Compound with tricyclic structure, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a compound with a tricyclic structure, a pharmaceutical composition thereof and the use thereof. The compound with a tricyclic structure of the present invention comprises a compound with a tricyclic structure as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of the pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof or an isotopically labeled compound thereof. The compound with a tricyclic structure as shown in formula (I) of the present invention has a relatively good inhibitory effect on cells of various PI3K-mediated diseases, and is expected to be used for treating and / or preventing the various PI3K-mediated diseases.

Description

A tricyclic ring structure compound, its pharmaceutical composition and application Technical Field

[0001] The present invention relates to a tricyclic ring structure compound, a pharmaceutical composition and application thereof. Background Art

[0002] Cancer has become a common and frequently occurring disease that poses a serious threat to human health and life. The PI3K / AKt / mTOR signaling pathway is one of the many mechanisms regulating the cell cycle and apoptosis. Dysregulation of a component in this pathway can lead to tumorigenesis. Receptor tyrosine kinases (RTKs) regulate the PI3K / AKt signaling pathway in response to growth factors, including insulin-like growth factors (IGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF). These factors activate RTKs by phosphorylating tyrosine residues. PI3K binds to phosphorylated tyrosine residues and activates the catalytic subunit of PI3K. Upon activation of the catalytic subunit p110α of type IA PI3K, PI3K activates PI3K by binding to p85α, which further phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). As an important second messenger and mediator, PIP3 recruits AKt from the cytoplasm to the cell membrane by interacting with the PH domain of AKt. It mediates AKt membrane translocation, phosphorylation at Thr308 and Ser473 by phosphatidylinositol-dependent kinase 1 (PDK1) and phosphatidylinositol-dependent kinase 2 (PDK2), respectively, which are essential for AKt activation. Fully activated AKt regulates processes such as cell proliferation and apoptosis through its upstream and downstream regulation. Dysregulation of the PI3K signaling pathway is implicated in nearly all human cancers. PIK3CA (encoding the PI3K catalytic subunit α) is a commonly mutated oncogene in human tumors. Studies have found that approximately 2-5% of human solid tumors have mutations in the oncogene PIK3CA. The mutation rates in colon cancer, glioblastoma, gastric cancer, breast cancer and lung cancer are approximately 32%, 27%, 25%, 8% and 4%, respectively. Among other digestive tract tumors, the mutation rate in esophageal squamous cell carcinoma is 11%, and in esophageal adenocarcinoma it is 6%.

[0003] Summary of the Invention

[0004] The present invention addresses the technical problem of the lack of effective PI3K inhibitors for clinical treatment. To address this issue, the present invention provides a tricyclic compound, a pharmaceutical composition, and uses thereof. These inhibitors are expected to treat and / or prevent various PI3K-related diseases.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a tricyclic ring structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof:

[0007] in,

[0008] E is C or N;

[0009] Ring A is a 4-10 membered cycloolefin containing 1-3 heteroatoms independently selected from O, N and S or is replaced by one or more C 1-6 an alkyl-substituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S;

[0010] R 1 For at least two R 1-1 Substituted phenyl; R 1-1 are independently halogen or C 1-6 alkyl;

[0011] R 2 For one or more R 2-1 Substituted C 6-10 Aryl, or one or more R 2-2 Substituted benzofuranyl; R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0012] R 3 for Cl, F, Br, -NH2, H,

[0013] R 4 is hydrogen or halogen;

[0014] The tricyclic compound shown in Formula I is not one of the following compounds:

[0015] N-(7-bromo-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0016] N-(7-amino-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0017] N-(7-bromo-1-(2-bromo-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0018] N-(7-bromo-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0019] N-(7-amino-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0020] N-(7-amino-1-(2-chloro-5-(trifluoromethyl)phenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0021] N-(7-amino-1-(2,5-dichloro-4-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0022] N-(5-(2-chloro-5-fluorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0023] N-(5-(2,5-dichlorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0024] N-(5-(2-chloro-5-fluorophenyl)-8-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-di]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0025] N-(8-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(2,5-dichlorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0026] N-(1-(2-chloro-5-fluorophenyl)-7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0027] N-(7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2-1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0028] N-(7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2-1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0029] N-(1-(2-chloro-5-fluorophenyl)-7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0030] N-(5-(2,5-dichloro-4-fluorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0031] N-(1-(2-chloro-5-fluorophenyl)-7-(3-cyano-1H-pyrazol-4-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0032] N-(1-(2-chloro-5-fluorophenyl)-7-(5-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,21-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0033] N-(7-(2-cyanopyridin-3-yl)-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0034] N-(1-(2-chloro-5-fluorophenyl)-7-(2-cyanopyridin-3-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0035] N-(7-(5-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,21-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0036] N-(1-(2-chloro-5-fluorophenyl)-7-(3-cyano-1H-pyrazol-4-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0037] N-(7-(5-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,21-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0038] N-(1-(2-chloro-5-fluorophenyl)-7-(4-cyano-1H-indazol-5-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide.

[0039] In one embodiment, the structure of the tricyclic ring compound shown in Formula I is shown in Formula II:

[0040] in,

[0041] R1 For at least two R 1-1 Substituted phenyl; R 1-1 are independently halogen or C 1-6 alkyl;

[0042] R 2 For one or more R 2-1 Substituted C 6-10 Aryl, or one or more R 2-2 Substituted benzofuranyl; R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0043] R 3 for F, Br, -NH2,

[0044] R 4 is hydrogen or halogen.

[0045] In one embodiment, the structure of the tricyclic compound shown in Formula I is shown in Formula III:

[0046] Among them, R 1 For at least two R 1-1 Substituted phenyl; R 1-1 are independently halogen or C 1-6 alkyl;

[0047] R 2 For one or more R 2-1 Substituted C 6-10 Aryl, or one or more R 2-2 Substituted benzofuranyl; R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0048] R 3 for Cl, F, H,

[0049] R 4 is hydrogen or halogen.

[0050] In one embodiment, when the group R 1-1 、R 2-1 、R2-2 and R 4 When "halogen" is mentioned, the halogen is fluorine, chlorine, bromine or iodine.

[0051] In one embodiment, when ring A, group R 1-1 、R 2-1 and R 2-2 The definition of "C 1-6 When "alkyl", the C 1-6 Alkyl is C 1- 4-alkyl, further methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0052] In one embodiment, when ring A is a "4-10 membered cycloolefin containing 1-3 heteroatoms independently selected from O, N and S", the ring A is a "4-6 membered cycloolefin containing 1-3 heteroatoms N", for example, a "5 membered cycloolefin containing 1 heteroatom N".

[0053] In one embodiment, when ring A is surrounded by one or more C 1-6 When the alkyl-substituted "5-12 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S" is present, the ring A is replaced by one or more C 1-6 Alkyl-substituted "5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S", for example, substituted by one or more C 1-6 Alkyl-substituted pyrazole ring.

[0054] In one scenario, R 1 for

[0055] In one scenario, R 2 for

[0056] In one scenario, R 4 is hydrogen or fluorine.

[0057] In a certain embodiment, the tricyclic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, the tricyclic ring structure compound as shown in Formula I is any of the following structures:

[0058] In a certain embodiment, the three-ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, the three-ring structure compound as shown in Formula I is any of the following compounds:

[0059] The compound with a retention time of 0.693 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm;

[0060] The compound with a retention time of 1.326 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm;

[0061] The compound with a retention time of 3.379 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0062] The compound with a retention time of 1.543 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0063] The compound with a retention time of 3.246 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0064] The compound with a retention time of 3.833 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0065] The compound with a retention time of 0.987 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0066] The compound with a retention time of 3.033 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0067] The compound with a retention time of 1.235 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0068] The compound with a retention time of 4.026 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0069] The compound with a retention time of 3.381 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0070] Compounds with a retention time of 1.35 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column (R, R) Whelk-O1 4.6*100mm 5um; mobile phase: CO2 / EtOH=70 / 30; flow rate: 3.0mL / min; back pressure: 2000psi; detection wavelength: 254nm;

[0071] The compound with a retention time of 2.617 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: (R,R) Whelk-O1 4.6*100mm 5um; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm;

[0072] The compound with a retention time of 3.677 minutes under the following conditions Equipment: AD-3, 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm;

[0073] The compound with a retention time of 1.344 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm;

[0074] The compound with a retention time of 3.123 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm;

[0075] The compound with a retention time of 2.456 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm;

[0076] The compound with a retention time of 1.486 minutes under the following conditions Equipment: AD-3 0.46cm ID*5cm.L 20*250mm; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm;

[0077] The compound with a retention time of 3.136 minutes under the following conditions Equipment: AD-3 0.46cm ID*5cm.L 20*250mm; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm;

[0078] The compound with a retention time of 1.305 minutes under the following conditions Instrument: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Detection wavelength: 214 nm;

[0079] The compound with a retention time of 1.712 minutes under the following conditions Instrument: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Detection wavelength: 214 nm;

[0080] The compound with a retention time of 0.938 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: OD-3 4.6*100mm 3um; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0081] The compound with a retention time of 1.306 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: OD-3 4.6*100mm 3um; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0082] The compound with a retention time of 2.002 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0083] The compound with a retention time of 3.317 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0084] The compound with a retention time of 2.387 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm;

[0085] The compound with a retention time of 4.086 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm;

[0086] The compound with a retention time of 2.223 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm;

[0087] The compound with a retention time of 3.679 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 214 nm.

[0088] In a certain embodiment, the aforementioned tricyclic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, the tricyclic ring structure compound as shown in Formula I is any of the following structures:

[0089] The present invention also provides a pharmaceutical composition comprising substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the above-mentioned tricyclic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound.

[0090] The present invention also provides a use of a substance A in the preparation of a PI3K inhibitor, wherein the substance A is the above-mentioned tricyclic ring structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope compound thereof.

[0091] The present invention also provides a use of a substance A in the preparation of a drug, wherein the drug is used to treat or prevent PI3K-mediated diseases; the substance A is the above-mentioned tricyclic ring structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound.

[0092] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0093] The term "tautomer" refers to functional group isomers that result from the rapid shift of an atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can be interconverted by the rapid shift of a hydrogen atom between an oxygen and an α-carbon.

[0094] The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). The isotopic compounds of the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein.

[0095] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0096] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0097] The term "aryl" refers to an aromatic group consisting of carbon atoms, with each ring having aromatic properties, such as phenyl or naphthyl.

[0098] The term "cyano" refers to a -CN group.

[0099] The term "oxo" refers to a =0 group.

[0100] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0101] The reagents and raw materials used in the present invention are commercially available.

[0102] The positive progress of the present invention is that: the present invention provides a tricyclic ring structure compound, its pharmaceutical composition and application, which has a good inhibitory effect on various disease cells mediated by PI3K and is expected to treat and / or prevent various diseases mediated by PI3K. DETAILED DESCRIPTION

[0103] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0104] In the present invention, room temperature refers to ambient temperature, which is 10°C to 35°C. Overnight refers to 8 to 15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

[0105] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0106] Pd(dppf)Cl2 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride

[0107] HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0108] DIEA N,N-Diisopropylethylamine

[0109] PPA polyphosphoric acid

[0110] Eaton's reagent Eaton's reagent

[0111] Example 1 Synthesis route of compound 1 (1-p1 and 1-p2)

[0112] Synthesis of compound 1

[0113] To a 50 mL three-necked flask were added compound 23-a (350 mg, 0.523 mmol), 2-cyano-3-bromopyridine (210 mg, 1.105 mmol), potassium carbonate (216.84 mg, 1.569 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (38.04 mg, 0.05 mmol), 1,4-dioxane (15 mL), and water (3 mL). The mixture was reacted at 100°C for 1 hour under nitrogen. The reaction mixture was dried and purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 53 (120 mg, 0.187 mmol, 35.76%). LC-MS (ESI): m / z 645.3 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 8.79 (s, 1H), 8.31 (d, J=9.3Hz, 1H), 8.03-7.80 (m, 4H), 7.61 (d, J=9.1Hz, 1H), 7.52 (d, J=2.3H z, 1H), 7.25 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.13 (d, J=2.2Hz, 1H), 4.03 (qd, J=7.8, 7.0, 5.6Hz, 2H), 3.24 (m, J=13.6, 9.7, 7.0Hz, 2H).

[0114] Separation conditions were as follows: chromatographic column: OJ-H 4.6*100mm 5um; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm;

[0115] Compound 1-p1 (retention time 0.693 min): LC-MS (ESI): m / z 645.3 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.79 (s, 1H), 8.34 (d, J = 9.3Hz, 1H), 8.03-7.80 (m, 4H), 7.61 (d, J = 9.1Hz, 1H), 7.52 ( d, J=2.3Hz, 1H), 7.26 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.13 (d, J=2.2Hz, 1H), 4.03 (qd, J=7.8, 7.0, 5.6Hz, 2H), 3.26 (m, 2H).

[0116] Compound 1-p2 (retention time 1.326 min): LC-MS (ESI): m / z 645.3 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.79 (s, 1H), 8.34 (d, J=9.3Hz, 1H), 8.03-7.80 (m, 4H), 7.61 (d, J=9.1Hz, 1H), 7.52 (d, J=2.3Hz, 1H), 7.26 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.13 (d, J=2.2Hz, 1H), 4.03 (qd, J=7.8, 7.0, 5.6Hz, 2H), 3.26 (m, 2H).

[0117] Example 2 Synthesis routes of Compound 2 and Compound 3

[0118] Synthesis of compound 3-g

[0119] To a 100 mL three-necked flask were added 4-bromo-1H-indol-6-amine (compound 24, 1000 mg, 4.738 mmol), triethylamine (1.317 mL, 9.476 mmol), and dichloromethane (40 mL). The mixture was cooled to 0°C, followed by the addition of 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1180.73 mg, 5.212 mmol). The reaction was allowed to proceed at 0°C for 30 minutes, then the temperature was raised to room temperature and the reaction continued for 1 hour. The reaction solution was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate = 5:1 to 3:1) to yield compound 3-g (1809 mg, 4.509 mmol, 95.18%).

[0120] Synthesis of compound 3-f

[0121] To a 100 mL three-necked flask were added compound 3-g (802 mg, 1.999 mmol), acetic acid (30 mL), and sodium cyanoborohydride (376.89 mg, 5.998 mmol) in sequence. The mixture was allowed to react at room temperature for 18 h. The reaction solution was concentrated, and ethyl acetate and saturated aqueous sodium bicarbonate were added. The organic phase was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 3:1) to afford compound 3-f (350 mg, 0.868 mmol, 43.42%).

[0122] Synthesis of compound 3-e

[0123] Compound 3-f (320 mg, 0.794 mmol) and acetic acid (10 mL) were added sequentially to a 100 mL three-necked flask. The mixture was cooled to 0°C and potassium cyanate (128.77 mg, 1.587 mmol) was added. The mixture was allowed to react at 0°C for half an hour. The reaction solution was concentrated, water and saturated sodium bicarbonate aqueous solution were added, and the mixture was filtered. The filter cake was washed with water and dried to obtain compound 3-e (280 mg, 0.628 mmol, 79.06%).

[0124] Synthesis of compound 3-d

[0125] To a 100 mL three-necked flask, add polyphosphoric acid (20 mL) and heat to 105°C. Then, add compound 3-e (150 mg, 0.336 mmol) and 2-chloro-5-fluorobenzaldehyde (53.28 mg, 0.336 mmol) in sequence. Continue the reaction at this temperature for 30 min. Add dichloromethane and saturated aqueous sodium bicarbonate solution, and the organic phase is concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 20:1-10:1) to obtain compound 3-d (47 mg, 0.080 mmol, 23.83%).

[0126] LC-MS (ESI): m / z 587.9 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ10.16 (s, 1H), 7.95 (dt, J=8.6, 1.9Hz, 1H), 7.89–7.77 (m, 2H), 7.54 (d, J=2.6Hz, 1H), 7.32 (dd, J=8.8, 5.2Hz, 1H), 7.09 ( ddd, J=8.8, 8.0, 3.1Hz, 1H), 6.95 (s, 1H), 6.90 (dd, J=9.2, 3.1Hz, 1H), 6.14–5.97 (m, 1H), 4.16–3.87 (m, 2H), 3.17 (ddd, J=9.6, 6.9, 4.6Hz, 2H).

[0127] Synthesis of compound 3-c

[0128] Compound 3-d (0.5 g, 0.852 mmol), potassium acetate (250.85 mg, 2.556 mmol), pinacol diboronate (540.89 mg, 2.130 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (62.34 mg, 0.085 mmol) were placed in a reaction flask and dissolved in 1,4-dioxane (7 mL). The mixture was protected by nitrogen and heated to 100°C for two hours. Potassium acetate (83.6 mg, 0.852 mmol), pinacol diboronate (216.0 mg, 0.852 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (62.34 mg, 0.085 mmol) were added and the reaction was continued for two hours. After concentration, the crude product was purified by pre-TLC normal phase purification (developing solvent DCM:MeOH=10:1). The target compound 3-c (400 mg, 74.06%) was obtained as a yellow-brown solid. LC-MS (ESI): m / z 634.1 (M+H) + .

[0129] Synthesis of compound 3-b

[0130] Methyl 5-bromo-6-fluoro-1H-indazole-4-carboxylate (100 mg, 0.430 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.18 mL, 1.290 mmol) and Boc anhydride (140 mg, 0.645 mmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was dried and purified by column chromatography (petroleum ether / ethyl acetate ~20 / 1) to give compound 3-b (100 mg, 69.9%). LCMS (ESI): m / z 332.0 (M+H) + ;

[0131] Synthesis of compound 2

[0132] 3-c (150 mg, 0.237 mmol), compound 3-b (78.7 mg, 0.237 mmol), potassium carbonate (98 mg, 0.710 mmol), and Pd(dppf)Cl2 (17.3 mg, 0.024 mmol) were added to a reaction flask. 1,4-dioxane (2 mL) and water (0.4 mL) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 2 hours. The reaction solution was diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (dichloromethane / methanol ~ 20 / 1) to obtain compound 2 (50 mg, 1.9%). LCMS (ESI): m / z 659.0 (M+H) + ; YL220764-411-AH NMR: 1 H NMR (400MHz, DMSO-d6) δ14.15 (s, 1H), 10.26 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7. 95 (d, J=8.6Hz, 1H), 7.88 (d, J=14.8Hz, 2H), 7.59 (d, J=2.6Hz, 1H), 7.37 (dd, J=8.9 , 5.1Hz, 1H), 7.13 (td, J=8.4, 3.1Hz, 1H), 6.94 (dd, J=9.2, 3.1Hz, 1H), 6.79 (s, 1H) , 6.17 (d, J=2.5Hz, 1H), 4.01 (td, J=11.0, 10.5, 7.5Hz, 2H), 3.10 (q, J=8.2Hz, 2H).

[0133] Synthesis of compound 3

[0134] Compound 3-a (240 mg, 0.576 mmol) was dissolved in DMAC (1 mL), and zinc cyanide (13.4 mg, 0.114 mmol), zinc powder (1 mg, 0.015 mmol), Pd2(dba)3 (10.4 mg, 0.011 mmol), and DPPF (12.6 mg, 0.023 mmol) were added. The mixture was replaced with nitrogen and microwaved at 170°C for 1 hour. The reaction solution was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (dichloromethane / methanol ~ 20 / 1) to obtain compound 3 (13 mg). ESI: (m / z) = 650.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ14.14 (s, 1H), 10.33 (s, 1H), 8.85 (s, 1H), 8.47 (s, 1H), 7 .96 (dd, J=8.3, 2.2Hz, 1H), 7.93–7.86 (m, 2H), 7.64 (d, J=2.6Hz, 1H), 7.38 (dd, J= 8.8, 5.1Hz, 1H), 7.14 (td, J=8.4, 3.1Hz, 1H), 6.98–6.91 (m, 2H), 6.19 (d, J=2.6H z, 1H), 4.04 (dtd, J=28.3, 10.4, 6.7Hz, 2H), 3.23 (ddd, J=24.5, 10.2, 6.7Hz, 2H).

[0135] Example 3 Synthesis routes of compounds 4, 5 and 6

[0136] Synthesis of compound 5-e

[0137] 6-Bromo-3-fluoropyridin-2-amine (10 g, 52.356 mmol) was dissolved in dichloromethane (120 mL), and N-iodosuccinimide (14.14 g, 62.827 mmol) was added. The reaction mixture was allowed to react at room temperature for 48 hours. The reaction solution was dried by rotary evaporation and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate ~10 / 1) to obtain compound 5-e (15.56 g, 93.79%). ESI: (m / z) = 317.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.79 (d, J=10.0Hz, 1H), 6.87 (s, 2H).

[0138] Synthesis of compound 5-d

[0139] Compound 5-e (15.56 g, 49.10 mmol) was dissolved in isopropanol (160 mL), and N,N-dimethylformamide dimethyl acetal (11.70 g, 98.20 mmol) was added. The mixture was reacted at 80°C for 6 hours. The reaction mixture was cooled to 50°C, and hydroxylamine hydrochloride (6.82 g, 98.20 mmol) was added. The mixture was reacted at 50°C overnight. The reaction mixture was directly filtered, and the filter cake was rinsed twice with ethanol to obtain compound 5-d (15.86 g, 89.76%). ESI: (m / z) = 360.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.63 (s, 1H), 8.71 (d, J = 9.5Hz, 1H), 8.17 (d, J = 9.5Hz, 1H), 7.63 (d, J = 9.5Hz, 1H).

[0140] Synthesis of compound 5-c

[0141] Compound 5-d (15.86 g, 44.07 mmol) was dissolved in Eaton's reagent (160 mL) and reacted at 80°C for 3.5 hours. The reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-cold saturated sodium bicarbonate aqueous solution, adjusted to a weak alkaline solution. The mixture was extracted with ethyl acetate, and the aqueous phase was extracted twice with ethyl acetate and then twice with dichloromethane / methanol (10:1). The organic phases were combined, washed with water, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (3:1)) to obtain compound 5-c (14 g, 92.9%). ESI: (m / z) = 342.0 [M+H] + .

[0142] Synthesis of compound 5-b

[0143] Compound 3-c (8 g, 12.62 mmol), compound 5-c (4.1 g, 11.99 mmol), potassium carbonate (5.23 g, 37.866 mmol), and Pd(dppf)Cl2 (920 mg, 1.262 mmol) were added to a reaction flask, and 1,4-dioxane (70 mL) and water (14 mL) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 3 hours. The mixture was extracted with ethyl acetate and water, and dried by spin drying. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol ~ 20 / 1) to give compound 5-b (5.05 g, 55.43%). LCMS (ESI): m / z 721.0 (M+H) + ;

[0144] Synthesis of compound 4

[0145] Compound 5-b (5.05 g, 6.996 mmol), zinc cyanide (1.23 g, 10.494 mmol), zinc powder (50 mg, 0.70 mmol), Xantphos (1.62 g, 2.798 mmol), and palladium acetate (0.31 g, 1.399 mmol) were added to a reaction flask. N,N-dimethylacetamide (50 mL) was added, the atmosphere was replaced with nitrogen, and the mixture was reacted at 120°C for 1 hour. The mixture was extracted with ethyl acetate and water, dried, and purified by column chromatography (mobile phase: dichloromethane / methanol ~ 20 / 1) to obtain compound 4 (3.4 g). LCMS (ESI): m / z 668.0 (M+H) + ;

[0146] Synthesis of compound 5

[0147] Compound 4 (100 mg, 6.996 mmol) and ammonia water (2 mL) were placed in a reaction flask, methanol (1 mL) was added, and the mixture was reacted at room temperature overnight. The solvent was removed by spinning, and the mixture was extracted with ethyl acetate and water. The organic phase was dried by spinning to obtain compound 5 (25 mg) and compound 6 (27 mg).

[0148] Compound 5: LCMS (ESI): m / z 665.0 (M+H) + ;

[0149] 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.59 (s, 1H), 7.96 (d, J=8.5Hz, 1H), 7.8 8(d, J=14.8Hz, 2H), 7.62 (d, J=2.6Hz, 1H), 7.46 (s, 2H), 7.37 (dd, J=8.9, 5.1H z, 1H), 7.13 (td, J=8.4, 3.0Hz, 1H), 6.93 (dd, J=9.2, 3.1Hz, 1H), 6.87 (s, 1H), 6.59 (s, 1H), 6.17 (d, J = 2.5Hz, 1H), 4.13–3.94 (m, 2H), 3.22 (q, J = 7.7Hz, 2H).

[0150] Compound 6: LCMS (ESI): m / z 680.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.69(s,1H),7.96(d,J=8.5Hz,1H),7.94–7.87 (m,2H),7.66(d,J=2.7Hz,1H),7.38(dd,J=8.8,5.2Hz,1H),7.33(s,1H),7.14(ddd,J= 8.9,8.0,3.1Hz,1H),6.98(s,1H),6.94(dd,J=9.1,3.1Hz,1H),6.23–6.16(m,1H),4. 14(s,3H),4.12–3.96(m,2H),3.42–3.36(m,1H),3.23(ddd,J=16.5,10.4,6.0Hz,1H).

[0151] Example 4 Synthesis route of compound 7

[0152] Synthesis of compound 7-e

[0153] 2-Amino-6-cyanopyridine (15 g, 125.91 mmol) was dissolved in dichloromethane (60 mL) and methanol (60 mL), and tetrabutylammonium tribromide (69.82 g, 144.8 mmol) was added. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate ~3 / 1) to obtain compound 7-e (10.2 g, 40.11%).

[0154] Synthesis of compound 7-d

[0155] Compound 7-e (10.2 g, 51.51 mmol) was dissolved in isopropanol (150 mL), and N,N-dimethylformamide dimethyl acetal (7.98 g, 66.96 mmol) was added. The mixture was reacted at 80°C for 3 hours. The reaction mixture was cooled to 50°C, and hydroxylamine hydrochloride (4.65 g, 66.96 mmol) was added. The mixture was reacted at 50°C overnight. The reaction mixture was directly filtered, and the filter cake was rinsed with ethanol to obtain compound 7-d (10 g, 80.52%). ESI: (m / z) = 241.0 [M+H] + .

[0156] Synthesis of compound 7-c

[0157] Compound 7-d (5 g, 20.743 mmol) was dissolved in tetrahydrofuran (50 mL). The reaction mixture was cooled to 0°C and trifluoroacetic anhydride (8.71 g, 41.485 mmol) was added dropwise. The mixture was allowed to react at 60°C overnight. The reaction mixture was diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate ~2 / 1) to obtain compound 7-c (1.1 g, 23.76%). ESI: (m / z) = 223.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 8.20 (d, J=9.5Hz, 1H), 8.06 (d, J=9.5Hz, 1H).

[0158] Synthesis of compound 7-b

[0159] Compound 1-c (1 g, 2.178 mmol) was dissolved in Eaton's reagent (10 mL), and 2,5-dichloro-4-fluorobenzaldehyde (0.5 g, 2.613 mmol) was added. The reaction was allowed to react at 80°C for 2 hours. The reaction solution was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate ~3 / 1) to obtain compound 7-b (280 mg, 20.29%). ESI: (m / z) = 633.0 [M+H] + .

[0160] Synthesis of compound 7-a

[0161] Compound 7-b (280 mg, 0.442 mmol) was dissolved in 1,4-dioxane (5 mL), and diboronic acid pinacol ester (168 mg, 0.662 mmol), potassium acetate (130 mg, 1.325 mmol), and Pd(dppf)Cl2 (64.6 mg, 0.088 mmol) were added. The mixture was reacted at 100°C for 2 hours. The reaction solution was directly used for the next step.

[0162] Synthesis of compound 7

[0163] Compound 7-a (260 mg, 0.434 mmol), compound 7-c (145 mg, 0.651 mmol), potassium carbonate (180 mg, 1.302 mmol) and Pd(dppf)Cl2 (31.76 mg, 0.043 mmol) were added to a reaction flask, 1,4-dioxane (5 mL) and water (1 mL) were added, nitrogen was replaced, and the mixture was reacted at 100°C for 1 hour. The mixture was extracted with ethyl acetate and water, and after spin drying, it was purified by normal phase and reverse phase column chromatography to obtain compound 7 (80 mg). LCMS (ESI): m / z 697.3 (M+H) + ;

[0164] Example 5 Synthesis route of compound 8

[0165] Synthesis of compound 8

[0166] Compound 4 (100 mg, 0.15 mmol) was placed in a reaction flask, and L-cysteine ​​(18 mg, 0.15 mmol) and DMAC (3 mL) were added. The mixture was reacted at room temperature overnight and filtered to obtain compound 8 (26 mg). LCMS (ESI): m / z 769.5 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.74 (s, 1H), 7.99–7.87 (m, 4H), 7.85 (d, J=5.9H z, 1H), 7.65 (t, J=3.1Hz, 1H), 7.38 (ddd, J=8.9, 5.2, 2.1Hz, 1H), 7.19–7.10 (m, 1H), 7.0 0 (d, J=5.1Hz, 1H), 6.93 (dt, J=9.0, 3.0Hz, 1H), 6.19 (dd, J=5.8, 2.5Hz, 1H), 4.10–3.9 6 (m, 2H), 3.88 (ddd, J=14.1, 8.6, 3.1Hz, 1H), 3.55–3.42 (m, 4H), 2.00 (q, J=7.3Hz, 1H).

[0167] Example 6 Synthesis route of compound 9 (9-p1 and 9-p2)

[0168] Synthesis of compounds 9-p1 and 9-p2

[0169] Compound 7 (75 mg) was separated by SFC to give compound 9-p2 (26 mg). Separation conditions were: instrument: SFC-150 (Waters); column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes. The retention time of active compound 9-p2 was 3.379 minutes under this method. LCMS (ESI): m / z 697.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 8.39 (d, J = 9.3Hz, 1H), 8.19 (d, J = 9.3Hz, 1H), 7.98 (d, J=8.4Hz, 1H), 7.87 (d, J=9.2Hz, 1H), 7.76 (s, 1H), 7.66–7.58 (m, 2H), 7.36 (d, J=7.9Hz, 1H), 6.42 (s, 1H), 4.48 (s, 3H).

[0170] Example 7 Synthesis route of compound 10

[0171] Synthesis of compound 10

[0172] Compound 1-b (180 mg, 0.30 mmol), 1-amino-1-cyclopropyl cyanide hydrochloride (71 mg, 0.60 mmol), cesium carbonate (294 mg, 0.60 mmol), Brettphos (32 mg, 0.060 mmol), and Pd2dba3 (27.5 mg, 0.30 mmol) were placed in a sealed tube, 1,4-dioxane (3 mL) was added, and the mixture was reacted at 100°C for 2.5 hours. The mixture was extracted with ethyl acetate and water, and the organic phase was dried and purified by normal phase and reverse phase column chromatography to obtain compound 10 (56.5 mg). LCMS (ESI): m / z 601.0 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.31 (d, J=2.2Hz, 1H), 7.93 (dd, J=8.5, 2.1 Hz, 1H), 7.82 (dt, J=9.3, 1.9Hz, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.31 (dd, J=8.8, 5 .1Hz, 1H), 7.06 (td, J=8.3, 3.1Hz, 1H), 6.79 (dd, J=9.2, 3.1Hz, 1H), 6.39 (s, 1H), 6.25 (d, J=2.1Hz, 1H), 4.41 (s, 3H), 1.57 (t, J=3.7Hz, 2H), 1.29 (t, J=4.0Hz, 2H).

[0173] Example 8. Synthesis route of compound 11 (11-p1 and 11-p2)

[0174] Synthesis of compound 11-g

[0175] 7-Chloro-5-nitro-1H-benzimidazole (10 g, 50.612 mmol) was dissolved in DMF (100 mL), potassium hydroxide (5.68 g, 101.225 mmol) was added, the atmosphere was replaced with N2, iodine (32.11 g, 126.53 mmol) was added, and the mixture was allowed to react at 70°C overnight. The reaction solution was washed twice with a 5% aqueous sodium thiosulfate solution, the aqueous phase was adjusted to weak acidity with aqueous citric acid, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and slurried three times with dichloromethane / methanol = 10 / 1. The solid was collected, and the filtrate was purified by column chromatography (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to obtain compound 11-g (14.3 g, 87.35%). 1 H NMR (400MHz,) δ14.70 (s, 1H), 8.31 (d, J = 1.9Hz, 1H), 8.24 (d, J = 1.9Hz, 1H).

[0176] Synthesis of compound 11-f

[0177] Compound 11-g (14.3 g, 44.208 mmol) was dissolved in ethyl acetate (400 mL), and trimethyloxonium tetrafluoroboric acid (13.08 g, 88.416 mmol) was added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed overnight at room temperature. A solid precipitated from the reaction solution, which was filtered and slurried with dichloromethane / methanol. Crude compound 11-f (12.2 g, 81.77%) was obtained. ESI: (m / z) = 338.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.20 (t, J=1.4Hz, 1H), 8.04–7.98 (m, 1H), 4.25 (s, 3H).

[0178] Synthesis of compound 11-e

[0179] Compound 11-f (4.5 g, 30.631 mmol) was dissolved in DMF (20 mL) and methanol (20 mL), and triethylamine (5.56 mL, 91.894 mmol) and Pd(dppf)Cl2 (2.93 g, 4.0 mmol) were added. The mixture was replaced with CO gas and allowed to react at 70°C for 3 hours. The methanol was removed by swirl, and the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / dichloromethane ~40% / 60%) to obtain compound 11-e (1.4 g, 38.89%). ESI: (m / z) = 270.2 [M+H] + ; 1 H NMR (400MHz,) δ8.81 (d, J=2.0Hz, 1H), 8.26 (d, J=1.9Hz, 1H), 4.52 (s, 3H), 4.06 (s, 3H).

[0180] Synthesis of compound 11-d

[0181] Compound 11-e (1.4 g, 5.192 mmol) was dissolved in ethanol (20 mL) and water (4 mL). Solid ammonium chloride (0.83 g, 15.576 mmol) and iron powder (1.45 g, 25.961 mmol) were added and reacted at 70°C for 4 hours. The reaction solution was filtered through celite, rinsed with dichloromethane, and dried by rotary evaporation. Ethyl acetate and water were added for extraction. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain compound 11-d (1.2 g, 96.77%). ESI: (m / z) = 240.1 [M+H] + ;

[0182] Synthesis of compound 11-c

[0183] Compound 11-d (1.2 g, 5.007 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (2.088 mL, 15.021 mmol) was added. The atmosphere was replaced with N2, and the temperature was lowered to 0°C. 3-Fluoro-5-(trifluoromethyl)benzoyl chloride (1.70 g, 7.511 mmol) was added and allowed to react at room temperature for 1 hour. A solid precipitated from the reaction solution, which was filtered and slurried with dichloromethane. The filtrate was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate 1 / 0 to 3 / 1) to obtain compound 11-c (1.57 g, 73.02%). ESI: (m / z) = 430.2 [M+H] + .

[0184] Synthesis of compound 11-b

[0185] Compound 11-c (1.57 g, 3.653 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL). Lithium hydroxide (0.77 g, 18.266 mmol) was added and the mixture was reacted at 60°C for 1 hour. The solvent was removed by swirl, and 1N dilute hydrochloric acid was added to adjust the pH to 3-4. A solid precipitated and was extracted with ethyl acetate and dried to give a crude product, compound 11-b (1.52 g, crude). ESI: (m / z) = 416.1 [MH] + ;

[0186] Synthesis of compound 11-a

[0187] Compound 11-b (1.52 g, 3.656 mmol) was dissolved in DMF (15 mL) and solid ammonium chloride (0.39 g, 7.312 mmol), HATU (2.09 g, 5.484 mmol), and DIEA (1.42 g, 10.969 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain crude compound 11-a (1.2 g, 78.95%). ESI: (m / z) = 415.1 [M+H] + .

[0188] Synthesis of compound 11 (11-p1 and 11-p2)

[0189] Dissolve compound 11-a (600 mg, 1.447 mmol) in Eaton's reagent (10 mL), add 2-chloro-5-fluorobenzaldehyde (275 mg, 1.736 mmol), and react at 80°C for 2 hours. Pour the reaction solution dropwise into saturated sodium bicarbonate solution on ice, adjust the system to alkaline, and extract with ethyl acetate. The organic phases were combined, washed with aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol ~10 / 1) to give compound 11 (57 mg). Chiral preparation of compound 11 (11-p1 and 11-p2) was performed under the following separation conditions: instrument: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes;

[0190] Compound 11-p1 (retention time 1.543 min): 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.60 (d, J=2.2Hz, 1H), 7.96 (dt, J=8.5, 2.0Hz, 1H), 7.81 (dt, J=9.2, 1.9Hz, 1H), 7.7 6 (s, 1H), 7.36–7.28 (m, 2H), 7.06 (td, J=8.4, 3.1Hz, 1H), 6.95 (dd, J=9.2, 3.1Hz, 1H), 6.37 (d, J=1.9Hz, 1H), 4.47 (s, 3H).

[0191] Compound 11-p2 (the retention time of active compound 11-p2 under this method is 3.246 min), 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 8.60 (d, J=2.2Hz, 1H), 7.96 (dt, J=8.5, 2.0Hz, 1H), 7.81 (dt, J=9.3, 1.9Hz, 1H), 7 .76 (s, 1H), 7.35–7.28 (m, 2H), 7.06 (ddd, J=8.9, 8.0, 3.1Hz, 1H), 6.95 (dd, J=9.2, 3.1Hz, 1H), 6.37 (s, 1H), 4.47 (s, 3H).

[0192] Example 9 Synthesis route of compound 12 (compounds 12-p1 and 12-p2)

[0193] Synthesis of Compounds 12-p1 and 12-p2

[0194] Compound 11-a (600 mg, 1.447 mmol) was dissolved in Eaton's reagent (10 mL), and 2,5-dichloro-4-fluorobenzaldehyde (335 mg, 1.736 mmol) was added. The mixture was reacted at 80°C for 2 hours. The reaction solution was added dropwise to an icy, saturated aqueous sodium bicarbonate solution, the solution was adjusted to alkaline, and extracted with ethyl acetate. The organic phases were combined, washed with aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol ~10 / 1) to obtain compound 12. Compound 12 was then resolved to yield compound 12-p1 (53 mg) and compound 12-p2 (52 mg). The separation conditions were: instrument: SFC-150 (Waters); column: 0.46 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes; the retention time of the active compound 12-p2 under this method was 3.833 minutes.

[0195] Compound 12-p1: ESI: (m / z) = 589.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.38 (s, 1H), 8.53 (d, J=2.0Hz, 1H), 7.97 (dt, J=8.5, 1.9Hz, 1H), 7.83 (dt, J=9. 3, 1.9Hz, 1H), 7.72 (s, 1H), 7.57 (d, J=9.1Hz, 1H), 7.31 (d, J=8.7Hz, 2H), 6.49–6.25 (m, 1H), 4.47 (s, 3H).

[0196] Compound 12-p2: ESI: (m / z) = 589.0 [M+H] +1 H NMR (400MHz, DMSO-d6) δ10.38 (s, 1H), 8.53 (d, J=2.1Hz, 1H), 7.97 (dt, J=8.5, 1.9Hz, 1H), 7.83 (dt, J=9. 2, 1.9Hz, 1H), 7.72 (s, 1H), 7.57 (d, J=9.0Hz, 1H), 7.31 (d, J=9.7Hz, 2H), 6.36–6.27 (m, 1H), 4.47 (s, 3H).

[0197] Example 10 Synthetic routes of compounds 13-p1 and 13-p2

[0198] Synthesis of compound 13-a

[0199] Compound 1-b (300 mg, 0.50 mmol) was dissolved in 1,4-dioxane (5 mL), and diboronic acid pinacol ester (190 mg, 0.750 mmol), potassium acetate (147 mg, 1.325 mmol), and Pd(dppf)Cl2 (73 mg, 0.1 mmol) were added. The mixture was reacted at 100°C for 1 hour. The reaction mixture was directly used in the next step.

[0200] Synthesis of Compounds 13-p1 and 13-p2

[0201] Compound 13-a (280 mg, 0.496 mmol), 2-bromobenzonitrile (135 mg, 0.744 mmol), potassium carbonate (205 mg, 1.488 mmol), and Pd(dppf)Cl2 (36 mg, 0.05 mmol) were added to a reaction flask. 1,4-dioxane (5 mL) and water (1 mL) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 1 hour. The mixture was extracted with ethyl acetate and water, and dried. The mixture was purified and resolved using normal phase and reverse phase columns to obtain compound 13-p1 (68 mg) and compound 13-p2 (71.5 mg). LCMS (ESI): m / z 622.0 (M+H) + ;

[0202] The separation conditions were as follows: instrument: SFC-150 (Waters); column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes; the retention time of the active compound 13-p2 under this method was 3.033 minutes.

[0203] Compound 13-p1 (retention time 0.987 min): 1 H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.59 (d, J=2.2Hz, 1H), 8.02 (dt, J=7.7, 1.0Hz, 1H), 7.99–7.92 (m, 1H), 7.91–7.80 (m, 3H), 7.79 (s, 1H), 7.66 ( ddd, J=7.8, 6.8, 2.0Hz, 1H), 7.39–7.30 (m, 2H), 7.09 (ddd, J=8.8, 8.0, 3. 1Hz, 1H), 6.97 (dd, J=9.1, 3.1Hz, 1H), 6.46 (d, J=2.0Hz, 1H), 4.45 (s, 3H).

[0204] Compound 13-p2 (retention time 3.033 min): 1H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.59 (d, J = 2.2Hz, 1H), 8.06–7.99 (m, 1H), 7.99–7.94 (m, 1H), 7.92–7.81 (m, 3H), 7.79 (s, 1H), 7.66 (dd d, J=7.8, 6.8, 2.0Hz, 1H), 7.39–7.31 (m, 2H), 7.09 (ddd, J=8.9, 8.0, 3.1Hz, 1H), 6.97 (dd, J=9.1, 3.1Hz, 1H), 6.51–6.42 (m, 1H), 4.45 (s, 3H).

[0205] Example 11 Synthesis route of compound 14 (compounds 14-p1 and 14-p2)

[0206] Synthesis of Compounds 14-p1 and 14-p2

[0207] Compound 4 (1 g, 1.497 mmol), ammonia (16 mL), and methanol (8 mL) were placed in a reaction flask and reacted at room temperature overnight. The methanol was removed by spinning, and the mixture was extracted with ethyl acetate and water. The organic phase was dried and purified by normal phase column chromatography and SFC separation to obtain compound 14-1 (98 mg) and compound 14-2 (102.5 mg). LCMS (ESI): m / z 680.0 (M+H) + Separation conditions were: Instrument: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes; the retention time of active compound 14-p2 under this method was 4.026 minutes;

[0208] Compound 14-p1 (retention time: 1.235 min): ：1H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.69 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.90 (d, J=18.0Hz, 2H), 7.66 (d, J=2.7Hz, 1H), 7.38 (dd, J=8.9, 5.2Hz, 1H), 7.33 (s, 1 H), 7.14 (ddd, J=8.9, 8.0, 3.1Hz, 1H), 6.98 (s, 1H), 6.94 (dd, J=9.1, 3.1Hz, 1H), 6.22–6.16 (m, 1H), 4.14 (s, 3H), 4.11–3.97 (m, 1H), 3.39 (d, J=17.4Hz, 1H), 3.23 (ddd, J=16.4, 10.3, 5.9Hz, 1H).

[0209] Compound 14-p2 (retention time 4.026 min): 1 H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 8.69 (s, 1H), 7.96 (d, J=8.5Hz, 1H), 7.94–7.87 (m, 2H), 7.66 (d, J=2.7Hz, 1H), 7.38 (dd, J=8.8, 5.2Hz, 1H), 7.33 (s, 1H), 7.14 (ddd, J= 8.9, 8.0, 3.1Hz, 1H), 6.98 (s, 1H), 6.94 (dd, J=9.1, 3.1Hz, 1H), 6.23–6.16 (m, 1H), 4. 14 (s, 3H), 4.12–3.96 (m, 2H), 3.42–3.36 (m, 1H), 3.23 (ddd, J=16.5, 10.4, 6.0Hz, 1H).

[0210] Example 12 Synthetic routes of compounds 15-p1 and 15-p2

[0211] Synthesis of Compounds 15-p1 and 15-p2

[0212] Compound 4 (1 g, 1.497 mmol), aqueous ammonia (16 mL), and methanol (8 mL) were placed in a reaction flask and allowed to react overnight at room temperature. The methanol was removed by spinning, and the mixture was extracted with ethyl acetate and water. The organic phase was dried and purified by normal phase column chromatography and SFC separation to give compound 15-1 (196 mg) and compound 15-2 (191 mg). LCMS (ESI): m / z 665.0 (M+H) + ;

[0213] Compound 15-p1: 1H NMR (400MHz, DMSO-d6) δ10.29 (s, 1H), 8.59 (s, 1H), 7.96 (d, J=8.2Hz, 1H), 7. 93–7.85 (m, 2H), 7.61 (d, J=2.5Hz, 1H), 7.45 (s, 2H), 7.37 (dd, J=8.9, 5.2Hz, 1 H), 7.13 (ddd, J=8.8, 7.9, 3.1Hz, 1H), 6.93 (dd, J=9.2, 3.1Hz, 1H), 6.87 (s, 1 H), 6.59 (s, 1H), 6.20–6.13 (m, 1H), 4.14–3.96 (m, 2H), 3.22 (q, J=7.8Hz, 2H).

[0214] Compound 15-p2: 1 H NMR (400MHz, DMSO-d6) δ10.29 (s, 1H), 8.58 (s, 1H), 7.96 (d, J=8.4Hz, 1H), 7 .92–7.83(m, 2H), 7.61(d, J=2.6Hz, 1H), 7.45(s, 2H), 7.37(dd, J=8.9, 5.1Hz , 1H), 7.13 (ddd, J=8.9, 7.9, 3.1Hz, 1H), 6.93 (dd, J=9.2, 3.1Hz, 1H), 6.87 (s , 1H), 6.59(s, 1H), 6.19–6.15(m, 1H), 4.14–3.94(m, 2H), 3.27–3.16(m, 2H).

[0215] Separation conditions were as follows: instrument: SFC-150 (Waters); column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes; compound 15-2, which had a peak at a retention time of 3.381 min, was the active compound.

[0216] Example 13 Synthesis route of compound 16

[0217] Synthesis of compound 16-c

[0218] To a 100 mL three-necked flask were added 6-bromo-3H-imidazo[5,4-b]pyridine (3000 mg, 15.150 mmol), acetic acid (40 mL), and m-chloroperbenzoic acid (5228.56 mg, 30.300 mmol) in sequence. Under nitrogen protection, the mixture was allowed to react at room temperature for 18 hours. LCMS showed successful reaction. The reaction solution was spin-dried, 50 mL of ethyl acetate was added, and the temperature was raised to 80 degrees Celsius for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was dried to obtain 6-bromo-3H-imidazo[5,4-b]pyridine-4-oxide (2900 mg, 13.550 mmol, 89.44%). LC-MS (ESI): m / z 215.9 (M+H) + .

[0219] Synthesis of compound 16-b

[0220] Compound 16-c (5000 mg, 23.362 mmol) and phosphorus oxychloride (15 mL) were added sequentially to a 25 mL microwave tube. Under nitrogen protection, microwave reaction was carried out at 80 degrees Celsius for 30 minutes. LCMS showed that the reaction was complete. The reaction solution was poured into ice water, and then the pH was adjusted to about 6 with 2N sodium hydroxide solution. Ethyl acetate was added, and the organic phase was concentrated and column chromatography (dichloromethane:methanol = 30:1-20:1) was performed to obtain compound 16-b (310 mg, 1.334 mmol, 5.71%). LC-MS (ESI): m / z 233.8 (M+H) + .

[0221] Synthesis of compound 16-a

[0222] To a 25 mL microwave tube were added 3-c, compound 16-b (220.80 mg, 0.950 mmol), cesium carbonate (928.40 mg, 2.849 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (69.50 mg, 0.095 mmol), N,N-dimethylformamide (10 mL), and water (2 mL). The mixture was reacted at 120°C under a nitrogen atmosphere for 30 minutes. LCMS indicated a successful reaction. Water and ethyl acetate were added to the reaction solution, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 16-a (102 mg, 0.155 mmol, 16.29%). LC-MS (ESI): m / z 659.1 (M+H). + .

[0223] Synthesis of compound 16

[0224] To a 10 mL microwave tube were added compound 16-a (80 mg, 0.121 mmol), zinc cyanide (21.37 mg, 0.182 mmol), zinc powder (1.59 mg, 0.024 mmol), 1,1'-bis(diphenylphosphino)ferrocene (20.18 mg, 0.036 mmol), tris(dibenzylideneacetone)dipalladium (16.66 mg, 0.018 mmol), and N,N-dimethylacetamide (4 mL). Under nitrogen protection, the mixture was microwaved at 170°C for 1 hour. LCMS indicated a successful reaction. Water and ethyl acetate were added sequentially to the reaction mixture. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 30:1-20:1) to afford compound 16 (8 mg, 0.012 mmol, 10.14%). LC-MS (ESI): m / z 650.1 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.10-7.81 (m, 3H), 7.61 (d, J=2.6Hz, 1H), 7.37 (dd, J=8.9, 5.2 Hz, 1H), 7.22-7.08 (m, 1H), 6.95 (dd, J=9.1, 3.1Hz, 1H), 6.88 (s, 1H), 6.23-6.13 (m, 1H), 4.46-3.72 (m, 2H), 3.31-3.01 (m, 2H).

[0225] Example 14 Synthesis route of compound 17

[0226] Synthesis of compound 17

[0227] To a 50 mL three-necked flask were added compound 3-c (785.29 mg, 1.239 mmol), 5-bromo-1H-indazole-3-carbonitrile (275 mg, 1.239 mmol), potassium carbonate (513.69 mg, 3.717 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (90.66 mg, 0.124 mmol), 1,4-dioxane (20 mL), and water (4 mL). The mixture was allowed to react at 100°C for 2 hours under nitrogen. LCMS indicated a successful reaction. Ethyl acetate and water were added, and the organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 17 (81 mg, 0.125 mmol, 10.07%). LC-MS (ESI): m / z 649.2 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ10.24 (s, 1H), 8.04-7.85 (m, 5H), 7.76 (dd, J=8.8, 1 .6Hz, 1H), 7.58 (d, J=2.7Hz, 1H), 7.36 (dd, J=8.9, 5.2Hz, 1H), 7.12 (td, J=8. 3, 3.1Hz, 1H), 7.00 (s, 1H), 6.95 (dd, J=9.1, 3.1Hz, 1H), 6.18 (d, J=2.6Hz, 1H ), 4.02 (dtd, J=31.1, 10.3, 6.5Hz, 2H), 3.46 (ddd, J=17.3, 10.1, 7.2Hz, 2H).

[0228] Example 15 Synthesis route of compound 18

[0229] Synthesis of compound 18

[0230] To a 50 mL three-necked flask were added compound 1-a (431 mg, 0.666 mmol), 6-bromo-5-fluoro[1,2,4]triazolo[1,5-A]pyridine (259.09 mg, 1.199 mmol), potassium carbonate (276.27 mg, 1.999 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (48.76 mg, 0.067 mmol), 1,4-dioxane (10 mL), and water (2 mL). The mixture was reacted at 100°C for 1 hour under nitrogen. LCMS indicated a successful reaction. Ethyl acetate and water were added, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1 to 10:1) to afford compound 18 (62 mg, 0.095 mmol, 14.18%). LC-MS (ESI): m / z 656.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 10.51 (s, 1H), 8.70 (s, 1H), 8.61 (d, J = 2.2Hz, 1H), 8.37 (dd, J = 9.2, 7.6Hz, 1H), 7.95 (t, J = 8.5Hz, 2H), 7.85 (d, J = 9.2Hz, 1H), 7.79 ( s, 1H), 7.55 (d, J=1.1Hz, 1H), 7.35 (dd, J=8.8, 5.2Hz, 1H), 7.09 (td, J=8.4, 3.1Hz, 1H), 6.98 (dd, J=9.1, 3.1Hz, 1H), 6.46 (s, 1H), 4.49 (s, 3H).

[0231] Example 16 Synthesis route of compound 19

[0232] Synthesis of compound 19-b

[0233] To a 50 mL three-necked flask were added 6-bromo-5-iodopyridin-2-amine (1000 mg, 3.345 mmol), ethyl isothiocyanate (526.51 mg, 4.015 mmol), and 1,4-dioxane (15 mL). The mixture was reacted at room temperature under nitrogen for 18 hours. LCMS indicated a successful reaction. The reaction solution was concentrated and slurried with petroleum ether to obtain compound 19-b (1320 mg, 3.069 mmol, 91.75%). LC-MS (ESI): m / z 431.9 (M+H) + .

[0234] Synthesis of compound 19-a

[0235] To a 100 mL three-necked flask were added hydroxylamine hydrochloride (1066.44 mg, 15.347 mmol), N,N-diisopropylethylamine (1190.14 mg, 9.208 mmol), ethanol (10 mL), and methanol (10 mL). Under nitrogen protection, the mixture was reacted at room temperature for 1 hour. Compound 19-b (1320 mg, 3.069 mmol) was then added. The mixture was heated to 70 degrees Celsius and reacted for 18 hours. LCMS showed that the reaction was complete. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filter cake was dried to obtain compound 19-a (853 mg, 2.517 mmol, 82.00%). LC-MS (ESI): m / z 340.9 (M+H) + .

[0236] Synthesis of compound 19

[0237] To a 50 mL three-necked flask were added compound 3-c (634 mg, 1.000 mmol), compound 19-a (339.03 mg, 1.000 mmol), potassium carbonate (414.72 mg, 3.001 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (73.19 mg, 0.100 mmol), 1,4-dioxane (15 mL), and water (3 mL). The mixture was reacted at 75°C for 2 hours under nitrogen. LCMS indicated a successful reaction. Ethyl acetate and water were added to the reaction solution, and the organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 19 (275 mg, 0.383 mmol, 38.24%). LC-MS (ESI): m / z 720.0 (M+H). + ; 1H NMR (400MHz, DMSO-d6) δ10.26 (s, 1H), 8.02-7.82 (m, 3H), 7.57 (d, J=2.6Hz, 1H), 7.44 (s, 2H), 7.37 (dd, J=8.9, 5.1Hz, 1H), 7.13 (td, J=8. 4, 3.1Hz, 1H), 6.92 (dd, J=9.1, 3.1Hz, 1H), 6.74 (s, 1H), 6.35 (s, 2H), 6.19-6.09 (m, 1H), 4.22-3.83 (m, 2H), 3.08 (qt, J=16.5, 7.5Hz, 2H).

[0238] Example 17 Synthesis route of compound 20 (compounds 20-p1 and 20-p2)

[0239] Synthesis of Compound 20, Compound 20-p1, and Compound 20-p2

[0240] To a 10 mL microwave tube were added compound 19 (172 mg, 0.239 mmol), zinc cyanide (42.14 mg, 0.359 mmol), zinc powder (1.56 mg, 0.024 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55.38 mg, 0.096 mmol), palladium acetate (10.74 mg, 0.048 mmol), and N,N-dimethylacetamide (4 mL). The reaction was allowed to proceed at 120°C for 6 hours under nitrogen. LCMS indicated a successful reaction. Water and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 20 (105 mg, 0.158 mmol, 65.99%). LC-MS (ESI): m / z 665.1 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.00-7.85 (m, 3H), 7.77 (d, J=9.1Hz, 1H), 7.70-7.58 (m, 2H), 7.37 (dd, J=8.9, 5.2Hz, 1 H), 7.13 (td, J=8.4, 3.1Hz, 1H), 6.94 (d, J=9.5Hz, 2H), 6.58 (s, 2H), 6.24-6.14 (m, 1H), 4.19-3.93 (m, 2H), 3.31-3.08 (m, 2H).

[0241] SFC separation yielded 25 mg of compound 20-p1 and 35.6 mg of compound 20-2.

[0242] The separation conditions were as follows: instrument: SFC-150 (Waters); chromatographic column: (R, R) Whelk-O1 4.6*100mm 5um; flow rate: 3.0 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes; the peak position of the active compound 20-p1 was 1.35 minutes.

[0243] Example 19 Synthesis route of compound 22

[0244] Synthesis of compound 22-e

[0245] To the reaction flask, add 4-bromo-1H-indole-6-amine (13 g, 61.594 mmol), dichloromethane (200 mL), and TFA (17.123 mL, 123.188 mmol). Under nitrogen, slowly add 5-fluoro-3-trifluoromethylbenzoyl chloride (13 g, 61.594 mmol) dropwise in an ice-water bath. The mixture is stirred at room temperature for 2 hours. After the reaction, add aqueous solution. The organic phase is separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product is purified by column chromatography (mobile phase: dichloromethane / methanol solution) to obtain the target compound 22-e (23.7 g, 95%) as a yellow solid. LC-MS (ESI): m / z 401.1 (M+H) + .

[0246] Synthesis of compound 22-d

[0247] To the reaction flask, 22-e (23.7 g, 59.116 mmol) and acetic acid (500 mL) were added. Under nitrogen protection, sodium cyanoborohydride (7.43 g, 118.22 mmol) was added in batches in an ice-water bath, and the mixture was stirred at room temperature for overnight reaction. After the reaction, the acetic acid solvent was dried. Dissolved in dichloromethane, water was added, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by automatic column chromatography (mobile phase: petroleum ether / ethyl acetate solution) to obtain the target compound 22-d (11 g, 46%). LC-MS (ESI): m / z 403.1 (M+H) + .

[0248] Synthesis of compound 22-c

[0249] To the reaction flask, add 22-d (7.4 g, 18.35 mmol) and acetic acid (80 mL). Under nitrogen protection, add potassium cyanate (2.97 g, 36.709 mmol) in an ice-water bath. Stir the mixture for 30 minutes without removing the ice water. After the reaction, drain the acetic acid solvent. Add water and adjust the pH to a weak base with a saturated aqueous solution of sodium bicarbonate. After thorough stirring, filter, and lyophilize the filter cake to obtain the target compound 22-c (6.7 g, 77%). LC-MS (ESI): m / z 446.1 (M+H). + .

[0250] Synthesis of compound 22-b

[0251] Polyphosphoric acid was added to the reaction flask, and the temperature was raised to 105°C. 22-c (4.7 g, 10.533 mmol) was then added, followed by 2,5-dichlorobenzene-1-carboxaldehyde (3.69 g, 21.066 mmol). The mixture was stirred and reacted for one hour. After the reaction was completed, the reaction solution was poured into an icy sodium hydroxide aqueous solution and stirred thoroughly. After the solution became viscous, it was extracted with dichloromethane. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: dichloromethane:methanol solution) to obtain the target compound 22-b (4 g, 66%). LC-MS (ESI): m / z 602.19 (M+H) + .

[0252] Synthesis of compound 22-a

[0253] To a microwave tube were added 22-b (800 mg, 1.326 mmol), L-proline (60.95 mg, 0.530 mmol), potassium carbonate (549.76 mg, 3.978 mmol), and CuI (50.51 mg, 0.265 mmol). DMSO (6 mL) was added and the atmosphere was replaced with nitrogen 3 to 5 times. Aqueous ammonia (25%) (116.19 mg, 0.3193.315 mmol) was injected with a syringe. The temperature was raised to 100°C and the reaction was allowed to react overnight. The reaction was monitored, extracted with ethyl acetate, washed twice with water, and purified on a normal phase column (dichloromethane:methanol = 20:1) to obtain the target compound 22-a (530 mg, 74%).

[0254] Synthesis of compound 22

[0255] To a 50 mL three-necked flask were added 22-a (500 mg, 0.927 mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (361.28 mg, 1.020 mmol), and acetic acid (10 mL). The mixture was allowed to react at room temperature for 18 hours under nitrogen. LCMS indicated a successful reaction. Excess acetic acid was removed by saturated sodium bicarbonate and dichloromethane were added. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 22 (70 mg, 0.126 mmol, 13.55%). LC-MS (ESI): m / z 557.2 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 8.18-7.71 (m, 3H), 7.43-7.09 (m, 3H), 7.01 (d, J=2 .4Hz, 1H), 5.85 (d, J=2.4Hz, 1H), 5.40 (s, 2H), 4.17-3.55 (m, 2H), 3.02 (t, J=8.5Hz, 2H).

[0256] Example 20 Synthetic routes of compounds 23-p1 and 23-p2

[0257] Synthesis of compound 23-b

[0258] To a 100 mL three-necked flask were added compound 3-e (500 mg, 1.121 mmol), 2,5-dichloro-4-fluoro-benzaldehyde (324.41 mg, 1.681 mmol), and Eaton's reagent (30 mL). The mixture was reacted at 90°C for 1.5 hours under nitrogen. LCMS indicated a successful reaction. The reaction solution was poured into water, filtered, washed with water, and the filter cake dried to afford compound 23-b (650 mg, 1.046 mmol, 93.38%). LC-MS (ESI): m / z 622.2 (M+H) + .

[0259] Synthesis of compound 23-a

[0260] Compound 23-b (650 mg, 1.046 mmol), pinacol diboron (531.44 mg, 2.093 mmol), potassium acetate (308.08 mg, 3.139 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (76.57 mg, 0.105 mmol), and 1,4-dioxane (15 mL) were added to a 50 mL three-necked flask in sequence. The mixture was reacted at 100 degrees Celsius for 1.5 hours under nitrogen protection. LCMS showed that the reaction was successful, and the reaction solution was used directly in the next reaction. LC-MS (ESI): m / z 668.3 (M+H) + .

[0261] Synthesis of compound 23

[0262] To a 50 mL three-necked flask were added compound 23-a (699 mg, 1.046 mmol), 6-bromo[1,2,4]triazolo[1,5-A]pyridine-5-carbonitrile (513.24 mg, 2.301 mmol), potassium carbonate (433.68 mg, 3.138 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (76.54 mg, 0.105 mmol), 1,4-dioxane (15 mL), and water (3 mL). The mixture was reacted at 100°C for 1 hour under nitrogen. LCMS indicated a successful reaction. The reaction mixture was purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 23 (470 mg, 0.687 mmol, 65.65%). LC-MS (ESI): m / z 684.3 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.79 (s, 1H), 8.31 (d, J = 9.3Hz, 1H), 8.03-7.80 (m, 4H), 7.61 (d, J = 9.1Hz, 1H), 7.52 (d, J = 2.3Hz , 1H), 7.25 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.13 (d, J=2.2Hz, 1H), 4.03 (qd, J=7.8, 7.0, 5.6Hz, 2H), 3.24 (ddd, J=13.6, 9.7, 7.0Hz, 2H).

[0263] SFC separation yielded 140 mg of compound 23-p1 and 145 mg of compound 23-p2.

[0264] Separation conditions were as follows: instrument: SFC-150 (Waters); column: (R,R) Whelk-O1 4.6*100mm 5um; mobile phase: CO2 / MeOH=30 / 70; flow rate: 3.0 mL / min; back pressure: 2000 psi; wavelength: 254 nm; cycle time: 5.0 minutes;

[0265] Compound 23-p1 (retention time 2.617 min): LC-MS (ESI): m / z 684.3 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.74 (s, 1H), 8.34 (d, J = 9.3Hz, 1H), 8.01-7.81 (m, 4H), 7.61 (d, J = 9.1Hz, 1H), 7.52 (d, J = 2.3Hz , 1H), 7.25 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.13 (d, J=2.2Hz, 1H), 4.02 (qd, J=7.8, 7.0, 5.6Hz, 2H), 3.24 (ddd, J=13.6, 9.7, 7.0Hz, 2H).

[0266] Compound 23-p2 (retention time 3.677 min): LC-MS (ESI): m / z 684.3 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.79 (s, 1H), 8.34 (d, J = 9.3Hz, 1H), 8.03-7.80 (m, 4H), 7.61 (d, J = 9.1Hz, 1H), 7.52 ( d, J=2.3Hz, 1H), 7.26 (d, J=7.8Hz, 1H), 6.96 (s, 1H), 6.13 (d, J=2.2Hz, 1H), 4.03 (qd, J=7.8, 7.0, 5.6Hz, 2H), 3.26 (m, 2H).

[0267] Example 21 Synthesis route of compound 24

[0268] Synthesis of compound 24

[0269] To a 50 mL three-necked flask were added compound 1-a (377 mg, 0.583 mmol), 5-bromo-4-fluoro-1H-indazole (213.12 mg, 0.991 mmol), potassium carbonate (241.65 mg, 1.749 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (42.65 mg, 0.058 mmol), 1,4-dioxane (10 mL), and water (2 mL). The mixture was reacted at 100°C for 1 hour under nitrogen. LCMS indicated a successful reaction. Ethyl acetate and water were added, and the organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 24 (93 mg, 0.142 mmol, 24.35%). LC-MS (ESI): m / z 655.1 (M+H). + .

[0270] 1 H NMR (400MHz, DMSO-d6) δ13.52 (s, 1H), 10.45 (s, 1H), 8.54 (d, J = 2.2Hz, 1H), 8.28 (t, J = 1.2Hz, 1H), 8.04-7.82 (m, 3H), 7.79 (s, 1H), 7.55 (dd .

[0271] Example 22 Synthesis route of compound 25

[0272] To a 50 mL three-necked flask, compound 18-2 (200 mg, 0.305 mmol) and a solution of ammonia in 1,4-dioxane (7 mL) were added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 18 hours. LCMS indicated a successful reaction. The reaction solution was concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) afforded compound 25 (112 mg, 0.172 mmol, 56.26%). LC-MS (ESI): m / z 653.3 (M+H). + . 1H NMR(400 MHz, DMSO-d6) δ10.44 (s, 1H), 8.56 (d, J=2.3Hz, 1H), 8.49 (s, 1H), 7.95 (dt, J=8.5, 1.9Hz, 1H), 7.84 (dt, J=9.4, 1.9Hz, 1H), 7.80- 7.72 (m, 2H), 7.38-7.27 (m, 2H), 7.15 (d, J=8.9Hz, 1H), 7.12-7.05 (m, 1H), 7.00-6.89 (m, 3H), 6.51 (d, J=2.1Hz, 1H), 4.46 (s, 3H).

[0273] Example 23 Synthesis route of compound 26

[0274] Synthesis of compound 26-f

[0275] To a 250 mL three-necked flask were added 5-bromo-7-fluoro-1H-indazole (5075 mg, 23.601 mmol), iodine (11980.52 mg, 47.203 mmol), potassium hydroxide (5297.09 mg, 94.405 mmol), and N,N-dimethylformamide (60 mL) in sequence. Under nitrogen protection, the reaction was allowed to proceed at 70°C for 2 hours. LCMS indicated a successful reaction. 10% citric acid was added to the reaction solution to adjust the acidity, followed by a large amount of ethyl acetate. A 5% aqueous sodium thiosulfate solution was then added to the organic phase. The organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 20:1-10:1) to afford compound 26-f (4400 mg, 12.906 mmol, 54.68%). LC-MS (ESI) M - :m / z 338.8.

[0276] Synthesis of compound 26-e

[0277] Compound 26-f (3700 mg, 10.853 mmol), trimethyloxonium tetrafluoroboric acid (1765.79 mg, 11.938 mmol), and ethyl acetate (50 mL) were added sequentially to a 50 mL three-necked flask. The mixture was allowed to react overnight at room temperature under nitrogen. LCMS indicated a successful reaction, and the reaction solution was filtered to yield compound 26-e (2300 mg, 6.480 mmol, 59.71%). LC-MS (ESI): m / z 354.9 (M+H) + .

[0278] Synthesis of compound 26-d

[0279] To a 100 mL three-necked flask were added compound 26-e (2650 mg, 7.466 mmol), triethylamine (3.113 mL, 22.398 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (546.28 mg, 0.747 mmol), N,N-dimethylformamide (15 mL), and methanol (15 mL). Under carbon monoxide protection, the mixture was reacted at 70°C for 3 hours. LCMS indicated a successful reaction. The methanol was removed by evaporation, and ethyl acetate and water were added. The organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 20:1-10:1) to afford compound 26-d (1660 mg, 5.782 mmol, 77.45%). LC-MS (ESI): m / z 287.0 (M+H). + .

[0280] Synthesis of compound 26-c

[0281] To a 50 mL three-necked flask were added compound 26-d (1060 mg, 3.692 mmol), 5-fluoro-3-(trifluoromethyl)benzene-1-carboxamide (917.72 mg, 4.431 mmol), cesium carbonate (2406.00 mg, 7.384 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (315.85 mg, 0.369 mmol), and 1,4-dioxane (20 mL). The mixture was incubated at 90°C for 3 hours under nitrogen. LCMS indicated a successful reaction. The reaction solution was directly concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to obtain compound 26-c (1420 mg, 3.436 mmol, 93.05%). LC-MS (ESI): m / z 414.1 (M+H) + .

[0282] Synthesis of compound 26-b

[0283] Compound 26-c (1680 mg, 4.065 mmol), lithium hydroxide (487.78 mg, 20.324 mmol), methanol (15 mL), tetrahydrofuran (15 mL), and water (7 mL) were added sequentially to a 100 mL three-necked flask. Under nitrogen protection, the mixture was reacted at room temperature for 1 hour. LCMS showed that the reaction was complete. The excess methanol and tetrahydrofuran were removed by spinning, and 1N hydrochloric acid was added to adjust the pH to approximately 4. Ethyl acetate was added, and the organic phase was concentrated to obtain compound 26-b (1600 mg, 4.01 mmol, 98.6%). LC-MS (ESI): m / z 400.1 (M+H) + .

[0284] Synthesis of compound 26-a

[0285] To a 50 mL three-necked flask were added compound 26-b (1600 mg, 4.007 mmol), ammonium chloride (321.52 mg, 6.011 mmol), N,N,N,N-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (1828.44 mg, 4.809 mmol), N,N-diisopropylethylamine (1553.80 mg, 12.022 mmol), and N,N-dimethylformamide (20 mL). Under nitrogen protection, the mixture was reacted at room temperature for 1 hour. LCMS showed that the reaction was successful. Water and ethyl acetate were added thereto, and the organic phase was concentrated to give compound 26-a (1100 mg, 2.762 mmol, 68.92%). LC-MS (ESI): m / z 399.2 (M+H) + .

[0286] Synthesis of compound 26

[0287] To a 50 mL three-necked flask were added compound 26-a (398 mg, 0.999 mmol), 2-chloro-5-fluorobenzaldehyde (237.67 mg, 1.499 mmol), and Eaton's reagent (10 mL). The mixture was allowed to react at 80°C for 1.5 hours under nitrogen. LCMS indicated a successful reaction. The reaction solution was poured into a large amount of saturated cold sodium bicarbonate solution, to which ethyl acetate was added. The organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 5:1-3:1) to afford compound 26 (220 mg, 0.408 mmol, 40.86%). LC-MS (ESI): m / z 539.2 (M+H). + .

[0288] Example 25 Synthesis of Compound 28 (Compound 28-p1 and Compound 28-p2)

[0289] Compound 3-c (800 mg, 1.262 mmol), 5-bromo-1H-indazole-4-carbonitrile (308.29 mg, 1.388 mmol), potassium carbonate (523.31 mg, 3.787 mmol), and Pd(dppf)Cl2 (138.54 mg, 0.189 mmol) were added to a reaction flask. 1,4-dioxane (85 mL) and water (14 mL) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 1.5 hours. The mixture was then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 6 to 100 / 7) to obtain the target compound 28 as a solid (180 mg, purity: 93.1%, yield: 20.46%). ESI: (m / z) = 649.2 [M+H] + .

[0290] Chiral separation (instrument: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm, 2 uL (injection); mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; wavelength: 254 nm; cycle time: 13.8 min) gave 28-1 (retention time 1.344 min, 70 mg, purity: 97.2%, yield: 8.31%), 1 H NMR (400MHz, DMSO-d6) δ13.82 (s, 1H), 10.29 (s, 1H), 8.33 (s, 1H), 7.95 (dt, J= 36.3, 13.1Hz, 4H), 7.65–7.57 (m, 2H), 7.37 (dd, J=8.9, 5.1Hz, 1H), 7.13 (dd, J= 9.7, 6.7Hz, 1H), 6.94 (dd, J=9.0, 3.1Hz, 1H), 6.85 (s, 1H), 6.22–6.15 (m, 1H), 4.01(dq, J=18.6, 10.0, 8.4Hz, 2H), 3.26–3.09(m, 2H).ESI: (m / z)=649.2[M+H] + .

[0291] 28-p2 (retention time 3.123 min, 65 mg, purity: 99.2%, yield: 7.87%), 1H NMR (400MHz, DMSO-d6) δ13.82 (s, 1H), 10.29 (s, 1H), 8.33 (s, 1H), 8.08–7.84 (m, 4H), 7.65–7.55 (m, 2H), 7.37 (dd, J=8.9, 5.1Hz, 1H), 7.13 (td, J =8.4, 3.1Hz, 1H), 6.94 (dd, J=9.2, 3.1Hz, 1H), 6.85 (s, 1H), 6.19 (d, J=2 .6Hz, 1H), 4.12–3.93 (m, 2H), 3.26–3.07 (m, 2H).ESI: (m / z)=649.2[M+H] +

[0292] Example 26 Synthesis of Compound 29 (Compound 29-p1 and Compound 29-p2)

[0293] Synthesis of compound 29-a

[0294] To a solution of 5-bromo-1H-indazole-4-carbonitrile (500 mg, 2.252 mmol) in acetonitrile (170 mL) were added 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate (selective fluorine)) (1595.48 mg, 4.504 mmol) and acetic acid (6 mL) at room temperature. The reaction mixture was heated to 90 degrees Celsius under nitrogen protection and stirred for 16 hours. 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate (selective fluorine)) was added. Octane bis(tetrafluoroborate (selective fluorine)) (1595.48 mg, 4.504 mmol) and acetic acid (6 mL) were reacted for 48 hours. The reaction was completed and extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: methanol / dichloromethane 1% to 2%) to obtain compound 29-a (310 mg, yield: 48.75%, purity: 85%). LC-MS (ESI): m / z 241.0 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ13.38 (s, 1H), 7.84–7.77 (m, 2H).

[0295] 3-c (600 mg, 0.947 mmol), compound 29-a, potassium carbonate (392.48 mg, 2.840 mmol), and Pd(dppf)Cl2 (103.90 mg, 0.142 mmol) were added to a reaction flask. 1,4-dioxane (90 mL) and water (18 mL) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 1.5 hours. The mixture was then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 6). The crude product was purified (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) and finally lyophilized to afford the target compound 29 (80 mg, purity: 96.6%) as a solid. ESI: (m / z) = 667.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 7.92 (dt, J=16.9, 9.2Hz, 4H), 7.63 (dd, J=15.3, 5.8Hz, 2H), 7.37 (dd, J=8.9, 5.1Hz, 1H), 7. 13 (dt, J=8.7, 4.4Hz, 1H), 6.94 (dd, J=9.1, 3.2Hz, 1H), 6.86 (s, 1H), 6.19 (s, 1H), 4.11–3.94 (m, 2H), 3.17 (dt, J=27.2, 7.0Hz, 2H).

[0296] Compound 29 was subjected to SFC separation (instrument: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm, 2 uL (injection); mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; wavelength: 254 nm; cycle time: 13.8 min) to obtain the target compound 29-p2 (retention time 2.456, 38 mg, 0.056 mmol, 5.94%). 1H NMR (400MHz, DMSO-d6) δ13.32 (s, 1H), 10.30 (s, 1H), 7.99–7.85 (m, 4H), 7.69–7.59 (m, 2H), 7.37 (dd, J=8.9, 5.1Hz, 1H), 7.13 (td, J=8.3, 3.1Hz, 1H ), 6.94 (dd, J=9.1, 3.1Hz, 1H), 6.86 (s, 1H), 6.18 (d, J=2.6Hz, 1H), 4.03 ( dtd, J=20.9, 10.5, 4.9Hz, 2H), 3.26–3.11(m, 2H).ESI: (m / z)=667.2[M+H] + .

[0297] Example 27 Synthesis of Compound 30

[0298] Synthesis of compound 30-e

[0299] 4-Bromo-6-aminoindole (10 g, 47.380 mmol) was dissolved in dichloromethane (150 mL), and triethylamine (19.757 mL, 142.140 mmol) was added. The atmosphere was purged with N2, and trifluoroacetic anhydride (19.90 g, 94.760 mmol) was added at 0°C. The reaction mixture was allowed to warm to room temperature and react for 3 hours. The mixture was diluted with ethyl acetate and water. The organic phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to directly obtain compound 30-e (14.2 g, purity 87.16%, yield 82.15). ESI: (m / z) = 308.7 [M+H] + .

[0300] Synthesis of compound 30-d

[0301] Compound 30-e (14.2 g, 46.244 mmol) was dissolved in acetic acid (250 mL) and sodium cyanoborohydride (5.81 g, 92.487 mmol) was added. The mixture was allowed to react at room temperature for 16 hours. The reaction solution was spin-dried and poured into an ice-cold saturated aqueous sodium bicarbonate solution, which was then diluted with dichloromethane and water. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate 100 / 13 to 100 / 14) to obtain compound 30-d (4.6 g, purity 96%, yield 30.90%). ESI: (m / z) = 310.6 [M+H] + .

[0302] Synthesis of compound 30-c

[0303] Compound 30-d (4.5 g, 14.559 mmol) was dissolved in acetic acid (100 mL), the temperature was lowered to 10°C, potassium cyanate (2.36 g, 29.118 mmol) was added, and the mixture was allowed to react at 10°C for 0.5 hours. The reaction solution was spin-dried, saturated sodium bicarbonate aqueous solution was added to make the solution alkaline, and water was added and filtered to obtain crude compound 30-c (5.15 g, purity 74.4%, yield 74.74%). ESI: (m / z) = 353.8 [M+H] + .

[0304] Synthesis of compound 30-b

[0305] Compound 30-c (5.1 g, 14.484 mmol) was dissolved in Eaton's reagent (45 mL), and 2-chloro-5-fluorobenzaldehyde (4.59 g, 28.968 mmol) was added. The mixture was reacted at 80°C for 2 hours. The mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to give compound 30-b (6.8 g, 70% purity, 66.71% yield). ESI: (m / z) = 493.8 [M+H] + .

[0306] Synthesis of compound 30-a

[0307] Compound 30-b (6.8 g, 9.662 mmol) was dissolved in methanol (150 mL) and water (50 mL), and lithium hydroxide (10.14 g, 241.551 mmol) was added. The reaction mixture was allowed to react at 80°C for 7 hours. The reaction solution was dried and diluted with dichloromethane and water. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain crude compound 30-a (3.7 g, purity 63.8%, yield 61.60%). ESI: (m / z) = 397.8 [M+H] + .

[0308] Synthesis of compound 30

[0309] Compound 30-a (113.11 mg, 0.285 mmol), 5,7-difluoro-3-methyl-1-benzofuran-2-carboxylic acid) (55 mg, 0.259 mmol), HATU (147.87 mg, 0.389 mmol), DMF (25 mL) and triethylamine (78.70 mg, 0.778 mmol) were added to the reaction flask, and then the reaction was continued at room temperature for 72 hours. Although the product appeared, the reaction raw materials were still not consumed. The reaction was then stopped, the reaction solvent was vortexed, and the sample was directly mixed and purified by an automatic column analyzer (Biotage) (mobile phase: methanol / dichloromethane 100 / 1 to 100 / 2) to obtain crude compound 30 (180 mg, purity: 32.3%). The crude product was prepared and purified (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM ammonium bicarbonate) / acetonitrile, flow rate 30mL / min, column temperature 25°C, detection wavelength 254nm), and finally lyophilized to obtain the solid target compound 30 (10mg, purity: 92%, yield: 6.01%). ESI: (m / z) = 590.0 / 592.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.06 (s, 1H), 7.57–7.49 (m, 3H), 7.29 (dd, J=8.8, 5.1Hz, 1H), 7.05 (td, J=8.4, 3. 1Hz, 1H), 7.02–6.93 (m, 2H), 6.17 (d, J=2.5Hz, 1H), 4.06–3.97 (m, 2H), 3.16 (t, J=8.1Hz, 2H), 2.40 (s, 3H).

[0310] Example 28 Synthesis of Compound 31

[0311] Compound 3-c (500 mg, 0.789 mmol), 5-bromo-3-fluoro-1H-indazole-4-carbonitrile (227.24 mg, 0.947 mmol), potassium carbonate (109.02 mg, 0.789 mmol), and Pd(dppf)Cl2 (577.23 mg, 0.789 mmol) were added to a reaction flask. 1,4-dioxane (75 mL) and water (15 mL) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 1.5 hours. The mixture was then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) and finally lyophilized to afford the target compound 31 (28 mg, 0.043 mmol, 5.41%) as a solid. ESI: (m / z) = 649.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.94 (d, J = 11.5Hz, 2 H), 7.88 (d, J=9.2Hz, 1H), 7.77 (d, J=7.1Hz, 1H), 7.62–7.54 (m, 2H), 7.36 (dd, J=8. 8, 5.2Hz, 1H), 7.11 (td, J=8.4, 3.1Hz, 1H), 6.98 (s, 1H), 6.92 (dd, J=9.2, 3.1Hz, 1 H), 6.24 (d, J=2.6Hz, 1H), 4.13–3.92 (m, 2H), 3.05 (ddd, J=16.1, 10.2, 5.4Hz, 2H).

[0312] Example 29 Synthesis of Compound 32

[0313] Synthesis of compound 32-a

[0314] Compound 1-c (6.7 g, 14.591 mmol), Pd / C 10% (6.21 g, 58.362 mmol), and methanol (515 mL) were added to the reaction flask. Under hydrogen protection, the reaction was continued at room temperature overnight. After the reaction was completed, the product was filtered. Most of the product still remained in the filter residue. The filter residue was then rinsed with a large amount of ethyl acetate and methanol mixed solvent. The filtrate was concentrated and enriched, and purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 6) to obtain compound 32-a (3.05 g, 8.020 mmol, 54.97%), ESI: (m / z) = 381.1 [M+H] + .

[0315] Synthesis of compound 32

[0316] 32-a (558 mg, 1.467 mmol) was dissolved in Eaton's reagent (65 mL), and 2-chloro-4,5-difluorobenzene-1-carbaldehyde (388.57 mg, 2.201 mmol) was added. The mixture was reacted at 90°C under nitrogen for 3 hours. Upon completion, the reaction solution was added dropwise to an ice-cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 4) to afford compound 32 (111 mg, purity: 90%), ESI: (m / z) = 539.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.43 (d, J=2.2Hz, 1H), 7.97 (dt, J=8.6, 1.9Hz, 1H), 7.85 (dt, J=9.3, 1.9Hz, 1H) , 7.74 (s, 1H), 7.67 (dd, J=8.9, 1.0Hz, 1H), 7.56 (dd, J=10.4, 7.3Hz, 1H), 7.21–7.10 (m, 2H), 6.36 (s, 1H), 4.44 (s, 3H).

[0317] Example 30 Synthesis route of compound 33

[0318] Synthesis of compound 33

[0319] Compound 32-a (675 mg, 1.775 mmol) was dissolved in Eaton's reagent (65 mL), and 2,4-dichloro-5-fluorobenzene-1-carbaldehyde (513.84 mg, 2.662 mmol) was added. The mixture was reacted at 90°C under nitrogen for 3 hours. Upon completion, the reaction solution was added dropwise to an ice-cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 4) to give compound 33 (210 mg). The crude product was prepared and purified (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) and lyophilized to give solid compound 33 (68 mg, yield 7%). 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.45 (s, 1H), 7.97 (d, J=8.4Hz, 1H), 7.87–7.74 (m, 2H), 7.64 (dd , J=18.3, 7.8Hz, 2H), 7.14 (dd, J=22.5, 9.2Hz, 2H), 6.36 (s, 1H), 4.43 (s, 3H). (ESI: (m / z)=555.0[M+H] + .

[0320] Example 31 Synthesis of Compound 34

[0321] Dissolve compound 32-a (849 mg, 2.232 mmol) in Eaton's reagent (65 mL), add 2-chloro-5,6-difluorobenzaldehyde (591.21 mg, 3.349 mmol), and react at 90°C under nitrogen for 3 hours. Upon completion, the reaction solution is added dropwise to an ice-cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 4) to give compound 34 (420 mg). The crude product was prepared and purified (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) and lyophilized to give solid compound 34 (60 mg). 1H NMR (400MHz, DMSO-d6) δ10.32 (d, J=35.9Hz, 1H), 8.56 (d, J=82.4Hz, 1H), 7.96 (d, J=8.4Hz, 1H), 7 .91–7.61(m, 3H), 7.44–7.04(m, 3H), 6.65(d, J=11.3Hz, 1H), 4.44(s, 3H).ESI: (m / z)=539.1[M+H] + .

[0322] Example 32 Synthesis of Compound 35

[0323] Dissolve compound 32-a (775 mg, 2.038 mmol) in Eaton's reagent (65 mL), add 2-chloro-5-fluoro-3-methylbenzene-1-carbaldehyde (351.69 mg, 2.038 mmol), and react at 90°C under nitrogen for 3 hours. Upon completion, the reaction solution was added dropwise to an ice-cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous NaSO, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 4) to afford compound 35 (340 mg). The crude product was purified (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) and lyophilized to afford solid compound 35 (70 mg). 1 H NMR (400MHz, DMSO-d6) δ10.31 (s, 1H), 8.42 (s, 1H), 8.06–7.87 (m, 1H), 7.86–7.62 (m, 3H), 7.13 (d, J=22.6Hz, 2H), 6.56 (d, J=100.3Hz, 2H), 4.44 (s, 3H), 2.09 (s, 3H).ESI: (m / z)=535.2[M+H] + .

[0324] Example 33 Synthesis of Compound 36 (Compound 36-p1 and Compound 36-p2)

[0325] Synthesis of compound 36-b

[0326] 3-e (360 mg, 0.807 mmol) was dissolved in Eaton's reagent (30 mL), and 2-chloro-4,5-difluorobenzaldehyde (213.66 mg, 1.210 mmol) was added. The reaction was allowed to proceed at 90°C for 2.5 hours. The reaction solution was cooled to room temperature and slowly added dropwise to ice water. A large amount of water was then added to precipitate a solid product. The solid product was filtered and washed with water and saturated NaCl. The filter cake was then enriched and lyophilized to obtain compound 36-b (510 mg, 0.628 mmol, 77.85%). ESI: (m / z) = 605.8 [M+H] + .

[0327] Synthesis of compound 36-a

[0328] Compound 36-b (500 mg, 0.827 mmol), pinacol diboron (629.88 mg, 2.480 mmol), potassium acetate (324.57 mg, 3.307 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (121.00 mg, 0.165 mmol), and 1,4-dioxane (30 mL) were added to the reaction flask and dissolved. The mixture was heated to 110 ° C. under nitrogen protection and stirred for 2.5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by automatic column analyzer (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 4 to 100 / 5) to give brown semi-solid compound 36-a (660 mg, 0.836 mmol, 101.16%). LC-MS (ESI): m / z 652.0 (M+H) + .

[0329] Synthesis of compound 36

[0330] Compounds 36-a (350 mg, 0.537 mmol) and 7-c (155.69 mg, 0.698 mmol) were dissolved in dioxane (15 mL), and water (3 mL) was added. 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (78.58 mg, 0.107 mmol) and potassium carbonate (222.63 mg, 1.611 mmol) were then added. Under nitrogen, the mixture was stirred at 100°C for 1.5 hours and cooled to room temperature. The mixture was then diluted with 30 mL of water. The resulting mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was spin-dried. The crude product was purified (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) to obtain the target compound 36;

[0331] Compound 36 was subjected to SFC separation (instrument: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm, 2 uL (injection); mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; wavelength: 254 nm; cycle time: 13.8 min) and finally lyophilized to obtain solid compound 36-p1 (retention time 1.567 min, 26 mg, 0.038 mmol, 7.05%). 1 HNMR (400MHz, DMSO-d6) δ10.31 (s, 1H), 8.79 (s, 1H), 8.32 (d, J=9.3Hz, 1H), 7.99–7.88 (m, 4H), 7.65–7.58 (m, 2H), 7.19 (dd, J=10.9, 8.4Hz, 1H), 7.00 (s, 1H), 6.15 (d, J=2.3Hz, 1H), 4.12–3.98 (m, 2H), 3.30–3.16 (m, 2H).

[0332] Compound 36-p2 (retention time 2.434 min, 28 mg, 0.041 mmol, 7.70%), 1HNMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.79 (s, 1H), 8.32 (d, J=9.2Hz, 1H), 7.99–7.88 (m, 4H), 7.65–7.57 (m, 2H), 7.19 (dd, J=1 0.9, 8.3Hz, 1H), 6.99 (s, 1H), 6.15 (d, J=2.3Hz, 1H), 4.11–3.98 (m, 2H), 3.24 (qd, J=10.2, 5.3Hz, 2H). (ESI: (m / z)=668.3[M+H] + .

[0333] Example 34 Synthesis of Compound 37

[0334] Synthesis of compound 37

[0335] Compound 1-a (160 mg, 0.247 mmol), 29-b (59.38 mg, 0.247 mmol), potassium carbonate (102.56 mg, 0.742 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (36.20 mg, 0.049 mmol) were added to a reaction flask. 1,4-dioxane (30 mL) and water (6 mL) were added. The atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 2 hours. The mixture was then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (Welch Xtimate C18, 20 g, water (0.05% ammonium bicarbonate) / acetonitrile, flow rate 20 mL / min, room temperature, detection wavelength 254 nm) and finally lyophilized to afford the target compound 37 (6 mg, 0.009 mmol, 3.48%) as a solid. ESI: (m / z) = 680.3 [M+H] + . 1 H NMR (400MHz, DMSO) δ13.37 (s, 1H), 10.53 (s, 1H), 8.68–8.54 (m, 1H), 8.02 (dd, J=8.9, 2.1Hz, 1H), 7.95 (dd, J=14.0, 8.8Hz, 2H), 7.88–7. 77 (m, 2H), 7.43 (s, 1H), 7.35 (dd, J=8.8, 5.1Hz, 1H), 7.10 (td, J=8.4, 3.0Hz, 1H), 6.99 (dd, J=9.2, 3.2Hz, 1H), 6.47 (s, 1H), 4.46 (s, 3H).

[0336] Example 37 Synthesis route of compound 41 (compound 41-p1 and compound 41-p2)

[0337] Synthesis of compound 41-b

[0338] DMF-DMA (N,N-dimethylformamide dimethyl acetal) (8.11 g, 68.063 mmol) was added to a solution of 5-bromo-6-fluoropyridin-2-amine (10.00 g, 52.356 mmol) in isopropanol (20 mL) and heated to 90°C for 3 hours. TLC (ethyl acetate / petroleum ether (v / v) = 1:3) detected an intermediate and the starting material disappeared. The reaction solution was cooled to 50°C, hydroxylamine hydrochloride (4.73 g, 68.063 mmol) was added, and the reaction was continued at 50°C for 16 hours. The reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 50% to 90%) to obtain compound 41-b (11.00 g, yield 89.80%). (ESI): m / z 233.7, 235.8 [M+H] + ; tR=1.891min. 1 H NMR (400MHz, DMSO-d6) δ10.38 (s, 1H), 9.88 (d, J=9.8Hz, 1H), 8.01 (dd, J=9.3, 8.5Hz, 1H), 7.61 (d, J=9.8Hz, 1H), 6.94 (dd, J=8.5, 1.2Hz, 1H).

[0339] Synthesis of compound 41-a

[0340] Compound 41-b (6.00 g, 25.638 mmol) was added to a solution of Eaton's Reagent (phosphorus pentoxide methanesulfonic acid) (50 mL) and heated to 80°C for 2 hours. The reaction solution was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution in an ice-water bath until neutral. The organic phase was separated and concentrated, and then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-30%) to give compound 41-a (3.00 g, yield 54.15%). (ESI): m / z 216.0, 218.0 [M+H] + ; tR=1.605min. 1 HNMR (400MHz, DMSO-d6) δ8.64 (s, 1H), 7.99 (dd, J=9.4, 7.2Hz, 1H), 7.76 (d, J=9.4Hz, 1H).

[0341] Synthesis of compound 41

[0342] Under nitrogen protection, Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride) (69 mg, 0.095 mmol) was added to a mixed solution of compound 41 (23 mg, 0.118 mmol), 3-c (300 mg, 0.473 mmol) and potassium carbonate (131 mg, 0.947 mmol) in 1,4-dioxane (15 mL) and water (3 mL), and the mixture was heated to 90°C for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was separated and quickly filtered through a celite filter cake. The filtrate was concentrated and purified by preparative HPLC (alkaline method) to give compound 41 (40 mg, yield 13.14%). (ESI): m / z 643.1 [M+H] + ; tR=4.664min. 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 8.68 (s, 1H), 7.96 (d, J=8.4Hz, 1H), 7. 90 (d, J=6.5Hz, 2H), 7.89–7.84 (m, 2H), 7.61 (d, J=2.6Hz, 1H), 7.36 (dd, J=8.9 , 5.1Hz, 1H), 7.13 (td, J=8.4, 3.0Hz, 1H), 7.01–6.95 (m, 1H), 6.94 (s, 1H), 6. 24–6.12(m, 1H), 4.11–4.04(m, 1H), 4.04–3.95(m, 1H), 3.25(t, J=8.8Hz, 2H).

[0343] A solid sample of 41 (105 mg, 0.163 mmol) was subjected to SFC separation using a mobile phase SFC (instrument: SFC-150 (Waters); column: AD-3 0.46 cm ID*5 cm.L 20*250 mm, 2 uL (injection); mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; wavelength: 254 nm; cycle time: 13.8 min) to obtain 41-p1 (retention time 1.486 min, 36 mg, yield 68.57%) and 42-p2 (retention time 3.136 min, 34 mg, yield 64.76%). (ESI): m / z 643.0 [M+H] + ;tR=2.122min.1:ee=99.92%, 2:ee=100%.

[0344] Compound 41-p1: (ESI): m / z 643.1 [M+H] + ; tR=4.664min. 1H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 8.68 (s, 1H), 7.96 (d, J=8.4Hz, 1H), 7. 90 (d, J=6.5Hz, 2H), 7.89–7.84 (m, 2H), 7.61 (d, J=2.6Hz, 1H), 7.36 (dd, J=8.9 , 5.1Hz, 1H), 7.13 (td, J=8.4, 3.0Hz, 1H), 7.01–6.95 (m, 1H), 6.94 (s, 1H), 6. 24–6.12(m, 1H), 4.11–4.04(m, 1H), 4.04–3.95(m, 1H), 3.25(t, J=8.8Hz, 2H).

[0345] Compound 41–p2: (ESI): m / z 643.1 [M+H] + ; tR=4.664min. 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 8.68 (s, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.90 (d, J = 6.5Hz, 2H), 7.89–7.84 (m, 2H), 7.61 (d, J=2.6Hz, 1H), 7.36 (dd, J=8.9, 5.1Hz, 1H), 7.13 (td, J=8.4, 3.0Hz, 1H), 7.01–6.95 (m, 1H), 6 .94(s, 1H), 6.24–6.12(m, 1H), 4.11–4.04(m, 1H), 4.04–3.95(m, 1H), 3.25(t, J=8.8Hz, 2H).

[0346] Example 39 Synthesis route of compound 43

[0347] Synthesis of compound 43

[0348] Under nitrogen protection, Pd2(dba)3(tris(dibenzylideneacetone)dipalladium) (31 mg, 0.034 mmol) was added to a mixture of 3-d (200 mg, 0.341 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (117 mg, 0.511 mmol), cesium carbonate (389 mg, 1.193 mmol) and RuPhos(2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl) (32 mg, 0.068 mmol) in 1,4-dioxane (8 mL), and the mixture was heated to 110 °C for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give a crude product. The crude product was then purified by preparative HPLC (alkaline method) to give 43 (55 mg, yield 23.11%). (ESI): m / z 698.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 7.95 (d, J=8.4Hz, 1H), 7.88 (s, 1H), 7.86 (d, J=8.6H z, 1H), 7.48 (d, J=2.6Hz, 1H), 7.32 (dd, J=8.8, 5.1Hz, 1H), 7.09 (td, J=8.3, 3.1Hz, 1H), 6. 84 (dd, J=9.2, 3.1Hz, 1H), 6.45 (s, 1H), 6.09–6.00 (m, 1H), 4.64–4.44 (m, 2H), 4.28 (t, J=5 .3Hz, 2H), 4.00 (dp, J=19.4, 9.9, 9.0Hz, 2H), 3.64 (t, J=5.4Hz, 2H), 3.26 (t, J=8.5Hz, 2H).

[0349] Example 40 Synthesis route of compound 44

[0350] Synthesis of compound 44

[0351] Under nitrogen protection, Pd2(dba)3(tris(dibenzylideneacetone)dipalladium) (31 mg, 0.034 mmol) was added to a mixture of compound 3-d (200 mg, 0.341 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (82 mg, 0.511 mmol), cesium carbonate (389 mg, 1.193 mmol) and RuPhos(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (32 mg, 0.068 mmol) in 1,4-dioxane (8 mL), and the mixture was heated to 110°C for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give a crude product. The crude product was then purified by preparative HPLC (alkaline method) to give 44 (35 mg, yield 16.30%). (ESI): m / z 630.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.15 (s, 1H), 8.51 (s, 1H), 7.95 (d, J=8.4Hz, 1H), 7 .91–7.79 (m, 2H), 7.46 (s, 1H), 7.19–7.02 (m, 1H), 7.09 (dd, J=10.8, 5.3Hz, 1 H), 6.97–6.78(m, 1H), 6.41(s, 1H), 6.02(s, 1H), 4.53–4.35(m, 2H), 4.15(t , J=5.4Hz, 2H), 3.99 (q, J=8.8Hz, 2H), 3.59–3.56 (m, 2H), 3.28–3.23 (m, 2H).

[0352] Example 41. Synthesis route of compound 45

[0353] Synthesis of compound 45-b

[0354] Ethyl isothiocyanate (377.66 mg, 2.880 mmol) was added to a solution of 5-bromo-6-fluoropyridin-2-amine (500 mg, 2.618 mmol) in 1,4-dioxane (20 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated to give compound 45-b (900 mg, crude). (ESI): m / z 322.0 [M( 79 Br)+H] + , 324.0[M( 81 Br)+H] + ;

[0355] Synthesis of compound 45-a

[0356] Hydroxylamine hydrochloride (970.78 mg, 13.970 mmol) was added to a mixture of methanol (5 mL) and ethanol (10 mL) of compound 45-b (900 mg, 2.794 mmol) and N, N-diisopropylethylamine (1083 mg, 8.382 mmol), stirred at room temperature for 1 hour, and then heated to 70 ° C for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, it was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:20) to give compound 45-a (100 mg, yield 15.49%). (ESI): m / z 231.0 [M ( 79 Br)+H] + ,233.0[M( 81 Br)+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.71 (dd, J=9.3, 7.5Hz, 1H), 7.23 (d, J=9.3Hz, 1H), 6.39 (s, 2H).

[0357] Synthesis of compound 45

[0358] Under nitrogen, Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) (17 mg, 0.024 mmol) was added to a mixture of 3-c (150 mg, 0.237 mmol), compound 45-a (60 mg, 0.260 mmol), and potassium carbonate (65 mg, 0.473 mmol) in water (2 mL) and 1,4-dioxane (10 mL). The mixture was heated to 80°C for 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was separated and concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:20) to afford an off-white solid. The off-white solid was further purified by C18 alkaline method to afford the target compound 45 (65 mg, 41.74% yield). (ESI): m / z 658.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.27 (s, 1H), 7.96 (d, J=8.5Hz, 1H), 7.91 (s, 1H), 7.8 8(d, J=8.9Hz, 1H), 7.63(d, J=8.7Hz, 1H), 7.61–7.54(m, 1H), 7.35(td, J=8.9, 5.6Hz, 2H), 7.13 (td, J=8.4, 3.0Hz, 1H), 6.95 (dd, J=9.3, 3.1Hz, 1H), 6.87 (s, 1H), 6.38 (s, 2H), 6.16 (d, J=2.5Hz, 1H), 4.14–3.93 (m, 2H), 3.27–3.11 (m, 2H).

[0359] Example 42 Preparation route of compounds 45-p1, 45-p2

[0360] Compound 45 (60 mg, 0.091 mmol) was subjected to SFC separation (separation conditions: instrument: SFC-150 (Waters); chromatographic column: AS 20*250 mm, 10 um (Daicel); mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55; flow rate: 120 g / min; back pressure: 100 bar; wavelength: 214 nm; cycle time: 13.8 min) to give 45-p1 (retention time 14.7 mg, yield 24.50%) and 45-p2 (retention time 17.3 mg, yield 28.83%).

[0361] Example 43 Synthesis route of compound 47

[0362] Synthesis of compound 47-c

[0363] Under nitrogen protection, iron powder (13.75 g, 246.305 mmol) was added to a mixed solution of 5-bromo-2-nitropyridine (10.00 g, 49.261 mmol) and ammonium chloride (7.90 g, 147.783 mmol) in ethanol (100 mL) and water (20 mL), and the mixture was heated to 70°C for 10 hours. The reaction solution was diluted with dichloromethane, filtered through a celite filter cake, and the filtrate was concentrated to remove the organic solvent. Ethyl acetate and water were then added to dilute the mixture, the organic phase was separated, dried over anhydrous sodium sulfate, and filtered again. After the filtrate was concentrated, it was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 30% to 90%) to give compound 47-c (6.50 g, yield 76.29%). (ESI): m / z 173.0, 175.0 [M+H] + .

[0364] Synthesis of compound 47-b

[0365] DMF-DMA (N,N-dimethylformamide dimethyl acetal) (0.90 g, 7.514 mmol) was added to a solution of compound 47-c (1.00 g, 5.780 mmol) in isopropanol (2 mL), and the mixture was heated to 90°C for 3 hours. LCMS analysis showed the formation of an intermediate (ESI: m / z 227.8, 229.8 [M+H] + , tR = 1.737 min.). The reaction solution was cooled to 50°C, hydroxylamine hydrochloride (0.52 g, 7.514 mmol) was added, and the reaction was continued at 50°C for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 50% to 90%) to obtain compound 47-b (1.00 g, yield 80.00%). (ESI): m / z 215.8, 217.8 [M+H] + , tR=1.270min. 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 9.56 (d, J=9.9Hz, 1H), 8.23 ​​(dd, J=2.5, 0.6Hz, 1H), 7.80 (dd, J=8.8, 2.5Hz, 1H), 7.77 (d, J=9.9Hz, 1H), 7.05 (dd, J=8.9, 0.7Hz, 1H).

[0366] Synthesis of compound 47-a

[0367] Trifluoroacetic anhydride (1.26 g, 6.017 mmol) was added dropwise to a solution of compound 47-b (1.00 g, 4.629 mmol) in tetrahydrofuran (20 mL) and heated to 80°C for 4 hours. The reaction solution was quenched with saturated sodium bicarbonate solution until neutral, extracted with ethyl acetate, and the organic phase was separated. The filtrate was dried over anhydrous sodium sulfate and filtered to obtain a filtrate. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound 47-a (700 mg, yield 76.09%). (ESI): m / z 197.8, 199.8 [M+H] + , tR=1.603min.

[0368] Synthesis of compound 47

[0369] Under nitrogen protection, Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride) (69 mg, 0.095 mmol) was added to a mixed solution of compound 47-a (141 mg, 0.710 mmol), 3-c (300 mg, 0.473 mmol) and potassium carbonate (196 mg, 1.420 mmol) in 1,4-dioxane (18 mL) and water (3 mL), and the mixture was heated to 90°C for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was separated and quickly filtered through a diatomaceous earth filter cake. The filtrate was concentrated and purified by preparative HPLC (alkaline method) to give compound 47 (70 mg, yield 23.66%). (ESI): m / z 625.0 [M+H] + , tR=1.603min. 1 H NMR (400MHz, DMSO-d6) δ10.27(s, 1H), 9.17(s, 1H), 8.57(s, 1H), 7.98(s, 1H), 7.95(d, J=3.6Hz, 2H), 7.92–7.83 (m, 2H), 7.62 (d, J=2.7Hz, 1H), 7.36 (dd, J=8.9, 5.1Hz, 1H), 7. 12 (td, J=8.4, 3.1Hz, 1H), 7.03 (s, 1H), 6.95 (dd, J=9.2, 3.1Hz, 1H), 6.19 (d, J=2.6Hz, 1H), 4.06 (dd, J=10.3, 5.7Hz, 1H), 3.99 (q, J=9.8Hz, 1H), 3.51 (dt, J=17.2, 9.0Hz, 1H).

[0370] Example 44 Synthesis route of compound 48 (48-p1 and 48-p2)

[0371] Compound 26-a (200 mg, 0.519 mmol), Eaton's reagent (10 mL), and 2,5-dichlorobenzaldehyde (136 mg, 0.779 mmol) were added sequentially to a 50 mL three-necked flask. Under nitrogen, the temperature was raised to 80°C for 2 hours. The reaction solution was cooled to room temperature and added to ice water. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7-8. Extraction was performed with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then purified to obtain compound 48 (151 mg, 0.278 mmol, 53.64%). LC-MS (ESI): m / z 542.2 (M+H) + .

[0372] 1H NMR (400MHz, Chloroform-d) δ7.50 (m, J=8.1, 2.3Hz, 2H), 7.39 (s, 1H), 7.34 (d, J=8.6Hz, 1H), 7.28 (d, J=2.4Hz, 1H), 7.25–7.18 ( m, 2H), 7.05 (d, J=2.4Hz, 1H), 6.25–6.19 (m, 1H), 5.19 (d, J=2.4Hz, 1H), 4.16 (tt, J=6.9, 3.1Hz, 2H), 3.32 (dd, J=9.8, 7.4Hz, 2H).

[0373] Compounds 48-p1 and 48-p2 were obtained by SFC separation (separation conditions: instrument: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; flow rate: 3.0 mL / min; detection wavelength: 214 nm): 48-p1 46 mg (retention time 1.305 min) and 48-p2: 40 mg (RT = 1.712 min).

[0374] Example 45 Synthesis route of compound 49 (49-p1 and 49-p2)

[0375] Synthesis of compound 49-d

[0376] Compound 3-a (8 g, 17.929 mmol) was dissolved in Eaton's reagent (80 mL), and 2,5-dichlorobenzaldehyde (3.77 g, 21.515 mmol) was added. The mixture was reacted at 80°C for 2 hours. The reaction solution was poured into ice water, adjusted to pH ~7 with 1N sodium hydroxide aqueous solution, and extracted with ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (dichloromethane / methanol ~ 20 / 1) to obtain compound 49-d (2.2 g, 20.35%). ESI: (m / z) = 604.1 [M+H] + .

[0377] Synthesis of compound 49-c

[0378] Compound 49-d (2.2 g, 3.647 mmol) was dissolved in 1,4-dioxane (25 mL), and diboronic acid pinacol ester (1.39 g, 5.471 mmol), potassium acetate (1.07 g, 10.942 mmol), and Pd(dppf)Cl2 (530 mg, 0.729 mmol) were added. The mixture was reacted at 100°C for 1 hour to obtain compound 49-c (2.37 g), which was directly used in the next step.

[0379] Synthesis of compound 49-b

[0380] Compound 49-c (2.37 g, 3.739 mmol), compound 5-e (1.28 g, 3.739 mmol), potassium carbonate (1.55 g, 11.218 mmol), and Pd(dppf)Cl2 (0.27 g, 0.374 mmol) were added to a reaction flask. 1,4-dioxane (25 mL) and water (5 mL) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 1 hour. The mixture was extracted three times with ethyl acetate and water. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 49-b (1.8 g, 66.6%). LCMS (ESI): m / z 739.2 (M+H) + ;

[0381] Synthesis of compound 49-a

[0382] Compound 49-b (1.7 g, 2.303 mmol), zinc cyanide (0.41 g, 3.454 mmol), zinc powder (0.02 g, 0.230 mmol), Xantphos (0.53 g, 0.921 mmol), and palladium acetate (0.10 g, 0.461 mmol) were added to a reaction flask. DMAC (20 mL) was added, the atmosphere was replaced with nitrogen, and the mixture was reacted at 120°C for 1 hour. The mixture was then extracted with ethyl acetate and water. The organic phase was dried and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 49-a (1 g, 63.3%). LCMS (ESI): m / z 684.3 (M+H). + ;

[0383] Synthesis of compound 49 (49-p1 and 49-p2)

[0384] Compound 49-a (200 mg, 0.292 mmol) was added to a reaction flask, and methanol (5 mL) and sodium methoxide (32 mg, 0.584 mmol) were added. The nitrogen atmosphere was replaced and the reaction was allowed to react at room temperature overnight. The reaction solution was spin-dried and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 49. LCMS (ESI): m / z 696.3 (M+H) + The crude product was separated by SFC to give compound 49-p1 (42 mg, 21%) and compound 49-p2 (43 mg, 21.1%).

[0385] Separation conditions were as follows: instrument: SFC-150 (Waters); chromatographic column: OD-3 4.6*100mm 3um; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 214 nm; cycle time: 2.0 minutes.

[0386] Compound 49-p1: retention time: 0.938 min; 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.69(s,1H),7.96(d,J=8.4Hz,1H),7. 89(d,J=16.2Hz,2H),7.57(d,J=2.4Hz,1H),7.38(d,J=8.6Hz,1H),7.34–7.2 8(m,2H),7.11(d,J=2.5Hz,1H),6.95(s,1H),6.16(d,J=2.4Hz,1H),4.14(s, 3H), 4.06 (dq, J=18.9, 7.4, 5.8Hz, 2H), 3.42–3.35 (m, 1H), 3.28–3.17 (m, 1H).

[0387] Compound 49-p2: P2 peak time: 1.306 min, 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.69(s,1H),7.96(d,J=8.5Hz,1H),7. 93–7.85(m,2H),7.57(d,J=2.4Hz,1H),7.38(d,J=8.5Hz,1H),7.34–7.29(m,2 H),7.11(d,J=2.5Hz,1H),6.95(s,1H),6.16(d,J=2.4Hz,1H),4.14(s,3H),4. 10–3.99(m,2H),3.37(d,J=10.0Hz,1H),3.22(ddd,J=16.6,10.2,6.3Hz,1H).

[0388] Example 46 Synthesis route of compound 50 (50-p1 and 50-p2)

[0389] Synthesis of compound 50-b

[0390] Compound 1-c (3.5 g, 7.622 mmol), Eaton's reagent (70 mL), and 2-chloro-5-fluorobenzaldehyde (2.18 g, 13.720 mmol) were added to a 100 mL three-necked flask in sequence. Under nitrogen protection, the temperature was raised to 70°C and the reaction was allowed to react for 2 hours. The reaction solution was added dropwise to 0°C water to quench, extracted with ethyl acetate, separated, and dried by spin drying. Dichloromethane was added to dissolve the solution, and a 1M sodium hydroxide solution was used to adjust the solution to a strong base. The mixture was stirred for 30 minutes, separated, and the aqueous layer was extracted with dichloromethane. The dichloromethane layers were combined, and the organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (methanol / dichloromethane = 0-2%) to give compound 50-b (955 mg, 1.592 mmol, 20.89%). LC-MS (ESI): m / z 599.1, 601.1 (M+H) + .

[0391] Synthesis of compound 50-a

[0392] To a 50 mL three-necked flask were added compound 50-b (300 mg, 0.487 mmol), potassium acetate (147 mg, 1.501 mmol), pinacol diboron (190 mg, 0.750 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (36 mg, 0.050 mmol), and 1,4-dioxane (8 mL). Under nitrogen protection, the temperature was raised to 100°C and the reaction was allowed to proceed for 1 hour. LCMS monitoring indicated the formation of 90% of the target compound 50-a. The product was used directly in the next reaction. LC-MS (ESI): m / z 565.1 (M+H) + 。

[0393] Synthesis of Compound 50 (50-p1 and 50-p2)

[0394] To a 50 mL three-necked flask were added compound 50-a (282 mg, 0.487 mmol), 1-bromo-2-fluorobenzene (131 mg, 0.749 mmol), potassium carbonate (207 mg, 1.498 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (36 mg, 0.050 mmol), 1,4-dioxane (8 mL), and water (1 mL). Under nitrogen, the mixture was heated to 100°C and reacted for 1 hour. The mixture was diluted with water and ethyl acetate, filtered, and the filter cake was washed with ethyl acetate. The filtrate was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (methanol / dichloromethane = 0-3%) and then by reverse phase column purification (acetonitrile / water = 5-65%) to afford compound 50 (145 mg, 0.236 mmol, 47.22%). LC-MS (ESI): m / z 615.2 (M+H) +

[0395] Compound 50 was separated by SFC (separation conditions: instrument: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; detection wavelength: 254 nm;

[0396] 50-p1 53 mg (retention time 2.002 min) and 50-p2 58 mg (retention time 3.317 min) were obtained.

[0397] 1 H NMR (400MHz, DMSO-d6) δ10.45 (s, 1H), 8.56 (d, J=2.2Hz, 1H), 8.03–7.92 (m, 2H), 7.84 (dt, J=9.3, 2.0Hz, 1H), 7.78 (s, 1H), 7.5 6–7.45 (m, 1H), 7.43–7.30 (m, 4H), 7.09 (m, J=8.4, 3.1Hz, 1H), 6.95 (dd, J=9.2, 3.1Hz, 1H), 6.44 (d, J=2.1Hz, 1H), 4.47 (s, 3H).

[0398] Example 47 Synthesis route of compound 51 (51-p1 and 51-p2)

[0399] Compound 49-c (320 mg, 0.492 mmol), 3-bromo-2-cyanopyridine (135 mg, 0.738 mmol), potassium carbonate (204 mg, 1.476 mmol) and Pd(dppf)Cl2 (36 mg, 0.049 mmol) were added to a reaction flask, and 1,4-dioxane (10 mL) and water (2 mL) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 1 hour. The mixture was extracted with ethyl acetate and water, and the mixture was spin-dried. The mixture was purified by normal phase purification and SFC separation under the following separation conditions: instrument: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; flow rate: 3.0 mL / min; detection wavelength: 214 nm) to obtain compound 51-p1 (73 mg) and compound 51-p2 (76.5 mg). LCMS (ESI): m / z 626.3 (M+H) + ;

[0400] Separation conditions were as follows: instrument: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL; back pressure: 100 bar; wavelength: 254 nm; cycle time: 5 min; 51-p1 retention time: 2.387 min; 51-p2 retention time: 4.086 min

[0401] Compound 51-p1: 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.81 (dd, J=4.7, 1.5Hz, 1H), 8.16 (dd, J= 8.1,1.6Hz,1H),7.96(d,J=8.1Hz,1H),7.92–7.80(m,3H),7.55(d,J=2.4Hz,1H) ,7.37(d,J=8.6Hz,1H),7.30(dd,J=8.6,2.5Hz,1H),7.10(d,J=2.5Hz,1H),6.85 (s,1H),6.14(d,J=2.4Hz,1H),4.03(pd,J=10.4,6.7Hz,2H),3.29–3.04(m,2H).

[0402] Compound 51-p2: 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 8.81 (dd, J = 4.7, 1.5Hz, 1H), 8.16 (dd, J=8.1,1.6Hz,1H),7.96(d,J=8.4Hz,1H),7.92–7.81(m,3H),7.55(d,J=2.4Hz ,1H),7.37(d,J=8.6Hz,1H),7.30(dd,J=8.6,2.5Hz,1H),7.09(d,J=2.5Hz,1 H),6.85(s,1H),6.14(d,J=2.4Hz,1H),4.13–3.94(m,2H),3.29–3.02(m,2H).

[0403] Example 48 Synthesis route of compound 52 (52-p1 and 52-p2)

[0404] Synthesis of compound 52-a

[0405] Compound 1-c (2 g, 4.355 mmol) was dissolved in Eaton's reagent (20 mL), and 2,5-dichloro-4-fluorobenzaldehyde (1.01 g, 5.226 mmol) was added. The reaction mixture was allowed to react at 80°C for 2 hours. The reaction mixture was poured into ice water, adjusted to pH ~7 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (dichloromethane / methanol ~20 / 1) to obtain compound 52-a (360 mg, 13%). ESI: (m / z) = 635.0 [M+H] + .

[0406] Synthesis of compound 52-b

[0407] 52-a (360 mg, 0.568 mmol) was dissolved in 1,4-dioxane (10 mL), and diboronic acid pinacol ester (216 mg, 0.851 mmol), potassium acetate (167 mg, 1.703 mmol), and Pd(dppf)Cl2 (83 mg, 0.114 mmol) were added. The mixture was reacted at 100°C for 1 hour to obtain compound 52-b (390 mg), which was used directly in the next step.

[0408] Synthesis of Compound 52 (52-p1 and 52-p2)

[0409] Compound 52-b (390 mg, 0.572 mmol), 2-bromobenzonitrile (156 mg, 0.859 mmol), potassium carbonate (237 mg, 1.717 mmol) and Pd(dppf)Cl2 (42 mg, 0.057 mmol) were added to a reaction flask, and 1,4-dioxane (10 mL) and water (2 mL) were added. The nitrogen atmosphere was replaced and the reaction was carried out at 100°C for 1 hour. The mixture was extracted with ethyl acetate and water, and dried. The mixture was purified by normal phase purification and separated by SFC (separation conditions were: instrument: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; flow rate: 3.0 mL / min; detection wavelength: 214 nm) to obtain compound 52-p1 (64 mg) and compound 52-p2 (52 mg). LCMS (ESI): m / z 656.2 (M+H) + ;

[0410] Separation conditions were as follows: instrument: SFC-150 (Waters); column: AD-3; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL; back pressure: 100 bar; wavelength: 254 nm; cycle time: 5 min; P1 retention time: 2.223 min; P2 retention time: 3.679 min

[0411] Compound 52-p1: 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.51(s,1H),8.03(d,J=7.8Hz,1H),7.97(d,J=8.4Hz,1H),7.92–7.8 4(m,3H),7.75(s,1H),7.66(ddd,J=8.6,6.7,2.2Hz,1H),7.60(d,J=9.0Hz,1H),6.40(s,1H),4.45(s,3H).

[0412] Compound 52-p2: 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.51(s,1H),8.02(d,J=7.7Hz,1H),7.97(d,J=8.5Hz,1H),7.87(h,J=5.8Hz,3H), 7.75(s,1H),7.66(ddd,J=8.4,6.6,2.1Hz,1H),7.60(d,J=9.0Hz,1H),7.33(t,J=4.0Hz,2H),6.40(s,1H),4.45(s,3H).

[0413] Effect Example PI3Kα, PI3KαH1047R enzyme activity inhibition IC 50 Evaluation experiment

[0414] The ADP-Glo ​​Kinase Assay Kit was used. The following buffer solution was prepared: 50 mM HEPES, pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, and 2 mM DTT. Test compound samples were dissolved in DMSO and diluted 3-fold to a specific starting concentration, such as 10 μM, before being added to the screening system. A DMSO control and a no-kinase control were also established. Optimal concentrations of PI3Kα, PI3KαH1047R, substrate (PIP2), and ATP were prepared using the buffer. The enzyme reaction system consisted of: buffer, 25 μM ATP, kinase substrate (PIP2, 50 μg / mL), kinases PI3Kα (0.15 μg / mL), and PI3KδH1047R (0.05 μg / mL). The reaction system was incubated at room temperature for 1 hour. The reaction was terminated by adding a stop reagent (ADP-Glo ​​reagent, 5 μL) and the ADP content in the system was detected using a detection reagent (Kinase Detection Reagent, 10 μL). Signal data were collected using an Envision instrument. Inhibition was calculated according to the following formula: % Inhibition = (DMSO control signal value - sample signal value) / (DMSO control signal value - no kinase control signal value). The curve was fitted using the formula Y = Bottom + (Top - Bottom) / (1 + (IC50 / X)^HillSlope) to obtain the IC50. 50 The results are shown in Table 1. The result + represents IC 50 <=250nM++ represents 250nM <IC 50 <=10μM+++ represents IC 50 >10μM

[0415] Table 1

[0416] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A tricyclic ring structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof: in, E is C or N; Ring A is a 4-10 membered cycloolefin containing 1-3 heteroatoms independently selected from O, N and S or is replaced by one or more C 1-6 an alkyl-substituted 5-12 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S; R 1 For at least two R 1-1 Substituted phenyl; R 1-1 are independently halogen or C 1-6 alkyl; R 2 For one or more R 2-1 Substituted C 6-10 Aryl, or one or more R 2-2 Substituted benzofuranyl; R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; R 3 for Cl、F、Br、-NH2、H、 R 4 is hydrogen or halogen; The three-ring structure compound shown in formula I is not one of the following compounds: N-(7-bromo-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-amino-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-bromo-1-(2-bromo-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-bromo-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-amino-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-amino-1-(2-chloro-5-(trifluoromethyl)phenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-amino-1-(2,5-dichloro-4-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(5-(2-chloro-5-fluorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(5-(2,5-dichlorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(5-(2-chloro-5-fluorophenyl)-8-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-di]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(8-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(2,5-dichlorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2-1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2-1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(5-cyano-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(5-(2,5-dichloro-4-fluorophenyl)-2-methyl-3-oxo-2,3,4,5-tetrahydropyrazolo[3,4,5-de]isoquinolin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(3-cyano-1H-pyrazol-4-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(5-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,21-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-(2-cyanopyridin-3-yl)-1-(2,5-dichlorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(2-cyanopyridin-3-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-(5-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,21-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(3-cyano-1H-pyrazol-4-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-(5-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(2-chloro-5-fluorophenyl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,21-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(1-(2-chloro-5-fluorophenyl)-7-(4-cyano-1H-indazol-5-yl)-3-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[3,2,1-ij]quinazolin-9-yl)-3-fluoro-5-(trifluoromethyl)benzamide.

2. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: The structure of the tricyclic compound shown in Formula I is shown in Formula II: in, R 1 For at least two R 1-1 Substituted phenyl; R 1-1 are independently halogen or C 1-6 alkyl; R 2 For one or more R 2-1 Substituted C 6-10 Aryl, or one or more R 2-2 Substituted benzofuranyl; R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; R 3 for F、Br、-NH2、 R 4 is hydrogen or halogen.

3. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: The structure of the three-ring structure compound shown in formula I is shown in formula III: Among them, R 1 For at least two R 1-1 Substituted phenyl; R 1-1 are independently halogen or C 1-6 alkyl; R 2 For one or more R 2-1 Substituted C 6-10 Aryl, or one or more R 2-2 Substituted benzofuranyl; R 2-1 and R 2-2 are independently halogen, C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; R 3 for Cl、F、H、 R 4 is hydrogen or halogen.

4. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: When the group R 1-1 、R 2-1 、R 2-2 and R 4 When the definition of "halogen" is mentioned, the halogen mentioned is fluorine, chlorine, bromine or iodine; and / or, when ring A, group R 1-1 、R 2-1 and R 2-2 The definition of "C 1-6 When "alkyl", the C 1-6 Alkyl is C 1-4 Alkyl, further methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; And / or, when Ring A is a "4-10 membered cycloolefin containing 1-3 heteroatoms independently selected from O, N and S", Ring A is a "4-6 membered cycloalkene containing 1-3 heteroatom N", for example, a "5 membered cycloalkene containing 1 heteroatom N"; and / or, when ring A is surrounded by one or more C 1-6 When the alkyl-substituted "5-12 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S" is present, the ring A is replaced by one or more C 1-6 Alkyl-substituted "5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S".

5. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: R 1 for and / or, R 2 for and / or, R 4 is hydrogen or fluorine.

6. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: The three-ring structure compound shown in Formula I is any of the following structures:

7. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: The three-ring structure compound shown in Formula I is any of the following structures: The compound with a retention time of 0.693 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm; The compound with a retention time of 1.326 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm; The compound with a retention time of 3.379 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 1.543 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 3.246 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 3.833 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 4.6 cm ID*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 0.987 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 3.033 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 1.235 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 4.026 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 3.381 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: 0.46 cm I, D.*5 cm L; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; Compounds with a retention time of 1.35 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column (R, R) Whelk-O1 4.6*100mm 5um; mobile phase: CO2 / EtOH=70 / 30; flow rate: 3.0mL / min; Back pressure: 2000psi; Detection wavelength: 254nm; The compound with a retention time of 2.617 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: (R,R) Whelk-O1 4.6*100mm 5um; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm; The compound with a retention time of 3.677 minutes under the following conditions Equipment: AD-3, 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm; The compound with a retention time of 1.344 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm; The compound with a retention time of 3.123 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3 0.46 cm ID*5 cm.L 20*250 mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 100 bar; detection wavelength: 254 nm; The compound with a retention time of 2.456 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3 0.46cm ID*5cm.L 20*250mm; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm; The compound with a retention time of 1.486 minutes under the following conditions Equipment: AD-3 0.46cm ID*5cm.L 20*250mm; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm; The compound with a retention time of 3.136 minutes under the following conditions Equipment: AD-3 0.46cm ID*5cm.L 20*250mm; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 2.5mL / min; back pressure: 100bar; detection wavelength: 254nm; The compound with a retention time of 1.305 minutes under the following conditions Instrument: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Detection wavelength: 214 nm; The compound with a retention time of 1.712 minutes under the following conditions Instrument: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; flow rate: 3.0 mL / min; detection wave Length: 214nm; The compound with a retention time of 0.938 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: OD-3 4.6*100mm 3um; mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 1.306 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: OD-3 4.6*100mm 3um; Mobile phase: MeOH [0.2% NH3 (7M in MeOH)]; Flow rate: 3.0 mL / min; Back pressure: 2000psi; Detection wavelength: 254nm; The compound with a retention time of 2.002 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / EtOH = 70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wavelength: 254 nm; The compound with a retention time of 3.317 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / EtOH=70 / 30; flow rate: 2.5 mL / min; back pressure: 2000 psi; detection wave Length: 254nm; The compound with a retention time of 2.387 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm; The compound with a retention time of 4.086 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm; The compound with a retention time of 2.223 minutes under the following conditions Equipment: SFC-150 (Waters); Chromatographic column: AD-3; Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; Flow rate: 3.0 mL / min; Back pressure: 2000 psi; Detection wavelength: 214 nm; The compound with a retention time of 3.679 minutes under the following conditions Equipment: SFC-150 (Waters); chromatographic column: AD-3; mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 30 / 70; flow rate: 3.0 mL / min; back pressure: 2000 psi; detection wavelength: 214 nm.

8. The tricyclic ring structure compound as shown in Formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: The three-ring structure compound shown in Formula I is any of the following structures:

9. A pharmaceutical composition, characterized in that It comprises substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of a tricyclic ring structure compound as shown in Formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope compound thereof.

10. Use of a substance A in the preparation of a PI3K inhibitor, wherein the substance A is a tricyclic ring structure compound as shown in Formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

11. Use of a substance A in the preparation of a medicament for treating or preventing a PI3K-mediated disease; the substance A is a tricyclic ring compound as shown in Formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

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