.73(brs,1H),8.62(s,1H),8.16(s,1H),8.01(t,J=55.4Hz,1H),7.82-7.89(m,1H),7.66-7.82(m,4H),7.19(s,1H),6.46(s, 1H),5.62(brs,1H),3.34-3.39(m,1H),3.32(s,3H),3.20(s,3H),3.10-3.16(m,1H),2.30-2.40(m,2H),1.75(s,3H),1.71(s,3H).

[0471] Biological evaluation

[0472] Test Example 1: Determination of the Factor XIa protease activity of the compounds of the present invention

[0473] The following method is used to determine the degree of inhibition of the compound of the present invention on the activity of Native human Factor XIa protease under in vitro conditions. This method uses the colorimetric substrate of Factor XIa to test the inhibition of Factor XIa protease activity. Native human Factor XIa protein was purchased from Abcam (Cat. No. ab62411), and S-2366 was purchased from Chromogenix (Cat. No. 82109039).

[0474] The experimental process 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 diluted 4-fold using 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 to 0.61 nM. The reaction was carried out in a 384-well microplate. First, 2 μL of the test compound diluted with reaction buffer at different concentrations was added to the wells, and 2 μL of 1% DMSO (the final concentration of DMSO in the reaction system was 0.1%) was used instead in the blank and control wells; then 8 μL of enzyme working solution (the final concentration of Factor XIa was 1.25 μg / uL) was added to each well, and 8 μL of Factor XIa reaction buffer was used instead in the blank wells, centrifuged for 30 seconds, and incubated on ice for 5 minutes; finally, 10 μL of 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 started. The absorbance at 405 nm was measured after incubation at 37°C for 10 minutes, and the percentage inhibition rate of the compound at each concentration was calculated by comparing it with the light absorption value of the control group (0.1% DMSO), and the nonlinear regression analysis of the compound concentration logarithm-inhibition rate was performed by GraphPad Prism 5 software to obtain the IC of the compound. 50 Values ​​are shown in Table 1.

[0475] Table 1 IC of the compounds of the present invention against Factor XIa protease activity 50 data

[0476]

[0477]

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

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

[0480] The following method is used to determine the in vitro anticoagulant effect of the compound of the present invention in human plasma. This method uses the APTT and PT kits of MediRox. The APTT kit was purchased from MediRox (article number MRX930), and human plasma was prepared in-house.

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

[0482] The APTT test process is briefly described as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then the test compound is diluted 3 times with DMSO. The final concentration range of the test compound in the reaction system is 217μM~0.03μM. Take 4μL of the test compound diluted with DMSO at different concentrations and add it to a centrifuge tube containing 180μL plasma. Add 4μL DMSO to the blank group, shake and mix, and incubate at 37℃ for 5min. Then put the APTT reagent in the reagent bracket according to the instrument requirements, take the incubated plasma sample, put it into the detection position of the coagulation analyzer, measure the coagulation time, and record the coagulation time (s). With the final concentration of the compound as the horizontal axis and Ratio (Ratio=Ti / T0, T0 is the coagulation time of the blank control, Ti is the coagulation time of the test compound) as the vertical axis, use Graph Pad Prism5 to draw the coagulation dose-effect curve, and calculate the compound concentration when the coagulation time is extended by 2 times, that is, the CT2 value, as shown in Table 2.

[0483] Table 2 CT2 data of the in vitro anticoagulant effect of the compounds of the present invention on human plasma

[0484]

[0485]

[0486] It can be seen from Table 2 that the compounds of the present invention have good in vitro anticoagulant effect in human plasma.

[0487] Test Example 3 Permeability Test

[0488] The Caco-2 monolayer cell model was used to determine the bidirectional permeability and efflux rate of the test compounds. 5Caco-2 cells (transmission no more than 50 generations) at a concentration of 10 μM were inoculated into 24-well cell culture plates and cultured for 19-21 days for transport experiments. The corresponding test compounds were administered bidirectionally without verapamil (P-glycoprotein (P-gP) inhibitor) at a concentration of 10 μM. After incubation at 37°C and 300 rpm for 90 minutes, samples from the top and base were collected, and the integrity of the Caco-2 monolayer cells was detected by measuring sodium fluorescein and transepithelial electrical resistance (TEER); the standard curve of the configured samples was determined by liquid chromatography tandem mass spectrometry (LC / MS / MS) to detect the content of each test compound in the sample. The permeability data of the compounds of the present invention are shown in Table 3.

[0489] Table 3 Permeability data of compounds of the present invention

[0490]

[0491] Conclusion: The compounds of the present invention are highly permeable compounds with no significant efflux.

Claims

1. A compound represented by general formula (VI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: L is C1-C 10 Alkylene, wherein the C1-C 10 The alkylene group is optionally further substituted with one or more substituents selected from halogen or hydroxy; R L Selected from C1-C6 alkoxy or phenyl; X is selected from C; R 1 is selected from halogen; R 2 is selected from 5-membered heteroaryl, wherein the heteroaryl is optionally further substituted with one or more halogens; R 3 are the same or different, and are independently selected from a hydrogen atom, a C1-C6 alkoxy group; R 5 the same or different, each independently selected from a hydrogen atom, a C1-C 10 Alkyl, halogen, wherein the C1-C 10 The alkyl group is optionally further substituted with one or more halogens; R 6 and R 7 Selected from C1-C 10 alkyl; m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; r is selected from 0, 1 or 2.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof represented by general formula (VI-A) or (VI-B): in: X, L, R 1 ~R 3 , R L , R 5 ~R 7 , m, n and r as described in claim 1.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from triazolyl or tetrazolyl; wherein the triazolyl is optionally further substituted by halogen.

4. The compound according to claim 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the halogen is Cl.

5. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: L is -(CRaRb)s-, where s is 1,2; R a and R b selected from hydrogen atoms; R L Selected from methoxy or phenyl.

6. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 5 is a hydrogen atom, a methyl group, a fluorine group, a chlorine group, a difluoromethyl group or a trifluoromethyl group.

7. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 and R 7 are the same or different and are each independently selected from methyl or ethyl.

8. The compound according to any one of claims 1 to 7, or its stereoisomer, or its pharmaceutically acceptable salt, wherein the compound is:

9. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 8 or its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

10. Use of the compound according to any one of claims 1 to 8 or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a coagulation factor XIa inhibitor or a dual inhibitor of coagulation factor XIa and plasma kallikrein.

11. Use of the compound according to any one of claims 1 to 8 or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating or preventing a disease mediated by coagulation factor XIa.

12. The use according to claim 11, wherein the disease mediated by coagulation factor XIa is cardiovascular and cerebrovascular disease.

13. The use according to claim 12, wherein the cardiovascular and cerebrovascular diseases are selected from blood coagulation disorders or thromboembolic diseases.

14. The use according to claim 13, wherein the thromboembolic disease is selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders or thromboembolic disorders of the ventricular or peripheral circulation.

15. The use according to claim 13, wherein the thromboembolic disease is selected from the group consisting of 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 caused by medical implants, devices or surgical contacts with blood that can promote thrombosis.

16. The use according to claim 15, wherein the venous thrombosis is deep vein thrombosis.

17. Use of the compound according to any one of claims 1 to 8, or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of an anti-blood coagulation drug.

18. Use of the compound according to any one of claims 1 to 8, or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating or preventing thromboembolic diseases.

19. The use according to claim 18, 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.

20. The use according to claim 19, wherein the thromboembolic disease is selected from the group consisting of 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 caused by medical implants, devices or surgical contact with blood that can promote thrombosis.

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

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