Aromatic heterocycle pyrrolidone compound and application thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a PI3K gamma inhibitor, a preparation method thereof and application of the PI3K gamma inhibitor in medicine. The invention provides a PI3K gamma inhibitor as shown in a formula (Ia), (IIa), (Ib) or (IIb) as well as a composition and application thereof. The compound can be used for treating or preventing diseases or symptoms related to abnormal expression of a PI3K gamma signaling pathway. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and relates to an aromatic heterocyclic pyrrolidone compound, and specifically relates to the free base, isomers, isotope derivatives, solvates and pharmaceutically acceptable salts of the compound; further, the present invention also discloses a preparation method of the aromatic heterocyclic pyrrolidone compound and its pharmaceutical use, which can be used as a PI3Kγ inhibitor for treating diseases related to abnormal expression of the PI3Kγ signaling pathway, and has 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 difference in structure and physiological function, 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 showed that PI3Kγ inhibitors can alleviate the severity of multiple sclerosis and improve clinical scores (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 subtypes 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 compound, which is a compound represented by the general formula (I) or a pharmaceutically acceptable salt, isotope derivative, solvate or isomer thereof:

[0009]

[0010] in:

[0011] R 1 Selected from -NHC(O)-R 1a or -NH-R 1b ;

[0012] R 1a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, NR 1c R 1d OR 1c ; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0013] R 1b Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 The aryl or 5-14 membered heteroaryl is unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, mercapto, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0014] R 1c , R 1d are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6The cycloalkyl or 4-10 membered heterocyclic group is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; or

[0015] R 1c and R 1d The atoms connected to each other may also be connected to form a 3-8 membered aliphatic ring or heterocyclic ring, wherein the aliphatic ring and heterocyclic ring may be saturated or unsaturated; the aliphatic ring or heterocyclic ring may be unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl;

[0016] Ring A is selected from the following structures:

[0017]

[0018] Ring B is selected from benzene ring, pyridine or pyrimidine;

[0019] R 2 Selected from hydrogen, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 2a )-C(O)-R 2b 、-N(R 2a )-SO2-R 2b 、-C(O)-NR 2a R 2b 、-C(O)-R2a 、-OR 2a -、C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl;

[0020] R 2a , R 2b are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; or

[0021] R 2a and R 2b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl;

[0022] n is selected from 0, 1, 2 or 3;

[0023] X is selected from N or CR 2c ;

[0024] R 2c Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, 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;

[0025] R 3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 3a )-CO-R 3b 、-C(O)-NR 3a R 3b 、-C(O)-R 3a 、-N(R 3a )-SO2-R 3b 、-P(O)R 3a R 3b , C 6-12aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0026] R 3a , R 3b Each independently selected from hydrogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C1-6 Alkylthio, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl, or 5-14 membered heteroaryl; or

[0027] R 3a and R 3b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl;

[0028] R 4 , R 5 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl group is unsubstituted or 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

[0029] 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;

[0030] R 6 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; said C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 The cycloalkyl group is unsubstituted or substituted by one or more of the following substituents: halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl.

[0031] In some embodiments, in the aforementioned general structural formula (I), R 4 and R 5 are independently preferably selected from hydrogen, R 6 Select from

[0032] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0033]

[0034] Among them, ring A, R 1b , R 2 , n, X and R 3 The definition of is as described in the general formula (I).

[0035] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (II) or a pharmaceutically acceptable salt thereof:

[0036]

[0037] Among them, ring A, R 1a , R 2 , n, X and R 3 The definition of is as described in the general formula (I).

[0038] In some embodiments, the ring A is selected from

[0039] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (Ia), (IIa), (Ib) or (IIb) or a pharmaceutically acceptable salt thereof:

[0040]

[0041] Among them, R 1a , R 1b , R 2 , n, and X are as defined in Formula (I);

[0042] R3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 3a )-CO-R 3b 、-C(O)-NR 3a R 3b 、-C(O)-R 3a 、-N(R 3a )-SO2-R 3b 、-P(O)R 3a R 3b 、-NHCO-R 3a 、-C(O)NH-R 3a 、-NHSO2-R 3a , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0043] R 3a , R 3b Each independently selected from hydrogen, hydroxyl, amino, C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl, or 5-14 membered heteroaryl; or

[0044] R 3a and R 3b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl.

[0045] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (Ia) or a pharmaceutically acceptable salt thereof:

[0046]

[0047] Among them, R 3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a 、-P(O)R 3a R 3b , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0048] R 3a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-12The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl;

[0049] R 3b Selected from hydrogen, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Alkylamino;

[0050] R 1b , R 2 and X are as defined in the general formula (I).

[0051] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (Ib) or a pharmaceutically acceptable salt thereof:

[0052]

[0053] wherein n is selected from 1 or 2;

[0054] R 3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 3a )-CO-R 3b 、-C(O)-NR 3a R 3b 、-C(O)-R 3a 、-N(R 3a )-SO2-R 3b 、-P(O)R 3a R 3b , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0055] R 3a , R 3b Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; or

[0056] R 3a and R 3b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl;

[0057] R 1b , R 2 and X are as defined in the general formula (I).

[0058] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (IIa) or a pharmaceutically acceptable salt thereof:

[0059]

[0060] Among them, R 1a , R 2 and X are as defined in general formula (I);

[0061] R 3 The definition of is as described in the general formula (Ia).

[0062] In some embodiments, an aromatic heterocyclic pyrrolidone compound may be a compound represented by the general structural formula (IIb) or a pharmaceutically acceptable salt thereof:

[0063]

[0064] Among them, R 1a , R 2 and X are as defined in general formula (I);

[0065] n and R 3 The definition of is as described in the general formula (Ib).

[0066] In some embodiments, the compound has a structural compound represented by the following formula (Ic), (IIc), (Id) or (IId), or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof:

[0067]

[0068]

[0069] wherein n is selected from 1 or 2;

[0070] R 1a Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 1-6 Haloalkyl;

[0071] R 1b is selected from hydrogen, deuterium, hydroxyl, amino or C 1-6 Alkyl, the C 1-6 The alkyl group is unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 1-6 Alkylthio;

[0072] R 2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, -OR 2a 、-C(O)-NR 2a R 2b , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Alkylamino, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl;

[0073] R 2a , R 2b are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl or C 1-6 Alkoxy; or

[0074] R 2a and R 2b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring, wherein the aliphatic ring or heterocyclic ring is unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl or C 1-6 Alkoxy;

[0075] R 3 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, -P(O)R 3a R 3b , C 1-6 Alkylsulfone, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl or C 1-6 Alkoxy;

[0076] R 3a and R 3b are each independently selected from hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0077] In some embodiments, the R 1a Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl; said R 1b Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group is unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 1-6Alkylthio.

[0078] In some embodiments, the R 1a is selected from methyl, ethyl or cyclopropyl; said R 1b Selected from hydrogen,

[0079] In some embodiments, the R 2 Selected from hydrogen, -OR 2a , C 1-6 Alkyl, -C(O)-NR 2a R 2b , C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy;

[0080] The R 2a , R 2b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy; or

[0081] R 2a and R 2b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring, wherein the aliphatic ring or heterocyclic ring is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0082] In some embodiments, the R 2 Selected from hydrogen, methyl,

[0083] In some embodiments, the R 3Selected from hydrogen, halogen, cyano, -P(O)R 3a R 3b , C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 4-10 membered heterocyclic group; 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 The alkylsulfone group or the 4-10 membered heterocyclic group is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy;

[0084] R 3a and R 3b Each independently selected from hydrogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl.

[0085] In some embodiments, the R 3 is selected from hydrogen, fluorine, cyano, methyl, trifluoromethyl,

[0086] In some embodiments, the aromatic heterocyclic pyrrolidone compounds provided by the present invention, or pharmaceutically acceptable salts, isotopic derivatives, solvates or isomers thereof, are preferably selected from the following compounds, including compounds numbered I-1 to I-11, II-1 to II-11, III-1 to III-24 and IV-1 to IV-8, and the specific structural formulas are shown below:

[0087]

[0088]

[0089]

[0090] In some embodiments, the present invention provides an intermediate compound A-1, the chemical name of which is (S)-5-bromo-2-(1-cyclopropylethyl)-7-difluoromethoxyisoindolin-1-one, and the structural formula is as follows:

[0091]

[0092] In some embodiments, the present invention provides an intermediate compound B-1, the chemical name of which is (S)-2-(1-cyclopropylethyl)-7-difluoromethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one, and the structural formula is as follows:

[0093]

[0094] In some embodiments, the present invention provides an intermediate compound IV-SM1, the chemical name of which is 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester, and the structural formula is as follows:

[0095]

[0096] In some embodiments, the present invention provides an intermediate compound F-7, the chemical name of which is N-(5-bromo-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide, and the structural formula is as follows:

[0097]

[0098] The aforementioned "compounds" of 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) and the like.

[0099] The aforementioned "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms may be isolated in an optically pure form or in a racemic form. The optically pure form may be obtained by resolution of a racemic mixture, synthesis using chiral raw materials or chiral reagents.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] The terms used in this document have the following meanings:

[0105] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0106] 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.

[0107] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom.

[0108] 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.

[0109] 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 (ie 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.

[0110] 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.

[0111] The term "cycloalkyl" refers to a monocyclic alkyl group consisting of carbon atoms and hydrogen atoms, such as C 3-8Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptane, cyclooctane, and the like.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] The term "alkylamino" refers to an open chain alkyl group containing a nitrogen atom, such as C 1-6 Alkylamino includes, but is not limited to, methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon, which is a non-aromatic structure and contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Bicyclic or polycyclic heterocycles include spirocyclic, condensed and bridged heterocycles. Bicyclic or polycyclic "heterocycles" include those in which one ring is aromatic and the other rings are non-aromatic, including spirocyclic, condensed and bridged heterocycles. Bicyclic heterocycles may contain one or more heteroatoms in one or both rings. In some embodiments, heterocycle also includes a ring system in which a heterocycle as defined above is fused to one or more carbocyclic groups, wherein the point of attachment is on the ring of the carbocyclic or heterocyclic ring; or, in some embodiments, a heterocycle as defined above is fused to one or more aromatic / heteroaromatic rings, wherein the point of attachment is on the ring of the aromatic / heteroaromatic ring or heterocyclic ring; or, in some embodiments, a heterocycle as defined above is fused to one or more heterocycles as defined above, wherein the point of attachment is on the ring of either heterocycle. In the above cases, the number of members of the heterocycle ring system is the number of ring atoms in the ring system after fusion. In some embodiments, heterocycle is optionally substituted, for example, unsubstituted (unsubstituted heterocycle) or substituted (substituted heterocycle) with one or more substituents. Exemplary 3-membered heterocycles containing 1 heteroatom include (but are not limited to) aziridine, oxirane, and thiirane. Exemplary 4-membered heterocycles containing 1 heteroatom include, but are not limited to, azetidine, oxetane, and thietane. Exemplary 5-membered heterocycles containing 1 heteroatom include, but are not limited to, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole, and 2,5-pyrrolidinedione. Exemplary 5-membered heterocycles containing 2 heteroatoms include, but are not limited to, dioxolane, oxathiolane, dithiolane, and 2-oxoxazolidine. Exemplary 5-membered heterocycles containing 3 heteroatoms include, but are not limited to, triazole, oxadiazole, and thiadiazole. Exemplary 6-membered heterocycles containing 1 heteroatom include, but are not limited to, piperidine, tetrahydropyran, dihydropyridine, and tetrahydrothiopyran. Exemplary 6-membered heterocycles containing 2 heteroatoms include, but are not limited to, piperazine, morpholine, thiomorpholine, and the like. Exemplary 6-membered heterocycles containing 3 heteroatoms include, but are not limited to, triazine, oxadiazine, thiadiazine, oxathiazine, and dioxazine. Exemplary 7-membered heterocycles containing 1 heteroatom include, but are not limited to, azepane, oxepane, and thiepane. Exemplary 8-membered heterocycles containing 1 heteroatom include, but are not limited to, azocane, oxepane, and thiecane. Exemplary 5-membered heterocycles fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indoline, isoindoline, dihydrobenzofuran, dihydrobenzothiophene, benzoxazolinone. Exemplary 6-membered heterocycles fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinoline, tetrahydroisoquinoline.

[0120] The term "heterocyclyl" refers to a substituent generated on the basis of the above-mentioned definition of heterocycle. Exemplary 3-membered heterocyclyls containing 1 heteroatom include (but are not limited to) aziridine, oxirane and thiirane. Exemplary 4-membered heterocyclyls containing 1 heteroatom include (but are not limited to) azetidinyl, oxetanyl and thiidine. Exemplary 5-membered heterocyclyls containing 1 heteroatom include (but are not limited to) tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and 2,5-dioxopyrrolidinyl. Exemplary 5-membered heterocyclyls containing 2 heteroatoms include (but are not limited to) dioxolanyl, oxathiolanyl, dithiolanyl and 2-oxoxazolidinyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include (but are not limited to) triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and tetrahydrothiopyranyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazinyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazinyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl. Exemplary 6-membered heterocyclyls (also referred to herein as 6,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl.

[0121] The term "aromatic heterocycle" refers to an aromatic monocyclic, bicyclic or polycyclic ring system containing 5-16 members, preferably 5-14 members, 5-12 members, 5-10 members, 5-8 members, and more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Bicyclic or polycyclic heteroaromatic rings include fused-ring heteroaromatic rings. Examples of heteroaromatic rings include, but are not limited to, furan, thiophene, oxazole, thiazole, isoxazole, oxadiazole, thiadiazole, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, thiodiazole, triazine, phthalazine, quinoline, isoquinoline, pteridine, purine, indole, isoindole, indazole, benzofuran, benzothiophene, benzopyridine, benzopyrimidine, benzopyrazine, benzimidazole, benzo Phthalocyanine, pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyridine.

[0122] The term "aromatic heterocyclic group" refers to a substituent generated on the basis of the above definition of aromatic heterocyclic ring. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, Benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl.

[0123] The present invention also provides a method for preparing the aforementioned compound, which is prepared by the following steps, including but not limited to the following method:

[0124] Route 1: When R in the general structural formula (I) 4 =R 5 =H, R 6 for When the aromatic heterocyclic pyrrolidone core is connected to ring A via a CC bond, the preparation method of some I series target compounds is as follows:

[0125]

[0126] Among them, X, ring A, R 1 , R 2 , R 3 and n are as described in the general formula (I).

[0127] The specific reaction process is as follows:

[0128] 5-Bromoisoindolinone raw material A is subjected to Miyaura boric acid esterification to obtain boric acid ester intermediate B;

[0129] The borate intermediate B undergoes Suzuki coupling with the aryl bromide intermediate C under the catalysis of a palladium reagent to obtain the target product.

[0130] Route 2: When R in the general structural formula (I) 4 =R 5 =H, R 6 for When the aromatic heterocyclic pyrrolidone core is connected to ring A via a CN bond, the preparation method of some I series target compounds is as follows:

[0131]

[0132] Among them, X, ring A, R 1 , R 2 , R 3 and n are as described in the general formula (I).

[0133] The specific reaction process is as follows:

[0134] 5-Bromoisoindolinone raw material A is coupled with intermediate D under the catalysis of palladium reagent to obtain the target product.

[0135] Route 3: When R in the general structural formula (I) 4 =R 5 =H, R 6 for And ring A is When, the preparation method of series I target compounds is as follows:

[0136]

[0137] Among them, X, ring A, R 1 , R 2 , R 3 and n are as described in the general formula (I).

[0138] The specific reaction process is as follows:

[0139] 5-Bromoisoindolinone raw material A reacts with tert-butyl carbamate under the catalysis of palladium reagent to generate intermediate A1, and the Boc protecting group is removed under acidic conditions to obtain aromatic amine intermediate A2;

[0140] The aromatic amine intermediate A2 is condensed with the corresponding acyl chloride raw material E to obtain the target product.

[0141] Route 4: When R in the general structural formula (II) 1 =-NHCOCH3, R 4 =R 5 =H and R 6 for When, the preparation method of the II series target compounds is as follows:

[0142]

[0143] Among them, X, ring A, R 2 , R 3 and n are as described in the general formula (I).

[0144] The specific reaction process is as follows:

[0145] The target products of series I are reacted with acetyl chloride or acetic anhydride to obtain target compounds of series II of acetamide.

[0146] Route 5: When X is CH, R 4 =R 5 =H and R 6 for When, the preparation method of the III series target compound is as follows:

[0147]

[0148] Among them, R 1 , R 2 and R 3 As described in general formula (I).

[0149] The specific reaction process is as follows:

[0150] The iodide intermediate F and the borate intermediate B undergo Suzuki coupling under the catalysis of a palladium reagent to obtain the intermediate G;

[0151] Intermediate G is coupled with primary amide or amine raw materials under the catalysis of palladium reagent to obtain intermediate H;

[0152] The intermediate H is deprotected from SEM to obtain the target compounds of series III.

[0153] Route 6: When X is CH, R 2 Selected from -C(O)-NR 2a R 2b, n=1, R 4 =R 5 =H and R 6 for When the IV series target compounds are prepared as follows:

[0154]

[0155] Among them, R 1 , R 2a , R 2b and R 3 As described in general formula (I).

[0156] The specific reaction process is as follows:

[0157] The starting material 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (Compound IV-SM1) is coupled with a primary amide or amine raw material under the catalysis of a palladium reagent to obtain intermediate J;

[0158] Intermediate J undergoes ester hydrolysis reaction in a tetrahydrofuran / water mixed solution of lithium hydroxide to generate carboxylic acid intermediate K;

[0159] The carboxylic acid intermediate K is condensed with different amine fragments to obtain the amide intermediate L, which is then reacted with N-bromosuccinimide to obtain the bromide M;

[0160] The brominated intermediate M is coupled with the intermediate B under the catalysis of a palladium reagent to obtain the intermediate IV-pro-1, and finally the SEM protecting group is removed to obtain the IV series target compounds.

[0161] The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0162] Furthermore, the pharmaceutical composition also includes one or more pharmaceutically acceptable carriers.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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).

[0169] 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.

[0170] In some embodiments, the aforementioned compounds or pharmaceutical compositions 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; 1) Systemic diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, meningitis, headache, neuropathic pain, etc.; 2) Autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic vasculitis; 3) Respiratory system diseases, such as COPD, asthma, pneumonia, tuberculosis, etc.; 4) Metabolic syndrome, such as obesity, hyperglycemia, hypertension, dyslipidemia, hyperuricemia, hyperinsulinemia, etc.; 5) Digestive system, such as viral hepatitis, cirrhosis, liver fibrosis, enteritis, etc.; 6) Tumors, tumor metastasis, tumor complications, etc.

[0171] In some embodiments, the aforementioned compound or pharmaceutical composition provided by the present invention is used to prevent or treat atopic dermatitis or psoriasis.

[0172] Compared with the prior art, the present invention has the following beneficial effects:

[0173] Based on the PI3Kγ target design, the present invention has developed a series of novel aromatic heterocyclic pyrrolidone compounds. Biological experiments have shown that the related compounds exhibit strong PI3Kγ kinase inhibitory activity, especially when ring A is selected from The series of compounds have significant inhibitory activity on PI3Kγ kinase, high selectivity for PI3Kγ isoforms, good safety, and potent inhibitory effect on cytokine secretion of lymphocytes from atopic dermatitis model mice, and have 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. DETAILED DESCRIPTION

[0174] 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.

[0175] The solvents, equipment, codes and full names involved in the embodiments of the present invention are as follows:

[0176] The following abbreviations are used in the examples: HNMR: hydrogen nuclear magnetic resonance; AcOH: acetic acid; Ac2O: acetic anhydride; KOAc: potassium acetate; THF: tetrahydrofuran; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; NBS: N-bromosuccinimide; DME: ethylene glycol dimethyl ether; TMSOK: potassium trimethylsilanolate; MeC N: acetonitrile; BPO: dibenzoyl peroxide; AIBN: azobisisobutyronitrile; m-CPBA: m-chloroperoxybenzoic acid; DCM: dichloromethane; AcCl: acetyl chloride; HMDS: hexamethyldisilazane; SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); TFA: trifluoroacetic acid; TEA: triethylamine; Tol: toluene; TMSCN: trimethylsilyl cyanide; DPPA: diphenylphosphoryl azide; t BuOH: tert-butyl alcohol; TsCl: p-toluenesulfonyl chloride; NMP: N-methylpyrrolidone; i PrONa: sodium isopropoxide; DCE: 1,2-dichloroethane; 3×20mL: 3 times, 20mL each time; LC-MS: liquid chromatography-mass spectrometry; AD: atopic dermatitis.

[0177] Preparation route: Preparation of key intermediate A-1

[0178]

[0179] Step 1: Synthesis of methyl 4-bromo-2-fluoro-6-methylbenzoate (Intermediate A-1-1a)

[0180] Dissolve 4-bromo-2-fluoro-6-methylbenzoic acid (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, use ethyl acetate three times (3×300 mL), combine the organic phases, wash twice with water, wash once with saturated brine, and then dry and concentrate to obtain intermediate A-1-1a (10.20 g), which is used directly in the next step.

[0181] LC-MS (m / z): 247.0 [M+H] + .

[0182] 1H 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).

[0183] Step 2: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (Intermediate A-1-1b)

[0184] The intermediate A-1-1a (10.20 g, 41.28 mmol) was dissolved in acetonitrile (100 mL), and 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 dried by rotation, and the residue was dissolved in petroleum ether, filtered, and the filtrate was dried by rotation to obtain the intermediate A-1-1b (13.5 g), and the crude product was directly used in the next step.

[0185] LC-MS (m / z): 325.0 [M+H] + .

[0186] Step 3: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one (Intermediate A-1-1c)

[0187] The intermediate A-1-1b (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 was 0-20% ethyl acetate in petroleum ether solution, and the intermediate A-1-1c (3.17 g) was obtained, and the three-step yield was 26.3%.

[0188] LC-MS (m / z): 298.0 [M+H] + .

[0189] Step 4: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-hydroxyisoindolin-1-one (Intermediate A-1-1d)

[0190] Dissolve intermediate A-1-1c (3.17 g, 10.63 mmol) in ethylene glycol dimethyl ether (30 mL), replace with nitrogen three times, and add potassium trimethylsilane (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 three times (3×30 mL), combine the organic phases, wash once with water, wash once with saturated brine, dry and concentrate to obtain intermediate A-1-1d (3.00 g), with a yield of 95.2%.

[0191] LC-MS (m / z): 296.0 [M+H] + .

[0192] Step 5: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-difluoromethoxyisoindolin-1-one (Intermediate A-1)

[0193] The intermediate A-1-1d (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 (3×30 mL), the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography, and the eluent was 0-10% ethyl acetate in petroleum ether to obtain intermediate A-1 (1.50 g), with a yield of 42.9%.

[0194] LC-MS (m / z): 346.0 [M+H] + .

[0195] 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).

[0196] Preparation of key intermediate B-1

[0197]

[0198] 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 (Intermediate B-1)

[0199] The intermediate A-1 (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] palladium dichloride (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, with the eluent being 0-10% ethyl acetate: petroleum ether, to obtain the intermediate B-1 (1.70 g), with a yield of 99.4%.

[0200] LC-MS (m / z): 394.0 [M+H] + .

[0201] 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).

[0202] Preparation of key intermediate IV-SM1

[0203]

[0204] Step 1: Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (Intermediate IV-SM1-1a)

[0205] 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (500 mg, 3.08 mmol) was dissolved in 20 mL of methanol, 2 drops of concentrated sulfuric acid were added, and the system was heated to 70°C for overnight reaction. The solvent was removed by concentration under reduced pressure, and the residue was extracted with water (20 mL) and ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure to obtain intermediate IV-SM1-1a (260 mg) with a yield of 47.9%.

[0206] LC-MS (m / z): 177.0 [M+H] + .

[0207] 1 H NMR (400MHz, DMSO-d6): δ12.09(s,1H),8.80(d,J=2.0Hz,1H),8.54(dd,J1=2.0Hz,J2=0.8H z,1H),7.62(dd,J1=3.6Hz,J2=2.4Hz,1H),6.62(dd,J1=3.6Hz,J2=2.0Hz,1H),3.87(s,3H).

[0208] Step 2: Synthesis of 5-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (Intermediate IV-SM1-1b)

[0209] The product of the previous step (260 mg, 1.48 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (280 mg, 1.62 mmol) was added, and the system was heated to 50 ° C for 4 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×20 mL), and the organic phases were combined, dried, and concentrated under reduced pressure to obtain intermediate IV-SM1-1b (158 mg), which was used directly in the next step.

[0210] LC-MS (m / z): 193.0 [M+H] + .

[0211] Step 3: Synthesis of 1-acetyl-6-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (Intermediate IV-SM1-1c)

[0212] The crude product obtained in the previous step was dissolved in ultra-dry tetrahydrofuran (5 mL), the system was replaced with nitrogen, and a tetrahydrofuran solution of hexamethyldisilazane (1 mol / L, 1 mL) was added dropwise under an ice bath, and acetyl chloride (161 mg, 2.06 mmol) was added dropwise after stirring for 5 minutes, and the system was stirred at room temperature for 1 hour. Water was added to quench, and the mixture was extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure, and the residue was separated by column chromatography to obtain intermediate IV-SM1-1c (40 mg), with a two-step yield of 10.8%.

[0213] LC-MS (m / z): 253.0 [M+H] + .

[0214] 1 H NMR (400MHz, DMSO-d6): δ8.61 (s, 1H), 8.11 (d, J = 4.4Hz, 1H), 6.90 (d, J = 4.4Hz, 1H), 3.91 (s, 3H), 2.93 (s, 3H).

[0215] Step 4: Synthesis of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Intermediate IV-SM1-1d)

[0216] The intermediate IV-SM1-1c (250 mg, 1.00 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), sodium hydroxide (79 mg, 1.98 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water was added to quench, and the pH was adjusted to weak acidity with 1N citric acid solution, and extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water and then with saturated brine, dried, and concentrated under reduced pressure to obtain the intermediate IV-SM1-1d (210 mg) with a yield of 99.9%.

[0217] LC-MS (m / z): 211.0 [M+H] + .

[0218] 1 H NMR (400MHz, DMSO-d6): δ12.21(s,1H),8.53(s,1H),7.64(d,J=3.2Hz,1H),6.62(d,J=3.2Hz,1H),3.87(s,3H).

[0219] Step 5: Synthesis of methyl 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Intermediate IV-SM1)

[0220] The intermediate IV-SM1-1d (210 mg, 1.00 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (60 mg, 1.50 mmol) was added under ice bath, 2-(trimethylsilyl)ethoxymethyl chloride (249 mg, 1.50 mmol) was added after stirring for 15 minutes, and the mixture was stirred at room temperature for 1 hour. Water was added to quench, and the mixture was extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and then with saturated brine, dried, and concentrated under reduced pressure to obtain the intermediate IV-SM1 (240 mg) with a yield of 70.6%.

[0221] LC-MS (m / z): 341.0 [M+H] + .

[0222] Preparation of key intermediate F-7

[0223]

[0224] Step 1: Synthesis of 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-7-1a)

[0225] 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 53.19 mmol) was dissolved in DMF (20 mL), and NaH (3.2 g, 79.78 mmol) was added under ice bath. After stirring for 15 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (10.6 mg, 63.83 mmol) was added and reacted at room temperature for 1 hour. The system was quenched with water (30 mL), extracted with EA (3×20 mL), and the organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in turn, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:1) to obtain intermediate F-7-1a (7.67 g) with a yield of 45.5%.

[0226] LC-MS (m / z): 318.0 [M+H] + .

[0227] Step 2: Synthesis of 2-chloro-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-7-1b)

[0228] The intermediate F-7-1a (7.67 g, 24.01 mmol) was dissolved in methanol (20 mL), sodium methoxide (1.95 g, 36.15 mmol) was added, and the system was heated to 70 ° C and stirred for 1 hour. 30 mL of water was added to the reaction, and it was extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in turn, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate F-7-1b (7.56 g) with a yield of 99.8%.

[0229] LC-MS (m / z): 314.0 [M+H] + .

[0230] Step 3: Synthesis of N-(4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (Intermediate F-7-1c)

[0231] The intermediate F-7-1b (7.56 g, 24.09 mmol), acetamide (2.13 g, 36.13 mmol), tris(dibenzylideneacetone)dipalladium (2.21 g, 2.41 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (2.30 g, 4.82 mmol) and cesium carbonate (15.70 g, 48.17 mmol) were dissolved in toluene (20 mL), replaced with nitrogen three times, and the system was heated to 100 ° C and stirred for 2 hours. The system was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in sequence, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=2:1) ​​to give compound F-7-1c (5.50 g) with a yield of 67.8%.

[0232] LC-MS (m / z): 337.0 [M+H] + .

[0233] Step 4: Synthesis of N-(5-bromo-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (Intermediate F-7)

[0234] Compound F-7-1c (5.50 g, 16.35 mmol) was dissolved in DMF (10 mL), and a DMF solution (10 mL) of NBS (2.91 g, 16.35 mmol) was added dropwise under an ice bath, and the system was heated to room temperature and stirred for 1 hour. Water was added to quench (30 mL), and the mixture was extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in sequence, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=2:1) ​​to obtain intermediate F-7 (6.30 g) with a yield of 92.7%.

[0235] LC-MS (m / z): 415.0 [M+H] + .

[0236] Example 1, (S)-5-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-1)

[0237]

[0238] Step 1: Synthesis of N-(5-bromo-2-nitrophenyl)-1-methyl-1H-pyrazol-4-amine (Intermediate C-1-1a)

[0239] 2-Fluoro-4-bromonitrobenzene (500g, 2.27mmol), 1-methyl-1H-pyrazole-4-amine (243mg, 2.50mmol) and potassium carbonate (628mg, 4.55mmol) were dissolved in N,N-dimethylformamide (10mL), and the reaction solution was heated to 100°C and stirred for 2 hours. The system was cooled to room temperature, and a large amount of solid was precipitated after adding water. It was filtered under reduced pressure, and the filter cake was washed with water and dried to obtain intermediate C-1-1a (689mg), which was used directly in the next step.

[0240] LC-MS (m / z): 297.0 [M+H] + .

[0241] Step 2: Synthesis of 5-bromo-N-(1-methyl-1H-pyrazol-4-yl)benzene-1,2-diamine (Intermediate C-1-1b)

[0242] The crude intermediate C-1-1a obtained in the previous step was dissolved in 20 mL of methanol and 2 mL of water, and 639 mg of reduced iron powder and 1.23 g of ammonium chloride were added, and the temperature was raised to 70 ° C and stirred for 1 hour. The system was filtered while hot, and the filter cake was washed with ethyl acetate. The filtrate was combined, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3×20 mL), washed with saturated brine (50 mL), and concentrated under reduced pressure to obtain the intermediate C-1-1b (478 mg), which was used directly in the next step.

[0243] LC-MS (m / z): 267.0 [M+H] + .

[0244] Step 3: Synthesis of 6-bromo-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine (Intermediate C-1)

[0245] The crude intermediate C-1-1b obtained in the previous step was dissolved in 15 mL of methanol, 379 mg of cyanogen bromide was added, and the temperature was raised to 60°C and stirred for 2 hours. Water was added to quench the mixture, and the mixture was extracted three times with ethyl acetate (3×20 mL), and the combined organic phase was washed with saturated brine (30 mL), and concentrated under reduced pressure to obtain the intermediate C-1 (510 mg), which was used directly in the next step.

[0246] LC-MS (m / z): 292.0 [M+H] + .

[0247] Step 4: Synthesis of (S)-5-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-1)

[0248] Dissolve 70 mg of the crude intermediate C-1 obtained in the previous step in 5 mL of dioxane and 1 mL of water, add intermediate B-1 (141 mg), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (17 mg) and potassium carbonate (157 mg), heat to 100°C and stir for 1 hour. Quench with water, extract with ethyl acetate three times (3×20 mL), wash with saturated brine (30 mL), concentrate under reduced pressure, and purify the residue by full preparative liquid chromatography to obtain the target compound I-1 (20 mg), with a total yield of 14.0%.

[0249] LC-MS (m / z): 480.0 [M+H] + .

[0250] 1 H NMR (400MHz, DMSO-d6): δ8.17(d,J=4.8Hz,1H),7.76(d,J=0.4Hz,1H),7.71(d,J=1.2 Hz,1H),7.66(t,J=75.2Hz,1H),7.42-7.39(m,1H),7.29(d,J=8.0Hz,1H),7.18(d,J= 1.6Hz,1H),6.47(s,2H),4.57(s,2H),3.94(s,3H),3.59-3.52(m,1H),1.28(d,J=6.8 Hz,3H),1.15-1.06(m,1H),0.60-0.54(m,1H),0.44-0.34(m,2H),0.27-0.22(m,1H).

[0251] Example 2, (S)-5-(2-amino-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-2)

[0252]

[0253] Step 1: Synthesis of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate C-2-1a)

[0254] 2,4-Dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.00 g, 6.37 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (229 mg, 9.56 mmol) was added, the mixture was stirred at room temperature for 15 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (1.59 g, 9.56 mmol) was added and stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with ethyl acetate three times (3×20 mL), the combined organic phase was washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, eluted with petroleum ether:ethyl acetate = 10%, to obtain intermediate C-2-1a (2.35 g), with a yield of 83.0%.

[0255] LC-MS (m / z): 444.0 [M+H] + .

[0256] 1 H NMR (400MHz, DMSO-d6): δ8.15(s,1H),5.58(s,2H),3.57-3.51(m,2H),0.86-0.82(m,2H),-0.07(s,9H).

[0257] Step 2: Synthesis of 2-chloro-5-iodo-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate C-2)

[0258] Dissolve the intermediate C-2-1a (2.35 g, 5.29 mmol) in methanol (10 mL), add sodium methoxide (372 mg, 6.88 mmol), heat to 50 ° C and stir for 3 hours. The mixture is evaporated under reduced pressure to remove methanol, the concentrate is quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases are combined, the organic phases are washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to obtain the intermediate C-2 (2.32 g) with a yield of 99.6%.

[0259] LC-MS (m / z): 440.0 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6): δ7.78(s,1H),5.48(s,2H),4.07(s,3H),3.52-3.48(m,2H),0.87-0.81(m,2H),-0.09(s,9H).

[0261] Step 3: Synthesis of (S)-5-(2-chloro-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (Intermediate I-2-pro1)

[0262] Intermediate C-2 (200 mg, 0.46 mmol), intermediate B-1 (198 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (17 mg, 0.02 mmol) and cesium carbonate (370 mg, 1.14 mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (10 mL / 1 mL), replaced with nitrogen three times, and heated to 80 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate I-2-pro1 (204 mg) with a yield of 77.6%.

[0263] LC-MS (m / z): 579.0 [M+H] + .

[0264] Step 4: Synthesis of tert-butyl (S)-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)carbamate (Intermediate I-2-pro2)

[0265] The intermediate I-2-pro1 (204 mg, 0.35 mmol), tert-butyl carbamate (62 mg, 0.53 mmol), tris(dibenzylideneacetone)dipalladium (32 g, 0.04 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (44 mg, 0.07 mmol) and cesium carbonate (287 mg, 0.88 mmol) were dissolved in toluene (10 mL), replaced with nitrogen three times, and heated to 100 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, eluted with petroleum ether: ethyl acetate = 30%, to obtain the intermediate I-2-pro2 (143 mg), with a yield of 61.6%.

[0266] LC-MS (m / z): 660.0 [M+H] + .

[0267] 1 H NMR (400MHz, DMSO-d6): δ9.76(s,1H),7.82(s,1H),7.76(s,1H),7.56(s,1H) ,7.53(t,J=50.0Hz,1H),5.56(s,2H),4.59(s,2H),4.02(s,3H),3.60-3.55( m,3H),1.48(s,9H),1.30(d,J=4.8Hz,3H),1.19-1.11(m,1H),0.91-0.88(m, 2H),0.60-0.56(m,1H),0.44-0.36(m,2H),0.27-0.23(m,1H),-0.07(s,9H).

[0268] Step 5: Synthesis of (S)-5-(2-amino-7-(hydroxymethyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-2)

[0269] The intermediate I-2-pro2 (140 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2.5 mL) was added dropwise, and stirred at room temperature for 1 hour. The mixture was quenched with water, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and extracted with dichloromethane three times (3×20 mL), the organic phases were combined, the organic phases were washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the target compound I-2 (90 mg) with a yield of 98.9%.

[0270] LC-MS (m / z): 430.0 [M+H] + .

[0271] 1 H NMR (400MHz, DMSO-d6): δ11.57(s,1H),7.72(s,1H),7.54(s,1H),7.51(t,J=50.4Hz,1H),7.34(d,J=1.6Hz,1H),6.32(s,2H),4.56(s,2 H),3.94(s,3H),3.58-3.53(m,1H),1.29(d,J=4.4Hz,3H),1.16-1.10(m,1H),0.60-0.56(m,1H),0.44-0.36(m,2H),0.27-0.23(m,1H).

[0272] Example 3, (S)-5-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-3)

[0273]

[0274] Step 1: Synthesis of (5-nitro-1H-pyrazol-3-yl)methanol (Intermediate D-1-1a)

[0275] 5-Nitro-1H-pyrazole-3-carboxylic acid (1.00 g, 6.40 mmol) was dissolved in tetrahydrofuran (15 mL), the reaction system was cooled to -5 °C, nitrogen was replaced three times, borane tetrahydrofuran solution (19 mL / 19 mmol) was added dropwise at -5 °C, and the reaction solution was heated to room temperature for 16 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, 2M HCl (6 mL) was added to quench the reaction, and the temperature was raised to 75 °C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times (3×20 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain intermediate D-1-1a (916 mg) with a yield of 100%.

[0276] LC-MS (m / z): 144.0 [M+H] + .

[0277] 1 H NMR (400MHz, DMSO-d6): δ13.91 (s, 2H), 6.87 (s, 1H), 5.60 (t, J = 5.6Hz, 1H), 4.54 (d, J = 4.8Hz, 1H).

[0278] Step 2: Synthesis of tert-butyl (2-(5-(hydroxymethyl)-3-nitro-1H-pyrazol-1-yl)ethyl)carbamate (Intermediate D-1-1b)

[0279] The intermediate D-1-1a (866 mg, 6.05 mmol) was dissolved in N, N-dimethylformamide (15 mL), and cesium carbonate (3.94 g, 12.10 mmol) and (2-bromoethyl) tert-butyl carbamate (2.03 g, 9.08 mmol) were added in sequence, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and it was extracted three times with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography, eluted with 0-55% ethyl acetate in petroleum ether solution to obtain intermediate D-1-1b (1.08 g) with a yield of 62.4%.

[0280] LC-MS (m / z): 287.0 [M+H] + .

[0281] Step 3: Synthesis of (1-(2-aminoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (Intermediate D-1-1c)

[0282] Dissolve the intermediate D-1-1b (1.08 g, 5.06 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (7.5 mL), and react at room temperature for 2 hours. After the reaction is completed, concentrate the reaction mixture to dryness to obtain the intermediate D-1-1c (614 mg) with a yield of 65.1%.

[0283] LC-MS (m / z): 187.0 [M+H] + .

[0284] Step 4: Synthesis of 2-(5-(bromomethyl)-3-nitro-1H-pyrazol-1-yl)ethane-1-amine (Intermediate D-1-1d)

[0285] Dissolve the intermediate D-1-1c (614 mg, 5.06 mmol) in tetrahydrofuran (10 mL), cool to 0 ° C, add phosphorus tribromide (2.05 g, 7.60 mmol) dropwise, and warm to room temperature for 1 hour. After the reaction is completed, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with ethyl acetate three times (3×20 mL), wash the combined organic phase with saturated sodium chloride aqueous solution (30 mL), dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated to dryness to obtain the intermediate D-1-1d (358 mg), and the crude product is directly used in the next step.

[0286] LC-MS (m / z): 249.0 [M+H] + .

[0287] Step 5: Synthesis of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (Intermediate D-1)

[0288] The crude intermediate D-1-1d prepared in the previous step was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (700 mg, 5.06 mmol) was added, and the reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and it was extracted three times with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography, eluted with 0-50% methanol in ethyl acetate solution to obtain intermediate D-1 (216 mg), with a two-step yield of 25.4%.

[0289] LC-MS (m / z): 169.0 [M+H] + .

[0290] Step 6: Synthesis of (S)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)-5-(2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)isoindolin-1-one (Intermediate I-3-pro1)

[0291] Intermediate D-1 (60 mg, 0.36 mmol), intermediate A-1 (185 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (33 mg, 0.018 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (21 mg, 0.036 mmol) and potassium carbonate (100 mg, 0.72 mmol) were dissolved in 1,4-dioxane (2 mL) and replaced with nitrogen three times. The reaction solution was heated to 95 ° C and stirred for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and ethyl acetate was extracted three times (3×10 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography, eluted with 0-35% ethyl acetate in petroleum ether to obtain intermediate I-3-pro1 (51 mg) with a yield of 32.7%.

[0292] LC-MS (m / z): 434.0 [M+H] + .

[0293] Step 7: Synthesis of (S)-5-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-3)

[0294] The intermediate I-3-pro1 (51 mg, 0.12 mmol) was dissolved in ethanol / water (2 mL / 0.2 mL), and reduced iron powder (34.00 g, 0.60 mmol) and ammonium chloride (64 mg, 1.20 mmol) were added. The reaction solution was heated to 80 ° C for 3 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth and the filtrate was concentrated to dryness. Water (10 mL) was added to the residue, and it was extracted three times with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the target compound I-3 (48 mg) with a yield of 100%.

[0295] LC-MS (m / z): 404.0 [M+H] + .

[0296] 1 H NMR (400MHz, DMSO-d6): δ7.57(t,J=50.8Hz,1H),7.07(d,J=1.6Hz,1H),6.8 2(d,J=1.6Hz,1H),5.33(s,1H),4.57(s,2H),4.47(s,2H),4.45(s,2H),3.91 -3.89(m,2H),3.86-3.84(m,2H),3.52-3.47(m,1H),1.24(d,J=4.4Hz,3H), 1.11-1.05(m,1H),0.57-0.53(m,1H),0.41-0.32(m,2H),0.23-0.19(m,1H).

[0297] Example 4, (S)-2-amino-5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (target compound I-4)

[0298]

[0299] Step 1: Synthesis of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester (Intermediate D-2-1a)

[0300] Dissolve 5-nitro-1H-pyrazole-3-carboxylic acid (3.00 g, 19.10 mmol) in methanol (40 mL), cool the reaction system to 0 ° C, add dichlorothionyl (11.36 g, 95.50 mmol), add dropwise, and heat the reaction solution to 70 ° C for 4 hours. After the reaction is completed, the reaction solution is cooled to 0 ° C, 2M HCl (6 mL) is added to quench the reaction, and the temperature is raised to 75 ° C for 1 hour. After the reaction is completed, the reaction solution is concentrated to dryness, ethyl acetate (40 mL) is added, and the saturated sodium bicarbonate aqueous solution is washed twice (2×20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to dryness to obtain intermediate D-2-1a (2.85 g) with a yield of 86.4%.

[0301] 1 H NMR (400MHz, DMSO-d6): δ15.25(s,1H),7.53(s,1H),3.90(s,3H).

[0302] Step 2: Synthesis of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-nitro-1H-pyrazole-5-carboxylic acid methyl ester (Intermediate D-2-1b)

[0303] The intermediate D-2-1a (1.50 g, 8.77 mmol) was dissolved in N, N-dimethylformamide (40 mL), and cesium carbonate (5.71 g, 17.54 mmol) and (2-bromoethyl) tert-butyl carbamate (2.95 g, 13.15 mmol) were added in sequence, and stirred at room temperature for 5 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and ethyl acetate was extracted three times (3×60 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether solution to obtain intermediate D-2-1b (1.36 g) with a yield of 49.3%.

[0304] LC-MS (m / z): 315.0 [M+H] + .

[0305] 1 H NMR (400MHz, DMSO-d6): δ7.57(s,1H),6.96(t,J=6.4Hz,1H),4.64-4.58(m,2H),3.89(s,3H),3.40-3.35(m,2H),1.26(s,9H).

[0306] Step 3: Synthesis of 1-(2-aminoethyl)-3-nitro-1H-pyrazole-5-carboxylic acid methyl ester (Intermediate D-2-1c)

[0307] Dissolve intermediate D-2-1b (1.36 g, 4.33 mmol) in dichloromethane (16 mL), add trifluoroacetic acid (8 mL), and stir the reaction solution at room temperature for 2 hours. After the reaction is completed, concentrate the reaction mixture to dryness to obtain intermediate D-2-1c (927 mg), which is used directly in the next step.

[0308] LC-MS (m / z): 215.0 [M+H] + .

[0309] Step 4: Synthesis of 2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate D-2)

[0310] The crude intermediate D-2-1c (927 mg, 4.33 mmol) obtained in the previous step was dissolved in methanol (15 mL), and triethylamine (1.30 g, 13 mmol) was added to react for 4 hours. After the reaction was completed, it was concentrated to dryness, ethyl acetate (10 mL) was added to slurry, and the intermediate D-2 (437 mg) was obtained by filtration, with a two-step yield of 55.5%.

[0311] LC-MS (m / z): 183.0 [M+H] + .

[0312] 1 H NMR (400MHz, DMSO-d6): δ8.62(s,1H),7.43(s,1H),4.48-4.44(m,2H),3.71-3.68(m,2H);

[0313] Step 5: Synthesis of (S)-5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Intermediate I-4-pro1)

[0314] Intermediate D-2 (150 mg, 0.80 mmol), intermediate A-1 (420 mg, 1.20 mmol), cuprous iodide (8 mg, 0.04 mmol), N,N-dimethylethylenediamine (7 mg, 0.08 mmol) and potassium carbonate (220 mg, 1.60 mmol) were dissolved in toluene (5 mL), replaced with nitrogen three times, and the reaction solution was heated to 95 ° C and stirred for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and ethyl acetate was extracted three times (3×10 mL). The combined organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography, eluted with 0-45% ethyl acetate in petroleum ether to obtain intermediate I-4-pro1 (360 mg) with a yield of 97.8%.

[0315] LC-MS (m / z): 448.0 [M+H] + .

[0316] Step 6: Synthesis of (S)-2-amino-5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (target compound I-4)

[0317] The intermediate I-4-pro1 (360 mg, 0.80 mmol) was dissolved in methanol (10 mL), 10% palladium carbon (36 mg, 10%) was added, hydrogen was replaced three times, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain the target compound I-4 (323 mg) with a yield of 96.7%.

[0318] LC-MS (m / z): 418.0 [M+H] + .

[0319] 1 H NMR (400MHz, DMSO-d6): δ7.58(t,J=74.8Hz,1H),7.54(d,J=1.6Hz,1H),7.31(d,J=2.0Hz,1H),5.95(s,1H),4.97(s,2H),4.57(s,2H),4.26-4.23 (m,2H),4.20-4.17(m,2H),3.58-3.51(m,1H),1.29(d,J=6.8Hz,3H),1.1 7-1.08(m,1H),0.60-0.54(m,1H),0.44-0.35(m,2H),0.26-0.21(m,1H).

[0320] Example 5, (S)-2-amino-N-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)pyrimidine-5-carboxamide (target compound I-5)

[0321]

[0322] Step 1: Synthesis of tert-butyl (S)-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)carbamate (Intermediate A1-1)

[0323] The intermediate A-1 (500 mg, 1.44 mmol) was dissolved in toluene (5 mL), tert-butyl carbamate (203 mg, 1.73 mmol), cesium carbonate (941 mg, 2.89 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (90 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium (66 mg, 0.07 mmol) were added, and the mixture was replaced with nitrogen three times and heated to 100°C and stirred for 7 hours. After the reaction was completed, the reaction solution was dried by rotary evaporation, and the residue was separated by column chromatography, with the eluent being 0-20% ethyl acetate in petroleum ether solution, to obtain the intermediate A1-1 (240 mg), with a yield of 43.5%.

[0324] LC-MS (m / z): 383.0 [M+H] + .

[0325] Step 2: Synthesis of (S)-5-amino-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (Intermediate A2-1)

[0326] Intermediate A1-1 (240 mg, 0.63 mmol) was dissolved in 4M hydrochloric acid ethyl acetate solution (4 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was spin-dried to obtain intermediate A2-1 (160 mg), which was used directly in the next step.

[0327] LC-MS (m / z): 283.0 [M+H] + .

[0328] Step 3: Synthesis of (S)-2-amino-N-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)pyrimidine-5-carboxamide (target compound I-5)

[0329] Dissolve intermediate A2-1 (100 mg, 0.35 mmol) in dichloromethane (2 mL), add 2-aminopyrimidine-5-yl chloride (intermediate E-1, 167 mg, 1.06 mmol) and triethylamine (72 mg, 0.71 mmol). Stir the mixture at room temperature for 1 hour. After the reaction, add 5 mL of saturated sodium bicarbonate solution dropwise, extract with ethyl acetate three times (3×5 mL), combine the organic phases, dry and concentrate, and separate the residue by preparative separation to obtain the target compound I-5 (15 mg) with a yield of 10.5%.

[0330] LC-MS (m / z): 404.0 [M+H] + .

[0331] 1H NMR (400MHz, DMSO-d6): δ10.40(s,1H),8.82(s,2H),7.95(d,J=1.6Hz,1H),7.64(d,J=1.2Hz,1H),7.54(t,J=74.8Hz,1H),7.43(s,2H ), 4.56 (s, 2H), 3.57-3.49 (m, 1H), 1.28 (d, J = 6.8Hz, 3H), 1.16-1.07 (m, 1H), 0.60-0.54 (m, 1H), 0.44-0.33 (m, 2H), 0.26-0.21 (m, 1H).

[0332] Example 6, (S)-5-(6-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-6)

[0333]

[0334] Step 1: Synthesis of 1H-pyrrolo[2,3-b]pyridine-7-oxide (Intermediate C-3-1a)

[0335] 1H-pyrrolo[2,3-b]pyridine (5.00 g, 28.74 mmol) was dissolved in dichloromethane (30 mL), and m-chloroperbenzoic acid (9.92 g, 57.47 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was filtered under reduced pressure, and the filter cake was washed three times with dichloromethane (3×20 mL), and the filter cake was collected. The filter cake was dried under reduced pressure to obtain intermediate C-3-1a (7.07 g), and the crude product was used directly in the next step.

[0336] LC-MS (m / z): 135.0 [M+H] + .

[0337] Step 2: Synthesis of 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (Intermediate C-3-1b)

[0338] The intermediate C-3-1a (1.71 g, 12.75 mmol) was dissolved in acetonitrile (20 mL), trimethylsilyl cyanide (7.59 g, 76.49 mmol) and triethylamine (3.23 g, 31.87 mmol) were added, and the temperature was raised to 80 ° C for three days. After the mixture was cooled to room temperature, it was quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, the organic phases were washed with water three times (3×20 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, eluted with petroleum ether: ethyl acetate = 30%, and the intermediate C-3-1b (581 mg) was obtained, with a two-step yield of 31.9%.

[0339] LC-MS (m / z): 144.0 [M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6): δ12.26 (s, 1H), 8.18 (dd, J1 = 8.0Hz, J2 = 1.6Hz, 1H), 7.85-7.83 (m, 1H), 7.63 (d, J = 8.4Hz, 1H), 6.64 (dd, J1 = 3.2Hz, J2 = 1.6Hz, 1H).

[0341] Step 3: Synthesis of 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (Intermediate C-3-1c)

[0342] Intermediate C-3-1b (531 mg, 3.71 mmol) was dissolved in concentrated hydrochloric acid (2 mL), heated to 100°C and reacted for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain intermediate C-3-1c (480 mg), which was used directly in the next step.

[0343] LC-MS (m / z): 163.0 [M+H] + .

[0344] Step 4: Synthesis of 1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (Intermediate C-3-1d)

[0345] The intermediate C-3-1c prepared in the previous step was dissolved in methanol (20 mL), and two drops of concentrated sulfuric acid were added, and the temperature was raised to 60°C and stirred overnight. The mixture was cooled to room temperature and then evaporated under reduced pressure, quenched with water, and the pH was adjusted to 7-8 with a saturated sodium carbonate solution. A large amount of solid precipitated, and the filter cake was filtered under reduced pressure, and the filter cake was washed three times with ethyl acetate (3×20 mL) and dried to obtain the intermediate C-3-1d (571 mg), which was used directly in the next step.

[0346] LC-MS (m / z): 177.0 [M+H] + .

[0347] 1 H NMR (400MHz, DMSO-d6): δ12.14(s,1H),8.11(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),7.77(d,J=3.2Hz,1H),6.58(d,J=3.2Hz,1H),3.88(s,3H).

[0348] Step 5: Synthesis of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (Intermediate C-3-1e)

[0349] The crude intermediate C-3-1d (521 mg, 2.96 mmol) prepared in the previous step was dissolved in N, N-dimethylformamide (5 mL), sodium hydride (106 mg, 4.44 mmol) was added under ice bath, 2-(trimethylsilyl)ethoxymethyl chloride (740 mg, 4.44 mmol) was added after stirring for 15 minutes, and the mixture was reacted at room temperature for 2 hours. The reaction was quenched by adding water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography, eluted with petroleum ether: ethyl acetate = 18%, to obtain intermediate C-3-1e (446 mg), with a three-step yield of 48.7%.

[0350] LC-MS (m / z): 307.0 [M+H] + .

[0351] Step 6: Synthesis of methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (Intermediate C-3-1f)

[0352] Dissolve the intermediate C-3-1e (200 mg, 0.65 mmol) in N,N-dimethylformamide (2 mL), add N-bromosuccinimide (140 mg, 0.78 mmol), and stir at room temperature for 1 hour. The reaction is quenched by adding water, extracted three times with ethyl acetate (3×20 mL), the organic phases are combined, washed with water three times (3×20 mL), washed 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, eluted with petroleum ether: ethyl acetate = 15%, to obtain the intermediate C-3-1f (250 mg), with a yield of 99.6%.

[0353] LC-MS (m / z): 385.0 [M+H] + .

[0354] 1 H NMR (400MHz, DMSO-d6): δ8.22(s,1H),8.07(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H ),5.66(s,2H),3.91(s,3H),3.56-3.52(m,2H),0.87-0.83(m,2H),-0.12(s,9H).

[0355] Step 7: Synthesis of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (Intermediate C-3-1g)

[0356] Dissolve the intermediate C-3-1f (330 mg, 0.86 mmol) in tetrahydrofuran / water (2 mL / 1 mL), add lithium hydroxide monohydrate (72 mg, 1.71 mmol), and react for 5 hours. Remove the solvent under reduced pressure, add water (10 mL), adjust the pH to 4-5, extract with ethyl acetate three times (3×20 mL), combine the organic phases, wash the organic phases with water three times (3×20 mL), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure to obtain the intermediate C-3-1g (320 mg), with a yield of 100%.

[0357] LC-MS (m / z): 371.0 [M+H] + .

[0358] Step 8: Synthesis of tert-butyl (3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamate (Intermediate C-3)

[0359] Dissolve the intermediate C-3-1g (300mg, 0.81mmol), diphenylphosphoryl azide (267mg, 0.97mmol) and triethylamine (90mg, 0.89mmol) in tert-butyl alcohol (5mL), heat to 35℃ for reaction for 0.5 hours, and continue to heat to 80℃ for reaction for 1 hour. After the mixture is cooled to room temperature, it is quenched with water, extracted with ethyl acetate three times (3×20mL), the organic phases are combined, the organic phases are washed with water three times (3×20mL), washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography, eluted with petroleum ether: ethyl acetate = 5.8%, and intermediate C-3 (377mg) is obtained with a yield of 98.9%.

[0360] LC-MS (m / z): 442.0 [M+H] + .

[0361] Step 8: Synthesis of tert-butyl (S)-(3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamate (Intermediate I-6-pro1)

[0362] Intermediate C-3 (327 mg, 0.74 mmol), intermediate B-1 (320 mg, 0.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (54 mg, 0.07 mmol) and cesium carbonate (482 mg, 1.48 mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (5 mL / 1 mL), replaced with nitrogen three times, and heated to 90 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 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, eluted with petroleum ether: ethyl acetate = 20%, and intermediate I-6-pro1 (255 mg) was obtained with a yield of 55.0%.

[0363] LC-MS (m / z): 629.0 [M+H] + .

[0364] Step 10: Synthesis of (S)-5-(6-amino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy) (target compound I-6)

[0365] The intermediate I-6-pro1 (45 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was quenched with water, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, the organic phases were washed with water three times (3×20 mL), washed with saturated brine (50 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, methanol: dichloromethane = 10% to obtain the target compound I-6 (10 mg), with a yield of 27.0%.

[0366] LC-MS (m / z): 399.0 [M+H] + .

[0367] 1H NMR (400MHz, DMSO-d6): δ11.32(d,J=1.6Hz,1H),7.99(d,J=6.0Hz,1H),7.75(s, 1H),7.60(t,J=50.0Hz,1H),7.58(d,J=1.6Hz,1H),7.41(s,1H),6.40(d,J=5.6H z,1H),5.78(s,2H),4.58(d,J=1.2Hz,2H),3.59-3.54(m,1H),1.29(d,J=4.4Hz, 3H),1.15-1.09(m,1H),0.60-0.56(m,1H),0.44-0.36(m,2H),0.27-0.23(m,1H).

[0368] Example 7, (S)-5-(2-aminoimidazo[1,2-a]pyridin-6-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-7)

[0369]

[0370] Step 1: Synthesis of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (Intermediate C-4-1a)

[0371] Dissolve 2-amino-5-bromopyridine (1.00 g, 5.78 mmol) in 1,2-dichloroethane (10 mL), replace with nitrogen three times, add ethyl 3-bromopyruvate (1.13 g, 5.78 mmol), stir the mixture at room temperature for 6 hours, and a large amount of solid precipitates. Filter under reduced pressure to obtain 2.5 g of white solid, redissolve in ethanol (10 mL), heat to 70 ° C and react for 2 hours. Cool to room temperature and concentrate under reduced pressure to obtain intermediate C-4-1a (2.47 g), the crude product is directly used in the next step.

[0372] LC-MS (m / z): 269.0 [M+H] + .

[0373] Step 2: Synthesis of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid (Intermediate C-4-1b)

[0374] The intermediate C-4-1a prepared in the previous step was dissolved in tetrahydrofuran / methanol / water (5mL / 5mL / 2mL), and lithium hydroxide monohydrate (717mg, 17.09mmol) was added, and the reaction was carried out at room temperature for 2 hours. The organic solvent was removed under reduced pressure, and water (5mL) was added to adjust the pH to 6. A large amount of white solid precipitated, and the filter cake was collected under reduced pressure and slurried with 10mL of ethyl acetate, filtered again, and the filter cake was dried to obtain the intermediate C-4-1b (994mg), which was used directly in the next step.

[0375] LC-MS (m / z): 241.0 [M+H] + .

[0376] Step 3: Synthesis of tert-butyl (6-bromoimidazo[1,2-a]pyridin-2-yl)carbamate (Intermediate C-4)

[0377] Take the intermediate C-4-1b (900 mg) prepared in the previous step and dissolve it in tert-butanol (10 mL), add diphenylphosphoryl azide (1233 mg, 4.48 mmol) and triethylamine (416 mg, 4.11 mmol), heat to 35 ° C for 0.5 hours, and continue to heat to 80 ° C for overnight. After the mixture is cooled to room temperature, it is quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases are combined, the organic phases are washed with water three times (3×20 mL), washed 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, eluted with petroleum ether: ethyl acetate = 30%, and intermediate C-4 (303 mg) is obtained, with a total yield of 18.6% in three steps;

[0378] LC-MS (m / z): 312.0 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d6): δ10.02 (s, 1H), 8.83 (dd, J1=2.0Hz, J2=1.2Hz, 1H), 7. 86(s,1H),7.37-7.35(m,1H),7.29(dd,J1=9.2Hz,J2=1.2Hz,1H),1.48(s,9H).

[0380] Step 4: Synthesis of tert-butyl (S)-(6-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)imidazo[1,2-a]pyridin-2-yl)carbamate (Intermediate I-7-pro1)

[0381] Intermediate C-4 (253 mg, 0.81 mmol), intermediate B-1 (351 mg, 0.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (59 mg, 0.08 mmol) and cesium carbonate (528 mg, 1.62 mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (5 mL / 1 mL), replaced with nitrogen three times, and heated to 90 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 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, methanol: dichloromethane = 7% to obtain intermediate I-7-pro1 (460 mg), with a yield of 95.0%.

[0382] LC-MS (m / z): 499.0 [M+H] + .

[0383] Step 5: Synthesis of (S)-5-(2-aminoimidazo[1,2-a]pyridin-6-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-7)

[0384] The intermediate I-7-pro1 (410 mg, 0.82 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 hours. After the mixture was cooled to room temperature, water was added to quench it, and the pH was adjusted to 7-8 with saturated sodium bicarbonate. It was extracted three times with ethyl acetate (3×20 mL), and the organic phases were combined. The organic phases were washed with water three times (3×20 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 preparative thin layer chromatography, methanol: dichloromethane = 7% to obtain the target compound I-7 (123 mg), with a yield of 37.4%.

[0385] LC-MS (m / z): 399.0 [M+H] + .

[0386] 1H NMR (400MHz, DMSO-d6): δ8.83(d,J=1.6Hz,1H),7.79(d,J=1.2Hz,1H),7.67(t ,J=75.2Hz,1H),7.50(s,1H),7.44(dd,J1=9.2Hz,J2=2.0Hz,1H),7.31(s,1H), 7.04(s,1H),5.20(s,2H),4.60(s,2H),3.58-3.54(m,1H),1.30(d,J=6.8Hz,3H ),1.19-1.10(m,1H),0.61-0.55(m,1H),0.45-0.36(m,2H),0.27-0.23(m,1H).

[0387] Example 8, (S)-5-(2-aminoimidazo[1,2-a]pyridin-6-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-8)

[0388]

[0389] Step 1: Synthesis of 5-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (Intermediate D-3-1a)

[0390] 5-Bromo-1H-pyrrolo[3,2-b]pyridine (1.00 g, 5.08 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (122 mg, 7.61 mmol) was added, and p-toluenesulfonyl chloride (1.45 g, 7.61 mmol) was added after stirring at room temperature for 15 minutes, and stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 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, petroleum ether: ethyl acetate = 15% to obtain intermediate D-3-1a (1.60 g) with a yield of 89.8%.

[0391] LC-MS (m / z): 351.0 [M+H] + .

[0392] 1H NMR (400MHz, DMSO-d6): δ8.28 (dd, J1=8.4Hz, J2=0.8Hz, 1H), 8.21 (d, J=3.6Hz, 1H), 7.93-7.91 (m, 2H),7.55(d,J=8.8Hz,1H),7.43(d,J=8.4Hz,2H),6.97(dd,J1=3.6Hz,J2=0.8Hz,1H),2.33(s,3H).

[0393] Step 2: Synthesis of tert-butyl (1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (Intermediate D-3-1b) Intermediate D-3-1a (1.68 g, 4.78 mmol), tert-butyl carbamate (841 mg, 7.18 mmol), tris(dibenzylideneacetone)dipalladium (438 g, 0.48 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (596 g, 0.96 mmol) and cesium carbonate (3.90 g, 11.96 mmol) were dissolved in toluene (10 mL), replaced with nitrogen three times, and heated to 100 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), and the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography, eluting with petroleum ether:ethyl acetate = 30% to obtain intermediate D-3-1b (1.65 g) with a yield of 88.9%.

[0394] LC-MS (m / z): 388.0 [M+H] + .

[0395] Step 3: Synthesis of tert-butyl (1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (Intermediate D-3)

[0396] Dissolve the intermediate D-3-1b (1.64 g, 4.23 mmol) in tetrahydrofuran / water / methanol (5 mL / 3 mL / 3 mL), add NaOH (338 mg, 8.46 mmol), and heat to 70 ° C for 1 hour. After the mixture is cooled to room temperature, it is quenched with water and extracted with ethyl acetate three times (3×20 mL). The organic phases are combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to obtain the intermediate D-3 (666 mg) with a yield of 67.5%.

[0397] LC-MS (m / z): 234.0 [M+H] + .

[0398] 1H NMR (400MHz, DMSO-d6): δ11.16(s,1H),9.35(s,1H),7.72(d,J=5.6Hz,1H),7. 57(d,J=6.0Hz,1H),7.53(t,J=2.0Hz,1H),6.37(t,J=1.6Hz,1H),1.47(s,9H).

[0399] Step 4: Synthesis of tert-butyl (S)-(1-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (Intermediate I-8-pro1)

[0400] Intermediate D-3 (100 mg, 0.43 mmol), intermediate A-1 (223 mg, 0.64 mmol), cuprous iodide (16 mg, 0.09 mmol), (1R, 2R)-(-)-N, N'-dimethyl-1,2-cyclohexanediamine (24 mg, 0.17 mmol) and cesium carbonate (349 mg, 1.07 mmol) were dissolved in toluene (10 mL), replaced with nitrogen three times, and heated to 100 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 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, petroleum ether: ethyl acetate = 20% to obtain intermediate I-8-pro1 (60 mg), which was used directly in the next step.

[0401] LC-MS (m / z): 499.0 [M+H] + .

[0402] Step 5: Synthesis of (S)-5-(5-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (target compound I-8)

[0403] The intermediate I-8-pro1 (60 mg, 0.12 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with water, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, the organic phases were washed with water three times (3×20 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 preparative thin layer chromatography, methanol: dichloromethane = 7% to obtain the target compound I-8 (30 mg), with a two-step yield of 35.2%.

[0404] LC-MS (m / z): 399.0 [M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d6): δ7.82(d,J=9.2Hz,1H),7.78(d,J=2.8Hz,1H),7.71 (t,J=74.8Hz,1H),7.69(d,J=1.6Hz,1H),7.37(d,J=1.6Hz,1H),6.48-6.43( m,2H),5.67(s,2H),4.63(s,2H),3.61-3.54(m,1H),1.30(d,J=6.8Hz,3H), 1.18-1.09(m,1H),0.61-0.56(m,1H),0.46-0.36(m,2H),0.28-0.23(m,1H).

[0406] Example 9, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-3-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)acetamide (target compound II-1)

[0407]

[0408] The target compound I-1 (121 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), triethylamine (38 mg, 0.38 mmol) was added, acetyl chloride (30 mg, 0.38 mmol) was added dropwise under ice bath, and the system was stirred at room temperature for 1 hour. Water was added to quench, and ethyl acetate was used to extract three times (3×20 mL), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by full preparative liquid chromatography to obtain the target compound II-1 (82 mg) with a yield of 62.3%.

[0409] LC-MS (m / z): 522.0 [M+H] + .

[0410] 1H NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.20(s,1H),7.81(d,J=1.2Hz,1H),7.76(s,1H) ,7.75(t,J=23.2Hz,1H),7.65(dd,J1=8.4Hz,J2=2.0Hz,1H),7.56(d,J=1.6Hz,1H),7.51 (d,J=2.8Hz,1H),4.61(s,2H),3.95(s,3H),3.60-3.54(m,1H),2.05(s,3H),1.29(d,J= 6.8Hz,3H),1.44-1.09(m,1H),0.60-0.55(m,1H),0.44-0.35(m,2H),0.27-0.23(m,1H).

[0411] Example 10, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound II-2)

[0412]

[0413] Step 1: Synthesis of (S)-5-(2-amino-7-(hydroxymethyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindol-1-one (Intermediate II-2-pro1)

[0414] The intermediate I-2-pro2 (140 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and stirred at room temperature for 1 hour. The mixture was quenched with water, extracted three times with dichloromethane (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate II-2-pro1 (90 mg), which was used directly in the next step.

[0415] LC-MS (m / z): 460.0 [M+H] + .

[0416] Step 2: Synthesis of (S)-(2-acetylamino-5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid methyl ester (Intermediate II-2-pro2)

[0417] The intermediate II-2-pro1 (50 mg, 1.09 mmol) was dissolved in acetic anhydride (2 mL), heated to 80 ° C and stirred for 1 hour. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate II-2-pro2 (45 mg), which was used directly in the next step.

[0418] LC-MS (m / z): 544.0 [M+H] + .

[0419] Step 3: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound II-2)

[0420] The intermediate II-2-pro2 (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran / water (5 mL / 1 mL), sodium hydroxide (6 mg, 0.15 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water, extracted three times with dichloromethane (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to obtain the target compound II-2 (10 mg), with a three-step yield of 19.6%.

[0421] LC-MS (m / z): 472.0 [M+H] + .

[0422] 1 H NMR (400MHz, DMSO-d6): δ12.29(s,1H),10.24(s,1H),7.77(d,J=1.2Hz,1H),7.67(s,1H),7.59(t,J=75.2Hz,1H),7.58(s,1H),4.59(s,2H),4. 03(s,3H),3.60-3.52(m,1H),2.25(s,3H),1.30(d,J=6.8Hz,3H),1.17 -1.10(m,1H),0.60-0.55(m,1H),0.45-0.35(m,2H),0.28-0.23(m,1H).

[0423] Example 11, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-yl)acetamide (target compound II-3)

[0424]

[0425] The preparation method of the target compound II-3 refers to the preparation method of the target compound II-1, only the starting material I-1 is replaced by the target compound I-3 to obtain the target compound II-3 (4 mg) with a yield of 13.7%.

[0426] LC-MS (m / z): 446.0 [M+H] + .

[0427] 1 H NMR (400MHz, DMSO-d6): δ10.35(s,1H),7.64(t,J=76.0Hz,1H),7.09(d,J=2.0Hz, 1H),6.86(d,J=2.0Hz,1H),6.41(s,1H),4.59(s,2H),4.46(s,2H),4.08(t,J=5.6 Hz,2H),3.93(t,J=5.6Hz,2H),3.53-3.50(m,1H),1.98(s,3H),1.25(d,J=6.8Hz, 3H),1.13-1.04(m,1H),0.57-0.52(m,1H),0.40-0.31(m,2H),0.23-0.19(m,1H).

[0428] Example 12, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)acetamide (target compound II-4)

[0429]

[0430] The preparation method of the target compound II-4 refers to the preparation method of the target compound II-1, only the starting material I-1 is replaced by the target compound I-4 to obtain the target compound II-4 (58 mg) with a yield of 57.3%.

[0431] LC-MS (m / z): 460.0 [M+H] + .

[0432] 1H NMR (400MHz, DMSO-d6): δ10.66(s,1H),7.57(d,J=1.2Hz,1H),7.52(t,J=49 .6Hz,1H),7.34(d,J=1.2Hz,1H),7.01(s,1H),4.59(s,2H),4.45-4.43(m,2H ),4.27-4.25(m,2H),3.56-3.53(m,1H),2.04(s,3H),1.29(d,J=4.4Hz,3H), 1.16-1.10(m,1H),0.60-0.55(m,1H),0.43-0.36(m,2H),0.26-0.22(m,1H).

[0433] Example 13, (S)-N-(3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)acetamide (target compound II-6)

[0434]

[0435] Step 1: Synthesis of (S)-5-(6-amino-1-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (Intermediate II-6-pro1)

[0436] The intermediate I-6-pro1 (45 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was quenched with water, the pH was adjusted to 7-8 with saturated sodium bicarbonate, and extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, the organic phases were washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The intermediate II-6-pro1 (40 mg) was obtained, and the crude product was used directly in the next step.

[0437] LC-MS (m / z): 429.0 [M+H] + .

[0438] Step 2: Synthesis of (S)-(6-acetylamino-3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid methyl ester (Intermediate II-6-pro2)

[0439] The intermediate II-6-pro1 (40 mg, 0.09 mmol) was dissolved in acetic anhydride (2 mL), heated to 60 ° C for 1 hour. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate II-6-pro2 (30 mg), which was used directly in the next step.

[0440] LC-MS (m / z): 513.0 [M+H] + .

[0441] Step 3: Synthesis of (S)-N-(3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)acetamide (Intermediate II-6)

[0442] The intermediate II-6-pro2 (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran / water (2 mL / 1 mL), sodium hydroxide (21 mg, 0.52 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was quenched with water, extracted three times with ethyl acetate (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography, developed with dichloromethane: methanol = 5%, and the target compound II-6 (7 mg) was obtained, with a three-step yield of 22.2%.

[0443] LC-MS (m / z): 441.0 [M+H] + .

[0444] 1 H NMR (400MHz, DMSO-d6): δ11.92(s,1H),10.38(s,1H),8.36(d,J=8.4Hz,1H),7.99(s,2H),7.86(s,1H),7.68(t,J=76.4Hz,1H) ,7.51(s,1H),4.61(s,2H),3.58(s,1H),2.11(s,3H),1.30-1.23(m,3H),1.14(s,1H),0.58(s,1H),0.40(s,2H),0.26(s,1H).

[0445] Example 14, (S)-N-(6-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)imidazo[1,2-a]pyridin-2-yl)acetamide (target compound II-7)

[0446]

[0447] The preparation method of the target compound II-7 refers to the preparation method of the target compound II-1, only the starting material I-1 is replaced by the target compound I-7 to obtain the target compound II-7 (3 mg) with a yield of 45.2%.

[0448] LC-MS (m / z): 441.0 [M+H] + .

[0449] 1 H NMR (400MHz, DMSO-d6): δ10.76(s,1H),9.07(s,1H),8.15(s,1H),7.82(s,1H),7.67(t,J=74.8Hz,1H),7.65-7.62(m,1H),7.56-7.53(m,2H),4 .62(s,2H),3.59-3.53(m,1H),2.09(s,3H),1.31(d,J=6.8Hz,3H),1.16 -1.11(m,1H),0.60-0.56(m,1H),0.45-0.37(m,2H),0.27-0.24(m,1H).

[0450] Example 15, (S)-N-(1-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)acetamide (target compound II-8)

[0451]

[0452] The preparation method of the target compound II-8 refers to the preparation method of the target compound II-1, only the starting material I-1 is replaced by the target compound I-8 to obtain the target compound II-8 (3 mg) with a yield of 41.6%.

[0453] LC-MS (m / z): 441.0 [M+H] + .

[0454] 1H NMR (400MHz, DMSO-d6): δ11.57(s,1H),7.93(d,J=8.4Hz,1H),7.76(t,J=3. 2Hz,1H),7.54(t,J=75.2Hz,1H),7.32(s,1H),7.20(d,J=8.4Hz,2H),6.59( s,1H),4.50(s,2H),3.55-3.47(m,1H),1.97(s,3H),1.24(d,J=6.8Hz,3H), 1.09-1.01(m,1H),0.57-0.51(m,1H),0.41-0.31(m,2H),0.23-0.18(m,1H).

[0455] Example 16, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide (target compound III-1)

[0456]

[0457] Step 1: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide (Intermediate H-1)

[0458] The intermediate I-2-pro1 (174 mg, 0.30 mmol), propionamide (27 mg, 0.46 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (29 mg, 0.06 mmol) and cesium carbonate (197 mg, 0.61 mmol) were dissolved in toluene (10 mL), the system was replaced with nitrogen three times, and the temperature was raised to 100 ° C for 2 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with saturated brine, dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography, the eluent was 0-10% methanol in dichloromethane, and the intermediate H-1 (125 mg) was obtained with a yield of 60.9%.

[0459] LC-MS (m / z): 616.0 [M+H] + .

[0460] Step 2: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide (target compound III-1)

[0461] The intermediate H-1 (125 mg, 0.18 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), sodium hydroxide (29 mg, 0.72 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was quenched with water, extracted three times with ethyl acetate (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain the target compound III-1 (37 mg) with a yield of 41.8%.

[0462] LC-MS (m / z): 486.0 [M+H] + .

[0463] Example 17, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide (target compound III-2)

[0464]

[0465] The preparation method of the target compound III-2 refers to the preparation method of the target compound III-1, except that the starting material acetamide is replaced by cyclopropaneamide to obtain the target compound III-2 (18 mg) with a total yield of 22.6%.

[0466] LC-MS (m / z): 498.0 [M+H] + .

[0467] 1 H NMR (400MHz, DMSO-d6): δ12.27(s,1H),10.53(s,1H),7.77(s,1H),7.68( s,1H),7.59(s,1H),7.53(t,J=50.0Hz,1H),4.59(s,2H),4.03(s,3H),3.5 9-3.54(m,1H),2.21(s,1H),1.30(d,J=4.4Hz,3H),1.17-1.11(m,1H),0. 85-0.79(m,4H),0.61-0.56(m,1H),0.44-0.37(m,2H),0.27-0.23(m,1H).

[0468] Example 18, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-3)

[0469]

[0470] Step 1: Synthesis of 2-chloro-5-iodo-4-ethoxy-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-1)

[0471] The intermediate C-2-1a (500 mg, 1.13 mmol) was dissolved in ethanol (10 mL), sodium ethoxide (92 mg, 1.35 mmol) was added, and the temperature was raised to 50 ° C and stirred for 3 hours. The mixture was evaporated under reduced pressure to remove ethanol, the concentrate was quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, the organic phases were washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain intermediate F-1 (390 mg) with a yield of 76.4%.

[0472] LC-MS (m / z): 454.0 [M+H] + .

[0473] Step 2: Synthesis of (S)-5-(2-chloro-4-ethoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-(1-cyclopropylethyl)-7-(difluoromethoxy)isoindolin-1-one (Intermediate G-1)

[0474] Intermediate F-1 (390 mg, 0.86 mmol), intermediate B-1 (338 mg, 0.86 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (31 mg, 0.04 mmol) and cesium carbonate (560 mg, 1.72 mmol) were dissolved in a mixed solvent of 1,4-dioxane / water (10 mL / 1 mL), replaced with nitrogen three times, and heated to 80 ° C for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography, the eluent was 0-25% ethyl acetate in petroleum ether, and intermediate G-1 (360 mg) was obtained with a yield of 70.6%.

[0475] LC-MS (m / z): 593.0 [M+H]+ .

[0476] Step 3: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-ethoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (Intermediate H-3)

[0477] Intermediate G-1 (360 mg, 0.61 mmol), acetamide (54 mg, 0.91 mmol), tris(dibenzylideneacetone)dipalladium (56 mg, 0.06 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (58 mg, 0.12 mmol) and cesium carbonate (398 mg, 1.22 mmol) were dissolved in toluene (10 mL), the system was replaced with nitrogen three times, and the temperature was raised to 100 ° C for 2 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with saturated brine, dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography, the eluent was 0-10% methanol in dichloromethane, and intermediate H-3 (249 mg) was obtained with a yield of 66.4%.

[0478] LC-MS (m / z): 616.0 [M+H] + .

[0479] Step 4: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-3)

[0480] The intermediate H-3 (68 mg, 0.11 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), sodium hydroxide (9 mg, 0.22 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was quenched with water, extracted with ethyl acetate three times (3×20 mL), the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain the target compound III-3 (40 mg) with a yield of 74.6%.

[0481] LC-MS (m / z): 486.0 [M+H] + .

[0482] 1H NMR (400MHz, DMSO-d6): δ12.24(s,1H),10.20(s,1H),7.82(s,1H),7.67(s,1 H),7.61(s,1H),7.43(t,J=75.6Hz,1H),4.57(s,2H),4.55(q,J=7.2Hz,2H), 3.60-3.52(m,1H),2.23(s,3H),1.40(t,J=7.2Hz,3H),1.30(d,J=6.8Hz,3H) ,1.19-1.10(m,1H),0.61-0.55(m,1H),0.45-0.35(m,2H),0.28-0.23(m,1H).

[0483] Example 19, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-isopropoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-4)

[0484]

[0485] The preparation method of the target compound III-4 refers to the preparation method of the target compound III-3, except that the starting material sodium ethoxide is replaced by sodium isopropoxide to obtain the target compound III-4 (4 mg) with a total yield of 18.4%.

[0486] LC-MS (m / z): 500.0 [M+H] + .

[0487] 1 H NMR (400MHz, DMSO-d6): δ12.24(s,1H),10.18(s,1H),7.83(s,1H),7.66( s,1H),7.61(s,1H),7.44(t,J=75.6Hz,1H),5.57-5.50(m,1H),4.57(s,2H ),3.58-3.52(m,1H),2.23(s,3H),1.38(d,J=6.4Hz,6H),1.31(d,J=6.8Hz ,3H),1.15(s,1H),0.58(d,J=7.8Hz,1H),0.43-0.36(m,2H),0.25(s,1H).

[0488] Example 20, (S)-N-(4-cyclopropyloxy-5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-5)

[0489]

[0490] Step 1: Synthesis of 2-chloro-5-iodo-4-cyclopropyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-3)

[0491] The intermediate C-2-1a (444 mg, 1.00 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (60 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and cyclopropanol (116 mg, 2.00 mmol) was added, and the mixture was reacted at room temperature for 4 hours. Water was added to quench the mixture, and the mixture was extracted three times with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain the intermediate F-3 (330 mg) with a yield of 71.0%.

[0492] LC-MS (m / z): 466.0 [M+H] + .

[0493] Step 2 to Step 4: 2-Chloro-5-iodo-4-cyclopropyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Synthesis of target compound III-5)

[0494] Steps 2 to 4 in the preparation process of target compound III-5 refer to steps 2 to 4 in the preparation method of target compound III-3, only the starting material intermediate F-1 is replaced by intermediate F-3 to obtain target compound III-5 (4 mg) with a total yield of 23.8%.

[0495] LC-MS (m / z): 498.0 [M+H] + .

[0496] 1 H NMR (400MHz, DMSO-d6): δ12.32(s,1H),10.23(s,1H),7.72(s,1H),7.67(s ,1H),7.49(s,1H),7.42(t,J=75.2Hz,1H),4.57(s,2H),4.55-4.50(m,1H), 3.56-3.54(m,1H),2.30(s,3H),1.30(d,J=6.8Hz,3H),1.18-1.13(m,1H),0 .82-0.79(m,4H),0.63-0.55(m,1H),0.45-0.36(m,2H),0.28-0.23(m,1H).

[0497] Example 21, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-(difluoromethoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-6)

[0498]

[0499] Step 1: Synthesis of 2-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (Intermediate F-4-1a)

[0500] The intermediate C-2-1a (444 mg, 1.00 mmol) was dissolved in tetrahydrofuran / water (4 mL / 1 mL), sodium hydroxide (60 mg, 1.50 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The pH was adjusted to weak acidity with 1N citric acid solution, and the mixture was extracted three times with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), dried and concentrated under reduced pressure to obtain the intermediate F-4-1a (130 mg), with a yield of 30.6%.

[0501] LC-MS (m / z): 426.0 [M+H] + .

[0502] Step 2: Synthesis of 2-chloro-4-(difluoromethoxy)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-4)

[0503] The intermediate F-4-1a (130 mg, 0.31 mmol) was dissolved in N, N-dimethylformamide (4 mL), potassium carbonate (107 mg, 0.77 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours, sodium monochlorodifluoroacetate (86 mg, 0.46 mmol) was added, and the mixture was heated to 60°C for 2 hours. The mixture was quenched with water, extracted with ethyl acetate three times (3×20 mL), and the organic phases were combined, washed with water three times (3×20 mL), washed with saturated brine (50 mL), washed with saturated brine, dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography, and the eluent was 0-20% ethyl acetate in petroleum ether to obtain the intermediate F-4 (58 mg) with a yield of 39.9%.

[0504] LC-MS (m / z): 476.0 [M+H] + .

[0505] Step 3 to Step 5: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-(difluoromethoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-6)

[0506] Steps 3 to 5 in the preparation process of target compound III-6 refer to steps 2 to 4 in the preparation method of target compound III-3, only the starting material intermediate F-1 is replaced by intermediate F-4 to obtain target compound III-6 (8 mg) with a total yield of 18.0%.

[0507] LC-MS (m / z): 508.0 [M+H] + .

[0508] Example 22, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-((1-methylpiperidin-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-7)

[0509]

[0510] The preparation method of the target compound III-7 refers to the preparation method of the target compound III-5, except that the starting material cyclopropanol is replaced by 1-methylpiperidin-4-ol to obtain the target compound III-7 (2 mg) with a total yield of 19.8%.

[0511] LC-MS (m / z): 555.0 [M+H] + .

[0512] 1 H NMR (400MHz, DMSO-d6): δ12.25(s,1H),10.18(s,1H),7.81(s,1H),7.64(s,1H),7.57( s,1H),7.43(t,J=75.4Hz,1H),5.32-5.27(m,1H),4.58(s,2H),3.59-3.50(m,1H),2.5 4-2.53(m,4H),2.23(s,3H),2.14(s,3H),2.03(s,2H),1.79-1.71(m,2H),1.30(d,J=6 .8Hz,3H),1.19-1.10(m,1H),0.61-0.55(m,1H),0.44-0.36(m,2H),0.28-0.23(m,1H).

[0513] Example 23, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-8)

[0514]

[0515] Step 1: Synthesis of 2-chloro-4-methyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-6-1a)

[0516] 2-Chloro-4-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 6.30 mmol), methylboric acid (755 mg, 12.60 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (460 mg, 0.63 mmol) and potassium phosphate (2.7 g, 12.60 mmol) were dissolved in tetrahydrofuran (40 mL), the system was replaced with nitrogen three times, and the temperature was raised to 65 ° C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, extracted with water (40 mL) and ethyl acetate (3×20 mL), the organic phases were combined, washed with saturated brine, dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography, the eluent was 0-10% ethyl acetate in petroleum ether to obtain intermediate F-6-1a (862 mg), the yield was 46.0%.

[0517] LC-MS (m / z): 298.0 [M+H] + .

[0518] 1 H NMR (400MHz, DMSO-d6): δ7.69(d,J=3.6Hz,1H),6.80(d,J=3.6Hz,1H),5.55(s,2H),3.52-3.48(m,2H),2.66(s,3H),0.86-0.81(m,2H),0.10(s,9H).

[0519] Step 2: Synthesis of 2-chloro-5-iodo-4-methyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate F-6)

[0520] The intermediate F-6-1a (950 mg, 3.20 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-iodosuccinimide (1.08 g, 4.80 mmol) was added, and the reaction was carried out at room temperature for 1 hour. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure. The residue was separated and purified by column chromatography, and the eluent was 0-5% ethyl acetate in petroleum ether to obtain the intermediate F-6 (750 mg) with a yield of 78.9%.

[0521] LC-MS (m / z): 424.0 [M+H] + .

[0522] Step 3 to Step 5: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-8)

[0523] Steps 3 to 5 in the preparation method of the target compound III-8 are similar to steps 2 to 4 in the preparation method of the target compound III-3, except that the starting material intermediate F-1 is replaced by intermediate F-6 to obtain the target compound III-8 (13 mg) with a total yield of 26.1%.

[0524] LC-MS (m / z): 456.0 [M+H] + .

[0525] 1 H NMR (400MHz, DMSO-d6): δ12.27(s,1H),10.34(s,1H),7.60(s,1H),7.54(s,1H),7.45(t,J=74.8Hz,1H),7.34(s,1H),4.60(s,2H),3.61-3 .53(m,1H),2.47(s,3H),2.17(s,3H),1.30(d,J=6.8Hz,3H),1.17-1.10(m,1H),0.61-0.55(m,1H),0.46-0.36(m,2H),0.28-0.23(m,1H).

[0526] Example 24, (S)-N-(5-(2-(1-cyclopropylethyl)-7-fluoro-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-23)

[0527]

[0528] Step 1: Synthesis of (S)-2-(1-cyclopropylethyl)-7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (Intermediate B-2)

[0529] (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one (300 mg, 1.00 mmol), biboronic acid pinacol ester (341 mg, 1.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (25 mg, 0.03 mmol) and potassium acetate (132 mg, 1.34 mmol) were dissolved in dioxane (10 mL), replaced with nitrogen three times, and the system was heated to 90 ° C and stirred for 2 hours. The system was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in turn, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:1) to obtain intermediate B-2 (346 mg) with a yield of 99.9%.

[0530] LC-MS (m / z): 346.0 [M+H] + .

[0531] Step 2: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-fluoro-1-oxoisoindolin-5-yl)-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (Intermediate H-9)

[0532] Intermediate F-7 (378 mg, 0.91 mmol), intermediate B-2 (346 mg, 1.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (33 mg, 0.05 mmol) and cesium carbonate (593 mg, 1.82 mmol) were dissolved in dioxane (10 mL) and water (1 mL), replaced with nitrogen three times, and the system was heated to 90 ° C and stirred for 2 hours. The system was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in turn, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=1:1) to obtain intermediate H-9 (258 mg) with a yield of 51.2%.

[0533] LC-MS (m / z): 554.0 [M+H] + .

[0534] Step 3: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-fluoro-1-oxoisoindolin-5-yl)-7-(hydroxymethyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (Intermediate III-23-1a)

[0535] The intermediate H-9 (258 mg, 0.47 mmol) was dissolved in DCM (20 mL), trifluoroacetic acid (5 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution, and the pH was adjusted to neutral. The mixture was extracted with dichloromethane (3×20 mL), and the organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 97: 3) to obtain the intermediate III-23-1a (100 mg) with a yield of 47.3%.

[0536] LC-MS (m / z): 454.0 [M+H] + .

[0537] Step 4: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-fluoro-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-23)

[0538] The intermediate III-23-1a (100 mg, 0.22 mmol) was dissolved in THF (10 mL) and water (1 mL), sodium hydroxide (18 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid phase to obtain the target compound III-23 (41 mg) with a yield of 43.9%.

[0539] LC-MS (m / z): 424.0 [M+H] + .

[0540] 1H NMR (400MHz, DMSO-d6): δ12.30(s,1H),10.25(s,1H),7.75(s,1H),7.68(s,1H),7.57(d,J=11.2Hz,1H),4.60(s,2H),4.05(s,3H), 3.59-3.51(m,1H),2.25(s,3H),1.30(d,J=6.8Hz,3H),1.17-1.10(m,1H),0.60-0.54(m,1H),0.45-0.41(m,2H),0.27-0.22(m,1H).

[0541] Example 25, (S)-N-(5-(2-(1-cyclopropylethyl)-7-methoxy-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-9)

[0542]

[0543] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-methoxyisoindolin-1-one (Intermediate B-3-1a)

[0544] (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one (330 mg, 1.11 mmol) was dissolved in methanol (5 mL), potassium carbonate (306 mg, 2.22 mmol) was added, and the system was heated to 60°C and stirred for 2 hours. Water (10 mL) was added to quench, and the mixture was extracted three times with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:1) to obtain intermediate B-3-1a (140 mg) with a yield of 40.7%.

[0545] LC-MS (m / z): 310.0 [M+H] + .

[0546] Step 2 to Step 5: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-methoxy-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-9)

[0547] Steps 2 to 5 in the preparation method of the target compound III-9 refer to steps 1 to 4 in the preparation method of III-23 in Example 24, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one is replaced by intermediate B-3-1a to obtain the target compound III-9 (11 mg) with a total yield of 5.6% for four steps.

[0548] LC-MS (m / z): 436.0 [M+H] + .

[0549] 1 H NMR (400MHz, DMSO-d6): δ12.22(s,1H),10.22(s,1H),7.62(s,1H),7.41(s,1H),7.37(s,1H),4.47(s,2H),4.04(s,3H),3.90(s,3H) ,3.56-3.49(m,1H),2.25(s,3H),1.26(d,J=6.8Hz,3H),1.15-1.06(m,1H),0.58-0.53(m,1H),0.42-0.33(m,2H),0.24-0.20(m,1H).

[0550] Example 26, (S)-N-(5-(2-(1-cyclopropylethyl)-7-methyl-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-11)

[0551]

[0552] Step 1: Synthesis of (S)-5-chloro-2-(1-cyclopropylethyl)-7-methylisoindolin-1-one (Intermediate B-4-1a)

[0553] (S)-5-Chloro-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (350 mg, 0.97 mmol), (S)-methylboric acid (291 mg, 4.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (66 mg, 0.1 mmol) and cesium carbonate (632 mg, 1.94 mmol) were dissolved in dioxane (10 mL) and water (1 mL), replaced with nitrogen three times, and the system was heated to 80°C and stirred for 8 hours. The system was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in sequence, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=1:1) to give intermediate B-4-1a (280 mg) with a yield of 83.8%.

[0554] LC-MS (m / z): 250.0 [M+H] + .

[0555] Step 2 to Step 5: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-methyl-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-11)

[0556] Steps 2 to 5 in the preparation method of the target compound III-11 refer to steps 1 to 4 in the preparation method of III-23 in Example 24, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one is replaced by intermediate B-4-1a to obtain the target compound III-11 (56 mg) with a total yield of 11.9% for four steps.

[0557] LC-MS (m / z): 420.0 [M+H] + .

[0558] 1 H NMR (400MHz, DMSO-d6): δ12.17(s,1H),10.21(s,1H),7.67(s,1H),7.54(d,J=5.6Hz,2H),4.50(s,2H),4.02(s,3H),3.61-3.53(m, 1H),2.64(s,3H),2.25(s,3H),1.29(d,J=6.8Hz,3H),1.18-1.10(m,1H),0.60-0.54(m,1H),0.43-0.36(m,2H),0.26-0.21(m,1H).

[0559] Example 27, (S)-N-(5-(7-cyano-2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-14)

[0560]

[0561] Step 1: Synthesis of (S)-6-chloro-2-(1-cyclopropylethyl)-3-oxoisoindole-4-carbonitrile (Intermediate B-5-1a)

[0562] (S)-5-chloro-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (200 mg, 0.55 mmol) was dissolved in DMSO (5 mL), and cuprous cyanide (247 mg, 2.77 mmol) was added. The system was heated to 120°C under microwave conditions for 1 hour. After the reaction was completed, water (20 mL) was added to quench, and the mixture was extracted with ethyl acetate three times (3×30 mL). The organic phases were combined, washed with water (30 mL) and saturated NaCl (30 mL) in sequence, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=2:1) ​​to obtain intermediate B-5-1a (120 mg) with a yield of 83.3%.

[0563] LC-MS (m / z): 261.0 [M+H] + .

[0564] Step 2 to Step 5: (S)-N-(5-(7-cyano-2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-14)

[0565] Steps 2 to 5 in the preparation method of the target compound III-14 refer to steps 1 to 4 in the preparation method of III-23 in Example 24, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one is replaced by intermediate B-5-1a to obtain the target compound III-14 (43 mg) with a total yield of 21.7% for four steps.

[0566] LC-MS (m / z): 431.0 [M+H] + .

[0567] 1H NMR (400MHz, DMSO-d6): δ12.36(s,1H),10.27(s,1H),8.27-8.19(m,2H),7.77(s,1H),4.66(s,2H),4.05(s,3H),3.63-3.5 6(m,1H),2.25(s,3H),1.33(d,J=6.8Hz,3H),1.19-1.12(m,1H),0.62-0.57(m,1H),0.46-0.38(m,2H),0.30-0.25(m,1H).

[0568] Example 28, (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-15)

[0569]

[0570] Step 1: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one (Intermediate B-6-1a)

[0571] (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one (800 mg, 2.69 mmol) was dissolved in DMF (8 mL), sodium thiomethoxide (377 mg, 5.39 mmol) was added, and the system was stirred at room temperature for 1 hour. Water (20 mL) was added to quench, and the mixture was extracted three times with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=2:1) ​​to obtain intermediate B-6-1a (650 mg) with a yield of 74.3%.

[0572] LC-MS (m / z): 326.0 [M+H] + .

[0573] Step 2: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (Intermediate B-6-1b)

[0574] The intermediate B-6-1a (650 mg, 2.00 mmol) was dissolved in DCM (10 mL), and m-chloroperbenzoic acid (414 mg, 2.40 mmol) was added under ice bath, and the system was stirred at room temperature for reaction. After the reaction was completed, water (20 mL) was added to quench, and the mixture was extracted with dichloromethane three times (3×30 mL), and the organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=1:1) to obtain the intermediate B-6-1b (595 mg) with a yield of 83.1%.

[0575] LC-MS (m / z): 358.0 [M+H] + .

[0576] Step 3 to Step 6: Synthesis of (S)-N-(5-(2-(1-cyclopropylethyl)-7-(methylsulfonyl)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-15)

[0577] Steps 3 to 6 in the preparation method of the target compound III-15 refer to steps 1 to 4 in the preparation method of III-23 in Example 24, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one is replaced with intermediate B-6-1b to obtain the target compound III-15 (50 mg) with a total yield of 6.2% for four steps.

[0578] LC-MS (m / z): 484.0 [M+H] + .

[0579] 1 H NMR (400MHz, DMSO-d6): δ12.37(s,1H),10.26(s,1H),8.53(d,J=1.2Hz,1H),8.21(d,J=2.0Hz,1H),7.77(d,J=2.0Hz,1H),4.69(s,2H),4.05 (s,3H),3.66-3.57(m,4H),2.25(s,3H),1.33(d,J=6.8Hz,3H),1.21-1.15(m,1H),0.62-0.58(m,1H),0.48-0.38(m,2H),0.30-0.24(m,1H).

[0580] Example 29, (S)-N-(5-(7-(azetidin-1-yl)-2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-24)

[0581]

[0582] Step 1: Synthesis of (S)-7-(azetidin-1-yl)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one (Intermediate B-7-1a)

[0583] (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one (300 mg, 1.00 mmol) was dissolved in DMF (5 mL), triethylamine (303 mg, 3.00 mmol) and azetidine hydrochloride (112 mg, 1.20 mmol) were added, and the system was heated to 80 ° C and stirred for 4 hours. Water (20 mL) was added to quench, and the mixture was extracted with ethyl acetate three times (3×30 mL), and the organic phases were combined, washed with saturated NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=2:1) ​​to obtain intermediate B-7-1a (260 mg) with a yield of 77.8%.

[0584] LC-MS (m / z): 335.0 [M+H] + .

[0585] Step 2 to Step 5: Synthesis of (S)-N-(5-(7-(azetidin-1-yl)-2-(1-cyclopropylethyl)-1-oxoisoindolin-5-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)acetamide (target compound III-24)

[0586] Steps 2 to 5 in the preparation method of the target compound III-24 refer to steps 1 to 4 in the preparation method of III-23 in Example 24, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-fluoroisoindolin-1-one is replaced by intermediate B-7-1a to obtain the target compound III-24 (20 mg) with a total yield of 5.6% for four steps.

[0587] LC-MS (m / z): 461.0 [M+H] + .

[0588] 1H NMR (400MHz, DMSO-d6): δ12.15(s,1H),10.20(s,1H),7.53(s,1H),7.12(d ,J=1.2Hz,1H),6.76(d,J=1.2Hz,1H),4.42(s,2H),4.13(q,J=7.6Hz,4H),4 .03(s,3H),3.56-3.49(m,1H),2.29-2.22(m,5H),1.25(d,J=6.8Hz,3H),1 .10-1.04(m,1H),0.58-0.53(m,1H),0.41-0.32(m,2H),0.24-0.19(m,1H).

[0589] Example 30, (S)-6-amino-N-cyclopropyl-3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (target compound IV-1)

[0590]

[0591] Step 1: Synthesis of methyl 6-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (Intermediate J-1)

[0592] Intermediate IV-SM1 (300 mg, 0.88 mmol), tert-butyl carbamate (155 mg, 1.32 mmol), tris(dibenzylideneacetone)dipalladium (81 mg, 0.09 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (84 mg, 0.18 mmol) and cesium carbonate (573 mg, 1.76 mmol) were dissolved in toluene (5 mL), the system was replaced with nitrogen, and the temperature was raised to 100 ° C for 2 hours. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and then with saturated brine, dried and concentrated under reduced pressure, and the residue was separated by column chromatography, the eluent was 0-8% ethyl acetate in petroleum ether solution, and intermediate J-1 (240 mg) was obtained with a yield of 64.5%.

[0593] LC-MS (m / z): 422.0 [M+H] + .

[0594] Step 2: Synthesis of 6-((tert-butoxycarbonyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (Intermediate K-1)

[0595] Intermediate J-1 (240 mg, 0.57 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (48 mg, 1.14 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water and then with saturated brine, dried, and concentrated under reduced pressure to obtain intermediate K-1 (230 mg), which was used directly in the next step.

[0596] LC-MS (m / z): 408.0 [M+H] + .

[0597] Step 3: Synthesis of tert-butyl (5-(cyclopropylcarbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamate (Intermediate L-1)

[0598] The crude product prepared in the previous step, cyclopropylamine (48 mg, 0.85 mmol), HATU (322 mg, 0.85 mmol) and N,N-diisopropylethylamine (109 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at room temperature for 5 hours. The reaction solution was quenched with water, extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and then with saturated brine, dried and concentrated under reduced pressure, and the residue was separated by column chromatography, the eluent was 0-25% ethyl acetate in petroleum ether solution, and intermediate L-1 (114 mg) was obtained, with a two-step yield of 43.3%.

[0599] LC-MS (m / z): 447.0 [M+H] + .

[0600] Step 4: Synthesis of tert-butyl (3-bromo-5-(cyclopropylcarbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamate (Intermediate M-1)

[0601] The intermediate L-1 (114 mg, 0.26 mmol) was dissolved in N, N-dimethylformamide (5 mL), and N-bromosuccinimide (50 mg, 0.28 mmol) was added under ice bath, and the temperature was maintained and stirred for 1 hour. The reaction solution was quenched with water, extracted with ethyl acetate (3×20 mL), and the organic phases were combined, washed with water and then with saturated brine, dried and concentrated under reduced pressure to obtain the intermediate M-1 (110 mg), which was used directly in the next step.

[0602] LC-MS (m / z): 525.0 [M+H] + .

[0603] Step 5: Synthesis of tert-butyl (S)-(5-(cyclopropylcarbamoyl)-3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamate (Intermediate IV-1-pro1)

[0604] The crude product prepared in the previous step, intermediate B-1 (99 mg, 0.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (15 mg, 0.02 mmol) and cesium carbonate (136 mg, 0.42 mmol) were dissolved in dioxane (5 mL) and water (1 mL), the system was replaced with nitrogen three times, and the temperature was raised to 90 ° C for 1 hour. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with water and then with saturated brine, dried and concentrated under reduced pressure, and the residue was separated and purified by column chromatography, the eluent was 0-25% ethyl acetate in petroleum ether solution, and intermediate IV-1-pro1 (75 mg) was obtained, and the two-step yield was 41.3%.

[0605] LC-MS (m / z): 712.0 [M+H] + .

[0606] Step 6: Synthesis of (S)-6-amino-N-cyclopropyl-3-(2-(1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (target compound IV-1)

[0607] The intermediate IV-1-pro1 (75 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the system was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, and extracted with dichloromethane (3×20 mL), the organic phases were combined, washed with water and then with saturated brine, dried and concentrated under reduced pressure, and the residue was separated by preparative separation to obtain 22 mg of the target compound IV-1 (22 mg), with a yield of 43.3%.

[0608] LC-MS (m / z): 482.0 [M+H] + .

[0609] 1H NMR (400MHz, DMSO-d6): δ11.51(s,1H),8.47(d,J=4.0Hz,1H),8.35(s,1H),7.81( s,1H),7.68-7.67(m,1H),7.49(s,1H),7.48(t,J=75.6Hz,1H),6.90(s,2H),4.61( s,2H),3.61-3.53(m,1H),2.84-2.78(m,1H),1.31(d,J=6.8Hz,3H),1.20-1.11(m ,1H),0.74-0.69(m,2H),0.63-0.56(m,3H),0.46-0.36(m,2H),0.28-0.23(m,1H).

[0610] Example 31. PI3Kγ inhibitory activity of the compounds of the present invention

[0611] The present invention uses ADP Glo assay to test the ability of compounds to bind to and inhibit PI3Kγ activity in vitro.

[0612] 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.

[0613] 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 calculating the inhibition rate of each compound. The final results were entered into GraphpadPrism for plotting, and the curve and IC were obtained. 50 The results are shown in Table 1:

[0614] Table 1 PI3Kγ inhibitory activity of the compounds of the present invention

[0615] Compound <![CDATA[PI3KγIC 50 (nM)]]> Compound <![CDATA[PI3KγIC 50 (nM)]]> Compound <![CDATA[PI3KγIC 50 (nM)]]> I-1 388.39 I-2 4.58 I-3 973.22 I-4 1268.86 I-5 76.86 I-7 98.04 I-8 940.15 II-1 >10000 II-2 0.86 II-3 111.58 II-4 222.44 II-6 16.08 II-8 >10000 III-2 7.19 III-3 5.93 III-5 9.63 III-8 18.83 III-9 4.00 III-14 11.55 III-15 0.90 III-23 7.51 III-24 20.21 IV-1 8.14

[0616] It can be seen from the data in Table 1 that the compounds provided by the present invention generally exhibit strong PI3Kγ inhibitory activity and therefore have good application prospects.

[0617] Example 32: PI3Kα, PI3Kβ, and PI3Kδ inhibitory activities of the compounds of the present invention

[0618] 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.

[0619] 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.

[0620] 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.

[0621] Table 2 PI3Kα, PI3Kβ, PI3Kδ inhibitory activity of the compounds of the present invention

[0622] Compound <![CDATA[PI3KαIC 50 (nM)]]> <![CDATA[PI3KβIC 50 (nM)]]> <![CDATA[PI3KδIC 50 (nM)]]> I-2 >10000 >10000 8724.97 II-2 >10000 >10000 >10000

[0623] It can be seen from the data in Table 2 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.

[0624] Example 33: Effects of the compounds of the present invention on normal cell proliferation

[0625] HEK293 and Jurkat cells were selected to evaluate the effects of compounds on normal cell proliferation.

[0626] Preparation of compound solution: First dissolve the compound with DMSO, then dilute the compound to be tested 3-fold in sequence with culture medium to obtain compound solutions of 8 concentrations.

[0627] The toxicity of the compound to HEK293 cells was tested by SRB method: HEK293 cells growing in logarithmic phase were inoculated at 7000 / well in 96-well cell culture plates, and cultured in a 37°C, 5% CO2 incubator for 24 hours. Then, compound solutions of various gradient concentrations were added, and the culture was continued in a 37°C, 5% CO2 incubator for 3 days. After 3 days, 100 μL SRB fixative was added to the cell culture plate, fixed at 4°C for 2-3 hours, and the fixative was discarded. SRB cleaning solution B was added, 100 μL per well, and the cells were allowed to stand at room temperature for 30 seconds, and the cleaning solution B was discarded. Then, the cells were washed with pure water for 3-5 times and dried at room temperature. 100 μL SRB staining solution was added to each well, and the cells were incubated in the dark for 15 minutes at room temperature, and the staining solution was discarded. 100 μL SRB washing solution D was added to each well, and the washing solution D was discarded. The process was repeated 3-5 times quickly until the unbound staining solution was washed away. SRB dissolution solution was added, 100 μL per well, and incubated in the dark at room temperature for 5 min. The absorbance at a wavelength of 515 nM was measured using an ELISA reader, and the inhibition rate of each compound was calculated.

[0628] The toxicity of the compounds to Jurkat cells was tested by CCK8 method: Jurkat cells in logarithmic phase were inoculated at 5000 / well in a 96-well cell culture plate, and cultured in a 37°C, 5% CO2 incubator for 2 hours. Then, compound solutions of various gradient concentrations were added, and the plates were continued to be incubated in a 37°C, 5% CO2 incubator for 3 days. After 3 days, 10 μL of CCK-8 solution was added to the cell culture plate, and the plates were incubated in a 37°C incubator for 3 hours. Finally, the absorbance at a wavelength of 450 nM was measured with an ELISA reader, and the inhibition rate of each compound was calculated.

[0629] Table 3 Inhibition rate of the compounds of the present invention on normal cell proliferation

[0630] Compound <![CDATA[HEK293 IC 50 (μM)]]> <![CDATA[Jurkat IC 50 (μM)]]> II-2 >20 >40 III-9 >10 >10 III-15 >10 >10 III-23 >10 >10

[0631] It can be seen from the data in Table 3 that the representative compounds of the present invention have little effect on the proliferation of normal cells and have good safety.

[0632] Example 34: Inhibitory effect of the compounds of the present invention on human hERG ion channels

[0633] The effects of compounds on hERG ion channels were tested on HEK293 cells stably expressing hERG ion channels. The cells were transferred to a perfusion tank and perfused with extracellular solution. The intracellular solution (mM) was: K Aspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration). The intracellular solution was stored in small batches in a -80°C refrigerator and thawed on the day of the experiment. The electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, and noise was filtered using one-fifth of the sampling frequency. The cells were clamped at -80mV, then depolarized to 40mV with a 4-second square wave, and then hyperpolarized to -40mV 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:

[0634] Table 4 Inhibition rate of the compounds of the present invention on human hERG ion channels

[0635] Compound Inhibition rate of hERG ion channel (10μM) II-2 7.34％

[0636] It can be seen from the data in Table 4 that the representative compounds of the present invention have no obvious inhibitory effect on human hERG ion channels at high concentrations, which can reflect to a certain extent that the compounds of the present invention have lower cardiotoxicity and have positive significance for drug safety evaluation.

[0637] Example 35 Evaluation of the inhibitory activity of the compounds of the present invention on Th2 cytokine secretion from lymphocytes derived from MC903-induced atopic dermatitis (AD) mice

[0638] 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;

[0639] 2. Extraction, activation and incubation of ear drainage lymphocytes with test products:

[0640] (1) A 96-well plate was coated with 100 μL of 3 μg / mL CD3 antibody in advance and incubated at 4°C overnight. Afterwards, the plate was washed twice with sterile PBS to remove the free CD3 antibody in the plate for later use.

[0641] (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.

[0642] (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.

[0643] (4) The cell density of the counted lymphocytes was adjusted to 3×10 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 3×10 5 indivual.

[0644] 3. Grouping, medication and data collection:

[0645] 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.

[0646] Table 5 Inhibitory activity of the compounds of the present invention on Th2 cytokine secretion in lymphocytes derived from MC903-induced atopic dermatitis (AD) mice

[0647]

[0648] From the data in Table 5, it can be seen that the compounds of the present invention have a strong inhibitory effect on the secretion of Th2 cytokines (IL-5 and IL-13) of AD mouse-derived lymphocytes induced by MC903, and can be used to prevent or treat atopic dermatitis.

Claims

1. An aromatic heterocyclic pyrrolidone compound having the following structural formula (Ia), (IIa), (Ib) or (IIb), or a pharmaceutically acceptable salt thereof: in, R 1a Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-14 membered heteroaryl, NR 1c R 1d OR 1c ; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl; R 1b Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 Aryl or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl; R 1c , R 1d are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl and 4-10 membered heterocyclic groups are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl, 5-14 membered heteroaryl; or R 1c and R 1d The atoms connected to each other may also be connected to form a 3-8 membered aliphatic ring or heterocyclic ring, wherein the aliphatic ring and heterocyclic ring may be saturated or unsaturated; the aliphatic ring or heterocyclic ring may be unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; R 2 Selected from hydrogen, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 2a )-C(O)-R 2b 、-N(R 2a )-SO2-R 2b 、-C(O)-NR 2a R 2b 、-C(O)-R 2a 、-OR 2a , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; R 2a , R 2b are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; or R 2a and R 2b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; n is selected from 0, 1, 2 or 3; X is selected from N or CR 2c ; R 2c Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, 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; R 3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 3a )-CO-R 3b 、-C(O)-NR 3a R 3b 、-C(O)-R 3a 、-N(R 3a )-SO2-R 3b 、-P(O)R 3a R 3b 、-NHCO-R 3a 、-C(O)NH-R 3a 、-NHSO2-R 3a , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl; R 3a , R 3b Each independently selected from hydrogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl, or 5-14 membered heteroaryl; or R 3a and R 3b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl.

2. The aromatic heterocyclic pyrrolidone compound according to claim 1, characterized in that: A compound having the following structural formula (Ia) or (IIa) or a pharmaceutically acceptable salt thereof: in, R 3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-R 3a 、-C(O)NH-R 3a 、-C(O)-R 3a 、-NHSO2-R 3a 、-P(O)R 3a R 3b , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl; R 3a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; R 3b Selected from hydrogen, hydroxyl, amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Alkylamino; R 1a , R 1b , R 2 and X is as defined in claim 1.

3. The aromatic heterocyclic pyrrolidone compound according to claim 1, characterized in that: A compound having the following structural formula (Ib) or (IIb) or a pharmaceutically acceptable salt thereof: in, n is selected from 1 or 2; R 3 Selected from hydrogen, halogen, cyano, hydroxyl, amino, mercapto, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -N(R 3a )-CO-R 3b 、-C(O)-NR 3a R 3b 、-C(O)-R 3a 、-N(R 3a )-SO2-R 3b 、-P(O)R 3a R 3b , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, 4-10 membered heterocyclic group, C 6-12 The aryl and 5-14 membered heteroaryl groups are unsubstituted or substituted by one or more of the following substituents: halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 1-6 Alkylsulfone, -NHCO-C 1-6 Alkyl, -NHCO-C 3-8 Cycloalkyl, -NHSO2-C 1-6 Alkyl, -NHSO2-C 3-8 Cycloalkyl, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl; R 3a , R 3b Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl; said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 1-6 Alkylamino, C 6-12 The aryl, 4-10 membered heterocyclic or 5-14 membered heteroaryl are unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; or R 3a and R 3b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring; the aliphatic ring or heterocyclic ring is unsubstituted or 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, C 1-6 Alkylamino, 4-10 membered heterocyclic, C 6-12 Aryl or 5-14 membered heteroaryl; R 1a , R 1b , R 2 and X is as defined in claim 1.

4. The aromatic heterocyclic pyrrolidone compound according to claim 1-3, characterized in that: A compound having the following general structural formula (Ic), (IIc), (Id) or (IId) or a pharmaceutically acceptable salt thereof: in, n is selected from 1 or 2; R 1a Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl or C 1-6 Haloalkyl; R 1b is selected from hydrogen, deuterium, hydroxyl, amino or C 1-6 Alkyl, the C 1-6 The alkyl group is unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 1-6 Alkylthio; R 2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, -OR 2a 、-C(O)-NR 2a R 2b , C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Alkylamino, C 6-12 Aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl; R 2a , R 2b are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl or C 1-6 alkoxy; or R 2a and R 2b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring, wherein the aliphatic ring or heterocyclic ring is unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl or C 1-6 Alkoxy; R 3 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, -P(O)R 3a R 3b , C 1-6 Alkylsulfone, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, oxo, C 1-6 Alkyl or C 1-6 Alkoxy; R 3a and R 3b are each independently selected from hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

5. The compound according to claims 1-4, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, characterized in that: The R 1a Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl; said R 1b Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group is unsubstituted or substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 1-6 Alkylthio.

6. The compound according to claim 5, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, characterized in that: The R 1a is selected from methyl, ethyl or cyclopropyl; said R 1b Selected from hydrogen, 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, characterized in that: The R 2 Selected from hydrogen, -OR 2a , C 1-6 Alkyl, -C(O)-NR 2a R 2b , C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy; The R 2a , R 2b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 aryl, 4-10 membered heterocyclic group or 5-14 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 The aryl, 4-10 membered heterocyclyl or 5-14 membered heteroaryl are unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 alkoxy; or R 2a and R 2b The atoms connected to each other form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring, wherein the aliphatic ring or heterocyclic ring is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

8. The compound according to claim 7, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, characterized in that: The R 2 is hydrogen, methyl, 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, characterized in that: The R 3 Selected from hydrogen, halogen, cyano, -P(O)R 3a R 3b , C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 an alkylsulfone group or a 4-10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 The alkylsulfone group or the 4-10 membered heterocyclic group is unsubstituted or substituted by one or more of the following substituents: halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy; The R 3a and R 3b Each independently selected from hydrogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl.

10. The compound according to claim 9, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, characterized in that: The R 3 Preferably, it is hydrogen, fluorine, cyano, methyl, trifluoromethyl, 11. An aromatic heterocyclic pyrrolidone compound, which is a compound, isomer, solvate or a pharmaceutically acceptable salt thereof having the following structure:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 as an active ingredient, and at least one pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 in the preparation of a drug for preventing or treating a disease associated with the PI3Kγ signaling pathway.

14. The use according to claim 13, 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, psoriasis, 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.; preferably selected from atopic dermatitis or psoriasis.

15. Compound IV-SM1 or F-7, or a pharmaceutically acceptable salt, isotopic derivative, solvate or isomer thereof, for preparing a compound according to any one of claims 1 to 11:

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