Piperazine derivatives and preparation methods and uses thereof

Abstract

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

Description

Technical Field

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

[0002] Common cardiovascular diseases such as stroke, thrombosis, and myocardial infarction have become the leading cause of death worldwide. In 2017, cardiovascular disease accounted for approximately 32% of all deaths worldwide. The pathological processes of these diseases are often closely linked to thrombosis or impaired blood flow, leading to stroke or heart attack. Therefore, anticoagulants have been widely used in the treatment of these diseases. Traditional anticoagulants include vitamin K antagonists, fibrinolytics, heparin, and antiplatelet agents. However, these agents are limited by various factors, such as poor compliance, high inter-individual variability, and a narrow therapeutic window. In recent years, non-vitamin K antagonist oral anticoagulants have been continuously developed and marketed, primarily including antagonists that directly inhibit thrombin and antagonists that act on coagulation factors. While currently available non-vitamin K antagonist oral anticoagulants have significantly improved safety and efficacy, they are associated with the risk of bleeding. To overcome this issue, developing drugs with a reduced risk of bleeding is crucial. Domestic and international studies have demonstrated that FXIa inhibitors are potential therapeutic agents for cardiovascular and cerebrovascular diseases, particularly thromboembolic diseases, and also offer a new approach for overcoming the adverse effect of bleeding. Thromboembolic diseases include arterial cardiovascular thromboembolism, venous cardiovascular thromboembolism, arterial cerebrovascular thromboembolism, venous cerebrovascular thromboembolism, and ventricular or peripheral thromboembolic diseases. Thromboembolic diseases also 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 thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or surgeries in which blood comes into contact with artificial surfaces that can promote thrombosis. Venous thrombosis also includes deep vein thrombosis.

[0003] FXI is a serine protease with a molecular weight of approximately 80 kDa. It consists of two subunits linked by disulfide bonds, with each polypeptide chain containing 607 amino acids. Each subunit comprises a heavy chain and a light chain. The heavy chain has four AP domains, A1-A4. A1 binds thrombin; A2 binds high-molecular-weight kininogen; A3 binds coagulation factor IX and heparin; and A4 binds activated coagulation factor XII. Therefore, these four AP domains are the sites where FXI interacts with other protein kinases or factors. FXIa is the activated form of FXI and plays an active role in intrinsic coagulation. During the initial coagulation phase, coagulation factor XII is activated to form XIIa, which then activates FXI to form FXIa, triggering a series of cascade reactions that promote coagulation. Therefore, inhibiting FXIa is an effective approach to prevent thrombosis or blood flow impairment.

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

[0005] Currently, there is fierce competition for the clinical development of FXIa inhibitors both domestically and internationally. BMS-986177, a FXIa inhibitor developed by Bristol-Myers Squibb, has entered Phase II clinical trials for the prevention and treatment of major thrombosis and other diseases. Early clinical studies have shown that FXIa inhibitors slow the formation of blood clots while significantly reducing the risk of bleeding. A series of patent applications for FXIa inhibitors have been published, including WO2017151746A1, WO2017151018A1, and WO2018039094A1. While some progress has been made in the research and application of FXIa inhibitors, there is still significant room for improvement, and it is necessary to continue researching and developing new FXIa inhibitors. Summary of the Invention

[0006] The object of the present invention is to provide a piperazine derivative represented by general formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs:

[0007]

[0008] in:

[0009] X is selected from C=O or CR 7; Preferably, X is selected from C=O;

[0010] G is selected from a bond or -C(O)-NH-; preferably, G is selected from -C(O)-NH-;

[0011] Ring A is selected from aryl or heteroaryl;

[0012] Ring B is selected from cycloalkyl, heterocyclic, aryl, heteroaryl or condensed ring; wherein the heteroaryl is preferably a 5-10 membered heteroaryl;

[0013] R 1 The same or different, each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, nitro, cyano, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -OR 9 or -NR 10 R 11 ;

[0014] R 2 Selected from halogen, cyano, alkoxy, heteroaryl or -C(O)R 9 wherein the alkoxy or heteroaryl is optionally further substituted by one or more groups selected from 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 substituted by a substituent;

[0015] R 3 is selected from hydrogen, halogen or alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or alkoxy; R 3 Preferably a hydrogen atom;

[0016] R 4 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -OR 9 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally further substituted by one or more halogen, hydroxyl or R 6 substituted by a substituent;

[0017] R 5 The same or different, each independently selected from hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, -OR 9 、-C(O)R9 、-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 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are optionally further substituted by one or more deuterium atoms, 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 substituted by a substituent;

[0018] Or, two R 5 Together with the same carbon atom to which it is attached, it forms C=O;

[0019] R 6 is selected from deuterium atoms, halogen, alkyl, alkoxy, amino, nitro, cyano, hydroxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more R A substituted by a substituent;

[0020] R A is selected from deuterium atoms, halogen, alkyl, hydroxy, alkoxy, amino, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl or -NR 13 C(O)R 14wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted with one or more substituents selected from deuterium atoms, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy or cyano groups;

[0021] R 7 Selected from hydrogen atom, halogen or -OR B , preferably a hydrogen atom;

[0022] R B is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from deuterium atoms, halogen, alkyl, haloalkyl, hydroxy, alkoxy or haloalkoxy;

[0023] R 8 is selected from hydrogen, halogen or alkyl; wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl or alkoxy; R 8 Preferably a hydrogen atom;

[0024] R 9 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 14 substituted by a substituent;

[0025] R 10 and R 11 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 12 、-C(O)OR 12 、-OC(O)R 12 、-NR13 R 14 、-C(O)NR 13 R 14 、-SO2NR 13 R 14 or -NR 13 C(O)R 14 substituted by a substituent;

[0026] Or, R 10 and R 11 Together with the connected nitrogen atom, it forms a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O or S(O) r , and the 4- to 8-membered heterocyclic ring is optionally further substituted with one or more selected from hydroxy, 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 substituted by a substituent;

[0027] R 12 、R 13 and R 14 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0028] m is 0, 1, 2, 3 or 4;

[0029] n is 0, 1, 2, 3 or 4;

[0030] r is 0, 1, or 2.

[0031] The present invention provides a compound represented by the general formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, which is a compound represented by the general formula (II) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0032]

[0033] in:

[0034] L is selected from a bond or an alkylene group, wherein the alkylene group is optionally further substituted with one or more substituents selected from a deuterium atom, a halogen or a hydroxyl group;

[0035] Ring B, X, R 1 ~R 3 、R 5 、R 6 、R 8 , m and n are as defined in the general formula (I).

[0036] The present invention provides a compound represented by the general formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, which is a compound represented by the general formula (III) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0037]

[0038] Among them: 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).

[0039] The present invention provides a compound represented by the general formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, which is a compound represented by the general formula (IV) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0040]

[0041] Among them: 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).

[0042] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, wherein ring B is selected from a 3-6 membered cycloalkyl group, a 4-8 membered heterocyclic group, a phenyl group, a 5-10 membered heteroaryl group or an 8-10 membered fused ring; wherein the 3-6 membered cycloalkyl group is preferably a cyclohexyl group; and the 4-8 membered heterocyclic group is preferably a tetrahydropyranyl group or a piperidinyl group.

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

[0044]

[0045]

[0046] Where: R 5 and m are as defined in the general formula (I).

[0047] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, wherein Selected from:

[0048]

[0049] In a preferred embodiment of the present invention, the compound represented by general formula (II) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof is a compound represented by general formula (V) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0050]

[0051] Where: L, R 1 ~R 3 、R 5 、R 6 、R 8 and n are as defined in the general formula (II).

[0052] In a preferred embodiment of the present invention, the compound represented by general formula (V) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof is a compound represented by general formula (VA) or (VB) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0053]

[0054] Where: L, R 1 ~R 3 、R 5 、R 6 、R 8 and n are as defined in Formula (V).

[0055] In a preferred embodiment of the present invention, the compound represented by general formula (II) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof is a compound represented by general formula (VI) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0056]

[0057] in:

[0058] 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;

[0059] p is 0, 1, or 2;

[0060] L, R 1 ~R 3 、R 5 、R 6 、R 8 and n are as defined in the general formula (II).

[0061] In a preferred embodiment of the present invention, the compound represented by general formula (VI) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof is a compound represented by general formula (VI-A) or (VI-B) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof,

[0062]

[0063] Among them: Ring C, L, R 1 ~R 3 、R 5 、R 6 、R 8 , p and n are as defined in the general formula (VI).

[0064] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, wherein: 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.

[0065] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, wherein:

[0066] L is -(CR a R b )s-, where s is 1, 2, 3 or 4;

[0067] R a and R b are each independently selected from a hydrogen atom, a deuterium atom or an alkyl group;

[0068] R 6 is selected from alkyl, alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl is optionally further substituted by one or more R A substituted by a substituent;

[0069] R A is selected from a deuterium atom, a halogen, an alkyl, an alkoxy, a cyano group, an amino group, a phenyl group or a 5-10 membered heteroaryl group, wherein the alkyl, alkoxy, phenyl group or the 5-10 membered heteroaryl group is optionally further substituted with one or more substituents selected from a deuterium atom, a halogen, a hydroxyl group, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy group or a cyano group.

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

[0071] L is selected from -CH2-, -CD2- or -CH2CH2-;

[0072] R 6 is selected from alkyl, alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl is optionally further substituted by one or more R A substituted by a substituent;

[0073] R Ais selected from a deuterium atom, a halogen, an alkyl, an alkoxy, a cyano group, an amino group, a phenyl group or a 5-10 membered heteroaryl group, wherein the alkyl, alkoxy, phenyl group or the 5-10 membered heteroaryl group is optionally further substituted with one or more substituents selected from a deuterium atom, a halogen, a hydroxyl group, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy group or a cyano group.

[0074] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, wherein:

[0075] R 6 is selected from alkyl, alkoxy, phenyl, pyridyl, pyrazolyl, imidazolyl, 3-6 membered cycloalkyl or 4-6 membered heterocyclic group, wherein the alkyl, alkoxy, phenyl, pyridyl, pyrazolyl, imidazolyl, 3-6 membered cycloalkyl or 4-6 membered heterocyclic group is optionally further substituted by one or more R A substituted by a substituent;

[0076] R A is selected from a deuterium atom, a halogen, an alkyl, an alkoxy, a cyano group, an amino group, a phenyl group or a 5-10 membered heteroaryl group, wherein the alkyl, alkoxy, phenyl group or the 5-10 membered heteroaryl group is optionally further substituted with one or more substituents selected from a deuterium atom, a halogen, a hydroxyl group, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy group or a cyano group.

[0077] In a preferred embodiment of the present invention, the compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A) or (VI-B) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, wherein:

[0078] R 5 The same or different, each independently selected from hydrogen atom, alkyl, haloalkyl, halogen, cyano, heterocyclic group, -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 9or -S(O)r NR 10 R 11 ;

[0079] Or, two R 5 Together with the same carbon atom to which it is attached, it forms C=O;

[0080] R 9 is selected from hydrogen atom or C1-C4 alkyl, wherein said C1-C4 alkyl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano or -OC(O)OR 12 substituted by a substituent;

[0081] R 10 and R 11 Each is independently selected from a hydrogen atom, a C1-C4 alkyl group or a 5- to 6-membered heterocyclic group, wherein the C1-C4 alkyl group or the 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, C1-C4 alkoxy, nitro, cyano or =O.

[0082] In a preferred embodiment of the present invention, the compound represented by general formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof is a compound represented by general formula (VII) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof:

[0083]

[0084] in:

[0085] X is selected from C=O or CR 7 ;

[0086] G is selected from a bond or -C(O)-NH-;

[0087] Ring B is selected from a 3- to 6-membered cycloalkyl group, a 4- to 8-membered heterocyclyl group, a phenyl group, a 5- to 10-membered heteroaryl group, or an 8- to 10-membered fused ring;

[0088] R 1 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group or a haloalkyl group;

[0089] R 2 Selected from halogen, cyano, alkoxy, heteroaryl or -C(O)R 9 ; wherein the alkoxy or heteroaryl is optionally further substituted by one or more substituents selected from haloalkyl or halogen;

[0090] R 3 selected from hydrogen atoms;

[0091] R 4is selected from hydrogen atoms, deuterium atoms or alkyl groups, wherein the alkyl groups are optionally further substituted with one or more halogens, hydroxyl groups or R 6 substituted by a substituent;

[0092] R 5 The same or different, each independently selected from hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic group, 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 the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from deuterium atoms, halogen or =O;

[0093] Or, two R 5 Together with the same carbon atom to which it is attached, it forms C=O;

[0094] R 6 is selected from alkyl, alkoxy, phenyl, pyridyl, pyrazolyl, imidazolyl, 3-6 membered cycloalkyl or 4-6 membered heterocyclic group, wherein the alkyl, alkoxy, phenyl, pyridyl, pyrazolyl, imidazolyl, 3-6 membered cycloalkyl or 4-6 membered heterocyclic group is optionally further substituted by one or more R A substituted by a substituent;

[0095] R A is selected from a deuterium atom, a halogen, an alkyl group, an alkoxy group, a cyano group, an amino group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the alkyl group, the alkoxy group, the phenyl group or the 5- to 10-membered heteroaryl group is optionally further substituted with one or more substituents selected from a deuterium atom, a halogen, a hydroxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group or a cyano group;

[0096] R 7 selected from hydrogen atoms;

[0097] R 8 is selected from a hydrogen atom or a C1-C4 alkyl group;

[0098] R 9is selected from hydrogen atom or C1-C4 alkyl, wherein said C1-C4 alkyl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano or -OC(O)OR 12 substituted by a substituent;

[0099] R 10 and R 11 Each is independently selected from a hydrogen atom, a C1-C4 alkyl group or a 5- to 6-membered heterocyclic group, wherein the C1-C4 alkyl group or the 5- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, C1-C4 alkoxy, nitro, cyano or =O;

[0100] R 12 、R 13 and R 14 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group;

[0101] m is 0, 1, or 2;

[0102] n is 0, 1 or 2.

[0103] Typical compounds of the present invention include, but are not limited to:

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124] or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof.

[0125] The present invention provides a method for preparing a compound represented by general formula (II) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof, comprising the following steps:

[0126]

[0127] The compound represented by general formula (IIA) is subjected to a condensation reaction with the compound represented by general formula (IIB), and optionally further hydrolyzed under acidic conditions to obtain a compound represented by general formula (II);

[0128] Among them: 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).

[0129] The present invention provides a compound represented by general formula (IIA) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein:

[0130]

[0131] Where: X, L, R 1 ~R 3 、R 6 、R 8 and n are as defined in the general formula (II).

[0132] Typical compounds of formula (IIA) include, but are not limited to:

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0140] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0141] In another aspect, the present invention provides a pharmaceutical composition comprising an effective dose of a compound represented by formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0142] In another aspect, the present invention provides a method for inhibiting coagulation factor XIa protease, wherein the method comprises administering to a patient a pharmaceutical composition comprising an effective dose of a compound represented by formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or a stereoisomer, tautomer, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0143] In another aspect, the present invention provides a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, or its pharmaceutical composition (including the pharmaceutical composition provided by the present invention, the same below) for use in the preparation of a coagulation factor XIa inhibitor, or a dual inhibitor of coagulation factor XIa and plasma kallikrein.

[0144] Another aspect of the present invention relates to a method for preventing and / or treating a disease mediated by coagulation factor XIa, comprising administering to a patient a therapeutically effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition comprising the same;

[0145] Wherein, the disease mediated by coagulation factor XIa is preferably a cardiovascular and cerebrovascular disease;

[0146] The cardiovascular and cerebrovascular diseases are preferably selected from blood coagulation disorders or thromboembolic diseases;

[0147] The thromboembolic disease is preferably selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, thromboembolic disorders of the ventricular or peripheral circulation; wherein the thromboembolic disease is more preferably selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by the following: medical implants, devices or surgeries in which blood comes into contact with artificial surfaces that can promote thrombosis; the venous thrombosis is preferably deep vein thrombosis.

[0148] Another aspect of the present invention relates to a method for preventing and / or treating cardiovascular and cerebrovascular diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable salts thereof or prodrugs thereof or pharmaceutical compositions comprising the same.

[0149] Another aspect of the present invention relates to a method for anti-blood coagulation, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable salts thereof or prodrugs thereof or pharmaceutical compositions containing the same.

[0150] Another aspect of the present invention relates to a method for preventing and / or treating thromboembolic diseases, comprising administering to a patient a therapeutically effective dose of a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, or a pharmaceutical composition comprising the same;

[0151] Wherein: the thromboembolic disease is preferably selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, thromboembolic disorders of the ventricular or peripheral circulation; wherein the thromboembolic disease is more preferably selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by: medical implants, devices or surgeries in which blood comes into contact with artificial surfaces that can promote thrombosis; the venous thrombosis is preferably deep vein thrombosis.

[0152] Another aspect of the present invention relates to the use of a compound represented by formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing a disease mediated by coagulation factor XIa, wherein the disease mediated by coagulation factor XIa is preferably a cardiovascular or cerebrovascular disease;

[0153] Wherein, the disease mediated by coagulation factor XIa is preferably a cardiovascular and cerebrovascular disease;

[0154] The cardiovascular and cerebrovascular diseases are preferably selected from blood coagulation disorders or thromboembolic diseases;

[0155] The thromboembolic disease is preferably selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, thromboembolic disorders of the ventricular or peripheral circulation; wherein the thromboembolic disease is more preferably selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by the following: medical implants, devices or surgeries in which blood comes into contact with artificial surfaces that can promote thrombosis; the venous thrombosis is preferably deep vein thrombosis.

[0156] Another aspect of the present invention relates to a drug for inhibiting coagulation factor XIa, which includes a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers or mixtures thereof, pharmaceutically acceptable salts thereof or prodrugs thereof or pharmaceutical compositions containing the same.

[0157] In another aspect, the present invention provides a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII) or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions thereof for use in the preparation of anti-coagulation drugs.

[0158] In another aspect, the present invention provides a compound represented by general formula (I), (II), (III), (IV), (V), (VA), (VB), (VI), (VI-A), (VI-B) or (VII), or a stereoisomer, tautomer, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing thromboembolic diseases;

[0159] wherein the thromboembolic disease is selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders, and thromboembolic disorders of the ventricular or peripheral circulation; wherein the thromboembolic disease is more preferably selected from 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 arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by: medical implants, devices or surgeries in which blood comes into contact with artificial surfaces that can promote thrombosis; wherein the venous thrombosis is preferably deep vein thrombosis.

[0160] The pharmaceutical preparations of the present invention can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsules, intradermally, intraperitoneally, subcutaneously, subcutaneously, or by inhalation. The pharmaceutical compositions containing the active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The tablets contain the active ingredient and a nontoxic, pharmaceutically acceptable excipient suitable for tablet preparation in admixture.

[0161] The formulations of the present invention are suitably presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.

[0162] Dosage forms for topical or transdermal administration of the compounds of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0163] When the compounds of the present invention are administered to humans and animals in the form of medicines, the compounds can be provided alone or in the form of pharmaceutical compositions containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.

[0164] Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution. solution); (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrins, such as targeting ligands attached to nanoparticles, such as Accurins™; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.

[0165] Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as Such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0166] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum oxide hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0167] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0168] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The sprays may contain other customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.

[0169] Detailed Description of the Invention

[0170] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0171] "Bond" means that the indicated substituent does not exist and the two end portions of the substituent are directly linked to form a bond.

[0172] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0173] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples of which include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

[0174] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10 The alkynyl group of the present invention is substituted or unsubstituted. The alkynyl group of the present invention is substituted or unsubstituted.

[0175] "Alkylene" is a divalent alkyl group. Preferably, it is C1-C 10Alkylene, more preferably C1-C6 alkylene, particularly preferably C1-C4 alkylene. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -CH(CH3)2-n-propylene, etc. Alkylene can be substituted or unsubstituted.

[0176] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 12 Cycloalkyl, more preferably C3-C8 cycloalkyl, most preferably C3-C6 cycloalkyl. Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl can be optionally substituted or unsubstituted.

[0177] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0178] "Fused cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has completely conjugated π electrons. It is preferably 6 to 12 members, and more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthrenyl.

[0179] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is an aromatic system with preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0180] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to non-aromatic heterocyclic groups in which one or more of the ring atoms is a heteroatom, such as oxygen, nitrogen, or sulfur, and include monocyclic, fused, bridged, and spirocyclic rings. Preferably, the heterocyclic group has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "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. A heterocyclyl group may be substituted or unsubstituted.

[0181] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multiple spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered single spiro heterocyclyl. Non-limiting examples of "spiro heterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0182] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0183] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0184] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0185] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Preferably, it is a bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0186]

[0187]

[0188] Heteroaryl groups can be substituted or unsubstituted.

[0189] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, one or more rings may contain one or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, and at least one ring has a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, one or more selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclyl or monocyclic cycloalkyl. Preferably, it includes 7 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include but are not limited to:

[0190]

[0191]

[0192] The fused rings may be substituted or unsubstituted.

[0193] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0194] "Haloalkyl" refers to an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.

[0195] "Hydroxyalkyl" refers to an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0196] "Haloalkoxy" refers to an alkyl group (alkyl-O-) optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.

[0197] "Hydroxy" refers to an -OH group.

[0198] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0199] "Amino" refers to -NH2.

[0200] "Cyano" refers to -CN.

[0201] "Nitro" refers to -NO2.

[0202] "Benzyl" refers to -CH2-phenyl.

[0203] "Carboxyl" refers to -C(O)OH.

[0204] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0205] "Me" refers to methyl.

[0206] "DMSO" refers to dimethyl sulfoxide.

[0207] "Boc" refers to tert-butoxycarbonyl.

[0208] "T3P" refers to propylphosphonic anhydride.

[0209] "HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0210] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0211] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =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 substituted by a substituent;

[0212] R 9 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 substituted by a substituent;

[0213] R 10 and R 11 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, 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 substituted by a substituent;

[0214] Or, R 10and R 11 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O) r , and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, 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 substituted by a substituent;

[0215] R 12 、R 13 and R 14 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0216] r is 0, 1, or 2.

[0217] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0218] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0219] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts or amine salts formed with suitable acids.

[0220] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0221] Synthesis method of the compound of the present invention

[0222] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0223] The method for preparing the compound represented by general formula (II) of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof comprises the following steps:

[0224]

[0225] The compound represented by general formula (IIa) is hydrolyzed to obtain the compound represented by general formula (IIA); the compound represented by general formula (IIA) is subjected to a condensation reaction with the compound represented by general formula (IIB), and optionally further hydrolyzed under acidic conditions to obtain the compound represented by general formula (II);

[0226] in:

[0227] R g Selected from alkyl groups;

[0228] 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). DETAILED DESCRIPTION

[0229] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0230] Example

[0231] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0232] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0233] Preparative liquid separation was performed using a Gilson preparative high performance liquid chromatograph, model GX-281.

[0234] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0235] Column chromatography used Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0236] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Haohong Biotechnology Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., San Chemical Technology Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd.

[0237] CD3OD: deuterated methanol.

[0238] CDCl3: deuterated chloroform.

[0239] DMSO-d6: deuterated dimethyl sulfoxide.

[0240] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0241] The compound is purified using an eluent system for column chromatography and thin-layer chromatography, wherein the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; D: dichloromethane and ethanol system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, may also be added.

[0242] Room temperature: 20℃~30℃.

[0243] Example 1

[0244] tert-Butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0245]

[0246]

[0247] first step

[0248] 1-(4-chloro-2-nitrophenyl)-1H-tetrazole

[0249] 4-Chloro-2-nitroaniline 1a (10 g, 57.95 mmol), trimethylsilylazide (29.1 mL, 173.84 mmol), and trimethyl orthoformate (8.62 mL, 173.84 mmol) were added sequentially to acetic acid (300 mL) and stirred at 60°C for 28 hours. After completion of the reaction, saturated sodium nitrite solution (200 mL) was slowly added dropwise at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed sequentially with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 1-(4-chloro-2-nitrophenyl)-1H-tetrazole 1b (8 g) in a 36% yield.

[0250] MS m / z(ESI):226.0[M+H]

[0251] Step 2

[0252] 5-Chloro-2-(1H-tetrazol-1-yl)aniline

[0253] 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 sequentially dissolved in anhydrous ethanol (10 mL). Water (2 mL) was added, and the mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was further isolated 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 92% yield.

[0254] MS m / z(ESI):196.1[M+H]

[0255] Step 3

[0256] 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide

[0257] 5-Chloro-2-(1H-tetrazol-1-yl)aniline 1c (450 mg, 2.30 mmol) and potassium carbonate (317.47 mg, 2.30 mmol) were dissolved in acetonitrile (15 mL). A solution of chloroacetyl chloride (0.18 mL, 2.30 mmol) in acetonitrile (15 mL) was slowly added dropwise at 0°C, and stirring was continued at 0°C for 2 hours. The mixture was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (20 mL) and saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to provide 2-chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (0.57 g) in a 91% yield.

[0258] MS m / z(ESI):272.0[M+H]

[0259] Step 4

[0260] tert-Butyl (2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalaninate

[0261] 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (0.9 g, 3.31 mmol) and L-phenylalanine tert-butyl ester hydrochloride 1e (1.10 g, 4.96 mmol) were dissolved in N,N-dimethylformamide (100 mL), and N,N-diisopropylethylamine (547 μL, 3.31 mmol) was added. The mixture was reacted at 70°C for 18 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove most of the solvent, and then diluted with water (150 mL). The mixture 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, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System A) to give (2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl ester 1f (1.2 g) in a yield of 79%.

[0262] MS m / z(ESI):457.1[M+H]

[0263] Step 5

[0264] tert-Butyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate

[0265] Dissolve tert-butyl (2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalaninate 1f (1.2 g, 2.63 mmol) in acetonitrile (20 mL), add potassium carbonate (544.46 mg, 3.94 mmol), and slowly add chloroacetyl chloride (0.25 mL, 3.15 mmol) dropwise at 0°C. The mixture is reacted at 0°C for 3 hours. The reaction was quenched by adding water (20 mL). After stirring for 10 minutes, the liquid phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System A) to obtain 1 g (1 g) of tert-butyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate in a yield of 72%. MS m / z (ESI): 477.0 [M+H-56].

[0266] Step 6

[0267] tert-Butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate

[0268] 1 g (0.4 g, 0.75 mmol) of tert-butyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate was dissolved in methanol (20 mL). Sodium methoxide (0.14 mL, 5.4 M methanol solution, 0.75 mmol) was added at 0°C and allowed to react for 2 hours. After completion of the reaction, the pH was adjusted to neutral by adding 2N aqueous hydrochloric acid. The mixture was 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-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate (0.2 g) in a yield of 54%.

[0269] MS m / z(ESI):497.1[M+H]

[0270] Step 7

[0271] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid

[0272] Tert-butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate 1h (200 mg, 402.46 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.1 mL) was added. The mixture was reacted at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting 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-dioxapiperazin-1-yl)-3-phenylpropanoate 1i (144 mg) in an 81% yield. MS m / z (ESI): 441.1 [M+H]

[0273] Step 8

[0274] tert-Butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0275] 2-(4-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (140 mg, 317.58 μmol) and tert-butyl p-aminobenzoate 1j (92.05 mg, 476.36 μmol) were dissolved in ethyl acetate (10 mL). N,N-diisopropylethylamine (0.26 mL, 1.59 mmol) and 1-propylphosphonic anhydride (404 mg, 635.15 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60°C for 12 h. After the reaction is completed, the product is concentrated under reduced pressure, and the resulting residue is 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-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 1 (190 mg) in a yield of 97%.

[0276] MS m / z(ESI):615.9[M+H]

[0277] 1 H NMR(400MHz,DMSO-d6)δ10.48(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).

[0278] Example 2

[0279] (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)phenyl)carbamic acid

[0280] Methyl ester

[0281]

[0282] first step

[0283] Methyl (4-aminophenyl)carbamate

[0284] Under a hydrogen atmosphere, p-nitrobenzene isocyanate 2a (3 g, 18.28 mmol) was dissolved in dichloromethane (50 mL) and Raney nickel (0.5 g, 18.28 mmol) was added. The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford methyl (4-aminophenyl)carbamate 2b (3 g) in a 99% yield.

[0285] MS m / z(ESI):167.0[M+H]

[0286] Step 2 (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)phenyl)carbamic acid

[0287] Methyl ester

[0288] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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 1-propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added and reacted at room temperature for 5 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give methyl (4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)phenyl)carbamate 2 (81 mg) in a yield of 60%.

[0289] MS m / z(ESI):589.1[M+H]

[0290] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),9.71(s,1H),9.59(s,1H),7.86-7.64(m,3H),7.48(d,J=8.6Hz,2H),7.39(d,J=8 .5Hz,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).

[0291] Example 3

[0292] 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzamide

[0293]

[0294] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (100 mg, 226.84 μmol) and p-aminobenzamide 3a (46.33 mg, 340.26 μmol) were dissolved in ethyl acetate (10 mL). N,N-diisopropylethylamine (187 μL, 1.13 mmol) and 1-propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added and reacted at room temperature for 50 hours. After the reaction is completed, the product is concentrated under reduced pressure, and the resulting residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzamide 3 (69 mg) in a yield of 53%.

[0295] MS m / z(ESI):559.1[M+H]

[0296] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.71(s,1H),7.96-7.71(m,5H),7.65(d,J=8.4Hz,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).

[0297] Example 4

[0298] Ethyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0299]

[0300] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and ethyl p-aminobenzoate 4a (28.10 mg, 170.13 μmol) were dissolved in ethyl acetate (10 mL). N,N-diisopropylethylamine (94 μL, 567.10 μmol) and 1-propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at 60°C for 2 h. After the reaction is completed, the product is concentrated under reduced pressure, and the residue is further separated and purified by silica gel column chromatography (eluent: System A) to obtain ethyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 4 (52 mg) in a yield of 73%.

[0301] MS m / z(ESI):587.9[M+H]

[0302] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.71(s,1H),7.94(d,J=8.4Hz,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=7.1Hz,2H),3.28-3.18(m,1H),3.18-3.03(m,1H),1.32(t,J=7.1Hz,3H).

[0303] Example 5

[0304] Methyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0305]

[0306] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and methyl p-aminobenzoate 5a (25.72 mg, 170.13 μmol) were dissolved in ethyl acetate (6 mL). N,N-diisopropylethylamine (94 μL, 567.10 μmol) and 1-propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at 60°C for 2 h. After the reaction, the product was concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: System A) to give methyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 5 (50 mg) in a yield of 76%.

[0307] MS m / z(ESI):574.2[M+H]

[0308] 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 9.71 (s, 1H), 7.94 (d, J = 8.4Hz, 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).

[0309] Example 6

[0310] 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-N-methylbenzoyl

[0311] amine

[0312]

[0313] 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid 1 (60 mg, 107.15 μmol) and methylamine hydrochloride (14.5 mg, 214.30 μmol) were dissolved in ethyl acetate (6 mL), and N,N-diisopropylethylamine (89 μL, 535.75 μmol) and 1-propylphosphonic anhydride (205 mg, 321.45 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 60°C for 2 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-N-methylbenzamide 6 (14 mg) in a yield of 22%.

[0314] MS m / z(ESI):573.2[M+H]

[0315] 1 H NMR(400MHz,DMSO-d6)δ10.40(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=4.4Hz,3H).

[0316] Example 7

[0317] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-oxoisoindolin-5-yl)-3-phenylpropane

[0318] Amide

[0319]

[0320] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-amino-2,3-dihydroisoindole-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 1-propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at 70°C for 4 h. After the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-oxoisoindolin-5-yl)-3-phenylpropanamide 7 (21 mg) in a yield of 32%.

[0321] MS m / z(ESI):570.9[M+H]

[0322] 1 H NMR(400MHz,DMSO-d6)δ10.48(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).

[0323] Example 8

[0324] 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)indoline-1-carboxylic acid methyl ester

[0325]

[0326]

[0327] first step

[0328] Methyl 5-nitroindoline-1-carboxylate

[0329] 5-Nitroindoline 8a (1 g, 6.09 mmol) was dissolved in dichloromethane (12.5 mL). A solution of methyl chloroformate (863.45 mg, 9.14 mmol) in toluene (12.5 mL) and a solution of pyridine (493 μL, 6.09 mmol) in dichloromethane (12.50 mL) were added at 0°C, and the mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to obtain methyl 5-nitroindoline-1-carboxylate 8b (1.2 g) in an 89% yield.

[0330] MS m / z(ESI):223.0[M+H]

[0331] Step 2

[0332] 5-Aminoindoline-1-carboxylic acid methyl ester

[0333] Methyl 5-nitroindoline-1-carboxylate 8b (0.67 g, 3.02 mmol) was dissolved in ethanol (10 mL) and water (1 mL). Reduced iron powder (1.68 g, 30.15 mmol) and ammonium chloride (159.81 mg, 3.02 mmol) were added sequentially, and the mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford methyl 5-aminoindoline-1-carboxylate 8c (0.42 g) in a 72% yield.

[0334] MS m / z(ESI):193.1[M+H]

[0335] Step 3

[0336] 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)indoline-1-carboxylic acid methyl ester

[0337] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and methyl 5-aminodihydroindole-1-carboxylate 8c (32.70 mg, 170.13 μmol) were dissolved in ethyl acetate (10 mL). N,N-diisopropylethylamine (94 μL, 567.10 μmol) and 1-propylphosphonic anhydride (217 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at room temperature for 24 hours. After the reaction is completed, the product is concentrated under reduced pressure, and the residue is 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-dioxapiperazin-1-yl)-3-phenylpropionamido)indoline-1-carboxylate 8 (35 mg) in a yield of 49%.

[0338] MS m / z(ESI):614.8[M+H]

[0339] 1 H NMR(400MHz,DMSO-d6)δ10.09(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=9.4Hz,2H),3.73(s,3H),3.28-3.15(m,2H),3.09(t,J=9.4Hz,2H).

[0340] Example 9

[0341] 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0342]

[0343] first step

[0344] tert-Butyl 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0345] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (100 mg, 226.84 μmol) and tert-butyl 3-aminobenzoate 9a (65.75 mg, 340.26 μmol) were dissolved in ethyl acetate (15 mL). N,N-diisopropylethylamine (187 μL, 1.13 mmol) and 1-propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added and reacted at 60°C for 2 hours. After the reaction, the product was concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 9b (0.11 g) in a yield of 79%.

[0346] MS m / z(ESI):616.2[M+H]

[0347] Step 2

[0348] 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0349] Tert-butyl 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 9b (0.11 g, 178.55 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.5 mL) was added. The mixture was reacted at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid 9 (52 mg) in a 52% yield.

[0350] MS m / z(ESI):560.1[M+H]

[0351] 1 H NMR(400MHz,DMSO-d6)δ10.32(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=10.1,5.8Hz,1H),4.58-3.86(m,4H),3.18-3.00(m,1H),2.93-2.84(m,1H).

[0352] Example 10

[0353] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-phenylpropanamide

[0354]

[0355] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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). N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and 1-propylphosphonic anhydride (433 mg, 680.52 μmol, 50% ethyl acetate solution) were added and reacted at 70°C for 4 hours. After the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-phenylpropanamide 10 (34 mg) in a yield of 50%.

[0356] MS m / z(ESI):599.2[M+H]

[0357] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.71(s,1H),7.85-7.70(m,3H),7.59(q,J=9.0Hz,4H),7.37-7.17(m,5H),5.37-5.27( m,1H),4.56-3.90(m,4H),3.81(t,J=7.0Hz,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).

[0358] Example 11

[0359] 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0360]

[0361]

[0362] first step

[0363] 2-Chloro-N-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)acetamide

[0364] 5-Chloro-2-(triazol-1-yl)aniline 11a (2.4 g, 12.33 mmol, prepared according to patent publication CN 108863962, page 4, paragraphs

[0013] -

[0015] , step A-1) was dissolved in dichloromethane (40 mL), and 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 reacted for 1 hour. 30 mL of water was added to quench the reaction, and the layers were separated. The aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-chloro-N-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)acetamide 11b (2.4 g) in a yield of 72%.

[0365] MS m / z(ESI):271.0[M+H]

[0366] Step 2

[0367] tert-Butyl (2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalaninate

[0368] 2-Chloro-N-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)acetamide 11b (2.4 g, 8.85 mmol) and L-phenylalanine tert-butyl ester hydrochloride 1e (3.42 g, 13.28 mmol) were dissolved in N,N-dimethylformamide (50 mL), and 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 the reaction, the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with water (200 mL × 3), washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give (2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl ester 11c (3.3 g) in a yield of 82%.

[0369] MS m / z(ESI):456.7[M+H]

[0370] Step 3

[0371] tert-Butyl N-(2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate

[0372] Dissolve tert-butyl (2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalaninate 11c (2 g, 4.39 mmol) in dichloromethane (50 mL) and place in an ice bath. Add triethylamine (2.22 g, 21.93 mmol, 3.05 mL), then slowly add 2-chloroacetyl chloride (594.52 mg, 5.26 mmol, 418.68 μL) dropwise. Stir and react on ice for 1 hour. Add an additional 2-chloroacetyl chloride (594.52 mg, 5.26 mmol, 418.68 μL), and continue stirring on ice for 1 hour. LC-MS monitoring indicates the reaction is complete. 30 mL of water was added to quench the reaction. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl N-(2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate 11d (2 g) in a yield of 86%.

[0373] MS m / z(ESI):476.0[M+H-56]

[0374] Step 4

[0375] tert-Butyl 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate

[0376] Tert-butyl N-(2-((5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate 11d (2 g, 3.76 mmol) was dissolved in methanol (30 mL). Sodium methoxide solution (5.4 M, 765.20 μL) was slowly added dropwise under ice-cooling. The reaction was allowed to react for 30 minutes. LC-MS monitored the reaction for completion. The pH was adjusted to approximately 6 with 2 M dilute hydrochloric acid, and the product was concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate 11e (1.5 g) in an 81% yield. MS m / z(ESI):440.0[M+H-56]

[0377] Step 5

[0378] 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid

[0379] Tert-butyl 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate 11e (1.5 g, 3.02 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (344.85 mg, 3.02 mmol, 244.66 μL) was slowly added dropwise and allowed to react at room temperature for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was further isolated 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-dioxapiperazin-1-yl)-3-phenylpropanoate 11f (1.33 g) in a 100% yield.

[0380] MS m / z(ESI):440.1[M+H]

[0381] Step 6

[0382] tert-Butyl 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0383] 2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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 1-propylphosphonic anhydride (1.04 g, 1.64 mmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 65°C for 3 hours. After the reaction is completed, the mixture is concentrated under reduced pressure, and the resulting residue is further separated and purified by silica gel column chromatography (eluent: System B) to obtain 11 g (200 mg) of tert-butyl 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate in a yield of 60%.

[0384] MS m / z(ESI):615.2[M+H]

[0385] Step 7

[0386] 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0387] 11 g (200 mg, 325.16 μmol) of tert-butyl 4-(2-(4-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate was dissolved in dichloromethane (12 mL). Trifluoroacetic acid (37.08 mg, 325.16 μmol, 24.16 μL) was slowly added dropwise and allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated 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-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid 11 (110 mg) in a 59% yield.

[0388] MS m / z(ESI):558.8[M+H]

[0389] 1H NMR (400MHz, DMSO-d6) δ12.75(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).

[0390] Example 12

[0391] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-1-oxoisoindolin-5-yl)-3-phenylpropanamide

[0392]

[0393] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-amino-2-methylisoindol-1-one 12a (27.59 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL). N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and 1-propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at 70°C for 4 h. After the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-1-oxoisoindolin-5-yl)-3-phenylpropanamide 12 (35 mg) in a yield of 52%.

[0394] MS m / z(ESI):585.0[M+H]

[0395] 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),9.72(s,1H),7.95(s,1H),7.81(d,J=8.6Hz,1H),7.75(dd,J=8.7,2.2Hz,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).

[0396] Example 13

[0397] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-oxoindole-5-yl)-3-phenylpropanamide

[0398]

[0399] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-aminoindol-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 1-propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at 70°C for 4 h. After the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-oxoindole-5-yl)-3-phenylpropanamide 13 (33 mg) in a yield of 57%.

[0400] MS m / z(ESI):571.0[M+H]

[0401] 1H NMR (400MHz, DMSO-d6) δ10.32(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=8.4Hz,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).

[0402] Example 14

[0403] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(2-oxooxazolidin-3-yl)phenyl)-3-phenylpropanamide

[0404]

[0405] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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 patent publication CN105384739, pages 40-41, paragraphs

[0171] -

[0178] , method 1) were dissolved in ethyl acetate (5 mL), and 1-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 reacted at room temperature overnight. After the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-(2-oxooxazolidin-3-yl)phenyl)-3-phenylpropanamide 14 (22 mg) in a yield of 99%.

[0406] MS m / z(ESI):600.8[M+H]

[0407] 1H NMR (400MHz, DMSO-d6) δ10.19(s,1H),9.72(s,1H),7.81(d,J=8.6Hz,1H),7.75(dd,J=8.6,2.2Hz,1H),7.60(d,J=8.7Hz,2H),7.52(d,J=8.8Hz,2H),7.37 -7.17(m,5H),5.33(dd,J=10.0,5.7Hz,1H),4.65-3.91(m,4H),4.43(t,J =8.0Hz,2H),4.04(t,J=8.0Hz,2H),3.29-3.18(m,1H),3.15-3.03(m,1H).

[0408] Example 15

[0409] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(3-fluorophenyl)-3-phenylpropanamide

[0410]

[0411] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 3-fluoroaniline (18.90 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and 1-propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 70°C for 4 hours. After the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(3-fluorophenyl)-3-phenylpropanamide 15 (17 mg) in a yield of 28%.

[0412] MS m / z(ESI):534.1[M+H]

[0413] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.71(s,1H),7.93-7.65(m,3H),7.58(d,J=11.5Hz,1H),7.43-7.18( m,7H),6.92(t,J=8.5Hz,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).

[0414] Example 16

[0415] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-cyanophenyl)-3-phenylpropanamide

[0416]

[0417] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol), 4-aminobenzonitrile (13.40 mg, 113.42 μmol), N,N-diisopropylethylamine (73.29 mg, 567.10 μmol) and 1-propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were dissolved in ethyl acetate (7 mL) in sequence and the reaction was stirred at room temperature for 16 hours. After the reaction, the product was concentrated under reduced pressure, and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(4-cyanophenyl)-3-phenylpropanamide 16 (23 mg) in a yield of 37%.

[0418] MS m / z(ESI):541.1[M+H]

[0419] 1 H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.70(s,1H),7.94-7.60(m,7H),7.41-7.13(m,5H) ,5.31(dd,J=10.2,5.8Hz,1H),4.78-3.88(m,4H),3.30-3.17(m,1H),3.15-3.00(m,1H).

[0420] Example 17

[0421] N-(4-Acetylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide

[0422]

[0423]

[0424] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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 1-propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were added and reacted at 60°C for 4 h. After the reaction was completed, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-acetylphenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide 17 (35 mg) in a yield of 51%.

[0425] MS m / z(ESI):558.2[M+H]

[0426] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.72(s,1H),7.95(d,J=8.3Hz,2H),7.86-7.65(m,5H),7.41-7.15(m ,5H),5.35(dd,J=10.3,6.0Hz,1H),4.71-3.91(m,4H),3.30-3.19(m,1H),3.18-3.03(m,1H),2.54(s,3H).

[0427] Example 18

[0428] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide

[0429]

[0430] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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 1-propylphosphonic anhydride (129.92 mg, 204.16 μmol, 50% ethyl acetate solution) were dissolved in ethyl acetate (5 mL) in sequence and stirred at room temperature for 16 hours. After the reaction, the product was concentrated under reduced pressure and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide 18 (26 mg) in a yield of 67%.

[0431] MS m / z(ESI):567.9[M+H]

[0432] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),9.72(s,1H),8.90(s,1H),8.84(s,1H),8.50(s,1H),8.07(d,J=9.1Hz,1H),7. 95(d,J=9.2Hz,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).

[0433] Example 19

[0434] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide

[0435]

[0436] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (30 mg, 68.05 μmol), 2-methyl-2H-indazol-5-amine 19a (15.02 mg, 102.08 μmol), N,N-diisopropylethylamine (43.98 mg, 340.26 μmol) and 1-propylphosphonic anhydride (129.92 mg, 204.16 μmol, 50% ethyl acetate solution) were dissolved in ethyl acetate (4 mL) in sequence and reacted at room temperature for 16 hours. After the reaction, the product was concentrated under reduced pressure and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 19 (23 mg) in a yield of 59%.

[0437] MS m / z(ESI):570.2[M+H]

[0438] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),9.73(s,1H),8.27(s,1H),8.08(s,1H),7.93-7.65(m,3H),7.54(d,J=9.2Hz ,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).

[0439] Example 20

[0440] 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluoro-N-methylbenzamide

[0441]

[0442] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (30 mg, 68.05 μmol), 4-amino-2-fluoro-N-methylbenzamide 20a (17.17 mg, 102.08 μmol), N,N-diisopropylethylamine (43.98 mg, 340.26 μmol) and 1-propylphosphonic anhydride (129.92 mg, 204.16 μmol, 50% ethyl acetate solution) were dissolved in ethyl acetate (5 mL) in sequence and stirred at room temperature for 16 hours. After the reaction, the product was concentrated under reduced pressure and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluoro-N-methylbenzamide 20 (18 mg) in a yield of 40%.

[0443] MS m / z(ESI):591.1[M+H]

[0444] 1 H NMR(400MHz,DMSO-d6)δ10.54(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=4.5Hz,3H).

[0445] Example 21

[0446] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-phenylpropanamide

[0447]

[0448]

[0449] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and 5-aminoisobenzofuran-1(3H)-one 21a (25.37 mg, 170.13 μmol) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and 1-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 the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-phenylpropanamide 21 (24 mg) in a yield of 35%.

[0450] MS m / z(ESI):571.9[M+H]

[0451] 1 H NMR (400MHz, DMSO-d6) δ10.82(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).

[0452] Example 22

[0453] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-6-yl)

[0454] Propionamide

[0455]

[0456] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol) and pyrazolo[1,5-a]pyridin-6-amine 22a (22.65 mg, 170.13 μmol, prepared according to patent publication WO 2019099311, page 96, paragraph [000344]) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (87.95 mg, 680.52 μmol) and 1-propylphosphoric 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 the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-6-yl)propanamide 22 (18 mg) in a yield of 32%.

[0457] MS m / z(ESI):555.9[M+H]

[0458] 1 H NMR(400MHz,DMSO-d6)δ10.36(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).

[0459] Example 23

[0460] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide

[0461]

[0462] first step

[0463] 6-Bromo-1-methoxyisoquinoline

[0464] 6-Bromoisoquinolin-1(2H)-one 23a (500 mg, 2.23 mmol), iodomethane (1.58 g, 11.16 mmol), and silver carbonate (1.24 g, 4.46 mmol) were sequentially dissolved in toluene (5 mL) and stirred at 40°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 6-bromo-1-methoxyisoquinoline 23b (160 mg) in a 30% yield.

[0465] MS m / z(ESI):237.9[M+H]

[0466] Step 2

[0467] N-(1-methoxyisoquinolin-6-yl)-1,1-diphenylmethanimine

[0468] Under argon, 6-bromo-1-methoxyisoquinoline 23b (160 mg, 672.04 μmol), diphenylmethane 23c (243.59 mg, 1.34 mmol), tris(dibenzylideneacetone)dipalladium (61.54 mg, 67.20 μmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (41.85 mg, 67.20 μmol), and sodium tert-butoxide (129.17 mg, 1.34 mmol) were sequentially dissolved in toluene (10 mL). The argon atmosphere was replaced three times, and the reaction was carried out at 85°C for 20 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to give N-(1-methoxyisoquinolin-6-yl)-1,1-diphenylmethanimine 23d (200 mg) in an 88% yield.

[0469] MS m / z(ESI):339.1[M+H]

[0470] Step 3

[0471] 1-Methoxyisoquinolin-6-amine

[0472] N-(1-methoxyisoquinolin-6-yl)-1,1-diphenylcarbamylamine 23d (197.42 mg, 583.40 μmol) and 2M dilute hydrochloric acid (21.27 mg, 583.40 μmol) were sequentially dissolved in trifluoroacetic acid (6 mL) and allowed to react at room temperature for 18 hours. After completion of the reaction, the product was concentrated under reduced pressure to remove most of the trifluoroacetic acid. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford 1-methoxyisoquinolin-6-amine 23e (92 mg) in a 91% yield.

[0473] MS m / z(ESI):175.1[M+H]

[0474] Step 4

[0475] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropane

[0476] Amide

[0477] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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 mmol) and 1-propylphosphonic anhydride (216.53 mg, 340.26 μmol, 50% ethyl acetate solution) were dissolved in ethyl acetate (10 mL) in sequence and reacted at room temperature for 18 hours. After the reaction, the product was concentrated under reduced pressure and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide 23 (7 mg) in a yield of 10%.

[0478] MS m / z(ESI):597.2[M+H]

[0479] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),9.73(s,1H),8.28-8.24(m,1H),8.13(d,J=8.9Hz,1H),7.96(d,J=5.9Hz,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).

[0480] Example 24

[0481] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)

[0482] Propionamide

[0483]

[0484]

[0485] first step

[0486] 1-(4-chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole

[0487] 4-Chloro-2-nitroaniline 1a (5 g, 28.97 mmol) was dissolved in acetonitrile (300 mL) and stirred on ice for 20 minutes. Isoamyl nitrite (5.09 g, 43.46 mmol, 5.84 mL) and trimethylsilyl azide (5.01 g, 43.46 mmol, 5.72 mL) were added sequentially. After stirring on ice for 20 minutes, the ice bath was removed and the mixture was reacted at room temperature for 2 hours. Cuprous oxide (4.15 g, 28.97 mmol) and trimethylethynylsilane (8.54 g, 86.92 mmol, 12.28 mL) were added sequentially and the reaction was continued by stirring at room temperature for 4 hours. After the reaction, the product was filtered and concentrated under reduced pressure. The resulting residue was further isolated 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 58% yield. MS m / z (ESI): 297.0 [M+H]

[0488] Step 2

[0489] 4-Chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole

[0490] 1-(4-chloro-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 24a (5 g, 16.85 mmol) was dissolved in acetonitrile (93 mL), and silica gel (20.87 g, 16.85 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then N-chlorosuccinimide (11.25 g, 84.24 mmol) was added. The mixture was allowed to react at 80°C for 1 hour. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The resulting residue was further isolated 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 38% yield.

[0491] MS m / z(ESI):259.0[M+H]

[0492] Step 3

[0493] 5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline

[0494] 4-Chloro-1-(4-chloro-2-nitrophenyl)-1H-1,2,3-triazole 24b (1.75 g, 6.76 mmol) was dissolved in a mixture 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 reacted at 80°C overnight. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)aniline 24c (1.3 g) in an 84% yield. MS m / z (ESI): 228.9 [M+H]

[0495] Step 4

[0496] 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide

[0497] 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, and 2-chloroacetyl chloride (769.17 mg, 6.81 mmol, 541.67 μL) was slowly added dropwise at 0°C. The mixture was reacted at 0°C for 1 hour, and 30 mL of water was added. The reaction was quenched, the layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (1 g) in a yield of 58%.

[0498] MS m / z(ESI):304.8[M+H]

[0499] Step 5

[0500] tert-Butyl (2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalaninate

[0501] 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 ester hydrochloride 1e (1.09 g, 4.91 mmol) were dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (2.11 g, 16.36 mmol, 2.70 mL) was added, and the mixture was reacted at 80°C for 8 hours. After the reaction, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give (2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalanine tert-butyl ester 24e (1.3 g) in a yield of 81%.

[0502] MS m / z(ESI):489.9[M+H]

[0503] Step 6

[0504] tert-Butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate

[0505] Tert-butyl (2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)phenylalaninate 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 2-chloroacetyl chloride (359.29 mg, 3.18 mmol, 253.02 μL) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 30 mL of water was added to quench the reaction. The layers were separated and the aqueous phase 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. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalanine tert-butyl ester 24f (1.1 g) in a yield of 73%.

[0506] MS m / z(ESI):509.8[M+H-56]

[0507] Step 7

[0508] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate

[0509] Tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)phenylalaninate 24f (1.1 g, 1.94 mmol) was dissolved in methanol (15 mL). Sodium methoxide (5.4 M, 395.29 μL, 2.134 mmol) was slowly added dropwise at 0°C. The mixture was allowed to react for 1 hour at 0°C. After completion of the reaction, the pH was adjusted to approximately 6 with 2 M dilute hydrochloric acid. The product was concentrated under reduced pressure, and the residue was further isolated 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-dioxapiperazin-1-yl)-3-phenylpropanoate 24 g (916 mg) in an 89% yield.

[0510] MS m / z(ESI):529.8[M+H]

[0511] Step 8

[0512] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid

[0513] 24 g (916 mg, 1.73 mmol) of tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoate was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (196.91 mg, 1.73 mmol, 128.28 μL) was slowly added dropwise and allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to obtain 24 h of 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid (764 mg) in a 93% yield.

[0514] MS m / z(ESI):473.8[M+H]

[0515] Step 9

[0516] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(quinoxalin-6-yl)propanamide

[0517] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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), and 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 mixture was incubated at 65 ° C for 3 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-phenyl-N-(quinoxaline-6-yl)propanamide 24 (28 mg) in a yield of 44%.

[0518] MS m / z(ESI):600.8[M+H]

[0519] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),8.90(s,1H),8.84(d,J=1.9Hz,1H),8.64(s,1H),8.54(s,1H),8.07(d,J=9.0Hz,1H),7.94(d ,J=9.1Hz,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).

[0520] Example 25

[0521] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide

[0522]

[0523] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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), and 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 hours. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting 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-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide 25 (28 mg) in a 44% yield. MS m / z (ESI): 602.8 [M+H]

[0524] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.65(s,1H),8.26(s,1H),8.12(s,1H),7.81-7.62(m,3H),7.54(d,J=9.2Hz ,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).

[0525] Example 26

[0526] 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0527]

[0528] first step

[0529] tert-Butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0530] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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), and N,N-diisopropylethylamine (68.12 mg, 527.10 μmol) and 1-propylphosphonic anhydride (201.25 mg, 316.26 μmol, 50% ethyl acetate solution) were added, and the reaction was carried out at 60°C for 3 hours. After the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 26a (34 mg) in a yield of 50%.

[0531] MS m / z(ESI):648.8[M+H]

[0532] Step 2

[0533] 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0534] Tert-butyl 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)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. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid 26 (8 mg) in a 26% yield.

[0535] MS m / z(ESI):592.8[M+H]

[0536] 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),10.49(s,1H),8.64(s,1H),7.91(d,J=8.4Hz,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).

[0537] Example 27

[0538] N-(4-acetylphenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide

[0539]

[0540] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 24h (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 1-propylphosphonic anhydride (50% ethyl acetate solution, 201.25 mg, 316.26 μmol) were added and reacted at 65°C for 1 hour. After the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-acetylphenyl)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide 27 (27 mg) in a yield of 41%.

[0541] MS m / z(ESI):590.8[M+H]

[0542] 1 H NMR (400MHz, DMSO-d6) δ10.51(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).

[0543] Example 28

[0544] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide

[0545]

[0546] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 24h (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 1-propylphosphonic anhydride (50% ethyl acetate solution, 201.26 mg, 316.26 μmol, 93.99 μL) were dissolved in ethyl acetate (5 mL) in sequence and the reaction was stirred at room temperature for 16 hours. After the reaction, the product was concentrated under reduced pressure and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-methoxyisoquinolin-6-yl)-3-phenylpropanamide 28 (23 mg) in a yield of 33%.

[0547] MS m / z(ESI):630.2[M+H]

[0548] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.64(s,1H),8.29(s,1H),8.13(d,J=9.0Hz,1H),7.96(d,J=5.9Hz,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).

[0549] Example 29

[0550] 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-N-methylpyridinamide

[0551]

[0552] first step

[0553] 5-Amino-N-methylpyridinamide

[0554] 5-Amino-2-pyridinecarboxylic 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-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (668 mg, 1.81 mmol) and triethylamine (2.51 mL, 18.1 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (50 mL) and 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 resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 5-amino-N-methylpyridinamide 29b (260 mg) in a 48% yield.

[0555] MS m / z(ESI):152.1[M+H]

[0556] Step 2

[0557] 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-N-methylpyridinamide

[0558] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol), 5-amino-N-methylpyridinamide 29b (25.72 mg, 170.13 μmol), N,N-diisopropylethylamine (73.29 mg, 567.10 μmol, 93.72 μL) and 1-propylphosphonic anhydride (50% ethyl acetate solution, 216.53 mg, 340.26 μmol, 101.22 μL) were dissolved in ethyl acetate (5 mL) and stirred at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-N-methylpyridinamide 29 (15 mg). Yield: 22%

[0559] MS m / z(ESI):574.2[M+H]

[0560] 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.72(d,J=10.0Hz,1H),8.84(s,1H),8.73-8.64(m,1H),8.16(dd,J=8.6,2.5Hz,1H),8.01(d,J=8.5Hz, 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=4.8Hz,3H).

[0561] Example 30

[0562] N-(4-Acetyl-3-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide

[0563]

[0564] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (70 mg, 158.79 μmol) and 1-(4-amino-2-fluorophenyl)ethan-1-one 30a (36.48 mg, 238.18 μmol, prepared according to the literature Synthesis (2018), 50(3), 555-564, page 557, Table 2) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (123.13 mg, 952.73 μmol) and 1-propylphosphonic anhydride (50% ethyl acetate solution, 303.14 mg, 476.36 μmol) were added and reacted at 60°C for 1 hour. After the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-acetyl-3-fluorophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide 30 (15 mg) in a yield of 16%.

[0565] MS m / z(ESI):575.8[M+H]

[0566] 1H NMR (400MHz, DMSO-d6) δ10.67(s,1H),9.71(s,1H),7.89-7.67(m,5H),7.407.41(d,J=8.7Hz,1H),7.37-7.2 0(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=4.2Hz,3H).

[0567] Example 31

[0568] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-6-yl)-3-phenylpropanamide

[0569]

[0570] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (50 mg, 113.42 μmol), 2-methyl-6-amino-2H-indazole 31a (25.04 mg, 170.13 μmol), N,N-diisopropylethylamine (73.29 mg, 567.10 μmol, 93.72 μL) and 1-propylphosphonic anhydride (50% ethyl acetate solution, 216.41 mg, 340.26 μmol, 202.44 μL) were dissolved in ethyl acetate (5 mL) in sequence and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-6-yl)-3-phenylpropanamide 31 (21.7 mg) in a yield of 33%.

[0571] MS m / z(ESI):569.9[M+H]

[0572] 1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.72(s,1H),8.26(s,1H),8.01(s,1H),7 .82(d,J=8.5Hz,1H),7.75(dd,J=8.6,2.1Hz,1H),7.63(d,J=8.9Hz,1H),7.39- 7.17(m,5H),7.08(d,J=9.1Hz,1H),5.38(dd,J=10.1,5.8Hz,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).

[0573] Example 32

[0574] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)

[0575] Butanamide

[0576]

[0577]

[0578] first step

[0579] N-(tert-Butyloxycarbonyl)-O-methylhomoserine methyl ester

[0580] 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 under ice-cooling. After 20 minutes, iodomethane (2.59 g, 18.25 mmol, 1.14 mL) was slowly added dropwise and allowed to react at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford N-(tert-butyloxycarbonyl)-O-methylhomoserine methyl ester 32b (370 mg) in a 32% yield.

[0581] MS m / z(ESI):147.1[M-100]

[0582] Step 2

[0583] O-Methylhomoserine methyl ester

[0584] N-(tert-Butyloxycarbonyl)-O-methylhomoserine methyl ester 32b (370 mg, 1.50 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford O-methylhomoserine methyl ester 32c (384 mg), which was used directly in the next step.

[0585] MS m / z(ESI):148.1[M+H]

[0586] Step 3

[0587] Methyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine ester

[0588] 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), and N,N-diisopropylethylamine (1.05 g, 8.15 mmol, 1.35 mL) was added. The mixture was reacted at 80°C overnight. Water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 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%.

[0589] MS m / z(ESI):382.9[M+H]

[0590] Step 4

[0591] Methyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine

[0592] Methyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine ester 32d (400 mg, 1.04 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (528.68 mg, 5.22 mmol, 726.21 μL) was added. Chloroacetyl chloride (177.03 mg, 1.57 mmol, 124.67 μL) was slowly added dropwise under ice-bath, and the mixture was reacted under 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, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 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%.

[0593] MS m / z(ESI):458.9[M+H]

[0594] Step 5

[0595] Methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoate

[0596] Methyl N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine ester 32e (194 mg, 422.40 μmol) was dissolved in methanol (5 mL). Sodium methoxide (5.4 M in methanol, 86.04 μL, 2.28 mmol) was slowly added dropwise under ice-cooling. The reaction was allowed to proceed for 30 minutes. After completion of the reaction, 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The product was concentrated under reduced pressure, and the residue was further isolated 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-dioxapiperazin-1-yl)-4-methoxybutanoate 32f (100 mg) in a 56% yield. MS m / z (ESI): 422.9 [M+H].

[0597] Step 6

[0598] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoic acid

[0599] Methyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoate 32f (100 mg, 236.51 μmol) was dissolved in a mixture of tetrahydrofuran, methanol, and water (3 mL + 1 mL + 1 mL). Lithium hydroxide monohydrate (19.85 mg, 473.01 μmol) was added under ice-cooling and allowed to react for 1 hour. After completion of the reaction, 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The product was concentrated under reduced pressure, and the residue was further isolated and purified by silica gel column chromatography (eluent: System B) to obtain 32 g (65 mg) of 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoic acid in a 65% yield.

[0600] MS m / z(ESI):408.9[M+H]

[0601] Step 7

[0602] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[0603] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoic acid (32 g, 65 mg, 159.00 μmol) and 2-methyl-2H-indazol-5-amine 19a (35.10 mg, 238.51 μmol) were dissolved in ethyl acetate (5 mL). 1-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 mixture was reacted at 60°C for 2 h. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 32 (16 mg) in a yield of 17%.

[0604] MS m / z(ESI):537.9[M+H]

[0605] 1H NMR (400MHz, DMSO-d6) δ10.07(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).

[0606] Example 33

[0607] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-3-phenylpropanamide

[0608]

[0609] first step

[0610] 1-Difluoromethyl-5-nitroindazole 33b

[0611] 2-Difluoromethyl-5-nitroindazole 33c

[0612] 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 under ice-cooling. After stirring under ice-cooling for 10 minutes, sodium difluorochloroacetate (5.61 g, 36.78 mmol) was added. After the addition was complete, the mixture was reacted at room temperature for 30 minutes and then heated to 80°C for 2 hours. Water was added to the reaction solution to quench the reaction, and the product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System A) to give 1-difluoromethyl-5-nitroindazole 33b (1.3 g) in a 33% yield and 2-difluoromethyl-5-nitroindazole 33c (1.7 g) in a 43% yield.

[0613] 33b MS m / z(ESI):213.9[M+H]

[0614] 33c MS m / z(ESI):213.9[M+H]

[0615] Step 2

[0616] 1-(Difluoromethyl)-1H-indazol-5-amine

[0617] 1-Difluoromethyl-5-nitroindazole 33b (300 mg, 1.41 mmol) was dissolved in a mixture 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 reacted at 80°C for 2 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford 1-(difluoromethyl)-1H-indazol-5-amine 33d (214 mg) in an 83% yield.

[0618] MS m / z(ESI):184.0[M+H]

[0619] Step 3

[0620] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-3-phenylpropanamide

[0621] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(1-(difluoromethyl)-1H-indazol-5-yl)-3-phenylpropanamide 33 (12 mg) in a yield of 11%.

[0622] MS m / z(ESI):605.8[M+H]

[0623] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.73(s,1H),8.40(s,1H),8.24(s,1H),8.14(t,J=58.3Hz,1H),7.9 6-7.54(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).

[0624] Example 34

[0625] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide

[0626]

[0627]

[0628] first step

[0629] 2-(Difluoromethyl)-2H-indazol-5-amine

[0630] 2-Difluoromethyl-5-nitroindazole 33c (300 mg, 1.41 mmol) was dissolved in a mixture 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 reacted at 80°C for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 2-(difluoromethyl)-2H-indazol-5-amine 34a (200 mg) in a 78% yield.

[0631] MS m / z(ESI):184.0[M+H]

[0632] Step 2

[0633] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide

[0634] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 the reaction, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 34 (20 mg) in a yield of 19%.

[0635] MS m / z(ESI):605.8[M+H]

[0636] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.72(d,J=1.6Hz,1H),8.81(s,1H),8.22(s,1H),8.10(t,J=59.0Hz,1H),7.90-7.59(m ,4H),7.39(d,J=9.4Hz,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).

[0637] Example 35

[0638] 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluorobenzamide

[0639]

[0640]

[0641] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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 patent publication US20170275282A1, page 19, paragraphs

[0503] -

[0505] , Example 1.1B) were dissolved in ethyl acetate (6 mL), and 1-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 reaction was carried out at 60°C for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was further separated and purified by silica gel column chromatography (eluent: System B) to give 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluorobenzamide 35 (21 mg) in a yield of 27%.

[0642] MS m / z(ESI):576.8[M+H]

[0643] 1 H NMR (400MHz, DMSO-d6) δ10.55(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).

[0644] Example 36

[0645] 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluorobenzamide

[0646]

[0647] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 24h (50 mg, 105.42 μmol) and 4-amino-2-fluorobenzamide 35a (24.37 mg, 158.13 μmol, prepared according to US20170275282A1, specification page 19, paragraphs

[0503] -

[0505] , Example 1.1B) were dissolved in ethyl acetate (5 mL), and N,N-diisopropylethylamine (81.75 mg, 632.52 μmol) and 1-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 product was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to afford 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluorobenzamide 36 (17 mg) in a 26% yield. MS m / z (ESI): 609.8 [M+H]

[0648] 1 H NMR (400MHz, DMSO-d6) δ10.55(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).

[0649] Example 37

[0650] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide

[0651]

[0652] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (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). 1-Propylphosphonic anhydride (50% ethyl acetate solution, 346.45 mg, 544.42 μmol) and N,N-diisopropylethylamine (117.27 mg, 907.36 μmol) were added and the mixture was reacted at 60°C for 2 h. After the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide 37 (50 mg) in a yield of 49%.

[0653] MS m / z(ESI):555.7[M+H]

[0654] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),9.72(s,1H),8.61(d,J=7.5Hz,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=7.5Hz,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).

[0655] Example 38

[0656] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[0657]

[0658] first step

[0659] Methyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine

[0660] 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), and N,N-diisopropylethylamine (2.11 g, 16.36 mmol, 2.70 mL) was added and the reaction was carried out at 75°C overnight. The reaction was quenched by the addition of 30 mL of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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)-O-methylhomoserine methyl ester 38a (1.1 g) in an 81% yield.

[0661] MS m / z(ESI):415.9[M+H]

[0662] Step 2

[0663] Methyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine

[0664] Methyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-methylhomoserine 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 under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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%.

[0665] MS m / z(ESI):491.8[M+H]

[0666] Step 3

[0667] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoate

[0668] Methyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-methylhomoserine ester 38b (650 mg, 1.32 mmol) was dissolved in methanol (20 mL). Sodium methoxide (5.4 M in methanol, 268.72 μL, 1.45 mmol) was slowly added dropwise under ice-cooling. The reaction was allowed to proceed for 30 minutes. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The product was concentrated under reduced pressure, and the residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoate 38c (505 mg) in an 84% yield.

[0669] MS m / z(ESI):455.8[M+H]

[0670] Step 4

[0671] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoic acid

[0672] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoate 38c (470 mg, 1.03 mmol) was dissolved in a mixture of tetrahydrofuran (9 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide monohydrate (86.44 mg, 2.06 mmol) was added under ice-cooling and the mixture was allowed to react for 2 hours. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxybutanoic acid 38d (346 mg) in a 76% yield.

[0673] MS m / z(ESI):442.1[M+H]

[0674] Step 5

[0675] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-

[0676] Indazol-5-yl)butanamide

[0677] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 38 (65 mg) in a yield of 50%.

[0678] MS m / z(ESI):570.8[M+H]

[0679] 1 H NMR (400MHz, DMSO-d6) δ10.06(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=9.1Hz,1H),7. 27(d,J=9.4Hz,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).

[0680] Example 39

[0681] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)

[0682] Propionamide

[0683]

[0684] first step

[0685] tert-Butyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate

[0686] N-Benzhydrylene-glycine tert-butyl ester 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 portionwise at 0°C. The mixture was allowed to react for 15 minutes at 0°C. Bromomethylcyclobutane 39b (1.66 g, 11.17 mmol, 1.25 mL) was then added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate 39c (2.9 g), which was used directly in the next step.

[0687] MS m / z(ESI):364.2[M+H]

[0688] Step 2

[0689] tert-Butyl 2-amino-3-cyclobutylpropionate

[0690] The crude product, tert-butyl 3-cyclobutyl-2-((diphenylmethylene)amino)propanoate 39c, obtained in the previous step, was dissolved in tetrahydrofuran (20 mL) and 2M dilute hydrochloric acid (20 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-cyclobutylpropanoate 39d (1.06 g) in a 66% yield.

[0691] MS m / z(ESI):144.1[M+H-56]

[0692] Step 3

[0693] tert-Butyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate

[0694] 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (350 mg, 1.29 mmol) and tert-butyl 2-amino-3-cyclobutylpropionate 39d (563.98 mg, 2.83 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 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. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give 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%.

[0695] MS m / z(ESI):435.0[M+H]

[0696] Step 4

[0697] tert-Butyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate

[0698] 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 under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. The reaction was quenched by adding 30 mL of water, extracted with ethyl acetate (30 mL × 3), and 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 give crude product tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate 39f (282 mg), which was used directly in the next step.

[0699] MS m / z(ESI):510.9[M+H]

[0700] Step 5

[0701] tert-Butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate

[0702] The crude product, tert-butyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetamido)-3-cyclobutylpropanoate 39f (282 mg, 551.43 μmol), obtained in the previous step, was dissolved in methanol (9.88 mL). Sodium methoxide (5.4 M in methanol, 122.54 μL, 661.72 μmol) was slowly added dropwise at 0°C. The reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The product was concentrated under reduced pressure, and the residue was further isolated 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-dioxapiperazin-1-yl)-3-cyclobutylpropanoate 39g (96 mg) in a 37% yield.

[0703] MS m / z(ESI):475.1[M+H]

[0704] Step 6

[0705] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropionic acid

[0706] Dissolve tert-butyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate (39g, 90mg, 189.50μmol) in dichloromethane (8mL). Slowly add trifluoroacetic acid (2mL) dropwise and allow to react at room temperature for 1 hour. After completion of the reaction, concentrate under reduced pressure to obtain crude product 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate (39h, 79mg), which is used directly in the next reaction.

[0707] MS m / z(ESI):418.9[M+H]

[0708] Step 7

[0709] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide

[0710] The crude product 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropionic acid 39h (79 mg, 188.62 μmol) and 2-methyl-2H-indazol-5-amine 19a (41.64 mg, 282.93 μmol) obtained in the previous step were dissolved in ethyl acetate (6 mL). 1-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 reacted at 60°C for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide 39 (40 mg) in a 38% yield. MS m / z (ESI): 548.2 [M+H]

[0711] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.79(d,J=5.7Hz,1H),8.24(d,J=5.7Hz,1H),8.08(d,J=5.7Hz,1H),7.90(d,J=5.6Hz,1H),7.8 7-7.71(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=5.7Hz,3H),2.18-1.49(m,9H).

[0712] Example 40

[0713] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide

[0714]

[0715] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 24h (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). 1-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 reacted at 60°C for 15 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-phenyl-N-(pyrazolo[1,5-a]pyridin-5-yl)propanamide 40 (46.9 mg) in a yield of 75%.

[0716] MS m / z(ESI):588.8[M+H]

[0717] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.65(s,1H),8.61(d,J=7.5Hz,1H),8.12(s,1H),7.92(d,J=2.2Hz,1H),7.81-7.62(m,3H),7.37-7. 15(m,5H),6.92(dd,J=7.4,2.3Hz,1H),6.50(d,J=2.2Hz,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).

[0718] Example 41

[0719] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0720]

[0721] first step

[0722] Ethyl 2-((2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate

[0723] 2-Chloro-N-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acetamide 1d (0.3 g, 1.10 mmol) and L-4-fluorophenylalanine ethyl ester hydrochloride 41a (1.71 g, 6.55 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (712.48 mg, 5.51 mmol) was added. The mixture was stirred at 60°C for 16 hours. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give 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%.

[0724] MS m / z(ESI):446.9[M+H]

[0725] Step 2

[0726] Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(4-fluorophenyl)propanoate

[0727] 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 under ice-cooling, and the mixture was reacted under ice-cooling for 2 hours. The reaction was quenched by adding 30 mL of water, 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 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)acetylamino)-3-(4-fluorophenyl)propanoate 41c (250 mg) in a 61% yield.

[0728] MS m / z(ESI):523.2[M+H]

[0729] Step 3

[0730] Ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate

[0731] Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(4-fluorophenyl)propanoate 41c (260 mg, 496.81 μmol) was dissolved in methanol (5 mL). Sodium methoxide (5.4 M in methanol, 110.40 μL, 596.16 mmol) was slowly added dropwise under ice-cooling. The reaction was allowed to proceed for 2 hours. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The product was concentrated under reduced pressure, and the residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate 41d (100 mg) in a 41% yield.

[0732] MS m / z(ESI):487.1[M+H]

[0733] Step 4

[0734] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid

[0735] Ethyl 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate 41d (100 mg, 205.39 μmol) was dissolved in a mixture of tetrahydrofuran (3 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (12.94 mg, 308.08 μmol) was added under ice-cooling and the mixture was allowed to react for 4 hours. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6. The mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 41e (64 mg) in a 68% yield. MS m / z(ESI):459.0[M+H]

[0736] Step 5

[0737] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0738] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 41 (30 mg) in a yield of 36%.

[0739] MS m / z(ESI):588.2[M+H]

[0740] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),9.73(s,1H),8.27(s,1H),8.07(s,1H),7.90-7.68(m,3H),7.55(d,J=9.1Hz,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).

[0741] Example 42

[0742] 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluoro-N-methylbenzamide

[0743]

[0744] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 24h (50 mg, 105.42 μmol) and 4-amino-2-fluoro-N-methylbenzamide 20a (226.59 mg, 158.13 μmol) were dissolved in ethyl acetate (10 mL), and N,N-diisopropylethylamine (68.12 mg, 527.10 μmol) and 1-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 the reaction is completed, the product is concentrated under reduced pressure and the residue is further separated and purified by silica gel column chromatography (eluent: System B) to give 4-(2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)-2-fluoro-N-methylbenzamide 42 (57 mg) in a yield of 86%.

[0745] MS m / z(ESI):623.8[M+H]

[0746] 1 H NMR(400MHz,DMSO-d6)δ10.56(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=4.5Hz,3H).

[0747] Example 43

[0748] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazole-5-

[0749] yl)-3-(pyridin-3-yl)propionamide

[0750]

[0751] first step

[0752] tert-Butyl 2-((diphenylmethylene)amino)-3-(pyridin-3-yl)propanoate

[0753] N-Benzhydrylene-glycine tert-butyl ester 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 portionwise at 0°C. After 15 minutes at 0°C, 3-(bromomethyl)pyridine hydrobromide 43a (2.77 g, 11.00 mmol) was added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of 30 mL of water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-3-yl)propanoate 43b (3.86 g), which was used directly in the next step.

[0754] MS m / z(ESI):387.0[M+H]

[0755] Step 2

[0756] tert-Butyl 2-amino-3-(pyridin-3-yl)propanoate

[0757] The crude product, tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-3-yl)propanoate 43b (3.86 g, 10 mmol), was dissolved in tetrahydrofuran (20 mL) and 2M dilute hydrochloric acid (20 mL) was added. The mixture was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(pyridin-3-yl)propanoate 43c (1.06 g) in a 39% yield.

[0758] MS m / z(ESI):222.9[M+H]

[0759] Step 3

[0760] tert-2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-3-yl)propanoic acid

[0761] Butyl ester

[0762] 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), and 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. The reaction was quenched by adding 40 mL of water, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(pyridin-3-yl)propanoate 43d (299 mg) in a yield of 93%.

[0763] MS m / z(ESI):490.9[M+H]

[0764] Step 4

[0765] 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(pyridine-3-

[0766] tert-Butyl propionate

[0767] 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 under ice bath, and the reaction was carried out under ice bath for 2 hours. The reaction was quenched by adding 30 mL of water, extracted with dichloromethane (30 mL × 3), and 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 give crude product 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-(pyridin-3-yl)propanoate 43e (345 mg), which was used directly in the next reaction.

[0768] MS m / z(ESI):566.8[M+H]

[0769] Step 5

[0770] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-3-yl)propanoate

[0771] The crude product of the previous step, 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 (345 mg, 607.55 μmol), was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 135.01 μL, 729.05 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-3-yl)propanoate 43f (220 mg) in a yield of 68%.

[0772] MS m / z(ESI):531.1[M+H]

[0773] Step 6

[0774] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid

[0775] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-3-yl)propanoate 43f (220 mg, 414.01 μmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise. The mixture was reacted at room temperature for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid 43g (196 mg), which was used directly in the next reaction.

[0776] MS m / z(ESI):474.8[M+H]

[0777] Step 7

[0778] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-3-yl)propanamide

[0779] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-3-yl)propanoic acid (43 g, 196 mg, 412.38 μmol) and 2-methyl-2H-indazol-5-amine 19a (91.04 mg, 618.58 μmol) obtained in the previous step were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-3-yl)propanamide 43 (14 mg) in a yield of 5%.

[0780] MS m / z(ESI):603.8[M+H]

[0781] 1 H NMR(400MHz,DMSO-d6)δ10.20(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=9.1Hz,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).

[0782] Example 44

[0783] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0784]

[0785]

[0786] first step

[0787] tert-Butyl 2-((diphenylmethylene)amino)-3-(2-fluorophenyl)propanoate

[0788] N-Benzhydrylene-glycine tert-butyl ester 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 portionwise at 0°C. The mixture was allowed to react for 15 minutes at 0°C. 2-Fluorobenzyl bromide 44a (2.08 g, 11.00 mmol) was then added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of 40 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 2-((diphenylmethylene)amino)-3-(2-fluorophenyl)propanoate 44b (4 g), which was used directly in the next step.

[0789] MS m / z(ESI):404.0[M+H]

[0790] Step 2

[0791] tert-Butyl 2-amino-3-(2-fluorophenyl)propionate

[0792] The crude product, tert-butyl 2-((diphenylmethylene)amino)-3-(2-fluorophenyl)propanoate 44b (4 g, 10 mmol), was dissolved in tetrahydrofuran (20 mL) and 2M dilute hydrochloric acid (20 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL × 3), washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(2-fluorophenyl)propanoate 44c (1.41 g) in a 59% yield.

[0793] MS m / z(ESI):184.1[M+H-56]

[0794] Step 3

[0795] 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

[0796] ester

[0797] 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), and 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. The reaction was quenched by adding 80 mL of water, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed sequentially with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(2-fluorophenyl)propanoate 44d (286 mg) in a yield of 86%.

[0798] MS m / z(ESI):507.9[M+H]

[0799] Step 4

[0800] 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-(2-fluorophenyl)propanoate

[0801] 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 under ice bath, and the reaction was carried out under ice bath for 2 hours. The reaction was quenched by adding 30 mL of water, extracted with dichloromethane (30 mL × 3), and 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 give crude product 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-(2-fluorophenyl)propanoate 44e (329 mg), which was used directly in the next reaction.

[0802] MS m / z(ESI):584.4[M+H]

[0803] Step 5

[0804] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)propanoate

[0805] The crude product 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-(2-fluorophenyl)propanoate 44e (329 mg, 562.53 μmol) obtained in the previous step was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 114.59 μL, 618.79 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)propanoate 44f (230 mg) in a yield of 75%.

[0806] MS m / z(ESI):547.8[M+H]

[0807] Step 6

[0808] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)propanoic acid

[0809] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)propanoate 44f (230 mg, 419.41 μmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)propanoate 44g (206 mg), which was used directly in the next reaction.

[0810] MS m / z(ESI):491.8[M+H]

[0811] Step 7

[0812] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0813] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2-fluorophenyl)propanoic acid (44 g, 206 mg, 418.46 μmol) and 2-methyl-2H-indazol-5-amine 19a (92.38 mg, 627.68 μmol) obtained in the previous step were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(2-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 44 (136 mg) in a yield of 52%.

[0814] MS m / z(ESI):620.8[M+H]

[0815] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.69(s,1H),8.27(s,1H),8.07(s,1H),7.82-7.65(m,3H),7.53(d,J=9.1Hz,1H),7.3 8-7.26(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).

[0816] Example 45

[0817] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide

[0818]

[0819] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 24h (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). 1-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 reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 45 (20 mg) in a yield of 21%.

[0820] MS m / z(ESI):638.7[M+H]

[0821] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.82(s,1H),8.65(s,1H),8.25(s,1H),8.10(t,J=59.1Hz,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).

[0822] Example 46

[0823] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)-N-(2-methyl

[0824] -2H-indazol-5-yl)propionamide

[0825]

[0826] first step

[0827] tert-Butyl 2-((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate

[0828] N-Benzhydrylene-glycine tert-butyl ester 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 portionwise at 0°C. The mixture was allowed to react for 15 minutes at 0°C. 3-Fluorobenzyl bromide 46a (2 g, 10.58 mmol) was then added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of 40 mL of water and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 2-((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate 46b (4.269 g), which was used directly in the next step.

[0829] MS m / z(ESI):404.2[M+H]

[0830] Step 2

[0831] tert-Butyl 2-amino-3-(3-fluorophenyl)propionate

[0832] The crude product, tert-butyl 2-((diphenylmethylene)amino)-3-(3-fluorophenyl)propanoate 46b (4.269 g, 10.58 mmol), obtained in the previous step, was dissolved in tetrahydrofuran (10 mL) and 2M dilute hydrochloric acid (10 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(3-fluorophenyl)propanoate 46c (1.98 g) in a 78% yield.

[0833] MS m / z(ESI):184.1[M+H-56]

[0834] Step 3

[0835] 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

[0836] 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), and 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 quench the reaction, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed sequentially with water (80 mL) and saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(3-fluorophenyl)propanoate 46d (220 mg) in a yield of 53%.

[0837] MS m / z(ESI):508.1[M+H]

[0838] Step 4

[0839] 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-(3-fluorophenyl)propanoate

[0840] 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 then chloroacetyl chloride (73.31 mg, 649.13 μmol, 51.66 μL) was slowly added dropwise under ice bath, and the reaction was carried out under ice bath for 2 hours. The reaction was quenched by adding 30 mL of water, extracted with dichloromethane (30 mL × 3), and 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 give crude product 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-(3-fluorophenyl)propanoate 46e (232 mg), which was used directly in the next reaction.

[0841] MS m / z(ESI):527.7[M+H-56]

[0842] Step 5

[0843] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)propanoate

[0844] The crude product 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-(3-fluorophenyl)propanoate 46e (230 mg, 393.26 μmol) obtained in the previous step was dissolved in methanol (6 mL). Sodium methoxide (5.4 M methanol solution, 72.83 μL, 393.28 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 2 h. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)propanoate 46f (154 mg) in a yield of 71%.

[0845] MS m / z(ESI):491.8[M+H-56]

[0846] Step 6

[0847] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid

[0848] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)propanoate 46f (154 mg, 280.82 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid 46 g (100 mg), which was used directly in the next reaction.

[0849] MS m / z(ESI):491.8[M+H]

[0850] Step 7

[0851] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0852] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(3-fluorophenyl)propanoic acid (46 g, 100 mg, 203.13 μmol) and 2-methyl-2H-indazol-5-amine 19a (44.84 mg, 304.70 μmol) obtained in the previous step were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 15 hours. The product was concentrated under reduced pressure, and the 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-dioxapiperazin-1-yl)-3-(3-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 46 (49 mg) in a yield of 39%.

[0853] MS m / z(ESI):620.8[M+H]

[0854] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.65(s,1H),8.26(s,1H),8.10(s,1H),7.81-7.63(m,3H),7.55(d,J=9.2Hz,1H),7.36( q,J=7.4Hz,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).

[0855] Example 47

[0856] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[0857]

[0858] first step

[0859] Ethyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(4-fluorophenyl)propanoate

[0860] 2-Chloro-N-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)acetamide 24d (220 mg, 720.02 μmol) and L-4-fluorophenylalanine ethyl ester hydrochloride 41a (228.14 mg, 921.05 μmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (465.28 mg, 3.60 mmol) was added, and the mixture was stirred at 60°C for 5 hours. The reaction was quenched by adding 30 mL of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give 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%.

[0861] MS m / z(ESI):479.8[M+H]

[0862] Step 2

[0863] Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(4-fluorophenyl)propanoate

[0864] 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 under ice-cooling, and the mixture was reacted under ice-cooling for 2 hours. The reaction mixture was quenched by the addition of 30 mL of water, extracted with ethyl acetate (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give ethyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(4-fluorophenyl)propanoate 47b (150 mg) in a yield of 99.5%.

[0865] MS m / z(ESI):555.7[M+H]

[0866] Step 3

[0867] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate

[0868] Ethyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(4-fluorophenyl)propanoate 47b (150 mg, 269.40 μmol) was dissolved in methanol (8 mL). Sodium methoxide (5.4 M methanol solution, 49.89 μL, 269.41 mmol) was slowly added dropwise under ice-cooling and the mixture was reacted under ice-cooling for 2 h. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate 47c (87 mg, yield: 64%).

[0869] MS m / z(ESI):506.0[M+H]

[0870] Step 4

[0871] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid

[0872] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). Lithium hydroxide monohydrate (7.22 mg, 171.82 μmol) was added under ice-cooling and the mixture was reacted under ice-cooling for 3 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and the mixture was concentrated under reduced pressure. The 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-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (67 mg, yield: 79%).

[0873] MS m / z(ESI):491.8[M+H]

[0874] Step 5

[0875] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl

[0876] -2H-indazol-5-yl)propionamide

[0877] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-Propylphosphonic anhydride (50% ethyl acetate solution, 259.82 mg, 408.3 μmol) and N,N-diisopropylethylamine (87.9 mg, 680.5 μmol, 112.47 μL) were added and the reaction was carried out at 60°C for 3 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 47 (41 mg) in a yield of 47%.

[0878] MS m / z(ESI):620.8[M+H]

[0879] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.66(s,1H),8.26(s,1H),8.10(s,1H),7.87-7.63(m,3H),7.54(d,J=9.2Hz ,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).

[0880] Example 48 was synthesized according to the synthesis method of Examples 1-47 of the present invention. The spectrum parameters of Example 48 are shown in the following table:

[0881]

[0882] Example 49

[0883] 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0884]

[0885]

[0886] first step

[0887] (2-Bromo-5-chlorophenyl)glycine ethyl ester

[0888] 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 under ice-cooling. After stirring under ice-cooling for 10 minutes, the mixture was heated to 100°C and allowed to react overnight. The reaction was quenched by the addition of water (300 mL) and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with water (200 mL x 2), washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford (2-bromo-5-chlorophenyl)glycine ethyl ester 49c (7.08 g) in a 100% yield.

[0889] MS m / z(ESI):291.9[M+H]

[0890] Step 2

[0891] 2-((2-Bromo-5-chlorophenyl)amino)ethan-1-ol

[0892] (2-Bromo-5-chlorophenyl)glycine ethyl ester 49c (4 g, 13.7 mmol) was dissolved in tetrahydrofuran (40 mL). Lithium aluminum hydride (779 mg, 20.5 mmol) was added at 0°C and the mixture was allowed to react on ice for 30 minutes. Water (1 mL) was added to quench the reaction. 15% aqueous sodium hydroxide solution (1 mL) and water (3 mL) were then added. After stirring for 10 minutes, anhydrous sodium sulfate was added, the mixture was dried, filtered, and concentrated under reduced pressure to afford crude 2-((2-bromo-5-chlorophenyl)amino)ethan-1-ol 49d (1.8 g), which was used directly in the next reaction. MS m / z (ESI): 249.9 [M+H]

[0893] Step 3

[0894] 2-((2-bromo-5-chlorophenyl)amino)ethyl methanesulfonate

[0895] 2-((2-bromo-5-chlorophenyl)amino)ethane-1-ol 49d (1.8 g, 7.2 mmol) and triethylamine (3 mL, 21.6 mmol) were dissolved in dichloromethane (30 mL). Methanesulfonyl chloride (0.83 mL, 10.8 mmol) was added at 0°C, and the reaction was continued at 0°C for 1 hour. Water (30 mL) was added to quench the reaction. After stirring for 10 minutes, the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-((2-bromo-5-chlorophenyl)amino)ethyl methanesulfonate 49e (2.37 g), which was used directly in the next reaction.

[0896] MS m / z(ESI):327.9[M+H]

[0897] Step 4

[0898] (2-((2-bromo-5-chlorophenyl)amino)ethyl)phenylalanine methyl ester

[0899] 2-((2-bromo-5-chlorophenyl)amino)ethyl methanesulfonate 49e (5.1 g, 15.5 mmol) and phenylalanine methyl ester hydrochloride 49f (5 g, 23.3 mmol) were dissolved in acetonitrile (100 mL). Potassium carbonate (12.9 g, 93 mmol) was added and stirred at 80°C for 48 hours. The mixture was filtered and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to obtain methyl (2-((2-bromo-5-chlorophenyl)amino)ethyl)phenylalaninate 49 g (1.35 g) in a 21% yield.

[0900] MS m / z(ESI):410.9[M+H]

[0901] Step 5

[0902] Methyl 2-(4-(2-bromo-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoate

[0903] Dissolve 49 g (300 mg, 0.729 mmol) of (2-((2-bromo-5-chlorophenyl)amino)ethyl)phenylalanine methyl ester in acetonitrile (20 mL). Add potassium carbonate (302 mg, 2.187 mmol). Slowly add chloroacetyl chloride (90 mg, 0.802 mmol) dropwise at 0°C. Stirring is continued at 0°C for 30 minutes, followed by the addition of potassium iodide (363 mg, 2.187 mmol). Reflux for 6 hours. Filter and concentrate under reduced pressure. The resulting residue is further isolated and purified by silica gel column chromatography (eluent: System A) to obtain 49 h (240 mg) of methyl 2-(4-(2-bromo-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoate in a 73% yield.

[0904] MS m / z(ESI):450.8[M+H]

[0905] Step 6

[0906] Methyl 2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoate

[0907] Methyl 2-(4-(2-bromo-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoate 49h (240 mg, 0.53 mmol), tri-n-butyl(1-ethoxyvinyl)tin (959 mg, 2.66 mmol), and bistriphenylphosphine palladium dichloride (37.2 mg, 0.053 mmol) were dissolved in 1,4-dioxane (10 mL) and heated to 100°C under an argon atmosphere for overnight reaction. The product was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford methyl 2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoate 49i (220 mg) in a 90% yield.

[0908] MS m / z(ESI):414.9[M+H]

[0909] Step 7

[0910] 2-(4-(2-Acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionic acid

[0911] Methyl 2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoate 49i (220 mg, 0.578 mmol) was dissolved in a mixture 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 reaction was stirred for 3 hours. The pH was adjusted to approximately 5 with 2M dilute hydrochloric acid, and the mixture was concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoic acid 49j (200 mg) in an 86% yield.

[0912] MS m / z(ESI):401.0[M+H]

[0913] Step 8

[0914] tert-Butyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionamido)benzoate

[0915] 2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropanoic acid 49j (120 mg, 0.3 mmol) and tert-butyl p-aminobenzoate 1j (58 mg, 0.6 mmol) were dissolved in ethyl acetate (10 mL). N,N-diisopropylethylamine (232 mg, 1.8 mmol) and 1-propylphosphonic anhydride (572.72 mg, 900 μmol, 50% ethyl acetate solution) were added, and the mixture was reacted at 70°C overnight. The mixture was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionamido)benzoate 49k (160 mg) in a 93% yield.

[0916] MS m / z(ESI):576.2[M+H]

[0917] Step 9

[0918] 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0919] Tert-butyl 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionamido)benzoate 49k (160 mg, 0.278 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 4-(2-(4-(2-acetyl-5-chlorophenyl)-2-oxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid 49 (33 mg) in a 23% yield.

[0920] MS m / z(ESI):520.2[M+H]

[0921] 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),10.48(s,1H),7.90(d,J=8.3Hz,2H),7.73(d,J=8.3Hz,2H),7.41(d,J=8.5Hz,1H),7.34-7.25(m,4H),7.24-7. 17(m,1H),7.13-7.06(m,2H),5.53(dd,J=10.9,5.4Hz,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).

[0922] Examples 50-51 were synthesized according to the synthesis method of Examples 1-47 of the present invention. The spectrum parameters of Examples 50-51 are shown in the following table:

[0923]

[0924] Example 52

[0925] 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid

[0926]

[0927]

[0928] Tert-butyl 4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoate 1 (90 mg, 146.09 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.5 mL) was added. The mixture was reacted at room temperature for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated 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-dioxapiperazin-1-yl)-3-phenylpropionamido)benzoic acid 52 (45 mg) in a 54% yield.

[0929] MS m / z(ESI):560.1[M+H]

[0930] 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),10.50(s,1H),9.72(s,1H),7.91(d,J=8.3Hz,2H),7.81(d,J=8.6Hz,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).

[0931] Examples 53-75 were synthesized according to the synthesis method of Examples 1-47 of the present invention. The spectrum parameters of Examples 53-75 are shown in the following table:

[0932]

[0933]

[0934]

[0935]

[0936]

[0937] Example 76

[0938] 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

[0939]

[0940] first step

[0941] 1-(4-Amino-3-nitrophenyl)ethan-1-one

[0942] 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 slowly added at 0-5°C, and the reaction mixture was stirred at 0-5°C for 1 hour. Ethyl acetate (50 mL) was added to dilute the reaction solution, which was then poured into 50 mL of ice water. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford 1-(4-amino-3-nitrophenyl)ethan-1-one 76a (1.8 g) in a 27% yield.

[0943] MS m / z(ESI):181.0[M+H]

[0944] Step 2

[0945] 1-(3,4-Diaminophenyl)ethan-1-one

[0946] 1-(4-Amino-3-nitrophenyl)ethan-1-one 76a (11 g, 61.06 mmol) was dissolved in a mixture 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 reacted at 80°C for 4 hours. The mixture was filtered and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 1-(3,4-diaminophenyl)ethan-1-one 76b (720 mg) in a 48% yield.

[0947] MS m / z(ESI):151.1[M+H]

[0948] Step 3

[0949] N-(4-Acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropane

[0950] Amide

[0951] 2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanoic acid 1i (100 mg, 226.84 μmol) and 1-(3,4-diaminophenyl)ethan-1-one 76b (40.88 mg, 272.21 μmol) were dissolved in ethyl acetate (10 mL). N,N-diisopropylethylamine (175.90 mg, 1.36 mmol) and 1-propylphosphonic anhydride (433.06 mg, 680.52 μmol, 50% ethyl acetate solution) were added and reacted at 60°C for 3 h. The product was concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: System B) to give N-(4-acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-phenylpropanamide 76c (129 mg) in a 99% yield.

[0952] MS m / z(ESI):572.8[M+H]

[0953] Step 4

[0954] 1-(1-(6-acetyl-1H-benzo[d]imidazol-2-yl)-2-phenylethyl)-4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)piperazine-2,5-diol

[0955] ketone

[0956] N-(4-Acetyl-2-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,5-dioxapiperazin-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. LC-MS monitored the reaction completion. The product was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford 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 17% yield.

[0957] MS m / z(ESI):554.8[M+H]

[0958] 1H NMR(400MHz,DMSO-d6)δ9.75(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).

[0959] 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:

[0960]

[0961] Examples 80-94 were synthesized according to the synthesis method of Examples 1-47 of the present invention. The spectrum parameters of Examples 80-94 are shown in the following table:

[0962]

[0963]

[0964]

[0965]

[0966] Examples 95 and 96

[0967] (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 95

[0968] (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 96

[0969]

[0970] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 38 (2.9 g, 5.075 mmol) was chirally separated by SFC (column model: ChiralCel OJ, 250×30 mm ID, 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-dioxapiperazin-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-dioxapiperazin-1-yl)-4-methoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 96 (retention time (T R ): 1.944 min; 1.34 g). 95

[0972] MS m / z(ESI):571.1[M+H]

[0973] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.75(s,1H),8.25(s,1H),8.10(s,1H),7.88(d,J=2.0Hz,1H),7.82-7.69(m,2H),7.54(d,J=9.1 Hz,1H),7.27(dd,J=9.2,1.9Hz,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). 96

[0975] MS m / z(ESI):571.1[M+H]

[0976] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.75(s,1H),8.25(s,1H),8.10(s,1H),7.88(d,J=2.0Hz,1H),7.80-7.69(m,2H),7.54(d,J=9.1 Hz,1H),7.27(dd,J=9.3,1.9Hz,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).

[0977] Examples 97 and 98

[0978] (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-

[0979] Indazol-5-yl)-3-phenylpropionamide 97

[0980] (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-

[0981] Indazol-5-yl)-3-phenylpropionamide 98

[0982]

[0983] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 45 (900 mg, 1.407 mmol) was chirally separated by SFC (column model: ChiralCel OD, 250×30 mm ID, 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), (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-phenylpropanamide 98 (retention time (T R ): 3.978 min, 152 mg). 97

[0985] MS m / z(ESI):639.1[M+H]

[0986] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.81(s,1H),8.64(s,1H),8.24(s,1H),8.09(t,J=59.1Hz,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). 98

[0988] MS m / z(ESI):639.2[M+H]

[0989] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.81(s,1H),8.65(s,1H),8.24(s,1H),8.10(t,J=59.2Hz,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).

[0990] Examples 99 and 100

[0991] (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 99

[0992] (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 100

[0993]

[0994] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 47 (1.05 g, 1.690 mmol) was chirally separated by SFC (column model: ChiralPak AD, 250×30 mm ID, 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), (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 99 was obtained (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-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 100 (retention time (T R ): 4.017min, 462mg). 99

[0996] MS m / z(ESI):621.1[M+H]

[0997] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.66(s,1H),8.26(s,1H),8.10(s,1H),7.87-7.63(m,3H),7.54(d,J=9.2Hz ,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). 100

[0999] MS m / z(ESI):621.2[M+H]

[1000] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.66(s,1H),8.26(s,1H),8.10(s,1H),7.88-7.62(m,3H),7.54(d,J=9.1Hz ,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).

[1001] Examples 101-104 were synthesized according to the synthesis method of Examples 1-47 of the present invention. The spectrum parameters of Examples 101-104 are shown in the following table:

[1002]

[1003] Example 105

[1004] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazole-5-

[1005] 4-Pyridin-4-yl)-3-(Pyridin-4-yl)propionamide

[1006]

[1007]

[1008] first step

[1009] tert-Butyl 2-((diphenylmethylene)amino)-3-(pyridin-4-yl)propanoate

[1010] N-Benzhydrylene-glycine tert-butyl ester 39a (2.81 g, 9.53 mmol) was dissolved in N,N-dimethylformamide (30 mL). Potassium tert-butoxide (979.90 mg, 8.73 mmol) was added portionwise at 0°C. After 15 minutes at 0°C, 4-(bromomethyl)pyridine hydrobromide 105a (2 g, 7.94 mmol) was added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 2-((diphenylmethylene)amino)-3-(pyridin-4-yl)propanoate 105b (3.07 g), which was used directly in the next step.

[1011] MS m / z(ESI):387.0[M+H]

[1012] Step 2

[1013] tert-Butyl 2-amino-3-(pyridin-4-yl)propanoate

[1014] The crude product, 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 mixture was allowed to react overnight at room temperature. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(pyridin-4-yl)propanoate 105c (1.17 g) in a 66% yield.

[1015] MS m / z(ESI):223.0[M+H]

[1016] Step 3

[1017] tert-2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(pyridin-4-yl)propanoic acid

[1018] Butyl ester

[1019] 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), and N,N-diisopropylethylamine (105.74 mg, 818.2 μmol, 135.22 μL) was added, and the reaction was carried out at 70°C for 5 hours. Water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(pyridin-4-yl)propanoate 105d (250 mg) in a yield of 62%.

[1020] MS m / z(ESI):490.9[M+H]

[1021] Step 4

[1022] 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(pyridine-4-

[1023] tert-Butyl propionate

[1024] 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), and triethylamine (154.45 mg, 1.53 mmol, 212.16 μL) was added. Chloroacetyl chloride (86.20 mg, 763.17 μmol, 60.75 μL) was slowly added dropwise under ice-bath, and the mixture was reacted under ice-bath for 2 h. Water (30 mL) was added to quench the reaction, and 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 give crude product 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-(pyridin-4-yl)propanoate 105e (79 mg), which was used directly in the next reaction.

[1025] MS m / z(ESI):567.1[M+H]

[1026] Step 5

[1027] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-4-yl)propanoate

[1028] The crude product of the previous step, 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), was dissolved in methanol (5 mL). Sodium methoxide (5.4 M methanol solution, 25.76 μL, 139.10 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-4-yl)propanoate 105f (46 mg) in a yield of 62%.

[1029] MS m / z(ESI):531.2[M+H]

[1030] Step 6

[1031] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-4-yl)propanoic acid

[1032] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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 slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-4-yl)propanoic acid 105g (35 mg), which was used directly in the next reaction.

[1033] MS m / z(ESI):475.1[M+H]

[1034] Step 7

[1035] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazole-5-

[1036] 4-Pyridin-4-yl)-3-(Pyridin-4-yl)propionamide

[1037] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(pyridin-4-yl)propanoic acid (105 g, 35 mg, 73.64 μmol) and 2-methyl-2H-indazol-5-amine 19a (16.26 mg, 110.46 μmol) obtained in the previous step were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 3 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(pyridin-4-yl)propanamide 105 (24 mg) in a yield of 52%.

[1038] MS m / z(ESI):603.8[M+H]

[1039] 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.66(s,1H),8.50(d,J=5.0Hz,2H),8.26(s,1H),8.09(s,1H),7.83-7.67(m,3H),7.55(d,J=9.2Hz,1 H),7.31(d,J=5.0Hz,2H),7.24(d,J=9.1Hz,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).

[1040] Example 106

[1041] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazole-5-

[1042] methyl)-3-(p-tolyl)propionamide

[1043]

[1044] first step

[1045] 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

[1046] ester

[1047] 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), and N,N-diisopropylethylamine (126.89 mg, 981.84 μmol) was added. The mixture was stirred at 60°C for 7 hours. The reaction was quenched by the addition of water (30 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: 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-(p-tolyl)propanoate 106b (200 mg) in a 40% yield.

[1048] MS m / z(ESI):504.1[M+H]

[1049] Step 2

[1050] 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

[1051] 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 slowly added dropwise under ice-cooling, and the mixture was reacted under ice-cooling for 2 hours. Water (30 mL) was added 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 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%.

[1052] MS m / z(ESI):523.8[M+H-56]

[1053] Step 3

[1054] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(p-tolyl)propanoate

[1055] 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). Sodium methoxide (5.4 M methanol solution, 73.32 μL, 395.93 μmol) was slowly added dropwise under ice-cooling and the mixture was reacted under ice-cooling for 2 h. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 6, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(p-tolyl)propanoate 106d (129 mg) in a yield of 60%.

[1056] MS m / z(ESI):487.8[M+H-56]

[1057] Step 4

[1058] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(p-tolyl)propanoic acid

[1059] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(p-tolyl)propanoate 106d (129 mg, 236.95 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(p-tolyl)propanoic acid 106e (85 mg), which was used directly in the next reaction.

[1060] MS m / z(ESI):487.8[M+H]

[1061] Step 5

[1062] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(p-tolyl)propanamide

[1063] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(p-tolyl)propanamide 106 (43 mg) in a yield of 40%.

[1064] MS m / z(ESI):616.8[M+H]

[1065] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.64(s,1H),8.26(s,1H),8.11(s,1H),7.80-7.68(m,2H),7.54(d,J=9.2Hz,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).

[1066] Example 107

[1067] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1068]

[1069]

[1070] first step

[1071] tert-Butyl 3-(4-chlorophenyl)-2-((diphenylmethylene)amino)propanoate

[1072] N-Benzhydrylene-glycine tert-butyl ester 39a (4.31 g, 14.60 mmol) was dissolved in N,N-dimethylformamide (30 mL). Potassium tert-butoxide (1.64 g, 14.60 mmol) was added portionwise at 0°C. After 30 minutes at 0°C, 4-chlorobenzyl bromide 107a (2 g, 9.73 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 3-(4-chlorophenyl)-2-((diphenylmethylene)amino)propanoate 107b (4.09 g), which was used directly in the next step.

[1073] MS m / z(ESI):420.1[M+H]

[1074] Step 2

[1075] tert-Butyl 2-amino-3-(4-chlorophenyl)propionate

[1076] The crude product, tert-butyl 3-(4-chlorophenyl)-2-((diphenylmethylene)amino)propanoate 107b (4.09 g, 9.74 mmol), obtained in the previous step, was dissolved in tetrahydrofuran (10 mL) and 2M dilute hydrochloric acid (10 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(4-chlorophenyl)propanoate 107c (2 g) in 80% yield.

[1077] MS m / z(ESI):200.1[M+H-56]

[1078] Step 3

[1079] 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

[1080] ester

[1081] 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), and N,N-diisopropylethylamine (380.68 mg, 2.95 mmol, 486.8 μL) was added, and the reaction was carried out at 70°C for 5 hours. Water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(4-chlorophenyl)propanoate 107d (420 mg) in a yield of 82%.

[1082] MS m / z(ESI):524.1[M+H]

[1083] Step 4

[1084] 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-(4-chlorophenyl)propanoate

[1085] 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 under ice bath, and the reaction was carried out under ice bath for 2 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 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 to give crude 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-(4-chlorophenyl)propanoate 107e (430 mg), which was used directly in the next step.

[1086] MS m / z(ESI):543.7[M+H-56]

[1087] Step 5

[1088] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)propanoate

[1089] The crude product of the previous step, 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-(4-chlorophenyl)propanoate 107e (430 mg, 715.11 μmol), was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 132.43 μL, 715.12 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 2 h. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)propanoate 107f (250 mg) in a yield of 62%.

[1090] MS m / z(ESI):508.7[M+H-56]

[1091] Step 6

[1092] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)propanoic acid

[1093] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)propanoate 107f (250 mg, 442.60 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 19 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)propanoic acid 107g (200 mg), which was used directly in the next reaction. MS m / z (ESI): 507.7 [M+H]

[1094] Step 7

[1095] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-chlorophenyl)-N-(2-methyl

[1096] -2H-indazol-5-yl)propionamide

[1097] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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 were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 5 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(4-chlorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 107 (157 mg) in a yield of 61%.

[1098] MS m / z(ESI):636.7[M+H]

[1099] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.66(s,1H),8.26(s,1H),8.11(s,1H),7.84-7.63(m,3H),7.55(d,J=9.2Hz ,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).

[1100] Example 108

[1101] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1102]

[1103] first step

[1104] tert-Butyl 2-(((Benzyloxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate

[1105] Cbz-L-tyrosine tert-butyl ester 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, followed by iodomethane (1.15 g, 8.08 mmol). The mixture was reacted at 30°C overnight. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate 108b (2 g) in a 96% yield.

[1106] MS m / z(ESI):330.0[M+H-56]

[1107] Step 2

[1108] tert-Butyl 2-amino-3-(4-methoxyphenyl)propionate

[1109] tert-Butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-methoxyphenyl)propanoate 108b (2 g, 5.19 mmol) was dissolved in methanol (50 mL), and 10% palladium on carbon (200 mg, 1.88 mmol, approximately 50% water content) was added. The mixture was reacted overnight under a hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(4-methoxyphenyl)propanoate 108c (1.23 g) in a 94% yield.

[1110] MS m / z(ESI):252.0[M+H]

[1111] Step 3

[1112] 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

[1113] 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), and 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 quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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-(4-methoxyphenyl)propanoate 108d (310 mg) in a yield of 91%.

[1114] MS m / z(ESI):519.8[M+H]

[1115] Step 4

[1116] 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-(4-methoxyphenyl)propanoate

[1117] 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), and triethylamine (301.39 mg, 2.98 mmol, 413.99 μL) was added. Chloroacetyl chloride (80.73 mg, 714.82 μmol, 56.86 μL) was slowly added dropwise under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. Water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 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 to give crude product 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-(4-methoxyphenyl)propanoate 108e (355 mg), which was used directly in the next reaction.

[1118] MS m / z(ESI):595.7[M+H]

[1119] Step 5

[1120] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)propanoate

[1121] The crude product obtained in the previous step, 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-(4-methoxyphenyl)propanoate 108e (355 mg, 594.75 μmol), was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 121.15 μL, 654.21 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)propanoate 108f (230 mg) in a yield of 69%.

[1122] MS m / z(ESI):560.1[M+H]

[1123] Step 6

[1124] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)propanoic acid

[1125] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)propanoate 108f (230 mg, 410.40 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 19 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)propanoic acid 108g (206 mg), which was used directly in the next reaction. MS m / z (ESI): 504.1 [M+H]

[1126] Step 7

[1127] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1128] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)propanoic acid (206 mg, 408.47 μmol) and 2-methyl-2H-indazol-5-amine 19a (90.18 mg, 612.70 μmol) obtained in the previous step were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(4-methoxyphenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 108 (130 mg) in a yield of 48%.

[1129] MS m / z(ESI):633.2[M+H]

[1130] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.65(s,1H),8.26(s,1H),8.12(s,1H),7.80-7.61(m,3H),7.55(d,J=9.2Hz,1H),7.31-7.13( m,3H),6.88(d,J=8.1Hz,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).

[1131] Example 109

[1132] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(methyl-d3)-2H-indazol-5-yl)-3-phenylpropanamide

[1133]

[1134] first step

[1135] 1-(Methyl-d3)-5-nitro-1H-indazole 109b

[1136] 2-(Methyl-d3)-5-nitro-2H-indazole 109c

[1137] 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 deuterated iodomethane (1.33 g, 9.19 mmol, 572.06 μL) was slowly added dropwise. The mixture was allowed to react overnight at room temperature. The mixture was filtered and concentrated under reduced pressure. The resulting residue was further purified by silica gel column chromatography (eluent: System A) to afford 1-(methyl-d3)-5-nitro-1H-indazole 109b (359 mg) in a 33% yield, and 2-(methyl-d3)-5-nitro-2H-indazole 109c (359 mg) in a 33% yield.

[1138] 109b MS m / z(ESI):181.1[M+H]

[1139] 109c MS m / z(ESI):181.1[M+H]

[1140] Step 2

[1141] 2-(Methyl-d3)-2H-indazol-5-amine

[1142] 2-(Methyl-d3)-5-nitro-2H-indazole 109c (359 mg, 1.99 mmol) was dissolved in a mixture 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 reacted at 80°C for 2 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford 2-(methyl-d3)-2H-indazol-5-amine 109d (154 mg) in a 52% yield.

[1143] MS m / z(ESI):151.1[M+H]

[1144] Step 3

[1145] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(methyl-d3)-2H-indazol-5-yl)-3-phenylpropanamide

[1146] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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), and 1-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 reaction was carried out at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(2-(methyl-d3)-2H-indazol-5-yl)-3-phenylpropanamide 109 (50 mg) in a yield of 44%.

[1147] MS m / z(ESI):606.2[M+H]

[1148] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.65(s,1H),8.26(s,1H),8.12(s,1H),7.81-7.58(m,3H),7.54(d,J= 9.2Hz,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).

[1149] Example 110

[1150] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-(4-fluorophenyl)propanamide

[1151]

[1152]

[1153] first step

[1154] tert-Butyl 2-((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate

[1155] N-Benzhydrylene-glycine tert-butyl ester 39a (7.50 g, 25.39 mmol) was dissolved in N,N-dimethylformamide (50 mL). Potassium tert-butoxide (2.85 g, 25.39 mmol) was added portionwise at 0°C. The mixture was allowed to react for 20 minutes at 0°C. 4-Fluorobenzyl bromide 110a (3.2 g, 16.93 mmol) was then added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 2-((diphenylmethylene)amino)-3-(4-fluorophenyl)propanoate 110b (6.83 g), which was used directly in the next step.

[1156] MS m / z(ESI):404.0[M+H]

[1157] Step 2

[1158] tert-Butyl 2-amino-3-(4-fluorophenyl)propionate

[1159] The crude product 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), and 2M dilute hydrochloric acid (20 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 3) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated 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%.

[1160] MS m / z(ESI):184.1[M+H-56]

[1161] Step 3

[1162] 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

[1163] ester

[1164] 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), and 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 quench the reaction, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(4-fluorophenyl)propanoate 110d (4.02 g) in a yield of 97%.

[1165] MS m / z(ESI):507.9[M+H]

[1166] Step 4

[1167] 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-(4-fluorophenyl)propanoate

[1168] 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 under ice bath, and the mixture was reacted under ice bath for 2 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 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 to give crude product 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-(4-fluorophenyl)propanoate 110e (4.62 g), which was used directly in the next reaction.

[1169] MS m / z(ESI):528.8[M+H-56]

[1170] Step 5

[1171] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate

[1172] 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-(4-fluorophenyl)propanoate 110e (4.62 g, 7.90 mmol) obtained in the previous step was dissolved in methanol (20 mL). Sodium methoxide (5.4 M methanol solution, 1.46 mL, 7.90 mmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 2 hours. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The 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-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoate 110f (2.6 g) in a yield of 60%.

[1173] MS m / z(ESI):492.1[M+H-56]

[1174] Step 6

[1175] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid

[1176] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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 slowly added dropwise. The mixture was allowed to react at room temperature for 20 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)propanoic acid 47d (2.25 mg), which was used directly in the next reaction.

[1177] MS m / z(ESI):492.1[M+H]

[1178] Step 7

[1179] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-(difluoromethane)

[1180] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 the reaction, the product was concentrated under reduced pressure and the 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-dioxapiperazin-1-yl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-3-(4-fluorophenyl)propanamide 110 (58 mg) in a yield of 72%.

[1181] MS m / z(ESI):657.1[M+H]

[1182] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.81(s,1H),8.66(s,1H),8.24(s,1H),8.09(t,J=59.1Hz,1H),7.83-7.63(m,4 H),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).

[1183] Example 111

[1184] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazole-3-yl)

[1185] yl)-N-(2-methyl-2H-indazol-5-yl)propionamide

[1186]

[1187] first step

[1188] Methyl (Z)-2-((tert-Butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)acrylate

[1189] (±)-Boc-α-phosphonoglycine trimethyl ester 111b (6.07 g, 20.43 mmol) was dissolved in dichloromethane (10 mL) and 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 then added and stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)acrylate 111c (3.4 g) in an 89% yield.

[1190] MS m / z(ESI):182.1[M+H-100]

[1191] Step 2

[1192] Methyl 2-((tert-Butoxycarbonyl)amino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate

[1193] 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), and 10% palladium on carbon (907.93 mg, 8.53 mmol, 10%) was added. The mixture was stirred at 50°C under a hydrogen atmosphere for 25 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford crude 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.

[1194] MS m / z(ESI):284.2[M+H]

[1195] Step 3

[1196] Methyl 2-amino-3-(1-methyl-1H-pyrazol-3-yl)propanoate

[1197] 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), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, methyl 2-amino-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111e (832 mg).

[1198] MS m / z(ESI):184.2[M+H]

[1199] Step 4

[1200] 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(1-methyl-1H-pyrazole-3-

[1201] Methyl propionate

[1202] 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)propanoate 111e (269.82 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (507.57 mg, 3.93 mmol, 649.07 μL) was added, and the reaction was carried out at 60°C for 15 hours. The reaction was quenched by the addition of water (40 mL), followed by extraction with ethyl acetate (40 mL x 3). The combined organic phases were washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System A) to afford 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 90% yield. MS m / z (ESI): 451.9 [M+H].

[1203] Step 5

[1204] 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(1-methyl

[1205] -1H-pyrazol-3-yl)propionic acid methyl ester

[1206] 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), and 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 under ice bath, and the mixture was reacted under ice bath for 2 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 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 to give 111 g (420 mg) of crude methyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate, which was used directly in the next reaction.

[1207] MS m / z(ESI):528.1[M+H]

[1208] Step 6

[1209] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoate

[1210] The crude product obtained in the previous step, methyl 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(1-methyl-1H-pyrazol-3-yl)propanoate (111 g, 420 mg, 794.29 μmol), was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 147.09 μL, 794.29 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 2 hours. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoate 111h (130 mg) in a yield of 33%.

[1211] MS m / z(ESI):492.1[M+H]

[1212] Step 7

[1213] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid

[1214] Methyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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), and lithium hydroxide monohydrate (22.16 mg, 528.12 μmol) was added, and the reaction was stirred at 0°C for 3 hours. After the reaction was complete, 2 M dilute hydrochloric acid was added for neutralization, and the mixture was concentrated under reduced pressure. The 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-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)propanoic acid 111i (76 mg) in a yield of 60%.

[1215] MS m / z(ESI):478.0[M+H]

[1216] Step 8

[1217] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1218] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-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 h. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-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%.

[1219] MS m / z(ESI):606.8[M+H]

[1220] 1 H NMR (400MHz, DMSO-d6) δ10.15(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=10.4,5.6Hz,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).

[1221] Examples 112 and 113

[1222] (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 112

[1223] (R)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 113

[1224]

[1225] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 111 (149 mg, 0.245 mmol) was chirally separated by SFC (column model: ChiralCel AD, 250×30 mm ID, 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), (S)-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 112 was obtained (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-dioxapiperazin-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)-N-(2-methyl-2H-indazol-5-yl)propanamide 113 (retention time (T R ): 4.487min, 58mg). 112

[1227] MS m / z(ESI):607.1[M+H]

[1228] 1 H NMR (400MHz, DMSO-d6) δ10.12(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). 113

[1230] MS m / z(ESI):607.1[M+H]

[1231] 1H NMR (400MHz, DMSO-d6) δ10.12(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).

[1232] Example 114

[1233] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-(methyl-d3)-2H-indazol-5-yl)propanamide

[1234]

[1235] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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). 1-Propylphosphonic anhydride (50% ethyl acetate solution, 517.06 mg, 812.53 μmol) and N,N-diisopropylethylamine (131.26 mg, 1.02 mmol μmol, 167.85 μL) were added and the mixture was reacted at 60°C for 2 h. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(4-fluorophenyl)-N-(2-(methyl-d3)-2H-indazol-5-yl)propanamide 114 (103 mg) with a yield of 80%.

[1236] MS m / z(ESI):624.1[M+H]

[1237] 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.66(s,1H),8.26(s,1H),8.10(s,1H),7.82-7.65(m,3H),7.54(d,J=9.2Hz,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).

[1238] Example 115

[1239] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1240]

[1241]

[1242] first step

[1243] tert-Butyl 3-(4-cyanophenyl)-2-((diphenylmethylene)amino)propanoate

[1244] N-Benzhydrylene-glycine tert-butyl ester 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 portionwise at 0°C. After 15 minutes at 0°C, 4-cyanobenzyl bromide 115a (2.19 g, 11.17 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours. The reaction was quenched by the addition of water (60 mL) and extracted with ethyl acetate (60 mL × 3). The organic phases were combined and washed sequentially with water (60 mL × 3) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 3-(4-cyanophenyl)-2-((diphenylmethylene)amino)propanoate 115b (4.17 g), which was used directly in the next step.

[1245] MS m / z(ESI):411.2[M+H]

[1246] Step 2

[1247] tert-Butyl 2-amino-3-(4-cyanophenyl)propionate

[1248] The crude product, 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) and 2M dilute hydrochloric acid (10 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed sequentially with water (60 mL × 3) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(4-cyanophenyl)propanoate 115c (2 g) in 80% yield.

[1249] MS m / z(ESI):191.1[M+H-56]

[1250] Step 3

[1251] 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

[1252] 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), and 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 (60 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed sequentially with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(4-cyanophenyl)propanoate 115d (267 mg) in a yield of 79%.

[1253] MS m / z(ESI):515.1[M+H-56]

[1254] Step 4

[1255] 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-(4-cyanophenyl)propanoate

[1256] 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), and triethylamine (262.11 mg, 2.59 mmol, 360.04 μL) was added. Chloroacetyl chloride (87.77 mg, 777.08 μmol, 61.81 μL) was slowly added dropwise under ice-bath, and the mixture was reacted under ice-bath for 1 hour. Water (50 mL) was added to quench the reaction, and 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 give crude 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-(4-cyanophenyl)propanoate 115e (306 mg), which was used directly in the next step.

[1257] MS m / z(ESI):535.0[M+H-56]

[1258] Step 5

[1259] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)propanoate

[1260] ester

[1261] The crude product of the previous step, 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), was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 105.32 μL, 568.73 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)propanoate 115f (210 mg) in a yield of 73%.

[1262] MS m / z(ESI):555.0[M+H]

[1263] Step 6

[1264] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)propanoic acid

[1265] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)propanoate 115f (210 mg, 378.10 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The reaction was allowed to react at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)propanoic acid 115g (188 mg), which was used directly in the next reaction. MS m / z (ESI): 499.0 [M+H]

[1266] Step 7

[1267] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(4-cyanophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1268] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-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 were dissolved in ethyl acetate (10 mL). 1-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 reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(4-cyanophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 115 (110 mg) in a yield of 45%.

[1269] MS m / z(ESI):628.1[M+H]

[1270] 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.66(s,1H),8.26(s,1H),8.09(s,1H),

[1271] 7.87-7.63(m,5H),7.62-7.44(m,3H),7.23(d,J=9.1Hz,1H),5.43(dd,J=10.2,5.8Hz,1H),4.43-3.92(m,4H),4.14(s,3H),3.30-3.14(m,2H).

[1272] Example 116

[1273] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide

[1274]

[1275] first step

[1276] tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-cyclobutylpropanoate

[1277] 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-cyclobutylpropionate 39d (293.51 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 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 quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed sequentially with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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%.

[1278] MS m / z(ESI):468.1[M+H]

[1279] Step 2

[1280] 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

[1281] 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 slowly added dropwise under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. The reaction was quenched by the addition of water (50 mL), and 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 give crude 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), which was used directly in the next reaction.

[1282] MS m / z(ESI):488.0[M+H-56]

[1283] Step 3

[1284] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate

[1285] The crude product 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). Sodium methoxide (5.4 M methanol solution, 134.59 μL, 726.79 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2 M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate 116c (300 mg) in a yield of 89%.

[1286] MS m / z(ESI):508.0[M+H]

[1287] Step 4

[1288] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropionic acid

[1289] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate 116c (100 mg, 196.70 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure to afford crude 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropanoate 116d (88 mg), which was used directly in the next reaction.

[1290] MS m / z(ESI):452.1[M+H]

[1291] Step 5

[1292] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-

[1293] Indazol-5-yl)propionamide

[1294] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-cyclobutylpropionic 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 were dissolved in ethyl acetate (5 mL). 1-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 reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-cyclobutyl-N-(2-methyl-2H-indazol-5-yl)propanamide 116 (59 mg) in a yield of 52%.

[1295] MS m / z(ESI):580.9[M+H]

[1296] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.74(s,1H),8.24(s,1H),8.10(s,1H),7.87(d,J=2.0Hz,1H),7.81-7.68(m,2H),7. 54(d,J=9.2Hz,1H),7.28(dd,J=9.2,2.0Hz,1H),5.01(t,J=7.9Hz,1H),4.76-4.00(m,4H),4.13(s,3H),2.21-1.55(m,9H).

[1297] Example 117

[1298] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazole-5-

[1299] yl)-3-(tetrahydro-2H-pyran-2-yl)propanamide

[1300]

[1301] first step

[1302] Methyl (tetrahydro-2H-pyran-2-yl)trifluoromethanesulfonate

[1303] Tetrahydropyran-2-methanol 117a (3 g, 25.83 mmol, 2.92 mL) was dissolved in dichloromethane (50 mL), and pyridine (2.45 g, 30.99 mmol, 2.49 mL) was added. The mixture was cooled to 0°C under a nitrogen atmosphere, and trifluoromethanesulfonic anhydride (8.02 g, 28.41 mmol, 4.77 mL) was slowly added dropwise. Stirring was continued in an ice bath for 20 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 2M dilute hydrochloric acid (50 mL × 2) and then with saturated aqueous sodium chloride (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude (tetrahydro-2H-pyran-2-yl) methyl trifluoromethanesulfonate 117b (6.41 g), which was used directly in the next reaction.

[1304] Step 2

[1305] tert-Butyl 2-((diphenylmethylene)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate

[1306] N-Benzhydrylene-glycine tert-butyl ester 39a (5.09 g, 17.22 mmol) was dissolved in tetrahydrofuran (70 mL) and cooled to -78°C under argon protection. Lithium bistrimethylsilylamide (1 M tetrahydrofuran solution, 34.43 mL) was slowly added dropwise. After stirring for 15 minutes, (tetrahydro-2H-pyran-2-yl) trifluoromethanesulfonic acid methyl ester 117b (6.41 g, 25.82 mmol) was slowly added dropwise. After the addition was completed, stirring was continued for 15 minutes, and the temperature was slowly raised to room temperature. After reacting for 30 minutes, water (50 mL) was added to quench the reaction. The mixture 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 give crude tert-butyl 2-((diphenylmethylene)amino)-3-(tetrahydro-2H-pyran-2-yl)propanoate 117c (6.77 g), which was used directly in the next reaction.

[1307] MS m / z(ESI):394.2[M+H]

[1308] Step 3

[1309] tert-Butyl 2-amino-3-(tetrahydro-2H-pyran-2-yl)propanoate

[1310] The crude product, 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). 2M dilute hydrochloric acid (20 mL) was added and the mixture was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with water (100 mL × 3) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(tetrahydro-2H-pyran-2-yl)propanoate 117d (2 g) in a 51% yield.

[1311] MS m / z(ESI):174.1[M+H-56]

[1312] Step 4

[1313] 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)

[1314] tert-Butyl propionate

[1315] 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), and N,N-diisopropylethylamine (634.47 mg, 4.91 mmol, 811.34 μL) was added, and the reaction was carried out at 75 ° C overnight. The reaction was quenched by the addition of water (50 mL), and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed sequentially with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System A) to provide 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 63% yield. MS m / z (ESI): 497.9 [M+H].

[1316] Step 5

[1317] 2-(2-chloro-N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)acetylamino)-3-(tetrahydro

[1318] -tert-Butyl-2H-pyran-2-yl)propionate

[1319] 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 slowly added dropwise under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 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-(tetrahydro-2H-pyran-2-yl)propanoate 117f (357 mg), which was used directly in the next reaction.

[1320] MS m / z(ESI):574.8[M+H]

[1321] Step 6

[1322] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoate

[1323] The crude product of the previous step, 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), was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 126.50 μL, 683.10 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give 117 g (255 mg) of tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoate in a yield of 76%.

[1324] MS m / z(ESI):538.1[M+H]

[1325] Step 7

[1326] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propane

[1327] acid

[1328] 117 g (100 mg, 185.73 μmol) of tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoate was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was slowly added dropwise and allowed to react at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 117 h (89 mg) of crude 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid, which was used directly in the next reaction.

[1329] MS m / z(ESI):481.8[M+H]

[1330] Step 8

[1331] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazole-5-

[1332] yl)-3-(tetrahydro-2H-pyran-2-yl)propanamide

[1333] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)propanoic acid (117 g, 89 mg, 184.53 μmol) and 2-methyl-2H-indazol-5-amine 19a (40.74 mg, 276.79 μmol) obtained in the previous step were dissolved in ethyl acetate (5 mL). 1-Propylphosphonic anhydride (50% ethyl acetate solution, 234.85 mg, 369.05 μmol) and N,N-diisopropylethylamine (95.39 mg, 738.10 μmol, 121.99 μL) were added and reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-(tetrahydro-2H-pyran-2-yl)propanamide 117 (63 mg) in a yield of 55%.

[1334] MS m / z(ESI):611.2[M+H]

[1335] 1 H NMR(400MHz,DMSO-d6)δ10.13-9.93(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,1 H),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).

[1336] Example 118

[1337] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[1338]

[1339]

[1340] first step

[1341] 2-Isopropylethyl trifluoromethanesulfonate

[1342] Isopropoxyethanol 118a (3 g, 28.81 mmol) was dissolved in dichloromethane (50 mL), and pyridine (2.73 g, 34.57 mmol, 2.78 mL) was added. The mixture was cooled to 0°C under a nitrogen atmosphere, and trifluoromethanesulfonic anhydride (8.94 g, 31.69 mmol, 5.32 mL) was slowly added dropwise. Stirring was continued in an ice bath for 20 minutes. The reaction solution was diluted with ethyl acetate (100 mL) and washed with 2M dilute hydrochloric acid (50 mL × 2) and then with saturated aqueous sodium chloride (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-isopropylethyl trifluoromethanesulfonate 118b (4.6 g), which was used directly in the next reaction.

[1343] Step 2

[1344] tert-Butyl 2-((diphenylmethylene)amino)-4-isopropoxybutyrate

[1345] N-Diphenylmethylene-glycine tert-butyl ester 39a (8.63 g, 29.21 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -78°C under argon. Lithium bistrimethylsilylamide (1 M solution in tetrahydrofuran, 38.95 mL) was slowly added dropwise. After stirring for 15 minutes, 2-isopropylethyl trifluoromethanesulfonate 118b (4.6 g, 19.47 mmol) was slowly added dropwise. Stirring was continued for 15 minutes, and the mixture was slowly warmed to room temperature. After stirring for 30 minutes, the reaction was quenched by the addition of water (50 mL). Extraction was performed with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 2-((diphenylmethylene)amino)-4-isopropoxybutanoate 118c (7.43 g), which was used directly in the next reaction.

[1346] MS m / z(ESI):382.2[M+H]

[1347] Step 3

[1348] O-Isopropyl homoserine tert-butyl ester

[1349] The crude product, 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) and 2M dilute hydrochloric acid (20 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed sequentially with water (100 mL × 3) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl O-isopropylhomoserine 118d (1.6 g) in a 38% yield.

[1350] MS m / z(ESI):218.2[M+H]

[1351] Step 4

[1352] tert-Butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-isopropylhomoserine

[1353] 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-isopropylhomoserine 118d (320.04 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (380.68 mg, 2.95 mmol, 486.80 μL) was added, and the reaction was carried out at 70°C overnight. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed sequentially with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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-isopropylhomoserine 118e (380 mg) in 80% yield.

[1354] MS m / z(ESI):485.8[M+H]

[1355] Step 5

[1356] tert-Butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-isopropylhomoserine

[1357] Tert-butyl N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-O-isopropylhomoserine 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 under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. The reaction was quenched by the addition of water (50 mL), and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-isopropylhomoserine tert-butyl ester 118f (439 mg), which was used directly in the next reaction.

[1358] MS m / z(ESI):506.0[M+H-56]

[1359] Step 6

[1360] tert-Butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxybutanoate

[1361] The crude product N-(2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)-N-(2-chloroacetyl)-O-isopropylhomoserine tert-butyl ester 118f (439 mg, 779.93 μmol) obtained in the previous step was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 144.43 μL, 779.93 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to obtain 118 g (223 mg) of tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxybutyrate in a yield of 54%.

[1362] MS m / z(ESI):469.8[M+H-56]

[1363] Step 7

[1364] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxybutanoic acid

[1365] 118 g (223 mg, 423.62 μmol) of tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxybutanoate was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (1 mL) was slowly added dropwise and allowed to react at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 118 h (150 mg) of crude 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxybutanoic acid, which was used directly in the next reaction.

[1366] MS m / z(ESI):470.1[M+H]

[1367] Step 8

[1368] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxy-N-(2-methyl-2H-indazol-5-yl)butanamide

[1369] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-4-isopropoxybutanoic acid 118h (150 mg, 318.94 μmol) and 2-methyl-2H-indazol-5-amine 19a (70.88 mg, 481.60 μmol) obtained in the previous step were dissolved in ethyl acetate (15 mL). 1-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 added and reacted at 60°C for 1 hour. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-4-isopropoxy-N-(2-methyl-2H-indazol-5-yl)butanamide 118 (67 mg) in a yield of 34%.

[1370] MS m / z(ESI):598.8[M+H]

[1371] 1H NMR (400MHz, DMSO-d6) δ10.02(s,1H),8.74(s,1H),8.25(s,1H),8.10(s,1H),7.87(s,1H),7.80-7.70(m,2H),7.53(d,J=9.2Hz,1H),7.28(dd,J= 9.2,1.9Hz,1H),5.12(brs,1H),4.66-3.76(m,4H),4.13(s,3H),3.53(p ,J=5.9Hz,1H),3.47-3.26(m,2H),2.18-1.92(m,2H),1.15-1.01(m,6H).

[1372] Example 119

[1373] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1374]

[1375]

[1376] first step

[1377] tert-Butyl 3-(2,4-difluorophenyl)-2-((diphenylmethylene)amino)propanoate

[1378] N-Benzhydrylene-glycine tert-butyl ester 39a (4.28 g, 14.49 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium tert-butoxide (1.63 g, 14.49 mmol) was added portionwise at 0°C. After 15 minutes at 0°C, 2,4-difluorobenzyl bromide 119a (2 g, 9.66 mmol, 1.24 mL) was added. The reaction was allowed to warm to room temperature and allowed to react for 3 hours. The reaction was quenched by the addition of water (60 mL) and extracted with ethyl acetate (60 mL × 3). The organic phases were combined and washed sequentially with water (60 mL × 3) and saturated sodium chloride solution (60 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 3-(2,4-difluorophenyl)-2-((diphenylmethylene)amino)propanoate 119b (4.07 g), which was used directly in the next step.

[1379] MS m / z(ESI):422.0[M+H]

[1380] Step 2

[1381] tert-Butyl 2-amino-3-(2,4-difluorophenyl)propionate

[1382] The crude product, tert-butyl 3-(2,4-difluorophenyl)-2-((diphenylmethylene)amino)propanoate 119b (4.07 g, 9.66 mmol), obtained in the previous step, was dissolved in tetrahydrofuran (20 mL) and 2M dilute hydrochloric acid (15 mL) was added. The reaction was allowed to react at room temperature overnight. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8. The mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined and washed sequentially with water (60 mL × 3) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further isolated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 2-amino-3-(2,4-difluorophenyl)propanoate 119c (1.9 g) in a 76% yield.

[1383] MS m / z(ESI):202.1[M+H-56]

[1384] Step 3

[1385] tert-Butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(2,4-difluorophenyl)propanoate

[1386] 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-(2,4-difluorophenyl)propanoate 119c (241.83 mg, 981.378.91 mg, 1.47 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (380.68 mg, 2.95 mmol, 486.80 μL) was added and the reaction was carried out at 70°C overnight. Water (60 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed sequentially with water (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System 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-(2,4-difluorophenyl)propanoate 119d (497 mg) in a yield of 96%.

[1387] MS m / z(ESI):526.1[M+H]

[1388] Step 4

[1389] 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-(2,4-difluorophenyl)propanoate

[1390] Tert-butyl 2-((2-((5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)amino)-2-oxoethyl)amino)-3-(2,4-difluorophenyl)propanoate 119d (497 mg, 944.22 μmol) was dissolved in dichloromethane (10 mL), triethylamine (191.09 mg, 1.89 mmol, 262.49 μL) was added, and chloroacetyl chloride (159.96 mg, 1.42 mmol, 113.45 μL) was slowly added dropwise under ice-cooling, and the mixture was reacted under ice-cooling for 1 hour. Water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 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-(2,4-difluorophenyl)propanoate 119e (569 mg), which was used directly in the next reaction.

[1391] MS m / z(ESI):546.0[M+H-56]

[1392] Step 5

[1393] tert-2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)propanoic acid

[1394] Butyl ester

[1395] The crude product 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-(2,4-difluorophenyl)propanoate 119e (569 mg, 943.86 μmol) obtained in the previous step was dissolved in methanol (10 mL). Sodium methoxide (5.4 M methanol solution, 174.79 μL, 943.86 μmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. 2M dilute hydrochloric acid was added dropwise to adjust the pH to 7, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)propanoate 119f (300 mg) in a yield of 56%.

[1396] MS m / z(ESI):510.0[M+H-56]

[1397] Step 6

[1398] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)propanoic acid

[1399] Tert-butyl 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)propanoate 119f (300 mg, 529.68 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)propanoate 119g (250 mg), which was used directly in the next reaction. MS m / z (ESI): 509.8 [M+H]

[1400] Step 7

[1401] 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide

[1402] The crude product 2-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-2,5-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)propanoic acid 119 g (250 mg, 489.93 μmol) and 2-methyl-2H-indazol-5-amine 19a (108.16 mg, 734.89 μmol) obtained in the previous step were dissolved in ethyl acetate (10 mL). 1-Propylphosphonic anhydride (50% ethyl acetate solution, 1.247 g, 1.96 mmol) and N,N-diisopropylethylamine (316.59 mg, 2.45 mmol, 404.85 μL) were added and reacted at 60°C for 2 hours. After the reaction is completed, the product is concentrated under reduced pressure and the residue is 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-dioxapiperazin-1-yl)-3-(2,4-difluorophenyl)-N-(2-methyl-2H-indazol-5-yl)propanamide 119 (90 mg) in a yield of 29%.

[1403] MS m / z(ESI):639.1[M+H]

[1404] 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.69(s,1H),8.26(s,1H),8.06(s,1H),7.84-7.68(m,3H),7.53(d,J=9.2Hz,1H),7.42-7.33(m ,1H),7.28-7.14(m,2H),7.09-6.98(m,1H),5.39-5.25(m,1H),4.40-3.95(m,4H),4.13(s,3H),3.25-3.18(m,1H),3.17-3.06(m,1H).

[1405] Example 120

[1406] 2-(4-(2-(4-chloro-1H-1,2,3-triazol-1-yl)-5-methylphenyl)-2,5-dioxapiperazin-1-yl)-N-(2-methyl-2H-indazol-5-yl)-3-phenylpropanamide

[1407]

[1408] first step

[1409] 1-(4-Methyl-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole

[1410] Dissolve 4-methyl-2-nitroaniline 120a (10 g, 65.72 mmol) in acetonitrile (200 mL), add isoamyl nitrite (11.55 g, 98.59 mmol), cool to 0°C, and slowly add trimethylsilylazide (11.36 g, 98.59 mmol) dropwise. Stir for 1 minute, remove the ice bath, warm to room temperature, and react for 2 hours. Monitor by TLC until complete reaction of the starting material. Then, add cuprous oxide (9.40 g, 65.72 mmol) and trimethylethynylsilane (19.37 g, 197.17 mmol) in sequence, and continue stirring at room temperature for 16 hours. The mixture was filtered through celite, and ethyl acetate (200 mL) and water (200 mL) were added. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further separated and purified by silica gel column chromatography (eluent: System A) to give 1-(4-methyl-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 120b (5.0 g) in a yield of 28%.

[1411] MS m / z(ESI):277.1[M+H]

[1412] Step 2

[1413] 4-Chloro-1-(4-methyl-2-nitrophenyl)-1H-1,2,3-triazole

[1414] 1-(4-Methyl-2-nitrophenyl)-4-(trimethylsilyl)-1H-1,2,3-triazole 120b (5 g, 18.09 mmol), N-chlorosuccinimide (24.16 g, 180.92 mmol), and potassium fluoride (10.51 g, 180.92 mmol) were sequentially dissolved in acetonitrile (200 mL), heated to 90°C, and stirred for 36 hours. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction solution, and the layers were separated. The organic phase was...

Claims

1. A compound represented by general formula (II) or its stereoisomer, or a pharmaceutically acceptable salt thereof: in: L is selected from C1-C4 alkylene; X is selected from C=O; Selected from: R 1 The same or different, each independently selected from halogen or C1-C6 alkyl; R 2 Selected from 5-membered heteroaryl; wherein the heteroaryl is optionally further substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 haloalkyl or halogen; R 3 Selected from a hydrogen atom or a C1-C6 alkyl group; R 5 are the same or different and are independently selected from hydrogen, C1-C6 alkyl, halogen, cyano, 5-7 membered heterocyclic group, -OR 9 、-C(O)R 9 、-C(O)OR 9 、-NHC(O)OR 9 、-C(O)NR 10 R 11 、-CH2NHC(O)OR 9 or -S(O) r R 9 wherein the alkyl or heterocyclic group is optionally further substituted by one or more substituents selected from deuterium atoms, halogens or =O; Or, two R 5 Together with the same carbon atom to which it is attached, it forms C=O; R 6 is selected from C1-C6 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the alkoxy, cycloalkyl, heterocyclic group, phenyl or heteroaryl is optionally further substituted by one or more R A Substituted by a substituent; R A is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano or C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally further substituted by one or more substituents selected from deuterium atoms or halogen; R 8 Selected from a hydrogen atom or a C1-C6 alkyl group; R 9 Selected from a hydrogen atom or a C1-C6 alkyl group; R 10 and R 11 Each is independently selected from a hydrogen atom or a C1-C6 alkyl group; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; r is 0, 1 or 2.

2. The compound according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R 8 A hydrogen atom.

3. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: Ring B, X, L, R 1 ~R 3 , R 5 , R 6 , R 8 , m and n are as defined in claim 1.

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

5. The compound according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, wherein: Selected from:

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

7. The compound according to claim 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VA) or (VB) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: L, R 1 ~R 3 , R 5 , R 6 , R 8 and n are as defined in claim 6.

8. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VI) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: Ring C is selected from 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclic group; p is 0, 1, or 2; L, R 1 ~R 3 , R 5 , R 6 , R 8 and n are as defined in claim 1.

9. The compound according to claim 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VI-A) or (VI-B) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: Ring C, L, R 1 ~R 3 , R 5 , R 6 , R 8 , p and n are as defined in claim 8.

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

11. The compound according to claim 10 or its stereoisomer, or its pharmaceutically acceptable salt, wherein: The triazole group is optionally further substituted by Cl.

12. The compound according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, wherein: L is selected from -CH2- or -CH2CH2-; R 6 is selected from C1-C6 alkoxy, C3-C6 cycloalkyl, 4-8 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the alkoxy, cycloalkyl, heterocyclic group, phenyl or heteroaryl is optionally further substituted by one or more R A Substituted by a substituent; R A is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano or C3-C6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally further substituted by one or more substituents selected from deuterium atoms or halogen.

13. The compound according to claim 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 is selected from methoxy, tert-butoxy, isopropoxy, phenyl, pyridyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or a 4-6 membered heterocyclic group containing one nitrogen atom, wherein the phenyl, pyridyl, pyrazolyl, imidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl or a 4-6 membered heterocyclic group containing one nitrogen atom is optionally further substituted by one or more R A Substituted by a substituent; R A is selected from halogen, methyl, methoxy, cyclopropyl or cyano, wherein the methyl is optionally further substituted by one or more substituents selected from deuterium atoms or halogen.

14. The compound according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, wherein: R 5 are the same or different and are independently selected from methyl, deuterated methyl, methyl substituted by one or more fluorine groups, fluorine, cyano, -OR 9 、-C(O)R 9 、-C(O)OR 9 、-NHC(O)OR 9 、-C(O)NR 10 R 11 、-CH2NHC(O)OR 9 or -S(O) r R 9 ; Or, two R 5 Together with the same carbon atom to which it is attached, it forms C=O; R 9 is selected from a hydrogen atom, a methyl group, an ethyl group or a tert-butyl group; R 10 and R 11 Each is independently selected from a hydrogen atom or a methyl group.

15. A compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is:

16. A method for preparing the compound represented by general formula (II) according to claim 1 or its stereoisomer, or its pharmaceutically acceptable salt, comprising the following steps: The compound represented by the general formula (IIA) is subjected to a condensation reaction with the compound represented by the general formula (IIB), and optionally further hydrolyzed under acidic conditions to obtain a compound represented by the general formula (II); Among them: Ring B, X, L, R 1 ~R 3 , R 5 , R 6 , R 8 , m and n are as defined in claim 1.

17. A compound represented by general formula (IIA) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: X, L, R 1 ~R 3 , R 6 , R 8 and n are as defined in claim 1.

18. The compound according to claim 17 or its stereoisomer, or its pharmaceutically acceptable salt, wherein the compound is:

19. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 15 or its stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

20. Use of the compound according to any one of claims 1 to 15 or its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating or preventing a disease mediated by coagulation factor XIa, wherein the disease mediated by coagulation factor XIa is selected from blood coagulation disorders or thromboembolic diseases.

21. The use according to claim 20, wherein: The thromboembolic disease is selected from arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, arterial cerebrovascular thromboembolic disease, venous cerebrovascular thromboembolic disease, ventricular or peripheral circulation thromboembolic disease.

22. The use according to claim 20, wherein: The thromboembolic disease is selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by the following: medical implants, devices or surgeries in which blood comes into contact with artificial surfaces that promote thrombosis.

23. The use according to claim 22, wherein: The venous thrombosis is deep vein thrombosis.

24. Use of the compound according to any one of claims 1 to 15 or its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of an anti-blood coagulation drug.

25. Use of the compound according to any one of claims 1 to 15 or its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating or preventing thromboembolic diseases.

26. The use according to claim 25, wherein: The thromboembolic disease is selected from arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, arterial cerebrovascular thromboembolic disease, venous cerebrovascular thromboembolic disease, and ventricular or peripheral circulation thromboembolic disease.

27. The use according to claim 25, wherein: The thromboembolic disease is selected from unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by the following: medical implants, devices or surgeries in which blood comes into contact with artificial surfaces that promote thrombosis.

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

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