Aromatic heterocycle pyrrolidone compound and application thereof

Abstract

The invention discloses an aromatic heterocycle pyrrolidone derivative with a brand new structure, the aromatic heterocycle pyrrolidone derivative can be developed as a targeted micromolecule PI3K gamma inhibitor, and the PI3K gamma inhibitor has high selectivity and remarkable biological activity and has considerable potential in prevention or treatment of diseases related to abnormal expression of a PI3K gamma signal channel.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to an aromatic heterocyclic pyrrolidone compound and a preparation method and application thereof. The compound and its pharmaceutically acceptable salts, isotope derivatives, solvates or isomers can be used as highly selective PI3Kγ inhibitors for preventing or treating diseases related to abnormal expression of PI3Kγ signaling pathways, and have broad application prospects. Background Art

[0002] PI3Ks (phosphoinostitide 3-kinases) are a large family of lipid kinases, which are responsible for catalyzing the phosphorylation of PIP2 (4,5-phosphatidylinositol diphosphate) in the body into PIP3 (3,4,5-phosphatidylinositol triphosphate). PI3K is involved in regulating many important cellular processes such as cell growth, proliferation, differentiation and migration. Its disorder can lead to the occurrence of many human diseases, including inflammation, autoimmune diseases and tumors. According to the different structures and physiological functions, PI3K can be divided into three subfamilies: Class I, II and III. Among them, Class I is currently the most important and most studied subfamily, which can be further divided into four subtypes: α, β, δ and γ. α and β are widely distributed in tissues throughout the body, and δ and γ are mainly distributed in the hematopoietic system.

[0003] PI3Kγ is considered to be one of the subtypes most closely related to immune regulation. It was first discovered in leukocytes and is an important element for the function of myeloid cells, including mast cell degranulation, neutrophil / macrophage / dendritic cell migration, etc. In recent years, studies have found that the activation of PI3Kγ can lead to the occurrence and development of multiple sclerosis. The results of EAE animal model experiments show that PI3Kγ inhibitors can alleviate the severity of multiple sclerosis and bring clinical improvement (Neuroscience. 2013, 253, 89-99). In addition, PI3Kγ inhibitors are also used in tumor immunity. PI3Kγ promotes macrophage polarization to M2 type, leading to the formation of tumor immune escape. PI3Kγ inhibitors can reshape the phenotype of macrophages, promote their polarization to M1 type, improve the tumor immune microenvironment, enhance the efficacy of immune checkpoint inhibitors, and play a synergistic anti-cancer role (Nature. 2016, 439, 437-442). Therefore, the development of PI3Kγ inhibitors has great scientific research significance and clinical use value.

[0004] At present, various structural types of selective PI3Kγ inhibitors have been reported, including propeller configuration (ACS Med. Chem. Lett. 2016, 7, 862-867 and WO2021004421), aryl urea derivatives (J. Med. Chem. 2015, 58, 517-521 and ACS Med. Chem. Lett. 2021, 12, 129-135) and isoindolinone derivatives (WO2017153527A1, WO2020247496A1, WO2020210379A1). However, existing inhibitors often have many problems in terms of inhibitory activity and selectivity of the target, pharmacokinetic properties and safety, which limits their further development.

[0005] In summary, how to provide a PI3Kγ inhibitor with a novel structure, significant biological activity and high selectivity is a technical problem that has not yet been solved by those skilled in the art. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a targeted small molecule PI3Kγ inhibitor with a completely new structure, which has high selectivity for PI3Kγ and significant biological activity, and is used to prevent or treat diseases related to abnormal PI3Kγ expression.

[0007] In order to solve the above technical problems, the technical solutions provided by the present invention are as follows:

[0008] The present invention provides an aromatic heterocyclic pyrrolidone derivative, which is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] In the formula, ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and ring A contains at least one substituent R 2 ;

[0011] R 1 Selected from NR 1a R 1b OR 1a ;

[0012] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1bMiddle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0013] R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0014] R 2 , R 2a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, thiol, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0015] X and Y are each independently selected from N or CR 2a ;

[0016] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NR 3a R 3c 、-NH-R 3a、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0017] R 3a , R 3b , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c Middle C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0018] R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; R 4 , R 5 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl groups may be independently monosubstituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; or

[0019] R 4 and R 5 Connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring;

[0020] R 6 Selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; R 6 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl groups may be mono- or poly-substituted independently by one or more of the following substituents: halogen, cyano, C1 -6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0021] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0022] Preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0023]

[0024] In the formula, ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and ring A contains at least one substituent R 2 ;

[0025] R 1 Selected from NR 1a R 1b OR 1a ;

[0026] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0027] R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0028] R 2 , R 2a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, thiol, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0029] X and Y are each independently selected from N or CR 2a ;

[0030] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3bor -C(O)-R 3b ;

[0031] R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0032] R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 4 , R 5 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; or

[0033] R 4 and R 5 Connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring;

[0034] R 6 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 6 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, C1 -6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0035] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0036] Preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0037]

[0038] In the formula, ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and ring A contains at least one substituent R 2 ;

[0039] R 1 Selected from NR 1a R 1b OR 1a ;

[0040] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0041] R1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0042] R 2 , R 2a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, thiol, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0043] X and Y are each independently selected from N or CR 2a ;

[0044] R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 4 , R 5 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; or

[0045] R 4 and R 5 Connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring;

[0046] R 6 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 6 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, C1 -6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0047] R 3 Select from -OR 3a or -NR 3a R 3c ;in,

[0048] When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When there are substituents in the 4-10 membered heterocyclic group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0049] When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c Middle C 1-6 Alkyl, C 3-6When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0050] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0051] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0052]

[0053] In the formula, R 1 Selected from NR 1a R 1b ;

[0054] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0055] R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0056] R 2 Selected from hydrogen, halogen or C 1-6 alkyl;

[0057] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0058] R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0059] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0060] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0061] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0062] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] In the formula, R 1 Selected from NR 1a R 1b ;

[0065] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0066] R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0067] R 2 Selected from hydrogen, halogen or C 1-6 alkyl;

[0068] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0069] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0070] R 3 Select from -OR 3a or -NR 3a R 3c ;in,

[0071] When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When there are substituents in the 4-10 membered heterocyclic group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0072] When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c Middle C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0073] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0074] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (II) or a pharmaceutically acceptable salt thereof:

[0075]

[0076] In the formula, R 1 Selected from NR 1a R 1b ;

[0077] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0078] R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0079] R 2 Selected from hydrogen, halogen or C 1-6 alkyl;

[0080] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0081] R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0082] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0083] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0084] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0085] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (II) or a pharmaceutically acceptable salt thereof:

[0086]

[0087] In the formula, R 1 Selected from NR 1a R 1b ;

[0088] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or

[0089] R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring;

[0090] R 2 Selected from hydrogen, halogen or C 1-6 alkyl;

[0091] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0092] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0093] R 3 Select from -OR 3a or -NR 3a R 3c ;in,

[0094] When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When there are substituents in the 4-10 membered heterocyclic group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0095] When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c Middle C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0096] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0097] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof:

[0098]

[0099] Wherein, X is selected from N or CR 2a ;

[0100] R 1 Selected from NR 1a R 1b ;

[0101] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl;

[0102] R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl;

[0103] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0104] R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0105] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0106] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0107] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0108] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof:

[0109]

[0110] Wherein, X is selected from N or CR 2a ;

[0111] R 1 Selected from NR 1a R 1b ;

[0112] R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1bMiddle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl;

[0113] R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl;

[0114] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0115] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0116] R 3 Select from -OR 3a or -NR 3a R 3c ;in,

[0117] When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When there are substituents in the 4-10 membered heterocyclic group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0118] When R 3Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c Middle C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0119] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0120] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (IV) or a pharmaceutically acceptable salt thereof:

[0121]

[0122] Wherein, X is selected from N or CR 2a ;

[0123] R 1 Selected from OR 1a ;

[0124] R 1a is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl;

[0125] R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl;

[0126] R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 Middle C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0127] R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0128] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0129] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0130] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0131] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula (IV) or a pharmaceutically acceptable salt thereof:

[0132]

[0133] Wherein, X is selected from N or CR 2a ;

[0134] R 1 Selected from OR 1a ;

[0135] R 1a is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a Middle C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl;

[0136] R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl;

[0137] R 4 , R 5 Selected from hydrogen or C 1-6 alkyl;

[0138] R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl;

[0139] R 3 Select from -OR 3a or -NR 3a R 3c ;in,

[0140] When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When there are substituents in the 4-10 membered heterocyclic group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0141] When R 3 Selected from -NR 3a R3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c Middle C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0142] The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

[0143] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula IV-1 or a pharmaceutically acceptable salt thereof:

[0144]

[0145] In the formula, R 3 is selected from substituted or unsubstituted C 1-6 Alkyl or -OR 3a ; When R 3 Middle C 1-6 When there are substituents in the alkyl group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0146] R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or 4-10 membered heterocyclic group;

[0147] The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

[0148] More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula II-1 or a pharmaceutically acceptable salt thereof:

[0149]

[0150] R 3 is selected from substituted or unsubstituted 4-10 membered heterocyclic group, -OR 3a 、-NR 3a R 3c 、-NH-R 3a ; When R 3 When there are substituents in the 4-10 membered heterocyclic group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ;

[0151] R 3a , R 3b , R 3c are each independently selected from hydrogen, C 1-6Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or 4-10 membered heterocyclic group;

[0152] The 4-10 membered heterocyclic group is selected from the following groups:

[0153] The present invention also provides an aromatic heterocyclic pyrrolidone derivative selected from the following characteristic compounds numbered I-1 to I-17, II-1 to II-40, III-1 to III-3 and IV-1 to IV-12 or their isomers or pharmaceutically acceptable salts thereof:

[0154]

[0155]

[0156]

[0157] The "compounds" described in the present invention include but are not limited to the following forms of compounds: free base, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters), etc.

[0158] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0159] The "pharmaceutically acceptable salt" in the present invention refers to the salt of the compound of the present invention, which is a compound with a specific substituent discovered by the present invention and 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, When the compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts.

[0160] In the present invention, "isotope" means that unless otherwise specified, the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest amount of atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotope labels are: hydrogen isotopes, including but not limited to 2 H and 3 H; Carbon isotopes: including but not limited to 13 C and 14 C; Chlorine isotopes: including but not limited to 35 Cl and 37 Cl; Fluorine isotopes: including but not limited to 18 F; Iodine isotopes: including but not limited to 123 I and 125 I; Nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O. 17 O and 18 O; Sulfur isotopes: including but not limited to 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues, especially 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2H) substitution can enhance metabolic stability and prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like non-isotope-labeled compounds.

[0161] In the present invention, "isomer" means, unless otherwise specified, including stereoisomers or tautomers. Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans) isomers, and atropisomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in a solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0162] The term "prodrug" in the present invention refers to a prodrug of a compound of the present invention that is easily converted into a compound of the present invention by chemical changes under physiological conditions. In addition, a prodrug can be converted into a compound of the present invention by chemical or biochemical methods in an in vivo environment.

[0163] The terms used in this document have the following meanings:

[0164] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0165] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl and 2,2-dimethylbutyl), etc.

[0166] The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond, ie, =0.

[0167] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl), preferably 2-8 carbon atoms (i.e. C 2-8 Alkenyl), more preferably 2-6 carbon atoms (i.e. C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e. C 2-4 alkenyl), 2-3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example, "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0168] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), preferably 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably 2-6 carbon atoms (i.e. C 2-6 Alkynyl), 2-5 carbon atoms (i.e. C 2-5 Alkynyl), 2-4 carbon atoms (i.e. C 2-4 Alkynyl), 2-3 carbon atoms (i.e. C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl), for example, "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, 1,3-butadiynyl, 1-pentynyl, 3-methyl-1-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 3,3-dimethyl-1-butynyl, 3-ethyl-1-butynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 3-methyl-1,4-pentadiynyl, 1,5-hexadiynyl, and the like.

[0169] The term "cycloalkyl" refers to a monocyclic alkyl group consisting of carbon atoms and hydrogen atoms, such as C 3-8 Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0170] The term "alkoxy" refers to a straight or branched chain alkyl group attached through an oxygen atom, such as C 1-6 Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy (n-hexyloxy, 2-methylpentoxy, 3-methylpentoxy, 2,3-dimethylbutoxy and 2,2-dimethylbutoxy), and the like.

[0171] The term "alkylthio" refers to a straight or branched chain alkyl group attached through a sulfur atom, i.e., -S-alkyl, such as C 1-6 Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio and neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio and 2,2-dimethylbutylthio) and the like.

[0172] The term "alkylsulfonyl" refers to a straight or branched chain alkyl group linked through a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkylsulfone groups include, but are not limited to, methylsulfone, ethylsulfone, propylsulfone (including n-propylsulfone and isopropylsulfone), butylsulfone (including n-butylsulfone, isobutylsulfone, sec-butylsulfone and tert-butylsulfone), pentylsulfone (including n-pentylsulfone, isopentylsulfone and neopentylsulfone), hexylsulfone (n-hexylsulfone, 2-methylpentylsulfone, 3-methylpentylsulfone, 2,3-dimethylbutylsulfone and 2,2-dimethylbutylsulfone), and the like.

[0173] The term "alkylamino" refers to an open chain alkyl group containing a nitrogen atom, such as C 1-6 The alkylamino group includes, but is not limited to, methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, and diethylamino.

[0174] The term "aliphatic ring" refers to a monocyclic aliphatic hydrocarbon containing a specific number of carbon atoms connected to each other by carbon-carbon single bonds and double bonds, preferably containing 3-6 carbon atoms. Non-limiting examples of aliphatic rings include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene, etc.

[0175] The term "aromatic ring" refers to an all-carbon monocyclic ring or fused polycyclic ring of 6-16 carbon atoms, having a completely conjugated π-electron system, including but not limited to a benzene ring, a naphthalene ring, anthracene ring, etc., preferably a benzene ring.

[0176] The term "aryl" refers to an all-carbon monocyclic or condensed polycyclic group of 6 to 16 carbon atoms with a completely conjugated π-electron system, including but not limited to phenyl, naphthyl, anthracenyl, etc., preferably phenyl.

[0177] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic ring (such as a spirocyclic ring, a bridged ring, etc.) containing 3-20 ring atoms, which is a non-aromatic structure; the polycyclic ring may be a non-aromatic ring in which all rings are non-aromatic rings, or at least one ring is an aromatic ring and the remaining rings are non-aromatic rings. The aforementioned 3-20 ring atoms contain one or more (such as 2, 3, 4 or more) heteroatoms, and the rest are carbon atoms, and the heteroatoms are selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic ring may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. Non-limiting examples of "heterocycle" include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, furan, piperidine, piperazine, morpholine, and the like.

[0178] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., spirocyclic, bridged ring, etc.) group containing 3-20 ring atoms, which is a non-aromatic structure; the polycyclic group may be a non-aromatic ring in which all rings are non-aromatic, or at least one ring is an aromatic ring and the remaining rings are non-aromatic. The aforementioned 3-20 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, and the rest are carbon atoms, and the heteroatoms are selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic ring may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. Non-limiting examples of "heterocyclic group" include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, furanyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0179] The term "heteroaromatic ring" refers to an aromatic monocyclic or polycyclic ring (such as a condensed ring, etc.) containing 5-16 ring atoms, wherein the aforementioned 5-16 ring atoms contain one or more (such as 2, 3, 4 or more) heteroatoms, and the rest are carbon atoms, and the heteroatoms are selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic ring may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. The aforementioned "heteroaromatic ring" preferably contains 5-14, 5-12, 5-10, 5-8 ring atoms, and more preferably contains 5-6 ring atoms. Non-limiting examples of "heteroaromatic rings" include, but are not limited to, tetrahydrofuran, thiophene, oxazole, thiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazinyl, pyridazine, quinoline, indole, benzofuran, benzothiophene, benzimidazole, benzopyridine, benzopyrimidine, benzopyrazine, and the like.

[0180] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic (e.g., fused ring, etc.) group containing 5-16 ring atoms, wherein the aforementioned 5-16 ring atoms contain one or more (e.g., 2, 3, 4 or more) heteroatoms, and the rest are carbon atoms, and the heteroatoms are selected from one or more of N, O, and S. The aforementioned monocyclic or polycyclic ring may include the same or different heteroatoms in one or more rings, and the number of heteroatoms may be one or more. The aforementioned "heteroaryl" preferably contains 5-14, 5-12, 5-10, 5-8 ring atoms, and more preferably contains 5-6 ring atoms. Non-limiting examples of "heteroaryl" include, but are not limited to, tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, and the like.

[0181] The present invention also provides a method for preparing the above-mentioned series I, II, III, and IV compounds, including but not limited to the following method:

[0182] Route 1: When R in the general structural formula (I) 1 NHR 1a , Ring A is thiazole, X=Y=CH and R 6 for When the target compound is prepared as follows:

[0183]

[0184] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0185] The reaction process is as follows:

[0186] 2-Aminothiazole compound Ia-1 and amine fragment are condensed under the action of CDI to obtain urea intermediate Ia-2; urea intermediate Ia-2 and isoindolinone intermediate Ia-3 undergo coupling of the thiazole 5-position CH bond and aromatic halide under palladium reagent and microwave reaction conditions to obtain the target product Ia.

[0187] Route 2: When R in the general structural formula (I) 1 NHR 1a , Ring A is thiazole, X=Y=CH and R 6 for When the target compound is prepared as follows:

[0188]

[0189] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0190] The reaction process is as follows:

[0191] The halogenated isoindolinone derivative Ib-1 undergoes Miyaura boronation reaction to generate the boron ester intermediate Ib-2, which is then coupled with the urea intermediate Ib-3 under palladium catalysis to obtain the target product Ib.

[0192] Route 3: When R in the general structural formula (I) 1 NHR 1a , Ring A is thiazole, X=N, Y=CH and R 6 for When the target compound is prepared as follows:

[0193]

[0194] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0195] The reaction process is as follows:

[0196] Pyridopyrrolidine compound IIa-1 and nucleophilic reagent undergo SnAr reaction under alkaline conditions to obtain intermediate IIa-2; urea intermediate IIa-3 and intermediate IIa-2 undergo coupling of thiazole 5-position CH bond and aromatic halide under palladium reagent and microwave reaction conditions to obtain the target product IIa.

[0197] Route 4: When R in the general structural formula (I) 1 NHR 1a , Ring A is thiazole, X=N, Y=CH and R 6 for When the target compound is prepared as follows:

[0198]

[0199] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0200] The reaction process is as follows:

[0201] Pyridopyrrolidine compound IIb-1 reacts with various nucleophilic reagents under alkaline conditions to obtain intermediate IIb-2; intermediate IIb-2 and tin reagent IIb-3 undergo Stille coupling to obtain compound IIb-4; compound IIb-4 removes the Boc protecting group to generate compound IIb-5, and finally reacts with methylaminoformyl chloride under alkaline conditions to obtain the target product IIb.

[0202] Route 5: When R in the general structural formula (I) 1 NHR 1a , Ring A is pyridine, Y=CH and R 6 for When the target compound is prepared as follows:

[0203]

[0204] Among them, X, R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0205] The reaction process is as follows:

[0206] The 2-amino-5-bromopyridine intermediate III-1 is condensed with an amine fragment under the action of CDI to obtain the pyridine urea intermediate III-2; the intermediate III-2 and the intermediate III-3 undergo Suzuki coupling under the catalysis of a palladium reagent to obtain the target product III.

[0207] Route 6: When R in the general structural formula (I) 1 For-OR 1a , Ring A is thiazole, Y=CH and R 6 for When the target compound is prepared as follows:

[0208]

[0209] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0210] The reaction process is as follows:

[0211] 2-Aminothiazole compound IVa-1 and chloroformate fragments are condensed to obtain carbamate intermediate IVa-2; intermediate IVa-2 and intermediate IVa-3 undergo coupling of the thiazole 5-position CH bond and aromatic halide under palladium reagent and microwave reaction conditions to obtain the target product IVa.

[0212] Route 7: When R in the general structural formula (I) 1 For-OR 1a , Ring A is thiazole, Y=CH and R 6 for When the target compound is prepared as follows:

[0213]

[0214] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0215] The reaction process is as follows:

[0216] The boron ester intermediate IVb-1 and the thiazole carbamate intermediate IVb-2 are coupled under palladium catalysis to obtain the target product IVb.

[0217] Route 8: When R in the general structural formula (I) 1 For-OR 1a , Ring A is thiazole, Y=CH and R 6 for When the target compound is prepared as follows:

[0218]

[0219] Where R 1a , R 2 , R 3 , R 4 and R 5 The definition of is as mentioned above.

[0220] The reaction process is as follows:

[0221] Intermediate IVc-1 reacts with R under alkaline conditions. 1a OH undergoes ester exchange reaction to obtain the target product IVc.

[0222] In the aforementioned routes 1 to 10, the palladium reagent can be selected from one or more of tetrakistriphenylphosphine palladium, bis(triphenylphosphine)palladium chloride, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.

[0223] In the aforementioned routes 1, 3 and 6, the reaction conditions for synthesizing the target compound can be microwave or oil bath.

[0224] The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0225] Furthermore, the pharmaceutical composition also includes one or more pharmaceutically acceptable carriers.

[0226] The term "pharmaceutical composition" in the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (such as a human). The purpose of a pharmaceutical composition is to facilitate administration and delivery to an organism.

[0227] In the present invention, "pharmaceutically acceptable carrier" refers to a substance that is co-administered with an active ingredient and is conducive to the administration of the active ingredient, including but not limited to any pharmaceutically acceptable glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier for humans or animals (such as livestock). Non-limiting examples of "pharmaceutically acceptable carrier" include but are not limited to calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol, etc.

[0228] The pharmaceutical composition provided by the present invention can be manufactured by methods well known in the art, including but not limited to mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

[0229] The pharmaceutical composition provided by the present invention can be formulated into solid, semisolid, liquid or gas preparations, including but not limited to tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc.

[0230] The pharmaceutical composition provided by the present invention has administration routes including but not limited to oral administration, injection, inhalation, transdermal administration, mucosal administration, topical administration, intracavitary administration, etc., and administration sites including but not limited to oral cavity, sublingual administration, intravenous administration, intramuscular administration, lung, gastrointestinal tract administration, epidermal administration, subcutaneous administration, intranasal administration, intraocular administration, intraauricular administration, intraperitoneal administration, intravaginal administration, rectal administration, acupuncture points, etc. The preferred administration route is oral administration.

[0231] For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with a pharmaceutically acceptable carrier. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients. For example, for a pharmaceutical composition for oral administration, tablets can be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and a small amount of excipients is added if necessary to process into a mixture or granules to form tablets or tablet cores. Further, if necessary, the tablet core can be coated with a suitable coating material and processed into a coated preparation form that is more conducive to absorption by an organism (such as a human).

[0232] The present invention also provides a use of the above-mentioned compound or pharmaceutical composition in the preparation of a drug for preventing or treating a disease associated with abnormal expression of the PI3Kγ signaling pathway.

[0233] Preferably, the aforementioned compound or pharmaceutical composition provided by the present invention can prevent or treat the following diseases by blocking the activation of the PI3Kγ-mediated signaling pathway: 1) chronic inflammatory diseases, such as gout, nephritis, atherosclerosis, non-alcoholic fatty hepatitis, hepatitis, diabetes, enteritis, etc.; 2) acute inflammatory diseases, such as traumatic brain injury, wounds, toothache, acute nephritis, viral infection, sepsis, burns, septic shock; 3) cardiovascular diseases, such as myocardial ischemia, heart failure, etc.; 4) nervous system diseases , such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, meningitis, headache, neuropathic pain, etc.; 5) Autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic vasculitis; 6) Respiratory system diseases, such as COPD, asthma, pneumonia, tuberculosis, etc.; 7) Metabolic syndrome, such as obesity, hyperglycemia, hypertension, dyslipidemia, hyperuricemia, hyperinsulinemia, etc.; 8) Digestive system, such as viral hepatitis, cirrhosis, liver fibrosis, enteritis, etc.; 9) Tumors and tumor metastasis, tumor complications, etc.

[0234] Preferably, the aforementioned compound or pharmaceutical composition provided by the present invention is used for preventing or treating atopic dermatitis.

[0235] Compared with the prior art, the present invention has the following beneficial effects:

[0236] Based on the target design of PI3Kγ inhibitors, the present invention has developed a series of novel aromatic heterocyclic pyrrolidone derivatives. Relevant biological experiments have shown that most compounds have significant PI3Kγ activity inhibition and high selectivity for PI3Kγ, and some compounds even show pharmacokinetic properties superior to control drugs, with great clinical application value. In addition, the compound synthesis route provided by the present invention is novel, safe, environmentally friendly, and has good production feasibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0237] Figure 1 The figure is a comparison of the inhibition rate of the compounds of the present invention on the cytokine secretion of lymphocytes from AD model mice.

[0238] Figure 2 The figure is a comparison of the inhibition rate of the compounds of the present invention on IL-17A secretion from lymphocytes derived from psoriasis model mice. DETAILED DESCRIPTION

[0239] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0240] In addition, all operations involving raw materials that are easily oxidized or hydrolyzed are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification.

[0241] Explanation of the abbreviations of reagents or materials used:

[0242] mw: microwave reaction; CDI: N,N'-carbonyldiimidazole; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium; Cs2CO3: cesium carbonate; DMF: N,N-dimethylformamide; CH3I: iodomethane; K2CO3: potassium carbonate; NBS: N-bromosuccinimide; BPO: azobisisobutyronitrile; B(OH)3: boric acid; CH3CN: acetonitrile; ClCONHCH3: methylaminoformyl chloride; DCM: dichloromethane; TEA: triethylamine; TMSOK: potassium trimethylsilanolate; DME: ethylene glycol dimethyl ether; NaSCH3: sodium methylthiolate; THF: tetrakis Hydrofuran; diethylphosphite: diethyl phosphite; (Bpin)2: diboronic acid pinacol ester; KOAc: potassium acetate; 1,4-dioxane: 1,4-dioxane; CCl4: carbon tetrachloride; NMP: N-methylpyrrolidone; K3PO4: potassium phosphate; PhI(OAc)2: iodophenyldiacetic acid; I2: iodine; Pd(OAc)2: palladium acetate; AIBN: dibenzoyl peroxide; DMAP: 4-dimethylaminopyridine; LDA: lithium diisopropylamide; NaCO3: sodium carbonate; m-CPBA: m-chloroperoxybenzoic acid; HCl: hydrochloric acid; CataCxium A: n-butyldi(1-adamantyl)phosphine; SeF: cesium fluoride; CuCN: cuprous cyanide; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Tol: toluene; CuI: cuprous iodide; EA: ethyl acetate; RT: room temperature; DIPEA: N-diisopropylethylamine; SOCl2: dichlorothionyl; TFA: trifluoroacetic acid; NaH: sodium hydride; NaOMe: sodium methoxide; MeOH: methanol; n-BuOH: n-butanol; EtOH: ethanol; DMA: N,N-dimethylacetamide.

[0243] The present invention involves a common intermediate that needs to be prepared in-house, and the preparation process is as follows:

[0244] 1. Preparation of common intermediate (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindol-1-one (A1)

[0245]

[0246] Step 1: Synthesis of methyl 4-bromo-2-fluoro-6-methylbenzoate (A1-2)

[0247] Dissolve 4-bromo-2-fluoro-6-methylbenzoic acid: A1-1 (10.00 g, 42.91 mmol) in N,N-dimethylformamide (100 mL), add iodomethane (12.18 g, 83.82 mmol) and potassium carbonate (17.79 g, 128.74 mmol), and stir the reaction at 80°C for 1 hour. Add 200 mL of water to the reaction, extract with ethyl acetate (300 mL*3), combine the organic phases, wash twice with water, wash once with saturated brine, and then dry and concentrate to obtain 10.20 g (crude) of yellow oil A1-2, which is directly used in the next step.

[0248] ESI-MS: m / z = 247.0 [M+H] + .

[0249] 1 H NMR (400MHz, DMSO-d6): δ7.56 (dd, J1=9.6Hz, J2=2.0Hz, 1H), 7.47 (d, J=0.8Hz, 1H), 3.88 (s, 3H), 2.34 (s, 3H).

[0250] Step 2: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (A1-3)

[0251] A1-2 (10.20 g, 41.28 mmol) was dissolved in carbon tetrachloride (100 mL), N-bromosuccinimide (8.08 g, 45.41 mmol) and azobisisobutyronitrile (677.95 mg, 4.13 mmol) were added, and the reaction was stirred at 85 ° C for 3 hours under nitrogen protection. The reaction solution was spin-dried, the residue was dissolved in petroleum ether, filtered, and the filtrate was spin-dried to obtain 13.5 g (crude) of A1-3.

[0252] ESI-MS: m / z=325.0, 327.0[M+H] + .

[0253] Step 3: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindol-1-one (A1)

[0254] A1-3 (13.05 g, 40.04 mmol) was dissolved in acetonitrile (120 mL), (S)-1-cyclopropylethane-1-amine hydrochloride (4.87 g, 40.04 mmol), boric acid (495.09 mg, 8.01 mmol) and potassium carbonate (16.60 g, 120.11 mmol) were added, and the mixture was stirred at 85°C for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, washed once with water, washed once with saturated brine, dried and concentrated, and the residue was separated by column chromatography, the eluent being 0-20% ethyl acetate in petroleum ether solution, to obtain 3.17 g of common intermediate A1 as a yellow solid, and the total yield of the three steps of step 1 to step 3 was 26.3%.

[0255] ESI-MS: m / z = 298.0 [M+H] + .

[0256] 2. Preparation of Common Intermediate (S)-5-Bromo-2-(1-cyclopropylethyl)-7-hydroxyisoindol-1-one (A2)

[0257]

[0258] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-hydroxyisoindol-1-one (A2)

[0259] Dissolve the common intermediate A1 (3.17 g, 10.63 mmol) in ethylene glycol dimethyl ether (30 mL), replace the atmosphere with nitrogen three times, and add potassium trimethylsilanolate (4.09 g, 31.90 mmol). Heat the mixture to 85°C and stir for 1 hour. Pour the reaction solution into 1M HCl (30 mL), extract with ethyl acetate (30 mL*3), combine the organic phases, wash once with water, wash once with saturated brine, dry and concentrate to obtain 3.00 g of common intermediate A2 as a red oil with a yield of 95.2%.

[0260] ESI-MS: m / z = 296.0 [M+H] + .

[0261] 3. Preparation of Common Intermediate (S)-5-Bromo-2-(1-cyclopropylethyl)-7-difluoromethoxyisoindol-1-one (A3)

[0262]

[0263] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-difluoromethoxyisoindol-1-one (A3)

[0264] The common intermediate A2 (3.00 g, 10.13 mmol) was dissolved in N-methylpyrrolidone (30 mL), sodium 2-chloro-2,2-difluoroacetate (1.85 g, 12.16 mmol) and potassium phosphate (4.30 g, 20.26 mmol) were added, and the mixture was heated to 90 ° C and stirred for 1 hour. The reaction solution was cooled to room temperature, poured into 2M HCl (40 mL), extracted with ethyl acetate (30 mL * 3), the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography, the eluent was 0-10% ethyl acetate in petroleum ether solution, and 1.50 g of the common intermediate A3 was obtained as a light yellow solid, with a yield of 42.9%.

[0265] ESI-MS: m / z = 346.0 [M+H] + .

[0266] 1 H NMR (400MHz, DMSO-d6): δ7.76(s,1H),7.61(t,J=74.4Hz,1H),7.48(s,1H),4.55(s,2H),3.56-3.49(m, 1H), 1.27 (d, J = 6.8Hz, 3H), 1.13-1.06 (m, 1H), 0.58-0.53 (m, 1H), 0.43-0.34 (m, 2H), 0.25-0.20 (m, 1H).

[0267] 4. Preparation of the common intermediate (S)-2-(1-cyclopropylethyl)-7-difluoromethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (D1)

[0268]

[0269] Step 1: Synthesis of (S)-2-(1-cyclopropylethyl)-7-difluoromethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (D1)

[0270] The common intermediate A3 (1.50 g, 4.33 mmol) was dissolved in 1,4-dioxane (15 mL), and diboric acid pinacol ester (1.32 g, 5.20 mmol), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium (157.22 mg, 0.22 mmol) and potassium acetate (1.28 g, 13.00 mmol) were added, and the reaction was stirred at 100 ° C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography, and the eluent was 0-10% ethyl acetate in petroleum ether solution to obtain 1.70 g of common intermediate D1 as an off-white solid, with a yield of 99.4%.

[0271] ESI-MS: m / z = 394.0 [M+H] + .

[0272] 1 H NMR (400MHz, DMSO-d6): 7.74 (s, 1H), 7.56 (t, J = 74.4Hz, 1H), 7.36 (s, 1H), 4.55 (s, 2H), 3.57-3.50 (m, 1H), 1.3 2(s,12H),1.28(d,J=6.8Hz,3H),1.12-1.08(m,1H),0.61-0.53(m,1H),0.43-0.33(m,2H),0.25-0.18(m,1H).

[0273] 5. Preparation of Common Intermediate (S)-5-Chloro-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (A4)

[0274]

[0275] Step 1: Synthesis of 4-chloro-2-iodo-6-methylbenzoic acid (A4-2)

[0276] 4-Chloro-2-methylbenzoic acid: A4-1 (5.0 g, 29.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), iodobenzenediacetic acid (18.89 g, 58.62 mmol), iodine (11.16 g, 43.97 mmol) and palladium acetate (332 mg, 1.47 mmol) were added, nitrogen was replaced three times, and the temperature was raised to 100 ° C for 2 hours. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with water (20 mL*3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the eluent was 4% ethyl acetate in petroleum ether to obtain 6.1 g of A4-2 as a white solid with a yield of 70.2%.

[0277] ESI-MS: m / z = 295.0 [MH] - .

[0278] 1 H NMR (400MHz, DMSO-d6): δ13.68 (s, 1H), 7.78 (d, J = 2.0Hz, 1H), 7.42 (dd, J1 = 2.0Hz, J2 = 0.8Hz, 1H), 2.29 (s, 3H).

[0279] Step 2: Synthesis of methyl 4-chloro-2-iodo-6-methylbenzoate (A4-3)

[0280] A4-2 (6.10 g, 20.57 mmol) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (4.27 g, 30.86 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (4.38 g, 30.86 mmol) was added, and the system was stirred at room temperature overnight. The reaction solution was quenched with water, extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, washed with water three times (20 mL*3), washed with saturated brine once (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the eluent was 7% ethyl acetate in petroleum ether to obtain 6.0 g of A4-3 as a yellow solid with a yield of 93.3%.

[0281] ESI-MS: m / z = 311.0 [M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d6): δ7.81 (dd, J1=2.0Hz, J2=0.8Hz, 1H), 7.46 (dd, J1=2.0Hz, J2=0.8Hz, 1H), 3.87 (s, 3H), 2.25 (t, J=0.8Hz, 3H).

[0283] Step 3: Synthesis of methyl 2-bromomethyl-4-chloro-6-iodobenzoate (A4-4)

[0284] A4-3 (6.0 g, 19.32 mmol), N-bromosuccinimide (6.19 g, 34.78 mmol) and dibenzoyl peroxide (317 mg, 1.93 mmol) were dissolved in carbon tetrachloride (10 mL), and the temperature was raised to 90 ° C for overnight reaction. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane three times (20 mL * 3), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the eluent was 2% ethyl acetate in petroleum ether solution to obtain 5.3 g of A4-4 as an oil, with a yield of 70.6%.

[0285] ESI-MS: m / z=389.0, 391.0[M+H] + .

[0286] Step 4: Synthesis of (S)-5-chloro-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (A4)

[0287] A4-4 (1.0 g, 2.568 mmol), (S)-1-cyclopropylethylamine hydrochloride (262 mg, 3.082 mmol), boric acid (191 mg, 3.08 mmol) and potassium carbonate (1.06 g, 7.70 mmol) were dissolved in acetonitrile (10 mL), heated to 60 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (20 mL*3). The organic phases were combined, washed with water once (20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with a 15% ethyl acetate petroleum ether solution as the eluent to obtain 300 mg of the common intermediate A4 as a yellow solid with a yield of 32.3%.

[0288] ESI-MS: m / z = 362.0 [M+H] + .

[0289] 1 H NMR (400MHz, DMSO-d6): δ7.98(d,J=2.0Hz,1H),7.76(d,J=2.0Hz,1H),4.46(s,2H),3.59-3.52(m,1H ),1.27(d,J=6.8Hz,3H),1.16-1.06(m,1H),0.61-0.53(m,1H),0.43-0.34(m,2H),0.25-0.16(m,1H).

[0290] VI. Preparation of Common Intermediate (S)-4,6-dichloro-2-(1-cyclopropylethyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (A5)

[0291]

[0292] Step 1: Synthesis of 2,6-dichloro-4-methylnicotinate (A5-2)

[0293] 2,6-Dichloro-4-methylnicotinic acid: A5-1 (2.00 g, 9.71 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (4.03 g, 29.12 mmol) was added, the mixture was stirred at room temperature for 15 minutes, iodomethane (4.13 g, 29.12 mmol) was added, the temperature was raised to 40 ° C and stirred for 2 hours. After cooling to room temperature, water was added to quench, and ethyl acetate was extracted three times (20 mL * 3), the combined organic phase was washed with water three times (20 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 85% ethyl acetate petroleum ether solution, and 2.07 g of A5-2 was obtained as a white solid with a yield of 97.0%.

[0294] ESI-MS: m / z = 220.0 [M + H] + .

[0295] 1 H NMR (400MHz, DMSO-d6): δ7.65 (d, J=0.8Hz, 1H), 3.92 (s, 3H), 2.32 (s, 3H).

[0296] Step 2: Synthesis of 2,6-dichloro-4-(dibromomethyl)nicotinate (A5-3)

[0297] A5-2 (1.4 g, 6.36 mmol), N-bromosuccinimide (4.53 g, 25.45 mmol) and dibenzoyl peroxide (1.08 g, 4.45 mmol) were dissolved in carbon tetrachloride (10 mL) and reacted at 70 ° C for 1 hour in a microwave oven. After the mixture was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (20 mL * 3). The organic phases were combined, washed with water three times (20 mL * 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with an eluent of 85% ethyl acetate petroleum ether solution to obtain 1.3 g (crude) of A5-3 as an oil.

[0298] ESI-MS: m / z=376.0, 378.0[M+H] + .

[0299] Step 3: Synthesis of methyl 4-(bromomethyl)-2,6-dichloronicotinate (A5-4)

[0300] A5-3 (2.4 g, 6.53 mmol) and triethylamine (1.29 g, 12.70 mmol) were dissolved in tetrahydrofuran (5 mL), and diethyl phosphite (1.75 g, 12.70 mmol) was added dropwise under ice bath. After the addition was completed, stirring was continued for 1 hour. The mixture was quenched with saturated sodium bicarbonate, extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, washed with water three times (20 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. 1.3 g (crude) of A5-4 was obtained as an oil.

[0301] ESI-MS: m / z = 298.0 [M+H] + .

[0302] Step 4: Synthesis of (S)-4,6-dichloro-2-(1-cyclopropylethyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (A5)

[0303] A5-4 (1.3 g, 4.35 mmol), (S)-1-cyclopropylethylamine hydrochloride (635 mg, 5.22 mmol), boric acid (323 g, 5.22 mmol) and potassium carbonate (1.8 g, 13.05 mmol) were dissolved in acetonitrile (10 mL), heated to 60 ° C for 2 hours. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (20 mL * 3), the organic phases were combined, the organic phases were washed with water three times (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 65% ethyl acetate petroleum ether solution, and 150 mg (crude product) of the common intermediate A5 was obtained as an oily substance. The total yield of the three-step reaction of step 2 to step 4 was 15.0%.

[0304] ESI-MS: m / z = 271.0 [M+H] + .

[0305] 1 H NMR (400MHz, DMSO-d6): δ7.89(s,1H),4.62(s,2H),3.58-3.51(m,1H),1.27(d,J=6.8 Hz,3H),1.16-1.07(m,1H),0.61-0.54(m,1H),0.44-0.35(m,2H),0.26-0.19(m,1H).

[0306] VII. Preparation of Common Intermediate (S)-6-Chloro-2-(1-cyclopropylethyl)-4-morpholinyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (A6)

[0307]

[0308] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-morpholinyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (A6)

[0309] The common intermediate A5 (100 mg, 0.37 mmol), morpholine (48 mg, 0.53 mmol) and triethylamine (56 mg, 0.53 mmol) were dissolved in N, N-dimethylformamide (3 mL), and the temperature was raised to 60 ° C for 2 hours. After the mixture was cooled to room temperature, water (15 mL) was added to quench it, and it was extracted with ethyl acetate three times (10 mL*3), and the organic phases were combined, washed with water three times (10 mL*3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography, and the developing solvent was 80% ethyl acetate petroleum ether solution to obtain 66 mg of the common intermediate A6 as a light green oil, with a yield of 55.9%.

[0310] ESI-MS: m / z = 322.0 [M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6): δ7.06(s,1H),4.48(s,2H),3.72-3.65(m,8H),3.57-3.46(m,1H),1.23 (d,J=6.8Hz,3H),1.11-1.02(m,1H),0.58-0.42(m,1H),0.40-0.30(m,2H),0.23-0.17(m,1H).

[0312] 8. Preparation of Common Intermediate 1-Methyl-3-(4-methylthiazol-2-yl)urea (B1)

[0313]

[0314] Step 1: Synthesis of 1-methyl-3-(4-methylthiazol-2-yl)urea (B1)

[0315] Dissolve 2-amino-4-methylthiazole hydrochloride: B1-1 (1.0g, 6.69mmol) in dichloromethane (10mL), add triethylamine (1.7g, 16.96mmol) dropwise, and stir at room temperature for 15 minutes. Add methylaminoformyl chloride (745mg, 7.97mmol) under ice bath and heat to 40℃ for 2 hours. After the mixture is cooled to room temperature, add water to quench, extract with dichloromethane three times (20mL*3), combine the organic phases, wash the organic phases with water three times (20mL*3), wash with saturated brine (20mL), dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography, the eluent is 50% ethyl acetate in petroleum ether solution, and 402mg of common intermediate B1 is obtained as a white solid with a yield of 35.3%.

[0316] ESI-MS: m / z = 172.0 [M + H]+ .

[0317] 1 H NMR (400MHz, DMSO-d6): δ10.36 (s, 1H), 6.53 (q, J = 1.2Hz, 1H), 6.41 (d, J = 4.8Hz, 1H), 2.67 (d, J = 4.8Hz, 3H), 2.18 (d, J = 1.2Hz, 3H).

[0318] IX. Preparation of Common Intermediate 1-(5-bromo-4-methylthiazol-2-yl)-3-methylurea (B2)

[0319]

[0320] Step 1: Synthesis of 1-(5-bromo-4-methylthiazol-2-yl)-3-methylurea (B2)

[0321] Dissolve 5-bromo-4-methylthiazole-2-amine: B2-1 (1.92 g, 10.0 mmol) in dichloromethane (10 mL), add triethylamine (2.02 g, 20.00 mmol), add methylaminoformyl chloride (1.12 g, 12.00 mmol) dropwise under ice bath, and react at room temperature for 2 h. After the reaction is completed, add water (30 mL) to quench, extract with dichloromethane twice (10 mL*2), then wash with saturated brine (30 mL), combine the organic phases, and concentrate to obtain 2.43 g of common intermediate B2 as a white solid with a yield of 97.6%.

[0322] ESI-MS: m / z = 250.0 [M + H] + .

[0323] 10. Preparation of Common Intermediate (4-methyl-5-(tributyltinyl)thiazol-2-yl)carbamic acid tert-butyl ester (B3)

[0324]

[0325] Step 1: Synthesis of tert-butyl (4-methylthiazol-2-yl)carbamate (B3-2)

[0326] Dissolve 2-amino-4-methylthiazole: B3-1 (6.0g, 52.56mmol) in dichloromethane (100mL), add triethylamine (5.32g, 52.56mmol) and 4-dimethylaminopyridine (642mg, 5.26mmol), and stir at room temperature for 15 minutes. Add di-tert-butyl dicarbonate (13.76g, 63.07mmol) under ice bath, and warm the reaction solution to room temperature for 12 hours. TLC monitoring reaction completion, add 100mL of water, extract with dichloromethane three times (50mL*3), wash with saturated brine (50mL*2), combine organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, the eluent is 25% ethyl acetate in petroleum ether solution, and 9.8g of B3-2 is obtained as a white solid with a yield of 86.7%.

[0327] ESI-MS: m / z = 215.0 [M+H] + .

[0328] Step 2: Synthesis of tert-butyl (4-methyl-5-(tributyltinyl)thiazol-2-yl)carbamate (B3)

[0329] B3-2 (10 g, 46.67 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to -78 ° C, and lithium diisopropylamide (49 mL, 98 mmol) was slowly added dropwise using a constant pressure dropping funnel. The reaction was allowed to react at -78 ° C for 1 h, and then tributyltin chloride (12.15 g, 37.33 mmol) was slowly added dropwise. The reaction was continued to stir overnight at -78 ° C, the temperature was raised to 0 ° C, quenched by adding 100 mL of 40% potassium fluoride solution, stirred for 30 min, and then 150 mL of ethyl acetate was added. The organic phase was separated and concentrated at low temperature. The residue was purified by column chromatography, and the eluent was 12.5% ​​ethyl acetate in petroleum ether to obtain 12 g of common intermediate B3 as an oily substance with a yield of 30.1%.

[0330] ESI-MS: m / z = 505.0 [M+H] + .

[0331] XI. Preparation of Common Intermediate (5-bromo-4-methylthiazol-2-yl)carbamic Acid Methyl Ester (B4)

[0332]

[0333] Step 1: Synthesis of methyl (5-bromo-4-methylthiazol-2-yl)carbamate (B4-2)

[0334] Dissolve 5-bromo-4-methylthiazole-2-amine: B4-1 (1.92 g, 10.00 mmol) in dichloromethane (10 mL), add triethylamine (2.02 g, 20.00 mmol), add phenyl chloroformate (1.88 g, 12.00 mmol) dropwise under ice bath, and react at room temperature for 2 h. After the reaction is completed, add water (30 mL) to quench, extract with dichloromethane twice (10 mL*2), then wash with saturated brine (30 mL), combine the organic phases, and concentrate to obtain 2.47 g of B4-2 as a yellow solid with a yield of 79.2%.

[0335] ESI-MS: m / z=313.0, 315.0[M+H] + .

[0336] Step 2: Synthesis of methyl (5-bromo-4-methylthiazol-2-yl)carbamate (B4)

[0337] B4-2 (265 mg, 0.85 mmol) was dissolved in methanol (10 mL), and then sodium methoxide (92 mg, 1.71 mmol) was added, and the mixture was reacted at 60°C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, 30 mL of ethyl acetate was added to the reaction solution, and then the reaction solution was washed three times with saturated brine (30 mL*3), the organic phases were combined, and the residue was concentrated and purified by column chromatography, with the eluent being 10-12% ethyl acetate in petroleum ether solution, to obtain 201 mg of the common intermediate B4 as a white solid, with a yield of 94.7%.

[0338] ESI-MS: m / z=251.0, 253.0[M+H] + .

[0339] 12. Preparation of Common Intermediate (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)phenylcarbamate (C1)

[0340]

[0341] Step 1: Synthesis of tert-butyl (tert-butyloxycarbonyl)(4-methylthiazol-2-yl)carbamate (C1-1)

[0342] Dissolve B1-1 (1.0 g, 8.76 mmol) in tetrahydrofuran (10 mL), then add di-tert-butyl dicarbonate (4.78 g, 21.90 mmol), sodium carbonate (2.32 g, 21.90 mmol) and 4-dimethylaminopyridine (107 mg, 0.88 mmol), and react at 60°C for 1 h. After the reaction is completed, cool to room temperature, add 30 mL of ethyl acetate to the reaction solution, then wash the reaction solution three times with saturated brine (30 mL*3), combine the organic phases, concentrate, and purify the residue by column chromatography, the eluent is 0-5% ethyl acetate in petroleum ether, and obtain 2.97 g of C1-1 as a crude oil.

[0343] ESI-MS: m / z = 315.0 [M + H] + .

[0344] Step 2: Synthesis of tert-butyl (5-bromo-4-methylthiazol-2-yl)(tert-butoxycarbonyl)carbamate (C1-2)

[0345] C1-1 (1.0 g, 3.18 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then N-bromosuccinimide (623 mg, 3.50 mmol) was added and reacted at 0°C for 1 h. After the reaction was completed, water was added to quench (30 mL), and then the reaction solution was extracted three times with ethyl acetate (30 mL*3), the organic phases were combined, and the residue was purified by column chromatography after concentration, with the eluent being 0-5% ethyl acetate in petroleum ether solution, to obtain 900 mg of C1-2 as a white solid, with a two-step yield of 97.1%.

[0346] ESI-MS: m / z = 393.0, 395.0 [M+H] + .

[0347] Step 3: Synthesis of tert-butyl (S)-(tert-butyloxycarbonyl)(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (C1-3)

[0348] C1-2 (2.40 g, 6.10 mmol) was dissolved in 1,4-dioxane / water (10 mL / 1 mL), and then the common intermediate D1 (2.0 g, 5.09 mmol), cesium carbonate (3.31 g, 10.17 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium(II) (185 mg, 0.25 mmol) were added, and the environment was replaced with N2, and the reaction was carried out at 90°C for 2 h. After the reaction was completed, it was cooled to room temperature, and then the reaction solution was extracted with water (30 mL) and ethyl acetate (30 mL*3), the organic phases were combined, and the residue was purified by column chromatography after concentration, and the eluent was 10-23% ethyl acetate in petroleum ether to obtain 2.87 g of C1-3 as a yellow solid with a yield of 97.3%.

[0349] ESI-MS: m / z = 580.0 [M + H] + .

[0350] Step 4: Synthesis of (S)-5-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (C1-4)

[0351] Dissolve C1-3 (2.87 g, 4.95 mmol) in dichloromethane (20 mL), then add trifluoroacetic acid (5 mL) and react at room temperature overnight. After the reaction is completed, add water (30 mL) to quench, then extract the reaction solution with dichloromethane (30 mL*2), combine the organic phases, concentrate, and purify the residue by column chromatography, with the eluent being 0-5% methanol in dichloromethane solution, to obtain 1.85 g of C1-4 as a yellow solid, with a yield of 98.4%.

[0352] ESI-MS: m / z = 380.0 [M+H] + .

[0353] 1 H NMR (400MHz, DMSO-d6): δ8.47(s,2H),7.62(t,J=74.8Hz,1H),7.51(d,J=1.2Hz,1H),7.17(s,1H),4.58(s,2H),3.59-3.5 2(m,1H),2.29(s,3H),1.28(d,J=6.8Hz,3H),1.15-1.07(m,1H),0.60-0.53(m,1H),0.44-0.35(m,2H),0.26-0.20(m,1H).

[0354] Step 5: Synthesis of (S)-phenyl(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (C1)

[0355] Dissolve C1-4 (500 mg, 1.32 mmol) in dichloromethane (20 mL), then add triethylamine (200 mg, 1.98 mmol) and phenyl chloroformate (248 mg, 1.58 mmol) and react at room temperature for 1 hour. After the reaction is completed, add water to quench, then extract the reaction solution with dichloromethane (30 mL*3), combine the organic phases, concentrate, and purify the residue by column chromatography, the eluent is 0-5% methanol in dichloromethane solution, and 350 mg of common intermediate C1 is obtained as a white solid with a yield of 53.2%.

[0356] ESI-MS: m / z = 500.0 [M + H] + .

[0357] Example 1. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-methyl-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-1)

[0358]

[0359] Step 1: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-methylbenzoate (I-1-2)

[0360] Dissolve methyl 4-bromo-2,6-dimethylbenzoate: I-1-1 (1.21 g, 5.00 mmol) in carbon tetrachloride (10 mL), add N-bromosuccinimide (1.07 g, 6.00 mmol) and azobisisobutyronitrile (84 mg, 0.50 mmol), and stir the reaction at 85 ° C for 4 hours under nitrogen protection. The reaction solution is dried by rotation, the residue is dissolved in petroleum ether, filtered, and the filtrate is dried by rotation to obtain 1.71 g (crude) of I-1-2.

[0361] ESI-MS: m / z=320.0, 322.0[M+H] + .

[0362] Step 2: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-methylisoindolin-1-one (I-1-3)

[0363] I-1-2 (1.71 g, 5.36 mmol) was dissolved in acetonitrile (20 mL), (S)-1-cyclopropylethane-1-amine hydrochloride (651 mg, 5.36 mmol), boric acid (66 mg, 1.07 mmol) and potassium carbonate (3.70 g, 26.80 mmol) were added, and the mixture was stirred at 85 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed once with water, washed once with saturated brine, dried and concentrated, and the residue was separated by column chromatography, the eluent was 0-20% ethyl acetate in petroleum ether solution, and 478 mg of I-1-3 was obtained as a yellow solid. The total yield of step 2 and step 3 was 32.6%.

[0364] ESI-MS: m / z = 294.0 [M+H] + .

[0365] Step 3: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-methyl-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-1)

[0366] I-1-3 (59 mg, 0.20 mmol), common intermediate B1 (41 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (7 mg, 0.01 mmol) and cesium carbonate (130 mg, 0.4 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at 100 ° C for 1 h under microwave conditions. After the mixture was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (10 mL*3), the organic phases were combined, the organic phases were washed with water three times (10 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by full preparative liquid chromatography to obtain the target compound I-1.

[0367] ESI-MS: m / z = 385.0 [M+H] + .

[0368] Example 2. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-2)

[0369]

[0370] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one (I-2-1)

[0371] The common intermediate A1 (295 mg, 1.00 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium thiomethoxide (140 mg, 2.00 mmol) was added. The reaction was stirred at 50 ° C for 4 hours. 20 mL of water was added to the reaction, and it was extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with water twice, washed with saturated brine once, and then dried and concentrated. The eluent was 0-10% ethyl acetate in petroleum ether to obtain 260 mg of I-2-1 as a yellow solid with a yield of 80.0%.

[0372] ESI-MS: m / z = 326.0 [M+H] + .

[0373] Step 2: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (I-2-2)

[0374] I-2-1 (260 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (207 mg, 1.20 mmol) was added under ice bath, and the mixture was warmed to room temperature and stirred for 3 h. A small amount of sodium thiosulfate aqueous solution (3 mL) and water (10 mL) were added to the reaction solution, and the aqueous layer was extracted with dichloromethane (10 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was separated and purified by column chromatography, and the eluent was 0-20% ethyl acetate in petroleum ether solution to obtain 256 mg of I-2-2 as a light yellow solid with a yield of 89.3%.

[0375] ESI-MS: m / z = 358.0 [M+H] + .

[0376] Step 3: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-2)

[0377] The preparation of target compound I-2 refers to step 3 in the preparation method of target compound I-1, except that intermediate I-1-3 is replaced by intermediate I-2-2, and the rest of the preparation method remains unchanged to obtain target compound I-2.

[0378] ESI-MS: m / z = 449.0 [M+H] + .

[0379] Example 3. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-morpholine-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-3)

[0380]

[0381] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-morpholinoisoindole-1-one (I-3-1)

[0382] Dissolve the common intermediate A1 (295 mg, 1.00 mmol) in N,N-dimethylformamide (5 mL), add triethylamine (202 mg, 2.00 mmol) and morpholine (130 mg, 1.50 mmol). Stir the reaction at 50 ° C for 8 hours. Add 20 mL of water to the reaction, extract with ethyl acetate (15 mL*3), combine the organic phases, wash twice with water, wash once with saturated brine, dry and concentrate, eluent 0-30% ethyl acetate in petroleum ether solution, to obtain 308 mg of product I-3-1 as a white solid, yield 84.4%.

[0383] ESI-MS: m / z = 365.0 [M+H] + .

[0384] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-morpholin-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-3)

[0385] The preparation of the target compound I-3 refers to step 3 in the preparation method of the target compound I-1, except that the intermediate I-1-3 is replaced by the intermediate I-3-1, and the rest of the preparation method remains unchanged to obtain the target compound I-3.

[0386] ESI-MS: m / z = 456.0 [M + H] + .

[0387] Example 4, (S)-1-(5-(2-(1-cyclopropylethyl)-7-methoxy-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-4)

[0388]

[0389] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-methoxyisoindol-1-one (I-4-1)

[0390] The common intermediate A2 (295 mg, 1.00 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (276 mg, 2.00 mmol) and iodomethane (170 mg, 1.2 mmol) were added, and the reaction was stirred at 50 ° C for 4 hours. 20 mL of water was added to the reaction, and it was extracted with ethyl acetate (15 mL*3), and the organic phases were combined, washed twice with water, washed once with saturated brine, and then dried and concentrated. The eluent was 0-10% ethyl acetate in petroleum ether to obtain 282 mg of I-4-1 as a light yellow solid with a yield of 91.3%.

[0391] ESI-MS: m / z = 310.0 [M+H] + .

[0392] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-methoxy-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-4)

[0393] The preparation of target compound I-4 refers to step 3 in the preparation method of target compound I-1, except that intermediate I-1-3 is replaced by intermediate I-4-1, and the rest of the preparation method remains unchanged to obtain target compound I-4.

[0394] ESI-MS: m / z = 401.0 [M+H] + .

[0395] Example 5. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxy-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-5)

[0396]

[0397] Step 1: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxy-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-5)

[0398] The preparation of target compound I-5 refers to step 3 in the preparation method of target compound I-1, only intermediate I-1-3 is replaced by common intermediate A3, and the rest of the preparation method remains unchanged to obtain target compound I-5 as a white solid with a yield of 18.2%.

[0399] ESI-MS: m / z = 437.0 [M+H] + .

[0400] 1H NMR (400MHz, DMSO-d6): δ10.74(s,1H),7.63(t,J=74.8Hz,1H),7.52(s,1H),7.19(s,1H),6.56(s,1H),4.59(s,2H),3.59-3.51(m,1H), 2.70(d,J=4.4Hz,3H),2.35(s,3H),1.28(d,J=6.8Hz,3H),1.14-1.08(m,1H),0.60-0.55(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0401] Example 6. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-(2-hydroxypropane-2-yl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-6)

[0402]

[0403] Step 1: Synthesis of (S)-5-chloro-2-(1-cyclopropylethyl)-7-(1-ethoxyvinyl)isoindolin-1-one (I-6-1)

[0404] The common intermediate A4 (1.0 g, 2.77 mmol), tributyl (1-ethoxyvinyl) stannane (1.498 g, 4.15 mmol), bistriphenylphosphine palladium dichloride (194 mg, 0.28 mmol) and triethylamine (700 mg, 6.91 mmol) were dissolved in N, N-dimethylformamide (10 mL), replaced with nitrogen three times, and heated to 100 ° C for overnight reaction. The mixture was cooled to room temperature, quenched with saturated potassium fluoride solution (40 mL), stirred at room temperature for half an hour, and extracted with ethyl acetate three times (20 mL * 3), the organic phases were combined, the organic phases were washed with water three times (20 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 2.1 g (crude) of compound I-6-1 as a yellow solid.

[0405] ESI-MS: m / z = 306.0 [M+H] + .

[0406] Step 2: Synthesis of (S)-7-acetyl-5-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (I-6-2)

[0407] Dissolve I-6-1 (840 mg, 2.77 mmol) in dioxane (10 mL), add 3N aqueous hydrochloric acid solution dropwise, and stir at room temperature for 1 hour. Quench the mixture with water, adjust the pH to 6-7 with saturated sodium bicarbonate, extract with ethyl acetate three times (20 mL*3), combine the organic phases, wash the organic phase with water once (20 mL), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography with 15% ethyl acetate in petroleum ether as the eluent to obtain 836 mg (crude) of I-6-2 as a yellow solid.

[0408] ESI-MS: m / z = 278.0 [M+H] + .

[0409] 1 H NMR (400MHz, DMSO-d6): δ7.83(d,J=2.0Hz,1H),7.46(d,J=2.0Hz,1H),4.60(s,2H),3.58-3.51(m,1H),2.63 (s,3H),1.28(d,J=6.8Hz,3H),1.16-1.07(m,1H),0.60-0.53(m,1H),0.43-0.36(m,2H),0.25-0.19(m,1H).

[0410] Step 3: Synthesis of (S)-5-chloro-2-(1-cyclopropylethyl)-7-(2-hydroxypropan-2-yl)isoindolin-1-one (I-6-3)

[0411] I-6-2 (836 mg, 3.01 mmol) was dissolved in ultra-dry tetrahydrofuran (10 mL), and methylmagnesium bromide (3.2 mL, 4.55 mmol) was added dropwise under an ice bath, and the reaction was continued for 1 hour. The mixture was quenched with water, the pH was adjusted to 6-7 with 1M citric acid, and extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, the organic phases were washed with water once (20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 20% ethyl acetate in petroleum ether solution, and 540 mg of I-6-3 was obtained as a yellow solid, and the total yield of the three-step reaction was 61.1%.

[0412] ESI-MS: m / z = 294.0 [M+H] + .

[0413] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-(2-hydroxypropan-2-yl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-6)

[0414] I-6-3 (250 mg, 0.85 mmol), common intermediate B1 (219 mg, 1.28 mmol), palladium acetate (19 mg, 0.17 mmol), n-butyldi(1-adamantyl)phosphine (61 mg, 0.17 mmol) and cesium fluoride (259 mg, 1.70 mmol) were dissolved in N,N-dimethylformamide (2 mL), nitrogen was blown for 30 seconds, and microwave reaction was performed at 90 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (20 mL * 3), the organic phases were combined, the organic phases were washed with water three times (20 mL * 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography, the eluent was 70% ethyl acetate in petroleum ether, and 5.0 mg of the target compound I-6 was obtained as a yellow solid with a yield of 1.4%.

[0415] ESI-MS: m / z = 429.0 [M+H] + .

[0416] 1 H NMR (400MHz, DMSO-d6): δ10.77(s,1H),7.54(d,J=1.2Hz,1H),7.40(d,J=1. 6Hz,1H),7.20(s,1H),6.62(s,1H),4.65(s,2H),3.67-3.59(m,1H),2.69(d ,J=4.8Hz,3H),2.35(s,3H),1.55(d,J=1.6Hz,6H),1.31(d,J=6.8Hz,3H),1 .18-1.11(m,1H),0.62-0.56(m,1H),0.45-0.38(m,2H),0.28-0.22(m,1H).

[0417] Example 7. Preparation of (S)-1-(5-(7-cyano-2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-7)

[0418]

[0419] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-3-oxoisoindoline-4-carbonitrile (I-7-1)

[0420] The common intermediate A4 (200 mg, 0.55 mmol) and cuprous cyanide (198 mg, 2.21 mmol) were dissolved in dimethyl sulfoxide (5 mL) and subjected to microwave reaction at 120 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (20 mL * 3). The organic phases were combined, washed with water three times (20 mL * 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with a 20% ethyl acetate solution in petroleum ether as the eluent to obtain 137 mg of I-7-1 as a white solid with a yield of 95.1%.

[0421] ESI-MS: m / z = 261.0 [M+H] + .

[0422] 1 H NMR (400MHz, DMSO-d6): δ8.17(d,J=2.0Hz,1H),8.09(d,J=2.0Hz,1H),4.61(s,2H),3.60-3.52(m,1H ),1.29(d,J=6.8Hz,3H),1.17-1.09(m,1H),0.62-0.54(m,1H),0.44-0.36(m,2H),0.27-0.21(m,1H).

[0423] Step 2: Synthesis of (S)-2-(1-cyclopropylethyl)-3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-4-carbonitrile (I-7-2)

[0424] I-7-1 (137 mg, 0.53 mmol), biboric acid pinacol ester (267 mg, 1.05 mmol), tris (dibenzylideneacetone) dipalladium (48 mg, 0.05 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (50 mg, 0.11 mmol) and cesium carbonate (342 mg, 1.05 mmol) were dissolved in toluene (10 mL), replaced with nitrogen three times, and reacted at 100 ° C for 2 hours. After the mixed solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (20 mL * 3), the organic phases were combined, the organic phases were washed once with water (20 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. 200 mg (crude) of I-7-2 was obtained as an oil.

[0425] ESI-MS: m / z = 353.0 [M+H] + .

[0426] Step 3: Synthesis of (S)-1-(5-(7-cyano-2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-7)

[0427] I-7-2 (185 mg, 0.53 mmol), common intermediate B2 (131 mg, 0.53 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (19 mg, 0.03 mmol) and cesium carbonate (342 mg, 1.05 mmol) were dissolved in a mixed solvent of dioxane / water (10 mL / 1 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. After the mixed solution was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, the organic phases were washed once with water (20 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography, the eluent was 4% methanol in dichloromethane, and 5.0 mg of the target compound I-7 was obtained as a white solid. The total yield of step 2 and step 3 was 2.4%.

[0428] ESI-MS: m / z = 396.0 [M+H] + .

[0429] 1 H NMR (400MHz, DMSO-d6): δ10.77(s,1H),7.95(s,2H),6.55(s,1H),4.64(s,2H),3.62-3.55(m,1H),2.70(d,J=4.4Hz, 3H), 2.36 (s, 3H), 1.31 (d, J = 6.8Hz, 3H), 1.16-1.12 (m, 1H), 0.60-0.56 (m, 1H), 0.45-0.39 (m, 2H), 0.28-0.23 (m, 1H).

[0430] Example 8. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-8)

[0431]

[0432] Step 1: Synthesis of (S)-5-chloro-2-(1-cyclopropylethyl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)isoindolin-1-one (I-8-1)

[0433] The common intermediate A4 (200 mg, 0.55 mmol), 2-methyl-3-butyn-2-ol (69 mg, 0.83 mmol), bistriphenylphosphine palladium dichloride (78 mg, 0.11 mmol), cuprous iodide (21 mg, 0.11 mmol) and triethylamine (280 mg, 2.77 mmol) were dissolved in toluene (10 mL), replaced with nitrogen three times, and reacted at 100 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, the organic phases were washed with water once (20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 45% ethyl acetate in petroleum ether solution, and 168 mg of I-8-1 was obtained as an oil with a yield of 95.7%.

[0434] ESI-MS: m / z = 318.0 [M+H] + .

[0435] Step 2: Synthesis of (S)-2-(1-cyclopropylethyl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (I-8-2)

[0436] The preparation of compound I-8-2 can refer to the preparation method of compound I-7-2 in step 2 of Example 7, only replacing intermediate I-7-1 with intermediate I-8-1, and the rest of the preparation method remains unchanged to obtain 230 mg (crude) of compound I-8-2 with a yield of 89.1%.

[0437] ESI-MS: m / z = 410.0 [M + H] + .

[0438] Step 3: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)-3-methylurea (I-8)

[0439] The preparation of the target compound I-8 can refer to the preparation method of the target compound I-7 in step 3 of Example 7, except that the intermediate I-7-2 is replaced by the intermediate I-8-2, and the rest of the preparation method remains unchanged to obtain 13.6 mg of the target compound I-8 as a white solid, with a total yield of 5.6% for the three-step reaction.

[0440] ESI-MS: m / z = 453.0 [M + H] + .

[0441] 1H NMR (400MHz, DMSO-d6): δ10.61(s,1H),7.61(d,J=1.6Hz,1H),7.38(d,J=1.6Hz,1H),6.49(s,1H),5.47(s,1H),4.52(s,2H),3.59-3.53(m,1H),2. 70(d,J=4.8Hz,3H),2.34(s,3H),1.49(s,6H),1.28(d,J=6.8Hz,3H),1.1 2-1.09(m,1H),0.58-0.56(m,1H),0.42-0.35(m,2H),0.25-0.21(s,1H).

[0442] Example 9. Preparation of (S)-1-cyclopropyl-3-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)urea (I-9)

[0443]

[0444] Step 1: Synthesis of 1-cyclopropyl-3-(4-methylthiazol-2-yl)urea (I-9-1)

[0445] Dissolve B1-1 (570 mg, 5.00 mmol) in tetrahydrofuran (10 mL), add triethylamine (1.52 g, 15.00 mmol) dropwise, add cyclopropylamine (342 mg, 6.00 mmol) and N, N'-carbonyldiimidazole (1.22 g, 7.50 mmol) in sequence, and heat to 60 ° C for 6 hours. The mixture is cooled to room temperature and concentrated under reduced pressure, water (20 mL) is added, and extracted with ethyl acetate three times (20 mL*3), the organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography, the eluent is 50% ethyl acetate in petroleum ether solution, and 532 mg of I-9-1 is obtained as a white solid with a yield of 54.0%.

[0446] ESI-MS: m / z = 198.0 [M + H] + .

[0447] Step 2: Synthesis of (S)-1-cyclopropyl-3-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)urea (I-9)

[0448] The preparation of target compound I-9 refers to step 3 in the preparation method of target compound I-1, only replacing common intermediate B1 with intermediate I-9-1 and intermediate I-1-3 with common intermediate A3 to obtain target compound I-9.

[0449] ESI-MS: m / z = 463.0 [M + H] + .

[0450] Example 10. Preparation of (S)-N-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxy-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)pyrrolidine-1-carboxamide (I-10)

[0451]

[0452] Step 1: Synthesis of N-(4-methylthiazol-2-yl)pyrrolidine-1-carboxamide (I-10-1)

[0453] The preparation of compound I-10-1 refers to the synthesis of intermediate I-9-1 in step 1 of Example 9, except that the intermediate cyclopropylamine is replaced by pyrrolidine and the rest of the preparation method remains unchanged to obtain intermediate I-10-1.

[0454] ESI-MS: m / z = 212.0 [M+H] + .

[0455] Step 2: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxy-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)pyrrolidine-1-carboxamide (I-10)

[0456] The preparation of target compound I-10 refers to step 3 in the preparation method of target compound 1, except that common intermediate B1 is replaced by intermediate I-10-1, and intermediate I-1-3 is replaced by common intermediate A3 to obtain target compound I-10.

[0457] ESI-MS: m / z = 477.0 [M+H] + .

[0458] Example 11. Preparation of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)morpholine-4-carboxamide (I-11)

[0459]

[0460] Step 1: Synthesis of phenyl (4-methylthiazol-2-yl)carbamate (I-11-1)

[0461] Dissolve B1-1 (378 mg, 3.32 mmol) in dichloromethane (10 mL), add triethylamine (740 mg, 7.30 mmol), stir the mixture in an ice bath for 5 minutes, add phenyl chloroformate (572 mg, 3.65 mmol), warm to room temperature and stir for 1 hour. Quench with water, extract with dichloromethane three times (20 mL*3), wash the combined organic phase with water once (20 mL), wash with saturated brine once (50 mL), dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure to obtain 315 mg of I-11-1 as a white solid with a yield of 40.6%.

[0462] ESI-MS: m / z = 235.0 [M+H] + .

[0463] Step 2: Synthesis of N-(4-methylthiazol-2-yl)morpholine-4-carboxamide (I-11-2)

[0464] Dissolve I-11-1 (60 mg, 0.26 mmol) in N, N-dimethylformamide (5 mL), add triethylamine (39 mg, 0.384 mmol) and morpholine (33 mg, 0.38 mmol), and heat to 70 ° C for 1 hour. After the mixture is cooled to room temperature, it is quenched with water, extracted with ethyl acetate three times (20 mL * 3), the organic phases are combined, the organic phases are washed with water three times (20 mL * 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to obtain 45 mg of I-11-2 as a yellow solid with a yield of 77.6%.

[0465] ESI-MS:m / z=MS(m / z):228.0[M+H] + .

[0466] Step 3: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)morpholine-4-carboxamide (I-11)

[0467] The preparation of the target compound I-11 refers to step 3 in the preparation method of the target compound I-1, except that the common intermediate B1 is replaced by the intermediate I-11-2, and the intermediate I-1-3 is replaced by the common intermediate A3 to obtain the target compound I-11.

[0468] ESI-MS: m / z = 493.0 [M+H] + .

[0469] 1H NMR (400MHz, DMSO-d6): δ11.29(s,1H),7.63(t,J=74.8Hz,1H),7.53(s,1H),7.20(s,1H),4.59(s,2H),3.60-3.55(m,5H),3.53 -3.50(m,4H),2.37(s,3H),1.28(d,J=6.8Hz,3H),1.15-1.07(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0470] Example 12. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-methylpiperazin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-1)

[0471]

[0472] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(4-methylpiperazin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-1-1)

[0473] The common intermediate A5 (200 mg, 0.74 mmol) was dissolved in N, N-dimethylformamide (2 mL), 4-methylpiperidine (170 mg, 1.48 mmol) and triethylamine (224 mg, 2.21 mmol) were added, and the temperature was raised to 60 ° C for 2 h. After the reaction was completed, water was added to quench, and ethyl acetate was extracted three times (20 mL * 3), and the organic phases were combined. The organic phase was washed with water three times (20 mL * 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the eluent was 1% to 2.5% methanol in dichloromethane to obtain 220 mg of II-1-1 as a yellow oil with a yield of 89.1%.

[0474] ESI-MS: m / z = 335.0 [M+H] + .

[0475] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-(4-methylpiperazin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-1-2)

[0476] II-1-1 (184 mg, 0.55 mmol) was dissolved in 1,4-dioxane (5 mL), and tert-butyl (4-methyl-5-(tributyltinyl)thiazol-2-yl)carbamate (415 mg, 0.82 mmol) and tetrakistriphenylphosphine palladium (63 mg, 0.11 mmol) were added, and N2 was replaced and microwaved at 120°C for 1 h. After the reaction was completed, it was cooled to room temperature, and a 40% potassium fluoride aqueous solution (30 mL) was added to the reaction solution and stirred for 30 min, and extracted with ethyl acetate (30 mL*3), and the organic phase was combined. After concentration, the residue was purified by column chromatography, and the eluent was 1% to 5% methanol in dichloromethane to obtain 60 mg of II-1-2 as a black oil with a yield of 21.3%.

[0477] ESI-MS: m / z = 513.0 [M+H] + .

[0478] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(4-methylpiperazin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one hydrochloride (II-1-3)

[0479] II-1-2 (60 mg, 0.117 mmol) was dissolved in hydrochloric acid-ethyl acetate solution (5 mL, 4 M) and stirred at room temperature for 4 h. After the reaction was completed, the hydrochloric acid and ethyl acetate were removed by concentration to obtain 52 mg of crude II-1-3, which was used directly in the next step.

[0480] ESI-MS: m / z = 413.0 [M+H] + .

[0481] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-methylpiperazin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-1)

[0482] The crude product of II-1-3 obtained in the previous step was dissolved in dichloromethane (2 mL), and methylaminoformyl chloride (22 mg, 0.23 mmol) and triethylamine (35 mg, 0.35 mmol) were added, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by full preparative liquid chromatography to obtain 4 mg of the target product II-1 (formate) as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 6.5%.

[0483] ESI-MS: m / z = 470.0 [M + H] + .

[0484] 1 H NMR (400MHz, DMSO-d6): δ10.64(s,1H),8.19(s,1H),7.16(s,1H),6.54(d ,J=5.0Hz,1H),4.50(s,2H),3.70(s,4H),3.56-3.49(m,1H),2.70(d,J=4. 8Hz,3H),2.52(s,3H),2.49(s,4H),2.24(s,3H),1.24(d,J=6.8Hz,3H),1. 09-1.04(m,1H),0.57-0.54(m,1H),0.41-0.32(m,2H),0.23-0.92(m,1H).

[0485] Example 13. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-2)

[0486]

[0487] Step 1: Synthesis of (S)-4-((6-chloro-2-(1-cyclopropylethyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino)butyric acid (II-2-1)

[0488] The common intermediate A5 (200 mg, 0.74 mmol) was dissolved in N, N-dimethylformamide (10 mL), triethylamine (224 mg, 2.21 mmol) and β-alanine (99 mg, 1.11 mmol) were added, and the temperature was raised to 60 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (20 mL * 3), the organic phases were combined, the organic phases were washed with water three times (20 mL * 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 242 mg of the crude product of II-2-1 as an oil, which was directly used in the next step.

[0489] ESI-MS: m / z = 338.0 [M+H] + .

[0490] Step 2: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(2-oxopyrrolidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-2-2)

[0491] The crude product of II-2-1 obtained in the previous step was dissolved in dichloromethane (10 mL), and oxalyl chloride (94 mg, 0.74 mmol) and a drop of N, N-dimethylformamide were added dropwise under ice bath, and the temperature was maintained for 1 h. The system was quenched with water, extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, the organic phases were washed with water three times (20 mL*3), washed with saturated brine once (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, the eluent was 30% ethyl acetate in petroleum ether solution, and 162 mg of II-2-2 was obtained as a yellow solid. The total yield of step 1 and step 2 was 68.6%.

[0492] ESI-MS: m / z = 320.0 [M + H] + .

[0493] Step 3: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-2-3)

[0494] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced by II-2-2, and the rest of the preparation method remained unchanged to obtain 181 mg of II-2-3 as a black oil with a yield of 55.2%.

[0495] ESI-MS: m / z = 498.0 [M + H] + .

[0496] Step 4: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(2-oxopyrrolidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-2-4)

[0497] Referring to the synthesis of intermediate II-1-3 in step 3 of Example 12, only intermediate II-1-2 is replaced by II-2-3, and the acidic system is replaced by trifluoroacetic acid in dichloromethane solution by hydrochloric acid in ethyl acetate solution. The rest of the preparation method remains unchanged, and the crude product II-2-4 is directly used in the next step.

[0498] ESI-MS: m / z = 398.0 [M+H] + .

[0499] Step 5: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-2)

[0500] Referring to the synthesis of the target compound II-1 in step 4 of Example 12, only the intermediate II-1-3 was replaced by II-2-4, and the rest of the preparation method remained unchanged to obtain 15 mg of the target compound II-2 as a white solid. The total yield of the two-step reaction of step 4 and step 5 was 9.1%.

[0501] ESI-MS: m / z = 455.0 [M + H] + .

[0502] 1 H NMR (400MHz, DMSO-d6): δ10.78(s,1H),7.69(s,1H),6.60(s,1H),4.61(s,2 H),3.95-3.90-3.83(m,2H),3.55-3.48(m,1H),2.70(d,J=4.8Hz,3H),2.55( s,3H),2.47(t,J=8.0Hz,2H),2.14(p,J=7.6Hz,2H),1.26(d,J=6.8Hz,3H), 1.13-1.05(m,1H),0.60-0.53(m,1H),0.43-0.33(m,2H),0.25-0.21(m,1H).

[0503] Example 14. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-methoxypiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-3)

[0504]

[0505] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(4-methoxypiperidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-3-1)

[0506] Referring to the synthesis of intermediate II-1-1 in step 1 of Example 12, only methylpiperazine was replaced by 4-methoxypiperidine, and the rest of the preparation method remained unchanged to obtain 260 mg of II-3-1 as a yellow oily product with a yield of 67.9%.

[0507] ESI-MS: m / z = 350.0 [M + H] + .

[0508] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-(4-methoxypiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-3-2)

[0509] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-3-1, and the rest of the preparation method remained unchanged to obtain 200 mg of II-3-2 as a black oily product with a yield of 50.5%.

[0510] ESI-MS: m / z = 528.0 [M+H] + .

[0511] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(4-methoxypiperidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-3-3)

[0512] Refer to the synthesis of intermediate II-1-3 in step 3 of Example 12, only II-1-2 is replaced by II-3-2, and the rest of the preparation method remains unchanged. The obtained crude product II-3-3 is directly used in the next step.

[0513] ESI-MS: m / z = 428.0 [M+H] + .

[0514] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-methoxypiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-3)

[0515] Referring to the synthesis of the target compound II-1 in step 4 of Example 12, only II-1-3 was replaced by II-3-3, and the rest of the preparation method remained unchanged to obtain 26 mg of the target product II-3 as a white solid. The yield of steps 3 and 4 was 10.9%.

[0516] ESI-MS: m / z = 485.0 [M + H] + .

[0517] 1H NMR (400MHz, DMSO-d6): δ10.57(s,1H),7.14(s,1H),6.46(d,J=5.2Hz,1H),4.49(s,2H),4 .10(d,J=13.2Hz,2H),3.55-3.11(m,1H),3.43-3.38(m,1H),3.28(s,3H),3.25-3.22(m,2H ),2.70(d,J=4.4Hz,3H),2.52(s,3H),1.96(d,J=12.8Hz,2H),1.54-1.50(m,2H),1.24(d, J=6.8Hz,3H),1.09-1.04(m,1H),0.58-0.53(m,1H),0.41-0.32(m,2H),0.24-0.20(m,1H).

[0518] Example 15. Preparation of 1-(5-(2-((S)-1-cyclopropylethyl)-4-((2S,6R)-2,6-dimethylmorpholinyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-4)

[0519]

[0520] Step 1: Synthesis of 6-chloro-2-((S)-1-cyclopropylethyl)-4-((2S,6R)-2,6-dimethylmorpholinyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-4-1)

[0521] Referring to the synthesis of intermediate II-1-1 in step 1 of Example 12, only methylpiperazine was replaced by (2R,6S-2,6)-dimethylmorpholine, and the rest of the preparation method remained unchanged to obtain 300 mg of II-4-1 as a yellow oily product with a yield of 78.3%.

[0522] ESI-MS: m / z = 350.0 [M + H] + .

[0523] Step 2: Synthesis of tert-butyl (5-(2-((S)-1-cyclopropylethyl)-4-((2S,6R)-2,6-dimethylmorpholinyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-4-2)

[0524] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-4-1, and the rest of the preparation method remained unchanged to obtain 200 mg of II-4-2 as a black oil with a yield of 44.2%.

[0525] ESI-MS: m / z = 528.0 [M+H] + .

[0526] Step 3: Synthesis of 6-(2-amino-4-methylthiazol-5-yl)-2-((S)-1-cyclopropylethyl)-4-((2S,6R)-2,6-dimethylmorpholinyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-4-3)

[0527] Refer to the synthesis of intermediate II-1-3 in step 3 of Example 12, only II-1-2 is replaced by II-4-2, and the rest of the preparation method remains unchanged. The obtained crude product II-4-3 is directly used in the next step.

[0528] ESI-MS: m / z = 428.0 [M+H] + .

[0529] Step 4: Synthesis of 1-(5-(2-((S)-1-cyclopropylethyl)-4-((2S,6R)-2,6-dimethylmorpholinyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-4)

[0530] Referring to the synthesis of the target compound II-1 in step 4 of Example 12, only II-1-3 was replaced by II-4-3, and the rest of the preparation method remained unchanged to obtain 20 mg of the target product II-4 as a white solid. The total yield of the two-step reaction of steps 3 and 4 was 7.3%.

[0531] ESI-MS: m / z = 485.0 [M + H] + .

[0532] 1H NMR (400MHz, DMSO-d6): δ10.61(s,1H),7.16(s,1H),6.48(s,1H),4.50(s,2H),4.48 -4.41(m,2H),3.73-3.66(m,2H),3.56-3.52(m,1H),2.70(d,J=4.4Hz,3H),2.58-2.54(m,2H),2.52(s,3H),1.24(d,J=6. 8Hz,3H),1.14(dd,J1=6.0Hz,J2=1.6Hz,6H),1.09-1.06(m,1H),0.58-0.53(m,1H),0.42-0.32(m,2H),0.25-0.20(m,1H).

[0533] Example 16. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxo-7-azaspiro[3.5]non-7-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-5)

[0534]

[0535] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(2-oxa-7-azaspiro[3.5]non-7-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-5-1)

[0536] Referring to the synthesis of intermediate II-1-1 in step 1 of Example 12, only methylpiperazine was replaced by 2-oxa-7-azaspiro[3.5]nonane hemioxalate, and the rest of the preparation method remained unchanged to obtain 240 mg of II-5-1 as a yellow oil with a yield of 63.3%.

[0537] ESI-MS: m / z = 362.0 [M+H] + .

[0538] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxo-7-azaspiro[3.5]non-7-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-5-2)

[0539] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate 11-1-1 was replaced with II-5-1, and the rest of the preparation method remained unchanged to obtain 170 mg of II-5-2 as a black oil with a yield of 47.9%.

[0540] ESI-MS: m / z = 540.0 [M + H] + .

[0541] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(2-oxo-7-azaspiro[3.5]non-7-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-5-3)

[0542] Refer to the synthesis of intermediate II-1-3 in step 3 of Example 12, except that II-1-2 is replaced by II-5-2, and the acidic system is changed from ethyl acetate hydrochloride to dichloromethane trifluoroacetate. The rest of the preparation method remains unchanged, and the obtained crude product II-5-3 is directly used in the next step.

[0543] ESI-MS: m / z = 440.0 [M + H] + .

[0544] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxo-7-azaspiro[3.5]non-7-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-5)

[0545] Referring to the synthesis of the target compound II-1 in step 4 of Example 12, only II-1-3 was replaced by II-5-3, and the rest of the preparation method remained unchanged to obtain 8 mg of the target product II-5 as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 5.1%.

[0546] ESI-MS: m / z = 497.0 [M+H] + .

[0547] 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.14(s,1H),6.49(d,J=4.8Hz,1H), 4.49(s,2H),4.36(s,4H),3.58(t,J=5.2Hz,4H),3.54-3.51(m,1H),2.70(d ,J=4.8Hz,3H),2.52(s,3H),1.91(t,J=5.6Hz,4H),1.24(d,J=6.8Hz,3H),1 .10-1.04(m,1H),0.58-0.53(m,1H),0.42-0.33(m,2H),0.24-0.20(m,1H).

[0548] Example 17, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-fluoro-4-methylpiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-6)

[0549]

[0550] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(4-fluoro-4-methylpiperidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-6-1)

[0551] Referring to the synthesis of intermediate II-1-1 in step 1 of Example 12, only methylpiperazine was replaced by 4-fluoro-4-methylpiperidine, and the rest of the preparation method remained unchanged to obtain 203 mg of II-6-1 as a yellow oil with a yield of 78.2%.

[0552] ESI-MS: m / z = 352.0 [M+H] + .

[0553] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-(4-fluoro-4-methylpiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-6-2)

[0554] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-6-1, and the rest of the preparation method remained unchanged to obtain 220 mg of II-6-2 as a black oil with a yield of 73.1%.

[0555] ESI-MS: m / z = 530.0 [M + H] + .

[0556] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(4-fluoro-4-methylpiperidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one hydrochloride (II-6-3)

[0557] Refer to the synthesis of intermediate II-1-3 in step 3 of Example 12, only II-1-2 is replaced by II-6-2, and the rest of the preparation method remains unchanged. The obtained crude product II-6-3 is directly used in the next step.

[0558] ESI-MS: m / z = 430.0 [M + H] +.

[0559] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-fluoro-4-methylpiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-6)

[0560] Referring to the synthesis of the target compound II-1 in step 4 of Example 12, only II-1-3 was replaced by II-6-3, and the rest of the preparation method remained unchanged to obtain 43 mg of the target product II-6 as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 21.7%.

[0561] ESI-MS: m / z = 487.0 [M+H] + .

[0562] 1 H NMR (400MHz, DMSO-d6): δ10.63(s,1H),7.16(s,1H),6.50(d,J=4.8Hz,1H),4.50( s,2H),4.20(d,J=13.2Hz,2H),3.55-3.50(m,1H),3.26-3.23(m,2H),2.70(d,J=4. 8Hz,3H),2.52(s,3H),1.85-1.77(m,4H),1.40(d,J=22.0Hz,3H),1.24(d,J=6.8Hz ,3H),1.11-1.06(m,1H),0.57-0.53(m,1H),0.41-0.33(m,2H),0.25-0.21(m,1H).

[0563] Example 18, (S)-1-(5-(2-(1-cyclopropylethyl)-4-(6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-7)

[0564]

[0565] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (II-7-1)

[0566] Referring to the synthesis of intermediate II-1-1 in step 1 of Example 12, only methylpiperazine was replaced by 4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazine dihydrochloride, and the rest of the preparation method remained unchanged to obtain 270 mg of II-7-1 as a yellow solid with a yield of 51.5%.

[0567] ESI-MS: m / z = 358.0 [M+H] + .

[0568] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-(6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-7-2)

[0569] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-7-1, and the rest of the preparation method remained unchanged to obtain 180 mg of II-7-2 as a black oil with a yield of 48.1%.

[0570] ESI-MS: m / z = 536.0 [M+H] + .

[0571] Step 3: Synthesis of ((S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one hydrochloride (II-7-3)

[0572] Refer to the synthesis of intermediate II-1-3 in step 3 of Example 12, only II-1-2 is replaced by II-7-2, and the rest of the preparation method remains unchanged. The obtained crude product II-7-3 is directly used in the next step.

[0573] ESI-MS: m / z = 436.0 [M + H] + .

[0574] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-7)

[0575] Referring to the synthesis of the target compound II-7 in step 4 of Example 12, only II-1-3 was replaced by II-7-3, and the rest of the preparation method remained unchanged to obtain 20 mg of the target product II-7 as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 18.8%.

[0576] ESI-MS: m / z = 493.0 [M+H] + .

[0577] 1 H NMR (400MHz, DMSO-d6): δ10.65(s,1H),7.43(d,J=2.0Hz,1H),7.27(s,1H),6.48(d,J =4.8Hz,1H),6.17(d,J=2.0Hz,1H),4.89(s,2H),4.55(s,2H),4.32-4.29(m,2H),4.2 0-4.17(m,2H),3.59-3.55(m,1H),2.71(d,J=4.4Hz,3H),2.54(s,3H),1.26(d,J=6.8 Hz,3H),1.10-1.08(m,1H),0.58-0.55(m,1H),0.42-0.35(m,2H),0.25-0.21(m,1H).

[0578] Example 19. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-8)

[0579]

[0580] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-8-1)

[0581] Sodium hydride (66 mg, 2.78 mmol) was added to 2,2-difluoroethane-1-ol (136 mg, 1.66 mmol), stirred at room temperature for 15 minutes, and then a dioxane solution (10 mL) of the common intermediate A5 (300 mg, 1.11 mmol) was added dropwise, and the system was heated to 60°C for 2 hours. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, washed with water three times (20 mL*3), washed with saturated brine once (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, the eluent was 30% ethyl acetate in petroleum ether, and 245 mg of II-8-1 was obtained as a yellow solid with a yield of 69.9%.

[0582] ESI-MS: m / z = 317.0 [M+H] + .

[0583] 1 H NMR (400MHz, DMSO-d6): δ7.47 (s, 1H), 6.55 (tt, J1 = 54.4Hz, J2 = 3.6Hz, 1H), 4.73 (td, J1 = 14 .8Hz,J2=3.6Hz,2H),4.57(s,2H),3.52-3.45(m,1H),1.25(d,J=6.8Hz,3H),1.13-1.04(dm 1H),0.60-0.52(m,1H),0.42-0.33(m,2H),0.23-0.17(m,1H).

[0584] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-8-2)

[0585] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-8-1, and the rest of the preparation method remained unchanged to obtain 208 mg of II-8-2 with a yield of 54.7%.

[0586] ESI-MS: m / z = 495.0 [M + H] + .

[0587] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-8-3)

[0588] Dissolve II-8-2 (208 mg, 0.42 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL) dropwise, and stir at room temperature overnight. Quench the mixture with water, adjust the pH to 6-7 with saturated sodium bicarbonate, extract with dichloromethane three times (20 mL*3), combine the organic phases, wash the organic phase with water once (20 mL), wash it with saturated brine once (50 mL), dry it with anhydrous sodium sulfate, and filter it. Concentrate the filtrate under reduced pressure to obtain the crude product of II-8-3, which is used directly in the next step.

[0589] ESI-MS: m / z = 395.0 [M+H] + .

[0590] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-8)

[0591] The crude product II-8-3 obtained in the previous step was dissolved in dichloromethane (10mL), triethylamine (58mg, 0.57mmol) was added and stirred for 5 minutes, methylcarbamoyl chloride (58mg, 0.570mmol) was added dropwise in an ice bath, and the mixture was reacted at room temperature for 3 hours. The mixture was quenched with water, extracted with dichloromethane three times (20mL*3), the organic phases were combined, the organic phases were washed once with water (20mL), washed once with saturated brine (50mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography, the developing solvent was 1-5% methanol in dichloromethane solution, and 45mg of the target product II-8 was obtained as a yellow solid. The total yield of the two-step reaction of step 3 and step 4 was 23.8%.

[0592] ESI-MS: m / z = 452.0 [M + H] + .

[0593] 1 H NMR (400MHz, DMSO-d6): δ10.74(s,1H),7.44(s,1H),6.59(tt,J1=54.4Hz,J2 =3.6Hz,1H),6.52(s,1H),4.75(td,J1=14.8Hz,J2=3.6Hz,2H),4.58(s,2H), 3.54-3.47(m,1H),2.70(d,J=4.4Hz,3H),2.55(s,3H),1.25(d,J=6.8Hz,3H) ,1.13-1.05(m,1H),0.58-0.53(m,1H),0.43-0.34(m,2H),0.24-0.20(m,1H).

[0594] Example 20, Preparation of 1-(5-(2-((S)-1-cyclopropylethyl)-3-oxo-4-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-9)

[0595]

[0596] Step 1: Synthesis of 6-chloro-2-((S)-1-cyclopropylethyl)-4-((tetrahydrofuran-3-yl)oxy)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-9-1)

[0597] Referring to the synthesis of intermediate II-8-1 in step 1 of Example 19, only 2,2-difluoroethane-1-ol was replaced with tetrahydrofuran-3-ol, and the rest of the preparation method remained unchanged to obtain 155 mg of II-9-1 as a yellow solid with a yield of 43.4%.

[0598] ESI-MS: m / z = 323.0 [M+H] + .

[0599] Step 2: Synthesis of tert-butyl (5-(2-((S)-1-cyclopropylethyl)-3-oxo-4-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-9-2)

[0600] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-9-1, and the rest of the preparation method remained unchanged to obtain 221 mg of II-9-2 as a yellow solid with a yield of 91.9%.

[0601] ESI-MS: m / z = 501.0 [M+H] + .

[0602] Step 3: Synthesis of 6-(2-amino-4-methylthiazol-5-yl)-2-((S)-1-cyclopropylethyl)-4-((tetrahydrofuran-3-yl)oxy)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-9-3)

[0603] Refer to the synthesis of intermediate II-8-3 in step 3 of Example 19, only II-8-2 is replaced by II-9-2, and the rest of the preparation method remains unchanged to obtain the crude product of II-9-3, which is directly used in the next step.

[0604] ESI-MS: m / z = 401.0 [M+H]+ .

[0605] Step 4: Synthesis of 1-(5-(2-((S)-1-cyclopropylethyl)-3-oxo-4-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-9)

[0606] Referring to the synthesis of the target compound II-8 in step 4 of Example 19, only II-8-3 was replaced by II-9-3, and the rest of the preparation method remained unchanged to obtain 45 mg of the target product II-9 as a yellow solid. The total yield of the two-step reaction of step 3 and step 4 was 22.4%.

[0607] ESI-MS: m / z = 458.0 [M + H] + .

[0608] 1 H NMR (400MHz, DMSO-d6): δ10.69(s,1H),7.38(s,1H),6.50(s,1H),5.59-5.55(m,1 H),4.54(s,2H),4.05-4.01(m,1H),3.91-3.75(m,3H),3.52-3.45(m,1H),2.70(d, J=4.8Hz,3H),2.54(s,3H),2.37-2.28(m,1H),2.08-2.03(m,1H),1.25(d,J=6.8Hz ,3H),1.12-1.04(m,1H),0.58-0.53(m,1H),0.43-0.32(m,2H),0.24-0.20(m,1H).

[0609] Example 21. Preparation of (S)-1-(5-(4-cyclopropyloxy-2-(1-cyclopropylethyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-10)

[0610]

[0611] Step 1: Synthesis of (S)-6-chloro-4-cyclopropyloxy-2-isopropylethyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-10-1)

[0612] Referring to the synthesis of intermediate II-8-1 in step 1 of Example 19, only 2,2-difluoroethane-1-ol was replaced with cyclopropanol, and the rest of the preparation method remained unchanged to obtain 285 mg of II-10-1 as a yellow solid with a yield of 88.0%.

[0613] ESI-MS: m / z = 293.0 [M+H] + .

[0614] Step 2: Synthesis of tert-butyl (S)-(5-(4-cyclopropyloxy-2-(1-cyclopropylethyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-10-2)

[0615] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-10-1, and the rest of the preparation method remained unchanged to obtain 300 mg of II-10-2 as an oil with a yield of 65.8%.

[0616] ESI-MS: m / z = 471.0 [M+H] + .

[0617] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-4-cyclopropyloxy-2-isopropylethyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-10-3)

[0618] Refer to the synthesis of intermediate II-8-3 in step 3 of Example 19, only II-8-2 is replaced by II-10-2, and the rest of the preparation method remains unchanged to obtain the crude product of II-10-3, which is directly used in the next step.

[0619] ESI-MS: m / z = 371.0 [M+H] + .

[0620] Step 4: Synthesis of (S)-1-(5-(4-cyclopropyloxy-2-(1-cyclopropylethyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-10)

[0621] Referring to the synthesis of the target compound II-8 in step 4 of Example 19, only II-8-3 was replaced with II-10-3, and the rest of the preparation method remained unchanged to obtain 19 mg of the target product II-10 as a yellow solid. The total yield of the two-step reaction of step 3 and step 4 was 7.0%.

[0622] ESI-MS: m / z = 428.0 [M+H] + .

[0623] 1H NMR (400MHz, DMSO-d6): δ10.68(s,1H),7.36(s,1H),6.48(s,1H),4.54(s,2H),4.38-4.34(m,1H),3.51-3.44(m,1H),2.70(d,J=4.8Hz,3H),2.60 (s,3H),1.23(d,J=6.8Hz,3H),1.11-1.04(m,1H),0.85-0.78(m,2H),0.7 6-0.70(m,2H),0.58-0.52(m,1H),0.42-0.32(m,2H),0.22-0.17(m,1H).

[0624] Example 22, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-ethoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-11)

[0625]

[0626] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-ethoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-11-1)

[0627] Referring to the synthesis of intermediate II-8-1 in step 1 of Example 19, only 2,2-difluoroethane-1-ol was replaced with ethanol, and the rest of the preparation method remained unchanged to obtain 160 mg of II-11-1 as a yellow solid with a yield of 77.3%.

[0628] ESI-MS: m / z = 281.0 [M+H] + .

[0629] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-ethoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-11-2)

[0630] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-11-1, and the rest of the preparation method remained unchanged to obtain 200 mg of II-11-2 as a yellow solid with a yield of 76.5%.

[0631] ESI-MS: m / z = 459.0 [M+H] + .

[0632] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-ethoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-11-3)

[0633] Refer to the synthesis of intermediate II-8-3 in step 3 of Example 19, only replace II-8-2 with II-11-2, and keep the rest of the preparation method unchanged to obtain the crude product of II-11-3, which is directly used in the next step.

[0634] ESI-MS: m / z = 359.0 [M+H] + .

[0635] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-ethoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-11)

[0636] Referring to the synthesis of the target compound II-8 in step 4 of Example 19, only II-8-3 was replaced with II-11-3, and the rest of the preparation method remained unchanged to obtain 23 mg of the target product II-11 as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 12.4%.

[0637] ESI-MS: m / z = 416.0 [M + H] + .

[0638] 1 H NMR (400MHz, DMSO-d6): δ10.66(s,1H),7.35(s,1H),6.49(s,1H),4.54(s,2H),4.50(q,J=7.2Hz,2H),3.53-3.49(m,1H),2.71(d,J=4.8Hz, 3H),2.56(s,3H),1.40(t,J=6.8Hz,3H),1.26(d,J=6.8Hz,3H),1.11-1.08(m,1H),0.59-0.54(m,1H),0.42-0.35(m,2H),0.24-0.19(m,1H).

[0639] Example 23. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-isopropoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-12)

[0640]

[0641] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-isopropoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-12-1)

[0642] Referring to the synthesis of intermediate II-8-1 in step 1 of Example 19, only 2,2-difluoroethane-1-ol was replaced with isopropanol, and the rest of the preparation method remained unchanged to obtain 151 mg of II-12-1 with a yield of 27.8%.

[0643] ESI-MS: m / z = 295.0 [M+H] + .

[0644] Step 2: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-4-isopropoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (II-12-2)

[0645] Referring to the synthesis of intermediate II-1-2 in step 2 of Example 12, only intermediate II-1-1 was replaced with II-12-1, and the rest of the preparation method remained unchanged to obtain 180 mg of II-12-2 with a yield of 74.5%.

[0646] ESI-MS: m / z = 473.0 [M+H] + .

[0647] Step 3: Synthesis of (S)-6-(2-amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-4-isopropoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-12-3)

[0648] Refer to the synthesis of intermediate II-8-3 in step 3 of Example 19, only II-8-2 is replaced by II-12-2, and the rest of the preparation method remains unchanged to obtain the crude product of II-I2-3, which is directly used in the next step.

[0649] ESI-MS: m / z = 373.0 [M+H] + .

[0650] Step 4: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-isopropoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-12)

[0651] Referring to the synthesis of the target compound II-8 in step 4 of Example 19, only II-8-3 was replaced with II-12-3, and the rest of the preparation method remained unchanged to obtain 19 mg of the target compound II-12 as a yellow solid. The total yield of the two-step reaction of step 3 and step 4 was 11.7%.

[0652] ESI-MS: m / z = 430.0 [M + H] + .

[0653] 1 H NMR (400MHz, DMSO-d6): δ10.66(s,1H),7.33(s,1H),6.48(s,1H),5.43-5.37(m,1H),4.52(s,2H),3.52-3.44(m,1H),2.70(d,J=4.8Hz,3H),2.5 4(s,3H),1.37(dd,J1=6.4Hz,J1=3.2Hz,6H),1.25(d,J=6.8Hz,3H),1.1 -1.05(m,1H),0.58-0.52(m,1H),0.41-0.33(m,2H),0.23-0.19(m,1H).

[0654] Example 24. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(dimethylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-13)

[0655]

[0656] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(dimethylamino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-13-1)

[0657] The common intermediate A5 (200 mg, 0.74 mmol) was dissolved in N, N-dimethylformamide (10 mL), triethylamine (187 mg, 1.84 mmol) and dimethylamine hydrochloride (72 mg, 0.89 mmol) were added, and the temperature was raised to 60 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (20 mL * 3), the organic phases were combined, the organic phases were washed with water three times (20 mL * 3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 18% ethyl acetate in petroleum ether solution, and 165 mg of II-13-1 was obtained as a yellow solid with a yield of 80.1%.

[0658] ESI-MS: m / z = 280.0 [M + H] + .

[0659] 1 H NMR (600MHz, DMSO-d6): δ6.91(s,1H),4.44(s,2H),3.53-3.48(m,1H),3.16(s,6H),1.22(d ,J=6.8Hz,3H),1.08-1.03(m,1H),0.56-0.52(m,1H),0.40-0.31(m,2H),0.23-0.19(m,1H).

[0660] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(dimethylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-13)

[0661] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-13-1, and the rest of the preparation method remained unchanged to obtain 18.4 mg of the target compound II-13 as a yellow solid with a yield of 7.76%.

[0662] ESI-MS: m / z = 415.0 [M + H] + .

[0663] 1 H NMR (400MHz, DMSO-d6): δ10.54(s,1H),7.07(s,1H),6.45(s,1H),4.48(s,2H),3.57-3.50(m,1H),3.18(s,6H),2.70(d,J=4 .8Hz,3H),2.53(s,3H),1.24(d,J=6.8Hz,3H),1.10-1.04(m,1H),0.58-0.52(m,1H),0.41-0.32(m,2H),0.25-0.21(m,1H).

[0664] Example 25. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-14)

[0665]

[0666] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-methoxy-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-14-1)

[0667] The common intermediate A5 (300 mg, 1.11 mmol) was dissolved in methanol (10 mL), sodium methoxide (90 mg, 1.66 mmol) was added, and the temperature was raised to 60 ° C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water and extracted with ethyl acetate three times (20 mL*3). The organic phases were combined, washed with water once (20 mL), washed with saturated brine once (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the eluent was 25% ethyl acetate in petroleum ether to obtain 120 mg of II-14-1 as a yellow solid with a yield of 40.6%.

[0668] ESI-MS: m / z = 267.0 [M+H] + .

[0669] 1 H NMR (400MHz, DMSO-d6): δ7.36(s,1H),4.53(s,2H),3.95(s,3H),3.53-3.46(m,1H),1.24(d ,J=6.8Hz,3H),1.12-1.03(m,1H),0.57-0.51(m,1H),0.41-0.33(m,2H),0.22-0.18(m,1H).

[0670] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-methoxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-14)

[0671] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-14-1, and the rest of the preparation method remained unchanged to obtain 18.2 mg of the target compound II-14 as a white solid, with a yield of 9.29%.

[0672] ESI-MS: m / z = 402.0 [M + H] + .

[0673] 1H NMR (400MHz, DMSO-d6): δ10.68(s,1H),7.35(s,1H),6.49(d,J=5.2Hz,1H),4.55(s,2H),3.97(s,3H),3.55-3.48(m,1H),2.70(d ,J=4.8Hz,3H),2.57(s,3H),1.25(d,J=6.8Hz,3H),1.12-1.04(m,1H),0.58-0.52(m,1H),0.42-0.33(m,2H),0.23-0.17(m,1H).

[0674] Example 26, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(3,3-difluoropyrrolidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-15)

[0675]

[0676] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(3,3-difluoropyrrolidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-15-1)

[0677] Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 3,3-difluoropyrrolidine hydrochloride, and the rest of the preparation method remained unchanged to obtain 211 mg of II-15-1 as a yellow solid with a yield of 83.7%.

[0678] ESI-MS: m / z = 342.0 [M+H] + .

[0679] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(3,3-difluoropyrrolidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-15)

[0680] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-15-1, and the rest of the preparation method remained unchanged to obtain 24 mg of the target compound II-15 as a white solid with a yield of 10.3%.

[0681] ESI-MS: m / z = 477.0 [M+H] + .

[0682] 1 H NMR (400MHz, DMSO-d6): δ10.60(s,1H),7.14(s,1H),6.47(s,1H),4.51(s,2H),4.27 -4.17(m,2H),3.97-3.92(m,2H),3.57-3.50(m,1H),2.70(d,J=4.8Hz,3H),2.53(s,3H),2.47-2.43(m, 2H),1.25(d,J=6.8Hz,3H),1.12-1.03(m,1H),0.58-0.53(m,1H),0.42-0.33(m,2H),0.25-0.21(m,1H).

[0683] Example 27, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4,4-difluoropiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-16)

[0684]

[0685] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(4,4-difluoropiperidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-16-1)

[0686] Referring to the synthesis of target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 4,4-difluoropiperidine, and the rest of the preparation method remained unchanged to obtain 250 mg of II-16-1 as a yellow oil with a yield of 64.1%.

[0687] ESI-MS: m / z = 356.0 [M+H] + .

[0688] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4,4-difluoropiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-16)

[0689] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-16-1, and the rest of the preparation method remained unchanged to obtain 10 mg of the target compound II-16 as a yellow solid with a yield of 4.5%.

[0690] ESI-MS: m / z = 491.0 [M+H] +.

[0691] Example 28, Preparation of 1-(5-(2-((S)-1-cyclopropylethyl)-4-((R)-3-methylmorpholinyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-17)

[0692]

[0693] Step 1: Synthesis of 6-chloro-2-((S)-1-cyclopropylethyl)-4-((R)-3-methylmorpholinyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-17-1)

[0694] Referring to the synthesis of target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with (R)-3-methylmorpholine, and the rest of the preparation method remained unchanged to obtain 300 mg of II-17-1 as a yellow oil with a yield of 81.5%.

[0695] ESI-MS: m / z = 336.0 [M+H] + .

[0696] Step 2: Synthesis of 1-(5-(2-((S)-1-cyclopropylethyl)-4-((R)-3-methylmorpholinyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-17)

[0697] Referring to the synthesis of the target compound II-17 in step 4 of Example 6, only I-6-3 was replaced with II-17-1, and the rest of the preparation method remained unchanged to obtain 2.2 mg of the target compound II-17 as a white solid with a yield of 1.0%.

[0698] ESI-MS: m / z = 471.0 [M+H] + .

[0699] 1H NMR (400MHz, DMSO-d6): δ10.63(s,1H),7.16(s,1H),6.52(d,J=5.2Hz,1H),4.77(d ,J=7.2Hz,1H),4.51(s,2H),4.09-4.06(m,1H),3.92(d,J=10.8Hz,1H),3.72-3.49 (m,5H),2.69(d,J=4.8Hz,3H),2.52(s,3H),1.25(d,J=6.4Hz,3H),1.19(d,J=6.4H z,3H),1.09-1.05(m,1H),0.58-0.52(m,1H),0.40-0.32(m,2H),0.3-0.19(m,1H).

[0700] Example 29, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-18)

[0701]

[0702] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(pyrrolidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-18-1)

[0703] Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with tetrahydropyrrole, and the rest of the preparation method remained unchanged to obtain 250 mg of II-18-1 as a light green solid with a yield of 88.7%.

[0704] ESI-MS: m / z = 306.0 [M+H] + .

[0705] 1 H NMR (400MHz, DMSO-d6): δ6.82(s,1H),4.42(s,2H),3.67(d,J=2.4Hz,4H),3.53-3.46(m,1H),1.87-1.82( m,4H),1.22(d,J=6.8Hz,3H),1.09-1.00(m,1H),0.57-0.51(m,1H),0.41-0.30(m,2H),0.23-0.17(m,1H).

[0706] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(pyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-18)

[0707] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-18-1, and the rest of the preparation method remained unchanged to obtain 24 mg of the target compound II-18 as a yellow solid with a yield of 16.7%.

[0708] ESI-MS: m / z = 441.0 [M+H] + .

[0709] 1 H NMR (400MHz, DMSO-d6): δ10.58(s,1H),6.98(s,1H),6.49(d,J=5.2Hz,1H),4.46(s,2H),3.75-3.68(m,4H),3.56-3.48(m,1H),2.69(d,J=4. 4Hz,3H),2.52(s,3H),1.90-1.84(m,4H),1.23(d,J=6.8Hz,3H),1.09- 1.02(m,1H),0.58-0.52(m,1H),0.41-0.31(m,2H),0.24-0.19(m,1H).

[0710] Example 30, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(diethylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-19)

[0711]

[0712] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(diethylamino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-19-1)

[0713] Referring to the synthesis of target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with diethylamine hydrochloride, and the rest of the preparation method remained unchanged to obtain 150 mg of II-19-1 as an oil with a yield of 66.0%.

[0714] ESI-MS: m / z = 308.0 [M+H] + .

[0715] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(diethylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-19)

[0716] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-19-1, and the rest of the preparation method remained unchanged to obtain 24 mg of the target compound II-19 as a yellow solid with a yield of 16.7%.

[0717] ESI-MS: m / z = 443.0 [M+H] + .

[0718] 1 H NMR (400MHz, DMSO-d6): δ10.57(s,1H),7.03(s,1H),6.49(d,J=4.8Hz,1H),4.45(s,2H),3.78-3.68(m,4H),3.58-3.50(m,1H),2.70(d, J=4.8Hz,3H),2.51(s,3H),1.23(d,J=6.8Hz,3H),1.17(t,J=6.8Hz,6H),1.09-1.03(m,1H),0.59-0.52(m,1H),0.42-0.31(m,2H),0.24 -0.19(m,1H).

[0719] Example 31. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-((2-methoxyethyl)(methyl)amino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-20)

[0720]

[0721] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-((2-methoxyethyl)(methyl)amino)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-20-1)

[0722] Referring to the synthesis of target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 2-methoxy-N-methylethane-1-amine, and the rest of the preparation method remained unchanged to obtain 120 mg of II-20-1 with a yield of 50.2%.

[0723] ESI-MS: m / z = 324.0 [M+H] + .

[0724] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-((2-methoxyethyl)(methyl)amino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-20)

[0725] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-20-1, and the rest of the preparation method remained unchanged to obtain 5.8 mg of the target compound II-20 as a yellow solid with a yield of 1.6%.

[0726] ESI-MS: m / z = 459.0 [M+H] + .

[0727] 1 H NMR (400MHz, DMSO-d6): δ10.58(s,1H),7.05(s,1H),6.48(d,J=4.4Hz,1H),4. 47(s,2H),3.97-3.93(m,2H),3.60(t,J=5.6Hz,2H),3.54-3.50(m,1H),3.22( s,3H),3.20(s,3H),2.70(d,J=4.8Hz,3H),2.52(s,3H),1.23(d,J=6.8Hz,3H) ,1.09-1.03(m,1H),0.58-0.52(m,1H),0.42-0.32(m,2H),0.24-0.20(m,1H).

[0728] Example 32, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-21)

[0729]

[0730] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(8-oxa-2-azaspiro[4.5]decane-2-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-21-1)

[0731] Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 8-oxa-2-azaspiro[4.5]decane, and the rest of the preparation method remained unchanged to obtain 260 mg of II-21-1 with a yield of 93.7%.

[0732] ESI-MS: m / z = 376.0 [M+H] + .

[0733] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-21)

[0734] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-21-1, and the rest of the preparation method remained unchanged to obtain 3.6 mg of the target compound II-21 as a white solid with a yield of 1.3%.

[0735] ESI-MS: m / z = 511.0 [M+H] + .

[0736] 1 H NMR (400MHz, DMSO-d6): δ10.59(s,1H),6.99(s,1H),6.51(s,1H),4.46(s,2H) ,3.81-3.72(m,2H),3.69(d,J=7.6Hz,1H),3.65-3.50(m,6H),2.70(d,J=4.4Hz ,3H),2.52(s,3H),1.86-1.82(m,2H),1.54-1.45(m,4H),1.23(d,J=6.8Hz,3H ),1.09-1.02(m,1H),0.58-0.52(m,1H),0.41-0.32(m,2H),0.25-0.20(m,1H).

[0737] Example 33, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-(oxetane-3-yl)piperazine-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-22)

[0738]

[0739] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(4-(oxetane-3-yl)piperazin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-22-1)

[0740] Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 1-(3-oxetanyl)piperazine, and the rest of the preparation method remained unchanged to obtain 220 mg of II-22-1 as a yellow solid with a yield of 79.1%.

[0741] ESI-MS: m / z = 377.0 [M+H] + .

[0742] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-(oxetan-3-yl)piperazin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-22)

[0743] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-22-1, and the rest of the preparation method remained unchanged to obtain 20 mg of the target compound II-22 as a white solid with a yield of 7.0%.

[0744] ESI-MS: m / z = 512.0 [M+H] + .

[0745] 1 H NMR (400MHz, DMSO-d6): δ10.57(s,1H),7.16(s,1H),6.48(s,1H),4.57(t,J=6.4Hz ,2H),4.50(s,2H),4.48-4.47(m,2H),3.71(s,4H),3.54-3.50(m,1H),3.47-3.42( m,1H),2.69(d,J=4.4Hz,3H),2.52(s,3H),2.41(d,J=5.2Hz,4H),1.24(d,J=6.8Hz ,3H),1.09-1.04(m,1H),0.57-0.52(m,1H),0.40-0.32(m,2H),0.23-0.19(m,1H).

[0746] Example 34. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-hydroxy-4-methylpiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-23)

[0747]

[0748] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(4-hydroxy-4-methylpiperidin-1-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-23-1)

[0749] Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 4-methyl-4-hydroxypiperidine, and the rest of the preparation method remained unchanged to obtain 203 mg of II-23-1 as a yellow solid with a yield of 78.7%.

[0750] ESI-MS: m / z = 350.0 [M + H] + .

[0751] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-(4-hydroxy-4-methylpiperidin-1-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-23)

[0752] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-23-1, and the rest of the preparation method remained unchanged to obtain 20 mg of the target compound II-23 as a white solid with a yield of 8.5%.

[0753] ESI-MS: m / z = 485.0 [M + H] + .

[0754] 1H NMR (400MHz, DMSO-d6): δ10.43(s,1H),7.09(s,1H),6.88(s,1H),4.47(s,2H), 4.31(s,1H),3.98-3.94(m,2H),3.54-3.50(m,1H),3.44-3.33(m,2H),2.70(d, J=4.4Hz,3H),2.52(s,3H),1.60-1.53(m,4H),1.24(d,J=6.8Hz,3H),1.16(s,3 H),1.09-1.04(m,1H),0.57-0.54(m,1H),0.41-0.32(m,2H),0.23-0.20(m,1H).

[0755] Example 35, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxo-6-azaspiro[3.3]heptane-6-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-24)

[0756]

[0757] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (II-24-1)

[0758] Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced with 2-oxa-6-azaspiro[3.3]heptane, and the rest of the preparation method remained unchanged to obtain 400 mg of II-24-1 as a yellow oil with a yield of 64.9%.

[0759] ESI-MS: m / z = 334.0 [M+H] + .

[0760] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(2-oxo-6-azaspiro[3.3]heptane-6-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-24)

[0761] Referring to the synthesis of the target compound I-6 in step 4 of Example 6, only I-6-3 was replaced with II-24-1, and the rest of the preparation method remained unchanged to obtain 50.0 mg of the target product II-24 as a white solid with a yield of 10.7%.

[0762] ESI-MS: m / z = 469.0 [M+H] + .

[0763] 1 H NMR (400MHz, DMSO-d6): δ10.56(s,1H),7.03(s,1H),6.46(s,1H),4.72(s,4H),4.48(s,2H),4.40-4.34(m,4H),3.52-3.48(m,1H),2. 70(d,J=4.4Hz,3H),2.53(s,3H),1.24(d,J=6.8Hz,3H),1.07-1.05(m,1H),0.57-0.52(m,1H),0.40-0.32(m,2H),0.23-0.19(m,1H).

[0764] Example 36, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-morpholine-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-25)

[0765]

[0766] Step 1: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-morpholin-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-methylurea (II-25)

[0767] The preparation of target compound II-25 refers to step 3 of the preparation method of target compound I-1 in Example 1, only the intermediate I-1-3 is replaced by the common intermediate A6 and the rest of the preparation method remains unchanged to obtain target compound II-25 as a white solid with a yield of 13.2%.

[0768] ESI-MS: m / z = 457.0 [M+H] + .

[0769] 1H NMR (400MHz, DMSO-d6): 8.45 (s, 1H), 7.19 (s, 1H), 6.79 (d, J = 5.2Hz, 1H), 4.52 (s, 2H), 3.75 (t, J = 4.4Hz, 4H), 3.68 (t, J = 4.0Hz, 4H), 3.56-3.49 (m,1H),2.69(d,J=4.8Hz,3H),2.53(s,3H),1.25(d,J=6.8Hz,3H),1.11 -1.04(m,1H),0.60-0.53(m,1H),0.43-0.31(m,2H),0.24-0.19(m,1H).

[0770] Example 37, Preparation of (S)-1-cyclopropyl-3-(5-(2-(1-cyclopropylethyl)-4-morpholine-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)urea (II-26)

[0771]

[0772] Step 1: Synthesis of (S)-1-cyclopropyl-3-(5-(2-(1-cyclopropylethyl)-4-morpholin-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)urea (II-26)

[0773] The preparation of target compound II-26 refers to step 3 of the preparation method of target compound I-1 in Example 1, except that intermediate I-1-3 is replaced by common intermediate A6, and common intermediate B1 is replaced by intermediate I-9-1. The rest of the preparation method remains unchanged to obtain target compound II-26.

[0774] ESI-MS: m / z = 483.0 [M + H] + .

[0775] Example 38, Preparation of (S)-1-cyclobutyl-3-(5-(2-(1-cyclopropylethyl)-4-morpholine-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)urea (II-27)

[0776]

[0777] Step 1: Synthesis of 1-cyclobutyl-3-(4-methylthiazol-2-yl)urea (II-27-1)

[0778] Referring to the synthesis of intermediate I-9-1 in step 1 of Example 9, only the intermediate cyclopropylamine is replaced by cyclobutylamine, CDI is replaced by methylcarbamoyl chloride, and the solvent is replaced by dichloromethane from tetrahydrofuran. The rest of the preparation method remains unchanged to prepare intermediate II-27-1.

[0779] ESI-MS: m / z = 212.0 [M+H] + .

[0780] Step 2: Synthesis of (S)-1-cyclobutyl-3-(5-(2-(1-cyclopropylethyl)-4-morpholin-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)urea (II-27)

[0781] The preparation of target compound II-27 refers to step 3 of the preparation method of target compound I-1 in Example 1, except that intermediate I-1-3 is replaced by common intermediate A6, and common intermediate B1 is replaced by intermediate II-27-1. The rest of the preparation method remains unchanged to obtain target compound II-27.

[0782] ESI-MS: m / z = 497.0 [M+H] + .

[0783] Example 39, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-morpholine-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-(oxetane-3-yl)urea (II-28)

[0784]

[0785] Step 1: Synthesis of 1-(4-methylthiazol-2-yl)-3-(oxetane-3-yl)urea (II-28-1)

[0786] Referring to the synthesis of intermediate I-9-1 in step 1 of Example 9, only the intermediate cyclopropylamine is replaced by oxetane-3-amine, CDI is replaced by carbamoyl chloride, and the solvent is replaced by dichloromethane from tetrahydrofuran. The rest of the preparation method remains unchanged to prepare intermediate II-28-1.

[0787] ESI-MS: m / z = 214.0 [M+H] + .

[0788] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-morpholin-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-(oxetane-3-yl)urea (II-28)

[0789] The preparation of target compound II-28 refers to step 3 of the preparation method of target compound I-1 in Example 1, except that intermediate I-1-3 is replaced by common intermediate A6, and common intermediate B1 is replaced by intermediate II-28-1. The rest of the preparation method remains unchanged to obtain target compound II-28.

[0790] ESI-MS: m / z = 499.0 [M+H] + .

[0791] Example 40, Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-4-morpholine-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-(2-morpholineethyl)urea (II-29)

[0792]

[0793] Step 1: Synthesis of 1-(4-methylthiazol-2-yl)-3-(2-morpholinoethyl)urea (II-29-1)

[0794] Referring to the synthesis of intermediate I-9-1 in step 1 of Example 9, only the intermediate cyclopropylamine is replaced by 2-morpholinoethanolamine, CDI is replaced by methylcarbamoyl chloride, and the solvent is replaced by dichloromethane from tetrahydrofuran. The rest of the preparation method remains unchanged to prepare intermediate II-29-1.

[0795] ESI-MS: m / z = 271.0 [M+H] + .

[0796] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-4-morpholin-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)-3-(2-morpholinoethyl)urea (II-29)

[0797] The preparation of target compound II-29 refers to step 3 of the preparation method of target compound I-1 in Example 1, except that intermediate I-1-3 is replaced by common intermediate A6, and common intermediate B1 is replaced by intermediate II-29-1. The rest of the preparation method remains unchanged to obtain target compound II-29.

[0798] ESI-MS: m / z = 556.0 [M+H]+ .

[0799] Example 41. Preparation of (S)-N-(5-(2-(1-cyclopropylethyl)-4-morpholine-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)pyrrolidine-1-carboxamide (II-30)

[0800]

[0801] Step 1: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-4-morpholinyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)pyrrolidine-1-carboxamide (II-30)

[0802] The preparation of target compound II-30 refers to step 3 of the preparation method of target compound I-1 in Example 1, except that intermediate I-1-3 is replaced by common intermediate A6, and common intermediate B1 is replaced by intermediate I-10-1. The rest of the preparation method remains unchanged to obtain 5.0 mg of target compound II-30 as a white solid with a yield of 3.1%.

[0803] ESI-MS: m / z = 497.0 [M+H] + .

[0804] 1 H NMR (600MHz, DMSO-d6): δ10.77(s,1H),7.20(s,1H),4.52(s,2H),3.75(t,J=4.8Hz,4H),3.68(t,J=4.8Hz,4H),3.55-3.50(m,1H),3.3 9(s,4H),2.56(s,3H),1.85(s,4H),1.24(d,J=4.4Hz,3H),1.10-1.05(m,1H),0.58-0.54(m,1H),0.42-0.37(m,2H),0.36-0.32(m,1H).

[0805] Example 42. Preparation of 2,2-difluoroethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-1)

[0806]

[0807] Step 1: Synthesis of (S)-2,2-difluoroethyl (5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-1)

[0808] Sodium hydride (14 mg, 0.60 mmol) was added to 2,2-difluoroethane-1-ol (1 mL) and stirred at room temperature for 15 minutes. Then, the common intermediate C1 (100 mg, 0.20 mmol) was dissolved in dioxane (5 mL) and added dropwise to the above mixture. The system was heated to 50 ° C and reacted for 1 hour. After the reaction was completed, it was cooled to room temperature and quenched with water. The reaction solution was then extracted with ethyl acetate (30 mL*3), the organic phases were combined, and the residue was purified by column chromatography after concentration. The eluent was 0-3% methanol in dichloromethane to obtain 19.5 mg of the target compound IV-1 as a white solid with a yield of 20.4%.

[0809] ESI-MS: m / z = 488.0 [M+H] + .

[0810] 1 H NMR (400MHz, DMSO-d6): δ12.23(s,1H),7.64(t,J=74.8Hz,1H),7.57(d,J=1.2H z,1H),7.24(s,1H),6.48(tt,J1=54.0Hz,J2=3.2Hz,1H),4.60(s,2H),4.54(td, J1=15.2Hz, J2=3.2Hz,2H),3.59-3.52(m,1H),2.38(s,3H),1.28(d,J=6.8Hz,3 H),1.16-1.07(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.26-0.22(m,1H).

[0811] Example 43. Preparation of tetrahydrofuran-3-yl(5-(2-((S)-1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindol-5-yl)-4-methylthiazol-2-yl)carbamate (IV-2)

[0812]

[0813] Step 1: Synthesis of tetrahydrofuran-3-yl(5-(2-((S)-1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindol-5-yl)-4-methylthiazol-2-yl)carbamate (IV-2)

[0814] The synthesis method of the target compound IV-2 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced with 3-hydroxytetrahydrofuran to obtain 15 mg of the target compound IV-2 as a white solid with a yield of 18.4%.

[0815] ESI-MS: m / z = 494.0 [M + H] + .

[0816] 1 H NMR (400MHz, DMSO-d6): δ11.93(s,1H),7.63(t,J=74.8Hz,1H),7.56(d,J=1.2Hz,1H) ,7.22(s,1H),5.34-5.31(m,1H),4.60(s,2H),3.86-3.80(m,3H),3.77-3.71(m,1H), 3.59-3.52(m,1H),2.36(s,3H),2.26-2.17(m,1H),2.01-1.95(m,1H),1.28(d,J=6.8 Hz,3H),1.16-1.07(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.27-0.20(m,1H).

[0817] Example 44. Preparation of (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamic acid ethyl ester (IV-3)

[0818]

[0819] Step 1: Synthesis of ethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-3)

[0820] The synthesis method of the target compound IV-3 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced by ethanol to obtain 8 mg of the target compound IV-3 as a white solid with a yield of 21.1%.

[0821] ESI-MS: m / z = 452.0 [M + H] + .

[0822] 1H NMR (400MHz, DMSO-d6): δ11.86(s,1H),7.63(t,J=74.8Hz,1H),7.56(d,J=1.2Hz,1H),7.22(s,1H),4.60(s,2H),4.24(q,J=6.8Hz,2 H),3.60-3.52(m,1H),2.37(s,3H),1.28-1.23(m,6H),1.15-1.08(m,1H),0.60-0.55(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0823] Example 45. Preparation of cyclopropylmethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-4)

[0824]

[0825] Step 1: Synthesis of cyclopropylmethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-4)

[0826] The synthesis method of the target compound IV-4 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced by cyclopropylmethanol to obtain 21 mg of the target compound IV-4 as a white solid with a yield of 25.1%.

[0827] ESI-MS: m / z = 478.0 [M+H] + .

[0828] 1 H NMR (400MHz, DMSO-d6): δ11.89(s,1H),7.63(t,J=74.8Hz,1H),7.54(s,1H),7.21(s,1H),4.59(s,2H),4.00(d,J=7.6Hz,2H),3.59-3.51( m,1H),2.36(s,3H),1.28(d,J=6.8Hz,3H),1.19-1.07(m,2H),0.60-0.53(m,3H),0.44-0.36(m,2H),0.35-0.30(m,2H),0.27-0.22(m,1H).

[0829] Example 46. Preparation of (S)-isobutyl (5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-5)

[0830]

[0831] Step 1: Synthesis of isobutyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-5)

[0832] The synthesis method of the target compound IV-5 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced by isobutanol to obtain 8 mg of the target compound IV-5 as a white solid with a yield of 11.8%.

[0833] ESI-MS: m / z = 480.0 [M + H] + .

[0834] 1 H NMR (400MHz, DMSO-d6): δ11.87(s,1H),7.63(t,J=74.8Hz,1H),7.56(d,J=1.2H z,1H),7.22(d,J=0.8Hz,1H),4.60(s,2H),3.97(d,J=6.4Hz,2H),3.59-3.52(m, 1H),2.37(s,3H),2.00-1.89(m,1H),1.28(d,J=6.8Hz,3H),1.15-1.07(m,1H), 0.93(d,J=6.4Hz,6H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0835] Example 47. Preparation of 2-methoxyethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-6)

[0836]

[0837] Step 1: Synthesis of 2-methoxyethyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-6)

[0838] The synthesis method of the target compound IV-6 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced with ethylene glycol methyl ether to obtain 25 mg of the target compound IV-6 as a white solid with a yield of 28.1%.

[0839] ESI-MS: m / z = 482.0 [M + H] + .

[0840] 1 H NMR (400MHz, DMSO-d6): δ11.94(s,1H),7.63(t,J=74.8Hz,1H),7.56(d,J=1 .2Hz,1H),7.22(d,J=1.2Hz,1H),4.60(s,2H),4.31-4.29(m,2H),3.59-3.57 (m,2H),3.56-3.52(m,1H),3.28(s,3H),2.37(s,3H),1.28(d,J=6.8Hz,3H), 1.15-1.07(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0841] Example 48. Preparation of 3-(dimethylamino)propyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindol-5-yl)-4-methylthiazol-2-yl)carbamate (IV-7)

[0842]

[0843] Step 1: Synthesis of 3-(dimethylamino)propyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindol-5-yl)-4-methylthiazol-2-yl)carbamate (IV-7)

[0844] The synthesis method of the target compound IV-7 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced by 3-dimethylamino-1-propanol to obtain 5 mg of the target compound IV-7 as a white solid with a yield of 7.9%.

[0845] ESI-MS: m / z = 509.0 [M+H] + .

[0846] 1H NMR (400MHz, DMSO-d6): δ7.63(t,J=74.8Hz,1H),7.56(d,J=1.2Hz,1H),7.22( d,1H),4.60(s,2H),4.21(t,J=6.4Hz,2H),3.59-3.50(m,1H),2.37(s,3H),2. 35(t,J=7.2Hz,2H),2.17(s,6H),1.82(p,J=6.8Hz,2H),1.28(d,J=6.8Hz,3H) ,1.16-1.07(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0847] Example 49. Preparation of 3-morpholinopropyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindol-5-yl)-4-methylthiazol-2-yl)carbamate (IV-8)

[0848]

[0849] Step 1: Synthesis of 3-morpholinopropyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindol-5-yl)-4-methylthiazol-2-yl)carbamate (IV-8)

[0850] The synthesis method of the target compound IV-8 refers to step 1 of Example 42, except that 2,2-difluoroethane-1-ol is replaced by 3-(4-morpholine)-1-propanol to obtain 12 mg of the target compound IV-8 as a white solid with a yield of 15.9%.

[0851] ESI-MS: m / z = 551.0 [M+H] + .

[0852] 1 H NMR (400MHz, DMSO-d6): δ11.85(s,1H),7.63(t,J=74.8Hz,1H),7.55(d,J=1 .2Hz,1H),7.22(d,J=1.2Hz,1H),4.59(s,2H),4.22(t,J=6.4Hz,2H),3.59-3 .52(m,5H),2.38-2.33(m,9H),1.83(q,J=6.8Hz,2H),1.28(d,J=6.8Hz,3H), 1.16-1.07(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.27-0.22(m,1H).

[0853] Example 50. Preparation of (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-9)

[0854]

[0855] Step 1: Synthesis of methyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-9)

[0856] The preparation of target compound IV-9 can refer to the preparation method of target compound I-7 in step 3 of Example 7, except that intermediate I-7-2 is replaced by common intermediate B4. The rest of the preparation method remains unchanged to obtain 5 mg of target compound IV-9 as a white solid with a yield of 2.9%.

[0857] ESI-MS (m / z): 438.0 [M+H] + .

[0858] 1 H NMR (400MHz, DMSO-d6): δ11.92(s,1H),7.63(t,J=74.8Hz,1H),7.56(d,J=1.2Hz,1H),7.22(s,1H),4.60(s,2H),3.76(s,3H),3. 58-3.54(m,1H),2.37(s,3H),1.29(d,J=6.8Hz,3H),1.13-1.11(m,1H),0.60-0.55(m,1H),0.44-0.35(m,2H),0.27-0.23(m,1H).

[0859] Example 51. Preparation of (S)-(5-(2-(1-cyclopropylethyl)-7-(2-hydroxypropane-2-yl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-10)

[0860]

[0861] Step 1: Synthesis of (S)-2-(1-cyclopropylethyl)-7-(2-hydroxypropan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (IV-10-1)

[0862] The preparation of compound IV-10-1 can refer to the preparation method of compound I-7-2 in step 2 of Example 7, only the intermediate I-7-1 is replaced by compound I-6-3, and the rest of the preparation method remains unchanged to obtain 610 mg of IV-10-1 as a white solid with a yield of 93.0%.

[0863] ESI-MS (m / z): 386.0 [M+H] + .

[0864] Step 2: Synthesis of (S)-(5-(2-(1-cyclopropylethyl)-7-(2-hydroxypropan-2-yl)-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamic acid methyl ester (IV-10)

[0865] The preparation of target compound IV-10 can refer to the preparation method of target compound I-7 in step 3 of Example 7, except that intermediate I-7-2 is replaced by compound IV-10-1, and the rest of the preparation method remains unchanged to obtain 2 mg of target compound IV-10 as a white solid with a yield of 1.2%.

[0866] ESI-MS (m / z): 430.0 [M+H] + .

[0867] 1 H NMR (400MHz, DMSO-d6): δ11.89(s,1H),7.57(d,J=1.2Hz,1H),7.43(d,J=1.6Hz,1H),7.17(s,1H),4.66(s,2H),3.75(s,3H),3.67-3.60(m, 1H),2.37(s,3H),1.56(d,J=2.0Hz,6H),1.32(d,J=6.8Hz,3H),1.18-1.11(m,1H),0.62-0.56(m,1H),0.46-0.37(m,2H),0.29-0.24(m,1H).

[0868] Example 52. Preparation of (S)-(5-(2-(1-cyclopropylethyl)-7-morpholinyl-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamate (IV-11)

[0869]

[0870] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-morpholinoisoindolin-1-one (IV-11-1)

[0871] The common intermediate A1 (400 mg, 1.48 mmol) was dissolved in N, N-dimethylacetamide (10 mL), followed by the addition of morpholine (578 mg, 2.96 mmol) and triethylamine (597 mg, 5.95 mmol), and the reaction was carried out under microwave at 130°C for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature, 30 mL of ethyl acetate was added to the reaction mixture, and then the reaction mixture was washed with saturated brine (30 mL*3), the organic phases were combined, and the residue was concentrated and purified by column chromatography, the eluent being 10-25% ethyl acetate in petroleum ether, to obtain 180 mg of IV-11-1 as a yellow solid, with a yield of 73.5%.

[0872] ESI-MS: m / z = 365.0 [M+H] + .

[0873] Step 2: Synthesis of (S)-2-(1-cyclopropylethyl)-7-morpholinyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (IV-11-2)

[0874] The preparation of compound IV-11-2 can refer to the preparation method of compound I-7-2 in step 2 of Example 7, only replacing intermediate I-7-1 with compound IV-11-1, and the rest of the preparation method remains unchanged to obtain 400 mg of IV-11-2 as a white solid with a yield of 97.0%.

[0875] ESI-MS: m / z = 413.0 [M+H] + .

[0876] Step 3: Synthesis of (S)-(5-(2-(1-cyclopropylethyl)-7-morpholinyl-1-oxoisoindolin-5-yl)-4-methylthiazol-2-yl)carbamic acid methyl ester (IV-11)

[0877] The preparation of the target compound IV-11 can refer to the preparation method of the target compound I-7 in step 3 of Example 7, except that the intermediate I-7-2 is replaced by compound IV-11-2. The rest of the preparation method remains unchanged to obtain 101 mg of the target product IV-11 as a yellow solid with a yield of 46.3%.

[0878] ESI-MS: m / z = 457.0 [M+H] + .

[0879] 1H NMR (400MHz, DMSO-d6): δ11.88(s,1H),7.16(d,J=1.2Hz,1H),6.84(d,J=1.2Hz,1H),4.48(s,2H),3.77-3.75(m,7H),3.58-3.51(m,1H) ),3.27-3.20(m,4H),2.37(s,3H),1.25(d,J=6.8Hz,3H),1.12-1.04(m,1H),0.60-0.53(m,1H),0.42-0.31(m,2H),0.24-0.19(m,1H).

[0880] Example 53. Preparation of (S)-(5-(2-(1-cyclopropylethyl)-4-morpholinyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (IV-12)

[0881]

[0882] Step 1: Synthesis of methyl (4-methylthiazol-2-yl)carbamate (IV-12-1)

[0883] I-11-1 (200 mg, 0.85 mmol) was dissolved in methanol (10 mL), and then sodium methoxide (92 mg, 1.71 mmol) was added, and the mixture was reacted at 60°C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, 30 mL of ethyl acetate was added to the reaction solution, and then the reaction solution was washed with saturated brine (30 mL*3), the organic phases were combined, and the residue was concentrated and purified by column chromatography, with the eluent being 10-12% ethyl acetate in petroleum ether, to obtain 130 mg of IV-12-1 as a white solid, with a yield of 88.4%.

[0884] ESI-MS: m / z = 173.0 [M+H] + .

[0885] Step 2: Synthesis of (S)-(5-(2-(1-cyclopropylethyl)-4-morpholinyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-4-methylthiazol-2-yl)carbamate (IV-12)

[0886] IV-12-1 (100 mg, 0.31 mmol) was dissolved in N, N-dimethylformamide (10 mL), followed by the addition of common intermediate A6 (54 mg, 0.31 mmol), palladium acetate (14 mg, 0.06 mmol), cesium fluoride (94 mg, 0.62 mmol) and n-butyldi(1-adamantyl)phosphine (22 mg, 0.06 mmol), replaced with N2 environment, and reacted at 100 ° C for 2 h in microwave. After the reaction was completed, it was cooled to room temperature, and then the reaction solution was extracted with ethyl acetate (30 mL*3), the organic phases were combined, and the residue was purified by full preparative liquid chromatography after concentration to obtain 40 mg of the target compound IV-12 as a white solid with a yield of 28.2%.

[0887] ESI-MS: m / z = 458.0 [M + H] + .

[0888] 1 H NMR (400MHz, DMSO-d6): δ11.86(s,1H),7.25(s,1H),4.53(s,2H),3.75-3.71(m,7H),3.68-3.66(m,4H),3.58-3.49(m ,1H),2.55(s,3H),1.25(d,J=6.8Hz,3H),1.12-1.05(m,1H),0.60-0.53(m,1H),0.43-0.31(m,2H),0.25-0.19(m,1H).

[0889] Example 54. Preparation of (S)-1-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxy-1-oxoisoindolin-5-yl)pyridin-2-yl)-3-methylurea (III-1)

[0890]

[0891] Step 1: Synthesis of 1-(5-bromopyridin-2-yl)-3-methylurea (III-1-2)

[0892] The preparation of intermediate III-1-2 refers to the preparation method of common intermediate B1, except that 2-amino-4-methylthiazole hydrochloride is replaced by 2-amino-5-bromopyridine to obtain the target intermediate III-1-2 with a yield of 73.2%.

[0893] ESI-MS: m / z = 230.0 [M + H] + .

[0894] Step 2: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxy-1-oxoisoindolin-5-yl)pyridin-2-yl)-3-methylurea (III-1)

[0895] The intermediate III-1-2 (39 mg, 0.10 mmol) and the common intermediate D1 (28 mg, 0.12 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (7 mg, 0.01 mmol) and potassium carbonate (42 mg, 0.30 mmol) were added. The reaction was stirred at 100 ° C for 4 hours under nitrogen protection. After the mixture was cooled to room temperature, it was quenched with water (10 mL), extracted with ethyl acetate three times (10 mL*3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography, and the developing solvent was 0-40% ethyl acetate in petroleum ether to prepare the target compound III-1.

[0896] ESI-MS: m / z = 417.0 [M+H] + .

[0897] Control compound 1:

[0898]

[0899] It was prepared by referring to the preparation method of compound 34 in CN114025756A.

[0900] Reference compound 2 (IPI-549):

[0901] Prepared by referring to the preparation method of compound 4 in Example 1 in WO2015051244A1.

[0902]

[0903] Example 55: PI3Kγ inhibitory activity of the compounds of the present invention

[0904] The present invention uses IPI-549 as a control and adopts ADP Glo assay to test the ability of the compound to bind to and inhibit PI3Kγ activity in vitro.

[0905] Preparation of compound solution: First dissolve the compound with DMSO, then dilute the compound to be tested 3-fold in sequence with sterile deionized ultrapure water to obtain compound solutions of 8 concentrations.

[0906] Experimental method: 2×PI3Kγ enzyme solution was prepared in kinase buffer, and substrate solution containing 2×PIP2:3PS and ATP was prepared in substrate buffer. 1μL of compound solution of each gradient concentration was added to the 384-well plate, centrifuged, and then 5μL of 2×PI3Kγ enzyme solution and enzyme-free kinase buffer were added, centrifuged, and 5μL of 2×PIP2:3PS and ATP substrate solution was added to each well, mixed and centrifuged, and incubated at room temperature for 90 minutes. 10μL ADP-Glo ​​reagent was added to each well to stop the reaction, mixed and centrifuged, and incubated at room temperature for 60 minutes. Then 20μL ADP-Glo ​​Kinase Detection Reagent was added to each well, centrifuged, and balanced for 60 minutes before reading on the microplate reader and determining the inhibition rate of each compound. The final results were entered into GraphpadPrism for plotting to obtain the curve and IC 50 The results are shown in the table below:

[0907] Table 1. PI3Kγ inhibitory activity of aromatic heterocyclic pyrrolidone compounds

[0908]

[0909]

Note

[0910] It can be seen from the data in the table that the compounds provided by the present invention generally exhibit strong PI3Kγ inhibitory activity, which is better than the control compound IPI-549, and therefore has good application prospects.

[0911] Example 56: PI3Kα, PI3Kβ, and PI3Kδ inhibitory activities of the compounds of the present invention

[0912] Preparation of compound solution: First dissolve the compound with DMSO, then dilute the compound to be tested 3-fold in sequence with sterile deionized ultrapure water to obtain 8 concentrations of compound solution.

[0913] The ADP Glo assay was used to test the ability of compounds to bind and inhibit the activity of PI3Kα, PI3Kβ, and PI3Kδ in vitro.

[0914] Prepare 2×PI3Kα / β / δ enzyme solution in kinase buffer, prepare substrate solution containing 2×PIP2:3PS and ATP in substrate buffer. Add 1μL of compound solution of each gradient concentration to 384-well plate, centrifuge, add 5μL of 2×PI3Kβ enzyme solution and enzyme-free kinase buffer, centrifuge, add 5μL of 2×PIP2:3PS and ATP substrate solution to each well, mix and centrifuge, incubate at room temperature for 90 minutes, add 10μL ADP-Glo ​​reagent to each well to stop the reaction, mix and centrifuge, incubate at room temperature for 60 minutes, then add 20μL ADP-Glo ​​Kinase Detection Reagent to each well, centrifuge, balance for 60 minutes, read on the microplate reader and determine the inhibition rate of each compound.

[0915] Table 2. PI3Kα, PI3Kβ, PI3Kδ inhibitory activity of the compounds of the present invention

[0916] serial number <![CDATA[PI3KαIC 50 (nM)]]> <![CDATA[PI3KβIC 50 (nM)]]> <![CDATA[PI3KδIC 50 (nM) <!-- 67 -->]]> II-3 5659.1 >10000 731.9 II-4 5499.1 >10000 664.5 II-5 7956.7 >10000 3065.2 II-7 4796.4 >10000 912.3 II-14 >10000 >10000 7711.3 II-15 >10000 >10000 6873.1 II-17 3970.6 >10000 937.9 II-18 10000 >10000 665.6 II-19 6098.5 >10000 784.4 II-20 3838.7 >10000 603.4 II-23 >10000 >10000 2083.9 II-24 >10000 >10000 2094.0 II-25 >10000 >10000 2602.68 IV-10 7384.6 >10000 2036.8 IPI-549 642.93 725.64 407.7

[0917] From the data in Table 2, it can be seen that the compounds provided by the present invention have significantly stronger selectivity for PI3Kγ subtype than PI3Kα, PI3Kβ, and PI3Kδ, indicating that the compounds provided by the present invention have reduced off-target effects compared with IPI-549.

[0918] Example 57 Evaluation of the inhibitory activity of the compounds of the present invention on Th2 cytokine secretion from lymphocytes derived from mice with atopic dermatitis induced by MC903

[0919] 1. AD mouse modeling method: Weigh an appropriate amount of MC903, add an appropriate amount of anhydrous ethanol, dissolve and fully stir to prepare a 100μM MC903 solution as a modeling agent. The model group mice were smeared with 20μL of modeling agent on the right ear every day, 10μL each on the inner and outer ears, and the normal group was given an equal amount of anhydrous ethanol every day for 14 consecutive days;

[0920] 2. Extraction, activation and incubation of ear drainage lymphocytes with test products:

[0921] (1) A 96-well plate was pre-coated with 100 μL of 3 μg / ml CD3 antibody and incubated at 4°C overnight. The plate was then washed twice with sterile PBS to remove free CD3 antibody from the plate for later use.

[0922] (2) Control and AD mice were killed by cervical dislocation and immersed in 75% ethanol solution for 5 min. The ear drainage lymph nodes were then removed in a clean bench and ground into a single cell suspension using an appropriate amount of RPMI-1640 blank culture medium on a 200-mesh sieve. The suspension was sieved through a 70 μM cell sieve and centrifuged at 4°C, 1200 rpm to obtain lymphocytes.

[0923] (3) Grind and separate single lymphocytes using a 70 μM cell sieve. Centrifuge at 300 g for 5 min. Resuspend in complete medium and count.

[0924] (4) Adjust the cell density of the counted lymphocytes to 3 x 10 6 / mL, 1 μg / mL LCD28 was added to the above cell suspension, and 100 μL of cell suspension was added to each well, that is, the number of lymphocytes in each well was 3 x 10 5 indivual.

[0925] 3. Grouping, medication and data collection:

[0926] The experiment was divided into a blank control group, a model group, and a test drug group. 10 μL of each test drug was added to each well, so that the final compound solubility was 10 μM. After 5 days of continuous culture, the cell supernatant was collected, and the Th2 cytokines IL-5 and IL-13 were detected according to the ELISA test instructions of each cytokine, where IL-5 and IL-13 were diluted 2 times. The results and data of the measurement and observation required by the protocol were recorded in appropriate tables and analyzed uniformly in Excel tables. The quantitative data were expressed as mean ± standard error. All data statistics were performed using Prism statistical software, and the Oneway-ANOVA method was used for statistics, with P ≤ 0.05 as statistically significant.

[0927] The experimental results are shown in Figure 1 .

[0928] Depend on Figure 1 It can be seen that the compound of the present invention has a strong inhibitory effect on the secretion of Th2 cytokines (IL-5 and IL-13) of MC903-induced AD mouse-derived lymphocytes, and can be used to prevent or treat atopic dermatitis.

[0929] Example 58 Evaluation of the inhibitory activity of the compounds of the present invention on the secretion of IL-17A cytokine by lymphocytes derived from psoriasis mice induced by imiquimod cream

[0930] 1. PSO mouse modeling method:

[0931] The model group mice were smeared with 62.5 mg of 5% imiquimod cream on their backs every day, and the normal group mice were given the same amount of vaseline every day for 7 consecutive days;

[0932] 2. Lymphocyte extraction, activation and test sample incubation:

[0933] (1) A 96-well plate was pre-coated with 100 μL of 3 μg / ml CD3 antibody and incubated at 4°C overnight. The plate was then washed twice with sterile PBS to remove free CD3 antibody from the plate for later use.

[0934] (2) Control and PSO mice were killed by cervical dislocation and immersed in 75% ethanol solution for 5 min. Then, inguinal lymph nodes were removed in a clean bench and ground into single-cell suspension using an appropriate amount of RPMI-1640 blank culture medium on a 200-mesh sieve. After sieving through a 70 μM cell sieve, lymphocytes were obtained by centrifugation at 4°C and 1200 rpm.

[0935] (3) Grind and separate single lymphocytes using a 70 μm cell sieve. Centrifuge at 300 g for 5 min. Resuspend in complete medium and count.

[0936] (4) Adjust the cell density of the counted lymphocytes to 3 x 10 6 / mL, 1 μg / mL LCD28 was added to the above cell suspension, and 100 μL of cell suspension was added to each well, that is, the number of lymphocytes in each well was 3 x 10 5 indivual.

[0937] 3. Grouping, medication and data collection:

[0938] The experiment was divided into a blank control group, a model group, and a test drug group, with 4 wells in each group. 10 μL of each test drug was added to each well, so that the final compound solubility was 10 μM. After 5 days of continuous culture, the cell supernatant was collected and IL-17A was detected according to the ELISA test instructions, where IL-17A was diluted 10 times. The results and data of the measurements and observations required by the protocol were recorded in appropriate tables and analyzed uniformly in Excel tables. The quantitative data were expressed as mean ± standard error. All data statistics were performed using Prism statistical software, and the Oneway-ANOVA method was used for statistics, with P ≤ 0.05 as statistically significant.

[0939] The experimental results are shown in Figure 2 .

[0940] Depend on Figure 2 It can be seen that the compound of the present invention has a strong inhibitory effect on the secretion level of IL-17A in lymphocytes derived from psoriasis mice induced by imiquimod cream, and can be used to prevent or treat psoriasis.

[0941] Example 59: Pharmacokinetics of the compounds of the present invention

[0942] Detection method: Male SD rats, weighing about 200g, were randomly divided into 2 groups, 3 rats in each group, one group was injected intravenously with 0.5mg / kg compound once, and the other group was gavaged with 5mg / kg compound once. Blood was collected at the specified time points, plasma was separated, and stored in a -80℃ refrigerator for later use. After the above plasma samples were precipitated with acetonitrile protein, the supernatant was extracted and mixed with water in a ratio of 1:1, 10μL was taken for LC-MS / MS detection, and the average value was calculated.

[0943] Table 3. Pharmacokinetic parameters of the compounds of the present invention

[0944]

[0945]

[0946] The experimental results show that compared with IPI-549, the plasma exposure and oral bioavailability of some compounds of the present invention after oral administration are significantly improved.

[0947] Example 60: Inhibitory effect of the compounds of the present invention on human hERG ion channels

[0948] Effects of compounds on hERG ion channels were tested on HEK293 cells stably expressing hERG ion channels. Cells were transferred to a perfusion tank and perfused with extracellular solution. Intracellular solution (mM) was: K Aspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration). Intracellular solution was stored in batches in small amounts at -80 degrees and thawed on the day of the experiment. Electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, and noise was filtered at one-fifth of the sampling frequency. The cells were clamped at -80 mV, then depolarized to 40 mV with a 4-second square wave, and then hyperpolarized to -40 mV with a 2-second square wave to obtain hERG tail currents. This procedure was repeated every 20 seconds. The maximum current induced by the second square wave was detected. After it stabilized, the test compound was perfused using a perfusion system that utilized its own gravity. At least one cell was tested for each concentration. When the reaction stabilized, the current changes before and after the compound was used were compared to calculate the blocking effect of the compound. pCLAMP 10 (Molecular Devices, Union City, CA) was used to collect and analyze the data, and the experimenter reviewed the analysis results. The results of the inhibitory effect of the compounds of the present invention on human hERG ion channels are shown in the following table:

[0949] Table 4. Blocking rate of the compounds of the present invention on hERG ion channels

[0950] Compd. hERG inhibition rate at 10μM II-25 9.37％ II-15 3.94％

[0951] The experimental results show that some compounds of the present invention have good safety after oral administration.

Claims

1. An aromatic heterocyclic pyrrolidone derivative, which is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof: In the formula, Ring A is selected from a 5-16 membered aromatic ring or heteroaromatic ring, and contains at least one substituent R 2 ; R 1 Selected from NR 1a R 1b OR 1a ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 , R 2a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, thiol, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino; X and Y are each independently selected from N or CR 2a ; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NR 3a R 3c 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; R 4 , R 5 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl groups may be independently monosubstituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; or R 4 and R 5 Connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; R 6 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl groups may be mono- or poly-substituted independently by one or more of the following substituents: halogen, cyano, C1 -6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

2. The aromatic heterocyclic pyrrolidone derivative according to claim 1, characterized in that: It is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof: In the formula, Ring A is selected from a 5-16 membered aromatic ring or heteroaromatic ring, and contains at least one substituent R 2 ; R 1 Selected from NR 1a R 1b OR 1a ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 , R 2a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, thiol, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino; X and Y are each independently selected from N or CR 2a ; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 4 , R 5 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; or R 4 and R 5 Connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; R 6 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, C1 -6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

3. The aromatic heterocyclic pyrrolidone derivative according to claim 1, characterized in that: It is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof: In the formula, Ring A is selected from a 5-16 membered aromatic ring or heteroaromatic ring, and contains at least one substituent R 2 ; R 1 Selected from NR 1a R 1b OR 1a ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 , R 2a Each is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, thiol, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino; X and Y are each independently selected from N or CR 2a ; R 4 , R 5 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 4 , R 5 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; or R 4 and R 5 Connected to each other and together with the C atoms on the ring to form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; R 6 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl or substituted or unsubstituted C 3-6 Cycloalkyl; when R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When a cycloalkyl group has a substituent, it can be independently substituted by one or more of the following substituents: halogen, cyano, C1 -6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; R 3 Select from -OR 3a or -NR 3a R 3c ;in, When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When the 4-10 membered heterocyclic group has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

4. The aromatic heterocyclic pyrrolidone derivative according to any one of claims 1 to 3, characterized in that: In the general structural formula (I), ring A is selected from thiazole, oxazole, pyridine or pyrimidine.

5. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula I or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from NR 1a R 1b ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 Selected from hydrogen, halogen or C 1-6 alkyl; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

6. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula I or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from NR 1a R 1b ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 Selected from hydrogen, halogen or C 1-6 alkyl; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; R 3 Select from -OR 3a or -NR 3a R 3c ;in, When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When the 4-10 membered heterocyclic group has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

7. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula II or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from NR 1a R 1b ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 Selected from hydrogen, halogen or C 1-6 alkyl; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

8. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula II or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from NR 1a R 1b ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 aryl; or R 1a and R 1b Connected to each other and together with the N atom to form a 3-8 membered saturated or unsaturated heterocyclic ring; R 2 Selected from hydrogen, halogen or C 1-6 alkyl; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; R 3 Select from -OR 3a or -NR 3a R 3c ;in, When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When the 4-10 membered heterocyclic group has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

9. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula III or a pharmaceutically acceptable salt thereof: In the formula, X is selected from N or CR 2a ; R 1 Selected from NR 1a R 1b ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

10. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula III or a pharmaceutically acceptable salt thereof: In the formula, X is selected from N or CR 2a ; R 1 Selected from NR 1a R 1b ; R 1a , R 1b are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a , R 1b C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; R 3 Select from -OR 3a or -NR 3a R 3c ;in, When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When the 4-10 membered heterocyclic group has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

11. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula IV or a pharmaceutically acceptable salt thereof: In the formula, X is selected from N or CR 2a ; R 1 Selected from OR 1a ; R 1a is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl; R 3 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 6-12 aryl, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR 3a 、-SR 3a 、-SO2-R 3a 、-NH-R 3a 、-NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a or -P(O)R 1a R 1b ; When R 3 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 When aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they can be substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

12. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: It is a compound represented by the general structural formula IV or a pharmaceutically acceptable salt thereof: In the formula, X is selected from N or CR 2a ; R 1 Selected from OR 1a ; R 1a is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when R 1a C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl; R 2 , R 2a are each independently selected from hydrogen, halogen or C 1-6 alkyl; R 4 , R 5 Selected from hydrogen or C 1-6 alkyl; R 6 Selected from C 3-6 Cycloalkyl substituted C 1-6 alkyl; R 3 Select from -OR 3a or -NR 3a R 3c ;in, When R 3 Select from -OR 3a When R 3a is selected from substituted or unsubstituted 4-10 membered heterocyclic groups; further when R 3a When the 4-10 membered heterocyclic group has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; When R 3 Selected from -NR 3a R 3c When R 3a , R 3c are each independently selected from substituted or unsubstituted C 1-6 Alkyl, halogenated C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further when R 3a , R 3c C 1-6 Alkyl, C 3-6 When cycloalkyl and 4-10 membered heterocyclic groups have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfone, C 1-6 Alkylthio or C 1-6 Alkylamino; The heterocycle, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

13. The aromatic heterocyclic pyrrolidone derivative according to claim 11 or 12, characterized in that: It is a compound represented by the general structural formula IV-1 or a pharmaceutically acceptable salt thereof: In the formula, R 3 is selected from substituted or unsubstituted C 1-6 Alkyl or -OR 3a ; When R 3 C 1-6 When there are substituents in the alkyl group, they can be independently substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or 4-10 membered heterocyclic group; the heteroaryl group or heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S and O.

14. The aromatic heterocyclic pyrrolidone derivative according to claim 7 or 8, characterized in that: It is a compound represented by the general structural formula II-1 or a pharmaceutically acceptable salt thereof: R 3 is selected from substituted or unsubstituted 4-10 membered heterocyclic group, -OR 3a 、-NR 3a R 3c 、-NH-R 3a ; When R 3 When the 4-10 membered heterocyclic group has substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR 3b 、-SR 3b 、-SO2-R 3b 、-NH-R 3b 、-NHCO-R 3b 、-NHSO2-R 3b 、-C(O)NH-R 3b or -C(O)-R 3b ; R 3a , R 3b , R 3c are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or 4-10 membered heterocyclic group; The 4-10 membered heterocyclic group is selected from the following groups:

15. The aromatic heterocyclic pyrrolidone derivative according to any one of claims 1 to 14, characterized in that: Selected from the following characteristic compounds or their isomers or pharmaceutically acceptable salts: 。 16. A pharmaceutical composition comprising at least one active ingredient as described in any one of claims 1 to 15 and at least one pharmaceutically acceptable carrier or excipient.

17. Use of the compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 16 in preventing or treating diseases associated with the PI3Kγ signaling pathway.

18. The use according to claim 17, characterized in that The diseases include but are not limited to: 1) chronic inflammatory diseases, such as gout, nephritis, atherosclerosis, non-alcoholic fatty liver disease, hepatitis, diabetes, enteritis, etc.; 2) acute inflammatory diseases, such as traumatic brain injury, wounds, toothache, acute nephritis, viral infection, sepsis, burns, septic shock; 3) cardiovascular diseases, such as myocardial ischemia, heart failure, etc.; 4) nervous system diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, meningitis, headache, neuropathic pain, etc.; 5) autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic vasculitis; 6) respiratory system diseases, such as COPD, asthma, pneumonia, tuberculosis, etc.; 7) metabolic syndrome, such as obesity, hyperglycemia, hypertension, dyslipidemia, hyperuricemia, hyperinsulinemia, etc.; 8) digestive system, such as viral hepatitis, cirrhosis, liver fibrosis, enteritis, etc.; 9) tumors and tumor metastasis, tumor complications, etc.

19. The use according to claim 17, characterized in that The disease is selected from atopic dermatitis.

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