Piperazine derivatives, process for their preparation and their use

Abstract

The present invention relates to piperazine derivatives, their preparation methods, and their use in medicine. In particular, the present invention relates to piperazine derivatives represented by general formula (I), their preparation methods, and pharmaceutically acceptable salts or prodrugs thereof, as well as their use as therapeutic agents, particularly as inhibitors of blood coagulation factor XIa (FXIa), wherein the definitions of each substituent in general formula (I) are the same as those in the present specification. [Formula 1] JPEG2023541309000178.jpg37169

Description

Detailed Description of the Invention

[0001] 〔Technical Field〕 The present invention relates to piperazine derivatives, methods for producing them, pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, particularly as inhibitors of coagulation factor XIa (FXIa).

[0002] 〔Background〕 Common cardiovascular diseases such as stroke, thrombosis, and myocardial infarction have become the leading causes of death worldwide. In the global death statistics in 2017, deaths due to cardiovascular diseases accounted for approximately 32% of the total global deaths. The pathological processes of these diseases are often closely related to thrombosis, or the onset of stroke or heart disease caused by slow blood flow. Therefore, anticoagulants are widely used in the treatment of such diseases. Currently, traditional anticoagulants include vitamin K antagonists, fibrinolytic agents, heparin, antiplatelet aggregation, and other drugs. However, due to limitations such as poor compliance, a large coefficient of variation among individuals, a narrow therapeutic range, and other factors of such drugs, in recent years, non-vitamin K antagonist oral anticoagulants have been continuously developed and marketed, mainly including antagonists that directly inhibit thrombin and antagonists that act on coagulation factors. Currently, the safety and efficacy of commercially available non-vitamin K antagonist oral anticoagulants have been significantly improved, but they have bleeding side effects. To overcome this problem, it is very important to develop drugs with a low bleeding risk. Research at home and abroad has proven that FXIa inhibitors are promising drugs for treating cardiovascular and cerebrovascular diseases, especially thromboembolic diseases, and have also provided a new direction for overcoming bleeding side effects. Thromboembolic diseases include arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism. Thromboembolic diseases further include unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or procedures in which artificial surfaces that can promote thrombosis come into contact with blood. On the other hand, venous thrombosis further includes deep vein thrombosis.

[0003] FXI is a serine protease with a molecular weight of approximately 80 kD and is composed of two subunits linked by disulfide bonds, with 607 amino acids present on each polypeptide chain. Each subunit contains a heavy chain region and a light chain region. The heavy chain has four AP structural domains A1 - A4, where A1 binds to thrombin; A2 binds to high molecular weight kininogen; A3 binds to coagulation factor IX and heparin; A4 binds to activated coagulation factor XII. Thus, the four AP domains are the sites where FXI interacts with other protein kinases or factors. FXIa is the active state of FXI and plays an active role in intrinsic coagulation. At the initiation of coagulation, coagulation factor XII is activated to form XIIa, and XIIa activates the activity of FXI to form FXIa, as a result, a series of cascade reactions are triggered to promote coagulation. Therefore, the inhibition of FXIa is an effective method for preventing thrombosis or slow blood flow.

[0004] Plasma prekallikrein is a liver-derived precursor of the trypsin-like serine protease plasma kallikrein and circulates in plasma bound to high molecular weight kininogen. Plasma prekallikrein is activated by activated coagulation factor XII or prolidase to form plasma kallikrein. Plasma kallikrein regulates the activities of several 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 in the clinical development of FXIa inhibitors both at home and abroad. BMS-986177, an FXIa inhibitor developed by BMS, has entered Phase II clinical trials and is used for the prevention and treatment of major thrombosis and other diseases. Initial clinical studies have shown that FXIa inhibitors can delay thrombosis and at the same time greatly reduce the risk of bleeding. At present, a series of patent applications for FXIa inhibitors, including WO2017151746A1, WO2017151018A1, WO2018039094A1, etc., have been published. Although the research and application of FXIa inhibitors have made some progress, there is still much room for improvement. Therefore, it is still necessary to continue researching and developing new FXIa inhibitors.

[0006] 〔Summary〕 The present invention aims to provide a piperazine derivative of general formula (I), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug.

[0007]

Chemical formula

[0008] In the formula: X is selected from C=O or CR 7 and preferably, X is selected from C=O; G is selected from a bond or -C(O)-NH-; preferably, G is selected from -C(O)-NH-; Ring A is selected from aryl or heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or a fused ring; wherein, the heteroaryl is preferably a 5- to 10-membered heteroaryl; R 1 are the same or different and each independently is a hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 9or -NR 10 R 11 is selected from; R 2 is halogen, cyano, alkoxy, heteroaryl or -C(O)R 9 is selected from; wherein said alkoxy or said heteroaryl is alkyl, haloalkyl, nitro, cyano, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 9 , -C(O)R 9 , -C(O)OR 9 , -NHC(O)R 9 , -NHC(O)OR 9 , -NR 10 R 11 or -C(O)NR 10 R 11 and is optionally further substituted by one or more substituents selected from; R 3 is selected from a hydrogen atom, halogen or alkyl; wherein said alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or alkoxy; R 3 is preferably a hydrogen atom; R 4 is selected from a hydrogen atom, deuterium atom, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -OR 9 ; wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or R 6 ; R 5 are the same or different and each independently is a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 9 , -C(O)R 9 , -C(O)OR 9 , -NHC(O)R 9 , -NHC(O)OR 9 , -NR 10 R 11, -C(O)NR 10 R 11 , -CH2NHC(O)OR 9 , -CH2NR 10 R 11 , -S(O) r R 9 or -S(O) r NR 10 R 11 selected from, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is a deuterium atom, halogen, nitro, cyano, hydroxyl, =O, -OR 9 , -C(O)R 9 , -C(O)OR 9 , -NHC(O)R 9 , -NHC(O)OR 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -CH2NHC(O)OR 9 , -CH2NR 10 R 11 or -S(O) r R 9 optionally further substituted by one or more substituents selected from; alternatively, two Rs 5 together with the same carbon atom to which they are attached form C=O; R 6 is selected from a deuterium atom, halogen, alkyl, alkoxy, amino, nitro, cyano, hydroxyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, said alkoxy, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is optionally further substituted by one or more R A substituents; R A is a deuterium atom, halogen, alkyl, hydroxyl, alkoxy, amino, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl or -NR 13 C(O)R 14selected from, wherein said alkyl, said alkoxy, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is optionally further substituted by one or more substituents selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano; R 7 is a hydrogen atom, halogen or -OR B selected from, preferably a hydrogen atom; R B is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is optionally further substituted by one or more substituents selected from deuterium atom, halogen, alkyl, haloalkyl, hydroxyl, alkoxy or haloalkoxy; R 8 is selected from a hydrogen atom, halogen or alkyl; wherein said alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or alkoxy; R 8 is preferably a hydrogen atom; R 9 is selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-OC(O)OR 12 、-NR 13 R 14 、-C(O)NR 13 R 14 、-SO2NR 13 R 14 or -NR 13 C(O)R 14optionally further substituted by one or more substituents selected from; R 10 and R 11 are each independently selected from a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, where said alkyl, said alkoxy, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl are hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 -C(O)OR 12 -OC(O)R 12 -NR 13 R 14 -C(O)NR 13 R 14 -SO2NR 13 R 14 or -NR 13 C(O)R 14 optionally further substituted by one or more substituents selected from; or, R 10 and R 11 together with the linked N atom form a 4- to 8-membered heterocyclyl, where said 4- to 8-membered heterocyclyl contains one or more N, O or S(O) r within, and said 4- to 8-membered heterocyclyl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 -C(O)OR 12 -OC(O)R 12 -NR 13 R 14 -C(O)NR 13 R 14 -SO2NR 13 R 14 or -NR 13 C(O)R 14 optionally further substituted by one or more substituents selected from; R 12 R 13and R 14 is independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; r is 0, 1 or 2.

[0009] The present invention provides a compound represented by general formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, which are a compound represented by general formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof.

[0010]

Chemical formula

[0011] Wherein: L is selected from a bond or alkylene, wherein the alkylene is optionally further substituted by one or more substituents selected from deuterium atom, halogen or hydroxyl; Ring B, X, R 1 ~R 3 、R 5 、R 6 、R 8 、m and n are as defined in general formula (I).

[0012] The present invention provides a compound represented by general formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, which is a compound represented by general formula (III), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof.

[0013]

Chemical formula

[0014] In the formula: Ring B, X, L, R 1 ~R 3 、R 5 、R 6 、R 8 、m and n are as defined in general formula (II).

[0015] The present invention provides a compound represented by general formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, which is a compound represented by general formula (IV), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof.

[0016]

Chemical formula

[0017] In the formula: Ring B, X, L, R 1 ~R 3 、R 5 、R 6 、R 8 、m and n are as defined in general formula (II).

[0018] In a preferred solution of the present invention, in the compound represented by general formula (I), (II), (III) or (IV), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug, ring B is selected from 3- to 6-membered cycloalkyl, 4- to 8-membered heterocyclyl, phenyl, 5- to 10-membered heteroaryl or 8- to 10-membered fused ring; here, the 3- to 6-membered cycloalkyl is preferably cyclohexyl; the 4- to 8-membered heterocyclyl is preferably tetrahydropyranyl or piperidinyl.

[0019] In a preferred embodiment of the present invention, in the compound represented by general formula (I), (II), (III) or (IV), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug,

[0020]

Chemical formula

[0021] is

[0022]

Chemical formula

[0023] selected from where R 5 and m are as defined in general formula (I).

[0024] In a preferred embodiment of the present invention, in the compound represented by general formula (I), (II), (III) or (IV), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug,

[0025]

Chemical formula

[0026] is

[0027] [Chemical formula]

[0028] selected from

[0029] In a preferred embodiment of the present invention, the compound represented by the general formula (II), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug is the compound represented by the general formula (V), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug.

[0030] [Chemical formula]

[0031] wherein: L, R 1 ~R 3 R 5 R 6 R 8 and n are as defined in the general formula (II).

[0032] In a preferred embodiment of the present invention, the compound represented by the general formula (V), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug is the compound represented by the general formula (V-A) or (V-B), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug.

[0033] [Chemical formula]

[0034] wherein: L, R 1 ~R 3 R 5 R 6 R 8 and n are as defined in the general formula (V).

[0035] In a preferred embodiment of the present invention, the compound represented by the general formula (II), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug, is the compound represented by the general formula (VI), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug.

[0036]

Chemical formula

[0037] Wherein: Ring C is selected from 5- to 6-membered heteroaryl, 5- to 6-membered aryl, 4- to 8-membered heterocyclyl or 4- to 8-membered cycloalkyl; p is 0, 1 or 2; L, R 1 ~R 3 、R 5 、R 6 、R 8 and n are as defined in the general formula (II).

[0038] In a preferred embodiment of the present invention, the compound represented by the general formula (VI), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug, is the general formula (VI-A) or (VI-B), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug.

[0039]

Chemical formula

[0040] Wherein: Ring C, L, R 1 ~R 3 、R 5 、R 6 、R 8 、p and n are as defined in the general formula (VI).

[0041] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug, 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, haloalkyl, cyano 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.

[0042] In a preferred embodiment of the present invention, in the compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B), or its stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug: L is -(CR a R b )s-, where s is 1, 2, 3 or 4; R a and R b are each independently selected from a hydrogen atom, a deuterium atom or alkyl; R 6 is selected from alkyl, alkoxy, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocyclyl, phenyl or 5- to 10-membered heteroaryl, where the alkyl, the alkoxy, the 3- to 8-membered cycloalkyl, the 4- to 8-membered heterocyclyl, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more R A substituents; R Ais selected from a deuterium atom, halogen, alkyl, alkoxy, cyano, amino, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, the alkoxy, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more substituents selected from a deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano.

[0043] In a preferred embodiment of the present invention, in the compounds represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B), or their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs: L is selected from -CH2-, -CD2- or -CH2CH2-; R 6 is selected from alkyl, alkoxy, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocyclyl, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, the alkoxy, the 3- to 8-membered cycloalkyl, the 4- to 8-membered heterocyclyl, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more A R substituents; R A is selected from a deuterium atom, halogen, alkyl, alkoxy, cyano, amino, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, the alkoxy, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more substituents selected from a deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano.

[0044] In a preferred embodiment of the present invention, in the compounds represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B), or their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs: R 6is selected from alkyl, alkoxy, phenyl, pyridinyl, pyrazolyl, imidazolyl, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl, wherein the alkyl, the alkoxy, the phenyl, the pyridinyl, the pyrazolyl, the imidazolyl, the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclyl is optionally further substituted by one or more R A substituents; R A is selected from a deuterium atom, halogen, alkyl, alkoxy, cyano, amino, phenyl or 5- to 10-membered heteroaryl, wherein the alkyl, the alkoxy, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more substituents selected from a deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano.

[0045] In a preferred embodiment of the present invention, in the compounds represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A) or (VI-B), or their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs: R 5 are the same or different and each independently is a hydrogen atom, alkyl, haloalkyl, halogen, cyano, heterocyclyl, -OR 9 , -C(O)R 9 , -C(O)OR 9 , -NHC(O)R 9 , -NHC(O)OR 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -CH2NHC(O)OR 9 , -CH2NR 10 R 11 , -S(O) r R 9 or -S(O) r NR 10 R 11 selected from; or, two Rs5 forms a C=O with the same carbon atom to which they are attached; R 9 is selected from a hydrogen atom or C1-C4 alkyl, where said C1-C4 alkyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano or -OC(O)OR 12 ; R 10 and R 11 are each independently selected from a hydrogen atom, C1-C4 alkyl or 5-6 membered heterocyclyl, where said C1-C4 alkyl or said 5-6 membered heterocyclyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, C1-C4 alkoxy, nitro, cyano or =O.

[0046] In a preferred embodiment of the present invention, the compound represented by formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, is a compound represented by general formula (VII), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof.

[0047]

Chemical formula

[0048] In the formula: X is selected from C=O or CR 7 ; G is selected from a bond or -C(O)-NH-; Ring B is selected from 3-6 membered cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl or 8-10 membered fused ring; R 1 are the same or different and are each independently selected from a hydrogen atom, deuterium atom, halogen, alkyl or haloalkyl; R 2 is halogen, cyano, alkoxy, heteroaryl or -C(O)R 9selected from; wherein said alkoxy or said heteroaryl is optionally further substituted by one or more substituents selected from haloalkyl or halogen; R 3 is selected from a hydrogen atom; R 4 is selected from a hydrogen atom, a deuterium atom or alkyl, wherein said alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or R 6 ; R 5 are the same or different and each independently is a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, haloalkyl, aryl, heteroaryl, -OR 9 , -C(O)R 9 , -C(O)OR 9 , -NHC(O)R 9 , -NHC(O)OR 9 , -NR 10 R 11 , -C(O)NR 10 R 11 , -CH2NHC(O)OR 9 , -CH2NR 10 R 11 , -S(O)2R 9 or -S(O)2NR 10 R 11 , wherein said alkyl, said cycloalkyl, said heterocyclyl, said aryl or said heteroaryl is optionally further substituted by one or more substituents selected from deuterium atom, halogen or =O; or two R 5 form C=O together with the same carbon atom to which they are attached; R 6 is selected from alkyl, alkoxy, phenyl, pyridinyl, pyrazolyl, imidazolyl, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl, wherein said alkyl, said alkoxy, said phenyl, said pyridinyl, said pyrazolyl, said imidazolyl, said 3- to 6-membered cycloalkyl or said 4- to 6-membered heterocyclyl is one or more RA optionally further substituted by a substituent; R A is selected from a deuterium atom, a halogen, an alkyl, an alkoxy, a cyano, an amino, a phenyl or a 5- to 10-membered heteroaryl, wherein the alkyl, the alkoxy, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more substituents selected from a deuterium atom, a halogen, a hydroxyl, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy or a cyano; R 7 is selected from a hydrogen atom; R 8 is selected from a hydrogen atom or a C1-C4 alkyl; R 9 is selected from a hydrogen atom or a C1-C4 alkyl, wherein the C1-C4 alkyl is optionally further substituted by one or more substituents selected from a hydroxyl, a halogen, a nitro, a cyano or -OC(O)OR 12 ; R 10 and R 11 are each independently selected from a hydrogen atom, a C1-C4 alkyl or a 5- to 6-membered heterocyclyl, wherein the C1-C4 alkyl or the 5- to 6-membered heterocyclyl is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a C1-C4 alkoxy, a nitro, a cyano or =O; R 12 R 13 and R 14 are each independently selected from a hydrogen atom, an alkyl or a cycloalkyl; m is 0, 1 or 2; n is 0, 1 or 2.

[0049] Typical compounds of the present invention include, but are not limited to, the following.

[0050] [Table 1] JPEG0007700218000015.jpg254169 JPEG0007700218000016.jpg249169 JPEG0007700218000017.jpg229169 JPEG0007700218000018.jpg238169 JPEG0007700218000019.jpg238169 JPEG0007700218000020.jpg249169 JPEG0007700218000021.jpg238169 JPEG0007700218000022.jpg224169 JPEG0007700218000023.jpg254169 JPEG0007700218000024.jpg244169 JPEG0007700218000025.jpg254169 JPEG0007700218000026.jpg227169 JPEG0007700218000027.jpg254169 JPEG0007700218000028.jpg249169 JPEG0007700218000029.jpg249169 JPEG0007700218000030.jpg249169 JPEG0007700218000031.jpg254169 JPEG0007700218000032.jpg243169 JPEG0007700218000033.jpg166169

[0051] The present invention provides a method for producing a compound represented by the general formula (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof. The production method includes the following steps:

[0052]

Chemical formula

[0053] A step of subjecting the compound represented by the general formula (IIA) and the compound represented by the general formula (IIB) to a condensation reaction, and Optionally, further, a step of hydrolyzing the mixture under acidic conditions to obtain the compound represented by the general formula (II); comprising wherein: ring B, X, L, R 1 ~R 3 、R 5 、R 6 、R 8 、m and n are as defined in the general formula (II).

[0054] The present invention provides a compound represented by the general formula (IIA), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0055]

Chemical formula

[0056] wherein X, L, R 1 ~R 3 、R 6 、R 8 and n are as defined in the general formula (II).

[0057] Typical compounds of formula (IIA) include, but are not limited to, the following.

[0058]

Table 2

[0059] Note: If there is a difference between the illustrated structure and the name attached to the structure, the illustrated structure is given more weight.

[0060] 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), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0061] In another aspect, the present invention provides a method for inhibiting the protease of coagulation factor XIa, the method comprising administering to a patient a pharmaceutical composition comprising an effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0062] In another aspect, the present invention provides the use of a pharmaceutical composition thereof (including the pharmaceutical composition provided by the present invention, the same applies hereinafter) in the manufacture of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or an inhibitor of coagulation factor XIa, or a dual inhibitor of coagulation factor XIa and plasma kallikrein.

[0063] Another aspect of the present invention relates to a method for preventing and / or treating a disease mediated by coagulation factor XIa. The method comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition comprising the compound.

[0064] Here, the disease mediated by coagulation factor XIa is preferably a cardiovascular disease and a cerebrovascular disease.

[0065] The cardiovascular disease and the cerebrovascular disease are preferably selected from coagulation diseases or thromboembolic diseases.

[0066] The thromboembolic disease is preferably selected from arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism; the thromboembolic disease is more preferably unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic 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 a medical implant, device or surgery in which blood contacts an artificial surface that can promote thrombosis. Venous thrombosis is preferably deep venous thrombosis.

[0067] Another aspect of the present invention relates to a method for preventing and / or treating cardiovascular and cerebrovascular diseases. The method comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition comprising the compound.

[0068] Another aspect of the present invention relates to a method of anticoagulation. The method comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition comprising the compound.

[0069] Another aspect of the present invention relates to a method for preventing and / or treating thromboembolic diseases. The method comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition comprising the compound.

[0070] Thromboembolic diseases are preferably selected from arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism; the thromboembolic disease is more preferably unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic 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 surgeries in which blood contacts an artificial surface that can promote thrombosis. Venous thrombosis is preferably deep vein thrombosis.

[0071] Another aspect of the present invention relates to the use of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing a disease mediated by coagulation factor XIa. The disease mediated by coagulation factor XIa is preferably a cardiovascular disease and a cerebrovascular disease.

[0072] Here, the disease mediated by coagulation factor XIa is preferably a cardiovascular disease and a cerebrovascular disease.

[0073] Cardiovascular diseases and cerebrovascular diseases are preferably selected from coagulation diseases or thromboembolic diseases.

[0074] Thromboembolic diseases are preferably selected from arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism; the thromboembolic diseases are more preferably unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic 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 surgeries in which an artificial surface that can promote thrombosis comes into contact with blood. Venous thrombosis is preferably deep vein thrombosis.

[0075] Another aspect of the present invention relates to a pharmaceutical for inhibiting coagulation factor XIa. The pharmaceutical comprises a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a mesomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition containing the compound.

[0076] In another aspect, the present invention provides the use of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition thereof, in the manufacture of an anticoagulant.

[0077] In another aspect, the present invention provides the use of a compound represented by general formula (I), (II), (III), (IV), (V), (V-A), (V-B), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing a thromboembolic disease.

[0078] The thromboembolic disease is selected from arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism; the thromboembolic disease is preferably unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic 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 a medical implant, device or surgery in which an artificial surface that can promote thrombosis comes into contact with blood. Venous thrombosis is preferably deep vein thrombosis.

[0079] The pharmaceutical preparation of the present invention can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subepidermally or by inhalation. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, or syrups or elixirs. Tablets contain the active ingredient suitable for preparing tablets and non-toxic pharmaceutically acceptable excipients used for mixing.

[0080] The formulations of the present invention are suitable for being present in the form of unit measurements and can be manufactured by any method known in pharmaceutical technology. The amount of the active ingredient that can be combined with a carrier substance to produce a single dosage form can vary depending on the host being treated and the particular mode of administration. The amount of the active ingredient that can be combined with a carrier substance to produce a single dosage form generally refers to the amount of the compound that can exert a therapeutic effect.

[0081] Dosage forms for topical or transdermal administration of the compounds of the present invention can include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed with a pharmaceutically acceptable carrier under aseptic conditions and, optionally, with any preservatives, buffers, or propellants that may be required.

[0082] When the compounds of the present invention are administered to humans and animals in the form of pharmaceuticals, the compounds can be provided alone or in the form of a pharmaceutical composition, which contains an active ingredient combined with a pharmaceutically acceptable carrier, such as from 0.1% to 99.5% (more preferably from 0.5% to 90%) of the active ingredient.

[0083] Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diols 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; (19) ethanol; (20) phosphate buffer; (21) cyclodextrins such as targeted ligands conjugated to nanoparticles, such as AccurinsTM; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.

[0084] Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. Solid dosage forms (such as capsules, lozenges, pills, troches, powders, granules, etc.) may contain one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or may include: (1) fillers or extenders such as starch, lactose, sucrose, mannitol, and / or silicic acid; (2) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) wetting agents such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retardants such as paraffin wax; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, 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 solubilizing and emulsifying agents such as inert diluents commonly used in the art, for example, water or other solvents; and ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0085] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and tragacanth, and mixtures thereof.

[0086] In addition to the active compound, ointments, pastes, creams and gels may also contain excipients such as animal fats, vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0087] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of the above substances. Sprays may contain other commonly used propellants such as chlorofluorocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0088] 〔Detailed Description of the Invention〕 Unless otherwise specified, several terms used in the description and claims of the present invention are defined as follows.

[0089] "Bond" refers to the absence of a labeled substituent and the two terminal moieties of the substituent are directly joined to form a bond.

[0090] "Alkyl" means, when considered as a group or part of a group, C1 to C 20 It refers to an aliphatic hydrocarbon group having a straight or branched chain. Preferably, alkyl is C1-C 10 It is alkyl, more preferably, the alkyl is C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl may be substituted or unsubstituted.

[0091] "Alkenyl" refers to an alkyl, 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, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. Alkenyl may be optionally substituted or unsubstituted.

[0092] "Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be linear or branched. Preferably, alkynyl is a C2-C 10is alkynyl, more preferably, the alkynyl is C2-C6 alkynyl, and most preferably, the alkynyl is C2-C4 alkynyl. Embodiments of the alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl may or may not be substituted.

[0093] "Alkylene" is a divalent alkyl. Preferably, the alkylene is C1-C 10 is alkylene, more preferably, the alkylene is C1-C6 alkylene, and particularly preferably, the alkylene is C1-C4 alkylene. Embodiments of the alkylene group include, but are not limited to, methylene, ethylene, -CH(CH3)2-, n-propylidene, etc. The alkylene may or may not be substituted.

[0094] "Cycloalkyl" refers to a saturated or partially saturated carbon atom ring of a monocyclic ring, a fused ring, a bridged ring and a spirocyclic ring. Preferably, the cycloalkyl is C3-C 12 is cycloalkyl, more preferably, the cycloalkyl is C3-C8 cycloalkyl, and most preferably, the cycloalkyl is C3-C6 cycloalkyl. Embodiments of the monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. The cycloalkyl may or may not be optionally substituted.

[0095] "Spiroalkyl" refers to a 5- to 18-membered polycyclic group having two or more cyclic structures, where the monocycles share one carbon atom (referred to as a spiro atom) with each other, and the rings contain one or more double bonds but do not have a fully conjugated π-electron aromatic system. Preferably, the spiroalkyl is 6- to 14-membered, and more preferably, the spiroalkyl is 7- to 10-membered. Spirolalkyl is classified into mono-, di- or multi-spiroalkyl according to the number of shared carbon atoms between the rings, preferably mono- and di-spiroalkyl, preferably 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered. Non-limiting embodiments of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl and spiro[2.4]heptyl.

[0096] "Fused cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group having two or more cyclic structures that share a pair of carbon atoms, where one or more of the rings may contain one or more double bonds but do not have a fully conjugated π-electron aromatic system. Preferably, the fused cycloalkyl is 6- to 12-membered, and more preferably, the fused cycloalkyl is 7- to 10-membered. Fused cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting embodiments of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl-1-alkenyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthryl.

[0097] "Bridged cycloalkyl" refers to a C5-C18 all-carbon polycyclic group having two or more cyclic structures that share two carbon atoms not directly linked to each other, where one or more of the rings may contain one or more double bonds but do not have a fully conjugated π-electron aromatic system. Preferably, the bridged cycloalkyl is 6-12 membered, more preferably 7-10 membered. Preferably, the bridged cycloalkyl is 6-14 membered, more preferably 7-10 membered. Depending on the number of constituent rings, the bridged cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting embodiments 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, and (1r,5r)-bicyclo[3.3.2]decyl.

[0098] "Heterocyclyl", "heterocycle" or "heterocyclic" may be used interchangeably in this application and all refer to non-aromatic heterocyclyls, where one or more ring-forming atoms are heteroatoms such as oxygen, nitrogen and sulfur atoms, and include monocyclic rings, fused rings, bridged rings and spirocyclic rings. Preferably, the heterocyclyl is a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring and 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 may or may not be substituted.

[0099] "Spiro - heterocyclyl" refers to a polycyclic group of 5 to 18 members having two or more cyclic structures, where the monocycles share one atom with each other, and the ring contains one or more double bonds but does not have a fully conjugated π - electron aromatic system. Here, one or more ring atoms are selected from heteroatoms of nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2), and the remaining ring atoms are carbon. Preferably, spiro - heterocyclyl is 6 to 14 members, more preferably, spiro - heterocyclyl is 7 to 10 members. Spiro - heterocyclyl is divided into mono -, di - or multi - spiro - heterocyclyl according to the number of shared spiro atoms between the rings, preferably mono - and di - spiro - heterocyclyl, more preferably 4 - member / 4 - member, 4 - member / 5 - member, 4 - member / 6 - member, 5 - member / 5 - member or 5 - member / 6 - member mono - spiro - heterocyclyl. Non - limiting embodiments of "spiro - heterocyclyl" include, but are not limited to, 1,7 - dioxane[4.5]decyl, 2 - oxa - 7 - azaspiro[4.4]nonyl, 7 - oxaspiro[3.5]nonyl and 5 - oxaspiro[2.4]heptyl.

[0100] "Fused heterocyclyl" refers to an all - carbon polycyclic group having two or more cyclic structures that share a pair of atoms with each other, where one or more rings may contain one or more double bonds but do not have a fully conjugated π - electron aromatic system. Here, one or more ring atoms are nitrogen, oxygen or S(O) r(Here, r is selected from 0, 1, or 2) and is selected from heteroatoms, and the remaining ring atoms are carbon. Preferably, the fused heterocyclyl is 6 to 14 membered, more preferably, the fused heterocyclyl is 7 to 10 membered. The fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl according to the number of constituent rings, preferably bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting embodiments of "fused heterocyclyl" include octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl and octahydrobenzo[b][1,4]dioxin, but are not limited thereto.

[0101] "Bridged heterocyclyl" refers to a polycyclic group of 5 to 14 members or 5 to 18 members having two or more cyclic structures that share two atoms not directly linked to each other, and one or more rings may contain one or more double bonds, but do not have a completely conjugated π-electron aromatic system. Here, one or more ring atoms are nitrogen, oxygen or S(O) r (Here, r is selected from 0, 1, or 2) and is selected from heteroatoms, and the remaining ring atoms are carbon. Preferably, the bridged heterocyclyl is 6 to 14 membered, more preferably, the bridged heterocyclyl is 7 to 10 membered. The bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Non-limiting embodiments of "bridged heterocyclyl" include 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl, but are not limited thereto.

[0102] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, where the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl such as aromatic groups of phenyl, naphthyl, and tetrahydronaphthyl. Preferably, aryl is C6-C 10 aryl, more preferably, aryl is phenyl and naphthyl, and most preferably, aryl is naphthyl. Aryl may or may not be substituted.

[0103] "Heteroaryl" refers to a 5- to 6-membered aromatic monocyclic ring or an 8- to 10-membered aromatic bicyclic ring that may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Preferably, heteroaryl is bicyclic heteroaryl. Embodiments of "heteroaryl" are furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothiophenyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl,

[0104] [Chemical formula]

[0105] including, but not limited to, these.

[0106] Heteroaryl may or may not be substituted.

[0107] "Condensed ring" refers to a polycyclic group having two or more cyclic structures that share a pair of atoms with each other, where one or more rings may contain one or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system. On the other hand, at least one ring has a completely conjugated π-electron aromatic system, where zero or one or more ring atoms are selected from heteroatoms of nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2), and the remaining ring atoms are carbon. The condensed ring preferably includes a bicyclic or tricyclic condensed ring, where the bicyclic condensed ring is preferably a condensed ring of aryl or heteroaryl with a monocyclic heterocyclyl or a monocyclic heterocyclyl. Preferably, the condensed ring has 7 to 14 members, and more preferably, the condensed ring has 8 to 10 members. Embodiments of the "condensed ring" are

[0108] [Chemical formula]

[0109] including, but not limited to, these. The condensed ring may or may not be substituted.

[0110] "Alkoxy" refers to a group of (alkyl - O-). Alkyl is defined herein. Preferably, C1 - C6 alkoxy is selected. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, isobutoxy, tert - butoxy, etc.

[0111] "Haloalkyl" refers to a group in which alkyl is optionally further substituted by one or more halogens, where alkyl is defined herein.

[0112]

[0113] "Hydroxyalkyl" refers to a group in which alkyl is optionally further substituted by one or more hydroxyls, where alkyl is defined herein."Haloalkoxy" refers to a group in which the alkyl of (alkyl-O-) is optionally further substituted by one or more halogens, where alkoxy is defined herein.

[0114] "Hydroxyl" refers to the -OH group.

[0115] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0116] "Amino" refers to -NH2.

[0117] "Cyano" refers to -CN.

[0118] "Nitro" refers to -NO2.

[0119] "Benzyl" refers to -CH2-phenyl.

[0120] "Carboxyl" refers to -C(O)OH.

[0121] "Carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, where alkyl and cycloalkyl are defined as above.

[0122] "Me" refers to methyl.

[0123] "DMSO" refers to dimethyl sulfoxide.

[0124] "Boc" refers to tert-butoxycarbonyl.

[0125] "T3P" refers to propylphosphonic anhydride.

[0126] "HATU" refers to 2-(7-azabenzotriazol)-N,N,N’,N’-tetramethylurea hexafluorophosphate.

[0127] "Replaced" means that one or more hydrogen atoms in the group, preferably up to 5 hydrogen atoms, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are present only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) whether a substitution is possible or not without undue experimentation. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0128] As used herein, "substituted" or "being substituted", unless otherwise specified, means that the group is substituted with one or more groups selected from the following substituents: alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthiol, heterocycloalkylthiol, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate group, =O, -C(O)R 9 、-C(O)OR 9 、-NHC(O)R 9 、-NHC(O)OR 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-CH2NHC(O)OR 9 、-CH2NR 10 R 11 or -S(O) r R 9 ; which means that it may be substituted with one or more groups selected from.

[0129] R 9is selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, the cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -NR 13 R 14 , -C(O)NR 13 R 14 , -SO2NR 13 R 14 or -NR 13 C(O)R 14 and is optionally further substituted by one or more substituents selected from

[0130] R 10 and R 11 are independently selected from a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, the alkoxy, the cycloalkyl, the heterocyclyl, the aryl or the heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -NR 13 R 14 , -C(O)NR 13 R 14 , -SO2NR 13 R 14 or -NR 13 C(O)R 14 and is optionally further substituted by one or more substituents selected from

[0131] Alternatively, R 10 and R 11 are R 10 and R11 forms a 4- to 8-membered heterocyclyl together with the atom to which it is attached, where the 4- to 8-membered heterocyclyl contains one or more N, O or S(O) r and is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -NR 13 R 14 , -C(O)NR 13 R 14 , -SO2NR 13 R 14 or -NR 13 C(O)R 14 and is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R, -C(O)OR, -OC(O)R, -NRR, -C(O)NRR, -SO2NRR or -NRC(O)R

[0132] R 12 and R 13 and R 14 are independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate

[0133] r is 0, 1 or 2

[0134] The compounds of the present invention may contain asymmetric centers or chiral centers and thus may exist in various stereoisomeric forms. All stereoisomers of the compounds of the present invention are expected to include, but not be limited to, diastereomers, enantiomers, as well as atropisomers and geometric (conformational) isomers, and mixtures thereof such as racemic mixtures, and all of these are within the scope of the present invention

[0135] Unless otherwise specified, the structures described in the present invention include all isomers of this structure (for example, in the form of diastereomers, enantiomers, and atropisomers and geometric (conformational) isomers; for example, R and S configurations of asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, single stereoisomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (conformational) isomers, are all within the scope of the present invention.

[0136] "Pharmaceutically acceptable salts" refer to some salts of the above compounds that are suitable for medical use and can maintain the original biological activity. The pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts or amine salts formed using suitable acids.

[0137] "Pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof and other chemical components, and other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, which is beneficial for the absorption of the active ingredient and thus exerts biological activity.

[0138] 〔Synthesis method of the compounds of the present invention〕 To achieve the object of the present invention, the following technical solutions are adopted by the present invention.

[0139] The method for producing a compound represented by general formula (II), or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof according to the present invention comprises the following steps:

[0140]

Chemical formula

[0141] A process of subjecting a compound of general formula (IIa) to hydrolysis to obtain a compound of general formula (IIA); a process of subjecting the compound of general formula (IIA) and the compound of general formula (IIB) to a condensation reaction; and optionally, further, a process of hydrolyzing the mixture under acidic conditions to obtain a compound of general formula (II); comprising wherein: R g is selected from alkyl; ring B, X, L, R 1 ~R 3 R 5 R 6 R 8 m and n are as defined in general formula (II).

[0142] [Detailed Description] The following examples are used to further illustrate the present invention, but these examples do not limit the scope of the present invention.

[0143] [Examples] The examples show the preparation of representative compounds represented by formula (I) and related structure identification data. It should be noted that the following examples are for explaining the present invention and do not limit the present invention. 1 The 1H NMR spectrum was measured by a Bruker instrument (400 MHz), and the chemical shift was expressed in ppm using tetramethylsilane internal standard (0.00 ppm). 1 1H NMR was represented as s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = double doublet, dt = double triplet. When the coupling constant was given, it was in the unit of Hz.

[0144] The mass spectrum was determined by LC / MS, and the ionization method may be ESI or APCI.

[0145] For preparative liquid separation, a Gilson preparative high performance liquid chromatograph with model number GX - 281 was used.

[0146] As the silica gel plate for thin layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used. The silica gel plate used for thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the product separated and purified by TLC had a specification of 0.4 mm to 0.5 mm.

[0147] Yantai Huanghai silica gel of 200 - 300 mesh was used as the carrier for column chromatography.

[0148] In the following examples, unless otherwise specified, all temperatures were in degrees Celsius. Unless otherwise specified, various starting materials and reagents were commercially available or synthesized according to known methods, and commercially available materials and reagents were used directly without further purification. Unless otherwise specified, commercially available manufacturers include, but are not limited to, Shanghai Accela ChemBio Inc., Shanghai Hao Hong Biomedical Technology Co., Ltd., Shanghai Bide Pharmatech Ltd., Sa’en Chemical Technology Co., Ltd., and Shanghai LinkChem Co., Ltd.

[0149] CD3OD: Deuterated methanol.

[0150] CDCl3: Deuterated chloroform.

[0151] DMSO - d6: Deuterated dimethyl sulfoxide.

[0152] Unless otherwise specified in the examples, the solution during the reaction refers to an aqueous solution.

[0153] The compound was purified by the eluent systems of column chromatography and thin-layer chromatography, where the system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; and D: dichloromethane and ethanol system. The volume ratio of the solvents varied according to the polarity of the compound and could also be adjusted by adding a small amount of acidic or basic reagent such as acetic acid or triethylamine.

[0154] Room temperature: 20 °C to 30 °C.

[0155] Example 1 Tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzoate

[0156]

Chemical formula

[0157] Step 1 1-(4-chloro-2-nitrophenyl)-1H-tetrazole 4-chloro-2-nitroaniline 1a (10 g, 57.95 mmol), azidotrimethylsilane (29.1 mL, 173.84 mmol) and trimethyl orthoformate (8.62 mL, 173.84 mmol) were sequentially added to acetic acid (300 mL), and the reaction was carried out with stirring at 60 °C for 28 hours. After completion of the reaction, saturated sodium nitrite solution (200 mL) was gradually added dropwise at 0 °C to quench the reaction, and the reaction solution was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed successively with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-(4-chloro-2-nitrophenyl)-1H-tetrazole 1b (8 g) in a yield of 36%.

[0158] MS m / z (ESI): 226.0 [M+H]+.

[0159] Step 2 5-Chloro-2-(1H-tetrazol-1-yl)aniline 1-(4-Chloro-2-nitrophenyl)-1H-tetrazole 1b (0.5 g, 2.22 mmol), ammonium chloride (124.12 mg, 2.22 mmol) and reduced iron powder (1.24 g, 22.16 mmol) were successively dissolved in anhydrous ethanol (10 mL), then water (2 mL) was added, and the mixture was stirred at 80 °C for 2 h. After completion of the reaction, the system was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 5-chloro-2-(1H-tetrazol-1-yl)aniline 1c (0.4 g) in a yield of 92%.

[0160] MS m / z (ESI): 196.1 [M+H]+.

[0161] Step 3 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 5-Chloro-2-(1H-tetrazol-1-yl)aniline 1c (450 mg, 2.30 mmol) and potassium carbonate (317.47 mg, 2.30 mmol) were successively dissolved in acetonitrile (15 mL), and an acetonitrile solution (15 mL) containing chloroacetyl chloride (0.18 mL, 2.30 mmol) was slowly added dropwise at 0 °C, and the mixture was continuously stirred at 0 °C for 2 h. After quenching with water, the reaction solution was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed successively with water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 2-chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (0.57 g) in a yield of 91%.

[0162] MS m / z (ESI): 272.0 [M+H]+.

[0163] Step 4 (2 - ((5 - chloro - 2 - (1H - tetrazol - 1 - yl)phenyl)amino)-2 - oxoethyl)phenylalanine tert - butyl 2 - chloro - N - (5 - chloro - 2 - (1H - tetrazol - 1 - yl)phenyl)acetamide 1d (0.9 g, 3.31 mmol) and 3 - phenyl - L - alanine tert - butyl hydrochloride 1e (1.10 g, 4.96 mmol) were dissolved in N,N - dimethylformamide (100 mL), N,N - diisopropylethylamine (547 μL, 3.31 mmol) was added, and the mixture was reacted at 70 °C for 18 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure. After removing most of the solvent, water (150 mL) was added for dilution, and the reaction solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with water (100 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (2 - ((5 - chloro - 2 - (1H - tetrazol - 1 - yl)phenyl)amino)-2 - oxoethyl)phenylalanine tert - butyl 1f (1.2 g) in a yield of 79%.

[0164] MS m / z (ESI): 457.1 [M + H].

[0165] Step 5 N - (2 - ((5 - chloro - 2 - (1H - tetrazol - 1 - yl)phenyl)amino)-2 - oxoethyl)-N - (2 - chloroacetyl)phenylalanine tert - butyl (2-((5-Chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl 1f (1.2 g, 2.63 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (544.46 mg, 3.94 mmol) was added, and chloroacetyl chloride (0.25 mL, 3.15 mmol) was gradually added dropwise at 0 °C. The reaction was carried out at 0 °C for 3 hours. Water (20 mL) was added to quench the reaction, and then the reaction solution was stirred for 10 minutes to separate the liquid. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl 1g (1 g) in a yield of 72%.

[0166] MS m / z (ESI): 477.0 [M + H - 56].

[0167] Step 6 tert-Butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate N-(2-((5-Chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl 1g (0.4 g, 0.75 mmol) was dissolved in methanol (20 mL), and sodium methylate (0.14 mL, 5.4 M methanol solution, 0.75 mmol) was added at 0 °C. The reaction was carried out at 0 °C for 2 hours. After the reaction was completed, 2N hydrochloric acid aqueous solution was added to adjust the pH to neutral, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate 1h (0.2 g) in a yield of 54%.

[0168] MS m / z (ESI): 497.1 [M+H]+.

[0169] Step 7 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid tert-butyl ester (200 mg, 402.46 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was reacted at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (144 mg) in a yield of 81%.

[0170] MS m / z (ESI): 441.1 [M+H]+.

[0171] Step 8 Tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropionic acid 1i (140 mg, 317.58 μmol) and tert-butyl 4-aminobenzoate 1j (92.05 mg, 476.36 μmol) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (0.26 mL, 1.59 mmol) and propylphosphonic anhydride (404 mg, 635.15 μmol, 50% ethyl acetate solution) were added. The mixture was reacted at 60 °C for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzoate 1 (190 mg) in a yield of 97%.

[0172] MS m / z(ESI): 615.9 [M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.71 (s, 1H), 7.97 - 7.60 (m, 7H), 7.40 - 7.16 (m, 5H), 5.41 - 5.27 (m, 1H), 4.76 - 3.87 (m, 4H), 3.33 - 3.17 (m, 1H), 3.16 - 3.04 (m, 1H), 1.54 (s, 9H).

[0173] Example 2 Methyl (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)phenyl)carbamate

[0174]

Chemical formula

[0175] Step 1 (4-Aminophenyl)methylcarbamate In a hydrogen atmosphere, 1-isocyanato-4-nitrobenzene 2a (3 g, 18.28 mmol) was dissolved in dichloromethane (50 mL), Raney nickel (0.5 g, 18.28 mmol) was added, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, the system was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain methyl (4-aminophenyl)carbamate 2b (3 g) in a yield of 99%.

[0176] MS m / z(ESI): 167.0[M+H].

[0177] Step 2 (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)phenyl)methyl carbamate 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (100 mg, 226.84 μmol) and methyl (4-aminophenyl)carbamate 2b (56.54 mg, 340.26 μmol) were dissolved in ethyl acetate (20 mL), N,N-diisopropylethylamine (187 μL, 1.13 mmol) and propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain methyl (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)phenyl)carbamate 2 (81 mg) in a yield of 60%.

[0178] MS m / z(ESI): 589.1[M+H] 11H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.71 (s, 1H), 9.59 (s, 1H), 7.86 - 7.64 (m, 3H), 7.48 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.36 - 7.16 (m, 5H), 5.37 - 5.23 (m, 1H), 4.64 - 3.88 (m, 4H), 3.65 (s, 3H), 3.28 - 3.13 (m, 1H), 3.13 - 2.96 (m, 1H).

[0179] Example 3 4-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzamide

[0180]

Chemical Structure

[0181] 1i (100 mg, 226.84 μmol) of 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid and 3a (46.33 mg, 340.26 μmol) of p-aminobenzamide were dissolved in ethyl acetate (10 mL), N,N-diisopropylethylamine (187 μL, 1.13 mmol) and propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at room temperature for 50 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 3 (69 mg) of 4-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzamide in a yield of 53%.

[0182] MS m / z (ESI): 559.1 [M + H] 11H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.71 (s, 1H), 7.96 - 7.71 (m, 5H), 7.65 (d, J = 8.4 Hz, 2H), 7.40 - 7.12 (m, 5H), 5.41 - 5.26 (m, 1H), 4.78 - 3.89 (m, 4H), 3.28 - 3.18 (m, 1H), 3.15 - 3.02 (m, 1H).

[0183] Example 4 Ethyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate

[0184] [Chemical formula]

[0185] 1i (50 mg, 113.42 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid and 4a (28.10 mg, 170.13 μmol) of ethyl p-aminobenzoate were dissolved in ethyl acetate (10 mL), N,N-diisopropylethylamine (94 μL, 567.10 μmol) and propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 4 (52 mg) of ethyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate in a yield of 73%.

[0186] MS m / z (ESI): 587.9 [M + H] 11H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.71 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.87 - 7.64 (m, 5H), 7.41 - 7.15 (m, 5H), 5.40 - 5.27 (m, 1H), 4.68 - 3.89 (m, 4H), 4.29 (q, J = 7.1 Hz, 2H), 3.28 - 3.18 (m, 1H), 3.18 - 3.03 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H).

[0187] Example 5 Methyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate

[0188]

Chemical Structure

[0189] 1i (50 mg, 113.42 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid and 5a (25.72 mg, 170.13 μmol) of methyl p-aminobenzoate were dissolved in ethyl acetate (6 mL), N,N-diisopropylethylamine (94 μL, 567.10 μmol) and propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 5 (50 mg) of methyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate in a yield of 76%.

[0190] MS m / z (ESI): 574.2 [M + H] 11H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.71 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.87 - 7.62 (m, 5H), 7.44 - 7.13 (m, 5H), 5.41 - 5.26 (m, 1H), 4.62 - 3.90 (m, 4H), 3.83 (s, 3H), 3.28 - 3.20 (m, 1H), 3.16 - 3.03 (m, 1H).

[0191] Example 6 4-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-N-methylbenzamide

[0192] [Chemical formula]

[0193] 4-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzoic acid 1 (60 mg, 107.15 μmol) and methylamine hydrochloride (14.5 mg, 214.30 μmol) were dissolved in ethyl acetate (6 mL), N,N-diisopropylethylamine (89 μmol, 535.75 μmol) and propylphosphonic anhydride (205 mg, 321.45 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-N-methylbenzamide 6 (14 mg) in a yield of 22%.

[0194] MS m / z (ESI): 573.2 [M + H] 11H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.70 (s, 1H), 8.46 - 8.26 (m, 1H), 7.99 - 7.52 (m, 7H), 7.44 - 7.11 (m, 5H), 5.45 - 5.19 (m, 1H), 4.64 - 3.87 (m, 4H), 3.15 - 2.97 (m, 2H), 2.76 (d, J = 4.4 Hz, 3H).

[0195] Example 7 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-oxoisoindolin-5-yl)-3-phenylpropanamide

[0196]

Chemical formula

[0197] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-aminoisoindolin-1-one 7a (25.21 mg, 170.13 μmol) were dissolved in ethyl acetate (6 mL), N,N-diisopropylethylamine (112 μL, 680.52 μmol) and propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 70 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-oxoisoindolin-5-yl)-3-phenylpropanamide 7 (21 mg) in a yield of 32%.

[0198] MS m / z (ESI): 570.9 [M + H] 11H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.73 (s, 1H), 8.43 (s, 1H), 7.94 (s, 1H), 7.87 - 7.72 (m, 3H), 7.67 - 7.53 (m, 2H), 7.38 - 7.19 (m, 5H), 5.41 - 5.29 (m, 1H), 4.60 - 3.90 (m, 4H), 4.35 (s, 2H), 3.31 - 3.02 (m, 2H).

[0199] Example 8 Methyl 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)indoline-1-carboxylate

[0200] [Chemical Formula]

[0201] Step 1 Methyl 5-nitroindoline-1-carboxylate 5-Nitroindoline 8a (1 g, 6.09 mmol) was dissolved in dichloromethane (12.5 mL), and a toluene solution (12.5 mL) containing methyl chloroformate (863.45 mg, 9.14 mmol) and a dichloromethane solution (12.50 mL) containing pyridine (493 μL, 6.09 mmol) were added thereto, and the mixture was stirred at 80 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain methyl 5-nitroindoline-1-carboxylate 8b (1.2 g) in a yield of 89%.

[0202] MS m / z (ESI): 223.0 [M+H].

[0203] Step 2 Methyl 5-aminoindoline-1-carboxylate Methyl 5-nitroindoline-1-carboxylate 8b (0.67 g, 3.02 mmol) was dissolved in ethanol (10 mL) and water (1 mL), and reduced iron powder (1.68 g, 30.15 mmol) and ammonium chloride (159.81 mg, 3.02 mmol) were added sequentially, followed by reaction with stirring at 80 °C for 1 hour. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain methyl 5-aminoindoline-1-carboxylate 8c (0.42 g) in a yield of 72%.

[0204] MS m / z (ESI): 193.1 [M+H].

[0205] Step 3 Methyl 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)indoline-1-carboxylate 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and methyl 5-aminoindoline-1-carboxylate 8c (32.70 mg, 170.13 μmol) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (94 μL, 567.10 μmol) and propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added, followed by reaction at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain methyl 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)indoline-1-carboxylate 8 (35 mg) in a yield of 49%.

[0206] MS m / z (ESI): 614.8 [M+H] 11H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.72 (s, 1H), 7.86 - 7.47 (m, 5H), 7.38 - 7.12 (m, 6H), 5.34 - 5.25 (m, 1H), 4.52 - 3.86 (m, 4H), 3.95 (t, J = 9.4 Hz, 2H), 3.73 (s, 3H), 3.28 - 3.15 (m, 2H), 3.09 (t, J = 9.4 Hz, 2H).

[0207] Example 9 3-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid

[0208]

Chemical formula

[0209] Step 1 tert-Butyl 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 1i (100 mg, 226.84 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid and 9a (65.75 mg, 340.26 μmol) of tert-butyl 3-aminobenzoate were dissolved in ethyl acetate (15 mL), N,N-diisopropylethylamine (187 μL, 1.13 μmol) and propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 9b (0.11 g) of tert-butyl 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate in a yield of 79%.

[0210] MS m / z (ESI): 616.2 [M+H]+

[0211] Project 2 3-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid 3-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid tert-butyl 9b (0.11 g, 178.55 μmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid 9 (52 mg) in a yield of 52%.

[0212] MS m / z (ESI): 560.1 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.72 (s, 1H), 8.16 (s, 1H), 7.92 - 7.57 (m, 5H), 7.46 - 7.16 (m, 6H), 5.31 (dd, J = 10.1, 5.8 Hz, 1H), 4.58 - 3.86 (m, 4H), 3.18 - 3.00 (m, 1H), 2.93 - 2.84 (m, 1H).

[0213] Example 10 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-phenylpropanamide

[0214]

Chemical Structure

[0215] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 1-(4-aminophenyl)pyrrolidin-2-one 10a (29.98 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added, followed by reaction at 70 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-phenylpropanamide 10 (34 mg) in a yield of 50%.

[0216] MS m / z(ESI): 599.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.71 (s, 1H), 7.85 - 7.70 (m, 3H), 7.59 (q, J = 9.0 Hz, 4H), 7.37 - 7.17 (m, 5H), 5.37 - 5.27 (m, 1H), 4.56 - 3.90 (m, 4H), 3.81 (t, J = 7.0 Hz, 2H), 3.29 - 3.18 (m, 1H), 3.13 - 3.02 (m, 1H), 2.48 - 2.45 (m, 2H), 2.11 - 2.00 (m, 2H).

[0217] Example 11 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid

[0218]

Chemical formula

[0219] Project 1 2-Chloro-N-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)acetamide 5-Chloro-2-(triazol-1-yl)aniline 11a (2.4 g, 12.33 mmol, prepared according to the description on page 4, paragraphs 0013 - 0015, step A-1 of Patent Publication CN108863962) was dissolved in dichloromethane (40 mL), triethylamine (3.74 g, 37.00 mmol) was added, 2-chloroacetyl chloride (2.78 g, 24.66 mmol, 1.96 mL) was added at 0 °C, and the reaction was carried out for 1 hour. After quenching with 30 mL of water, the reaction solution was subjected to liquid separation, and then 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, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-chloro-N-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)acetamide 11b (2.4 g) in a yield of 72%.

[0220] MS m / z (ESI): 271.0 [M + H].

[0221] Project 2 (2-((5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl 2-Chloro-N-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)acetamide 11b (2.4 g, 8.85 mmol) and 3-phenyl-L-alanine tert-butyl hydrochloride 1e (3.42 g, 13.28 mmol) were dissolved in N,N-dimethylformamide (50 mL), N,N-diisopropylethylamine (5.72 g, 44.26 mmol, 7.32 mL) was added, and the reaction was carried out at 60 °C overnight. After completion of the reaction, the reaction solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with water (200 mL × 3) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl (2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine 11c (3.3 g) in a yield of 82%.

[0222] MS m / z (ESI): 456.7 [M+H].

[0223] Step 3 N-(2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl (2-((5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl 11c (2 g, 4.39 mmol) was dissolved in dichloromethane (50 mL), placed in an ice bath, triethylamine (2.22 g, 21.93 mmol, 3.05 mL) was added, and then 2-chloroacetyl chloride (594.52 mg, 5.26 mmol, 418.68 μL) was slowly added dropwise, and the reaction was stirred in the ice bath for 1 hour. 2-Chloroacetyl chloride (594.52 mg, 5.26 mmol, 418.68 μL) was added, and the reaction was continuously stirred in the ice bath for 1 hour. The LC-MS test showed that the reaction was complete. After quenching with 30 mL of water, the reaction solution was subjected to liquid separation, and then 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, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain N-(2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl 11d (2 g) in a yield of 86%.

[0224] MS m / z(ESI): 476.0[M + H - 56].

[0225] Step 4 tert-Butyl 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate N-(2-((5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl 11d (2g, 3.76 mmol) was dissolved in methanol (30 mL), and a sodium methoxide solution (5.4 M, 765.20 μL) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 30 minutes. The LC-MS test indicated that the reaction was complete. 2 M dilute hydrochloric acid was added to adjust the pH to about 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate 11e (1.5 g) in a yield of 81%.

[0226] MS m / z(ESI): 440.0 [M + H - 56].

[0227] Step 5 2-(4-(5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid tert-Butyl 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate 11e (1.5 g, 3.02 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (344.85 mg, 3.02 mmol, 244.66 μL ) was slowly added dropwise, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 11f (1.33 g) in a yield of 100%.

[0228] MS m / z(ESI): 440.1 [M + H].

[0229] Step 6 tert-Butyl 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 2-(4-(5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 11f (240 mg, 545.64 μmol) and tert-butyl 4-aminobenzoate 1j (126.53 mg, 654.77 μmol) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (423.11 mg, 3.27 mmol) and propylphosphonic anhydride (1.04 g, 1.64 mmol, 50% ethyl acetate solution) were added, followed by reaction at 65 °C for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 11g (200 mg) in a yield of 60%.

[0230] MS m / z (ESI): 615.2 [M+H].

[0231] Step 7 4-(2-(4-(5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxoperazin-1-yl)-3-phenylpropanamido)benzoic acid tert-Butyl 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 11g (200 mg, 325.16 μmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (37.08 mg, 325.16 μmol, 24.16 μL) was slowly added dropwise thereto, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzoic acid 11 (110 mg) in a yield of 59%.

[0232] MS m / z(ESI):558.8[M+H] 1 H NMR(400MHz, DMSO-d6) δ 12.75(s, 1H), 10.49(s, 1H), 8.19(s, 1H), 7.92(d, J = 8.5Hz, 2H), 7.81 - 7.58(m, 6H), 7.37 - 7.23(m, 5H), 5.36(dd, J = 10.3, 5.8Hz, 1H), 4.45 - 3.90(m, 4H), 3.31 - 3.21(m, 1H), 3.19 - 3.06(m, 1H).

[0233] Example 12 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-1-oxoisoindolin-5-yl)-3-phenylpropanamide

[0234]

Chemical formula

[0235] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-amino-2-methylisoindolin-1-one 12a (27.59 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added. The mixture was reacted at 70 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-1-oxoisoindolin-5-yl)-3-phenylpropanamide 12 (35 mg) in a yield of 52%.

[0236] MS m / z(ESI): 585.0 [M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.72 (s, 1H), 7.95 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75 (dd, J = 8.7, 2.2 Hz, 1H), 7.69 - 7.48 (m, 2H), 7.36 - 7.21 (m, 5H), 5.41 - 5.29 (m, 1H), 4.60 - 3.90 (m, 4H), 4.44 (s, 2H), 3.30 - 3.20 (m, 1H), 3.15 - 3.08 (m, 1H), 3.05 (s, 3H).

[0237] Example 13 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-oxoisoindolin-5-yl)-3-phenylpropanamide

[0238]

Chemical formula

[0239] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-aminoindolin-2-one 13a (25.21 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 70 °C for 4 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-oxoindolin-5-yl)-3-phenylpropanamide 13 (33 mg) in a yield of 57%.

[0240] MS m / z (ESI): 571.0 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 10.02 (s, 1H), 9.72 (s, 1H), 7.86 - 7.72 (m, 2H), 7.47 (s, 1H), 7.37 - 7.15 (m, 7H), 6.75 (d, J = 8.4 Hz, 1H), 5.36 5.26 (m, 1H), 4.57 - 3.88 (m, 4H), 3.47 (s, 2H), 3.26 - 3.15 (m, 1H), 3.11 - 2.98 (m, 1H).

[0241] Example 14 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(4-(2-oxooxazolidin-3-yl)phenyl)-3-phenylpropanamide

[0242]

Chemical formula

[0243] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 3-(4-aminophenyl)oxazolidin-2-one 14a (30.32 mg, 170.13 μmol, prepared according to the method described in pages 40 - 41, paragraphs 0171 - 0178 of Patent Publication CN105384739) were dissolved in ethyl acetate (5 mL), propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol, 112.47 μL) were added, and the reaction was carried out overnight at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(4-(2-oxooxazolidin-3-yl)phenyl)-3-phenylpropanamide 14 (22 mg) in a yield of 99%.

[0244] MS m / z(ESI): 600.8[M + H] 1 H NMR(400 MHz, DMSO-d6) δ 10.19(s, 1H), 9.72(s, 1H), 7.81(d, J = 8.6 Hz, 1H), 7.75(dd, J = 8.6, 2.2 Hz, 1H), 7.60(d, J = 8.7 Hz, 2H), 7.52(d, J = 8.8 Hz, 2H), 7.37 - 7.17(m, 5H), 5.33(dd, J = 10.0, 5.7 Hz, 1H), 4.65 - 3.91(m, 4H), 4.43(t, J = 8.0 Hz, 2H), 4.04(t, J = 8.0 Hz, 2H), 3.29 - 3.18(m, 1H), 3.15 - 3.03(m, 1H).

[0245] Example 15 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(3-fluorophenyl)-3-phenylpropanamide

[0246] [Chemical formula]

[0247] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 113.42 μmol) and 3-fluoroaniline (18.90 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 70 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(3-fluorophenyl)-3-phenylpropanamide 15 (17 mg) in a yield of 28%.

[0248] MS m / z (ESI): 534.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.71 (s, 1H), 7.93 - 7.65 (m, 3H), 7.58 (d, J = 11.5 Hz, 1H), 7.43 - 7.18 (m, 7H), 6.92 (t, J = 8.5 Hz, 1H), 5.37 - 5.24 (m, 1H), 4.69 - 3.88 (m, 4H), 3.28 - 3.15 (m, 1H), 3.15 - 3.01 (m, 1H).

[0249] Example 16 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(4-cyanophenyl)-3-phenylpropanamide

[0250] [Chemical formula]

[0251] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 113.42 μmol), 4-aminobenzonitrile (13.40 mg, 113.42 μmol), N,N-diisopropylethylamine (73.29 mg, 567.10 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were successively dissolved in ethyl acetate (7 mL), and reacted continuously with stirring at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was subjected to liquid phase purification (separatory column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), and 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(4-cyanophenyl)-3-phenylpropanamide 16 (23 mg) was obtained in a yield of 37%.

[0252] MS m / z (ESI): 541.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.70 (s, 1H), 7.94 - 7.60 (m, 7H), 7.41 - 7.13 (m, 5H), 5.31 (dd, J = 10.2, 5.8 Hz, 1H), 4.78 - 3.88 (m, 4H), 3.30 - 3.17 (m, 1H), 3.15 - 3.00 (m, 1H).

[0253] Example 17 N-(4-acetylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide

[0254]

Chemical formula

[0255] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 1-(4-aminophenyl)ethan-1-one 17a (23.00 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain N-(4-acetylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide 17 (35 mg) in a yield of 51%.

[0256] MS m / z(ESI): 558.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.72 (s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.86 - 7.65 (m, 5H), 7.41 - 7.15 (m, 5H), 5.35 (dd, J = 10.3, 6.0 Hz, 1H), 4.71 - 3.91 (m, 4H), 3.30 - 3.19 (m, 1H), 3.18 - 3.03 (m, 1H), 2.54 (s, 3H).

[0257] Example 18 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide

[0258]

Chemical formula

[0259] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (30 mg, 68.05 μmol), quinoxalin-6-amine 18a (14.82 mg, 102.08 μmol), N,N-diisopropylethylamine (43.98 mg, 340.26 μmol), and propylphosphonic anhydride (129.92 mg, 204.16 μmol, 50% ethyl acetate solution) were successively dissolved in ethyl acetate (5 mL) and reacted at room temperature for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid chromatography purification (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide 18 (26 mg) in a yield of 67%.

[0260] MS m / z (ESI): 567.9 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.72 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H), 8.50 (s, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.89 - 7.62 (m, 3H), 7.41 - 7.18 (m, 5H), 5.45 - 5.33 (m, 1H), 4.65 - 3.94 (m, 4H), 3.23 - 3.06 (m, 2H).

[0261] Example 19 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide

[0262]

Chemical Structure

[0263] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (30 mg, 68.05 μmol), 19a of 2-methyl-2H-indazole-5-amine (15.02 mg, 102.08 μmol), N,N-diisopropylethylamine (43.98 mg, 340.26 μmol) and propylphosphonic anhydride (129.92 mg, 204.16 μmol, 50% ethyl acetate solution) were successively dissolved in ethyl acetate (4 mL) and reacted at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase purification (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 19 (23 mg) in a yield of 59%.

[0264] MS m / z (ESI): 570.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.73 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.93 - 7.65 (m, 3H), 7.54 (d, J = 9.2 Hz, 1H), 7.43 - 7.16 (m, 6H), 5.44 - 5.28 (m, 1H), 4.57 - 3.90 (m, 4H), 4.13 (s, 3H), 3.31 - 3.20 (m, 1H), 3.15 - 3.02 (m, 1H).

[0265] Example 20 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-2-fluoro-N-methylbenzamide

[0266]

Chemical formula

[0267] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (30 mg, 68.05 μmol), 20a of 4-amino-2-fluoro-N-methylbenzamide (17.17 mg, 102.08 μmol), N,N-diisopropylethylamine (43.98 mg, 340.26 μmol) and propylphosphonic anhydride (129.92 mg, 204.16 μmol, 50% ethyl acetate solution) were successively dissolved in ethyl acetate (5 mL), and the reaction was carried out with stirring at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase purification (separatory column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), and 20 of 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-2-fluoro-N-methylbenzamide (18 mg) was obtained in a yield of 40%.

[0268] MS m / z(ESI): 591.1[M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.54(s, 1H), 9.71(s, 1H), 8.10(s, 1H), 7.89 - 7.72(m, 3H), 7.71 - 7.59(m, 2H), 7.43 - 7.17(m, 6H), 5.38 - 5.23(m, 1H), 4.73 - 3.89(m, 4H), 3.30 - 3.19(m, 1H), 3.15 - 3.03(m, 1H), 2.77(d, J = 4.5 Hz, 3H).

[0269] Example 21 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-phenylpropanamide

[0270] [Chemical formula]

[0271] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 113.42 μmol) and 21a of 5-aminoisobenzofuran-1(3H)-one (25.37 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-phenylpropanamide 21 (24 mg) in a yield of 35%.

[0272] MS m / z (ESI): 571.9 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.73 (s, 1H), 8.05 (s, 1H), 7.93 - 7.54 (m, 5H), 7.47 - 7.04 (m, 5H), 5.52 - 5.22 (m, 1H), 4.68 - 3.82 (m, 4H), 4.00 (s, 2H), 3.19 - 2.97 (m, 2H).

[0273] Example 22 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-6-yl)propanamide

[0274] [Chemical formula]

[0275] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 113.42 μmol) and pyrazolo[1,5-a]pyridin-6-amine 22a (22.65 mg, 170.13 μmol, prepared according to the specification on page 96, paragraph [000344] of Patent Publication WO2019099311) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 60 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-6-yl)propanamide 22 (18 mg) in a yield of 32%.

[0276] MS m / z(ESI):555.9[M+H] 1 H NMR(400MHz, DMSO-d6) δ 10.36(s, 1H), 9.74(s, 1H), 9.23(s, 1H), 7.95(s, 1H), 7.87 - 7.59(m, 4H), 7.40 - 7.12(m, 6H), 6.59(s, 1H), 5.40 - 5.26(m, 1H), 4.66 - 3.91(m, 4H), 3.33 - 3.19(m, 1H), 3.16 - 3.03(m, 1H).

[0277] Example 23 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide

[0278]

Chemical Structure

[0279] Project 1 6-Bromo-1-methoxyisoquinoline 6-Bromoisoquinolin-1(2H)-one 23a (500 mg, 2.23 mmol), methyl iodide (1.58 g, 11.16 mmol) and silver carbonate (1.24 g, 4.46 mmol) were successively dissolved in toluene (5 mL), and the mixture was stirred at 40 °C for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 6-bromo-1-methoxyisoquinoline 23b (160 mg) in a yield of 30%.

[0280] MS m / z (ESI): 237.9 [M+H].

[0281] Project 2 N-(1-Methoxyisoquinolin-6-yl)-1,1-diphenylmethanimine Under argon protection, 6-bromo-1-methoxyisoquinoline 23b (160 mg, 672.04 μmol), diphenylmethylamine 23c (243.59 mg, 1.34 mmol), tris(dibenzylideneacetone)dipalladium (61.54 mg, 67.20 μmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (41.85 mg, 67.20 μmol) and sodium tert-butoxide (129.17 mg, 1.34 mmol) were successively dissolved in toluene (10 mL), and the mixture was subjected to three argon replacements and reacted at 85 °C for 20 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain N-(1-methoxyisoquinolin-6-yl)-1,1-diphenylmethanimine 23d (200 mg) in a yield of 88%.

[0282] MS m / z (ESI): 339.1 [M+H].

[0283] Project 3 1-Methoxyisoquinolin-6-amine N-(1-Methoxyisoquinolin-6-yl)-1,1-diphenylmethanimine 23d (197.42 mg, 583.40 μmol) and 2M dilute hydrochloric acid (21.27 mg, 583.40 μmol) were successively dissolved in trifluoroacetic acid (6 mL) and reacted at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to transfer most of the trifluoroacetic acid, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 1-methoxyisoquinolin-6-amine 23e (92 mg) in a yield of 91%.

[0284] MS m / z (ESI): 175.1 [M+H].

[0285] Step 4 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol), 1-methoxyisoquinolin-6-amine 23e (29.64 mg, 170.13 μmol), N,N-diisopropylethylamine (219.88 mg, 1.70 μmol) and propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were successively dissolved in ethyl acetate (10 mL) and reacted at room temperature for 18 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid phase purification (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide 23 (7 mg) in a yield of 10%.

[0286] MS m / z (ESI): 597.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.73 (s, 1H), 8.28 - 8.24 (m, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 5.9 Hz, 1H), 7.84 - 7.73 (m, 3H), 7.71 - 7.65 (m, 1H), 7.37 - 7.23 (m, 6H), 5.42 - 5.34 (m, 1H), 4.40 - 3.92 (m, 4H), 4.04 (s, 3H), 3.18 - 3.07 (m, 2H).

[0287] Example 24 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide

[0288]

Chemical Structure

[0289] Step 1 1-(4-Chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 4-Chloro-2-nitroaniline 1a (5 g, 28.97 mmol) was dissolved in acetonitrile (300 mL), stirred in an ice bath for 20 minutes, isoamyl nitrite (5.09 g, 43.46 mmol, 5.84 mL) and azidotrimethylsilane (5.01 g, 43.46 mmol, 5.72 mL) were added in sequence, allowed to stand in an ice bath for 20 minutes, then the ice bath was removed, and the reaction solution was reacted at room temperature for 2 hours. After that, cuprous oxide (4.15 g, 28.97 mmol) and trimethylsilylacetylene (8.54 g, 86.92 mmol, 12.28 mL) were added in sequence, and the reaction was carried out with continuous stirring at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, concentrated under reduced pressure, and the obtained 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 24a (5 g) in a yield of 58%.

[0290] MS m / z (ESI): 297.0 [M+H].

[0291] Step 2 4-Chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole 1-(4-Chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 24a (5 g, 16.85 mmol) was dissolved in acetonitrile (93 mL), silica gel (20.87 g, 16.85 mmol) was added, stirred at room temperature for 10 minutes, then N-chlorosuccinimide (11.25 g, 84.24 mmol) was added, and the reaction was carried out at 80 °C for 1 hour. After the reaction was completed, the reaction solution was filtered, concentrated under reduced pressure, and the obtained 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 24b (1.65 g) in a yield of 38%.

[0292] MS m / z (ESI): 259.0 [M+H].

[0293] Step 3 5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline 4-Chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole 24b (1.75 g, 6.76 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (5 mL), ammonium chloride (722.72 mg, 13.51 mmol) and iron powder (3.77 g, 67.55 mL) were added, and the reaction was carried out at 80 °C overnight. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline 24c (1.3 g) in a yield of 84%.

[0294] MS m / z (ESI): 228.9 [M+H].

[0295] Step 4 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline 24c (1.3 g, 5.68 mmol) was dissolved in dichloromethane (20 mL), triethylamine (3.45 g, 34.05 mmol, 4.73 mL) was added, 2-chloroacetyl chloride (769.17 mg, 6.81 mmol, 541.67 μL) was slowly added dropwise at 0 °C, and the reaction was carried out at 0 °C for 1 hour. 30 mL of water was added to quench the reaction, and then the reaction solution was subjected to liquid separation. The aqueous phase was extracted with dichloromethane (50 mL×3). The organic phases were mixed, 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: system B) to obtain 2-chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (1 g) in a yield of 58%.

[0296] MS m / z (ESI): 304.8 [M+H].

[0297] Project 5 (2 - ((5 - chloro - 2 - (4 - chloro - 1H - 1,2,3 - triazol - 1 - yl)phenyl)amino)-2 - oxoethyl)phenylalanine tert - butyl 2 - chloro - N - (5 - chloro - 2 - (4 - chloro - 1H - 1,2,3 - triazol - 1 - yl)phenyl)acetamide 24d (1 g, 3.27 mmol) and L - phenylalanine tert - butyl hydrochloride 1e (1.09 g, 4.91 mmol) were dissolved in N,N - dimethylformamide (20 mL), N,N - diisopropylethylamine (2.11 g, 16.36 mmol, 2.70 mL) was added, and the mixture was reacted at 80 °C for 1 hour. After completion of the reaction, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (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: system B) to obtain (2 - ((5 - chloro - 2 - (4 - chloro - 1H - 1,2,3 - triazol - 1 - yl)phenyl)amino)-2 - oxoethyl)phenylalanine tert - butyl 24e (1.3 g) in a yield of 81%.

[0298] MS m / z (ESI): 489.9 [M + H].

[0299] Project 6 N - (2 - ((5 - chloro - 2 - (4 - chloro - 1H - 1,2,3 - triazol - 1 - yl)phenyl)amino)-2 - oxoethyl)-N - (2 - chloroacetyl)phenylalanine tert - butyl (2-((5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl 24e (1.3 g, 2.65 mmol) was dissolved in dichloromethane (25 mL), triethylamine (1.61 g, 15.91 mmol, 2.21 mL) was added, and then 2-chloroacetyl chloride (359.29 mg, 3.18 mmol, 253.02 μL) was slowly added dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 hour. After quenching with 30 mL of water, the reaction solution was subjected to liquid separation, and then 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, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) 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 24f (1.1 g) in a yield of 73%.

[0300] MS m / z (ESI): 509.8 [M+H-56].

[0301] Step 7 tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate N-(2-((5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl 24f (1.1 g, 1.94 mmol) was dissolved in methanol (15 mL), and sodium methylate (395.29 μL, 2.134 mmol) was slowly added dropwise at 0 °C, followed by reaction at 0 °C for 1 hour. After completion of the reaction, 2 M dilute hydrochloric acid was added to adjust the pH to about 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate 24g (916 mg) in a yield of 89%.

[0302] MS m / z (ESI): 529.8 [M+H].

[0303] Step 8 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoate 24g (916 mg, 1.73 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (196.91 mg, 1.73 mmol, 128.28 μL ) was slowly added dropwise, followed by reaction at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 24h (764 mg) in a yield of 93%.

[0304] MS m / z (ESI): 473.8 [M+H]+

[0305] Project 9 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 24h (50 mg, 105.42 μmol) and quinoxalin-6-amine 18a (22.95 mg, 158.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (81.75 mg, 632.52 μmol) and 1-propylphosphonic anhydride (201.25 mg, 316.26 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 65 °C for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide 24 (28 mg) in a yield of 44%.

[0306] MS m / z (ESI): 600.8 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.90 (s, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.82 - 7.65 (m, 3H), 7.40 - 7.16 (m, 5H), 5.49 - 5.37 (m, 1H), 4.45 - 3.97 (m, 4H), 3.38 - 3.29 (m, 1H), 3.23 - 3.08 (m, 1H).

[0307] Example 25 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide

[0308]

Chem.

[0309] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 24h (50 mg, 105.42 μmol) and 2-methyl-2H-indazol-5-amine 19a (23.27 mg, 158.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (81.75 mg, 632.52 μmol) and propylphosphonic anhydride (201.25 mg, 316.26 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 65 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 25 (28 mg) in a yield of 44%.

[0310] MS m / z (ESI): 602.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.81 - 7.62 (m, 3H), 7.54 (d, J = 9.2 Hz, 1H), 7.40 - 7.15 (m, 6H), 5.47 - 5.31 (m, 1H), 4.42 - 3.92 (m, 4H), 4.13 (s, 3H), 3.36 - 3.21 (m, 1H), 3.16 - 3.03 (m, 1H).

[0311] Example 26 4-(2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid

[0312]

Chemical formula

[0313] Step 1 tert-Butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 24h (50 mg, 105.42 μmol) and tert-butyl 4-aminobenzoate 1j (30.56 mg, 158.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (68.12 mg, 527.10 μmol) and propylphosphonic anhydride (201.25 mg, 316.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 26a (34 mg) in a yield of 50%.

[0314] MS m / z (ESI): 648.8 [M+H].

[0315] Step 2 4-(2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid tert-Butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 26a (34 mg, 52.35 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (9.00 g, 78.93 mmol, 3 mL) was slowly added dropwise, followed by reaction at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid 26 (8 mg) in a yield of 26%.

[0316] MS m / z (ESI): 592.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.49 (s, 1H), 8.64 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.81 - 7.60 (m, 5H), 7.34 - 7.15 (m, 5H), 5.42 - 5.34 (m, 1H), 4.44 - 3.93 (m, 4H), 3.29 - 3.20 (m, 1H), 3.15 - 3.06 (m, 1H).

[0317] Example 27 N-(4-Acetylphenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide

[0318]

Chemical Structure

[0319] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 105.42 μmol) and 1-(4-aminophenyl)ethan-1-one 17a (21.37 mg, 158.13 μmol) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (81.75 mg, 632.52 μmol) and propylphosphonic anhydride (201.25 mg, 316.26 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 65 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain N-(4-acetylphenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide 27 (27 mg) in a yield of 41%.

[0320] MS m / z(ESI):590.8[M+H] 1 H NMR(400MHz, DMSO-d6) δ 10.51(s, 1H), 8.64(s, 1H), 7.95(d, J = 8.8Hz, 2H), 7.86 - 7.58(m, 5H), 7.39 - 7.16(m, 5H), 5.43 - 5.34(m, 1H), 4.34 - 3.91(m, 4H), 3.32 - 3.22(m, 1H), 3.20 - 3.07(m, 1H), 2.54(s, 3H).

[0321] Example 28 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide

[0322]

Chemical formula

[0323] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 105.42 μmol), 1-methoxyisoquinolin-6-amine 23e (27.55 mg, 158.13 μmol), N,N-diisopropylethylamine (68.12 mg, 527.10 μmol, 87.11 μL) and propylphosphonic anhydride (50% ethyl acetate solution, 201.26 mg, 316.26 μmol, 93.99 μL) were successively dissolved in ethyl acetate (5 mL), and reacted continuously with stirring at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was subjected to preparative liquid purification (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), and 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide 28 (23 mg) was obtained in a yield of 33%.

[0324] MS m / z (ESI): 630.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 5.9 Hz, 1H), 7.81 - 7.58 (m, 5H), 7.42 - 7.14 (m, 5H), 5.49 - 5.35 (s, 1H), 4.53 - 3.90 (m, 4H), 4.03 (s, 3H), 3.21 - 3.08 (m, 2H).

[0325] Example 29 5-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)-N-methylpicolinamide

[0326] [Chemical formula]

[0327] Project 1 5-Amino-N-methylpicolinamide 5-Aminopicolinic acid 29a (500 mg, 3.62 mmol) and methylamine hydrochloride (367 mg, 5.43 mmol) were dissolved in N,N-dimethylformamide (20 mL). 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (668 mg, 1.81 mmol) and triethylamine (2.51 mL, 18.1 mmol) were added in sequence, and the mixture was stirred at room temperature for 16 hours to react. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (50 mL × 2) and saturated sodium chloride solution (30 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: system B) to obtain 5-amino-N-methylpicolinamide 29b (260 mg) in a yield of 48%.

[0328] MS m / z (ESI): 152.1 [M+H].

[0329] Project 2 5-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-N-methylpicolinamide 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol), 5-amino-N-methylpicolinamide 29b (25.72 mg, 170.13 μmol), N,N-diisopropylethylamine (73.29 mg, 567.10 μmol, 93.72 μL), and propylphosphonic anhydride (50% ethyl acetate solution, 216.53 mg, 340.26 μmol, 101.22 μL) were successively dissolved in ethyl acetate (5 mL), and then continuously stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-N-methylpicolinamide 29 (15 mg) in a yield of 22%.

[0330] MS m / z(ESI): 574.2[M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.61(s, 1H), 9.72(d, J = 10.0 Hz, 1H), 8.84(s, 1H), 8.73 - 8.64(m, 1H), 8.16(dd, J = 8.6, 2.5 Hz, 1H), 8.01(d, J = 8.5 Hz, 1H), 7.85 - 7.71(m, 3H), 7.37 - 7.16(m, 5H), 5.34 - 5.27(m, 1H), 4.60 - 3.91(m, 4H), 3.30 - 3.22(m, 1H), 3.17 - 3.06(m, 1H), 2.81(d, J = 4.8 Hz, 3H).

[0331] Example 30 N-(4-Acetyl-3-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide

[0332]

Chemical Structure

[0333] 1i (70 mg, 158.79 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid and 30a (36.48 mg, 238.18 μmol) of 1-(4-amino-2-fluorophenyl)ethan-1-one (prepared according to Table 2 on page 557 of Synthesis (2018), 50(3), 555 - 564) were dissolved in ethyl acetate (10 mL), N,N-diisopropylethylamine (123.13 mg, 952.73 μmol) and propylphosphonic anhydride (50% ethyl acetate solution, 303.14 mg, 476.36 μmol) were added, and the reaction was carried out at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain N-(4-acetyl-3-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide 30 (15 mg) in a yield of 16%.

[0334] MS m / z(ESI): 575.8[M + H] 1 H NMR(400 MHz, DMSO-d6) δ 10.67(s, 1H), 9.71(s, 1H), 7.89 - 7.67(m, 5H), 7.40 7.41(d, J = 8.7 Hz, 1H), 7.37 - 7.20(m, 5H), 5.35 - 5.24(m, 1H), 4.63 - 3.89(m, 4H), 3.31 - 3.18(m, 1H), 3.17 - 3.03(m, 1H), 2.54(d, J = 4.2 Hz, 3H).

[0335] Example 31 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-6-yl)-3-phenylpropanamide

[0336]

Chemical formula

[0337] 1i of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 113.42 μmol), 31a of 2-methyl-2H-indazol-6-amine (25.04 mg, 170.13 μmol), N,N-diisopropylethylamine (73.29 mg, 567.10 μmol, 93.72 μL) and propylphosphonic anhydride (50% ethyl acetate solution, 216.41 mg, 340.26 μmol, 202.44 μL) were successively dissolved in ethyl acetate (5 mL), and reacted continuously with stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-6-yl)-3-phenylpropanamide 31 (21.7 mg) in a yield of 33%.

[0338] MS m / z (ESI): 569.9 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.72 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.75 (dd, J = 8.6, 2.1 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.39 - 7.17 (m, 5H), 7.08 (d, J = 9.1 Hz, 1H), 5.38 (dd, J = 10.1, 5.8 Hz, 1H), 4.54 - 4.07 (m, 4H), 4.13 (s, 3H), 3.99 (d, J = 17.2, 1H), 3.33 - 3.19 (m, 1H), 3.18 - 3.04 (m, 1H).

[0339] Example 32 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[0340]

Chemical Structure

[0341] Step 1 N-(tert-Butoxycarbonyl)O-methyl homoserine methyl ester N-Boc-L-homoserine 32a (1 g, 4.56 mmol) was dissolved in N,N-dimethylformamide (20 mL). Sodium hydride (383.15 mg, 9.58 mmol, 60%) was added in an ice bath and reacted for 20 minutes. Then, methyl iodide (2.59 g, 18.25 mmol, 1.14 mL) was slowly added dropwise and reacted overnight at room temperature. Water was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain N-(tert-butoxycarbonyl)O-methyl homoserine methyl ester 32b (370 mg) in a yield of 32%.

[0342] MS M / z (ESI): 147.1 [M - 100].

[0343] Step 2 O-Methyl homoserine methyl ester N-(tert-Butoxycarbonyl)O-methyl homoserine methyl ester 32b (370 mg, 1.50 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain O-methyl homoserine methyl ester 32c (384 mg), which was directly used in the next step.

[0344] MS m / z (ESI): 148.1 [M+H].

[0345] Step 3 N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine methyl ester 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (369.76 mg, 1.36 mmol) and O-methylhomoserine methyl ester 32c (390 mg, 1.49 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (1.05 g, 8.15 mmol, 1.35 mL) was added, and the mixture was reacted at 80 °C overnight. Water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine methyl ester 32d (400 mg) in a yield of 77%.

[0346] MS m / z (ESI): 382.9 [M+H].

[0347] Step 4 N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine methyl ester N-(2-((5-Chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine methyl ester 32d (400 mg, 1.04 mmol) was dissolved in dichloromethane (10 mL), triethylamine (528.68 mg, 5.22 mmol, 726.21 μL) was added, and then chloroacetyl chloride (177.03 mg, 1.57 mmol, 124.67 μL) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 1 hour. Water was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine methyl ester 32e (194 mg) in a yield of 41%.

[0348] MS m / z(ESI): 458.9[M+H].

[0349] Step 5 Methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)4-methoxybutanoate N-(2-((5-Chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine methyl ester 32e (194 mg, 422.40 μmol) was dissolved in methanol (5 mL), and sodium methylate (5.4 M methanol solution, 86.04 μL, 2.28 mmol) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 30 minutes. After the reaction was completed, 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)4-methoxybutanoate 32f (100 mg) in a yield of 56%.

[0350] MS m / z (ESI): 422.9 [M+H].

[0351] Step 6 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoic acid Methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)4-methoxybutanoate 32f (100 mg, 236.51 μmol) was dissolved in a mixed solution of tetrahydrofuran, methanol and water (3 mL + 1 mL + 1 mL), lithium hydroxide monohydrate (19.85 mg, 473.01 μmol) was added in an ice bath, and the reaction was carried out in an ice bath for 1 hour. After the reaction was completed, 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoic acid 32g (65 mg) in a yield of 65%.

[0352] MS m / z (ESI): 408.9 [M+H].

[0353] Step 7 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 32 g (65 mg, 159.00 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxoperazin-1-yl)-4-methoxybutanoic acid and 19a (35.10 mg, 238.51 μmol) of 2-methyl-2H-indazol-5-amine were dissolved in ethyl acetate (5 mL), propylphosphonic anhydride (50% ethyl acetate solution, 303.55 mg, 477.01 μmol) and N,N-diisopropylethylamine (123.30 mg, 954.02 μmol, 157.67 μL) were added, and the reaction was carried out at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 32 (16 mg) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide in a yield of 17%.

[0354] MS m / z(ESI):537.9[M+H] 1 H NMR(400MHz, DMSO-d6) δ 10.07(s, 1H), 9.81(s, 1H), 8.25(s, 1H), 8.08(s, 1H), 7.91(s, 1H), 7.88 - 7.73(m, 2H), 7.53(d, J = 9.1Hz, 1H), 7.27(d, J = 9.3Hz, 1H), 5.23 - 5.01(s, 1H), 4.80 - 4.00(m, 4H), 4.13(s, 3H), 3.97 - 3.69(m, 2H) 3.28(s, 3H), 2.18 - 1.91(m, 2H).

[0355] Example 33 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-3-phenylpropanamide

[0356]

Chemical Structure

[0357] Project 1 1-Difluoromethyl-5-nitroindazole 33b 2-Difluoromethyl-5-nitroindazole 33c 5-Nitroindazole 33a (3 g, 18.39 mmol) was dissolved in N,N-dimethylformamide (80 mL), sodium hydride (1.47 g, 36.78 mmol, 60%) was added in an ice bath, and the mixture was stirred in the ice bath for 10 minutes. Then, sodium difluorochloroacetate (5.61 g, 36.78 mmol) was added, and the reaction was carried out at room temperature for 30 minutes after addition. Then, it was heated to 80 °C and reacted for 2 hours. Water was added to the reaction solution to quench the reaction, and then it was extracted with ethyl acetate (30 mL × 3). The organic phases were mixed, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 1-difluoromethyl-5-nitroindazole 33b (1.3 g) in a yield of 33% and 2-difluoromethyl-5-nitroindazole 33c (1.7 g) in a yield of 43%.

[0358] 33b MS m / z (ESI): 213.9 [M+H] 33c MS m / z (ESI): 213.9 [M+H].

[0359] Project 2 1-(Difluoromethyl)-1H-indazol-5-amine 1-Difluoromethyl-5-nitroindazole 33b (300 mg, 1.41 mmol) was dissolved in a mixed solvent of ethanol (24 mL) and water (6 mL), iron powder (786.10 mg, 14.08 mmol) and ammonium chloride (150.58 mg, 2.82 mmol) were added, and the reaction was carried out at 80 °C for 2 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 1-(difluoromethyl)-1H-indazol-5-amine 33d (214 mg) in a yield of 83%.

[0360] MS m / z (ESI): 184.0 [M+H].

[0361] Project 3 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-3-phenylpropanamide 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (75 mg, 170.13 μmol) and 1-(difluoromethyl)-1H-indazol-5-amine 33d (47 mg, 255.2 μmol) were dissolved in ethyl acetate (8 mL), propylphosphonic anhydride (50% ethyl acetate solution, 324.61 mg, 510.39 μmol) and N,N-diisopropylethylamine (131.93 mg, 1.02 mmol, 168.70 μL) were added, and the reaction was carried out at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-3-phenylpropanamide 33 (12 mg) in a yield of 11%.

[0362] MS m / z (ESI): 605.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.73 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.14 (t, J = 58.3 Hz, 1H), 7.96 - 7.54 (m, 5H), 7.49 - 7.09 (m, 5H), 5.36 (s, 1H), 4.64 - 3.88 (m, 4H), 3.35 - 3.19 (m, 1H), 3.17 - 3.00 (m, 1H).

[0363] Example 34 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide

[0364]

Chem.

[0365] Step 1 2-(Difluoromethyl)-2H-indazol-5-amine 2-Difluoromethyl-5-nitroindazole 33c (300 mg, 1.41 mmol) was dissolved in a mixed solvent of ethanol (24 mL) and water (6 mL), iron powder (786.10 mg, 14.08 mmol) and ammonium chloride (150.58 mg, 2.82 mmol) were added, and the reaction was carried out at 80 °C for 2 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(difluoromethyl)-2H-indazol-5-amine 34a (200 mg) in a yield of 78%.

[0366] MS m / z (ESI): 184.0 [M+H].

[0367] Step 2 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (75 mg, 170.13 μmol) and 2-(difluoromethyl)-2H-indazol-5-amine 34a (47 mg, 255.2 μmol) were dissolved in ethyl acetate (8 mL), propylphosphonic anhydride (50% ethyl acetate solution, 324.61 mg, 510.39 μmol) and N,N-diisopropylethylamine (131.93 mg, 1.02 mmol, 168.70 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 34 (20 mg) in a yield of 19%.

[0368] MS m / z(ESI): 605.8[M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.25(s, 1H), 9.72(d, J = 1.6 Hz, 1H), 8.81(s, 1H), 8.22(s, 1H), 8.10(t, J = 59.0 Hz, 1H), 7.90 - 7.59(m, 4H), 7.39(d, J = 9.4 Hz, 1H), 7.37 - 7.17(m, 5H), 5.48 - 5.26(m, 1H), 4.73 - 3.87(m, 4H), 3.31 - 3.19(m, 1H), 3.17 - 3.02(m, 1H).

[0369] Example 35 4-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-2-fluorobenzamide

[0370]

Chemical formula

[0371] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 1i (60 mg, 136.10 μmol) and 4-amino-2-fluorobenzamide 35a (31.47 mg, 204.16 μmol, prepared according to the description on page 19, paragraphs 0503 - 0505, Example 1.1B of Patent Gazette US20170275282 A1) were dissolved in ethyl acetate (6 mL), propylphosphonic anhydride (50% ethyl acetate solution, 259.83 mg, 408.31 μmol) and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) were added, and the mixture was reacted at 60 °C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-2-fluorobenzamide 35 (21 mg) in a yield of 27%.

[0372] MS m / z(ESI): 576.8[M + H] 1 H NMR(400 MHz, DMSO-d6) δ 10.55(s, 1H), 9.72(s, 1H), 7.84 - 7.60(m, 5H), 7.60 - 7.50(m, 2H), 7.41 - 7.18(m, 6H), 5.39 - 5.21(m, 1H), 4.57 - 3.86(m, 4H), 3.29 - 3.16(m, 1H), 3.15 - 3.04(m, 1H).

[0373] Example 36 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-2-fluorobenzamide

[0374]

Chemical formula

[0375] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 105.42 μmol) and 4-amino-2-fluorobenzamide 35a (24.37 mg, 158.13 μmol, prepared according to the description on page 19, paragraphs 0503 - 0505, Example 1.1B of Patent Publication US20170275282 A1) were dissolved in ethyl acetate (5 mL), N,N-diisopropylethylamine (81.75 mg, 632.52 μmol) and propylphosphonic anhydride (50% ethyl acetate solution, 201.25 mg, 316.26 μmol) were added, and the reaction was carried out at 60 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)-2-fluorobenzamide 36 (17 mg) in a yield of 26%.

[0376] MS m / z (ESI): 609.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.64 (s, 1H), 7.86 - 7.61 (m, 5H), 7.60 - 7.46 (m, 2H), 7.44 - 7.18 (m, 6H), 5.44 - 5.24 (m, 1H), 4.54 - 3.91 (m, 4H), 3.29 - 3.22 (m, 1H), 3.19 - 3.05 (m, 1H).

[0377] Example 37 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide

[0378]

Chemical formula

[0379] 1i, 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (80 mg, 181.47 μmol) and pyrazolo[1,5-a]pyridin-5-amine 37a (36.24 mg, 272.21 μmol) were dissolved in ethyl acetate (5 mL), and propylphosphonic anhydride (50% ethyl acetate solution, 346.45 mg, 544.42 μmol) and N,N-diisopropylethylamine (117.27 mg, 907.36 μmol) were added. The mixture was reacted at 60 °C for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide 37 (50 mg) in a yield of 49%.

[0380] MS m / z (ESI): 555.7 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.72 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.89 - 7.65 (m, 2H), 7.44 - 7.13 (m, 6H), 6.92 (d, J = 7.5 Hz, 1H), 6.52 (s, 1H), 5.41 - 5.25 (m, 1H), 4.71 - 3.91 (m, 4H), 3.30 - 3.17 (m, 1H), 3.15 - 3.03 (m, 1H).

[0381] Example 38 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[0382]

Chemical formula

[0383] Project 1 N-(2-((5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl) O-methylhomoserine methyl ester 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (1 g, 3.27 mmol) and O-methylhomoserine methyl ester 32c (1.71 g, 6.55 mmol) were dissolved in N,N-dimethylformamide (15 mL), N,N-diisopropylethylamine (2.11 g, 16.36 mmol, 2.70 mL) was added, and the mixture was reacted at 75 °C overnight. 30 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl) O-methylhomoserine methyl ester 38a (1.1 g) in a yield of 81%.

[0384] MS m / z (ESI): 415.9 [M+H].

[0385] Project 2 N-(2-((5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl) O-methylhomoserine methyl ester N-(2-((5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl) O-methylhomoserine methyl ester 38a (400 mg, 1.04 mmol) was dissolved in acetonitrile (8 mL), potassium carbonate (1.66 g, 12.01 mmol) was added, and chloroacetyl chloride (542.66 mg, 4.80 mmol, 382.15 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 1 hour. 30 mL of water was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate (30 mL × 3). Then the organic phases were combined, 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: system A) to give N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine methyl ester 38b (700 mg) in a yield of 59%.

[0386] MS m / z(ESI): 491.8[M+H].

[0387] Step 3 Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoate N-(2-((5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)O-methylhomoserine methyl 38b (650 mg, 1.32 mmol) was dissolved in methanol (20 mL), and sodium methylate (5.4 M methanol solution, 268.72 μL, 1.45 mmol) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 30 minutes. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A), and methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoate 38c (505 mg) was obtained in a yield of 84%.

[0388] MS m / z(ESI): 455.8[M+H].

[0389] Step 4 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoic acid Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoate 38c (470 mg, 1.03 mmol) was dissolved in a mixed solvent of tetrahydrofuran (9 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide monohydrate (86.44 mg, 2.06 mmol) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 2 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B), and 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoic acid 38d (346 mg) was obtained in a yield of 76%.

[0390] MS m / z (ESI): 442.1 [M+H].

[0391] Project 5 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxybutanoic acid 38d (100 mg, 226.12 μmol) and 2-methyl-2H-indazol-5-amine 19a (49.92 mg, 339.17 μmol) were dissolved in ethyl acetate (8 mL), propylphosphonic anhydride (50% ethyl acetate solution, 431.67 mg, 678.35 μmol) and N,N-diisopropylethylamine (175.34 mg, 1.36 mmol, 224.22 μL) were added, and the mixture was reacted at 60 °C for 1 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 38 (65 mg) in a yield of 50%.

[0392] MS m / z (ESI): 570.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.74 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.80 - 7.68 (m, 2H), 7.53 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 9.4 Hz, 1H), 5.12 (s, 1H), 4.69 - 3.95 (m, 4H), 4.13 (s, 3H), 3.49 - 3.40 (m, 1H), 3.39 - 3.15 (m, 1H), 3.26 (s, 3H), 2.19 - 1.96 (m, 2H).

[0393] Example 39 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide

[0394]

Chemical formula

[0395] Step 1 tert-Butyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate tert-Butyl 2-((diphenylmethylene)amino)acetate 39a (3 g, 10.16 mmol) was dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (1.25 g, 11.17 mmol) was added in one portion at 0 °C, and the mixture was reacted at 0 °C for 15 minutes. Then, (bromomethyl)cyclobutane 39b (1.66 g, 11.17 mmol, 1.25 mL) was added, and the reaction was allowed to proceed to room temperature and then for 3 hours. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). Then, 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 a crude product (2.9 g) of tert-butyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate 39c, which was used directly in the next reaction.

[0396] MS m / z (ESI): 364.2 [M+H].

[0397] Step 2 Ethyl 2-amino-3-cyclobutylpropanoate The crude product of tert-butyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate 39c obtained in the previous step was dissolved in tetrahydrofuran (20 mL), 2 M dilute hydrochloric acid (20 mL) was added, and the mixture was reacted overnight at room temperature. A saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 2-amino-3-cyclobutylpropanoate 39d (1.06 g) in a yield of 66%.

[0398] MS m / z(ESI): 144.1[M + H - 56].

[0399] Step 3 tert-Butyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (350 mg, 1.29 mmol) and tert-butyl 2-amino-3-cyclobutylpropanoate 39d (563.98 mg, 2.83 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (831.23 mg, 6.43 mmol, 1.06 mL) was added, and the mixture was reacted at 70 °C for 15 hours. 30 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate 39e (390 mg) in a yield of 70%.

[0400] MS m / z (ESI): 435.0 [M+H]+.

[0401] Step 4 tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate tert-Butyl 2-((2-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate 39e (240 mg, 551.83 μmol) was dissolved in acetonitrile (10 mL), potassium carbonate (381.34 mg, 2.76 mmol) was added, and chloroacetyl chloride (124.65 mg, 1.10 mmol, 87.78 μL) was slowly added dropwise in an ice bath. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). Then the organic phases were combined, washed successively 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 (282 mg) of tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate 39f, which was used directly in the next reaction.

[0402] MS m / z (ESI): 510.9 [M+H]+.

[0403] Step 5 tert-Butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoate The crude product (282 mg, 551.43 μmol) of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate 39f obtained in the previous step was dissolved in methanol (9.88 mL), and sodium methylate (5.4 M methanol solution, 122.54 μL, 661.72 μmol) was slowly added dropwise at 0 °C, followed by continuous reaction at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoate 39g (96 mg) in a yield of 37%.

[0404] MS m / z(ESI): 475.1[M+H].

[0405] Step 6 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoic acid tert-Butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoate 39g (90 mg, 189.50 μmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise, followed by reaction at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product (79 mg) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoic acid 39h, which was directly used in the next reaction.

[0406] MS m / z(ESI): 418.9[M+H].

[0407] Step 7 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product (79 mg, 188.62 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoic acid 39h obtained in the previous step and 2-methyl-2H-indazol-5-amine 19a (41.64 mg, 282.93 μmol) were dissolved in ethyl acetate (6 mL), propylphosphonic anhydride (50% ethyl acetate solution, 360.09 mg, 565.86 μmol) and N,N-diisopropylethylamine (146.26 mg, 1.13 mmol) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propionamide 39 (40 mg) in a yield of 38%.

[0408] MS m / z (ESI): 548.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.79 (d, J = 5.7 Hz, 1H), 8.24 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.87 - 7.71 (m, 2H), 7.62 - 7.45 (m, 1H), 7.34 - 7.18 (m, 1H), 5.08 - 4.91 (m, 1H), 4.81 - 4.00 (m, 4H), 4.12 (d, J = 5.7 Hz, 3H), 2.18 - 1.49 (m, 9H).

[0409] Example 40 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide

[0410]

Chem.

[0411] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (50 mg, 150.42 μmol) and pyrazolo[1,5-a]pyridin-5-amine 37a (21.05 mg, 158.13 μmol) were dissolved in ethyl acetate (5 mL), propylphosphonic anhydride (50% ethyl acetate solution, 201.14 mg, 316.26 μmol, 188.16 μL) and N,N-diisopropylethylamine (68.12 mg, 527.10 μmol, 87.11 μL) were added, and the reaction was carried out at 60 °C for 15 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide 40 (46.9 mg) in a yield of 75%.

[0412] MS m / z (ESI): 588.8 [M+H] 11H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.65 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.81 - 7.62 (m, 3H), 7.37 - 7.15 (m, 5H), 6.92 (dd, J = 7.4, 2.3 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 5.47 - 5.22 (m, 1H), 4.48 - 3.91 (m, 4H), 3.34 - 3.20 (m, 1H), 3.18 - 3.03 (m, 1H).

[0413] Example 41 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0414] [Chemical formula]

[0415] Step 1 Ethyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (0.3 g, 1.10 mmol) and ethyl 2-amino-3-(4-fluorophenyl)propanoate 41a (1.71 g, 6.55 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (712.48 mg, 5.51 mmol) was added, and the mixture was stirred at 60 °C for 16 h to effect the reaction. 30 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain ethyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 41b (348 mg) in a yield of 71%.

[0416] MS m / z (ESI): 446.9 [M+H].

[0417] Step 2 Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate Ethyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 41b (348 mg, 778.76 μmol) was dissolved in acetonitrile (10 mL), potassium carbonate (214.94 mg, 1.56 mmol) was added, and chloroacetyl chloride (131.93 mg, 1.17 mmol, 93.57 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. 30 mL of water was added to the reaction solution to quench the reaction, and then it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to give ethyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate 41c (250 mg) in a yield of 61%.

[0418] MS m / z (ESI): 523.2 [M+H].

[0419] Step 3 Ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxoperazin-1-yl)-3-(4-fluorophenyl)ethylpropionate Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate 41c (260 mg, 496.81 μmol) was dissolved in methanol (5 mL), and sodium methylate (5.4 M methanol solution, 110.40 μL, 596.16 mmol) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate 41d (100 mg) in a yield of 41%.

[0420] MS m / z (ESI): 487.1 [M+H].

[0421] Step 4 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid Ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate 41d (100 mg, 205.39 μmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide monohydrate (12.94 mg, 308.08 μmol) was added in an ice bath, followed by reaction in the ice bath for 4 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 41e (64 mg) in a yield of 68%.

[0422] MS m / z (ESI): 459.0 [M+H]+

[0423] Project 5 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 41e (64 mg, 139.49 μmol) and 2-methyl-2H-indazol-5-amine 19a (30.79 mg, 209.23 μmol) were dissolved in ethyl acetate (8 mL), propylphosphonic anhydride (50% ethyl acetate solution, 266.29 mg, 418.46 μmol) and N,N-diisopropylethylamine (175.34 mg, 1.36 mmol, 224.22 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 41 (30 mg) in a yield of 36%.

[0424] MS m / z (ESI): 588.2 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.73 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.90 - 7.68 (m, 3H), 7.55 (d, J = 9.1 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.27 - 7.19 (m, 1H), 7.19 - 7.09 (m, 2H), 5.39 - 5.29 (m, 1H), 4.60 - 3.92 (m, 4H), 4.13 (s, 3H), 3.27 - 3.16 (m, 1H), 3.15 - 3.04 (m, 1H).

[0425] Example 42 4-(2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)-2-fluoro-N-methylbenzamide

[0426]

Chemical formula

[0427] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 24h (50 mg, 150.42 μmol) and 4-amino-2-fluoro-N-methylbenzamide 20a (226.59 mg, 158.13 μmol) were dissolved in ethyl acetate (10 mL), N,N-diisopropylethylamine (68.12 mg, 527.10 μmol) and propylphosphonic anhydride (50% ethyl acetate solution, 201.26 mg, 316.26 μmol) were added, and the mixture was reacted at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)-2-fluoro-N-methylbenzamide 42 (57 mg) in a yield of 86%.

[0428] MS m / z (ESI): 623.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.63 (s, 1H), 8.14 - 8.04 (m, 1H), 7.84 - 7.56 (m, 5H), 7.40 - 7.17 (m, 6H), 5.40 - 5.24 (m, 1H), 4.48 - 3.90 (m, 4H), 3.32 - 3.20 (m, 1H), 3.17 - 3.04 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H).

[0429] Example 43 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-3-yl)propanamide

[0430]

Chemical formula

[0431] Step 1 tert-Butyl 2-((diphenylmethylene)amino)-3-(pyridin-3-yl)propanoate tert-Butyl 2-((diphenylmethylene)amino)acetate 39a (2.95 g, 10 mmol) was dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (2.47 g, 22.00 mmol) was added batchwise at 0 °C, and the reaction was carried out at 0 °C for 15 minutes. Then, 3-(bromomethyl)pyridine hydrobromide 43a (2.77 g, 11.00 mmol) was added and the reaction was carried out. The temperature was raised to room temperature and then the reaction was carried out for 3 hours. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). Then, the organic phases were combined, washed successively 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 a crude product (3.86 g) of tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-3-yl)propanoate 43b, which was used directly in the next reaction.

[0432] MS m / z (ESI): 387.0 [M+H].

[0433] Step 2 tert-Butyl 2-amino-3-(pyridin-3-yl)propanoate The crude product (3.86 g, 10 mmol) of tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-3-yl)propanoate 43b obtained in the previous step was dissolved in tetrahydrofuran (20 mL), 2 M dilute hydrochloric acid (20 mL) was added, and the reaction was carried out overnight at room temperature. A saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 2-amino-3-(pyridin-3-yl)propanoate 43c (1.06 g) in a yield of 39%.

[0434] MS m / z(ESI): 222.9[M+H].

[0435] Step 3 tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-3-yl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (200 mg, 654.56 μmol) and tert-butyl 2-amino-3-(pyridin-3-yl)propanoate 43c (291.2 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (6 mL), N,N-diisopropylethylamine (422.98 mg, 3.27 mmol, 540.89 μL) was added, and the mixture was reacted at 75 °C for 6 hours. 40 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed successively with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-3-yl)propanoate 43d (299 mg) in a yield of 93%.

[0436] MS m / z (ESI): 490.9 [M+H].

[0437] Step 4 tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(pyridin-3-yl)propanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-3-yl)propanoate 43d (299 mg, 608.50 μmol) was dissolved in dichloromethane (10 mL), triethylamine (307.87 mg, 3.04 mmol, 422.90 μL) was added, and chloroacetyl chloride (103.09 mg, 912.76 μmol, 72.60 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). Then the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (345 mg) of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(pyridin-3-yl)propanoate 43e, which was used directly in the next reaction.

[0438] MS m / z (ESI): 566.8 [M+H].

[0439] Step 5 tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propanoate The crude product (345 mg, 607.55 μmol) of 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(pyridin-3-yl)propanoic acid tert-butyl 43e obtained in the previous step was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 135.01 μL, 729.05 μmol) was slowly added dropwise at 0 °C, and the reaction was continuously carried out at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid tert-butyl 43f (220 mg) in a yield of 68%.

[0440] MS m / z(ESI): 531.1[M+H].

[0441] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid tert-butyl 43f (220 mg, 414.01 μmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product (196 mg) of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid 43g, which was directly used in the next reaction.

[0442] MS m / z (ESI): 474.8 [M+H]+

[0443] Step 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-3-yl)propanamide 43 g of the crude product (196 mg, 412.38 μmol) of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid obtained in the previous step and 2-methyl-2H-indazol-5-amine 19a (91.04 mg, 618.58 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 524.85 mg, 824.77 μmol) and N,N-diisopropylethylamine (266.48 mg, 2.06 mmol, 340.77 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-3-yl)propanamide 43 (14 mg) in a yield of 5%.

[0444] MS m / z (ESI): 603.8 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.86 - 7.62 (m, 4H), 7.55 (d, J = 9.1 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.28 - 7.18 (m, 1H), 5.42 (s, 1H), 4.43 - 4.01 (m, 4H), 4.14 (s, 3H), 3.19 - 3.07 (m, 2H).

[0445] Example 44 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0446] [Chemical formula]

[0447] Step 1 tert-Butyl 2-((diphenylmethylene)amino)-3-(2-fluorophenyl)propanoate tert-Butyl 2-((diphenylmethylene)amino)acetate 39a (2.95 g, 10 mmol) was dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (1.23 g, 11.00 mmol) was added in one portion at 0 °C, and the mixture was reacted at 0 °C for 15 minutes. Then, 1-(bromomethyl)-2-fluorobenzene 44a (2.08 g, 11.00 mmol) was added, and the reaction was allowed to proceed to room temperature and then for 3 hours. 40 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). Then, the organic phases were combined, washed successively with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product (4 g) of tert-butyl 2-((diphenylmethylene)amino)-3-(2-fluorophenyl)propanoate 44b, which was used directly in the next reaction.

[0448] MS m / z (ESI): 404.0 [M+H].[[]END]]

[0449] Step 2 tert-Butyl 2-amino-3-(2-fluorophenyl)propanoate The crude product (4 g, 10 mmol) of tert-butyl 2-((diphenylmethylene)amino)-3-(2-fluorophenyl)propanoate 44b obtained in the previous step was dissolved in tetrahydrofuran (20 mL), 2 M dilute hydrochloric acid (20 mL) was added, and the mixture was reacted overnight at room temperature. A saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and then the mixture was extracted with ethyl acetate (30 mL × 3), washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 1.41 g of tert-butyl 2-amino-3-(2-fluorophenyl)propanoate 44c in a yield of 59%.

[0450] MS m / z(ESI): 184.1[M+H-56].

[0451] Step 3 tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(2-fluorophenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (200 mg, 654.56 μmol) and tert-butyl 2-amino-3-(2-fluorophenyl)propanoate 44c (313.25 mg, 1.31 mmol) were dissolved in N,N-dimethylformamide (6 mL), N,N-diisopropylethylamine (422.98 mg, 3.27 mmol, 540.89 μL) was added, and the mixture was reacted at 75 °C for 6 hours. 80 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed successively with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(2-fluorophenyl)propanoate 44d (286 mg) in a yield of 86%.

[0452] MS m / z (ESI): 507.9 [M+H].

[0453] Step 4 tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(2-fluorophenyl)propanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(2-fluorophenyl)propanoate 44d (286 mg, 562.58 μmol) was dissolved in dichloromethane (10 mL), triethylamine (284.64 mg, 2.81 mmol, 390.99 μL) was added, and chloroacetyl chloride (95.31 mg, 843.87 μmol, 67.12 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 h. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). Then the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (329 mg) of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(2-fluorophenyl)propanoate 44e, which was used directly in the next reaction.

[0454] MS m / z (ESI): 584.4 [M+H].

[0455] Step 5 tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)propanoate 2-(2-Chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(2-fluorophenyl)propanoic acid tert-butyl 44e (329 mg, 562.53 μmol) obtained in the previous step was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 114.59 μL, 618.79 μmol) was slowly added dropwise at 0 °C, and the reaction was continuously carried out at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)propanoic acid tert-butyl 44f (230 mg) in a yield of 75%.

[0456] MS m / z(ESI): 547.8[M+H].

[0457] Step 6 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)propionic acid 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)propanoic acid tert-butyl 44f (230 mg, 419.41 μmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product (206 mg) of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)propanoic acid 44g, which was directly used in the next reaction.

[0458] MS m / z (ESI): 491.8 [M+H]+

[0459] Step 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product (206 mg, 418.46 μmol) of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)propanoic acid 44 g obtained in the previous step and 2-methyl-2H-indazol-5-amine 19a (92.38 mg, 627.68 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 532.58 mg, 836.91 μmol) and N,N-diisopropylethylamine (270.41 mg, 2.09 mmol, 345.79 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(2-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 44 (136 mg) in a yield of 52%.

[0460] MS m / z (ESI): 620.8 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.69 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.82 - 7.65 (m, 3H), 7.53 (d, J = 9.1 Hz, 1H), 7.38 - 7.26 (m, 2H), 7.26 - 7.10 (m, 3H), 5.39 - 5.30 (m, 1H), 4.50 - 4.00 (m, 4H), 4.13 (s, 3H), 3.33 - 3.20 (m, 1H), 3.19 - 3.06 (m, 1H).

[0461] Example 45 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide

[0462] [Chemical Formula]

[0463] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid (67 mg, 141.26 μmol) and 2-(difluoromethyl)-2H-indazol-5-amine 34a (38.8 mg, 211.89 μmol) were dissolved in ethyl acetate (5 mL), propylphosphonic anhydride (50% ethyl acetate solution, 179.79 mg, 282.52 μmol) and N,N-diisopropylethylamine (73.03 mg, 565.05 μmol, 93.38 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 45 (20 mg) in a yield of 21%.

[0464] MS m / z (ESI): 638.7 [M+H] 11H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 8.25 (s, 1H), 8.10 (t, J = 59.1 Hz, 1H), 7.84 - 7.58 (m, 4H), 7.44 - 7.16 (m, 6H), 5.47 - 5.31 (m, 1H), 4.56 - 3.88 (m, 4H), 3.36 - 3.22 (m, 1H), 3.20 - 3.03 (m, 1H).

[0465] Example 46 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0466]

Chemical Structure

[0467] Step 1 tert-Butyl 2-((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate tert-Butyl 2-((diphenylmethylene)amino)acetate 39a (3.75 g, 12.70 mmol) was dissolved in N,N-dimethylformamide (30 mL). Potassium tert-butoxide (1.31 g, 11.64 mmol) was added batchwise at 0 °C, and the reaction was carried out at 0 °C for 15 minutes. Then 1-(bromomethyl)-3-fluorobenzene 46a (2 g, 10.58 mmol) was added and the reaction was carried out. The temperature was raised to room temperature and then the reaction was carried out for 3 hours. 40 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). Then the organic phases were combined, washed successively with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product (4.269 g) of tert-butyl 2-((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate 46b, which was used directly in the next reaction.

[0468] MS m / z (ESI): 404.2 [M+H]+.

[0469] Step 2 tert-Butyl 2-amino-3-(3-fluorophenyl)propanoate The crude product (4.269 g, 10.58 mmol) of tert-butyl 2-((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate 46b obtained in the previous step was dissolved in tetrahydrofuran (10 mL), 2 M dilute hydrochloric acid (10 mL) was added, and the mixture was reacted overnight at room temperature. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to obtain tert-butyl 2-amino-3-(3-fluorophenyl)propanoate 46c (1.98 g) in a yield of 78%.

[0470] MS m / z (ESI): 184.1 [M+H - 56]+.

[0471] Step 3 tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(3-fluorophenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (250 mg, 818.20 μmol) and tert-butyl 2-amino-3-(3-fluorophenyl)propanoate 46c (293.68 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (528.72 mg, 4.09 mmol, 676.11 μL) was added, and the mixture was reacted at 80 °C for 5 hours. 80 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed successively with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(3-fluorophenyl)propanoate 46d (220 mg) in a yield of 53%.

[0472] MS m / z (ESI): 508.1 [M+H].

[0473] Step 4 tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(3-fluorophenyl)propanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(3-fluorophenyl)propanoate 46d (220 mg, 432.75 μmol) was dissolved in dichloromethane (10 mL), triethylamine (43.71 mg, 432.75 μmol, 60.04 μL) was added, and chloroacetyl chloride (73.31 mg, 649.13 μmol, 51.66 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. 30 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). Then, the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (232 mg) of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(3-fluorophenyl)propanoate 46e, which was used directly in the next reaction.

[0474] MS m / z(ESI):527.7[M+H-56].

[0475] Step 5 tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)propanoate The crude product (230 mg, 393.26 μmol) of 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(3-fluorophenyl)propanoic acid tert-butyl 46e obtained in the previous step was dissolved in methanol (6 mL), and sodium methylate (5.4 M methanol solution, 72.83 μL, 393.28 μmol) was slowly added dropwise at 0 °C, and the reaction was continuously carried out at 0 °C for 2 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid tert-butyl 46f (154 mg) in a yield of 71%.

[0476] MS m / z(ESI): 491.8[M+H-56].

[0477] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid tert-butyl 46f (154 mg, 280.82 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product (100 mg) of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid 46g, which was directly used in the next reaction.

[0478] MS m / z (ESI): 491.8 [M+H].

[0479] Step 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product (100 mg, 203.13 μmol) of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid 46 g obtained in the previous step and 2-methyl-2H-indazol-5-amine 19a (44.84 mg, 304.70 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 387.80 mg, 609.40 μmol) and N,N-diisopropylethylamine (131.26 mg, 1.02 mmol, 167.85 μL) were added, and the mixture was reacted at 60 °C for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(3-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 46 (49 mg) in a yield of 39%.

[0480] MS m / z (ESI): 620.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.81 - 7.63 (m, 3H), 7.55 (d, J = 9.2 Hz, 1H), 7.36 (q, J = 7.4 Hz, 1H), 7.28 - 7.02 (m, 4H), 5.49 - 5.34 (m, 1H), 4.48 - 3.90 (m, 4H), 4.14 (s, 3H), 3.34 - 3.22 (m, 1H), 3.20 - 3.07 (m, 1H).

[0481] Example 47 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0482] [Chemical formula]

[0483] Step 1 Ethyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (220 mg, 720.02 μmol) and ethyl 2-amino-3-(4-fluorophenyl)propanoate 41a (228.14 mg, 921.05 μmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (465.28 mg, 3.60 mmol) was added, and the mixture was stirred at 60 °C for 5 hours to react. 30 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed successively with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain ethyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 47a (130 mg) in a yield of 38%.

[0484] MS m / z (ESI): 479.8 [M+H].

[0485] Step 2 Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate Ethyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate (47a, 130 mg, 270.65 μmol) was dissolved in dichloromethane (10 mL), triethylamine (109.55 mg, 1.08 mmol) was added, and chloroacetyl chloride (45.85 mg, 405.98 μmol, 32.33 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. 30 mL of water was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain ethyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate (47b, 150 mg) in a yield of 99.5%.

[0486] MS m / z (ESI): 555.7 [M+H].

[0487] Step 3 Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate 47b (150 mg, 269.40 μmol) was dissolved in methanol (8 mL), and sodium methylate (5.4 M methanol solution, 49.89 μL, 269.41 mmol) was slowly added dropwise in an ice bath, and the reaction was continuously carried out in the ice bath for 2 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate 47c (87 mg) in a yield of 64%.

[0488] MS m / z (ESI): 506.0 [M+H].

[0489] Step 4 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate 47c (87 mg, 171.82 μmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL), methanol (2 mL) and water (2 mL), and lithium hydroxide monohydrate (7.22 mg, 171.82 μmol) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 3 hours. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and then the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (67 mg) in a yield of 79%.

[0490] MS m / z(ESI): 491.8[M+H].

[0491] Step 5 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (67 mg, 136.10 μmol) and 2-methyl-2H-indazol-5-amine 19a (30.05 mg, 204.15 μmol) were dissolved in ethyl acetate (10 mL), and propylphosphonic anhydride (50% ethyl acetate solution, 259.82 mg, 408.3 μmol) and N,N-diisopropylethylamine (87.9 mg, 680.5 μmol, 112.47 μmol) were added, and the reaction was carried out at 60 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 47 (41 mg) in a yield of 47%.

[0492] MS m / z(ESI): 620.8[M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.12(s, 1H), 8.66(s, 1H), 8.26(s, 1H), 8.10(s, 1H), 7.87 - 7.63(m, 3H), 7.54(d, J = 9.2 Hz, 1H), 7.42 - 6.96(m, 5H), 5.46 - 5.28(m, 1H), 4.60 - 3.91(m, 4H), 4.13(s, 3H), 3.29 - 3.18(m, 1H), 3.16 - 3.04(m, 1H).

[0493] Example 48 was synthesized according to the synthesis methods of Examples 1 to 47 of the present invention. The spectral parameters of Example 48 are shown in the following table:

[0494]

Table 3

[0495] Example 49 4-(2-(4-(2-Acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid

[0496]

Chem.

[0497] Step 1 Ethyl (2-bromo-5-chlorophenyl)glycinate 2-Bromo-5-chloroaniline 49a (5 g, 24.2 mmol) and ethyl bromoacetate 49b (8.08 g, 5.4 mL, 48.4 mmol) were dissolved in N,N-dimethylformamide (60 mL). Potassium tert-butoxide (5.4 g, 48.4 mmol) was added in an ice bath and stirred for 10 minutes in the ice bath, then heated to 100 °C and reacted overnight. Water (300 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed successively with water (200 mL × 2) and saturated sodium chloride solution (20 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: system A) to obtain ethyl (2-bromo-5-chlorophenyl)glycinate 49c (7.08 g) in a yield of 100%.

[0498] MS m / z (ESI): 291.9 [M+H].

[0499] Step 2 2-((2-Bromo-5-chlorophenyl)amino)ethan-1-ol Ethyl (2-bromo-5-chlorophenyl)glycinate 49c (4 g, 13.7 mmol) was dissolved in tetrahydrofuran (40 mL), and lithium aluminum hydride (779 mg, 20.5 mmol) was added at 0 °C, followed by reaction in an ice bath for 30 minutes. After adding water (1 mL) to the reaction solution to quench the reaction, 15% aqueous sodium hydroxide solution (1 mL) and water (3 mL) were added, stirred for 10 minutes, anhydrous sodium sulfate was added, dried, filtered, and concentrated under reduced pressure to obtain a crude product of 2-((2-bromo-5-chlorophenyl)amino)ethan-1-ol 49d (1.8 g), which was used directly in the next reaction.

[0500] MS m / z (ESI): 249.9 [M+H].

[0501] Step 3 2-((2-Bromo-5-chlorophenyl)amino)ethyl methanesulfonate 2-((2-Bromo-5-chlorophenyl)amino)ethan-1-ol 49d (1.8 g, 7.2 mmol) and triethylamine (3 mL, 21.6 mmol) were dissolved in dichloromethane (30 mL), and methanesulfonyl chloride (0.83 mL, 10.8 mmol) was added at 0 °C, followed by continuous reaction at 0 °C for 1 hour. Water (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). Then the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 2-((2-bromo-5-chlorophenyl)amino)ethyl methanesulfonate 49e (2.37 g), which was used directly in the next reaction.

[0502] MS m / z (ESI): 327.9 [M+H].

[0503] Step 4 Methyl (2-((2-bromo-5-chlorophenyl)amino)ethyl)phenylalaninate 2-((2-Bromo-5-chlorophenyl)amino)ethyl methanesulfonate 49e (5.1 g, 15.5 mmol) and methyl phenylalaninate hydrochloride 49f (5 g, 23.3 mmol) were dissolved in acetonitrile (100 mL), potassium carbonate (12.9 g, 93 mmol) was added, and the mixture was stirred at 80 °C for 48 hours to cause a reaction. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain methyl (2-((2-bromo-5-chlorophenyl)amino)ethyl)phenylalaninate 49g (1.35 g) in a yield of 21%.

[0504] MS m / z (ESI): 410.9 [M+H].

[0505] Step 5 Methyl 2-(4-(2-bromo-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanoate Methyl (2-((2-bromo-5-chlorophenyl)amino)ethyl)phenylalaninate 49g (300 mg, 0.729 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (302 mg, 2.187 mmol) was added, and chloroacetyl chloride (90 mg, 0.802 mmol) was gradually added dropwise at 0 °C, followed by continuous stirring at 0 °C for 30 minutes. Then, potassium iodide (363 mg, 2.187 mmol) was added, and the mixture was refluxed for 6 hours. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain methyl 2-(4-(2-bromo-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanoate 49h (240 mg) in a yield of 73%.

[0506] MS m / z (ESI): 450.8 [M+H].

[0507] Step 6 2-(4-(2-Acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropionate Methyl 2-(4-(2-bromo-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanoate 49h (240 mg, 0.53 mmol), tributyl(1-ethoxyvinyl)tin (959 mg, 2.66 mmol), and bis(triphenylphosphine)palladium(II) chloride (37.2 mg, 0.053 mmol) were dissolved in 1,4-dioxane (10 mL), heated to 100 °C under an argon atmosphere, and reacted overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain methyl 2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanoate 49i (220 mg) in a yield of 90%.

[0508] MS m / z(ESI): 414.9[M+H].

[0509] Step 7 2-(4-(2-Acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-phenylpropanoic acid Methyl 2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanoate 49i (220 mg, 0.578 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL), lithium hydroxide monohydrate (49 mg, 1.16 mmol) was added at 0 °C, and the mixture was continuously stirred and reacted for 3 hours. After adjusting the pH to about 5 by dropping 2M dilute hydrochloric acid, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-phenylpropanoic acid 49j (200 mg) in a yield of 86%.

[0510] MS m / z(ESI): 401.0[M+H].

[0511] Step 8 Tert-butyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanamido)benzoate 49j (120 mg, 0.3 mmol) of 2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-phenylpropanoic acid and 1j (58 mg, 0.6 mmol) of tert-butyl 4-aminobenzoate were dissolved in ethyl acetate (10 mL), N,N-diisopropylethylamine (232 mg, 1.8 mmol) and propylphosphonic anhydride (572.72 mg, 900 μmol, ethyl acetate solution) were added, and the reaction was carried out at 70 °C overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 49k (160 mg) of tert-butyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanamido)benzoate in a yield of 93%.

[0512] MS m / z (ESI): 576.2 [M+H].

[0513] Step 9 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid 49k (160 mg, 0.278 mmol) of tert-butyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanamido)benzoate was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was gradually added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 49 (33 mg) of 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid in a yield of 23%.

[0514] MS m / z (ESI): 520.2 [M+H] 1 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.48 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 - 7.25 (m, 4H), 7.24 - 7.17 (m, 1H), 7.13 - 7.06 (m, 2H), 5.53 (dd, J = 10.9, 5.4 Hz, 1H), 3.72 - 3.59 (m, 2H), 3.57 - 3.41 (m, 2H), 3.31 - 3.20 (m, 2H), 3.19 - 3.08 (m, 2H), 2.34 (s, 3H).

[0515] Examples 50 - 51 were synthesized according to the synthesis methods of Examples 1 - 47 of the present invention. The spectral parameters of Examples 50 - 51 are shown in the following table:

[0516] [Table 4]

[0517] Example 52 4-(2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide)benzoic acid

[0518] [Chemical formula]

[0519] tert-Butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoate 1 (90 mg, 146.09 μmol) was dissolved in dichloromethane (15 mL), then trifluoroacetic acid (1.5 mL) was added, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamido)benzoic acid 52 (45 mg) in a yield of 54%.

[0520] MS m / z(ESI): 560.1[M+H] 1 H NMR(400 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.50 (s, 1H), 9.72 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.81 (d, J = 8.6 Hz, 1H), 7.78 - 7.67 (m, 4H), 7.38 - 7.19 (m, 5H), 5.39 - 5.28 (m, 1H), 4.62 - 3.86 (m, 4H), 3.31 - 3.18 (m, 1H), 3.18 - 3.05 (m, 1H).

[0521] Examples 53 to 75 were synthesized according to the synthesis methods of Examples 1 to 47 of the present invention. The spectral parameters of Examples 53 to 75 are shown in the following table:

[0522]

Table 5

[0523] Example 76 1-(1-(6-Acetyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)piperazine-2,5-dione

[0524]

Chemical formula

[0525] Step 1 1-(4-Amino-3-nitrophenyl)ethan-1-one 1-(4-Aminophenyl)ethan-1-one 17a (5 g, 36.99 mmol) was dissolved in concentrated sulfuric acid (50 mL), potassium nitrate (1.87 g, 18.50 mmol) was gradually added at 0 - 5 °C, and then the mixture was stirred at 0 - 5 °C for 1 hour. Ethyl acetate (50 mL) was added to dilute the reaction solution, and then the reaction solution was poured into 50 mL of ice water and subjected to liquid separation. The aqueous phase was extracted with ethyl acetate (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: system A) to obtain 1-(4-amino-3-nitrophenyl)ethan-1-one 76a (1.8 g) in a yield of 27%.

[0526] MS m / z (ESI): 181.0 [M + H].

[0527] Step 2 1-(3,4-Diaminophenyl)ethan-1-one 1-(4-Amino-3-nitrophenyl)ethan-1-one 76a (11 g, 61.06 mmol) was dissolved in a mixed solvent of ethanol (16 mL) and water (4 mL), iron powder (34.10 g, 610.57 mmol) and ammonium chloride (9.80 g, 183.17 mmol) were added, and the mixture was reacted at 80 °C for 4 hours. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 1-(3,4-diaminophenyl)ethan-1-one 76b (720 mg) in a yield of 48%.

[0528] MS m / z (ESI): 151.1 [M+H].

[0529] Project 3 N-(4-Acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide 1i (100 mg, 226.84 μmol) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid and 76b (40.88 mg, 272.21 μmol) of 1-(3,4-diaminophenyl)ethan-1-one were dissolved in ethyl acetate (10 mL), N,N-diisopropylethylamine (175.90 mg, 1.36 mmol) and propylphosphonic anhydride (433.06 mg, 680.52 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 76c (129 mg) of N-(4-acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide in a yield of 99%.

[0530] MS m / z (ESI): 572.8 [M+H].

[0531] Project 4 1-(1-(6-Acetyl-1H-benzo[d]imidazol-2-yl)-2-phenethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)piperazine-2,5-dione N-(4-Acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanamide 76c (129 mg, 225.13 μmol) was dissolved in glacial acetic acid (5 mL) and reacted at 120 °C for 10 hours. The LC-MS test indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 1-(1-(6-acetyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)piperazine-2,5-dione 76 (27 mg) in a yield of 17%.

[0532] MS m / z (ESI): 554.8 [M+H] 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.27 (s, 1H), 7.96 - 7.54 (m, 6H), 7.50 - 7.13 (m, 5H), 6.02 (s, 1H), 4.51 - 3.95 (m, 4H), 3.35 - 3.11 (m, 2H), 2.66 (s, 3H).

[0533] Examples 77 - 79 were synthesized according to the synthesis method of Example 76 of the present invention. The spectral parameters of Examples 77 - 79 are shown in the following table:

[0534]

Table 6

[0535] Examples 80 - 94 were synthesized according to the synthesis methods of Examples 1 - 47 of the present invention. The spectral parameters of Examples 80 - 94 are shown in the following table:

[0536]

Table 7

[0537] Examples 95 and 96 (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 95 (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 96

[0538] [Chemical formula]

[0539] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 38 (2.9 g, 5.075 mmol) was subjected to SFC chiral resolution (column type: ChiralCel OJ, 250×30 mm I.D., 5 μm; mobile phase: A for CO2 and B for ethanol; column pressure: 100 bar; flow rate: 50 mL / min; detection wavelength: 220 nm; column temperature: 38 °C) to obtain (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 95 (retention time (T R): 1.612 min; 1.33 g) and (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 96 (retention time (T R ): 1.944 min; 1.34 g).

[0540] 95 MS m / z (ESI): 571.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.82 - 7.69 (m, 2H), 7.54 (d, J = 9.1 Hz, 1H), 7.27 (dd, J = 9.2, 1.9 Hz, 1H), 5.13 (s, 1H), 4.71 - 3.89 (m, 4H), 4.13 (s, 3H), 3.39 - 3.15 (m, 2H), 3.27 (s, 3H), 2.18 - 1.97 (m, 2H).

[0541] 96 MS m / z (ESI): 571.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.54 (d, J = 9.1 Hz, 1H), 7.27 (dd, J = 9.3, 1.9 Hz, 1H), 5.12 (s, 1H), 4.78 - 3.87 (m, 4H), 4.13 (s, 3H), 3.39 - 3.15 (m, 2H), 3.27 (s, 3H), 2.17 - 1.96 (m, 2H).

[0542] Examples 97 and 98 (S)-2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 97 (R)-2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 98

[0543] [Chemical Structure]

[0544] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 45 (900 mg, 1.407 mmol) was subjected to SFC chiral resolution (column type: ChiralCel OD, 250×30 mm I.D., 5 μm; mobile phase: A for CO2 and B for ethanol; column pressure: 100 bar; flow rate: 70 mL / min; detection wavelength: 220 nm; column temperature: 38 °C) to obtain (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 97 (retention time (T R ): 2.863 min; 683 mg) and (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 98 (retention time (T R ): 3.978 min; 152 mg).

[0545] 97 MS m / z (ESI): 639.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.81 (s, 1H), 8.64 (s, 1H), 8.24 (s, 1H), 8.09 (t, J = 59.1 Hz, 1H), 7.78 - 7.63 (m, 4H), 7.44 - 7.18 (m, 6H), 5.45 - 5.34 (m, 1H), 4.35 - 3.95 (m, 4H), 3.32 - 3.24 (m, 1H), 3.16 - 3.03 (m, 1H).

[0546] 98 MS m / z (ESI): 639.2 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.81 (s, 1H), 8.65 (s, 1H), 8.24 (s, 1H), 8.10 (t, J = 59.2 Hz, 1H), 7.86 - 7.59 (m, 4H), 7.50 - 7.11 (m, 6H), 5.48 - 5.34 (m, 1H), 4.51 - 3.91 (m, 4H), 3.36 - 3.22 (m, 1H), 3.20 - 3.03 (m, 1H).

[0547] Examples 99 and 100 (S) -2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 99 (R) -2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 100

[0548] [Chemical formula]

[0549] 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 47 (1.05 g, 1.690 mmol) was subjected to SFC chiral resolution (column type: ChiralPak AD, 250×30 mm I.D., 10 μm; mobile phase: A for CO2 and B for isopropanol; column pressure: 100 bar; flow rate: 80 mL / min; detection wavelength: 220 nm; column temperature: 38 °C) to obtain (S) -2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 99 (retention time (T R ): 3.008 min, 478 mg) and (R) -2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide (retention time 100 (T R ): 4.017 min, 462 mg).

[0550] 99 MS m / z (ESI): 621.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.87 - 7.63 (m, 3H), 7.54 (d, J = 9.2 Hz, 1H), 7.42 - 6.96 (m, 5H), 5.48 - 5.27 (m, 1H), 4.41 - 3.95 (m, 4H), 4.14 (s, 3H), 3.30 - 3.20 (m, 1H), 3.17 - 3.04 (m, 1H).

[0551] 100 MS m / z (ESI): 621.2 [M+H] 11H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.88 - 7.62 (m, 3H), 7.54 (d, J = 9.1 Hz, 1H), 7.44 - 7.04 (m, 5H), 5.48 - 5.28 (m, 1H), 4.55 - 3.90 (m, 4H), 4.14 (s, 3H), 3.29 - 3.19 (m, 1H), 3.19 - 3.01 (m, 1H).

[0552] Examples 101 to 104 were synthesized according to the synthesis methods of Examples 1 to 47 of the present invention. The spectral parameters of Examples 101 to 104 are shown in the following table:

[0553] [Table 8]

[0554] Example 105 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-4-yl)propanamide

[0555] [Chemical formula]

[0556] Step 1 Tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-4-yl)propanoate Tert-butyl 2-((diphenylmethylene)amino)acetate 39a (2.81 g, 9.53 mmol) was dissolved in N,N-dimethylformamide (30 mL), and potassium tert-butoxide (979.90 mg, 8.73 mmol) was added in portions at 0 °C, and the reaction was carried out at 0 °C for 15 minutes. Then 4-(bromomethyl)pyridine hydrochloride 105a (2 g, 7.94 mmol) was added, and the reaction was carried out until the temperature reached room temperature and then for 3 hours. Water (30 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively 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 a crude product of tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-4-yl)propanoate 105b (3.07 g), which was used directly in the next reaction.

[0557] MS m / z(ESI): 387.0 [M+H].

[0558] Step 2 Tert-butyl 2-amino-3-(pyridin-4-yl)propanoate The crude product of tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-4-yl)propanoate 105b (3.07 g, 7.94 mmol) obtained in the previous step was dissolved in tetrahydrofuran (15 mL), 2M dilute hydrochloric acid (15 mL) was added, and the reaction was carried out overnight at room temperature. The reaction solution was adjusted to pH 8 by dropwise addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 3). Then the combined organic phases were washed successively with water (50 mL × 3) and 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: system B) to obtain tert-butyl 2-amino-3-(pyridin-4-yl)propanoate 105c (190 mg, 1.17 g) in a yield of 66%.

[0559] MS m / z(ESI): 223.0 [M+H].

[0560] Project 3 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-4-yl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (250 mg, 818.20 μmol) and tert-butyl 2-amino-3-(pyridin-4-yl)propanoate 105c (272.81 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (105.74 mg, 818.2 μmol, 135.22 μL) was added, and the mixture was reacted at 70 °C for 5 hours. Water (40 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). Then, it was washed successively with water (40 mL) and saturated sodium chloride solution (40 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-4-yl)propanoate 105d (250 mg) in a yield of 62%.

[0561] MS m / z (ESI): 490.9 [M+H].

[0562] Project 4 Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamide)-3-(pyridin-4-yl)propanoate Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-4-yl)propanoate 105d (250 mg, 508.78 μmol) was dissolved in dichloromethane (10 mL), triethylamine (154.45 mg, 1.53 mmol, 212.16 μL) was added, and chloroacetyl chloride (86.20 mg, 763.17 μmol, 60.75 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. Water (30 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(pyridin-4-yl)propanoate 105e (79 mg), which was used directly in the next reaction.

[0563] MS m / z(ESI): 567.1[M+H].

[0564] Step 5 Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxoperazin-1-yl)-3-(pyridin-4-yl)propionate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(pyridin-4-yl)propanoate 105e (79 mg, 139.12 μmol) obtained in the previous step was dissolved in methanol (5 mL), and sodium methoxide (5.4 M methanol solution, 25.76 μL, 139.10 μmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-4-yl)propanoate 105f (46 mg) in a yield of 62%.

[0565] MS m / z (ESI): 531.2 [M+H].

[0566] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-4-yl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-4-yl)propanoate 105f (46 mg, 86.57 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, followed by reaction at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-4-yl)propanoic acid 105g (35 mg), which was directly used in the next reaction.

[0567] MS m / z (ESI): 475.1 [M+H].

[0568] Project 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-4-yl)propanamide The crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(pyridin-4-yl)propanoic acid 105 (35 mg, 73.64 μmol) and 2-methyl-2H-indazol-5-amine 19a (16.26 mg, 110.46 μmol) was dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 184.5 mg, 294.56 μmol) and N,N-diisopropylethylamine (47.59 mg, 368.20 μmol, 60.86 μL) were added, and the mixture was reacted at 60 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-4-yl)propanamide 105 (24 mg) in a yield of 52%.

[0569] MS m / z (ESI): 603.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.66 (s, 1H), 8.50 (d, J = 5.0 Hz, 2H), 8.26 (s, 1H), 8.09 (s, 1H), 7.83 - 7.67 (m, 3H), 7.55 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 5.0 Hz, 2H), 7.24 (d, J = 9.1 Hz, 1H), 5.52 - 5.36 (m, 1H), 4.38 - 3.91 (m, 4H), 4.13 (s, 3H), 3.32 - 3.24 (m, 1H), 3.21 - 3.11 (m, 1H).

[0570] Example 106 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(p-tolyl)propanamide

[0571] [Chemical formula]

[0572] Step 1 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(p-tolyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (300 mg, 981.84 μmol) and tert-butyl 2-amino-3-(p-tolyl)propanoate 106a (323.47 mg, 1.37 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (126.89 mg, 981.84 μmol) was added, and the mixture was reacted at 60 °C for 7 hours. After adding water (30 mL) to the reaction solution to quench the reaction, the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were then washed successively with water (50 mL × 3) and 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(p-tolyl)propanoate 106b (200 mg) in a yield of 40%.

[0573] MS m / z (ESI): 504.1 [M+H].

[0574] Step 2 tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(p-tolyl)propanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(p-tolyl)propanoate 106b (200 mg, 396.50 μmol) was dissolved in dichloromethane (5 mL), triethylamine (160.49 mg, 1.59 mmol) was added, and chloroacetyl chloride (67.17 mg, 594.76 μmol, 47.34 μL) was gradually added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. Water (30 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were 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: system A) to give tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(p-tolyl)propanoate 106c (230 mg) in a yield of 99.9%.

[0575] MS m / z (ESI): 523.8 [M + H - 56].

[0576] Step 3 tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(p-tolyl)propanoate Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(p-tolyl)propanoate 106c (230 mg, 395.94 μmol) was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 73.32 μL, 395.93 μmol) was gradually added dropwise thereto in an ice bath, followed by reacting for 2 hours in the ice bath. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 6, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(p-tolyl)propanoate 106d (129 mg) in a yield of 60%.

[0577] MS m / z(ESI): 487.8[M + H - 56].

[0578] Step 4 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(p-tolyl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(p-tolyl)propanoate 106d (129 mg, 236.95 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added thereto, and the mixture was reacted at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(p-tolyl)propanoic acid 106e (85 mg), which was directly used in the next reaction.

[0579] MS m / z(ESI): 487.8[M + H].

[0580] Project 5 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(p-tolyl)propanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(p-tolyl)propanoic acid 106e (85 mg, 174.07 μmol) and 2-methyl-2H-indazol-5-amine 19a (38.43 mg, 261.10 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 332.31 mg, 522.20 μmol) and N,N-diisopropylethylamine (112.48 mg, 870.33 μmol, 143.84 μL) were added, and the reaction was carried out at 60 °C for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(p-tolyl)propanamide 106 (43 mg) in a yield of 40%.

[0581] MS m / z (ESI): 616.8 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.80 - 7.68 (m, 2H), 7.54 (d, J = 9.2 Hz, 1H), 7.31 - 7.04 (m, 6H), 5.44 - 5.28 (m, 1H), 4.33 - 3.94 (m, 4H), 4.13 (s, 3H), 3.27 - 3.15 (m, 1H), 3.11 - 2.99 (m, 1H), 2.28 (s, 3H).

[0582] Example 107 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0583]

Chemical Structure

[0584] Step 1 Tert-butyl 3-(4-chlorophenyl)-2-((diphenylmethylene)amino)propanoate 39a (4.31 g, 14.60 mmol) of tert-butyl 2-((diphenylmethylene)amino)acetate was dissolved in N,N-dimethylformamide (30 mL), and potassium tert-butoxide (1.64 g, 14.60 mmol) was added in portions at 0 °C and reacted at 0 °C for 30 minutes. Then 1-(bromomethyl)-4-chlorobenzene 107a (2 g, 9.73 mmol) was added, heated to room temperature, and then reacted for 3 hours. After adding water (30 mL) to the reaction solution to quench the reaction, it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively 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 a crude product of tert-butyl 3-(4-chlorophenyl)-2-((diphenylmethylene)amino)propanoate 107b (4.09 g), which was used directly in the next reaction.

[0585] MS m / z (ESI): 420.1 [M+H].

[0586] Step 2 Tert-butyl 2-amino-3-(4-chlorophenyl)propanoate The crude product of tert-butyl 3-(4-chlorophenyl)-2-((diphenylmethylene)amino)propanoate 107b (4.09, 9.74 mmol) obtained in the previous step was dissolved in tetrahydrofuran (10 mL), 2 M dilute hydrochloric acid (10 mL) was added, and the reaction was carried out overnight at room temperature. The reaction solution was adjusted to pH 8 by dropwise addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 3). Then the organic phases were combined, washed successively with water (50 mL × 3) and 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: system B) to obtain tert-butyl 2-amino-3-(4-chlorophenyl)propanoate 107c (2 g) in a yield of 80%.

[0587] MS m / z(ESI):200.1[M+H-56].

[0588] Step 3 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-chlorophenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (300 mg, 981.84 μmol) and tert-butyl 2-amino-3-(4-chlorophenyl)propanoate 107c (376.64 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (380.68 mg, 2.95 mmol, 486.8 μL) was added, and the mixture was reacted at 70 °C for 5 hours. Water (40 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). Then it was washed with water (40 mL) and saturated sodium chloride solution (40 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-chlorophenyl)propanoate 107d (420 mg) in a yield of 82%.

[0589] MS m / z (ESI): 524.1 [M+H].

[0590] Step 4 Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-chlorophenyl)propanoate Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-chlorophenyl)propanoate 107d (420 mg, 800.26 μmol) was dissolved in dichloromethane (10 mL), triethylamine (161.96 mg, 1.60 mmol, 222.47 μL) was added, and chloroacetyl chloride (135.58 mg, 1.20 mmol, 95.55 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. Water (30 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-chlorophenyl)propanoate 107e (430 mg), which was used directly in the next reaction.

[0591] MS m / z(ESI): 543.7[M + H - 56].

[0592] Step 5 Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)propanoate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-chlorophenyl)propanoate 107e (430 mg, 715.11 μmol) obtained in the previous step was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 132.43 μL, 715.12 μmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 2 hours. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)propanoate 107f (250 mg) in a yield of 62%.

[0593] MS m / z(ESI): 508.7[M+H-56].

[0594] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)propanoate 107f (250 mg, 442.60 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, followed by reaction at room temperature for 19 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)propanoic acid 107g (200 mg), which was directly used in the next reaction.

[0595] MS m / z (ESI): 507.7 [M+H]+.

[0596] Step 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)propanoic acid 107 g (200 mg, 393.13 μmol) and 2-methyl-2H-indazol-5-amine 19a (86.79 mg, 589.69 μmol) obtained in the previous step was dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 750.9 mg, 1.18 mmol) and N,N-diisopropylethylamine (254.04 mg, 1.97 mmol, 325.58 μL) were added, and the mixture was reacted at 60 °C for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-chlorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 107 (157 mg) in a yield of 61%.

[0597] MS m / z (ESI): 636.7 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 7.84 - 7.63 (m, 3H), 7.55 (d, J = 9.2 Hz, 1H), 7.44 - 7.18 (m, 5H), 5.44 - 5.30 (m, 1H), 4.39 - 3.94 (m, 4H), 4.14 (s, 3H), 3.32 - 3.20 (m, 1H), 3.20 - 3.03 (m, 1H).

[0598] Example 108 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0599]

Chemical formula

[0600] Step 1 Tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate Tert-butyl ((benzyloxy)carbonyl)-L-tyrosinate 108a (2 g, 5.38 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.49 g, 10.77 mmol) was added. Then methyl iodide (1.15 g, 8.08 mmol) was added, and the reaction was carried out at 30 °C overnight. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and 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: system A) to obtain tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate 108b (2 g) in a yield of 96%.

[0601] MS m / z (ESI): 330.0 [M + H - 56].

[0602] Step 2 Tert-butyl 2-amino-3-(4-methoxyphenyl)propanoate tert-Butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate 108b (2 g, 5.19 mmol) was dissolved in methanol (50 mL), 10% palladium on carbon (200 mg, 1.88 mmol, containing about 50% water) was added, and the reaction was carried out overnight in a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain tert-butyl 2-amino-3-(4-methoxyphenyl)propanoate 108c (1.23 g) in a yield of 94%.

[0603] MS m / z (ESI): 252.0 [M+H].

[0604] Step 3 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-methoxyphenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (200 mg, 654.56 μmol) and tert-butyl 2-amino-3-(4-methoxyphenyl)propanoate 108c (246.76 mg, 981.84 μmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (422.98 mg, 3.27 mmol, 540.89 μL) was added, and the reaction was carried out at 70 °C overnight. Water (50 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, then washed successively with water (50 mL) and 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-methoxyphenyl)propanoate 108d (310 mg) in a yield of 91%.

[0605] MS m / z (ESI): 519.8 [M+H].

[0606] Step 4 Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-methoxyphenyl)propanoate Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-methoxyphenyl)propanoate 108d (310 mg, 595.69 μmol) was dissolved in dichloromethane (10 mL), triethylamine (301.39 mg, 2.98 mmol, 413.99 μL) was added, and chloroacetyl chloride (80.73 mg, 714.82 μmol, 56.86 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 1 hour. Water (20 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-methoxyphenyl)propanoate 108e (355 mg), which was used directly in the next reaction.

[0607] MS m / z (ESI): 595.7 [M+H].

[0608] Step 5 Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)propanoate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-methoxyphenyl)propanoate 108e (355 mg, 594.75 μmol) was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 121.15 μL, 654.21 μmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)propanoate 108f (230 mg) in a yield of 69%.

[0609] MS m / z(ESI): 560.1[M+H].

[0610] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)propanoate 108f (230 mg, 410.40 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, followed by reaction at room temperature for 19 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)propanoic acid 108g (206 mg), which was used directly in the next reaction.

[0611] MS m / z(ESI): 504.1[M+H].

[0612] Project 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)propanoic acid 108 g (206 mg, 408.47 μmol) and 2-methyl-2H-indazol-5-amine 19a (90.18 mg, 612.70 μmol) obtained in the previous step was dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 519.87 mg, 816.94 μmol) and N,N-diisopropylethylamine (211.16 mg, 1.63 mmol, 270.03 μL) were added, and the reaction was carried out at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-methoxyphenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 108 (130 mg) in a yield of 48%.

[0613] MS m / z(ESI): 633.2 [M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.80 - 7.61 (m, 3H), 7.55 (d, J = 9.2 Hz, 1H), 7.31 - 7.13 (m, 3H), 6.88 (d, J = 8.1 Hz, 2H), 5.43 - 5.25 (m, 1H), 4.36 - 3.94 (m, 4H), 4.13 (s, 3H), 3.74 (s, 3H), 3.25 - 3.15 (m, 1H), 3.09 - 2.97 (m, 1H).

[0614] Example 109 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(methyl-d3)-2H-indazol-5-yl)-3-phenylpropanamide

[0615]

Chemical formula

[0616] Step 1 1-(methyl-d3)-5-nitro-1H-indazole 109b 2-(methyl-d3)-5-nitro-2H-indazole 109c 5-Nitroindazole 33a (1 g, 6.13 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (2.54 g, 18.39 mmol) was added, and then iodomethane-d3 (1.33 g, 9.19 mmol, 572.06 μL) was gradually added dropwise, and the reaction was carried out overnight at room temperature. The reaction solution was filtered and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 1-(methyl-d3)-5-nitro-1H-indazole 109b (359 mg) in a yield of 33% and 2-(methyl-d3)-5-nitro-2H-indazole 109c (359 mg) in a yield of 33%.

[0617] 109b MS m / z (ESI): 181.1 [M+H] 109c MS m / z (ESI): 181.1 [M+H].

[0618] Step 2 2-(methyl-d3)-2H-indazol-5-amine 2-(Methyl-d3)-5-nitro-2H-indazole 109c (359 mg, 1.99 mmol) was dissolved in a mixed solvent of methanol (8 mL) and water (2 mL). Iron powder (556.40 mg, 9.96 mmol) and ammonium chloride (213.16 mg, 3.98 mmol) were added, and the mixture was reacted at 80 °C for 2 hours. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 2-(methyl-d3)-2H-indazol-5-amine 109d (154 mg) in a yield of 52%.

[0619] MS m / z (ESI): 151.1 [M+H].

[0620] Step 3 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(methyl-d3)-2H-indazol-5-yl)-3-phenylpropanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-phenylpropanoic acid 24h (89 mg, 187.65 μmol) and 2-(methyl-d3)-2H-indazol-5-amine 109d (42.28 mg, 281.47 μmol) were dissolved in ethyl acetate (5 mL). Propylphosphonic anhydride (50% ethyl acetate solution, 238.82 mg, 375.29 μmol) and N,N-diisopropylethylamine (97.01 mg, 750.59 μmol, 124.05 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-(methyl-d3)-2H-indazol-5-yl)-3-phenylpropanamide 109 (50 mg) in a yield of 44%.

[0621] MS m / z (ESI): 606.2 [M+H] 1 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.65 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.81 - 7.58 (m, 3H), 7.54 (d, J = 9.2 Hz, 1H), 7.41 - 7.13 (m, 6H), 5.45 - 5.34 (m, 1H), 4.40 - 3.88 (m, 4H), 3.34 - 3.19 (m, 1H), 3.16 - 3.01 (m, 1H).

[0622] Example 110 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-(4-fluorophenyl)propanamide

[0623] [Chemical formula]

[0624] Step 1 Tert-butyl 2-((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate tert-Butyl 2-((diphenylmethylene)amino)acetate 39a (7.50 g, 25.39 mmol) was dissolved in N,N-dimethylformamide (50 mL), and potassium tert-butoxide (2.85 g, 25.39 mmol) was added in one portion at 0 °C, and the reaction was carried out at 0 °C for 20 minutes. Then 1-(bromomethyl)-4-fluorobenzene 110a (3.2 g, 16.93 mmol) was added and reacted, and after the temperature was raised to room temperature, the reaction was carried out for 3 hours. Water (50 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed successively 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 a crude product of tert-butyl 2-((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate 110b (6.83 g), which was used directly in the next reaction.

[0625] MS m / z (ESI): 404.0 [M+H].

[0626] Step 2 Tert-butyl 2-amino-3-(4-fluorophenyl)propanoate The crude product of tert-butyl 2-((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate 110b (6.83 g, 16.93 mmol) obtained in the previous step was dissolved in tetrahydrofuran (20 mL), 2 M dilute hydrochloric acid (20 mL) was added, and the reaction was carried out at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and the mixture was extracted with ethyl acetate (30 mL × 3). Then the combined organic phases were washed successively with water (50 mL × 3) and 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: system B) to obtain tert-butyl 2-amino-3-(4-fluorophenyl)propanoate 110c (4 g) in a yield of 99%.

[0627] MS m / z (ESI): 184.1 [M+H-56].

[0628] Step 3 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (2.5 g, 8.18 mmol) and tert-butyl 2-amino-3-(4-fluorophenyl)propanoate 110c (2.94 g, 12.27 mmol) were dissolved in N,N-dimethylformamide (40 mL), N,N-diisopropylethylamine (3.17 g, 24.55 mmol, 4.05 mL) was added, and the mixture was reacted at 70 °C for 6 hours. Water (40 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were then washed successively with water (40 mL) and saturated sodium chloride solution (40 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 110d (4.02 g) in a yield of 97%.

[0629] MS m / z (ESI): 507.9 [M+H].

[0630] Step 4 Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate 110d (4.02 g, 7.91 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.60 g, 15.82 mmol, 2.22 mL) was added, and chloroacetyl chloride (1.34 g, 11.86 mmol, 950.11 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 2 hours. Water (30 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate 110e (4.62 g), which was used directly in the next reaction.

[0631] MS m / z(ESI): 528.8[M+H-56].

[0632] Step 5 Tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-fluorophenyl)propanoate 110e (4.62 g, 7.90 mmol) obtained in the previous step was dissolved in methanol (20 mL), and sodium methoxide (5.4 M methanol solution, 1.46 mL, 7.90 mmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 2 hours. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and then the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate 110f (2.6 g) in a yield of 60%.

[0633] MS m / z(ESI): 492.1 [M+H-56].[[]END]]

[0634] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoate 110f (2.6 g, 4.74 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (3 mL) was gradually added dropwise, followed by reaction at room temperature for 20 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (2.25 mg), which was used directly in the next reaction.

[0635] MS m / z (ESI): 492.1 [M+H]+

[0636] Project 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-(4-fluorophenyl)propanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (100 mg, 203.13 μmol) and 2-(difluoromethyl)-2H-indazol-5-amine 34a (55.81 mg, 304.70 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 517.06 mg, 812.53 μmol) and N,N-diisopropylethylamine (131.26 mg, 1.02 mmol, 167.85 μL) were added, and the mixture was reacted at 60 °C for 2 h. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was further separated and 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-dioxopiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-(4-fluorophenyl)propanamide 110 (58 mg) in a yield of 72%.

[0637] MS m / z (ESI): 657.1 [M+H]+ 1 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.81 (s, 1H), 8.66 (s, 1H), 8.24 (s, 1H), 8.09 (t, J = 59.1 Hz, 1H), 7.83 - 7.63 (m, 4H), 7.44 - 7.26 (m, 3H), 7.20 - 7.07 (m, 2H), 5.44 - 5.31 (m, 1H), 4.54 - 3.92 (m, 4H), 3.30 - 3.21 (m, 1H), 3.18 - 3.07 (m, 1H).

[0638] Example 111 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0639]

Chemical formula

[0640] Step 1 Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)acrylate (+ / -)-Boc-α-phosphonoglycine trimethyl 111b (6.07 g, 20.43 mmol) was dissolved in dichloromethane (10 mL), stirred for 10 minutes, 1-methyl-1H-pyrazole-3-carbaldehyde 111a (1.5 g, 13.62 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.28 g, 14.98 mmol) were added, and the mixture was stirred at room temperature overnight to react. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)acrylate 111c (3.4 g) in a yield of 89%.

[0641] MS m / z (ESI): 182.1 [M + H - 100].

[0642] Step 2 Methyl 2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate Methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)acrylate 111c (2.4 g, 8.53 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (907.93 mg, 8.53 mmol, 10%) was added, and the mixture was stirred and reacted in a hydrogen atmosphere for 25 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of methyl 2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111d (1.8 g), which was used directly in the next reaction.

[0643] MS m / z (ESI): 284.2 [M+H].

[0644] Step 3 Methyl 2-amino-3-(1-methyl-1H-pyrazol-3-yl)propanoate Methyl 2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111d (1.8 g, 6.35 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (2 mL) was gradually added dropwise, and the mixture was stirred and reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of methyl 2-amino-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111e (832 mg).

[0645] MS m / z (ESI): 184.2 [M+H].

[0646] Step 4 Methyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (300 mg, 981.84 μmol) and methyl 2-amino-3-(1-methyl-1H-pyrazol-3-yl)methyl propanoate 111e (269.82 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (507.57 mg, 3.93 mmol, 649.07 μL) was added, and the mixture was reacted at 60 °C for 15 hours. Water (40 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were then washed successively with water (40 mL) and saturated sodium chloride solution (40 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: system A) to obtain methyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111f (400 mg) in a yield of 90%.

[0647] MS m / z (ESI): 451.9 [M+H].

[0648] Step 5 Methyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(1-methyl-1H-pyrazol-3-yl)methyl propanoate Methyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111f (400 mg, 884.38 μmol) was dissolved in dichloromethane (10 mL), triethylamine (268.47 mg, 2.65 mmol, 368.78 μL) was added, chloroacetyl chloride (149.83 mg, 1.33 mmol, 202.47 μL) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 2 hours. Water (30 mL) was added to the reaction solution to quench the reaction, and then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of methyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111g (420 mg), which was used directly in the next reaction.

[0649] MS m / z(ESI): 528.1[M+H].

[0650] Step 6 Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111 g (420 mg, 794.29 μmol) of the crude product of methyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(1-methyl-1H-pyrazol-3-yl)propanoate obtained in the previous step was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 147.09 μL, 794.29 μmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 2 hours. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain 111 h (130 mg) of methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoate in a yield of 33%.

[0651] MS m / z (ESI): 492.1 [M+H].

[0652] Step 7 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111h (130 mg, 264.06 μmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL), lithium hydroxide monohydrate (22.16 mg, 528.12 μmol) was added, and the reaction was carried out at 0 °C for 3 hours. 2M dilute hydrochloric acid was added dropwise to the reaction solution for neutralization, and the solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid 111i (76 mg) in a yield of 60%.

[0653] MS m / z(ESI): 478.0[M+H].

[0654] Step 8 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid 111i (76 mg, 158.90 μmol) and 2-methyl-2H-indazol-5-amine 19a (35.08 mg, 238.35 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 404.47 mg, 635.60 μmol) and N,N-diisopropylethylamine (102.68 mg, 794.50 μmol, 131.30 μL) were added, and the reaction was carried out at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 111 (61 mg) in a yield of 59%.

[0655] MS m / z(ESI): 606.8[M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.78 - 7.69 (m, 2H), 7.60 - 7.51 (m, 2H), 7.31 - 7.23 (m, 1H), 6.05 (s, 1H), 5.29 (dd, J = 10.4, 5.6 Hz, 1H), 4.37 - 4.05 (m, 4H), 4.13 (s, 3H), 3.79 (s, 3H), 3.21 - 3.12 (m, 1H), 3.11 - 2.99 (m, 1H).

[0656] Examples 112 and 113 (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxoperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propionamide 112 (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxoperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propionamide 113

[0657] [Chemical formula]

[0658] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 111 (149 mg, 0.245 mmol) was subjected to SFC chiral resolution (column type: ChiralCel AD, 250×30 mm I.D., 10 μm; mobile phase: A for CO2 and B for isopropanol; column pressure: 100 bar; flow rate: 80 mL / min; detection wavelength: 220 nm; column temperature: 38 °C), to obtain (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 112 (retention time (T R ): 3.527 min; 60 mg) and (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 113 (retention time (T R ): 4.487 min; 58 mg).

[0659] 112 MS m / z (ESI): 607.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.78 - 7.69 (m, 2H), 7.61 - 7.49 (m, 2H), 7.30 - 7.23 (m, 1H), 6.05 (s, 1H), 5.35 - 5.25 (m, 1H), 4.42 - 4.04 (m, 4H), 4.13 (s, 3H), 3.79 (s, 3H), 3.21 - 3.12 (m, 1H), 3.10 - 3.00 (m, 1H).

[0660] 113 MS m / z (ESI): 607.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.69 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.78 - 7.69 (m, 2H), 7.60 - 7.51 (m, 2H), 7.31 - 7.22 (m, 1H), 6.05 (s, 1H), 5.35 - 5.25 (m, 1H), 4.46 - 4.01 (m, 4H), 4.13 (s, 3H), 3.79 (s, 3H), 3.21 - 3.11 (m, 1H), 3.10 - 2.99 (m, 1H).

[0661] Example 114 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-(methyl-d3)-2H-indazol-5-yl)propanamide

[0662]

Chem.

[0663] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (100 mg, 203.13 μmol) and 2-(methyl-d3)-2H-indazol-5-amine 109d (45.76 mg, 304.70 μmol) were dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% solution in ethyl acetate, 517.06 mg, 812.53 μmol) and N,N-diisopropylethylamine (131.26 mg, 1.02 mmol, 167.85 μL) were added, and the mixture was reacted at 60 °C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-(methyl-d3)-2H-indazol-5-yl)propanamide 114 (103 mg) in 80% yield.

[0664] MS m / z(ESI): 624.1 [M+H] 1 H NMR(400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.82 - 7.65 (m, 3H), 7.54 (d, J = 9.2 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.28 - 7.19 (m, 1H), 7.19 - 7.06 (m, 2H), 5.41 - 5.32 (m, 1H), 4.47 - 3.92 (m, 4H), 3.29 - 3.19 (m, 1H), 3.15 - 3.06 (m, 1H).

[0665] Example 115 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0666] [Chemical]

[0667] Project 1 Tert-butyl 3-(4-cyanophenyl)-2-((diphenylmethylene)amino)propanoate 39a (3 g, 10.16 mmol) of tert-butyl 2-((diphenylmethylene)amino)acetate was dissolved in N,N-dimethylformamide (30 mL), and potassium tert-butoxide (1.25 g, 11.17 mmol) was added in portions at 0 °C, and the reaction was carried out at 0 °C for 15 minutes. Then 4-(bromomethyl)benzonitrile 115a (2.19 g, 11.17 mmol) was added, heated to room temperature, and then reacted for 3 hours. Water (60 mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed successively with water (60 mL × 3) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 3-(4-cyanophenyl)-2-((diphenylmethylene)amino)propanoate 115b (4.17 g), which was used directly in the next reaction.

[0668] MS m / z (ESI): 411.2 [M+H].

[0669] Project 2 Tert-butyl 2-amino-3-(4-cyanophenyl)propanoate The crude product of tert-butyl 3-(4-cyanophenyl)-2-((diphenylmethylene)amino)propanoate 115b (4.17 g, 10.16 mmol) obtained in the previous step was dissolved in tetrahydrofuran (20 mL), 2 M dilute hydrochloric acid (10 mL) was added, and the reaction was carried out overnight at room temperature. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and the mixture was extracted with ethyl acetate (60 mL × 3). Then the organic phases were combined, washed successively with water (60 mL × 3) and saturated sodium chloride solution (60 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: system B) to obtain tert-butyl 2-amino-3-(4-cyanophenyl)propanoate 115c (2 g) in a yield of 80%.

[0670] MS m / z(ESI): 191.1[M + H - 56].

[0671] Step 3 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-cyanophenyl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (200 mg, 654.56 μmol) and tert-butyl 2-amino-3-(4-cyanophenyl)propanoate 115c (241.83 mg, 981.84 μmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (422.98 mg, 3.27 mmol, 540.89 μL) was added, and the mixture was reacted at 70 °C overnight. Water (60 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were then washed with water (60 mL) and saturated sodium chloride solution (60 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-cyanophenyl)propanoate 115d (267 mg) in a yield of 79%.

[0672] MS m / z (ESI): 515.1 [M + H - 56].

[0673] Step 4 Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-cyanophenyl)propanoate Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-cyanophenyl)propanoate 115d (267 mg, 518.05 μmol) was dissolved in dichloromethane (10 mL), triethylamine (262.11 mg, 2.59 mmol, 360.04 μL) was added, and chloroacetyl chloride (87.77 mg, 777.08 μmol, 61.81 μL) was slowly added dropwise in an ice bath, followed by reaction in the ice bath for 1 hour. Water (50 mL) was added to the reaction solution to quench the reaction, and then the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-cyanophenyl)propanoate 115e (306 mg), which was used directly in the next reaction.

[0674] MS m / z (ESI): 535.0 [M+H-56].

[0675] Step 5 Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)propanoate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(4-cyanophenyl)propanoate 115e (306 mg, 517.00 μmol) obtained in the previous step was dissolved in methanol (10 mL), and sodium methoxide (5.4 M methanol solution, 105.32 μL, 568.73 μmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)propanoic acid 115f (210 mg) in a yield of 73%.

[0676] MS m / z (ESI): 555.0 [M+H].

[0677] Step 6 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)propanoate 115f (210 mg, 378.10 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, followed by reaction at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)propanoic acid 115g (188 mg), which was used directly in the next reaction.

[0678] MS m / z (ESI): 499.0 [M+H].

[0679] Step 7 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)propanoic acid 115 g (188 mg, 376.52 μmol) and 2-methyl-2H-indazol-5-amine 19a (83.12 mg, 564.78 μmol) obtained in the previous step was dissolved in ethyl acetate (10 mL), propylphosphonic anhydride (50% ethyl acetate solution, 479.21 mg, 753.05 μmol) and N,N-diisopropylethylamine (194.65 mg, 1.51 mmol, 248.91 μL) were added, and the reaction was carried out at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-(4-cyanophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 115 (110 mg) in a yield of 45%.

[0680] MS m / z (ESI): 628.1 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.87 - 7.63 (m, 5H), 7.62 - 7.44 (m, 3H), 7.23 (d, J = 9.1 Hz, 1H), 5.43 (dd, J = 10.2, 5.8 Hz, 1H), 4.43 - 3.92 (m, 4H), 4.14 (s, 3H), 3.30 - 3.14 (m, 2H).

[0681] Example 116 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide

[0682]

Chem.

[0683] Step 1 Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (300 mg, 981.84 μmol) and tert-butyl 2-amino-3-cyclobutylpropanoate 39d (293.51 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (634.47 mg, 4.91 mmol, 811.34 μL) was added, and the mixture was reacted at 70 °C overnight. Water (120 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were then washed successively with water (60 mL) and saturated sodium chloride solution (60 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: system A) to give tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate 116a (310 mg) in a yield of 67%.

[0684] MS m / z (ESI): 468.1 [M+H].

[0685] Step 2 tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate 116a (310 mg, 661.86 μmol) was dissolved in acetonitrile (10 mL), potassium carbonate (457.38 mg, 3.31 mmol) was added, and chloroacetyl chloride (89.70 mg, 794.23 μmol, 63.17 μL) was gradually added dropwise in an ice bath, followed by reaction in the ice bath for 1 hour. After adding water (50 mL) to the reaction solution to quench the reaction, the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate 116b (360 mg), which was used directly in the next reaction.

[0686] MS m / z (ESI): 488.0 [M + H - 56].

[0687] Step 3 tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-cyclobutylpropanoate 116b (360 mg, 660.72 μmol) obtained in the previous step was dissolved in methanol (10 mL), and sodium methoxide (5.4 M methanol solution, 134.59 μL, 726.79 μmol) was gradually added dropwise at 0 °C, followed by continuous reaction at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoate 116c (300 mg) in a yield of 89%.

[0688] MS m / z(ESI): 508.0[M+H].

[0689] Step 4 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoate 116c (100 mg, 196.70 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, followed by reaction at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoic acid 116d (88 mg), which was directly used in the next reaction.

[0690] MS m / z(ESI): 452.1[M+H].

[0691] Step 5 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide The crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-cyclobutylpropanoic acid 116d (88 mg, 194.57 μmol) and 2-methyl-2H-indazol-5-amine 19a (42.95 mg, 291.85 μmol) obtained in the previous step was dissolved in ethyl acetate (5 mL), propylphosphonic anhydride (50% ethyl acetate solution, 247.63 mg, 389.13 μmol) and N,N-diisopropylethylamine (100.58 mg, 778.26 μmol, 128.62 μL) were added, and the mixture was reacted at 60 °C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide 116 (59 mg) in a yield of 52%.

[0692] MS m / z (ESI): 580.9 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.74 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.81 - 7.68 (m, 2H), 7.54 (d, J = 9.2 Hz, 1H), 7.28 (dd, J = 9.2, 2.0 Hz, 1H), 5.01 (t, J = 7.9 Hz, 1H), 4.76 - 4.00 (m, 4H), 4.13 (s, 3H), 2.21 - 1.55 (m, 9H).

[0693] Example 117 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(tetrahydro-2H-pyran-2-yl)propanamide

[0694]

Chem.

[0695] Step 1 (Tetrahydro-2H-pyran-2-yl)methyl trifluoromethanesulfonate Tetrahydropyran-2-methanol 117a (3 g, 25.83 mmol, 2.92 mL) was dissolved in dichloromethane (50 mL), pyridine (2.45 g, 30.99 mmol, 2.49 mL) was added, and after cooling to 0 °C in a nitrogen atmosphere, trifluoromethanesulfonic anhydride (8.02 g, 28.41 mmol, 4.77 mL) was gradually added dropwise, and the mixture was continuously stirred in an ice bath for 20 minutes. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and after washing with 2 M dilute hydrochloric acid (50 mL × 2), it was washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of (tetrahydro-2H-pyran-2-yl)methyl trifluoromethanesulfonate 117b (6.41 g), which was used directly in the next reaction.

[0696] Step 2 Tert-butyl 2-((diphenylmethylene)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate Tert-butyl 2-((diphenylmethylene)amino)acetate 39a (5.09 g, 17.22 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to -78 °C under argon protection. Lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 34.43 mL) was slowly added dropwise and stirred for 15 minutes. (Tetrahydro-2H-pyran-2-yl)methyl trifluoromethanesulfonate 117b (6.41 g, 25.82 mmol) was slowly added dropwise, and the mixture was continuously stirred for 15 minutes after the addition. The mixture was gradually heated to room temperature, reacted for 30 minutes, and then water (50 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-((diphenylmethylene)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117c (6.77 g), which was used directly in the next reaction.

[0697] MS m / z (ESI): 394.2 [M+H].

[0698] Step 3 Tert-butyl 2-amino-3-(tetrahydro-2H-pyran-2-yl)propanoate The crude product of tert-butyl 2-((diphenylmethylene)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117c (6.77 g, 17.20 mmol) obtained in the previous step was dissolved in tetrahydrofuran (20 mL), 2 M dilute hydrochloric acid (20 mL) was added, and the mixture was reacted overnight at room temperature. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 8, and the mixture was extracted with ethyl acetate (100 mL × 3). Then the combined organic phases were washed successively with water (100 mL × 3) and saturated sodium chloride solution (100 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: system B) to obtain tert-butyl 2-amino-3-(tetrahydro-2H-pyran-2-yl)propanoate 117d (2 g) in a yield of 51%.

[0699] MS m / z (ESI): 174.1 [M+H-56].

[0700] Step 4 tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (300 mg, 981.84 μmol) and tert-butyl 2-amino-3-(tetrahydro-2H-pyran-2-yl)propanoate 117d (337.73 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (634.47 mg, 4.91 mmol, 811.34 μL) was added, and the mixture was reacted at 75 °C overnight. Water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were then washed successively with water (60 mL) and saturated sodium chloride solution (60 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: system A) to obtain tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117e (310 mg) in a yield of 63%.

[0701] MS m / z (ESI): 497.9 [M+H].

[0702] Step 5 Tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamide)-3-(tetrahydro-2H-pyran-2-yl)propanoate tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117e (310 mg, 621.99 μmol) was dissolved in acetonitrile (10 mL), potassium carbonate (429.83 mg, 3.11 mmol) was added, and chloroacetyl chloride (84.30 mg, 746.39 μmol, 59.37 μL) was gradually added dropwise in an ice bath, followed by reaction in the ice bath for 1 hour. After adding water (50 mL) to the reaction solution to quench the reaction, the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamide)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117f (357 mg), which was used directly in the next reaction.

[0703] MS m / z(ESI): 574.8[M+H].

[0704] Step 6 Tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoate The crude product of tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117f (357 mg, 621.00 μmol) obtained in the previous step was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 126.50 μL, 683.10 μmol) was gradually added dropwise at 0 °C, and the reaction was continuously carried out at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117g (255 mg) in a yield of 76%.

[0705] MS m / z(ESI): 538.1[M+H].

[0706] Step 7 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117g (100 mg, 185.73 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid 117h (89 mg), which was directly used in the next reaction.

[0707] MS m / z (ESI): 481.8 [M+H].

[0708] Project 8 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(tetrahydro-2H-pyran-2-yl)propanamide The crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid 117g (89mg, 184.53 μmol) and 2-methyl-2H-indazol-5-amine 19a (40.74mg, 276.79 μmol) obtained in the previous step was dissolved in ethyl acetate (5 mL), and propylphosphonic anhydride (50% ethyl acetate solution, 234.85mg, 369.05 μmol) and N,N-diisopropylethylamine (95.39mg, 738.10 μmol, 121.99 μL) were added, and the reaction was carried out at 60 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was further separated and 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)-2,5-dioxopiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(tetrahydro-2H-pyran-2-yl)propanamide 117 (63mg) in a yield of 55%.

[0709] MS m / z (ESI): 611.2 [M+H] 11H NMR (400 MHz, DMSO-d6) δ 10.13 - 9.93 (m, 1H), 8.85 - 8.64 (m, 1H), 8.30 - 8.19 (m, 1H), 8.16 - 8.04 (m, 1H), 7.88 (s, 1H), 7.82 - 7.69 (m, 2H), 7.59 - 7.47 (m, 1H), 7.36 - 7.23 (m, 1H), 5.35 - 5.13 (m, 1H), 4.70 - 3.93 (m, 4H), 4.13 (s, 3H), 3.93 - 3.78 (m, 1H), 3.35 - 3.05 (m, 2H), 2.10 - 1.70 (m, 4H), 1.67 - 1.37 (m, 4H).

[0710] Example 118 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[0711] [Chemical formula]

[0712] Step 1 2-Isopropylethyl trifluoromethanesulfonate Isopropyloxyethanol 118a (3 g, 28.81 mmol) was dissolved in dichloromethane (50 mL), pyridine (2.73 g, 34.57 mmol, 2.78 mL) was added, and after cooling to 0 °C in a nitrogen atmosphere, trifluoromethanesulfonic anhydride (8.94 g, 31.69 mmol, 5.32 mL) was gradually added dropwise, and the mixture was continuously stirred in an ice bath for 20 minutes. Ethyl acetate (100 mL) was added to the reaction solution for dilution, and after washing with 2 M dilute hydrochloric acid (50 mL × 2), it was washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 2-isopropylethyl trifluoromethanesulfonate 118b (4.6 g), which was used directly in the next reaction.

[0713] Step 2 tert-Butyl 2-((diphenylmethylene)amino)-4-isopropoxybutanoate 39a (8.63 g, 29.21 mmol) of tert-butyl 2-((diphenylmethylene)amino)acetate was dissolved in tetrahydrofuran (100 mL), cooled to -78 °C under argon protection, and lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 38.95 mL) was gradually added dropwise and stirred for 15 minutes. 118b (4.6 g, 19.47 mmol) of 2-isopropylethyl trifluoromethanesulfonate was gradually added dropwise, continuously stirred for 15 minutes, gradually heated to room temperature, and continuously stirred for 30 minutes. Then water (50 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl 2-((diphenylmethylene)amino)-4-isopropoxybutanoate 118c (7.43 g), which was used directly in the next reaction.

[0714] MS m / z (ESI): 382.2 [M+H].

[0715] Step 3 Tert-butyl O-isopropyl homoserinate The crude product of tert-butyl 2-((diphenylmethylene)amino)-4-isopropoxybutanoate 118c (7.43 g, 19.48 mmol) obtained in the previous step was dissolved in tetrahydrofuran (25 mL), 2 M dilute hydrochloric acid (20 mL) was added, and the reaction was carried out overnight at room temperature. The reaction solution was adjusted to pH 8 by dropwise addition of saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL × 3). Then the combined organic phases were washed successively with water (100 mL × 3) and saturated sodium chloride solution (100 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: system B) to obtain tert-butyl O-isopropyl homoserinate 118d (1.6 g) in a yield of 38%.

[0716] MS m / z (ESI): 218.2 [M+H]+

[0717] Step 4 Tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-isopropyl homoserinate 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (300 mg, 981.84 μmol) and tert-butyl O-isopropyl homoserinate 118d (320.04 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (380.68 mg, 2.95 mmol, 486.80 μL) was added, and the mixture was reacted at 70 °C overnight. Water (50 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were then washed successively with water (60 mL) and saturated sodium chloride solution (60 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: system A) to give tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-isopropyl homoserinate 118e (380 mg) in 80% yield.

[0718] MS m / z (ESI): 485.8 [M+H]+

[0719] Step 5 Tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-isopropyl homoserinate Tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-isopropyl homoserinate 118e (380 mg, 781.26 μmol) was dissolved in dichloromethane (10 mL), triethylamine (158.11 mg, 1.56 mmol) was added, and chloroacetyl chloride (132.36 mg, 1.17 mmol, 93.21 μL) was slowly added dropwise in an ice bath, and the reaction was carried out in the ice bath for 1 hour. After adding water (50 mL) to the reaction solution to quench the reaction, it was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-isopropyl homoserinate 118f (439 mg), which was used directly in the next reaction.

[0720] MS m / z(ESI): 506.0[M+H-56].

[0721] Step 6 Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxybutanoate The crude product of tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-isopropyl homoserinate 118f (439 mg, 779.93 μmol) obtained in the previous step was dissolved in methanol (10 mL), and sodium methylate (5.4 M methanol solution, 144.43 μL, 779.93 μmol) was gradually added dropwise at 0 °C, and the reaction was continuously carried out at 0 °C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 7, and the solution was concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxybutanoate 118g (223 mg) in a yield of 54%.

[0722] MS m / z(ESI): 469.8[M+H-56].

[0723] Step 7 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxybutanoic acid Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxybutanoate 118g (223 mg, 423.62 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was gradually added dropwise, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxybutanoic acid 118h (150 mg), which was directly used in the next reaction.

[0724] MS m / z(ESI): 470.1[M+H].

[0725] Engineering 8 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 2-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxopiperazin-1-yl)-4-isopropoxybutanoic acid 118 obtained in the immediately preceding step h (150 mg, 318.94 μmol) and the crude product of 2-methyl-2H-indazol-5-amine 19a (70.88 mg, 481.60 μmol) were dissolved in ethyl acetate (15 mL), propylphosphonic anhydride (50% ethyl acetate solution, 814.54 mg, 1.28 mmol) and N,N-diisopropylethylamine (206.10 mg, 1.59 mmol, 263.55 μL) were a...

Claims

1. A compound represented by the general formula (II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein: L is selected from a bond, -CH ２ - or -CH ２ CH ２ - and When L is a bond, R ６ is selected from methyl, ethyl or propyl, where the methyl, ethyl or propyl is optionally further substituted by methoxy; L is -CH ２ - or -CH ２ CH ２ - When it is, R ６ is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl or alkoxy, where the cycloalkyl, the heterocyclyl, the aryl, the heteroaryl or the alkoxy is optionally further substituted by one or more R Ａ substituents; R Ａ is selected from a deuterium atom, a halogen, an alkyl, an alkoxy, a cyano, and a cycloalkyl, wherein the alkyl is optionally further substituted by one or more substituents selected from a deuterium atom or a halogen; 【Chemical Formula 2】 is [Chemical Formula 3] selected from; X is selected from C=O; R １ are the same or different and each independently selected from halogen; R ２ is selected from heteroaryl; wherein said heteroaryl is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, or halogen; R ３ is selected from a hydrogen atom; R ５ are the same or different and each independently is a hydrogen atom, alkyl, halogen, cyano, heterocyclyl, -OR ９ , -C(O)R ９ , -C(O)OR ９ , -NHC(O)OR ９ , -C(O)NR １０ R １１ , or -S(O) ｒ R ９ and are selected from, wherein said alkyl, or said heterocyclyl, is optionally further substituted by one or more substituents selected from deuterium atoms, halogens, or =O; Alternatively, the two Rs ５ form a C=O together with the same carbon atom to which they are attached; R ９ is selected from a hydrogen atom or an alkyl, where the alkyl is optionally further substituted by -OC(O)OR １２ ; R １０ and R １１ are each independently selected from a hydrogen atom or an alkyl group; R １２ is a cycloalkyl; R ８ is selected from a hydrogen atom; m is 0, 1, 2, or 3; n is 1, and r is 2, a compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

2. The compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 【Chemical Formula 4】 wherein: ring B, X, L, R １ ~R ３ , R ５ , R ６ , R ８ , m and n are as defined in claim 1 the compound according to Claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

3. The compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IV), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 【Chemical Formula 5】 In the formula: Ring B, X, L, R １ ~R ３ , R ５ , R ６ , R ８ , m and n are as defined in claim 1 the compound according to Claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

4. 【Fig. 6】 is 【Chemical Formula 7】 selected from, the compound according to any one of Claims 1 to 3, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

5. The compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, [Chemical 8] where: L, R １ ~R ３ 、R ５ 、R ６ 、R ８ and n are as defined in claim 1 the compound according to Claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

6. The compound, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V-A) or (V-B), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 【Chemical Formula 9】 where: L, R １ ~R ３ 、R ５ 、R ６ 、R ８ and n are as defined in claim 5 the compound according to Claim 5, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

7. R ２ is selected from 5-membered heteroaryl; wherein said 5-membered heteroaryl is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, or halogen The compound according to any one of Claims 1 to 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

8. R ２ is selected from triazolyl or tetrazolyl; wherein said triazolyl is optionally further substituted by halogen, The compound according to Claim 7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

9. The halogen is Cl, the compound according to Claim 8, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

10. L is -CH ２ - or -CH ２ CH ２ -; R ６ is selected from alkoxy, 3- to 8-membered cycloalkyl, 4- to 8-membered heterocyclyl, phenyl or 5- to 10-membered heteroaryl, wherein the alkoxy, the 3- to 8-membered cycloalkyl, the 4- to 8-membered heterocyclyl, the phenyl or the 5- to 10-membered heteroaryl is optionally further substituted by one or more R Ａ substituents; R Ａ is selected from a deuterium atom, a halogen, an alkyl, an alkoxy, and a cyano, wherein the alkyl is optionally further substituted by one or more substituents selected from a deuterium atom and a halogen. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

11. R ６ is selected from alkoxy, phenyl, pyridinyl, pyrazolyl, imidazolyl, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl, wherein the alkoxy, the phenyl, the pyridinyl, the pyrazolyl, the imidazolyl, the 3- to 6-membered cycloalkyl or the 4- to 6-membered heterocyclyl is optionally further substituted by one or more R Ａ substituents; R Ａ is selected from a deuterium atom, a halogen, an alkyl, an alkoxy, and a cyano, wherein the alkyl is optionally further substituted by one or more substituents selected from a deuterium atom and a halogen. The compound according to claim 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

12. R ５ are the same or different and each independently is a hydrogen atom, alkyl, haloalkyl, halogen, cyano, -OR ９ , -C(O)R ９ , -C(O)OR ９ , -NHC(O)OR ９ , -C(O)NR １０ R １１ or -S(O) ｒ R ９ and is selected from; Alternatively, two Rs ５ together with the same carbon atom to which they are attached form a C=O; R ９ is selected from a hydrogen atom or C １ to C ４ alkyl; R １０ and R １１ each independently represents a hydrogen atom or a C １ to C ４ selected from alkyl The compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

13. The compound is 【Table 1】 as follows The compound represented by the general formula (II) according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

14. A method for producing the compound represented by the general formula (II) according to claim 1, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the following steps: 【Chemical 10】 Subjecting the compound represented by the general formula (IIA) and the compound represented by the general formula (IIB) to a condensation reaction, and Optionally further, a step of hydrolyzing the mixture under acidic conditions to obtain the compound represented by the general formula (II); comprising wherein: ring B, X, L, R １ ~R ３ 、R ５ 、R ６ 、R ８ 、m and n are as defined in claim 1 The production method.

15. A compound represented by the general formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: 【Chemical 11】 wherein X, L, R １ ~R ３ , R ６ , R ８ and n are as defined in claim 1 The compound represented by the general formula (IIA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

16. The compound is 【Chemical 12】 [Chemical] as follows The compound represented by the general formula (IIA) according to claim 15, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition, wherein the pharmaceutical composition comprises an effective dose of the compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof. The pharmaceutical composition.

18. Use of the compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, in the manufacture of an inhibitor of coagulation factor XIa or a dual inhibitor of coagulation factor XIa and plasma kallikrein.

19. Use of the compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, in the manufacture of a medicament for treating and / or preventing a disease mediated by coagulation factor XIa.

20. The use according to claim 19, wherein the disease mediated by the coagulation factor XIa is a cardiovascular disease and a cerebrovascular disease.

21. The use according to claim 20, wherein the cardiovascular disease and the cerebrovascular disease are coagulation diseases or thromboembolic diseases.

22. The use according to claim 21, wherein the thromboembolic disease is selected from arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism.

23. The use according to claim 21, wherein the thromboembolic disease is selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic death, transient cerebral ischemia attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by a medical implant, device or surgery in which blood contacts an artificial surface that can promote thrombosis.

24. The use according to claim 23, wherein the venous thrombosis is deep venous thrombosis.

25. Use of a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of an anticoagulant.

26. Use in the manufacture of a medicament for treating or preventing a thromboembolic disease of a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, wherein: The thromboembolic disease is selected from arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral circulatory thromboembolism. Use.

27. The use according to claim 26, wherein the thromboembolic disease is selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic death, transient cerebral ischemia attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by a medical implant, device or procedure in which blood contacts an artificial surface that can promote thrombosis.

28. The use according to claim 27, wherein the venous thrombosis is deep vein thrombosis.

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