WO2023222005A1

WO2023222005A1 - Aromatic heterocyclic compound and intermediate, pharmaceutical composition and use thereof

Info

Publication number: WO2023222005A1
Application number: PCT/CN2023/094659
Authority: WO
Inventors: 宋云龙; 刘天琪; 丁祥峰; 居捷; 苗新园; 王克柱; 汪笛莎; 寇红艳; 卢凯; 赵亮; 雷响
Original assignee: 上海翊石医药科技有限公司
Priority date: 2022-05-18
Filing date: 2023-05-17
Publication date: 2023-11-23
Also published as: CN117425660A

Abstract

The present invention belongs to the technical field of medicines, and relates to a class of aromatic heterocyclic compounds serving as an LRRK2 inhibitor. The present invention provides a class of compounds with a novel structure, which have a structure represented by formula (K), and provides a new direction for the development of LRRK2 inhibitor drugs. In-vitro enzyme and cell activity inhibition activity research shows that the compounds all have a relatively strong inhibitory effect and can be promising compounds for preventing or treating LRRK2-mediated diseases.

Description

An aromatic heterocyclic compound and its intermediates, pharmaceutical compositions and uses

References to related applications

The present invention requires an invention patent application titled "Aromatic heterocyclic compound and its preparation method" and application number 202210596201.7 submitted in China on May 18, 2022, and an invention patent application submitted in China on November 18, 2022. The priority of the invention patent application titled "Aromatic heterocyclic compound and its preparation method" and application number 202211452918.0 is incorporated into this article by reference.

Technical field

The present invention belongs to the field of medical technology. Specifically, it relates to an aromatic heterocyclic compound, an intermediate for preparing the compound, a pharmaceutical composition containing the compound, and a preparation method and use of the compound.

Background technique

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, affecting approximately 2% of the population over the age of 60. The etiology of Parkinson's disease is very complex, and is typically characterized by a decrease in dopaminergic neurons in the substantia nigra of the brain, resulting in clinical manifestations such as bradykinesia, resting tremor, myotonia, and postural gait disorder. Currently available treatments for Parkinson's disease are only symptomatic, such as dopamine replacement therapy, which can relieve symptoms. There is still a lack of a cure to stop the progression of the disease or reverse it. Therefore, the need for new treatment strategies for Parkinson's disease is clear. Furthermore, this demand is clearly growing as the world's population continues to age.

Only about 5-15% of PD cases have a family history, and most cases are idiopathic. Epidemiological studies have shown that Parkinson's disease has a strong genetic correlation. Research has found that the genes associated with PD autosomal dominant inheritance are SNCA (α-synuclein) and LRRK2 (leucine-rich repeat kinase 2); the genes associated with PD autosomal recessive inheritance are Parkin (Parkin) and PINK1 (PTEN). -induced kinase 1) etc. Of all identified risk genes, LRRK2 mutations are the most common cause of autosomal dominant Parkinson's disease, with the LRRK2G2019S mutation explaining 5% of PD cases. Recent studies have found that patients with idiopathic PD without mutations also have excessive activation, autophosphorylation or increased expression of LRRK2 protein. Therefore, LRRK2 has become an important player in the pathogenesis of Parkinson's disease, and LRRK2 inhibitors are promising therapeutic drugs for Parkinson's disease.

LRRK2 is a large protein containing 2527 amino acids and belongs to the ROCO protein kinase family. Compared with other members of the ROCO family, LRRK2 contains diverse structural domains, and its main functional domains from N-terminus to C-terminus are: ARM (Armadillo repeats), ANK (ankyrin repeats), LRR (leucine rich repeats), ROC ( Ras of complex proteins), COR (C-terminal of Roc), KIN (kinase) and WD40 (WD repeat domain). LRRK2 is widely expressed in the heart, kidneys, lungs, liver and some immune cells and the central nervous system. LRRK2 in neurons is distributed in the cytoplasm and exists on various membrane structures such as mitochondria, Golgi bodies, and lysosomes. It mediates It guides the phosphorylation of downstream proteins and plays an important role in synaptic transmission, vesicle transport, mitochondrial function, regulation of autophagy, regulation of microtubule stability, and inflammatory response. LRRK2 has both GTPase and kinase activities, and there is a mutual regulation mechanism between the two. The kinase activity of LRRK2 depends on the formation of LRRK2 dimers, and GTPase is crucial for the formation of dimers; conversely, upon activation of the kinase, it regulates the GTPase activity of LRRK2 through autophosphorylation of the ROC domain.

Currently, the latest advances in developing LRRK2 inhibitors are in the clinical stage. In terms of small molecule drugs, DNL151 and DNL201 have both completed Phase I clinical trials, and WXWH0226 has obtained clinical trial approval. Many pharmaceutical companies have published patents on LRRK2 inhibitors. The main structural types of compounds include pyrrolopyrimidines/pyridines/pyridazines (WO2015113451, WO2016130920, WO2017106771, WO2018155916, WO2015092592), aminopyrimidines (WO2017087905, WO201715649 3.WO2017218843, WO2018217946), pyrimidinyl/pyridyl isoindazoles (WO2014137719, WO2014137723, WO2014134774, WO2014137728) and macrocycles (for example, WO2013046029 containing two ring systems of benzene and pyrazolopyrimidine or imidazopyridazine in the macrocyclic structure) , WO2014140235, WO2016042089; another example, WO2019012093), which contains two ring systems of pyrazole and pyrimidine or pyridine in the macrocyclic structure, etc.

So far, there are still no LRRK2 inhibitors on the market, so it is still necessary to find more effective and safe LRRK2 inhibitors.

Contents of the invention

The technical problem solved by the invention

The object of the present invention is to provide a compound with a new structure as an LRRK2 inhibitor; at the same time, the object of the present invention is to provide intermediates for preparing the compound, and a preparation method of the compound, including the compound Pharmaceutical compositions, and uses of said compounds in preventing and/or treating diseases mediated by LRRK2.

Technical solutions to solve problems

In a first aspect, the present invention provides a compound represented by formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

Is a single bond or a double bond;

X ₁ , X ₂ , X ₃ and X ₄ are independently CH or N;

Y ₁ , Y ₂ and Y ₃ are independently O, S or N R ^Y ; each occurrence of R ^Y is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne group, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclic group contains 1 or 2 members independently selected from S , O and N heteroatoms; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally one or more independently selected from deuterium, halogen, The substituents of oxo, cyano, hydroxy, nitro, amino, C _1-6 alkyl, phenyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy replace;

Each occurrence of R ₁ and R ₂ are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Alkylthio group, C _1-6 hydroxyalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group and cyano group Substituted with substituents of , hydroxyl, nitro, amino, C _1-6 alkyl, phenyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy;

The number of R ₃ is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, mercapto, nitro, amino, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, 3-12 membered heterocyclyl, -C _1-3 alkyl Base-C _3-8 cycloalkyl, -C _1-3 alkyl-C _3-8 cycloalkenyl, -C _1-3 alkyl-3-12-membered heterocyclyl or -C(O)-3- 12-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 alkoxy, C 1-6 alkylthio, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, 3-12 membered heterocyclyl _, -C _1-3 alkyl -C _3-8 cycloalkyl, _-C _1-3 alkyl-C 3-8 cycloalkenyl, -C _1-3 alkyl-3-12 membered heterocyclyl or -C(O)-3-12 The heterocyclic group is optionally composed of one or more members independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy and optionally substituted by C _1-3 alkyl or halogen Substituted by substituents of 3-12 membered heterocyclyl;

Each occurrence of R ₄ is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, cyano, nitro, oxime, C _1-6 alkenyl, C _1-6 alkynyl, C _{1- 6} alkyl, C _1-6 alkoxy, C _1-6 alkylthio or C _1-6 haloalkyl;

The number of R ₅ is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, nitro, oxime group, C _1-6 alkenyl, C _{1- 6} alkynyl, C _1-6 alkyl, C 1-6 _alkoxy , C _1-6 alkylthio, C _1-6 haloalkyl, C _3-6 cycloalkyl, -NH-C _1-6 alkyl base, -N(C _1-6 alkyl) ₂ , -NH-C _3-6 cycloalkyl, -N(C _3-6 cycloalkyl) ₂ or cyano group;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2;

Ring A is a 5-6 membered heteroaryl group or Ring A does not exist.

In a specific embodiment of the invention, It is a single bond or a double bond, and the entire ring in which it is located is an aromatic ring.

In a specific embodiment of the invention, X ₁ , X ₂ , X ₃ and X ₄ are all N.

In a specific embodiment of the invention, X ₂ is CH, and X ₁ , X ₃ and X ₄ are all N.

In a specific embodiment of the invention, X ₁ and X ₂ are both CH, and X ₃ and X ₄ are both N.

In a specific embodiment of the invention, X ₁ , X ₂ and X ₄ are all CH, and X ₃ is N.

In a specific embodiment of the invention, Y ₂ is O or S, and Y ₁ and Y ₃ are each independently N R ^Y .

In a specific embodiment of the invention, Y ₂ is O, Y ₁ and Y ₃ are each independently ^NRY .

In a specific embodiment of the invention, Y ₁ is O or S, Y ₂ and Y ₃ are each independently N R ^Y .

In a specific embodiment of the invention, Y ₁ is O, Y ₂ and Y ₃ are each independently N R ^Y .

In a specific embodiment of the invention, Y ₁ is O, Y ₂ is O, and Y ₃ is NR ^Y .

In a specific embodiment of the invention, each occurrence of R ^Y is independently hydrogen, C _1-3 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-3 alkoxy , C _1-3 alkylthio group, C _3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclic group is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, hydroxyl group, Substituted with nitro and amino substituents.

In a specific embodiment of the invention, each occurrence of R ^Y is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy base, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butyl oxide; the methyl, ethyl, propyl, isopropyl, ethylene group, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butylene oxide, optionally Substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino.

In a specific embodiment of the invention, each occurrence of R ^Y is independently hydrogen.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl or C _3-8 cycloalkyl; the alkyl, alkenyl Alkyl, alkynyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, Substituted with substituents of C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 alkylthio, C _1-3 hydroxyalkyl or C _3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl optionally one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl group and C _1-3 haloalkoxy substituents.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, amino, C _1-3 alkyl, C _1-3 alkyl Oxygen group, C _1-3 alkylthio group, C _1-3 hydroxyalkyl group or C _3-6 cycloalkyl group; the alkyl group, alkoxy group, alkylthio group, hydroxyalkyl group or cycloalkyl group is optionally Substituted with one or more substituents each independently selected from deuterium, halogen, cyano, hydroxyl, amino and C _1-3 alkyl.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, cyano, hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclobutyl, methoxy, ethoxy, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl Fluoromethyl or trifluoromethyl.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy , -CH ₂ OCH ₃ , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl.

In a specific embodiment of the invention, the number of R ₃ is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, mercapto, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-8 cycloalkyl, 3-12 Membered heterocyclyl, -C _1-3 alkyl-C _3-8 cycloalkyl, -C _1-3 alkyl-3-12-membered heterocyclyl or -C(O)-3-12-membered heterocyclyl , the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, -C _1-3 alkyl-C _3-8 cycloalkyl, -C _1-3 alkyl-3-12 membered heterocyclyl or -C (O)-3-12-membered heterocyclyl is optionally composed of one or more members each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, -C _1-6 alkyl-OC _1-6 alkyl and optionally C _1- Substituted with _3- alkyl or halogen-substituted 3-12-membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N.

In a specific embodiment of the invention, the number of R ₃ is 1 or 2, and each occurrence is independently halogen, cyano group, hydroxyl, amino, C _1-4 alkyl, C _3-6 ring Alkyl, 3-9 membered heterocyclyl, -C _1-2 alkyl-C _3-6 cycloalkyl, -C _1-2 alkyl-3-9 membered heterocyclyl or -C(O)-3 -9-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C _1-4 alkyl, C _3-6 cycloalkyl, 3- 9-membered heterocyclyl, -C _1-2 alkyl-C _3-6 cycloalkyl, -C _1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocycle The group is optionally selected from one or more groups, each independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, Substituted with substituents of C _1-3 haloalkyl, -C _1-3 alkyl-OC _1-3 alkyl and 3-8 membered heterocyclyl optionally substituted by C _1-3 alkyl. The radical contains 1 or 2 heteroatoms each independently selected from S, O and N.

In a specific embodiment of the invention, the number of R ₃ is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, C _1-4 alkyl, C _3-6 cycloalkyl , 3-9 membered heterocyclyl, -C _1-2 alkyl-C _3-6 cycloalkyl, -C _1-2 alkyl-3-9 membered heterocyclyl or -C(O)-3-9 A membered heterocyclic group, the heterocyclic group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C _1-4 alkyl, C _3-6 cycloalkyl, 3-9 membered Heterocyclyl, -C _1-2 alkyl-C _3-6 cycloalkyl, -C _1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl, any One or more are independently selected from deuterium, cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH _3. Substituted with substituents of 3-6-membered heterocyclyl and methyl- or ethyl-substituted 3-6-membered heterocyclyl, the heterocyclyl containing 1 or 2 independently selected from S, O and N of heteroatoms.

In a specific embodiment of the invention, the number of R ₃ is 1 or 2, and each occurrence is independently fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-propyl, etc. Butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl , 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH ₂ -6-membered monoheterocyclyl, -CH ₂ CH ₂ -7-membered bridged heterocyclyl, -CH ₂ CH ₂ -6-membered monoheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or - C(O)-7-membered spiroheterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the methyl, ethyl, n-propyl, isopropyl base, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl Heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH ₂ -6-membered monoheterocyclyl, -CH ₂ CH ₂ -7-membered bridged heterocyclyl, -CH ₂ CH ₂ -6-membered monoheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl The base or -C(O)-7-membered spiroheterocyclyl is optionally one or more each independently selected from cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine , -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, methyl-substituted 4-membered monoheterocyclyl, methyl-substituted Substituted with substituents of 5-membered monoheterocyclyl, methyl-substituted 6-membered monoheterocyclyl and 7-membered bridged heterocyclyl, the heterocyclyl contains 1 or 2 each independently selected from S, O and N heteroatoms.

In a specific embodiment of the invention, each occurrence of R ₃ is independently Represents the R ₃ connection location.

In a specific embodiment of the invention, each occurrence of R ₄ is independently hydrogen, deuterium, halogen, amino, hydroxyl, sulfhydryl, carboxyl, cyano, nitro, oxime, C _1-3 alkenyl, C _1-3 alkynyl, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkyl.

In a specific embodiment of the invention, each occurrence of R ₄ is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, etc. Fluoromethyl or trifluoromethyl.

In a specific embodiment of the invention, each occurrence of R ₄ is independently hydrogen, fluorine, or methyl.

In a specific embodiment of the invention, the number of R ₅ is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, halogen, C _1-3 alkyl, C _1-3 alkoxy , C _1-3 alkylthio group, C _1-3 haloalkyl group, C _3-6 cycloalkyl group, -NH-C _1-3 alkyl group, -N(C _1-3 alkyl) ₂ , -NH-C _3-6 cycloalkyl, -N(C _3-6 cycloalkyl) ₂ or cyano group.

In a specific embodiment of the invention, the number of R ₅ is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, Isopropyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -NH-cyclopropyl, -N(cyclopropyl) ₂ or cyano.

In a specific embodiment of the invention, the number of R ₅ is 1, 2 or 3, and each occurrence is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, methyl sulfide. group, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -NH-cyclopropyl or cyano group.

In a specific embodiment of the invention, the number of R ₅ is 1, 2 or 3, and each occurrence is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, trifluoro Methyl, cyclopropyl, -NHCH ₃ , -NHCH ₂ CH ₃ , -NH-cyclopropyl or cyano.

In a specific embodiment of the invention, n1 is 3.

In a specific embodiment of the invention, n2 is 1.

In a specific embodiment of the invention, n2 is 2.

In a specific embodiment of the invention, Ring A is absent.

In a specific embodiment of the invention, Ring A is a 5-6 membered heteroaromatic ring.

In a specific embodiment of the invention, Ring A is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl.

In a specific embodiment of the invention, Ring A is a 5-membered heteroaromatic ring.

In a specific embodiment of the invention, Ring A is pyrrolyl, pyrazolyl or imidazolyl.

In a specific embodiment of the invention, Ring A is ** represents the fusion site.

Further, the present invention also provides a compound represented by any one of formulas (K1) to formula (K11), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable of salt:

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , Y ₁ , Y ₂ , Y ₃ and n1 are as defined in formula (K).

Furthermore, the present invention also provides a compound represented by formula (K1A) or formula (K1B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Among them, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in formula (K).

Furthermore, the present invention also provides a compound represented by formula (K2A), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Among them, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y ₁ are as defined in formula (K).

Furthermore, the present invention also provides a compound represented by formula (K3A) or formula (K3B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Furthermore, the present invention also provides a compound represented by formula (K4A), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Furthermore, the present invention also provides a compound represented by formula (K5A), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Furthermore, the present invention also provides a compound represented by formula (K8A) or formula (K8B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

In a specific embodiment of the invention, Y ₁ is O or NH.

In a specific embodiment of the invention, _Y1 is NH.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, halogen or C _1-3 alkyl; said alkyl is optionally replaced by one or more independently Substituted with substituents selected from deuterium and halogen.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, monofluoromethyl base, difluoromethyl or trifluoromethyl.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine.

In a specific embodiment of the invention, the number of R ₃ is 1 or 2, preferably 1.

In a specific embodiment of the invention, each occurrence of R ₃ is independently C _1-4 alkyl, C _3-6 cycloalkyl, 3-9 membered heterocyclyl or -C(O)-3 -9-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C _1-4 alkyl, C _3-6 cycloalkyl, 3- The 9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl is optionally selected from one or more groups, each independently selected from cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, Substituted with fluorine, chlorine, bromine, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 each independently selected from S , O and N heteroatoms.

In a specific embodiment of the invention, each occurrence of R ₃ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C( O)-7-membered spiroheterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocycle base, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl is optionally selected from one or more groups, each independently selected from cyano, hydroxyl, methyl, ethyl, methoxy base, ethoxy, fluorine, chlorine, bromine, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, methyl-substituted 4-membered monoheterocyclyl, methyl-substituted 5-membered Substituted with monoheterocyclyl, methyl-substituted 6-membered monoheterocyclyl and 7-membered bridged heterocyclyl substituents, the heterocyclyl contains 1 or 2 independently selected Heteroatoms from S, O and N.

In a specific embodiment of the invention, each occurrence of R ₄ is independently hydrogen, deuterium, halogen, or C _1-3 alkyl.

In a specific embodiment of the invention, each occurrence of R ₄ is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl.

In a specific embodiment of the invention, the number of _R5 is 1, 2 or 3, preferably 1 or 2, more preferably 1 indivual.

In a specific embodiment of the invention, each occurrence of R ₅ is independently hydrogen, deuterium, halogen, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In a specific embodiment of the invention, each occurrence of R ₅ is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, etc. Fluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl.

In a specific embodiment of the invention, each occurrence of _R5 is independently hydrogen, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₁ and R ₂ are independently hydrogen, halogen or C _1-3 alkyl each time they appear. .

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₁ and R ₂ are independently hydrogen, methyl, ethyl, n-propyl each time they appear. base, isopropyl, fluorine, chlorine or bromine.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), each occurrence of R ₁ and R ₂ is independently hydrogen, methyl or fluorine.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₃ is C _3-6 cycloalkyl or 3-9 membered heterocyclyl, and the heterocyclic The base contains 1 or 2 heteroatoms each independently selected from O and N; the C _3-6 cycloalkyl or 3-9 membered heterocyclic group is optionally replaced by one or more heteroatoms each independently selected from fluorine, chlorine , bromine and a 3-6 membered heterocyclyl substituent containing 1 or 2 heteroatoms each independently selected from O and N.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₃ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocycle base, 5-membered monoheterocyclyl or 6-membered monoheterocyclyl, the monoheterocyclyl contains 1 or 2 heteroatoms each independently selected from O and N; the cyclopropyl, cyclobutyl, cyclopropyl, Pentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl or 6-membered monoheterocyclyl are optionally selected from one or more fluorine, chlorine, bromine, 4-membered monoheterocyclyl , 5-membered monoheterocyclyl and 6-membered monoheterocyclyl substituents, the monoheterocyclyl contains 1 or 2 heteroatoms each independently selected from O and N.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₃ is Represents the R ₃ connection location.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₄ is C _1-3 alkyl.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₄ is methyl or ethyl.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₄ is methyl.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₅ is halogen, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₅ is fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl , cyclopropyl or cyclobutyl.

In a specific embodiment of the invention, in the compound represented by formula (K1A) or formula (K1B), R ₅ is fluorine, chlorine, trifluoromethyl or cyclopropyl.

In a specific embodiment of the invention, in the compound represented by formula (K2A), Y ₁ is O or NH.

In a specific embodiment of the invention, in the compound of formula (K2A), _Y1 is NH.

In a specific embodiment of the present invention, in the compound represented by formula (K2A), R ₁ and R ₂ each occurrence are independently hydrogen, halogen or C _1-3 alkyl.

In a specific embodiment of the invention, in the compound represented by formula (K2A), R ₁ and R ₂ each time they appear are independently hydrogen, methyl, ethyl, n-propyl, isopropyl , fluorine, chlorine or bromine.

In a specific embodiment of the invention, in the compound represented by formula (K2A), each occurrence of R ₁ and R ₂ is independently hydrogen, methyl or fluorine.

In a specific embodiment of the present invention, in the compound represented by formula (K2A), R ₃ is a 3-9-membered heterocyclyl group or -C(O)-3-9-membered heterocyclyl group, and the heterocyclic group The cyclic group contains 1 or 2 heteroatoms each independently selected from O and N; the 3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl is optionally replaced by one or more heteroatoms each independently Substitutions independently selected from hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl Substituted with a heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from O and N.

In a specific embodiment of the present invention, in the compound represented by formula (K2A), R ₃ is a 4-membered monoheterocyclyl group, a 5-membered monoheterocyclyl group, a 6-membered monoheterocyclyl group, or a 7-membered bridged heterocyclyl group. Cyclic group, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)- 7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from O and N; the 4-membered monoheterocyclyl , 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl is optionally one or more each independently selected from Hydroxy, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, methyl-substituted 4-membered monoheterocyclyl Heterocyclyl, methyl-substituted 5-membered monoheterocyclyl, methyl-substituted 6-membered monoheterocyclyl and 7-membered bridged heterocyclyl substituents, the heterocyclyl contains 1 or 2 independently Ground is a heteroatom selected from O and N.

In a specific embodiment of the invention, in the compound represented by formula (K2A), R ₃ is Represents the R ₃ connection location.

In a specific embodiment of the invention, in the compound of formula (K2A), each occurrence of R ₄ is independently hydrogen.

In a specific embodiment of the present invention, in the compound represented by formula (K2A), R ₅ is halogen, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In a specific embodiment of the invention, in the compound represented by formula (K2A), R ₅ is fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl.

In a specific embodiment of the invention, in the compound represented by formula (K2A), R ₅ is chloro, trifluoromethyl or cyclopropyl.

In addition, the present invention also provides compounds represented by formula (I), or their stereoisomers, tautomers or mixtures, or their pharmaceutically acceptable salts:

in,

Is a single bond or a double bond;

X ₁ , X ₂ , X ₃ and X ₄ are independently CH or N;

Y ₁ , Y ₂ and Y ₃ are independently O, S or N R ^Y ; each occurrence of R ^Y is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne base, C _1-6 alkoxy group, C _1-6 alkylthio group, C _3-8 cycloalkyl group or C _3-8 heterocyclyl group, the heterocyclyl group contains 1 or 2 groups each independently selected from S , O and N heteroatoms; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally one or more independently selected from deuterium, halogen, The substituents of oxo, cyano, hydroxy, nitro, amino, C _1-6 alkyl, phenyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy replace;

Each occurrence of R ₁ and R ₂ are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Alkylthio, _C _1-6 hydroxyalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl or C _3-8 heterocyclyl, The heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, hydroxyalkyl group, cycloalkyl group Or the heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C _1-6 alkyl, phenyl, C _1-6 alkoxy Substituted with substituents of base, C _1-6 haloalkyl and C _1-6 haloalkoxy;

R ₃ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-8 cycloalkyl, C _{3 -8} cycloalkenyl, C _3-12 heterocyclyl, -C _1-3 alkylene -C _3-8 cycloalkyl, -C _1-3 alkylene -C _3-8 cycloalkenyl or -C _1-3 alkylene-C _3-12 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, -C _1-6 alkyl-OC _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy Substituted with substituents of base and C _3-12 heterocyclyl;

Each occurrence of R ₄ and R ₅ is independently hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio or C _1-6 haloalkyl;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2; when n2 is 1, ring A is a 5-6 membered heteroaryl group; when n2 is 2, ring A is a 5-6 membered heteroaryl group or ring A does not exist.

In a specific embodiment of the invention, each occurrence of R ^Y is independently hydrogen, C _1-3 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-3 alkoxy , C _1-3 alkylthio group, C _3-8 cycloalkyl group or C _3-8 heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclic group is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, hydroxyl group, Substituted with nitro and amino substituents.

In a specific embodiment of the invention, each occurrence of R ₁ and R ₂ is independently hydrogen, deuterium, halogen, cyanide. group, hydroxyl, mercapto, amino, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 hydroxyalkyl or C _3-6 cycloalkyl; the alkyl group, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, cyano, hydroxyl, amino and C _1-3 alkyl. replace.

In a specific embodiment of the invention, each occurrence of R ₃ is independently C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-8 cycloalkyl , C _3-8 cycloalkenyl, C _3-12 heterocyclyl, -C _1-3 alkylene-C _3-8 cycloalkyl, -C _1-3 alkylene-C _3-8 cycloalkenyl Or -C _1-3 alkylene-C _3-12 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkoxy , alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl optionally be one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 haloalkoxy, -C _1-6 alkyl-OC _1-6 alkyl and C _3-12 heterocyclyl substituents containing 1 or 2 heteroatoms each independently selected from S, O and N.

In a specific embodiment of the invention, each occurrence of R ₃ is independently C _1-4 alkyl, C _3-8 cycloalkyl, C _3-9 heterocyclyl, -C _1-2 alkylene -C _3-8 cycloalkyl or -C _1-2 alkylene-C _3-9 heterocyclyl, the heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N ; The alkyl, cycloalkyl or heterocyclyl is optionally one or more independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, C _1-3 alkyl, C _1-3 Alkoxy, C _1-3 alkylthio, C _1-3 haloalkyl, -C _1-3 alkyl-OC _1-3 alkyl and C _3-8 heterocyclyl substituents, the heterocyclic The cyclic group contains 1 or 2 heteroatoms each independently selected from S, O and N.

In a specific embodiment of the invention, each occurrence of R ₄ and R ₅ is independently hydrogen, deuterium, halogen, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio group or C _1-3 haloalkyl group.

In a specific embodiment of the invention, each occurrence of R ₄ and R ₅ is independently hydrogen, deuterium, halogen, C _1-3 Alkyl or C _1-3 haloalkyl.

In a specific embodiment of the invention, each occurrence of R ₄ is independently hydrogen, deuterium, or methyl.

In a specific embodiment of the invention, each occurrence of R ₅ is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

In a specific embodiment of the invention, Ring A is absent.

Further, the present invention also provides a compound represented by formula (IA) or formula (IB), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Wherein, each substituent is as defined in formula (I).

Further, the present invention also provides a compound represented by formula (II-A) or formula (II-B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable of salt:

Wherein, each substituent is as defined in formula (I).

Further, the present invention also provides a compound represented by formula (III), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Wherein, each substituent is as defined in formula (I).

Further, the present invention also provides a compound represented by formula (IV), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Wherein, each substituent is as defined in formula (I).

Specifically, the compounds in the present invention, or their stereoisomers, tautomers or mixtures, or their pharmaceutically acceptable salts, are selected from:

In a second aspect, the present invention provides a compound represented by formula (I) or formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof Preparation.

The preparation methods include but are not limited to the following methods:

General formula preparation method one:

The intermediate (C) is obtained by substitution reaction between (A1) and (B1) or (A2) and (B2), and the intermediate (C) is obtained by intramolecular Buchwald-Hartwig coupling reaction, such as formula (I) or formula ( K) The compound shown;

Among them, Y _2' is -OH, -SH or -NHR ^Y ; LG ^a is a leaving group, preferably Cl, Br, I or OTf, OMs; LG ^b is a leaving group, preferably Cl, Br, I or OTf, OMs; Y _3' is -OH or -SH; Y ₃ is O or S; other substituents are as defined above.

Correspondingly, the present invention also provides a method for preparing compounds represented by formula (I) or formula (K), or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts Intermediate (C):

Wherein, LG ^b is Cl, Br, I, OTf or OMs; Y _3' is -OH or -SH; other substituents are as defined in formula (I) or formula (K).

General formula preparation method two:

The intermediate (C') is obtained by substitution reaction between (A1) and (B1') or (A2) and (B2'), the intermediate (D) is obtained by reduction reaction of (C'), and (D) is obtained through the molecule The compound represented by formula (I) or formula (K) is obtained by internal Buchwald-Hartwig coupling reaction;

Among them, Y _2' is -OH, -SH or -NHR ^Y ; LG ^a is a leaving group, preferably Cl, Br, I or OTf, OMs; LG ^b is a leaving group, preferably Cl, Br, I or OTf, Oms; other substituents are as defined above.

Correspondingly, the present invention also provides an intermediate for preparing compounds of formula (I) or formula (K), or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts. Body (C'):

Wherein, LG ^b is Cl, Br, I, OTf or OMs; other substituents are as defined in formula (I) or formula (K).

Correspondingly, the present invention also provides a method for preparing the compound represented by formula (I) or formula (K), or its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts. Intermediate (D):

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (especially a compound represented by formula (K) in the first aspect, any one of formula (K1) to formula (K11) The compound represented by the item, the compound represented by formula (I), such as formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III) or formula (IV) The compounds shown and specific compounds), or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts.

Further, the present invention also provides a pharmaceutical composition, which contains the compound of the present invention, or its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable salt thereof. Acceptable excipients.

In a fourth aspect, the present invention provides compounds of the present invention (especially compounds represented by formula (K) in the first aspect, compounds represented by any one of formula (K1) to formula (K11), such as formula ( Compounds represented by I), such as compounds represented by formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III) or formula (IV) and specific compounds), or the use of its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts in the preparation of medicaments for the treatment or prevention of diseases mediated by LRRK2 kinase.

Specifically, the present invention also provides the compounds of the present invention, or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts for the preparation of compounds for the treatment or prevention of Parkinson's disease (PD). ) in medicines.

In a fifth aspect, the present invention provides compounds of the present invention (especially compounds represented by formula (K) in the first aspect, compounds represented by any one of formula (K1) to formula (K11), such as formula ( Compounds represented by I), such as compounds represented by formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III) or formula (IV) and specific compounds), or its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts, for use as a medicament, in particular for the treatment or prevention of diseases mediated by LRRK2 kinase.

Specifically, the present invention also provides the compounds of the present invention, or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts, which are used for the treatment or prevention of Parkinson's disease.

In a sixth aspect, the present invention provides a method for treating or preventing diseases mediated by LRRK2 kinase, which includes the following steps: adding a therapeutically or preventively effective amount of a compound of the present invention (especially the formula of the first aspect) Compounds represented by (K), compounds represented by any one of formula (K1) to formula (K11), compounds represented by formula (I), such as formula (I-A), formula (I-B), formula (II) -A), compounds represented by formula (II-B), formula (III) or formula (IV) and specific compounds), or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable The salt received is administered to individuals in need of it.

Specifically, the present invention also provides a method for treating or preventing Parkinson's disease, which includes the following steps: adding a therapeutically or preventively effective amount of a compound of the present invention, or a stereoisomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, administered to an individual in need thereof.

Effect of invention

The present invention designs a class of compounds with novel structures and provides a new direction for the development of LRRK2 inhibitor drugs. In vitro enzyme and cell inhibitory activity studies show that these compounds have strong inhibitory effects, so they can be used as promising compounds for the treatment of LRRK2-mediated diseases. In addition, the present invention studies a specific synthesis method, which has simple process, convenient operation, and is conducive to large-scale industrial production and application.

Detailed ways

Definition of Terms

The terms "optionally," "any," "optionally" or "arbitrarily" mean that the subsequently described event or condition may, but need not, occur, and that the description includes circumstances in which the stated event or condition occurs and The event or condition described does not occur.

The term "oxo" means that two hydrogen atoms in the same substitution position are replaced by the same oxygen atom to form a double bond.

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C _{1 to 10} Alkyl), further preferably contains 1-8 carbon atoms (C _1-8 alkyl), more preferably contains 1-6 carbon atoms (i.e. C _1-6 alkyl), such as "C _1-6 alkyl" It means that the group is an alkyl group, and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1- Dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

Unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C _2-10 alkenyl), further preferably 2-8 carbon atoms (C _2-8 alkenyl), and more preferably 2-8 carbon atoms (C 2-8 alkenyl). 2-6 carbon atoms (i.e. C _2-6 alkenyl), 2-5 carbon atoms (i.e. C _2-5 alkenyl), 2-4 carbon atoms (i.e. C _2-4 alkenyl), 2- 3 carbon atoms (i.e. C _2-3 alkenyl), 2 carbon atoms (i.e. C ₂ alkenyl), for example "C _2-6 alkenyl" means that the group is alkenyl, and the carbon chain The number of carbon atoms is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

Unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C _2-10 alkynyl group), further preferably 2-8 carbon atoms (C _2-8 alkynyl group), and more preferably 2-8 carbon atoms (C 2-8 alkynyl group). 2-6 carbon atoms (i.e. C _2-6 alkynyl), 2-5 carbon atoms (i.e. C _2-5 alkynyl), 2-4 carbon atoms (i.e. C _2-4 alkynyl), 2- 3 carbon atoms (i.e. C _2-3 alkynyl), 2 carbon atoms (i.e. C ₂ alkynyl), for example "C _2-6 alkynyl" means that the group is an alkynyl group, and the carbon chain The number of carbon atoms is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.

Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C _3-12 cycloalkyl), More preferably, it contains 3-10 carbon atoms (C _3-10 cycloalkyl), further preferably 3-6 carbon atoms (C _3-6 cycloalkyl), 4-6 carbon atoms (C _4-6 cycloalkyl) base), 5-6 carbon atoms (C _5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is as defined above, that is, containing 1-20 carbon atoms, preferably 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy Oxygen, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.

Unless otherwise specified, the term "alkylthio" means replacing -O- with -S- in the above definition of "alkoxy".

Unless otherwise specified, the term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine. The term "haloalkyl" means an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl ₃ , CF ₃ , CHCl ₂ , CH ₂ Cl, CH ₂ Br, CH ₂ I, CH ₂ CF ₃ , CF ₂ CF ₃ , and the like.

Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent, which is a non-aromatic structure, and also includes polycyclic rings in which some of the rings are aromatic. Structure, containing 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, preferably containing 3-12 ring atoms, further preferably Contains 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3). Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, tetrahydropyranyl, morpholinyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.

Unless otherwise specified, the term "fused ring" refers to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system formed by two or more cyclic structures sharing two adjacent atoms with each other, including Condensed carbocyclyl and fused heterocyclyl, the "fused heterocyclyl" optionally containing one or more heteroatoms independently selected from oxygen, nitrogen and sulfur.

Unless otherwise specified, the term "spirocycloalkyl" refers to a saturated ring system with a specified number of carbon atoms formed by carbon atoms and hydrogen atoms sharing only one ring carbon atom. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. Non-limiting examples of single spirocyclic groups are single spirocyclic rings of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings. base, where the count of each ring includes a spiro atom. Non-limiting examples of single spirocyclyl groups include: wait.

Unless otherwise specified, the terms "heterospirocyclyl" and "spiroheterocyclyl" refer to a ring with a specific number of carbon atoms and heteroatoms formed by two or more saturated rings sharing one ring carbon atom. structure. The heteroatoms in the spiroheterocyclyl group are preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3), and the heteroatoms are independently selected from N, O and S. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. Non-limiting examples of spiroheterocyclyl groups are spiroheterocycles of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings. base, where the count of each ring includes a spiro atom. Non-limiting examples of heteromonospiryl include: wait.

Unless otherwise specified, the term "bridged cyclic group" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly connected, and it may contain one or more double bonds, but No ring has a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

Unless otherwise specified, the terms "heterobridged cyclyl" and "bridged heterocyclyl" refer to polycyclic heterocyclic groups with 5 to 14 members, and any two rings share two ring atoms that are not directly connected. Contains one or more double bonds, but no ring has a fully conjugated π electron system. The number of heteroatoms in the bridged heterocyclyl group is one or more, preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3), and the heteroatoms are independently selected from N, O or S (O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. The bridged heterocyclic group is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

Unless otherwise specified, the term "aryl" means a group containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms. or a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring system of 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring group". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, and the like.

Unless otherwise specified, the terms "heteroaryl" and "aryl hetero" represent aromatic monomers containing a 5-12-membered structure, or preferably a 5-10-membered structure, a 5-8-membered structure, and more preferably a 5-6-membered structure. Ring or polycyclic ring system, in which 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms is preferably 1 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazine, phthalazinyl, quinolyl, isoquinolinyl, pyridinyl, purinyl, indyl Indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrole Para[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazole [1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a] Pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" means salts that are suitable within the scope of reasonable medical judgment for contact with tissue of mammals, especially humans, without undue Toxicity, irritation, allergic reactions, etc. and are commensurate with a reasonable benefit/risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent.

Unless otherwise specified, the terms "solvate" and "solvate" mean the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be separated. The solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" and "solvate" encompass both solution phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methoxides, and isopropoxides. Solvation methods are well known in the art. Generally, the compounds described herein include solvates thereof.

Unless otherwise specified, the terms "isotope-labeled analogs", "isotope derivatives" and "stable isotope derivatives" refer to molecules in the compounds of the invention that are isotopically labeled, thereby providing isotopes that may have improved pharmacological activity Marked analogs. The isotopes commonly used as isotope labels are: hydrogen isotopes, ² H and ³ H; carbon isotopes: ¹¹ C, ¹³ C and ¹⁴ C; chlorine isotopes: ³⁵ Cl and ³⁷ Cl; fluorine isotopes: ¹⁸ F; iodine isotopes: ¹²³ I and ¹²⁵ I; nitrogen isotopes: ¹³ N and ¹⁵ N; oxygen isotopes: ¹⁵ O, ¹⁷ O and ¹⁸ O and sulfur isotope ³⁵ S. These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, deuterium ( ² H) and carbon ( ¹³ C) are more widely used because they are easy to label and detect. The substitution of certain heavy isotopes, such as deuterium ( ^2H ), can enhance metabolic stability, extend half-life, thereby reducing dosage and providing therapeutic advantages. Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques as for non-isotopically labeled compounds. Generally, the compounds of the present invention include isotopic derivatives (such as deuterated compounds) thereof.

Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.

Unless otherwise specified, the term "tautomers" refers to structural isomers with different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions through the reorganization of some of the bonding electrons.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.

Unless otherwise specified, the term "cocrystal" is used to describe a situation in which neutral molecular components are present in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutical cocrystals enables changes to the crystalline form of the active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, J. Wouters and L.Quere (eds., RSC Publishing, 2012). Generally, the compounds described in this invention include co-crystals thereof.

Unless otherwise specified, the term "polymorph" refers to the different arrangements of chemical drug molecules, generally represented by the existence of drug raw materials in a solid state. A drug can exist in multiple crystalline material states. Different crystalline forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation. Generally, the compounds described herein include polymorphic forms thereof.

Unless otherwise specified, the term "metabolite" refers to the product obtained by metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, etc. Accordingly, the invention includes metabolites of compounds, including metabolites produced by contacting a compound of the invention with a mammal for a period of time sufficient to do so. Generally, the compounds described herein include metabolites thereof.

Unless otherwise specified, the term "prodrug" refers to a drug that is converted in the body to the parent drug. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they are bioavailable via oral administration, whereas the parent body is not. Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of the invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility, but once inside Intracellular water solubility is beneficial and is subsequently metabolically hydrolyzed to carboxylic acids, the active entities. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety. Generally, the compounds of the present invention include prodrugs thereof.

Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable position of the group is unsubstituted or substituted by one or more substituents, which substituents are preferably selected from the group consisting of: Group: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _{1- 6} alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C _6-14 aryl and 5-10 membered heteroaromatic ring, wherein The following C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkylsulfonyl, 3- The 10-membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaromatic ring group is optionally selected from halogen, hydroxyl, amino, cyano, C _1-6 alkyl and C _1-6 alkoxy Substituted with one or more substituents.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as commonly understood by professionals in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials shown in this article are for demonstration purposes only.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). The instrument used for NMR is Bruker 400MHz or/and Varian 400MHz; the instrument used for LC-MS is Agilent 1260 Infinity II-6120/6125MSD; the instrument used for HPLC is Waters Acquity UPLC_2 or/and Shimadzu LC2030 or/and Agilent 1260 Infinity II.

Preparative HPLC conditions one (ammonia as additive): Instrument: Waters; Pump: 2545; Detector: 2489; Wavelength: 214nm and 254nm; Column model: Welch Xtimate C18, 21.2*250mm, 10μm; Mobile phase: A: 0.1% ammonia ,B: acetonitrile; running time: 15min; flow rate: 25ml/min.

Preparative HPLC condition two (formic acid as additive): Instrument: Waters; Pump: 2545; Detector: 2489; Wavelength: 214nm and 254nm; Column model: Welch Ultimate AQ-C18, 21.2*250mm, 10μm; Mobile phase: A: 0.1 % formic acid, B: acetonitrile; running time: 15min; flow rate: 25ml/min.

Preparative HPLC condition three (trifluoroacetic acid as additive): Instrument: Waters; Pump: 2545; Detector: 2489; Wavelength: 214nm and 254nm; Column model: Welch Ultimate AQ-C18, 21.2*250mm, 10μm; Mobile phase: A :0.1% trifluoroacetic acid, B: acetonitrile; running time: 15min; flow rate: 25ml/min.

The starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be used or in accordance with the present invention. synthesized by methods known in the art.

Explanation of terms or abbreviations

OTf: triflate group

OMs: Methanesulfonate group

DMF: N,N-dimethylformamide

DCM: dichloromethane

THF: Tetrahydrofuran

DMSO: dimethyl sulfoxide

EDTA: ethylenediaminetetraacetic acid

HMDSLi: Lithium bis(trimethylsilyl)amide (or lithium hexamethyldisilylamide)

NCS: 1-chloropyrrolidine-2,5-dione (or N-chlorosuccinimide)

SEMCl: [2-(chloromethoxy)ethyl]trimethylsilane (or 2-(trimethylsilyl)ethoxymethyl chloride)

TFA: trifluoroacetic acid

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium(0)

Xphos: Dicyclohexyl (2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (or 2-dicyclohexylphosphine-2',4' ,6'-triisopropylbiphenyl)

MsCl: methylsulfonyl chloride

TEA: triethylamine

EA: Ethyl acetate

NIS: N-iodosuccinimide

DIPEA: Diisopropylethylamine

DCE: dichloroethane

BTEAC: Benzyltriethylammonium Chloride

Preparation of compounds

Example 1

3-Chloro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge) Pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of tetrahydro-2H-pyran-3-ylmethanesulfonate

Dissolve tetrahydro-2H-pyran-3-ol (550mg, 5.39mmol, 1.0eq) and triethylamine (599.04mg, 5.92mmol, 1.1eq) in dichloromethane (30mL) at 0°C. Methanesulfonyl chloride (678.57 mg, 5.92 mmol, 1.1 eq) was added under nitrogen protection and stirred for 3 hours. TLC monitored reaction completion. Add water to the reaction solution to quench, extract with dichloromethane (3 x 50mL), combine the organic phases, and directly concentrate the organic phases to obtain the target product (560mg, yield 57.75%).

¹ H NMR (400MHz, CDCl ₃ ): δ4.73-4.67 (m, 1H), 3.86-3.81 (m, 1H), 3.69-3.61 (m, 3H), 3.04 (s, 3H), 2.10-2.00 ( m, 1H), 1.97-1.85 (m, 2H), 1.66-1.56 (m, 1H).

Step 2: 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(tetrahydro Preparation of mixtures of -2H-pyran-3-yl)-1H-pyrazoles

Tetrahydro-2H-pyran-3-ylmethanesulfonate (550mg, 3.05mmol, 1.0eq) and 3-methyl-4-nitro-1H-pyrazole (1.16g, 9.15mmol, 3.0eq) Dissolve in DMF (15 mL), add potassium carbonate (640 mg, 4.63 mmol, 1.52 eq) under nitrogen protection at 90°C, and stir for 16 hours. LC-MS monitored the reaction for completion. Add water to the reaction solution to quench, extract with dichloromethane (3 x 50mL), combine the organic phases, directly concentrate the organic phase and mix the sample, and separate and purify by column chromatography to obtain the target product (560 mg, yield 86.89%).

LC-MS (ESI) [M+H] ⁺ =212.0.

Step 3: Preparation of 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole

At -78°C, under nitrogen protection, add 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl To a solution of a mixture of 1-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (440 mg, 2.08 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added bis(tris) A THF solution of lithium methylsilyl)amide (1M, 6.24mL, 6.24mmol, 3eq) was stirred for 45 minutes at -78°C and then hexachloroethane (1.47g, 6.24mmol, 3eq) was added dropwise. Tetrahydrofuran (3 mL) solution was stirred at 15°C for 2 hours under nitrogen protection. LC-MS monitored the reaction for completion. Saturated ammonium chloride solution was added to the reaction solution to quench, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (200 mg, yield 39.14%).

LC-MS (ESI) [M+H] ⁺ =246.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ4.52-4.39 (m, 1H), 3.96-3.92 (m, 1H), 3.90-3.82 (m, 1H), 3.56 (s, 1H), 3.43 (s, 1H), 2.45 (s, 3H), 2.14-2.02 (m, 2H), 1.82-1.69 (m, 2H).

Step 4: Preparation of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (20.0g, 106.38mmol, 1.0eq) in N,N-dimethylformamide (200mL), and add it to the reaction system 1-Chloropyrrolidine-2,5-dione (17.05g, 127.65mmol, 1.2eq), stirred at 50°C for 5 hours. LC-MS monitored the reaction to be complete. Add water (200mL) to the reaction system and extract three times with ethyl acetate (3 x 200mL). The organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (21.0 g, yield 88.74%).

LC-MS (ESI) [M+H] ⁺ =224.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 13.11 (s, 1H), 7.94 (d, J = 13.2Hz, 1H).

Step 5: Preparation of 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (4.1g, 18.43mmol, 1.0eq) in dimethylformamide (40mL) at 0°C. Add sodium hydrogen (810.8mg, 20.27mmol, 1.1eq, 60%) to the reaction system, stir at 0°C for 0.5 hours, and add [2-(chloromethoxy)ethyl]trimethylsilane (3.69 g, 22.12mmol, 1.2eq), continue the reaction at 0°C for 2 hours. LC-MS monitored the reaction to completion. Add 20 mL of water to quench, and extract three times with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain the target product (5.2 g, yield 79.99%).

LC-MS (ESI) [M+H] ⁺ =352.0.

Step 6: 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 Preparation of -yl)amino)propan-1-ol

2,4,5-Trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5.2g, 14.74mmol, 1.0eq) was dissolved in isopropanol (20mL), and 3-aminopropan-1-ol (1.22g, 16.22mmol, 1.1eq) and diisopropylethylamine (5.72g, 44.23mmol, 3.0eq) were added. React for 2 hours at 85°C. LC-MS monitored the reaction to be complete. The target product (5.4 g, yield 93.61%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =391.0.

Step 7: 2,5-dichloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-5) Preparation of -yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((2,5-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Amino)propan-1-ol (403.26 mg, 1.03 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydrogen (74.15 mg, 3.09 mmol, 3.0 eq) was added to the reaction solution at 0°C. React at 0°C for 0.5 hours, add 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (253 mg, 1.03 mmol) to the reaction system , 1.0eq), continue the reaction for 1 hour at 0°C, and monitor the end of the reaction with LC-MS. Add water (15mL) to the reaction system to quench, extract three times with ethyl acetate (3 x 20mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography to obtain the target product (220mg, yield 35.56%).

LC-MS (ESI) [M+H] ⁺ =600.2; ¹ H NMR (400MHz, CDCl ₃ ): δ6.98 (s, 1H), 6.45 (t, J = 2.0Hz, 1H), 5.48 (s, 2H), 4.48 (t, J=1.6Hz, 2H), 4.38-4.31 (m, 1H), 4.19 (s, 1H), 3.99-3.91 (m, 4H), 3.75-3.68 (m, 1H), 3.57 -3.52(m, 2H), 3.49-3.42(m, 1H), 2.51-2.50(m, 4H), 2.33-2.27(m, 2H), 1.61(s, 2H), 0.96-0.92(m, 2H) , -0.01 (s, 9H).

Step 8: N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl Preparation of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,5-Dichloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl) Oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.33 mmol, 1.0eq) was dissolved in ethanol (10mL)/water (2mL) mixed solvent. Iron powder (92.98mg, 1.67mmol, 5.0eq) and ammonium chloride (106.88mg, 2mmol, 6.0eq) were added to the reaction system. The temperature was raised to 80°C and reacted for 2 hours. LC-MS monitored the reaction to completion. Filter the insoluble matter, add water (10 mL) to the filtrate, and extract three times with ethyl acetate (3 x 15 mL). The organic phases were combined, concentrated, and separated and purified using a preparation plate to obtain the target product (180 mg, yield 94.73%).

LC-MS (ESI) [M+H] ⁺ =570.2; ¹ H NMR (400MHz, CDCl ₃ ): δ6.95 (s, 1H), 6.41 (t, J = 5.2Hz, 1H), 5.45 (s, 2H), 4.33 (t, J=6.0Hz, 2H), 4.15 (d, J=4.8Hz, 1H), 3.95-3.82 (m, 4H), 3.63 (t, J=10.8Hz, 1H), 3.55- 3.48(m, 2H), 3.45-3.36(m, 1H), 2.40(s, 2H), 2.23-2.11(m, 6H), 2.00(d, J=3.7Hz, 1H), 1.80-1.73(m, 2H), 0.94-0.88(m, 2H), -0.03(s, 9H).

Step 9: 3-chloro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane

N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2 ,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50mg, 0.09mmol, 1.0 eq) was dissolved in dioxane (4mL), and tris(dibenzylideneacetone)dipalladium(0) (8.02mg, 0.01mmol, 0.1eq), dicyclohexyl (2',4 ',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (8.35mg, 0.02mmol, 0.2eq), cesium carbonate (85.65mg, 0.26mmol, 3.0eq), nitrogen The temperature was raised to 90°C for 3 hours in the atmosphere. The liquid quality monitoring response was complete. After passing through the column, the target product (25 mg, yield 53.41%) was obtained by separation and purification.

LC-MS (ESI) [M+H] ⁺ =534.2; ¹ H NMR (400MHz, CDCl ₃ ): δ6.70 (s, 1H), 5.99-5.97 (m, 2H), 5.35 (s, 2H), 4.34-4.29 (m, 3H), 4.12 (q, J=7.2Hz, 1H), 3.97-3.95 (m, 2H), 3.77-3.73 (m, 2H), 3.66 (t, J=10.8Hz, 1H) , 3.56-3.52(m, 2H), 3.48-3.42(m, 1H), 2.23(s, 3H), 2.09(s, 1H), 1.56(s, 4H), 0.95-0.90(m, 2H), - 0.03(s,9H).

Step 10: 3-chloro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14- Preparation of (nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6 ,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6 ,10] Triazacyclotridecane (23 mg, 0.04 mmol, 1.0 eq) was dissolved in 1 mL of methylene chloride, trifluoroacetic acid (0.5 mL) was added, stirred at room temperature for 1 hour, TLC (DCM: MeOH = 10: 1) Monitor that there is no raw material residue, spin the solvent to dryness, add tetrahydrofuran (1mL) to redissolve, and add ammonia water (0.5mL) to the reaction system. The reaction was continued at room temperature for 1 hour. LC-MS monitored the reaction to be complete. Concentrate, add methanol (3 mL), and obtain the target product (5.2 mg, yield 25%) through preparative high-performance liquid phase separation and purification.

LC-MS (ESI) [M+H] ⁺ =404.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.02 (s, 1H), 7.26 (s, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.83 (t, J=5.2Hz, 1H), 4.24-4.20 (m, 2H), 4.18-4.10 (m, 1H), 3.87-3.80 (m, 2H), 3.62-3.52 (m, 2H), 3.50-3.41(m, 2H), 2.11(s, 3H), 2.05-1.99(m, 1H), 1.98-1.90(m, 1H), 1.87-1.81(m, 2H), 1.75-1.70( m, 2H).

Example 2

3-Chloro-12-methyl-10-(oxetan-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo [3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: 5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and 3-methyl-4-nitro-1-(oxetan-3-yl) ) Preparation of mixtures of pyrazoles

Add 3-methyl-4-nitro-1H-pyrazole (2.2g, 17.31mmol, 1.0eq) and cesium carbonate (11.28g, 34.62mmol, 2.0eq) to DMF (20mL), and then add 3-iodine Oxetane (9.55g, 51.93mmol, 3.0eq) was reacted at 90°C for 3 hours under nitrogen protection. LC-MS monitored the reaction to be complete. Extract with dichloromethane (3 x 30mL), concentrate the organic phase, and separate and purify by column chromatography to obtain the target product (1.8g, yield 56.79%).

LC-MS (ESI) [M+H] ⁺ =184.0.

Step 2: Preparation of 5-chloro-3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole

In 5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and 3-methyl-4-nitro-1-(oxetan-3-yl)pyrazole To the mixture (1.7g, 9.28mmol, 1.0eq) in tetrahydrofuran (10mL), a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 4.66mL, 27.84mmol, 3.0eq) was added dropwise in a dry ice/acetone bath. ), stir at -78°C for 1 hour, add hexachloroethane (10.98g, 46.4mmol, 5.0eq) at this temperature, slowly rise to room temperature, and stir at 25°C for 4 hours. LC-MS monitored the reaction to be complete. Saturated ammonium chloride solution (20mL) was added to quench, extracted with ethyl acetate (2x 20mL), washed with saturated brine (2x 20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain the target product (800mg, Yield 39.66%).

LC-MS (ESI) [M+H] ⁺ =218.0.

Step 3: 2,5-Dichloro-N-(3-((3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazol-5-yl) Preparation of oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

In 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Amino) propan-1-ol (1.98g, 5.05mmol, 1.0eq) in tetrahydrofuran (10mL), add sodium hydrogen (60%, 303mg, 7.58mmol, 1.5eq) in an ice-water bath, stir for 1 hour, and add 5-chloro -3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazole (1.1g, 5.05mmol, 1.0eq), remove the ice water bath, and stir at 25°C for 4 hours. LC-MS monitored the reaction to be complete. The reaction solution was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, and separated and purified by column chromatography to obtain the target product (1.5 g, yield 51.88%).

LC-MS (ESI) [M+H] ⁺ =571.6; ¹ H NMR (400MHz, CDCl ₃ ) δ6.96 (s, 1H), 6.31 (t, J = 6.0Hz, 1H), 5.58-5.49 (m ,1H),5.46(s,2H),5.12-5.09(m,2H),4.97-4.93(m,2H),4.48-4.44(m,2H),3.91-3.86(m,2H),3.56-3.50 (m,2H),2.55(s,3H),2.27-2.20(m,2H),0.97-0.86(m,2H),-0.03(s,9H).

Step 4: N-(3-((4-amino-3-methyl-1-(oxetan-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2 , Preparation of 5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To ethanol (10 mL) and water (2 mL) was added 2,5-dichloro-N-(3-((3-methyl-4-nitro-1-(oxetan-3-yl)-1H -pyrazol-5-yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Amine (500mg, 0.87mmol, 1.0eq) and ammonium chloride (280.3mg, 5.24mmol, 6.0eq), then add iron powder (243.83mg, 4.37mmol, 5.0eq), react at 80°C under nitrogen protection 3 hours. LC-MS monitored the reaction to be complete. Extract with dichloromethane (3 x 20mL), combine the organic phases, concentrate, and separate and purify with a preparation plate to obtain the target product (200mg, yield 42.37%).

LC-MS (ESI) [M+H] ⁺ =571.6; ¹ H NMR (400MHz, CDCl ₃ ): δ6.96 (s, 1H), 6.33 (t, J = 5.6Hz, 1H), 5.46 (s, 2H),5.37-5.31(m,1H),5.12-5.08(m,2H),4.91-4.87(m,2H),4.35-4.33(m,2H),3.87-3.83(m,2H),3.54- 3.50(m,2H),2.18(s,3H),2.16-2.14(m,2H),0.97-0.83(m,2H),-0.03(s,9H).

Step 5: 3-chloro-12-methyl-10-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6 ,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6 ,10] Preparation of triazacyclotridecane

In N-(3-((4-amino-3-methyl-1-(oxetan-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2,5- Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.09 mmol, 1.0 eq) To 1,4-dioxane (3mL) solvent, add tris(dibenzylideneacetone)dipalladium (8mg, 0.01mmol, 0.1eq), dicyclohexyl (2',4',6'-triiso Propyl-[1,1'-biphenyl]-2-yl)phosphine (8.33mg, 0.02mmol, 0.2eq), cesium carbonate (85.36mg, 0.26mmol, 3.0eq), stir under nitrogen atmosphere at 90°C for 3 hours . LC-MS monitored the reaction to be complete. The reaction solution was filtered, concentrated, and separated and purified using a preparation plate to obtain the target product (10 mg, yield 21.96%).

LC-MS (ESI) [M+H] ⁺ =506.2.

Step 6: 3-chloro-12-methyl-10-(oxetan-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge ) Preparation of pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

In 3-chloro-12-methyl-10-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7, 8,10,13-Hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10] To triazacyclotridecane (20 mg, 0.04 mmol, 1.0 eq) in methylene chloride (1 mL), trifluoroacetic acid (0.5 mL, 4.38 mmol, 109.6 eq) was added and the mixture was stirred at 25°C for 1 hour. TLC monitored the reaction to be complete. The reaction solution was concentrated to obtain a crude product, tetrahydrofuran (2 mL) was added to dissolve, ammonia water (1 mL) was added, and the mixture was stirred at 25°C for 1 hour under nitrogen protection. LC-MS monitored the reaction to be complete. The reaction solution was concentrated, dissolved in methanol and filtered. The filtrate was purified by preparative high-performance liquid phase separation to obtain the target product (1.44 mg, yield 9.58%).

LC-MS (ESI) [M+H] ⁺ =376.2; ¹ H NMR (400MHz, CD ₃ OD) δ6.73 (s, 1H), 5.61-5.53 (m, 1H), 5.06-5.03 (m, 2H) ),4.98-4.92(m,2H),4.25-4.22(m,2H),3.71-3.68(m,2H),2.26(s,3H),1.97-1.92(m,2H).

Example 3

3-Chloro-12-methyl-11-(tetrahydro-2H-pyran-4-yl)-5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen bridge) Pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 4, the compound of Example 3 was prepared, and the LC-MS (ESI) [M+H] ⁺ =404.15.

Example 4

3-Chloro-12-methyl-11-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen bridge) Pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 3,4,5-tribromo-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole

Dissolve 3,4,5-tribromo-1H-pyrazole (4.8g, 15.75mmol, 1eq) in tetrahydrofuran (100mL). After nitrogen replacement, add tetrahydro-2H-pyran-3-ol ( 1.93g, 18.9mmol, 1.2eq), triphenylphosphine (8.26g, 31.5mmol, 2eq) and diethyl azodicarboxylate (5.49g, 31.5mmol, 2eq), continue stirring at 20°C for 12 hours. TLC monitored reaction completion. Water (50 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined and separated and purified by column chromatography to obtain the target product (2.1 g, yield 34.29%).

¹ H NMR (400MHz, CDCl ₃ ): δ4.50-4.30(m,1H),4.05-3.90(m,2H),3.63(m,1H),3.48-3.34(m,1H),2.26-2.06( m,2H),1.87-1.77(m,2H).

Step 2: Preparation of 3,4-dibromo-5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole

Dissolve 3,4,5-tribromo-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (500mg, 1.29mmol, 1eq) in tetrahydrofuran (5mL) under nitrogen protection, - Add n-butyllithium (0.52 mL, 1.29 mmol, 1 eq) at 78°C, stir for half an hour, then add methyl iodide (365 mg, 2.57 mmol, 2 eq) to the above system, and stir at -78°C for 2 hours. LC-MS monitored the reaction to completion. Add water (5mL) to the reaction solution to quench, extract with ethyl acetate (5mL*2), combine the organic phases, and separate and purify by column chromatography to obtain the target product 3,4-dibromo-5-methyl-1-(tetrahydrofuran). Hydrogen-2H-pyran-3-yl)-1H-pyrazole (220 mg, yield 52.81%).

LC-MS (ESI) [M+H] ⁺ =325.0; ¹ H NMR (400MHz, CDCl ₃ ) δ4.22-4.10 (m, 1H), 4.00-3.87 (m, 2H), 3.69 (t, J＝ 10.8Hz,1H),3.50-3.35(m,1H),2.31(s,3H),2.30-2.20(m,1H),2.10-2.00(m,1H),1.85-1.75(m,2H).

Step 3: Preparation of 3-bromo-5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole

Dissolve 3,4-dibromo-5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (850 mg, 2.62 mmol, 1 eq) in 98% concentrated sulfuric acid (10 mL) , slowly drop 97% concentrated nitric acid (9 mL) in an ice bath at 0°C, and keep stirring at 0°C for 3 hours. LC-MS monitored the reaction to completion. The reaction solution was slowly added to ice water (30 mL), extracted with ethyl acetate (50 mL*3), the organic phases were combined, and separated and purified by column chromatography to obtain the target product (760 mg, yield 99.99%).

LC-MS(ESI)[M+H] ⁺ =292.0; H NMR (400MHz, DMSO-d ₆ ): δ4.53-4.41(m,1H),3.98-3.91(m,1H),3.90-3.81( m,1H),3.52(t,J＝10.4Hz,1H),3.42-3.37(m,1H),2.67(s,3H),2.10-1.99(m,2H),1.82-1.68(m,2H) .

Step 4: Preparation of 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-ol

Dissolve 3-bromo-5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (360 mg, 1.24 mmol, 1.0 eq) in water (10 mL) , then add potassium hydroxide (1.46g, 26.02mmol, 20.97eq), and conduct a reflux reaction at 120°C for 18 hours under nitrogen protection. LC-MS monitored the reaction to be complete. Add water (10mL) to the reaction solution to quench, extract with ethyl acetate (10mL*2), adjust the aqueous phase to acidity (PH=3), extract with dichloromethane (20mL*3), and concentrate the organic phase to obtain Crude product (190 mg, yield 67.43%).

LC-MS(ESI)[M+H] ⁺ =228.1; ¹ H NMR (400MHz, DMSO-d6) δ11.36(s,1H),4.37-4.23(m,1H),3.97-3.80(m,2H) ), 3.48 (t, J = 10.4Hz, 1H), 2.58 (s, 3H), 2.05-1.90 (m, 2H), 1.80-1.65 (m, 2H), 1.23 (s, 1H).

Step 5: tert-butyl (3-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)oxy) Preparation of propyl) carbamate

5-Methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-ol (470 mg, 2.07 mmol, 1.0 eq), tert-butyl (3 -Bromopropyl)carbamate (492.55mg, 2.07mmol, 1.0eq), dissolved in N,N-dimethylformamide (10mL), then added potassium carbonate (571.77mg, 4.14mmol, 2eq), nitrogen Under protection, react at 60°C for 3 hours. LC-MS monitored the reaction to be complete. Water (15 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined and separated and purified by column chromatography to obtain the target product (570 mg, yield 96.85%).

¹ H NMR (400MHz, CDCl ₃ ): δ5.23 (s, 1H), 4.37 (t, J = 5.6Hz, 2H), 4.16-4.11 (m, 1H), 3.99-3.96 (m, 1H), 3.93 -3.88(m,1H),3.70(t,J＝10.8Hz,1H),3.47-3.40(m,1H),3.36-3.30(m,2H),2.63(s,3H),2.28-2.16(m ,1H),2.06-1.96(m,3H),1.86-1.83(m,2H),1.45(s,9H).

Step 6: 3-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl-oxy)propan-1- Preparation of amines

tert-Butyl(3-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)oxy)propyl) Carbamate (500 mg, 1.36 mmol, 1 eq) was dissolved in dioxane hydrochloride (4 M, 8 mL), and stirred at 30°C for 3 hours under nitrogen protection. LC-MS monitored the reaction to be complete. The reaction solution was concentrated to obtain the target product (360 mg, yield 98.97%).

LC-MS (ESI) [M+H] ⁺ =285.2.

Step 7: 2,5-dichloro-N-(3-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3) Preparation of -yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((5-Methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl-oxy)propan-1-amine (360 mg , 1.27mmol, 1.0eq) was dissolved in N,N-dimethylformamide (8mL, 100.0%), and then sodium hydride (60%, 152mg, 3.8mmol, 3.0eq) was added in batches under ice bath under nitrogen protection. Stir for half an hour at 0°C, and then 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d ]pyrimidine (491.46mg, 1.39mmol, 1.1eq) was added to the above system, and after nitrogen replacement, stirred at 30°C for 3 hours. LC-MS monitored that the reaction was complete. Add ice water (10mL) dropwise to the reaction solution to quench, and use acetic acid Extract with ethyl ester (10 mL*3), combine the organic phases, concentrate, and separate and purify using a preparation plate to obtain the target product (280 mg, yield 36.71%).

LC-MS (ESI) [M+H] ⁺ =600.2; ¹ H NMR (400MHz, CDCl ₃ ): δ6.97 (s, 1H), 6.18 (t, J = 5.6Hz, 1H), 5.48 (s, 2H),4.49-4.45(m,2H),4.22-4.13(m,1H),4.01-3.98(m,1H),3.95-3.93(m,1H),3.87-3.82(m,2H),3.73- 3.68(m,1H),3.57-3.52(m,2H),3.48-3.43(m,1H),2.65(s,3H),2.32-2.19(m,3H),2.07-2.03(m,1H), 1.89-1.79(m,2H),0.98-0.91(m,2H),0.00(s,9H).

Step 8: N-(3-((4-amino-5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)oxy)propyl Preparation of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,5-Dichloro-N-(3-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl) Oxygen) propylene ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.13 mmol, 1 eq) was dissolved in Ethanol (5mL)/water (1mL) mixed solvent. Iron powder (37.19 mg, 0.67 mmol, 5 eq) and ammonium chloride (42.75 mg, 0.8 mmol, 6 eq) were added to the reaction system. The temperature was raised to 80°C and reacted for 2 hours. LC-MS monitored the reaction to completion. Filter, concentrate the filtrate, wash with saturated brine, combine the organic phases, and concentrate to obtain the crude target product (70 mg, yield 94.37%).

LC-MS (ESI) [M+H] ⁺ =570.4; ¹ H NMR (400MHz, CDCl ₃ ) δ6.94 (s, 1H), 6.26 (d, J = 5.6Hz, 1H), 5.45 (s, 2H) ),4.34-4.28(m,2H),4.00-3.89(m,2H),3.87-3.78(m,2H),3.59(t,J＝10.8Hz,1H),3.54-3.49(m,2H), 3.44-3.35(m,1H),2.14(s,3H),2.02-1.91(m,2H),1.26(s,4H),0.94-0.82(m,5H),-0.03(s,9H).

Step 9: 3-chloro-12-methyl-11-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane

N-(3-((4-amino-5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)oxy)propyl)-2 ,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150mg, 0.26mmol, 1eq ) was dissolved in dioxane (5mL), and tris(dibenzylideneacetone)dipalladium(0)(24.07mg, 0.03mmol, 0.1eq), dicyclohexyl(2',4' , 6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (25.06 mg, 0.05 mmol, 0.2 eq), cesium carbonate (256.96 mg, 0.79 mmol, 3 eq). The temperature was raised to 90°C for 3 hours in a nitrogen atmosphere. LC-MS monitored the reaction to be complete. Filter through diatomaceous earth, concentrate the filtrate, and separate and purify using a preparation plate to obtain the target product (80 mg, yield 45.58%).

LC-MS (ESI) [M+H] ⁺ =534.2.

Step 10: 3-chloro-12-methyl-11-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,11,13-hexahydro-1H-4,14- Preparation of (nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-12-methyl-11-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6 ,7,8,11,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6 ,10] Triazacyclotridecane (80 mg, 0.15 mmol, 1 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated, tetrahydrofuran (3 mL) was added to redissolve, and ammonia water (2 mL) was added to the reaction system. Continue the reaction for 2 hours at room temperature. LC-MS monitored the reaction to be complete. The reaction solution was concentrated, 4 mL of methanol was added, and the target product (8 mg, yield 13.23%) was obtained by separation and purification by preparing high-performance liquid phase.

LC-MS (ESI) [M+H] ⁺ = 404.2; ¹ H NMR (400MHz, DMSO-d6) δ 10.96 (d, J = 2.0Hz, 1H), 7.78 (s, 1H), 6.79 (d, J＝2.4Hz,1H),6.72(t,J＝6.4Hz,1H),4.21(s,2H),4.08-4.00(m,1H),3.87-3.78(m,2H),3.49-3.44(m ,4H),2.15(s,3H),2.06-1.93(m,2H),1.70(s,4H).

Example 5

3-Chloro-12-methyl-11-(tetrahydrofuran-3-yl)-5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[3, 4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: 3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole and 5-methyl-4-nitro-1-(tetrahydro Synthesis of mixtures of -2H-pyran-2-yl)-1H-pyrazoles

Dissolve 3-methyl-4-nitro-1H-pyrazole (20g, 157.36mmol, 1eq) and p-toluenesulfonic acid monohydrate (1.5g, 7.87mmol, 0.05eq) in anhydrous ethyl acetate (200mL) , 3,4-dihydro-2H-pyran (19.86g, 236.03mmol, 1.5eq) was added dropwise at room temperature. The reaction was stirred at room temperature under nitrogen protection for 16 hours, and TLC monitored the reaction to be complete. The reaction solution was washed with saturated brine (200mL*3), dried over anhydrous sodium sulfate, filtered, and separated and purified by column chromatography to obtain the target product 3-methyl-4-nitro-1-(tetrahydro-2H-pyran- A mixture of 2-yl)-1H-pyrazole and 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole, NMR shows a ratio of approximately 3: 1 (30g, yield 90.26%).

Step 2: Synthesis of 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

At -78°C, under nitrogen protection, add 3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole and 5-methyl-4-nitro To a solution of a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (15 g, 71.02 mmol, 1 eq) in tetrahydrofuran (250 mL) was added bis(trimethylsilyl)amine Lithium solution in tetrahydrofuran (1M, 213.05mL, 213.05mmol, 3eq). After stirring for 45 minutes at -78°C, a solution of hexachloroethane (50.44g, 213.05mmol, 3eq) in tetrahydrofuran (100mL) was added dropwise, and stirred at 15°C for 2 hours under nitrogen protection. TLC monitored the reaction to be complete. Saturated ammonium chloride solution (300 mL) was added to the reaction solution to quench, extracted with ethyl acetate (200 mL*3), and separated and purified by column chromatography to obtain the target product (20 g, yield 57.32%).

¹ H NMR (400MHz, CDCl ₃ ): δ5.51 (dd, J＝10.0, 2.8Hz, 1H), 4.14-4.06 (m, 1H), 3.77-3.65 (m, 1H), 2.57 (s, 3H) ,2.417-2.33(m,1H),2.20-2.08(m,1H),1.94-1.82(m,1H),1.75-1.71(m,1H),1.66-1.60(m,1H).

Step 3: 2,5-Dichloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5) Synthesis of -yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((2,5-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Amino)propan-1-ol (10g, 26.55mmol, 1eq) was dissolved in tetrahydrofuran (150mL). At 0°C, sodium hydrogen (1.53g, 38.33mmol, 1.5eq, 60% content) was added to the reaction solution. Reaction at 0°C for 0.5 hours. Dissolve 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (7.53g, 30.66mmol, 1.2eq) in tetrahydrofuran (100mL ), and slowly added dropwise to the reaction system, continued the reaction for 1 hour at 0°C, and monitored the end of the reaction with LC-MS. The reaction system was slowly poured into methanol (50 mL), filtered, the organic phases were combined, and separated and purified by column chromatography to obtain the target product (9.5 g, yield 61.91%).

LC-MS (ESI) [M+H] ⁺ =602.1.

Step 4: N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxy)propyl Synthesis of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Dissolve cuprous chloride (0.16g, 1.67mmol, 0.2eq) and sodium borohydride (1.26g, 33.3mmol, 4eq) in tetrahydrofuran (50mL). Under nitrogen protection, 2,5-dichloro-N- (3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxy)propyl)-7-( (2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5g, 8.33mmol, 1eq) was dissolved in ethanol (50mL) and added reaction system. Stir at room temperature for 2 hours. LC-MS monitored the reaction to be complete. Filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (2 g, yield 42.08%).

LC-MS (ESI) [M+H] ⁺ =570.2.

Step 5: 3-chloro-12-methyl-10-(tetrahydro-2H-pyran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[ Synthesis of 4,6,10]triazacyclotridecane

N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxy)propyl)-2 ,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2g, 3.51mmol, 1eq ) was dissolved in dioxane (80 mL), and tris(dibenzylideneacetone) dipalladium (0) (0.32g, 0.35mmol, 0.1eq), dicyclohexyl (2', 4' , 6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.33g, 0.7mmol, 0.2eq), cesium carbonate (3.43g, 10.52mmol, 3eq), in nitrogen atmosphere The temperature was raised to 90°C and reacted for 3 hours. LC-MS monitored the reaction to be complete. Filter through diatomaceous earth, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (1 g, yield 53.41%).

LC-MS (ESI) [M+H] ⁺ =534.1.

Step 6: 3-chloro-12-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,10,13-hexahydro-1H Synthesis of -4,14-(nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-12-methyl-10-(tetrahydro-2H-pyran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6 ,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6 ,10] Triazacyclotridecane (1g, 1.87mmol, 1eq) was dissolved in acetic acid (20mL) and water (5mL), and stirred at 50°C for 1 hour. LC-MS monitored that the reaction was complete. The organic phase was directly concentrated on silica gel and mixed with sample. The target product (400 mg, yield 47.53%) was separated and purified by column chromatography.

LC-MS(ESI)[M+H] ⁺ =450.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.37(s,1H),8.02(s,1H),7.05(s,1H), 6.90(s,1H),5.35(s,2H),4.31-4.20(m,2H),3.58-3.51(m,2H),3.47-3.40(m,2H),2.13(s,3H),1.83- 1.73(m,2H),0.95-0.82(m,2H),-0.00(s,9H).

Step 7: 3-chloro-12-methyl-11-(tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7, 8,11,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10] Synthesis of Triazacyclotridecane

3-Chloro-12-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,10,13-hexahydro-1H-4, 14-(nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane (400mg, 0.89mmol, 1eq) was dissolved in DMF (4mL), sodium hydrogen (42.67mg, 1.78mmol, 2eq, 60% content) was added at room temperature, stirred for 30 minutes, and then tetrahydrofuran-3-methylsulfonate (221.6mg, 1.33mmol , 1.5eq) dissolved in DMF (1mL) was added dropwise to the system, and stirred at room temperature for 16 hours. LC-MS monitors that the reaction is complete. Add water (20 mL) to the reaction solution to quench, extract with ethyl acetate (20 mL*3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The target product (80 mg, yield 17.3%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =520.2.

Step 8: 3-chloro-12-methyl-11-(tetrahydrofuran-3-yl)-5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazole Synthesis of [3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-12-methyl-11-(tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,11 ,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triaza Dissolve cyclotridecane (80 mg, 0.15 mmol, 1 eq) in dichloromethane (1 mL), add trifluoroacetic acid (0.5 mL), and stir at room temperature for 1 hour. TLC monitors that the reaction is complete, concentrate the reaction solution, and add tetrahydrofuran (1 mL). ) was redissolved, and ammonia water (0.5 mL) was added to the reaction system. The reaction was continued at room temperature for 1 hour. LC-MS monitored the reaction to be complete. The organic phase was concentrated, separated and purified by column chromatography to obtain a crude product, which was then prepared by a chiral chromatography column to obtain the target product (8.5 mg, yield 14.54%).

LC-MS (ESI) [M+H] ⁺ =390.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.97 (s, 1H), 7.81 (s, 1H), 6.80 (d, J = 2.4 Hz,1H),6.73(t,J＝6.0Hz,1H),4.84(t,J＝6.4Hz,1H),4.22(d,J＝4.4Hz,2H),4.02-3.90(m,2H), 3.84-3.66(m,2H),3.37(d,J＝5.2Hz,2H),2.27-2.17(m,2H),2.15(s,3H),1.81-1.67(m,2H).

Example 6-129

Referring to the preparation methods of Examples 1-2 and 4-5, the compound of Example 6-65 was prepared; referring to the preparation methods of Examples 194, 196 and 197, the compound of Example 66-129 was prepared

Example 130

2-(5-Chloro-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[4,6,10]tri Azacyclotridec-13-yl)-2-methylpropionitrile

Step 1: Preparation of tert-butyl 2-(6-chloro-5-nitropyridin-2-yl)-2-cyanoacetate

At room temperature, add 2,6-dichloro-3-nitropyridine (10.0g, 1.0eq), potassium carbonate (18g, 2.5eq) and THF (100mL) into a 250mL three-neck reaction flask. Under stirring, add cyanide dropwise. tert-butyl acetate (11g, 1.5eq), and then the temperature of the reaction system was raised to 70°C and refluxed overnight. The reaction was monitored by TLC to be complete, filtered through diatomaceous earth, and the filtrate was concentrated and used directly in the next step (28.3g).

Step 2: Preparation of tert-butyl 2-(6-chloro-5-nitropyridin-2-yl)-2-cyanopropionate

Dissolve the mixture from the previous step in acetonitrile in a 250mL reaction bottle at 25°C, then add potassium carbonate (2.5eq), stir for 10 minutes, slowly add Mel (2.6eq) dropwise, and raise the temperature of the reaction system to 40 ℃, stir overnight. TLC monitored the reaction to be complete, and the reaction solution was concentrated and used directly in the next step (9.2g).

Step 3: Preparation of 2-(6-chloro-5-nitropyridin-2-yl)propionitrile

Dissolve the mixture in the previous step in DMSO (50 mL) and water (10 mL) at room temperature, then add sodium chloride (2w/w), raise the temperature of the reaction system to 150°C and stir for 2 hours. After TLC monitors that the reaction is complete, cool to room temperature, then add water (100 mL) and ethyl acetate (50 mL) and stir for 10 minutes; after 10 minutes, let stand for liquid separation, and the aqueous phase is extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (5.0 g).

¹ H NMR (400MHz, CDCl ₃ ): δ8.38 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 4.90 (q, J = 7.0 Hz, 1H), 1.81 ( d,J=7.1Hz,3H).

Step 4: Preparation of 2-(6-chloro-5-nitropyridin-2-yl)-2-methylpropionitrile

Dissolve 2-(6-chloro-5-nitropyridin-2-yl)propionitrile (5.0g, 23.6mmol, 1.0eq) in acetonitrile (125mL) at 25°C, and then add potassium carbonate (8.16g, 59.1 mmol, 2.5 eq), after stirring for 10 minutes, Mel (8.72 g, 61.4 mmol, 2.6 eq) was slowly added dropwise, and the temperature of the reaction system was raised to 40°C, and stirred overnight. After the reaction is complete, the reaction solution is concentrated under reduced pressure, water (100 mL) and ethyl acetate (125 mL) are added to the crude product and stirred for 10 minutes; after 10 minutes, let stand for liquid separation, and the aqueous phase is extracted with ethyl acetate (20 mL) 2 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (4.82g, yield 90.4%).

¹ H NMR (500MHz, CDCl ₃ ): δ 8.11 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 1.93 (s, 6H).

Step 5: 2-(6-(3-((2,5-dichloropyrimidin-4-yl)amino)propoxy)-5-nitropyridin-2-yl)-2-methylpropionitrile Preparation

At 0°C, under nitrogen protection, dissolve NaH (425.5 mg, 17.73 mmol, 2.0 eq) in DMF (50 mL) in a 250 mL three-neck reaction flask, and then slowly add 3-((2,5-dichloropyrimidine- 4-yl)amino)propan-1-ol (2.36g, 10.64 mmol, 1.2eq), at 0°C, after continuing to stir for 0.5 hours, slowly add 2-(6-chloro-5-nitropyridin-2-yl)-2-methylpropionitrile (2.0g, 8.86mmol, 1.0 eq). The reaction was heated to room temperature and continued to stir for 3 hours. Then, the reaction was quenched with ice water in an ice bath at 0°C. Extracted with EA (50 mL, 10 v/w). The organic phases were combined, washed three times with saturated brine, and anhydrous. It was dried over sodium sulfate, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (2.1 g, yield 57.4%).

LC-MS (ESI) [M+H] ⁺ =411.2.

Step 6: 2-(5-amino-6-(3-((2,5-dichloropyrimidin-4-yl)amino)propoxy)pyridin-2-yl)-2-methylpropionitrile preparation

At room temperature, in a 50 mL reaction bottle, 2-(6-(3-((2,5-dichloropyrimidin-4-yl)amino)propoxy)-5-nitropyridin-2-yl) -2-Methylpropionitrile (2.1g, 5.11mmol, 1.0eq), iron powder (1.43g, 25.53mmol, 5.0eq) and ammonium chloride (1.36g, 25.53mmol, 5.0eq) were dissolved in EtOH/H ₂ O (20/2mL), then the temperature of the reaction system was raised to 90°C and stirred for 2h. After TLC monitored the completion of the reaction, it was filtered through diatomaceous earth, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (1.9 g, yield 97.6%).

LC-MS (ESI) [M+H] ⁺ =381.2.

Step 7: 2-(5-chloro-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[4,6 ,10] Preparation of triazacyclotridecane-13-yl)-2-methylpropionitrile

Under nitrogen protection, in a 20mL reaction bottle, add Pd ₂ (dba) ₃ (182.5 mg, 10%), tBuXPhos (84.6 mg, 10%), 2-(5-amino-6-(3-((2, 5-Dichloropyrimidin-4-yl)amino)propoxy)pyridin-2-yl)-2-methylpropionitrile (762mg, 1.99mmol, 1.0eq) and potassium carbonate (826.5mg, 5.98mmol, 3.0eq) ) was dissolved in anhydrous dioxane (10 mL), and then replaced with nitrogen. Raise the temperature of the reaction system to 100°C and continue stirring for 2 hours under microwave conditions. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and separated and purified by column chromatography to obtain a crude product. The mixture was then pulped with methanol and filtered to obtain the target product (120 mg, yield 17.4%).

LC-MS (ESI) [M+H] ⁺ =345.4.

Examples 131-193

Referring to the preparation method of Example 130, the compounds of Examples 131-144 and 146-193 were prepared; referring to the preparation method of Example 194, the compound of Example 145 was prepared.

Example 194

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1,5,6,7,8,14-hexahydro-4,15-(nitrogen Bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (20.0g, 106.38mmol, 1.0eq) in N,N-dimethylformamide (200mL), and add it to the reaction system 1-Chloropyrrolidine-2,5-dione (17.05g, 127.65mmol, 1.2eq), stirred at 50°C for 5 hours. LC-MS monitored the reaction to be complete. Add 200mL of water to the reaction system and extract three times with ethyl acetate (3 x 200mL). The organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (21.0 g, yield 88.74%).

Step 2: Preparation of 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2,4,5-trichloro-7H-pyrrolo[2,3-d]pyrimidine (4.1g, 18.43mmol, 1.0eq) in dimethylformamide (40mL) at 0°C. Add sodium hydrogen (810.8mg, 20.27mmol, 1.1eq, 60%) to the reaction system, stir at 0°C for 0.5 hours, and add [2-(chloromethoxy)ethyl]trimethylsilane (3.69 g, 22.12mmol, 1.2eq), continue the reaction at 0°C for 2 hours. LC-MS monitored the reaction to completion. Add 20 mL of water to quench, and extract three times with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain the target product (5.2 g, yield 79.99%).

LC-MS (ESI) [M+H] ⁺ =352.0.

Step 3: 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 Preparation of -yl)amino)propan-1-ol

2,4,5-Trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5.2g, 14.74mmol, 1.0eq) was dissolved in 20 mL of isopropyl alcohol, and 3-aminopropan-1-ol (1.22g, 16.22mmol, 1.1eq) and diisopropylethylamine (5.72g, 44.23mmol, 3.0eq) were added. React for 2 hours at 85°C. LC-MS monitored the reaction to be complete. The target product (5.4 g, yield 93.61%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =391.0.

Step 4: 2,5-dichloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-7-((2-(trimethylsilane) Preparation of (ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((2,5-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) Amino)propan-1-ol (4g, 10.22mmol, 1eq) was dissolved in THF (100mL), add sodium hydrogen (490mg, 20.44mmol, 2eq), and after half an hour, add 2,6-dichloro-3-nitro Pyridine (1.97g, 10.22mmol, 1eq), react at 25°C for 2 hours. LC-MS monitored the reaction to be complete. Water (100mL) was added to the reaction solution, extracted with ethyl acetate (500mL*3), the organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain the target product (4g, Yield 71.44%).

LC-MS (ESI) [M+H]+=547.1.

Step 5: N-(3-((6-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-nitropyridin-2-yl)oxygen methyl)propyl)-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Preparation

2,5-Dichloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-7-((2-(trimethylsilyl)ethyl)ethyl Oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.2g, 2.19mmol, 1eq) was dissolved in isopropanol (100mL), and 2-oxa-5- Azabicyclo[2.2.1]heptane (217 mg, 2.19 mmol, 1 eq) and N,N-diisopropylethylamine (849 mg, 6.57 mmol, 3 eq) were reacted at 60°C for 16 hours. LC-MS monitored that the reaction was complete, and column chromatography separated and purified the target product (1.2 g, yield 89.74%).

LC-MS (ESI) [M+H] ⁺ =610.1.

Step 6: N-(3-((3-amino-6-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridin-2-yl)oxy)propyl Preparation of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

N-(3-((6-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-nitropyridin-2-yl)oxy)propanyl methyl)-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.2g , 1.97mmol, 1eq) was dissolved in ethanol (100mL) solution, add iron powder (1.1g, 19.7mmol, 10eq) and saturated aqueous ammonium chloride solution (1.05g, 19.7mmol, 10eq), stir at 60°C for 2 hours LC-MS monitored that the reaction was complete. Filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (600 mg, yield 52.46%).

LC-MS (ESI) [M+H] ⁺ =580.2.

Step 7: 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-((2-(trimethylsilyl)ethoxy) Methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa Preparation of [4,6,10]triazacyclotridecane

N-(3-((3-amino-6-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridin-2-yl)oxy)propyl)-2 ,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (600mg, 1.1mmol, 1eq ) was dissolved in dioxane (50mL), and tris(dibenzylideneacetone)dipalladium (95mg, 0.1mmol, 0.1eq), cesium carbonate (1.01g, 3.1mmol, 3eq) and X-Phos (49mg , 0.1mmol, 0.1eq). Under nitrogen protection, react at 90°C for 4 hours. LC-MS monitored the reaction to be complete. The target product (200 mg, yield 43.82%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =544.2.

Step 8: 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1,5,6,7,8,14-hexahydro-4, Preparation of 15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl) -1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4, 6,10] Triazacyclotridecane (180 mg, 0.33 mmol, 1 eq) was dissolved in methanol solution (5 mL), concentrated hydrochloric acid (10 mL) was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 2 hours. After LC-MS monitoring, the reaction has completely generated the intermediate. Spin to dryness, add methanol (5 mL), add ammonia water (10 mL), and continue stirring at room temperature for 1 hour. LC-MS monitors that the reaction is complete. The target product (25 mg, yield 18.31%) was obtained through preparative high-performance liquid phase separation and purification.

LC-MS (ESI) [M+H] ⁺ =414.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (s, 1H), 8.08 (s, 1H), 7.21 (d, J = 8.2 Hz,1H),6.82(d,J＝2.2Hz,1H),6.72(t,J＝6.0Hz,1H),6.00(d,J＝8.2Hz,1H),4.67(d,J＝43.8Hz, 2H),4.48(s,2H),3.77(d,J＝7.0Hz,1H),3.67(d,J＝7.2Hz,1H),3.42(d,J＝9.6Hz,1H),3.32-3.28( m, 2H), 3.18 (d, J = 9.8Hz, 1H), 1.89 (d, J = 8.8Hz, 1H), 1.83 (d, J = 9.2Hz, 1H), 1.75 (s, 2H).

Example 195

3-Fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge )pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 197, the compound of Example 195 was prepared, LC-MS (ESI) [M+H] ⁺ =426.2.

Example 196

11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro-4, 15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (10g, 53.19mmol, 1.0eq) was dissolved in dichloromethane (200mL) under nitrogen, and then N was slowly added at 0°C. - Iodosuccinimide (19.15g, 85.1mmol, 1.6eq), the reaction mixture was stirred at room temperature for 16 hours. LC-MS monitored the reaction to be complete. Filter, wash the filter cake with distilled water, and dry under reduced pressure to obtain the target product (16 g, yield 96%).

LC-MS (ESI) [M+H] ⁺ =313.9.

Step 2: Preparation of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2,4-dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (16g, 50.97mmol, 1.0eq) in tetrahydrofuran (200mL), and add triethylamine (15.4g, 152mmol , 3.0eq), then dropwise add [2-(chloromethoxy)ethyl]trimethylsilane (17g, 102mmol, 2.0eq), react at room temperature for 2 hours, and LC-MS monitors that the reaction is complete. Water (100 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (200 mL*3). The organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (20 g, yield 88%).

LC-MS (ESI) [M+H] ⁺ =444.0.

Step 3: 2,4-Dichloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidines

Add copper iodide (21.4g, 113mmol, 5.0eq) and potassium fluoride (6.5g, 113mmol, 5.0eq) into a three-necked flask, and add trimethyl (trifluoromethyl)silane (16g, 16g, 113 mmol, 5.0 eq) was dissolved in N-methylpyrrolidone (50 mL), and slowly added to the reaction bottle through a syringe, and reacted at room temperature for one hour. 2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (10 g , 23 mmol, 1.0 eq) was further dissolved in N-methylpyrrolidone (10 mL) and then slowly added via syringe. The resulting reaction mixture was stirred at 50°C for 12 hours. LC-MS monitored the reaction to be complete. The reaction solution was cooled to room temperature, then quenched by adding distilled water, extracted with ethyl acetate (100 mL*3), the organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (5 g, yield 57%).

LC-MS (ESI) [M+H] ⁺ =386.0.

Step 4: 3-((2-chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)amino)propan-1-ol

2,4-Dichloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5g, 12.94mmol, 1.0eq) was added to isopropyl alcohol (50mL), then 3-aminopropan-1-ol (1.94g, 25.89mmol) was added, and the reaction was carried out at 85°C for 1 hour. LC-MS monitored the reaction to be complete. The target product (3 g, yield 54%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =425.2.

Step 5: Preparation of 6-methoxy-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester

6-Hydroxy-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (6g, 28.13mmol) was dissolved in tetrahydrofuran (5mL), and sodium tert-butoxide (5.41g, 56.26mmol) was added at 0°C. ) and methyl iodide (5.99g, 42.19mmol), reacted at room temperature for 16 hours. LC-MS monitored the reaction to be complete. Water (100 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined and concentrated to obtain the crude target product (6 g, yield 93%).

LC-MS (ESI) [M+Na] ⁺ =250.2.

Step 6: Preparation of 6-methoxy-2-azaspiro[3.3]heptane

Dissolve 6-methoxy-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (6g, 26.4mmol) in dichloromethane (10mL), add trifluoroacetic acid (2mL), and incubate at room temperature React for 2 hours. LC-MS monitored the reaction to be complete. The reaction solution was concentrated to obtain the crude target product (3g).

LC-MS (ESI) [M+H] ⁺ =128.3.

Step 7: 2-chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)-7-((2 Preparation of -(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Dissolve pyrimidin-4-yl)amino)propan-1-ol (2g, 4.71mmol) into dry tetrahydrofuran (20mL), lower to 0°C, add sodium hydrogen (225mg, 9.41mmol, 60%), and stir at 0°C React for 0.5h, then add 2,6-dichloro-3-nitropyridine (908mg, 4.71mmol), and continue the reaction for 2 hours. LC-MS monitored the reaction to be complete. The reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (1.2 g, yield 43%).

LC-MS (ESI) [M+H] ⁺ =581.1.

Step 8: 2-chloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy methyl)propyl)-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Preparation of amines

2-Chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)-7-((2-(trifluoromethyl) Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.2g, 2.06mmol) was dissolved in isopropanol (10mL), and 6- Methoxy-2-azaspiro[3.3]heptane (262 mg, 2.06 mmol) and N,N-diisopropylethylamine (798 mg, 6.18 mmol), reaction stirred at 60°C for 2 hours, LC-MS Monitor response for completeness. The target product (1.2 g, yield 86%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =672.2.

Step 9: N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl]oxy)propyl) -2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Preparation of amines

2-Chloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy)propanyl ( 1.2g, 1.79mmol) was dissolved in ethanol (20mL) and water (4mL), iron powder (501mg, 8.95mmol) and ammonium chloride (957mg, 17.9mmol) were added, and the reaction was carried out at 60°C for 3 hours. LC-MS monitored the reaction to be complete. Filter, concentrate the filtrate, add water and extract with ethyl acetate (100 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude target product (1 g, yield 86%).

LC-MS (ESI) [M+H] ⁺ =642.2.

Step 10: 11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)) Ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][ Preparation of 1]oxa[4,6,10]triazacyclotridecane

N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl]oxy)propyl)-2- Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1g , 1.56mmol) was dissolved in 1,4-dioxane (20mL), and tris(dibenzylideneacetone)dipalladium (142mg, 0.16mmol), 2-bicyclohexylphosphine-2',4', 6'-Triisopropylbiphenyl (148 mg, 0.31 mmol) and cesium carbonate (1.52 g, 4.67 mmol) were reacted at 90°C for 3 hours. LC-MS monitored that the reaction was complete. Column chromatography separated and purified the target product ( 500mg, yield 53%).

LC-MS (ESI) [M+H] ⁺ =606.3.

Step 11: 11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1,5,6,7,8,14- Preparation of hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy )methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxy Hetero[4,6,10]triazacyclotridecane (200 mg, 0.33 mmol) was added to dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added, reacted at room temperature for 1 hour, and concentrated under reduced pressure. , add methanol (5mL), add ammonia water (1mL), and continue the reaction at room temperature for 1 hour. LC-MS detected that the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate (50 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The target product (37.5 mg, yield 23.9%) was obtained through preparative high-performance liquid phase separation and purification. ).

LC-MS (ESI) [M+H] ⁺ =476.2; ¹ H NMR (400MHz, CD ₃ OD): δ7.26-7.21 (m, 2H), 5.91 (d, J = 8.0Hz, 1H), 4.58 -4.57(m,2H),3.92(s,2H),3.87(s,2H),3.86-3.83(m,1H),3.45(t,J＝5.6Hz,2H),3.22(s,3H), 2.54-2.49(m,2H),2.12-2.08(m,2H),1.87-1.85(m,2H).

Example 197

3-Chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge )pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-amine

Dissolve crude 6-methoxy-2-azaspiro[3.3]heptane (3g) in anhydrous DMF at room temperature, then add potassium carbonate (4.15g, 30mmol, 3eq) and 6-chloro-3 in sequence. -Nitropyridin-2-amine (2.38g, 10mmol, 1eq), raise the temperature of the reaction system to 60°C and stir for 3 hours. TLC monitored the reaction to be complete. Cool to room temperature, then add water (50 mL) and ethyl acetate (30 mL) and stir for 10 minutes. Let stand for liquid separation, extract the aqueous phase with ethyl acetate (30mL*2), combine the organic phases, wash with saturated brine three times, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product. (2.3g, yield 87%).

LC-MS (ESI) [M+H] ⁺ =265.1.

Step 2: Preparation of 2-(6-bromo-5-nitropyridin-2-yl)-6-methoxy-2-azaspiro[3.3]heptane

Under nitrogen protection, add 6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-amine (2g, 7.57mmol) and tert-butyl nitrite (936.4 mg, 9.08 mmol, 1.2 eq) was dissolved in CHBr ₃ (20 mL), and the reaction was sealed at 90°C. LC-MS monitored that the reaction was complete, and column chromatography separated and purified the target product (570 mg, yield 23%).

LC-MS (ESI) [M+H] ⁺ =328.0.

Step 3: 2,5-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine-2- Preparation of methyl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

At 0°C, 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino)propan-1-ol (286.2mg, 0.73mmol, 1.2eq) was dissolved in anhydrous tetrahydrofuran, then NaH (29.2mg, 0.73mmol, 1.2eq, 60% content) was added and stirred for 10 minutes. , slowly add 2-(6-bromo-5-nitropyridin-2-yl)-6-methoxy-2-azaspiro[3.3]heptane (200mg, 0.61mmol, 1eq), and increase the reaction temperature Bring to room temperature and continue stirring for 2 hours. TLC monitored the reaction to be complete. Ice water was slowly added dropwise to the reaction solution to quench, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the target product was separated and purified by column chromatography. (372 mg, yield 95%).

LC-MS (ESI) [M+H] ⁺ =638.4.

Step 4: N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl) Preparation of -2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,5-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine-2) at room temperature -(yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (372 mg, 0.58mmol, 1.0eq), iron powder (163.1mg, 2.91mmol, 5.0eq) and ammonium chloride (155.8mg, 2.91mmol, 5.0eq) were dissolved in ethanol/water (20/2mL), and then the reaction system temperature Raise to 60°C and stir for 1 hour. TLC monitored the reaction to be complete, and column chromatography separated and purified the target product (300 m, yield 85%).

LC-MS (ESI) [M+H] ⁺ =608.3.

Step 5: 3-chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl base)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane

Under nitrogen protection, tris(dibenzylideneacetone)dipalladium(0) (45.1 mg, 10%) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (28.2 mg, 12%) was dissolved in anhydrous 1,4-dioxane and stirred for 10 minutes. Then N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl)-2 ,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300mg, 0.49mmol, 1.0 eq) and cesium carbonate (321.2 mg, 0.98 mmol, 2.0 eq) were added to the reaction system to replace nitrogen. The temperature of the reaction system was raised to 100°C, and stirring was continued for 16 hours. LC-MS monitored the reaction to be complete. The target product (160 mg, yield 57%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =572.3.

Step 6: 3-Chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15 Preparation of -(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

At 0°C, 3-chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa [4,6,10] Triazacyclotridecane (160 mg, 0.28 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was slowly added dropwise. After the dropwise addition, The temperature of the reaction system was raised to room temperature and stirring was continued for 2 hours. Then, the solvent and trifluoroacetic acid were concentrated under reduced pressure, ammonia-methanol solution (5 mL) was added, and stirring was continued at room temperature for 1 hour. TLC monitored the reaction to be complete. The target product (26.8 mg, yield 22%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =442.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.04 (d, J = 2.5Hz, 1H), 8.09 (s, 1H), 7.19 ( d,J＝8.0Hz,1H),6.82(d,J＝2.5Hz,1H),6.71(t,J＝6.2Hz,1H),5.84(d,J＝8.0Hz,1H),4.47(s, 2H),3.91-3.74(m,5H),3.30(s,2H),3.12(s,3H),2.48-2.39(m,2H),2.07-1.99(m,2H),1.74(s,2H) .

Example 198

Referring to the preparation method of Example 197, the compound of Example 198 was prepared

Example 199

3-Chloro-11-(2-oxa-7-azaspiro[3.5]non-7-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge) Pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of tert-butyl 3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)carbamate

Dissolve (3-hydroxypropyl) tert-butyl carbamate (7g, 39.95mmol, 1eq) in toluene (60mL), replace with nitrogen three times, and add sodium hydrogen (2.08g, 51.93mmol) to the reaction solution at 0°C. ,1.3eq, purity 60%). React at 0°C for 0.5 hours. Dissolve 2,6-dichloro-3-nitropyridine (9.25g, 47.94mmol, 1.2eq) in toluene (10mL) and slowly add it dropwise to the reaction system. Continue at 25°C. Reaction takes 3.5 hours. After the reaction is detected by LC-MS, slowly pour the reaction system into aqueous ammonium chloride solution (500mL), extract with ethyl acetate (400ml*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate , separated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the target compound (7.7g, yield 58%).

LC-MS (ESI) [M+H] ⁺ =332.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.50 (d, J = 8.4Hz, 1H), 7.33 (d, J = 8.4Hz, 1H),6.89(t,J＝5.2Hz,1H),4.42(t,J＝6.0Hz,2H),3.09(q,J＝6.4Hz,2H),1.86(p,J＝6.4Hz,2H) ,1.35(s,9H).

Step 2: 3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propyl)carbamic acid tert. Preparation of butyl ester

3-((6-Chloro-3-nitropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester (1g, 3.01mmol, 1.0eq), 2-oxa-7-azaspiro [3.5] Nonane (0.46g, 3.62mmol, 1.2eq), TEA (triethylamine) (0.76g, 7.54mmol, 2.5eq) were dissolved in DMF (10mL), and reacted at 80°C for 16 hours. After the reaction is detected by LC-MS, add water (50mL) to the reaction system, extract with ethyl acetate (50mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, then separate using flash chromatography. After purification (silica gel, PE:EA=1:1), the target compound (0.84g, yield 66%) was obtained.

LC-MS (ESI) [M+H] ⁺ =423.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.18 (d, J = 9.2Hz, 1H), 6.87 (s, 1H), 6.55 (d ,J＝9.2Hz,1H),4.39-4.32(m,6H),3.66(s,4H),3.10(q,J＝6.4Hz,2H),1.85(m,J＝4.8Hz,6H),1.37 (s,9H).

Step 3: 3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propan-1-amine preparation

Tert-butyl 3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propyl)carbamate ( 840mg, 1.99mmol, 1eq) was dissolved in 10mL dichloromethane, 3mL trifluoroacetic acid was added to the reaction solution, and the reaction was carried out at 5°C for 2 hours. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated to obtain the crude target compound (640 mg), which is directly used in the next step of the reaction.

LC-MS(ESI)[M+H] ⁺ =323.0.

Step 4: 2,5-dichloro-N-(3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl) )oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)oxy)propan-1-amine (630 mg, 1.95 mmol, 1.0eq), 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (827.2 mg, 2.35mmol, 1.2eq), DIPEA (N,N diisopropylethylamine) (1010.3mg, 7.82mmol, 4eq) dissolved in 10mL isopropyl alcohol, React at 85°C for 4 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the target compound (750 mg, yield 60%).

LC-MS (ESI) [M+H] ⁺ =638.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.23 (d, J = 9.2Hz, 1H), 7.57 (s, 1H), 7.26 ( d,J＝5.6Hz,1H),6.58(d,J＝9.2Hz,1H),5.46(s,2H),4.55(t,J＝6.4Hz,2H),4.39(s,4H),3.74( q,J＝6.4Hz,2H),3.70-3.61(m,4H),3.61-3.53(m,2H),2.18(p,J＝6.4Hz,2H),1.93-1.77(m,4H),0.96 -0.85(m,2H),-0.03(d,J＝20.0Hz,9H).

Step 5: N-(3-((3-amino-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propyl)- Preparation of 2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

At room temperature, in a 50mL reaction bottle, 2,5-dichloro-N-(3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]non-7-yl )pyridin-2-yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Amine (750mg, 1.17mmol, 1.0eq), iron powder (327.8mg, 5.87mmol, 5.0eq), ammonium chloride (408.3mg, 7.63mmol, 6.5eq) were dissolved in 10mL ethanol and 2mL water, and then the system was placed React in an 80°C oil bath for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=1:2) to obtain the target compound (590 mg, yield 83%).

LC-MS (ESI) [M+H] ⁺ =608.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.60 (s, 1H), 7.30 (t, J = 5.6Hz, 1H), 6.91 ( d,J＝8.0Hz,1H),6.20(d,J＝8.0Hz,1H),5.48(s,2H),4.41-4.31(m,6H),4.28-4.15(m,2H),3.72(q ,J＝6.4Hz,2H),3.58(m,J＝5.6Hz,2H),3.24-3.15(m,4H),2.12(p,J＝6.4Hz,2H),1.87-1.77(m,4H) ,0.95-0.86(m,2H),0.04-0.03(m,9H).

Step 6: 3-chloro-11-(2-oxa-7-azaspiro[3.5]non-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4 ,6,10] Preparation of triazacyclotridecane

N-(3-((3-amino-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propyl)-2,5- Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300mg, 0.49mmol, 1.0eq), Pd ₂ (dba) ₃ (22.6mg, 0.02mmol, 0.05eq), Xphos (35.2mg, 0.07mmol, 0.15eq), cesium carbonate (482.0mg, 1.48mmol, 3.0eq) dissolved in 1,4-dioxane In the ring (5 mL), replace the nitrogen three times and then transfer to a 100°C oil bath for reaction for 1 hour. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (100 mg, yield 36%).

LC-MS (ESI) [M+H] ⁺ =572.1.

Step 7: 3-Chloro-11-(2-oxa-7-azaspiro[3.5]non-7-yl)-1,5,6,7,8,14-hexahydro-4,15- Preparation of (nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-11-(2-oxa-7-azaspiro[3.5]non-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 ,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6, 10] Dissolve triazacyclotridecane (50 mg, 0.09 mmol, 1.0 eq) in tetrahydrofuran (1 mL), add TBAF (tetrabutylammonium fluoride) in tetrahydrofuran solution (1 mL), and stir at 65°C for 3 hours. After the reaction is detected by LC-MS, the reaction solution is spin-dried, dissolved in 20 mL of ethyl acetate, washed with saturated brine, and the organic phase is spin-dried. The crude product is separated and purified by Prep-HPLC to obtain the target compound (1.36 mg, yield 3%) .

LC-MS (ESI) [M+H] ⁺ =442.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (d, J = 2.0Hz, 1H), 8.13 (s, 1H), 7.21 ( d,J＝8.4Hz,1H),6.83(d,J＝2.4Hz,1H),6.72(t,J＝6.0Hz,1H),6.29(d,J＝8.4Hz,1H),4.47(s, 2H),4.35(s,4H),3.36(s,4H),3.30(s,2H),1.87-1.79(m,4H),1.75(s,2H).

Example 200

3-Chloro-11-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen Bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 200 was prepared, LC-MS (ESI) [M+H] ⁺ =498.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (d, J= 2.2Hz,1H),8.13(s,1H),7.21(d,J＝8.4Hz,1H),6.83(d,J＝2.4Hz,1H),6.72(t,J＝6.2Hz,1H),6.27 (d,J＝8.4Hz,1H),4.47(s,2H),4.16(d,J＝12.8Hz,2H),2.54-2.50(m,6H),2.38(s,4H),2.33-2.17( m,J＝1.8Hz,1H),2.17(s,3H),1.87-1.71(m,6H),1.40(d,J＝8.6Hz,2H).

Example 201-202

Compounds of Examples 201-202 were prepared with reference to the preparation methods of Examples 194 and 196-197.

Example 203

11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)imidazo[ 4,5-g]pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 203 was prepared, LC-MS (ESI) [M+Na] ⁺ =409.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ12.17 (s, 1H) ,8.12(s,1H),7.68(s,1H),7.50(t,J＝6.4Hz,1H),7.20(d,J＝8.0Hz,1H),5.84(d,J＝8.0Hz,1H) ,4.46(s,2H),3.86(s,2H),3.83-3.73(m,3H),3.26(d,J＝5.6Hz,2H),3.12(s,3H),2.46(m,J＝4.8 Hz,2H),2.07-1.98(m,2H),1.71(s,2H).

Example 204

8-Chloro-N,3-dimethyl-1-(tetrahydro-2H-pyran-3-yl)-1,4,10,11,12,13-hexahydro-5,9-(nitrogen bridge )Pyrazolo[3,4-b][1]oxa[4,6,10]triazatridecane-7-amine

The first step: 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(tetrahydro Preparation of mixtures of -2H-pyran-3-yl)-1H-pyrazoles

3-Methyl-4-nitro-1H-pyrazole (6.22g, 48.96mmol, 1eq), 3-hydroxytetrahydropyran (5g, 48.96mmol, 1eq) and triphenylphosphine (15.4g, 58.75 mmol, 1.2eq) was dissolved in tetrahydrofuran (100mL) and stirred at 0°C for 30 minutes. Then isopropyl azodicarboxylate (11.88g, 58.75mmol, 1.2eq) was added dropwise, and the temperature of the reaction solution was slowly raised to 20°C, and the reaction was carried out for 12 hours. LC-MS monitored the reaction to be complete. The target product (4.75g, yield 46%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =212.2.

Step 2: Preparation of 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole

The 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-( A mixture of tetrahydro-2H-pyran-3-yl)-1H-pyrazole (1.5g, 7.1mmol, 1eq) was dissolved in tetrahydrofuran (100mL), and 1M hexamethyldisilylamine was slowly added under nitrogen protection. A solution of lithium in tetrahydrofuran (14.2mL, 14.2mmol, 2eq) was reacted at -78°C for half an hour. Hexachloroethane (5.04g, 21.3mmol, 3eq) was added and the reaction was carried out at room temperature under nitrogen protection for 2 hours. LC-MS monitored the reaction to be complete. Add 50 mL of ammonia chloride aqueous solution to the reaction solution, concentrate, add ethyl acetate (200 mL*3) for extraction, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain the target product (1g, Yield 57.33%).

LC-MS (ESI) [M+H] ⁺ =246.1.

Step 3: Synthesis of 2,5,6-trichloro-N-methylpyrimidin-4-amine

Dissolve tetrachloropyrimidine (20g, 91.8mmol, 1.0eq) and methylamine hydrochloride (6.2g, 91.8mmol, 1.0eq) in 300ml of DMSO, stir in an ice bath for 10 minutes, and then add triethylamine ( 27.87g, 275.4mmol, 3.0eq) was slowly added dropwise to the above reaction solution, and the reaction system was continued to stir at room temperature for about 3 hours. LC-MS monitored the reaction to be complete. Slowly pour the reaction solution into a stirring ice-water bath, filter with suction, dissolve the filter cake in ethyl acetate (600ml), add a small amount of water (100ml) to wash, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and column layer The target product (14.5g, yield 74.34%) was obtained by analytical separation and purification.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.23 (s, 1H), 2.89 (d, J=4.0Hz, 3H).

Step 4: Synthesis of 3-((2,5-dichloro-6-(methylamino)pyrimidin-4-yl)amino)propan-1-ol

Dissolve 2,5,6-trichloro-N-methylpyrimidin-4-amine (3g, 14.2mmol, 1.0eq) in isopropanol (30mL), add Add 1,8-diazabicyclo[5.4.0]undec-7-ene (6.51g, 42.6mmol, 3.0eq) and 3-amino-1-propanol (1.11g, 14.9mmol, 1.05eq) , react at 90°C for 12 hours. LC-MS monitored the reaction to be complete. The crude target product (2.51g, purity 78.6%) was obtained by column chromatography separation and purification. The target product (0.75g, yield 21.2%) was obtained by reverse phase separation and purification.

LC-MS (ESI) [M+H] ⁺ =251.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ6.960-6.891 (m, 2H), 4.520 (t, J = 4.8Hz, 1H), 3.452-3.423(m,2H),3.352-3.336(m,2H),2.7945(d,J=2.2Hz,3H),1.687-1.621(m,2H).

Step 5: 2,5-dichloro-N ⁴ -methyl-N ⁶ -(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl) Synthesis of -1H-pyrazol-5-yl)oxy)propyl)pyrimidine-4,6-diamine

Dissolve 3-((2,5-dichloro-6-(methylamino)pyrimidin-4-yl)amino)propan-1-ol (100 mg, 0.4 mmol, 1 eq) in tetrahydrofuran (4 mL) under nitrogen protection Cool the temperature to 0°C, add sodium hydrogen (35.04 mg, 0.88 mmol, 60% content, 2.2 eq) and stir for 0.5 hours. Then 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (117.4 mg, 0.48 mmol, 1.2 eq) was dissolved in tetrahydrofuran ( 2 mL), slowly added dropwise to the above reaction system, and reacted at 0°C for 2 hours. LC-MS monitored the reaction to be complete. Anhydrous methanol (2 mL) was added to the system, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (140 mg, yield 76.03%).

LC-MS (ESI) [M+H] ⁺ =459.8.

Step 6: N ⁴ -(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propanyl Synthesis of -2,5-dichloro-N ⁶ -methylpyrimidine-4,6-diamine

Dissolve cuprous chloride (5.16mg, 0.05mmol, 0.2eq) and sodium borohydride (39.45mg, 1.04mmol, 4eq) in tetrahydrofuran (5mL). Under nitrogen protection, 2,5-dichloro-N ⁴ -Methyl-N ⁶ -(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy) Propyl)pyrimidine-4,6-diamine (120 mg, 0.26 mmol, 1 eq) was dissolved in ethanol (5 mL) and then added to the reaction system. Stir at room temperature for 2 hours. LC-MS monitored the reaction to be complete. Filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (60 mg, yield 53.48%).

LC-MS (ESI) [M+H] ⁺ =429.8.

Step 7: 8-Chloro-N,3-dimethyl-1-(tetrahydro-2H-pyran-3-yl)-1,4,10,11,12,13-hexahydro-5,9 Synthesis of -(Nitrogen-bridged)pyrazolo[3,4-b][1]oxa[4,6,10]triazacyclotridecane-7-amine

N ⁴ -(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl)- 2,5-Dichloro-N ⁶ -methylpyrimidine-4,6-diamine (50 mg, 0.12 mmol, 1 eq), tris(dibenzylideneacetone)dipalladium(0) (10.64 mg, 0.01 mmol, 0.1 eq), dicyclohexyl[2',4',6'-tris(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (11.08 mg, 0.02 mmol, 0.2 eq) and cesium carbonate (151.43 mg, 0.46 mmol, 4 eq) were dissolved in dioxane (2 mL), and stirred at 100°C for 1 hour under nitrogen protection. LC-MS monitored the reaction to be complete. Filter through diatomaceous earth, wash the filtrate with ethyl acetate, concentrate the filtrate, and separate and purify by column chromatography to obtain the crude target product, which is then prepared by high-performance liquid phase to obtain the target product (3.75 mg, yield 7.93%).

LC-MS (ESI) [M+H] ⁺ =393.4; ¹ H NMR (400MHz, DMSO-d ₆ ): δ6.66-6.58 (m, 1H), 6.26-6.18 (m, 1H), 4.28-4.03 (m,3H),3.91-3.74(m,2H),3.50-3.37(m,4H),2.83(d,J＝4.8Hz,3H),2.09(s,3H),2.04-1.88(m,2H ),1.82-1.65(s,4H).

Example 205-341

Referring to the preparation methods of Examples 204 and 354, the compounds of Examples 205-341 were prepared.

Example 342

5-Chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-N-methyl-7,8,9,10-tetrahydro-1H-2,6- (Nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazatridecane-4-amine

Step 1: Preparation of 4,5,6-trichloropyrimidin-2-amine

Under nitrogen protection, dissolve 4,6-dichloropyrimidin-2-amine (5g, 30.5mmol, 1eq) in chloroform (20mL), then add NCS (6.11g, 45.7mmol, 1.5eq) at room temperature, and The reaction temperature was raised to 60°C and the reaction was carried out for 16 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (3g, yield 50%).

LC-MS (ESI) [M+H] ⁺ =197.9.

Step 2: Preparation of 5,6-dichloro-N ⁴ -methylpyrimidine-2,4-diamine

Dissolve 4,5,6-trichloropyrimidin-2-amine (3g, 15.1mmol, 1.0eq) and methylamine hydrochloride (1.02g, 15.1mmol, 1.0eq) in DMSO at room temperature, and then slowly drop it Add triethylamine (2.3mL, 22.7mmol, 1.5eq) and react at room temperature for 2 hours. After the LC-MS detection reaction is completed, add water and ethyl acetate and stir for 10 minutes, let stand for liquid separation, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine in sequence, dry over anhydrous sodium sulfate, and filter. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (2.1g, yield 72%).

LC-MS (ESI) [M+H] ⁺ =193.0.

Step 3: Preparation of 3-((2-amino-5-chloro-6-(methylamino)pyrimidin-4-yl)amino)propan-1-ol

At room temperature, 5,6-dichloro-N ⁴ -methylpyrimidine-2,4-diamine (2g, 10.4mmol, 1.0eq) and aminoalcohol (1.17g, 15.5mmol, 1.5eq) were dissolved in DMSO ( 20 mL), then slowly add triethylamine (2.1 g, 20.8 mmol, 2.0 eq), and raise the reaction temperature to 130°C for overnight reaction. After 16 hours, cool to room temperature, then add water and ethyl acetate, stir for 10 minutes, let stand for liquid separation, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine in sequence, dry over anhydrous sodium sulfate, and filter. , after the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=4:1, DCM:MeOH=5:1) to obtain the target compound (1.5g, yield 62%).

LC-MS (ESI) [M+H] ⁺ =232.3.

Step 4: Preparation of 3-((2-bromo-5-chloro-6-(methylamino)pyrimidin-4-yl)amino)propan-1-ol

Under nitrogen protection, add 3-((2-amino-5-chloro-6-(methylamino)pyrimidin-4-yl)amino)propan-1-ol (500mg, 2.15mmol, 1.0eq) and tert-butyl nitrite The ester (265 mg, 2.58 mmol, 1.2 eq) was dissolved in CHBr ₃ (10 mL), and the reaction was sealed at 60°C. After LC-MS detection, the reaction was completed, and after concentration under reduced pressure, reversed-phase column chromatography (75% MeCN) was used to obtain the target compound (35 mg, yield 6%).

LC-MS (ESI) [M+H] ⁺ =295.0.

Step 5: 2-bromo-5-chloro-N ⁴ -(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine- Preparation of 2-yl)oxy)propyl)-N ⁶ -methylpyrimidine-4,6-diamine

Dissolve 3-((2-bromo-5-chloro-6-(methylamino)pyrimidin-4-yl)amino)propan-1-ol (35 mg, 0.11 mmol, 1.0 eq) in anhydrous THF at 0°C (10 mL), then add NaH (3.8 mg, 0.16 mmol, 1.2 eq), and after reacting for 10 minutes, slowly add 2-(6-bromo-5-nitropyridin-2-yl)-6-methoxy- 2-azaspiro[3.3]heptane (37.8 mg, 0.13 mmol, 1.2 eq), then the reaction was raised to room temperature and stirred for 2 hours. After the reaction is detected by LC-MS, ice water is slowly added dropwise to quench the reaction, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and rinsed with rapid The target compound was separated and purified by chromatography (silica gel, DCM:MeOH=20:1) to obtain the target compound (51 mg, yield 88%).

LC-MS (ESI) [M+H] ⁺ =542.2.

Step 6: N ⁴ -(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl Preparation of )-2-bromo-5-chloro-N ⁶ -methylpyrimidine-4,6-diamine

At room temperature, in a 25mL reaction bottle, 2-bromo-5-chloro-N ⁴ -(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl) -3-Nitropyridin-2-yl)oxy)propyl)-N ⁶ -methylpyrimidine-4,6-diamine (51mg, 0.09mmol, 1.0eq), iron powder (26.2mg, 0.47mmol, 5.0eq) and ammonium chloride (25.1mg, 0.47mmol, 5.0eq) were dissolved in EtOH/H ₂ O mixed solvent (10/2mL), and then the temperature of the reaction system was raised to 80°C and stirred for 1 hour. After TLC monitoring, the reaction was completed, filtered through diatomaceous earth, and the filtrate was concentrated, separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1) to obtain the target compound (40 mg, yield 83%).

LC-MS (ESI) [M+H] ⁺ =512.2.

Step 7: 5-chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-N-methyl-7,8,9,10-tetrahydro-1H- Preparation of 2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazatridecane-4-amine

Under nitrogen protection, dissolve Pd ₂ (dba) ₃ (10%) and XPhos (12%) in anhydrous 1,4-dioxane (20 mL) in a 20 mL three-neck reaction flask, and stir for 10 minutes. N ⁴ -(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl]oxy)propyl)-2 -Bromo-5-chloro-N ⁶ -methylpyrimidine-4,6-diamine (35mg, 0.07mmol, 1.0eq) and cesium carbonate (45.5mmol, 0.14mmol, 2.0eq) were added to the reaction system, and then replaced Nitrogen, raise the temperature of the reaction system to 90°C, and continue stirring for 16 hours. After the reaction is detected by LC-MS, the reaction solution is directly concentrated, and separated and purified by flash chromatography (silica gel, PE:EA=2:1, DCM: MeOH=10:1) to obtain the target compound (1.51 mg, yield 5%).

LC-MS (ESI) [M+H] ⁺ =432.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.10 (s, 1H), 7.17 (d, J = 8.1Hz, 1H), 6.40 ( t,J＝6.4Hz,1H),6.14(q,J＝4.5Hz,1H),5.82(d,J＝8.1Hz,1H),4.40(s,2H),3.84(s,2H),3.77( d,J＝13.3Hz,3H),3.17(q,J＝5.9,5.3Hz,2H),3.12(s,3H),2.81(d,J＝4.5Hz,3H),2.46-2.41(m,2H ),2.05-1.99(m,2H),1.67(s,2H).

Examples 343-352

Compounds of Examples 343-352 were prepared with reference to the preparation methods of Examples 204, 342 and 354.

Example 353

5-Chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen-bridged)pyridine And[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Step 1: 2,5-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine-2- Preparation of base)oxy)propyl)pyrimidin-4-amine

Dissolve 3-((2,5-dichloropyrimidin-4-yl)amino)propan-1-ol (162mg, 0.73mmol, 1.2eq) in anhydrous THF at 0°C, then add NaH (18mg, 0.73mmol, 1.2eq), after stirring for 10 minutes, slowly add 2-(6-bromo-5-nitropyridin-2-yl)-6-methoxy-2-azaspiro[3.3]heptane (200mg ,0.62mmol, 1.0eq), then the temperature was raised to room temperature, and the reaction was continued for 2 hours. After TLC monitors that the reaction is complete, ice water is slowly added dropwise to quench the reaction, then the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and subjected to flash chromatography The target compound (260 mg, yield 80%) was obtained by separation and purification (silica gel, DCM:MeOH=10:1).

LC-MS (ESI) [M+H] ⁺ =469.2.

Step 2: N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl) -Preparation of 2,5-dichloropyrimidin-4-amine

At room temperature, in a 50mL reaction bottle, 2,5-dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3 -Nitropyridin-2-yl)oxy)propyl)pyrimidin-4-amine (260mg, 1.0eq), iron powder (5.0eq) and ammonium chloride (5.0eq) were dissolved in EtOH/H ₂ O (20 /2mL), then the temperature was raised to 60°C for 1 hour. After TLC monitoring the reaction is complete, filter through diatomaceous earth. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1) to obtain the target compound (185 mg, yield 76%).

LC-MS (ESI) [M+H] ⁺ =438.2.

Step 3: 5-chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-7,8,9,10-tetrahydro-1H-2,6-( Preparation of nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Under nitrogen protection, dissolve Pd ₂ (dba) ₃ (10%) and XPhos (12%) in anhydrous 1,4-dioxane in a 20 mL reaction bottle, and stir for 10 minutes. After 10 minutes, N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl )-2,5-Dichloropyrimidin-4-amine (180 mg, 1.0 eq) and cesium carbonate (2.0 eq) were added to the reaction system, and then nitrogen was replaced. The temperature was raised to 100°C and the reaction was continued for 16 hours. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=2:1, DCM:MeOH=10:1) to obtain the target compound (22.3 mg, yield 13%) ).

LC-MS (ESI) [M+H] ⁺ =403.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.58 (s, 1H), 7.78 (s, 1H), 7.31 (t, J = 6.1 Hz,1H),7.20(d,J＝8.1Hz,1H),5.85(d,J＝8.1Hz,1H),4.54-4.29(m,2H),3.85(s,2H),3.78(d,J ＝13.1Hz,3H),3.22(d,J＝5.7Hz,2H),3.11(s,3H),2.44(dt,J＝6.6,3.0Hz,2H),2.05-1.98(m,2H),1.71 (s,2H).

Example 354

13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6- (nitrogen bridge)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)propan-1-ol

Dissolve 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2g, 9.22mmol, 1eq) in isopropanol (20mL), and add 3-amino-1-propanol (20mL) at 0°C. 831mg, 11.06mmol, 1.2eq). The reaction was carried out at 0° C. for half an hour and at room temperature for 16 hours. The target product (700 mg, yield 29%) was separated and purified by column chromatography.

LC-MS (ESI) [M+H] ⁺ =256.0.

Step 2: 2-Chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)pyrimidin-4-amine preparation

Dissolve 3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)propan-1-ol (1.5g, 5.87mmol, 1eq) in THF (20mL) at 0°C Add sodium hydrogen (60%) (211mg, 1.17mmol, 1.5eq) at 0°C for 0.5 hours. Add 2,6-dichloro-3-nitropyridine (1.36g, 7.04mmol, 1.2eq). The reaction was carried out at room temperature for 0.5 hours, and LC-MS monitored that the reaction was complete. The reaction solution was quenched with water, concentrated, extracted with ethyl acetate (100mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (1.2g, yield 49.6%).

LC-MS (ESI) [M+H] ⁺ =412.0.

Step 3: 2-Chloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy Preparation of methyl)propyl)-5-(trifluoromethyl)pyrimidin-4-amine

2-Chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)pyrimidin-4-amine (1.3g, 3.15mmol, 1eq) was dissolved in isopropyl alcohol (20mL), add N,N-diisopropylethylamine (1.22g, 9.46mmol, 3eq), add 6-methoxy-2-azaspiro [3.3 ] Heptane (401 mg, 3.15 mmol, 1.2 eq) was reacted at 0°C for 2 hours. LC-MS monitored the reaction to be complete. The target product (260 mg, yield 16.39%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =503.1.

Step 4: 13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H- Preparation of 2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

2-Chloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy)propanyl (200 mg, 0.4 mmol, 1 eq) was dissolved in ethanol (20 mL), and a saturated solution of iron powder (111 mg, 1.99 mmol, 5 eq) and ammonium chloride was added. (4 mL) and stirred at 100°C for 6 hours. LC-MS monitored the reaction to be complete. Filter, concentrate the filtrate, add water (50mL), extract with ethyl acetate (100mL*3), wash the organic phase with brine twice, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and obtain the target through preparative high-performance liquid phase separation and purification. Product (32 mg, yield 18.33%).

LC-MS (ESI) [M+H] ⁺ =437.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.03 (s, 1H), 8.06 (s, 1H), 7.32 (t, J = 5.8 Hz,1H),7.23(d,J＝8.4Hz,1H),5.87(d,J＝8.0Hz,1H),4.43(s,2H),3.87(s,2H),3.79(s,2H), 3.80-3.75(m,1H),3.30-3.25(m,2H),3.12(s,3H),2.48-2.43(m,2H),2.08-1.99(m,2H),1.73(s,2H).

Examples 355-356

Referring to the preparation method of Example 354, compounds of Examples 355-356 were prepared:

Example 357

13-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-chloro-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge) Pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 354, the compound of Example 357 was prepared, LC-MS (ESI) [M+H] ⁺ =375.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.57 (s, 1H) ,7.79(s,1H),7.31(q,J＝5.9Hz,1H),7.22(d,J＝8.2Hz,1H),6.02(d,J＝8.2Hz,1H),4.73(s,1H) ,4.62(d,J＝2.4Hz,1H),4.44(s,2H),3.77(d,J＝7.2Hz,1H),3.66(d,J＝7.2Hz,1H),3.24-3.16(m, 4H),1.93-1.79(m,2H),1.73(s,2H).

Examples 358-426

Referring to the preparation methods of Examples 353 and 354, compounds of Examples 358-376 and 378-426 were prepared: Referring to the preparation methods of Example 194, the compound of Example 377 was prepared.

Example 427

5-Chloro-14-fluoro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-7,8,9,10-tetrahydro-1H-2,6-( Nitrogen bridge) benzo[b][1]oxa[4,6,10]triazacyclotridecane

The first step: Preparation of: (3-(5-bromo-4-fluoro-2-nitrophenoxy)propyl)carbamic acid tert-butyl ester

Dissolve (3-hydroxypropyl)carbamic acid tert-butyl ester (1.77g, 10.1mmol, 1.2eq) in anhydrous THF at 0°C, then add NaH (302mg, 12.6mmol, 1.5eq), and react for 10 minutes Afterwards, 1-bromo-2,5-difluoro-4-nitrobenzene (2g, 8.4mmol, 1.0eq) was slowly added, and then the reaction was continued for 2 hours after rising to room temperature. After the reaction is detected by LC-MS, ice water is slowly added dropwise to quench the reaction, then the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and used After separation and purification by flash chromatography (silica gel, PE:EA=4:1), the target compound (3g, yield 91%) was obtained.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.09 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 5.8 Hz, 1H), 6.86 (t, J =5.7Hz, 1H), 4.18 (t, J = 6.1Hz, 2H), 3.06 (q, J = 6.5Hz, 2H), 1.81 (p, J = 6.4Hz, 2H), 1.36 (s, 9H).

Step 2: tert-butyl (3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrophenoxy)propyl) Preparation of urethane

Under nitrogen protection, put (3-(5-bromo-4-fluoro-2-nitrophenoxy)propyl)carbamic acid tert-butyl ester (2.5g, 6.4mmol, 1.0eq) in a 50mL three-neck reaction flask. , 6-methoxy-2-azaspiro[3.3]heptane (970.3mg, 7.6mmol, 1.2eq), cesium carbonate (4.1g, 12.7mmol, 2.0eq) and Pd-XPhos-G3 (10%) Dissolve in anhydrous dioxane (50 mL), replace nitrogen, raise the temperature of the reaction system to 100°C, and continue the reaction for 16 hours. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=4:1, DCM:MeOH=20:1) to obtain the target compound (1.5g, yield 54%) ).

LC-MS(ESI)[M-99]=340.2.

Step 3: 2,5-dichloro-N-(3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrobenzene Preparation of oxy)propyl)pyrimidin-4-amine

At room temperature, in a 50 mL reaction bottle, add tert-butyl (3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrobenzene Oxy)propyl)carbamate (880mg, 2mmol, 1.0eq) was dissolved in dichloromethane, then TFA (3v/w) was slowly added dropwise and the reaction continued for 10 minutes. Concentrate under reduced pressure to remove TFA and methylene chloride, and use them directly in the next step. The residue (678 mg) was dissolved in isopropanol (20 mL), triethylamine (3.0 eq) was slowly added dropwise at 0°C, and the reaction was carried out for 10 minutes. Then add 2,4,5-trichloropyrimidine (607 mg, 6 mmol, 1.2 eq), raise the temperature of the reaction system to 90°C, and continue the reaction for 16 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=4:1) to obtain the target compound (610 mg, yield 63%).

LC-MS (ESI) [M+H] ⁺ =486.2.

Step 4: N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)phenoxy)propyl)-2 , Preparation of 5-dichloropyrimidin-4-amine

At room temperature, in a 50mL reaction bottle, 2,5-dichloro-N-(3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl )-2-Nitrophenoxy)propyl)pyrimidin-4-amine (300mg, 0.62mmol, 1.0eq), iron powder (172mg, 3.1mmol, 5.0eq) and ammonium chloride (165mg, 3.1mmol, 5.0 eq) was dissolved in EtOH/H ₂ O (10/2 mL), and then the system was heated to 90°C and reacted for 2 hours. After the reaction was detected by LC-MS, filter through diatomaceous earth, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1) to obtain the target compound (254 mg, yield 90%).

LC-MS (ESI) [M+H] ⁺ =455.3.

Step 5: 5-chloro-14-fluoro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-7,8,9,10-tetrahydro-1H-2 , Preparation of 6-(nitrogen-bridged)benzo[b][1]oxa[4,6,10]triazacyclotridecane:

Under nitrogen protection, in a 20mL microwave reaction bottle, N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzene Oxy)propyl)-2,5-dichloropyrimidin-4-amine (190 mg, 0.42 mmol, 1 eq), Pd ₂ (dba) ₃ (10%), XPhos (12%) and cesium carbonate (273 mg, 0.84 mmol, 2.0 eq) was added to anhydrous 1,4-dioxane (10 mL), and nitrogen was replaced three times. Raise the temperature of the reaction system to 100°C and react under microwave reaction conditions for 4 hours. After the reaction is detected by LC-MS, water and ethyl acetate are added for extraction. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and subjected to flash chromatography. The target compound (26.48 mg, yield 15%) was obtained by separation and purification method (silica gel, PE:EA=4:1, DCM:MeOH=10:1).

LC-MS (ESI) [M+H] ⁺ =420.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.60 (s, 1H), 7.79 (s, 1H), 7.36 (t, J = 6.0 Hz,1H),6.73(d,J＝13.4Hz,1H),6.10(d,J＝8.8Hz,1H),4.13(t,J＝4.4Hz,2H),3.86-3.72(m,5H), 3.30-3.25(m,2H),3.12(s,3H),2.48-2.41(m,2H),2.05-1.98(m,2H),1.71(s,2H).

Examples 428-430

Referring to the preparation method of Example 354 or 427, the compounds of Examples 428-430 were prepared.

Example 431

5-Chloro-14-fluoro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-N-methyl-7,8,9,10-tetrahydro-1H- 2,6-(Nitrogen-bridged)benzo[b][1]oxa[4,6,10]triazacyclotridecane-4-amine

Referring to the preparation method of Example 427, the compound of Example 431 was prepared, LC-MS (ESI) [M+H] ⁺ =449.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.11 (s, 1H) ,6.71(d,J＝13.6Hz,1H),6.50(t,J＝6.0Hz,1H),6.15(d,J＝4.4Hz,1H),6.06(d,J＝8.8Hz,1H),4.10 (s,2H),3.82(s,2H),3.77(s,2H),3.22(d,J＝5.2Hz,2H),3.12(s,3H),2.81(d,J＝4.6Hz,3H) ,2.45(m,3H),2.06-1.98(m,2H),1.66(s,2H).

Examples 432-438

Compounds of Examples 432-438 were prepared with reference to the preparation methods of Example 342, 354 or 427.

Example 439

12-Methyl-10-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-5,6,7,8,10,13-hexahydro-1H-4,14 -(nitrogen-bridged)pyrazolo[2,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

LC-MS (ESI) [M+H] ⁺ =212.2.

The 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-( A mixture of tetrahydro-2H-pyran-3-yl)-1H-pyrazole (1.5g, 7.1mmol, 1eq) was dissolved in tetrahydrofuran (100mL), nitrogen Slowly add 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (14.2mL, 14.2mmol, 2eq) under protection, react at -78°C for half an hour, then add hexachloroethane (5.04g, 21.3mmol, 3eq) ), react at room temperature for 2 hours under nitrogen protection. LC-MS monitored the reaction to be complete. Add 50 mL of ammonia chloride aqueous solution to the reaction solution, concentrate, add ethyl acetate (200 mL*3) for extraction, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (1g , yield 57.33%).

LC-MS (ESI) [M+H] ⁺ =246.1.

Step 3: 2-chloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl) Oxy)propyl)-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 4-amine

3-((2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino)propan-1-ol (800mg, 1.88mmol, 1.0eq) was dissolved in dry tetrahydrofuran (20mL), lowered to 0°C, and sodium hydrogen (68mg, 2.82mmol, 1.5eq) was added, 0 React at ℃ for 0.5h. Then add 5-chloro-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole (462mg, 1.88mmol, 1.5eq) and continue the reaction for 2 hours . LC-MS monitored the reaction to be complete. Add water (50 mL) to the reaction solution to quench, extract with ethyl acetate (100 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (700 mg, yield 58%).

LC-MS (ESI) [M+H] ⁺ =634.2.

Step 4: N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl )-2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Preparation of amines

2-Chloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy) Propyl)-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (750 mg, 1.18 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (2 mL), iron powder (330 mg, 5.91 mmol) and ammonium chloride (632 mg, 11.83 mmol) were added, and the reaction was carried out at 60°C for 3 hours. LC-MS monitored the reaction to be complete. Filtration, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, separation and purification by column chromatography to obtain the target product (400 mg, yield 66%).

LC-MS (ESI) [M+H] ⁺ =604.2.

Step 5: 12-methyl-10-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl))ethoxy )methyl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][ Preparation of 1]oxa[4,6,10]triazacyclotridecane

N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2 -Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine( 400 mg, 0.66 mmol) was dissolved in 1,4-dioxane (20 mL), and tris(dibenzylideneacetone)dipalladium (60 mg, 0.07 mmol), 2-bicyclohexylphosphine-2',4' was added , 6'-triisopropylbiphenyl (62 mg, 0.13 mmol) and cesium carbonate (647 mg, 1.99 mmol) were reacted at 90°C for 3 hours, and LC-MS monitored that the reaction was complete. The target product (150 mg, yield 40%) was obtained by column chromatography separation and purification.

LC-MS (ESI) [M+H] ⁺ =568.3.

Step 6: 12-methyl-10-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-5,6,7,8,10,13-hexahydro-1H Preparation of -4,14-(nitrogen-bridged)pyrazolo[2,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Add 12-methyl-10-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)) to a 50mL single-neck bottle Ethoxy)methyl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3- g][1]oxa[4,6,10]triazacyclotridecane (130 mg, 0.23 mmol), then add concentrated hydrochloric acid (1 mL), react at room temperature for 1 hour, concentrate under reduced pressure to remove the hydrochloric acid, and add methanol (5mL), then add ammonia water (1mL), and continue the reaction at room temperature for 1 hour. LC-MS monitored the reaction to be complete. The reaction solution was concentrated, and the target product (22 mg, yield 21%) was obtained through preparative high-performance liquid phase separation and purification.

LC-MS (ESI) [M+H] ⁺ =438.2; ¹ H NMR (400MHz, CD ₃ OD): δ7.26-7.25 (m, 1H), 4.32-4.26 (m, 3H), 3.94-3.87 ( m,2H),3.76-3.70(m,2H),3.60(t,J＝10.8,1H),3.43-3.38(m,1H),2.20(s,3H),2.15-1.94(m,4H), 1.83-1.79(m,2H).

Example 440

2-(3-Chloro-12-methyl-1,5,6,7,8,13-hexahydro-10H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[ 2,3-g][1]oxa[4,6,10]triazacyclotridec-10-yl)-2-methylpropionitrile

Step 1: Preparation of methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionate

Dissolve 3-methyl-4-nitro-1H-pyrazole (6g, 47.21mmol, 1.0eq) in dimethylformamide (50mL), add sodium hydrogen (3.4g, 85mmol, purity 60%) at 0°C ,1.8eq), reaction time is 0.5 hours. Slowly add 2-bromo-2-methylpropionic acid methyl ester (12.82g, 70.81mmol, 1.5eq) into the reaction system, and continue the reaction at 10°C for 5 hours. After the LC-MS detection reaction is completed, add water (20mL) and extract with ethyl acetate (50mL*3). The organic phases were combined, concentrated, washed with lithium chloride solution (10%), and separated and purified by flash chromatography (silica gel, PE:EA=2:1) to obtain the target compound (3.3g, yield 31%).

LC-MS (ESI) [M+H] ⁺ =228.0; ¹ H NMR (400MHz, CDCl ₃ ): δ8.28 (s, 1H), 3.73 (s, 3H), 2.52 (s, 3H), 1.84 ( s,6H).

Step 2: Preparation of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionic acid

Dissolve methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionate (6.1g, 26.85mmol, 1.0eq) in tetrahydrofuran (30mL)/water (6mL) mixed solvent, add lithium hydroxide monohydrate (3.38g, 80.54mmol, 3.0eq) to the system, and react at 10°C for 16 hours. After the LC-MS detection reaction is completed, add water and adjust the acidity to pH 1-2 with dilute hydrochloric acid (2mol/L). Extract with ethyl acetate (50 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude target compound (5.3 g, 24.86 mmol, yield 92.6%).

LC-MS (ESI) [M+H] ⁺ =214.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.95 (s, 1H), 2.45 (s, 3H), 1.77 (s, 6H).

Step 3: Preparation of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionamide

Dissolve 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionic acid (2.5g, 11.73mmol, 1.0eq) in dichloromethane (10mL), N,N-dimethylformamide (0.1 mL) was added dropwise, and oxalyl chloride (4.47 g, 35.18 mmol, 3.0 eq) was added. Under nitrogen protection, react at 0°C for 3 hours. After TLC detects that the reaction is complete, the reaction solution is concentrated, the residue is dissolved in tetrahydrofuran (10 ml), and ammonia water (10 ml) is slowly added. Continue stirring for 1 hour. After LC-MS detection, the reaction was completed, extracted with dichloromethane, and the organic phase was concentrated to obtain the target product (2 g, yield 81%).

LC-MS (ESI) [M+H] ⁺ =213.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.83 (s, 1H), 7.32 (s, 2H), 2.426 (s, 3H), 1.74(s,6H).

Step 4: Preparation of 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionitrile

Dissolve 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionamide (6.5g, 30.63mmol, 1.0eq) in phosphorus oxychloride (15mL) . React at 90°C for 1 hour. After the LC-MS detection reaction is completed, the reaction solution is concentrated, water is slowly added to the reaction solution, extracted with ethyl acetate (100 mL*3), the organic phases are combined, and concentrated to obtain the crude target compound (4.2 g, yield 71%).

LC-MS (ESI) [M+H] ⁺ =195.2; ¹ H NMR (400MHz, CDCl ₃ ): δ8.39 (s, 1H), 2.57 (s, 3H), 2.01 (s, 6H).

Step 5: Preparation of 2-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)-2-methylpropionitrile

Dissolve 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionitrile (4.2g, 21.63mmol, 1.0eq) in tetrahydrofuran (10mL), -78 ℃ under nitrogen atmosphere, add HMDSLi (108.1ml, 108.14mmol, 5.0eq) to the reaction system. React at a low temperature of -78°C for half an hour, and slowly add hexachloroethane (15.36g, 64.88mmol, 3.0eq) to the reaction system. The reaction was continued for two hours at 10°C. After the LC-MS detection reaction is completed, add water (20mL) and extract with ethyl acetate (50mL*3). The organic phases were combined, concentrated, and separated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the target compound (3g, yield 61%).

LC-MS (ESI) [M+H] ⁺ =229.0; ¹ H NMR (400MHz, CDCl ₃ ): δ2.54 (s, 3H), 2.07 (s, 6H).

Step 6: Preparation of 2-(5-(3-aminopropoxy)-3-methyl-4-nitro-1H-pyrazol-1-yl)-2-methylpropionitrile

Dissolve N-(3-hydroxypropyl)carbamic acid tert-butyl ester (337.32mg, 1.93mmol, 1.1eq) in N,N-dimethylformamide (10ml, 100.0%), and then batch it under ice bath Add sodium hydride (60%, 210mg, 5.25mmol, 3.0eq), react in an ice bath under nitrogen protection for half an hour, and then add 2-(5-chloro-3-methyl-4-nitro-1H-pyrazole) -1-yl)-2-methylpropionitrile (400 mg, 1.75 mmol, 1.0 eq), after replacing nitrogen, reacted at 25°C for 16 hours. After the LC-MS detection reaction is completed, add ice water (10mL) dropwise to the reaction solution, extract with ethyl acetate (20mL), wash with saturated brine (20mL*3), concentrate the organic phase, and the crude product is separated by preparative TLC (PE :EA=2:1) to obtain the target compound (90 mg, yield 19%).

LC-MS (ESI) [M+H] ⁺ =268.2.

Step 7: 2-(5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)amino)propoxy)-3-methyl-4-nitro-1H-pyrazol-1-yl)-2-methylpropionitrile

Take a single-neck bottle and add 2-(5-(3-aminopropoxy)-3-methyl-4-nitro-1H-pyrazol-1-yl)-2-methylpropionitrile (200 mg, 0.75 mmol, 1.1eq) was dissolved in N,N-dimethylformamide (8ml, 100.0%), then sodium hydride (60%, 53.88mg, 2.24mmol, 3.0eq) was added in batches under ice bath, under nitrogen protection Continue the reaction in the ice bath for half an hour, then add 2,4,5-trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 -d]pyrimidine (263.93 mg, 0.75 mmol, 1 eq), after replacing nitrogen, react at 20°C for 3 hours. After the TLC detection reaction is completed, add ice water (10mL) dropwise to the reaction solution, extract with ethyl acetate (15mL*3), wash with saturated brine (10mL*2), concentrate the organic phase, and the crude product is separated by preparative TLC (PE :EA=2:1) to obtain the target compound (150 mg, yield 34%).

¹ H NMR (400MHz, CDCl ₃ ): δ7.14 (s, 1H), 5.54 (s, 2H), 4.64 (t, J = 6.0Hz, 2H), 4.44 (s, 2H), 3.58-3.53 (m ,2H),3.52(s,1H),2.55(s,3H),2.37-2.28(m,2H),1.64(s,6H),0.97-0.93(m,2H),-0.00(d,J＝ 3.2Hz,9H).

Step 8: 2-(4-amino-5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo Preparation of [2,3-d]pyrimidin-4-yl)amino)propoxy)-3-methyl-1H-pyrazol-1-yl)-2-methylpropionitrile

2-(5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino)propoxy)-3-methyl-4-nitro-1H-pyrazol-1-yl)-2-methylpropionitrile (150mg, 0.25mmol, 1.0eq) was dissolved in Ethanol (10 mL)/water (2 mL) mixed solvent. Iron powder (69.73 mg, 1.25 mmol, 5.0 eq) and ammonium chloride (80.16 mg, 1.5 mmol, 6.0 eq) were added to the reaction system, and the temperature was raised to 75°C for 2 hours. After the reaction was detected by LC-MS, filter, concentrate the filtrate, wash with saturated brine, combine the organic phases, and concentrate to obtain the crude target compound (130 mg, yield 91%).

LC-MS (ESI) [M+H] ⁺ =553.2.

Step 9: 2-(3-chloro-12-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,13-hexane Hydrogen-10H-4,14-(nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane Preparation of -10-yl)-2-methylpropionitrile

2-(4-Amino-5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)propoxy)-3-methyl-1H-pyrazol-1-yl)-2-methylpropionitrile (130 mg, 0.23 mmol, 1.0 eq) was dissolved in di Oxygen 6 ring (5mL), add tris(dibenzylideneacetone)dipalladium(0) (21.51mg, 0.02mmol, 0.1eq), dicyclohexyl [2',4',6'-triiso Propyl-[1,1'-biphenyl]-2-yl]phosphine (22.39 mg, 0.05 mmol, 0.2 eq), cesium carbonate (229.55 mg, 0.7 mmol, 3.0 eq). The temperature was raised to 90°C for 3 hours in a nitrogen atmosphere. After LC-MS detection, the reaction was completed, filtered through diatomaceous earth, and the filtrate was concentrated. The crude product was separated by preparative TLC (DCM:MeOH=15:1) to obtain the target compound (40 mg, yield 33%).

LC-MS (ESI) [M+H] ⁺ =517.2; ¹ H NMR (400MHz, CDCl ₃ ): δ6.82 (s, 1H), 6.13 (s, 1H), 5.40 (s, 2H), 5.23- 5.17(m,1H),4.20-4.16(m,1H),4.13-4.05(m,1H),3.90-3.85(m,1H),3.60-3.48(m,3H),2.86-2.82(m,1H ), 2.28 (s, 3H), 1.93-1.87 (m, 1H), 1.62 (d, J = 6.4Hz, 6H), 0.96-0.92 (m, 2H), -0.02 (s, 9H).

Step 10: 2-(3-chloro-12-methyl-1,5,6,7,8,13-hexahydro-10H-4,14-(nitrogen bridge)pyrazolo[3,4-b Preparation of ]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane-10-yl)-2-methylpropionitrile

2-(3-Chloro-12-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,13-hexahydro-10H -4,14-(Nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclodecane-10- (40 mg, 0.08 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. React at room temperature for 1 hour. After the LC-MS detection reaction is completed, spin the solvent to dryness, add tetrahydrofuran (2 mL) to redissolve, add ammonia water (1.5 mL) to the reaction system, and continue the reaction at room temperature for 1 hour. After the reaction was detected by LC-MS, the solvent was spin-dried and separated and purified by Prep-HPLC to obtain the target compound (9.21 mg, yield 31%).

LC-MS (ESI) [M+H] ⁺ =387.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.42 (d, J = 2.0Hz, 1H), 8.41 (s, 1H), 7.05 ( d,J＝2.4Hz,1H),5.09-5.03(m,1H),4.08-4.04(m,1H),3.82-3.67(m,2H),2.77(s,1H),2.13(s,3H) ,1.68-1.59(m,1H),1.47(d,J＝4.4Hz,6H),1.24(s,1H).

Example 441

12-Methyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[ 3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 1 or 439, the compound of Example 441 was prepared, LC-MS (ESI) [M+H] ⁺ =370.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.73 (s, 1H),7.54-7.52(m,1H),7.01(s,1H),6.74-6.69(m,1H),6.31-6.30(m,1H),4.23-4.21(m,2H),4.16-4.13( m,1H),3.85-3.80(m,2H),3.52-3.41(m,4H),2.11(s,3H),2.11-1.71(m,6H).

Example 442

3-Chloro-12-methyl-10-(tetrahydrofuran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[3, 4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 1 or 439, the compound of Example 442 was prepared, LC-MS (ESI) [M+H] ⁺ =390.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.04 (s, 1H),7.30(s,1H),6.88(s,1H),6.83(t,J＝5.4Hz,1H),4.93-4.91(m,1H),4.20-4.18(m,2H),4.00-3.90 (m,2H),3.83-3.76(m,1H),3.70-3.68(m, 1H),3.57-3.55(m,2H),2.24-2.16(m,2H),2.12(s,3H),1.84-1.82(m,2H).

Example 443

3-Chloro-10-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-12-methyl-5,6,7,8,10,13-hexahydro -1H-4,14-(Nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of tert-butyl 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

At 0°C, 3-methyl-4-nitro-1H-pyrazole (0.99g, 7.8mmol, 1.0eq) and 3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.71g ,7.8mmol, 1.0eq) and triphenylphosphine (2.25g, 8.68mmol, 1.1eq) were dissolved in anhydrous THF (30mL), and then diisopropyl azodicarboxylate (2.52g, 12.48mmol, 1.6eq), after the dropwise addition is completed, increase the reaction temperature to room temperature and continue the reaction overnight. TLC monitors that the substrate reaction is incomplete. Ice water is slowly added dropwise to quench the reaction. Then the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and used After separation and purification by flash chromatography (silica gel, PE:EA=10:1), the target compound (2.1 g, yield 82%) was obtained.

LC-MS(ESI)[M-55]=273.2.

Step 2: Preparation of 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine

At room temperature, under nitrogen protection, in a 100 mL reaction bottle, add 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester ( 5.1g, 15.53mmol, 1.0eq) was dissolved in dichloromethane (5v/w), then TFA (8.8mL, 77.65mmol, 5.0eq) was slowly added dropwise, and then reacted at room temperature. After the TLC detection reaction is completed, the reaction solution is concentrated to obtain the crude target compound, which is directly used in the next step.

Step 3: Preparation of 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)-1-(oxetan-3-yl)piperidine

At room temperature, 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine (2.13g, 9.33mmol, 1.0eq) and 3-oxetanone were mixed (1.68g, 23.32mmol, 2.5eq) was dissolved in DCE (30mL), and then DIPEA (1.81g, 14mmol, 1.5eq) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued at room temperature for 20 minutes. After the TLC detection reaction is completed, slowly add sodium triacetylborohydride (3.95g, 18.66mmol, 2.0eq) and glacial acetic acid (0.6g, 10.26mmol, 1.1eq), and continue the reaction at room temperature for 2 hours. After the reaction is detected by LC-MS, ice water is added dropwise to quench the reaction, and the aqueous phase is extracted with DCM. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated by flash chromatography. The target compound (2.09g, yield 79%) was obtained after purification.

LC-MS (ESI) [M+H] ⁺ =285.2.

Step 4: 4-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine preparation

Under nitrogen protection, at -78°C, add 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazole-1-) into a 100mL three-neck reaction bottle. (2.09 g, 7.35 mmol, 1.0 eq) and THF (30 mL). Then, HMDSLi (8.82 mmol, 1.2 eq) was slowly added dropwise, maintaining the system temperature without an obvious increase, and continuing the reaction for 30 minutes. Then C ₂ Cl ₆ (3.48g, 14.7mmol, 2.0eq) was slowly added. After the addition was completed, the temperature of the system was raised to room temperature and stirring continued. After TLC detects that the reaction is complete, slowly add ice water dropwise to quench the reaction, add ethyl acetate, continue stirring for 10 minutes, and let stand for liquid separation. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=2:1) to obtain Target compound (1.2g, yield 51%).

From the fifth step to the eighth step, refer to the preparation method of Example 1 or 439 to prepare the compound of Example 443.

LC-MS (ESI) [M+H] ⁺ =477.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.09 (s, 1H), 7.35 (s, 1H), 6.89 (d, J = 2.4 Hz,2H),4.86(dtd,J＝49.7,9.7,4.9Hz,1H),4.56(td,J＝6.5,1.9Hz,2H),4.46(dt,J＝12.7,6.1Hz,2H),4.19 (ddt,J＝18.4,8.4,3.9Hz,3H),3.69-3.49(m,3H),3.16(s,1H),2.74(s,1H),2.15(s,3H),2.12-1.94(m ,3H),1.91-1.70(m,3H).

Example 444

3-Chloro-12-methyl-10-(tetrahydro-2H-pyran-4-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge) Pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 1 or 439, the compound of Example 444 was prepared, LC-MS (ESI) [M+H] ⁺ =404.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.02 (s, 1H),7.25(s,1H),6.88(s,1H),6.82(t,J＝5.4Hz,1H),4.31-4.25(m,1H),4.21(t,J＝5.2Hz,2H), 3.96-3.90(m,2H),3.60-3.56(m,2H),3.49-3.43(m,2H),2.12(s,3H),2.03-1.90(m,2H),1.88-1.79(m,2H ),1.73-1.69(m,2H).

Example 445

3-Chloro-6,12-dimethyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-( Nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 1 or 439, the compound of Example 445 was prepared, LC-MS (ESI) [M+H] ⁺ =418.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.09 (s, 1H),7.36(d,J＝4.0Hz,1H),6.93-6.90(m,1H),5.77(t,J＝6.0Hz,1H),4.50-4.36(m,1H),4.32-4.22(m ,1H),4.19-3.99(m,2H),3.91-3.74(m,2H),3.54-3.38(m,2H),2.10(s,3H),2.09-1.87(m,3H),1.80-1.62 (m,3H),1.34(d,J=6.9Hz,3H).

Example 446

3-Chloro-7,12-dimethyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-( Nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 1 or 439, the compound of Example 446 was prepared, LC-MS (ESI) [M+H] ⁺ =418.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.03 (s, 1H),7.23(s,1H),6.89(d,J＝2.4Hz,1H),6.78-6.58(m,1H),4.18-4.01(m,2H),4.00-3.58(m,4H),3.49 -3.39(m,3H),2.11(s,3H),2.05-1.95(m,3H),1.81-1.62(m,2H),0.97(dd,J＝7.2,4.4Hz,3H).

Example 447

3-Chloro-12-methyl-10-(3-morpholinecyclobutyl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[ 3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 3-(benzyloxy)cyclobutan-1-ol

Dissolve 3-(benzyloxy)cyclobutan-1-one (6.5g, 36.89mmol, 1.0eq) in methanol (40mL), stir at 0°C, and slowly add sodium borohydride (2.79g, 73.78mmol) ,2.0eq), react for 1 hour. After the reaction is detected by LC-MS, pour the reaction solution into water (50mL), extract with ethyl acetate (20mL*3), wash with saturated sodium chloride aqueous solution, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate Afterwards, it was separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (6.5g, yield 100%).

LC-MS (ESI) [M+H] ⁺ =179.1.

Step 2: Preparation of 1-(3-(benzyloxy)cyclobutyl)-3-methyl-4-nitro-1H-pyrazole

Dissolve triphenylphosphine (14.35g, 54.7mmol, 1.5eq) in tetrahydrofuran (150mL), and react at 0°C for 10 minutes. Then isopropyl azodicarboxylate (11.06g, 54.7mmol, 1.5eq) was added dropwise, the reaction solution was reacted at 0°C for 15 minutes, and then 3-methyl-4-nitro-1H-pyrazole (4.64g) was added , 36.47mmol, 1.0eq), after reacting for 15 minutes, add 3-(benzyloxy)cyclobutan-1-ol (6.5g, 36.47mmol, 1.0eq). The temperature of the reaction solution was slowly raised to 25°C for 12 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (10 g, yield 95%).

LC-MS (ESI) [M+H] ⁺ =288.1.

Step 3: Preparation of 1-(3-(benzyloxy)cyclobutyl)-5-chloro-3-methyl-4-nitro-1H-pyrazole

1-(3-(Benzyloxy)cyclobutyl)-3-methyl-4-nitro-1H-pyrazole (6.0g, 20.88mmol, 1.0eq) was dissolved in tetrahydrofuran (150mL) at -78°C React for 15 minutes, then add lithium bis(trimethylsilyl)amide (42mL, 42.0mmol, 2.0eq), React for 30 minutes. Hexachloroethane (9.89g, 42.0mmol, 2.0eq) was then added, and the reaction solution was reacted at -78°C for 2 hours. After the LC-MS detection reaction is completed, the reaction solution is quenched with saturated aqueous ammonium chloride solution, poured into water (100mL), extracted with ethyl acetate (30mL*3), combined organic phases, washed with saturated aqueous sodium chloride solution, and the organic phase is Combine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, then separate and purify using flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (4.48g, yield 67%).

LC-MS (ESI) [M+H] ⁺ =322.0.

Step 4: Preparation of 3-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-ol

Dissolve 1-(3-(benzyloxy)cyclobutyl)-5-chloro-3-methyl-4-nitro-1H-pyrazole (4.23g, 13.15mmol) in anhydrous dichloromethane (50mL )middle. In a nitrogen atmosphere at 0°C, add boron trichloride (25 mL, 25 mmol, 1 M, 1.9 eq) and react for 1 hour. After the LC-MS detection reaction is completed, the reaction solution is washed with saturated sodium bicarbonate aqueous solution and saturated brine, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (silica gel, PE :EA=2:1) to obtain the target compound (2.97g, yield 98%).

LC-MS (ESI) [M+H] ⁺ =232.0.

Step 5: Preparation of 3-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-one

Dissolve 3-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-ol (2.97g, 12.82mmol) in dichloromethane (50mL). Dess-Martin reagent (10.88g, 25.64mmol) was added at room temperature and reacted for 1 hour. After the LC-MS detection reaction is completed, the reaction solution is washed with saturated sodium bicarbonate aqueous solution and saturated brine, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (silica gel, PE :EA=3:1) to obtain the target compound (2.64g, yield 90%).

LC-MS (ESI) [M+H] ⁺ =230.1.

Step 6: Preparation of 4-(3-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutyl)morpholine

3-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutan-1-one (2.64g, 11.5mmol), morpholine (3g, 34.49 mmol) and acetic acid (1.04 g, 17.25 mmol) were dissolved in dichloromethane (30 mL). After reacting at 0°C for 30 minutes, sodium cyanoborohydride (1.42g, 22.99mmol) was added, and the reaction was continued for 1 hour. After the reaction was detected by LC-MS, the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL) and brine (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography ( Silica gel, PE:EA=1:1), the target compound (2.81g, yield 81%) was obtained.

LC-MS (ESI) [M+H] ⁺ =301.1.

From the seventh step to the tenth step, refer to the preparation method of Example 1 or 439 to prepare the compound of Example 447, LC-MS (ESI) [M+H] ⁺ = 459.2; ¹ H NMR (400MHz, DMSO-d ₆ ) :δ11.03(s,1H),7.28(s,1H),6.88(s,1H),6.81(t,J＝5.4Hz,1H),4.54-4.40(m,1H),4.16(t,J ＝4.8Hz,2H),3.63-3.56(m,4H),3.56-3.51(m,2H),2.44-2.38(m,3H),2.29-2.17(m,6H),2.13(s,3H), 1.89-1.78(m,2H).

Example 448

3-Chloro-12-methyl-10-(3-morpholinecyclopentyl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[ 3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 439 or 447, the compound of Example 448 was prepared, LC-MS (ESI) [M+H] ⁺ = 473.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.02 (d, J＝2.0Hz,1H),7.24(s,1H),6.87(d,J＝2.4Hz,1H),6.80(d,J＝5.6Hz,1H),4.70-4.56(m,1H),4.18( s,2H),3.57-3.56(d,J＝4.0Hz,6H),2.57-2.56(d,J＝7.9Hz,1H),2.40(s,3H),2.11(s,4H),1.83(s ,7H),1.70-1.62(m,1H).

Example 449

3-Chloro-10-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-12-methyl-5,6,7,8,10,13-hexahydro-1H-4 ,14-(Nitrogen-bridged)pyrazole And[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 2,6-dimethyltetrahydro-2H-pyran-4-ol

Dissolve 2,6-dimethyl-4H-pyran-4-one (10g, 80.55mmol) in ethanol (100mL), add palladium on carbon (1.0g), and react at 40°C and 50psi of hydrogen for 16 Hour. After the reaction was detected by LC-MS, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude target compound (10 g).

LC-MS (ESI) [M+H] ⁺ =153.1.

Step 2: Preparation of 1-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methyl-4-nitro-1H-pyrazole

Dissolve triphenylphosphine (30.9g, 118.02mmol, 1.5eq) into tetrahydrofuran (150mL), and add diisopropyl azodicarboxylate (23.8g, 118.02mmol, 1.5eq) and 3-methyl at 0°C. Base-4-nitro-1H-pyrazole (10g, 78.68mmol, 1.0eq), 2,6-dimethyltetrahydro-2H-pyran-4-ol (10.2g, 78.68mmol, 1.0eq), React at room temperature for 12 hours. After the reaction is detected by LC-MS, add water (200mL) to the reaction solution, extract with ethyl acetate (200mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, use flash chromatography After separation and purification (silica gel, PE:EA=1:1), the target compound (15g) was obtained.

LC-MS (ESI) [M+H] ⁺ =240.2.

Step 3: Preparation of 5-chloro-1-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methyl-4-nitro-1H-pyrazole

Dissolve 1-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-3-methyl-4-nitro-1H-pyrazole (15g, 62.69mmol) in tetrahydrofuran (100mL ), add lithium bis(trimethylsilyl)amide (1M, 94mL) at -78°C, react at -78°C for 0.5 hours, add hexachloroethane (22g, 94.03mmol), and continue the reaction at room temperature. 2 hours. After the reaction is detected by LC-MS, add water (100mL) to the reaction solution, extract with ethyl acetate (200mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, and use flash chromatography After separation and purification (silica gel, PE:EA=5:1), the target compound (3 g, three-step yield 13%) was obtained.

LC-MS (ESI) [M+H] ⁺ =274.0.

From the fourth step to the seventh step, refer to the preparation method of Example 1 or 439 to prepare the compound of Example 449. LC-MS (ESI) [M+H] ⁺ = 432.1; ¹ H NMR (400MHz, CD ₃ OD): δ6.71(s,1H),4.66-4.60(m,1H),4.28-4.24(m,4H),3.72-3.70(m,2H),2.19(s,3H),1.96-1.92(m,4H ), 1.68-1.60 (m, 2H), 1.13 (d, J = 6.0Hz, 6H).

Example 450

Referring to the preparation method of Example 439 or 446, the compound of Example 450 was prepared.

Example 451

3,7,7-Trifluoro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14 -(Nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 1 or 439, the compound of Example 451 was prepared, LC-MS (ESI) [M+H] ⁺ =424.1; ¹ H NMR (400MHz, CD ₃ OD): δ6.54-6.53 (m ,1H),4.59-4.21(m,5H),3.94-3.91(m,2H),3.61-3.59(m,1H),3.42-3.86(m,1H),2.19(s,3H),2.07-2.03 (m,2H),1.82(br s,2H).

Example 452

3-Chloro-10-(2,2-difluorocyclopropyl)-12-methyl-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazole And[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 3-methyl-4-nitro-1-vinyl-1H-pyrazole

Dissolve 3-methyl-4-nitro-1H-pyrazole (10g, 78.68mmol, 1.0eq) and benzyltriethylammonium chloride (1.79g, 7.87mmol, 0.1eq) in dichloroethane ( 50 mL) and 50% NaOH aqueous solution (17.5 g, 440 mmol), the reaction was heated to 80°C and maintained for 6 hours. After the reaction was detected by LC-MS, the reaction solution was filtered. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (11.55g, yield 96%).

LC-MS (ESI) [M+H] ⁺ =154.1.

Step 2: Preparation of 5-chloro-3-methyl-4-nitro-1-vinyl-1H-pyrazole

Dissolve 3-methyl-4-nitro-1-vinyl-1H-pyrazole (5g, 32.65mmol, 1.0eq) in tetrahydrofuran (50mL), and react at -78°C for 15 minutes. Then add lithium bis(trimethylsilyl)amide (65.3mL, 65.3mmol, 2.0eq), react for 30 minutes, then add hexachloroethane (15.46g, 65.3mmol, 2.0eq), and incubate at -78°C Reaction takes 1 hour. After the reaction is detected by LC-MS, the reaction solution is quenched with saturated ammonium chloride aqueous solution, poured into water (50mL), extracted with ethyl acetate (30mL*3), the organic phases are combined, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (954 mg, yield 16%).

LC-MS (ESI) [M+H] ⁺ =188.0.

Step 3: Preparation of 5-chloro-1-(2,2-difluorocyclopropyl)-3-methyl-4-nitro-1H-pyrazole

Dissolve 5-chloro-3-methyl-4-nitro-1-vinyl-1H-pyrazole (950mg, 5.06mmol, 1.0eq) and sodium fluoride (22mg, 0.51mmol, 0.1eq) in benzoic acid Methyl ester (5 mL), heated to 110°C under nitrogen protection. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid trimethylsilyl ester (5.07g, 20.24mmol, 4.0eq) was slowly added dropwise to the reaction solution and reacted for 20 minutes. After the reaction is detected by LC-MS, pour the reaction solution into water (30mL), extract with ethyl acetate (15mL*3), wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate Afterwards, the product was separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (880 mg, yield 73%).

LC-MS (ESI) [M+H] ⁺ =238.0.

From the fourth step to the seventh step, refer to the preparation method of Example 1 or 439 to prepare the compound of Example 452, LC-MS (ESI) [M+H] ⁺ =396.1; ¹ H NMR (400MHz, DMSO-d ₆ ) : δ11.16(s,1H),7.58(s,1H),6.99(s,1H),6.91(d,J＝2.2Hz,1H),4.36-4.24(m,2H),4.18(dd,J =16.0,8.6Hz,1H),3.65-3.52(m,2H),2.28-2.19(m,2H),2.11(s,3H),1.91-1.82(m,2H).

Example 453

5-Chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-9,10-dihydro-1H,8H-2,6-(nitrogen-bridged)pyrido[ 2,3-b][1,10]dioxa[4,6]diazacyclotridecane

Step 1: Preparation of 2,5-dichloro-4-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propoxy)pyrimidine:

Dissolve 3-((2,5-dichloropyrimidin-4-yl)oxy)propan-1-ol (2g, 8.97mmol, 1.0eq) in anhydrous THF (50mL) at 0°C under nitrogen protection. , then add NaH (322.8mg, 13.5mmol, 1.5eq), stir for 10 minutes, slowly add 2,6-dichloro-3-nitropyridine (2.25g, 11.7mmol, 1.3eq), and then increase the reaction temperature Continue stirring at room temperature for 2 hours. After the substrate reaction is complete, slowly add ice water dropwise to quench the reaction, then extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine in sequence, dry over anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain a crude product. Column chromatography (DCM:MeOH＝ 100:1), the target compound (2.3g, yield 68%) was obtained.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.62 (s, 1H), 8.49 (dd, J = 8.6, 6.1Hz, 1H), 7.33 (d, J = 8.3Hz, 1H), 4.61 (td ,J＝6.1,3.2Hz,4H),2.29(p,J＝6.1Hz,2H).

Step 2: 2-(6-(3-((2,5-dichloropyrimidin-4-yl)oxy)propoxy)-5-nitropyridin-2-yl)-6-methoxy Preparation of -2-azaspiro[3.3]heptane:

Dissolve 6-methoxy-2-azaspiro[3.3]heptane trifluoroacetate (330.7mg, 2.6mmol, 1.3eq) in DMF (30mL) at room temperature, and then slowly add potassium carbonate (828mg ,6mmol,3eq), stir for 20 minutes. After 20 minutes, 2,5-dichloro-4-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propoxy)pyrimidine (760mg, 2mmol, 1eq) was added. After completion, the temperature of the reaction system was raised to 50°C and stirred for 16 hours. After the substrate reaction is complete, filter through diatomaceous earth. The filtrate is extracted with ethyl acetate and water. The organic phases are combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure to obtain a crude product. Column layer. After analysis (DCM:MeOH=100:1), the target compound (416 mg, yield 44%) was obtained.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.63 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 5.95 ( d, J = 9.0 Hz, 1H), 4.62 ( t, J ＝6.1Hz,2H),4.55(t,J＝6.1Hz,2H),4.10(s,2H),4.05(s,2H),3.78(p,J＝6.8Hz,1H),3.13(s,3H ),2.51-2.47(m,2H),2.26(p,J＝6.2Hz,2H),2.12-2.03(m,2H).

Step 3: 2-(3-((2,5-Dichloropyrimidin-4-yl)oxy)propoxy)-6-(6-methoxy-2-azaspiro[3.3]hept- Preparation of 2-yl)pyridin-3-amine:

At room temperature, in a 50 mL reaction bottle, 2-(6-(3-((2,5-dichloropyrimidin-4-yl)oxy)propoxy)-5-nitropyridin-2-yl )-6-methoxy-2-azaspiro[3.3]heptane (380mg, 0.81mmol, 1.0eq), iron powder (0.23g, 4.1mmol, 5.0eq) and ammonium chloride (0.22g, 4.1mmol ,5.0eq) was dissolved in EtOH/H ₂ O (10/2mL), and then the temperature of the reaction system was raised to 80°C and stirred for 2h. After TLC monitoring of complete reaction, filter through diatomaceous earth, and concentrate the organic phase under reduced pressure to obtain crude product. The crude product was subjected to column chromatography (DCM:MeOH=10:1) to obtain the target compound (355 mg, yield 100%).

LC-MS(ESI)[M+H] ⁺ =440.3.

Step 4: 5-chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-9,10-dihydro-1H,8H-2,6-(nitrogen bridge ) Preparation of pyrido[2,3-b][1,10]dioxa[4,6]diazacyclotridecane:

Under nitrogen protection, dissolve Pd ₂ (dba) ₃ (10%) and XPhos (12%) in anhydrous dioxane (30 mL) in a 50 mL three-neck reaction flask, and stir at room temperature for 0.5 hours. After 0.5 hours, 2-(6-(3-((2,5-dichloropyrimidin-4-yl)oxy)propoxy)-5-nitropyridin-2-yl)-6-methoxy Base-2-azaspiro[3.3]heptane (350 mg, 0.79 mmol, 1 eq) and cesium carbonate (513.5 mg, 1.58 mmol, 2.0 eq) were added to the reaction solution, and then nitrogen was replaced. The temperature of the reaction system was raised to 90°C, and stirring was continued for 16 hours. After the reaction is complete, the organic phase is concentrated under reduced pressure, and column chromatography is performed with petroleum ether: ethyl acetate (8:1 to 4:1), DCM: MeOH (10:1) to obtain the target compound (7 mg, yield 2%) .

LC-MS (ESI) [M+1] ⁺ =404.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.18 (s, 1H), 8.16 (s, 1H), 7.25 (d, J = 8.2 Hz,1H),5.90(d,J＝8.2Hz,1H),4.49(s,2H),4.41(t,J＝5.1Hz,2H),3.89(s,2H),3.83(s,2H), 3.78(t,J＝6.8Hz,1H),3.12(s,3H),2.47-2.42(m,2H),2.07-2.00(m,2H),1.89(s,2H).

Example 454

3-Chloro-11-(tetrahydro-2H-pyran-3-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo [2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of: (E)-N’-(dihydro-2H-pyran-3(4H)-ylidene)-4-methoxybenzenesulfonylhydrazide

Dissolve dihydro-2H-pyran-3(4H)-one (1.0g, 10mmol, 1.0eq) in anhydrous MeOH (15mL) in a 50mL reaction bottle at room temperature, and then add 4-methoxy Benzenesulfonyl hydrazide (2.02g, 10mmol, 1.0eq) was reacted for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated to obtain the crude target compound (2.8 g, yield 89%, purity 90%).

LC-MS (ESI) [M+H] ⁺ =284.7.

Step 2: N-(3-(5-bromo-2-nitrophenoxy)propyl)-2,5-dichloro-7-(2-(trimethylsilyl)ethoxy)methyl Preparation of 7H-pyrrolo[2,3-d]pyrimidin-4-amine

Under nitrogen protection, at 0°C, in a 250 mL reaction bottle, 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)propan-1-ol (4g, 10.22mmol, 1.0eq) was dissolved in anhydrous THF (60mL), and then NaH (1.64g, 40.88mmol, 4.0 eq), react for 30 minutes. Then add 4-bromo-2-fluoro-1-nitrobenzene (2.7g, 12.26mmol, 1.2eq), and then react at 0°C for 2 hours. After the reaction is detected by LC-MS, the reaction solution is slowly dropped into methanol at 0°C for quenching, the organic phase is concentrated under reduced pressure, and separated and purified by flash chromatography (silica gel, PE:EA=9:1) to obtain the target compound. (5g, yield 83%).

LC-MS (ESI) [M+H] ⁺ =592.0.

Step 3: (3-(3-(2,5-dichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine Preparation of -4-yl)amino)propoxy)-4-nitrophenyl)boronic acid

N-(3-(5-bromo-2-nitrophenoxy)propyl)-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl) -7H-pyrrolo[2,3-d]pyrimidin-4-amine (3g, 5.07mmol, 1.0eq), B ₂ Pin ₂ (pinacol diborate) (1.5g, 6.09mmol, 1.2eq), Pd(dppf)Cl ₂ ((1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride) (372mg, 0.5mmol, 0.1eq) and potassium acetate (1.5g, 15.22mmol, 3eq ) was dissolved in 40 mL of anhydrous 1,4-dioxane, replaced with nitrogen, and reacted overnight at 80°C. After the LC-MS detection reaction is completed, add water to dilute the reaction solution, extract with ethyl acetate (50mL*3), combine the organic phases, concentrate in vacuum, and use a C18 reverse-phase column (H ₂ O/CH ₃ CN = 75%) to separate and purify. , the target compound (1.5g, yield 53%) was obtained.

LC-MS (ESI) [M+H] ⁺ =556.1.

Step 4: 2,5-dichloro-N-(3-(2-nitro-5-(tetrahydro-2H-pyran-3-yl)phenoxy)propyl)-7-(2- Preparation of (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(3-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino)propoxy)-4-nitrophenyl)boronic acid (500mg, 0.9mmol, 1eq) and (E)-N'-(dihydro-2H-pyran-3(4H)-ylidene) 1,4-methoxybenzenesulfonylhydrazide (767 mg, 2.7 mmol, 3 eq) was dissolved in 10 mL of 1,4-dioxane, cesium carbonate (878 mg, 2.7 mmol, 3 eq) was added, and the mixture was heated at 100°C Reaction was allowed to take place overnight. After the reaction was detected by LC-MS, it was filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (150 mg, yield 30%).

LC-MS (ESI) [M+H] ⁺ =596.2.

Step 5: N-(3-(2-amino-5-(tetrahydro-2H-pyran-3-yl)phenoxy)propyl)-2,5-dichloro-7-(2-( trimethylsilyl) Preparation of ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,5-Dichloro-N-(3-(2-nitro-5-(tetrahydro-2H-pyran-3-yl)phenoxy)propyl)-7-(2-(trimethyl A mixed solution of silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200mg, 0.34mmol, 1eq) dissolved in ethanol (5mL) and water (1mL) , add iron powder (94mg, 1.68mmol, 5eq) and ammonium chloride (108mg, 2.01mmol, 6eq) in sequence, and react at 80°C for 2 hours. After the reaction was detected by LC-MS, it was filtered and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (120 mg, yield 47%) with a purity of 75%.

LC-MS (ESI) [M+H] ⁺ =566.2; ¹ H NMR (400MHz, CDCl ₃ ): δ6.95 (s, 1H), 6.79-6.56 (m, 3H), 6.18 (t, J = 5.6 Hz,1H),5.46(s,2H),4.16(t,J＝6.0Hz,2H),4.02-3.91(m,2H),3.86(dd,J＝12.8,6.4Hz,2H),3.53(dd ,J＝10.8,5.6Hz,2H),3.43(m,J＝11.2,2.8Hz,1H),3.32(t,J＝11.2Hz,1H),2.74(t,J＝4.0Hz,1H),2.22 (p,J=6.4Hz,2H),2.04-1.97(m,1H),1.78-1.60(m,4H),0.95-0.90(m,2H),-0.02(s,9H).

Step 6: 3-chloro-11-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6 ,7,8,14-hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclohexane Preparation of alkanes

N-(3-(2-amino-5-(tetrahydro-2H-pyran-3-yl)phenoxy)propyl)-2,5-dichloro-7-(2-(trimethyl) Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90mg, 0.16mmol, 1eq), Xphos Pd G3 (14mg, 0.02mmol, 0.1eq) and carbonic acid Cesium (155 mg, 0.48 mmol, 3 eq) was dissolved in 1,4-dioxane (4 mL), replaced with nitrogen, and the reaction solution was placed in a microwave reactor and reacted at 100°C for 2 hours. After the reaction was detected by LC-MS, it was filtered, and the filtrate was concentrated and separated and purified by preparative TLC to obtain the target compound (40 mg, 47.5%).

LC-MS (ESI) [M+H] ⁺ =530.2.

Step 7: 3-Chloro-11-(tetrahydro-2H-pyran-3-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[ Preparation of b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-11-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7, 8,14-Hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane (40mg ,0.08mmol, 1eq) was dissolved in dichloromethane (3mL), trifluoroacetic acid (1mL) was added, and the reaction was carried out at room temperature for 5 hours. After the reaction was detected by LC-MS, the reaction solution was concentrated, redissolved in tetrahydrofuran (3 mL), ammonia water (2 mL) was added, and the reaction was carried out at room temperature overnight. After the reaction was detected by LC-MS, the reaction solution was concentrated and separated and purified by Prep-HPLC to obtain the target compound (6.8 mg, yield 23%).

LC-MS(ESI)[M+H] ⁺ =400.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.08 (s, 1H), 8.36 (s, 1H), 7.01-6.75 (m, 4H ),6.70(d,J＝8.0Hz,1H),4.29-4.11(m,2H),3.85(dd,J＝15.6,12.0Hz,2H),3.38(d,J＝10.8Hz,2H),3.29 (d,J＝11.2Hz,2H),2.77-2.63(m,1H),1.92(d,J＝11.8Hz,1H),1.80-1.58(m,5H).

Example 455

3-Chloro-12-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15 -(Nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

The first step: N-(3-(5-bromo-4-fluoro-2-nitrophenoxy)propyl)-2,5-dichloro-7-(2-(trimethylsilyl)ethyl) Preparation of oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Under nitrogen protection, 3-[(2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]propan-1-ol (4g, 10.22mmol, 1.0eq) was dissolved in tetrahydrofuran (40mL). The system was lowered to 0°C, and then sodium hydride (1.23g, 30.66mmol, 3.02eq) was slowly added. , react at 0°C for 0.5 hours. Dissolve 1-bromo-2,5-difluoro-4-nitrobenzene (2.92g, 12.26mmol, 1.2eq) in tetrahydrofuran (10mL), and slowly drop it into the reaction solution. After the dropwise addition is completed, react at 0°C 2 Hour. After the reaction is detected by LC-MS, methanol (50 mL) is added dropwise to the system to quench it, filtered through diatomaceous earth, and the filtrate is concentrated and separated and purified by flash chromatography (silica gel, PE:EA=9:1) to obtain the target compound. (5.5g, yield 88%).

LC-MS (ESI) [M+H] ⁺ =607.9; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.16 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 6.0 Hz, 1H),7.57(s,1H),7.32(t,J＝6.0Hz,1H),5.46(s,2H),4.34(t,J＝6.0Hz,2H),3.71(m,2H),3.61- 3.53(m,2H),2.15(p,J＝6.4Hz,2H),0.95-0.86(m,2H),-0.00(s,9H).

Step 2: 2,5-dichloro-N-(3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrobenzene Preparation of oxy)propyl)-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Under nitrogen protection, N-(3-(5-bromo-4-fluoro-2-nitrophenoxy)propyl)-2,5-dichloro-7-(2-(trimethylsilyl)ethyl) Oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.16 mmol, 1.0 eq), 6-methoxy-2-azaspiro[3.3]heptane Trifluoroacetate (36.63mg, 0.16mmol, 1.0eq), 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)) (13.89 mg, 0.02mmol, 0.1eq), cesium carbonate (213.88mg, 0.66mmol, 4.0eq) was dissolved in 1,4-dioxane (4mL) and reacted at 100°C for 18 hours. After the reaction was detected by LC-MS, filter through diatomaceous earth, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=85:15) to obtain the target compound (25 mg, yield 23%).

LC-MS (ESI) [M+H] ⁺ =655.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.83 (d, J = 12.8Hz, 1H), 7.58 (s, 1H), 7.30 ( t,J＝6.0Hz,1H),6.11(d,J＝7.6Hz,1H),5.47(s,2H),4.26(t,J＝6.0Hz,2H),4.18(d,J＝25.6Hz, 4H),3.83(m,1H),3.74(m,2H),3.61-3.53(m,2H),3.19(s,3H),2.20-2.07(m,4H),1.35(m,2H),0.93 -0.88(m,2H),-0.00(s,9H).

Step 3: N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)phenoxy)propyl)-2 , Preparation of 5-dichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,5-Dichloro-N-(3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrophenoxy) Propyl)-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (180mg, 0.27mmol, 1.0eq), Reduced iron powder (76.65 mg, 1.37 mmol, 5.0 eq) and ammonium chloride (88.11 mg, 1.65 mmol, 6.0 eq) were added to ethanol/water = 5/1 mixed solvent (10 mL), and the reaction was carried out at 80°C for 3 hours. After the reaction was detected by LC-MS, it was filtered through diatomaceous earth. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=72:28) to obtain the target compound (157 mg, yield 91%).

LC-MS (ESI) [M+H] ⁺ =625.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.59 (s, 1H), 7.32 (s, 1H), 6.46 (d, J = 13.6 Hz,1H),6.10(d,J＝8.4Hz,1H),5.47(s,2H),4.44(s,2H),4.04(s,2H),3.82(s,1H),3.77-3.67(m ,6H),3.61-3.53(m,2H),3.19(s,3H),2.52-2.44(m,2H),2.09(d,J＝21.6Hz,4H),0.95-0.86(m,2H), 0.02-0.02(m,9H).

Step 4: 3-chloro-12-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethyl)ethyl Oxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane

Under nitrogen protection, N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)phenoxy)propyl)- 2,5-Dichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (140mg, 0.22mmol, 1.0 eq), tris(dibenzylideneacetone)dipalladium (10.25mg, 0.01mmol, 0.05eq), dicyclohexyl[2',4',6'-triisopropyl-[1,1'-biphenyl ]-2-yl]phosphine (16 mg, 0.03 mmol, 0.15 eq) and cesium carbonate (218.75 mg, 0.67 mmol, 3.0 eq) were dissolved in 1,4-dioxane (5 mL) and reacted at 90°C for 18 hours. After the LC-MS detection reaction is completed, filter through diatomaceous earth. After the filtrate is concentrated, it is separated and purified by flash chromatography (silica gel, PE:EA=65:35) to obtain the target compound (55 mg, purity 75%, yield 32%) .

LC-MS (ESI) [M+H] ⁺ =589.4; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.41 (s, 1H), 7.10 (s, 1H), 6.96 (t, J = 6.0 Hz,1H),6.77(d,J＝13.2Hz,1H),6.15(d,J＝8.8Hz,1H),5.36(s,2H),4.21(s,2H),3.91-3.80(m,5H ),3.58-3.52(m,2H),3.43(d,J＝5.2Hz,2H),3.17(s,3H),2.53-2.47(m,2H),2.10-2.04(m,2H),1.79( s,2H),0.91-0.86(m,3H),-0.00(s,9H).

Step 5: 3-Chloro-12-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydrogen Preparation of -4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotriene

3-Chloro-12-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1]oxa[4,6 ,10] Triazacyclotridecane (55 mg, purity 75%, 0.07 mmol, 1.0 eq) was dissolved in trifluoroacetic acid/dichloromethane=1/1 mixed solvent (4 mL), and reacted at room temperature for 2 hours. After the reaction is detected by LC-MS, the reaction solution is concentrated directly, the crude product is dissolved in ammonia/tetrahydrofuran=1/1 mixed solvent (4 mL), and stirred at room temperature for 1 hour. After LC-MS detection, the reaction was completed, filtered through diatomaceous earth, and the filtrate was concentrated and separated and purified by thin-layer preparative chromatography (silica gel, DCM:MeOH=20:1) to obtain the target compound (18 mg, yield 56%).

LC-MS (ESI) [M+H] ⁺ =459.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (s, 1H), 8.13 (s, 1H), 6.83 (d, J = 2.4 Hz,1H),6.78(s,1H),6.72(d,J＝13.2Hz,1H),6.10(d,J＝8.8Hz,1H),4.15(s,2H),3.79(m,5H), 3.37(d,J=5.2Hz,2H),3.12(s,3H),2.47-2.42(m,2H),2.06-1.98(m,2H),1.73(s,2H).

Example 456

3-Chloro-10-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15 -(Nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 455, the compound of Example 456 was prepared, LC-MS (ESI) [M+H] ⁺ =459.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (d, J＝2.0Hz,1H),8.15(s,1H),6.85(t,J＝5.6Hz,2H),6.68(d,J＝7.2Hz,1H),6.07(t,J＝9.2Hz,1H) ,4.26(s,2H),3.79(m,J＝16.4,9.2Hz,5H),3.39(m,J＝10.8,5.6Hz,2H),3.12(s,3H),2.45(m,J＝6.8 ,2.8Hz,2H),2.06-1.97(m,2H),1.75(s,2H).

Example 457

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1,5,6,7,8,14-hexahydro-4, 15-(Nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 455, the compound of Example 457 was prepared, LC-MS (ESI) [M+H] ⁺ = 430.8; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.05 (d, J＝2.4Hz,1H),8.15(s,1H),6.89-6.73(m,3H), 6.35(d,J＝8.8Hz,1H),4.51(d,J＝29.6Hz,2H),4.24-4.10(m,2H),3.84(d,J＝7.6Hz,1H),3.75(d,J =6.8Hz,1H),3.62-3.52(m,1H),3.41-3.35(m,2H),3.08-2.99(m,1H),1.92-1.66(m,4H).

Example 458

12-Fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge )benzo[b]imidazo[4,5-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 427, the compound of Example 457 was prepared, LC-MS (ESI) [M+H] ⁺ = 425.9; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.19 (s, 1H),8.18(s,1H),7.71(s,1H),7.61(s,1H),6.73(d,J＝13.6Hz,1H),6.10(d,J＝8.8Hz,1H),4.32- 4.04(m,2H),3.87-3.73(m,5H),3.12(s,3H),2.49-2.42(m,4H),2.09-1.94(m,2H),1.72(s,2H).

Example 459

2-(5-Chloro-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4,6,10]triazacycloten Tricarbon 13-yl)-2-methylpropionitrile

Step 1: Preparation of tert-butyl 2-(3-bromo-4-nitrophenyl)-2-cyanoacetate

Dissolve 2-bromo-4-fluoro-1-nitrobenzene (1g, 4.55mmol, 1.0eq) and potassium carbonate (1.88g, 13.65mmol, 3.0eq) in THF (30mL) at room temperature, and then add 2 -tert-butyl cyanoacetate (0.96g, 6.82mmol, 1.5eq), react at 60°C for 12 hours. After the TLC detection reaction is completed, filter through diatomaceous earth, add water and ethyl acetate to the filtrate, stir, let stand for liquid separation, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine in sequence, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and then separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (1.2g, yield 77%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.20-8.04(m,1H),8.00-7.92(m,1H),7.77-7.60(m,1H),5.80(s,1H),1.42( s,9H).

Step 2: Preparation of 2-(3-bromo-4-nitrophenyl)acetonitrile

Dissolve 2-(3-bromo-4-nitrophenyl)-2-cyanoacetic acid tert-butyl ester (1.2g, 3.52mmol, 1.0eq) in DMSO (10mL) at room temperature, and add LiCl (1.49 g, 35.2mmol, 10.0eq) and water (1mL), reacted at 150°C. After the TLC detection reaction is completed, cool to room temperature, then add water and EA, stir for 0.5 hours, let stand for liquid separation, extract the aqueous phase with ethyl acetate, combine the organic phases, wash twice with saturated brine, and anhydrous sulfuric acid After drying over sodium, filtering, and concentrating the filtrate, it was separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (800 mg, yield 94%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.08(d,J＝8.3Hz,1H),7.92(d,J＝1.8Hz,1H),7.63(dt,J＝8.2,1.2Hz,1H ),4.21(s,2H).

Step 3: Preparation of 2-(3-bromo-4-nitrophenyl)-2-methylpropionitrile

Dissolve 2-(3-bromo-4-nitrophenyl)acetonitrile (800mg, 3.32mmol, 1.0eq) in anhydrous THF (20mL) at 25°C, then add NaH (0.24g, 10mmol, 3eq) , after stirring for 10 minutes, Mel (1.41g, 10mmol, 3eq) was slowly added dropwise, and the reaction was carried out at room temperature overnight. After the LC-MS detection reaction is completed, add water and ethyl acetate, stir for 10 minutes, let stand for liquid separation, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and filter. , after the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=4:1) to obtain the target compound (517 mg, yield 58%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.11 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H ),1.74(s,6H).

Steps 4 to 6 refer to the preparation method of Example 130 or 354 to prepare the compound of Example 459, LC-MS (ESI) [M+H] ⁺ =344.2; ¹ H NMR (400MHz, DMSO-d ₆ ) :δ8.56(d,J＝9.0Hz,1H),8.40(s,1H),8.33(s,1H),7.86(s,1H),6.50(d,J＝9.0Hz,1H),4.40( t, J＝5.3Hz, 2H), 3.81 (q, J＝6.9Hz, 2H), 2.09 (d, J＝8.4Hz, 2H), 1.60 (s, 6H).

Example 460

(5-Chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4,6, 10]Triazacyclotridecane-13-yl)(morpholinyl)methanone

Step 1: Preparation of 3-((2,5-dichloropyrimidin-4-yl)amino)butan-1-ol

Dissolve 2,4,5-trichloropyrimidine (400 mg, 4.36 mol, 1.0 eq) in isopropyl alcohol (10 mL), and add diisopropylethylamine (1.13 g, 8.72 mol, 2.0 eq). 3-Aminobutanol (428 mg, 4.8 mmol, 1.1 eq) was added dropwise at 0°C and reacted for 0.5 hours. After the reaction is detected by LC-MS, pour the reaction solution into water and extract with ethyl acetate. The organic phase is dried with anhydrous sodium sulfate and filtered. After the filtrate is concentrated, it is separated and purified by flash chromatography (silica gel, PE:EA=5 :1), the target compound (800 mg, yield 77%) was obtained.

LC-MS (ESI) [M+H] ⁺ =236.1.

Step 2: Preparation of methyl 5-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-2-fluoro-4-nitrobenzoate

Dissolve 3-((2,5-dichloropyrimidin-4-yl)amino)butan-1-ol (1g, 4.2mmol, 1.0eq) in tetrahydrofuran (50mL), while cooling in an ice-water bath, add sodium hydrogen ( 330mg, 8.4mmol, 2.0eq, purity 60%), react for 30 minutes. Then, 2,5-difluoro-4-nitrobenzoic acid methyl ester (910 mg, 4.2 mmol, 1.0 eq) was added, and the reaction was carried out at 0°C for 1 hour. After the reaction is detected by LC-MS, the reaction solution is quenched with water, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (silica gel, PE:EA= 4:1), the target compound (900 mg, yield 70%) was obtained.

LC-MS (ESI) [M+H] ⁺ =433.0.

Step 3: Preparation of methyl 4-amino-5-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-2-fluorobenzoate

Dissolve 5-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-2-fluoro-4-nitrobenzoic acid methyl ester (850 mg, 1.96 mmol, 1.0 eq) in Ethanol (15 mL), add saturated aqueous ammonium chloride solution (10 mL) and iron powder (548 mg, 9.81 mmol, 5.0 eq), and react at 60°C for 2 hours. After the LC-MS detection reaction was completed, filter, and the filtrate was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography to obtain the target compound (560 mg, collected rate 70%).

LC-MS (ESI) [M+H] ⁺ =403.0.

Step 4: 5-chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4 ,6,10] Preparation of triazaheterocycle tridecane-13-carboxylic acid methyl ester

Dissolve 4-amino-5-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-2-fluorobenzoic acid methyl ester (510 mg, 1.26 mmol, 1.0 eq) in di Oxyhexanes (10mL), add dicyclohexyl[2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl]phosphine (121mg, 0.25mol, 0.2eq) , tris(dibenzylideneacetone)dipalladium) (232mg, 0.25mol, 0.2eq) and cesium carbonate (824mg, 2.53mol, 2.0eq). React at 90°C for 3 hours under nitrogen protection. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (260 mg, yield 56%).

LC-MS (ESI) [M+H] ⁺ =367.1.

Step 5: 5-chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4 ,6,10] Preparation of triazahetridedecane-13-carboxylic acid

5-Chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4,6, 10] Dissolve triazacyclodecane-13-carboxylic acid methyl ester (240mg, 0.65mmol, 1.0eq) in methanol (10mL), add sodium hydroxide aqueous solution (4.0mL, 2M), and react at 50°C for 1 hour . After the reaction is detected by LC-MS, concentrate the reaction solution, adjust the reaction solution to neutrality with dilute hydrochloric acid (1M), extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain The crude target compound (200 mg, yield 87%).

LC-MS (ESI) [M+H] ⁺ =353.1.

Step 6: (5-chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxo[ Preparation of 4,6,10]triazacyclotridecane-13-yl)(morpholinyl)methanone

5-Chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4,6, 10] Dissolve triazatrideca-13-carboxylic acid (180mg, 0.51mmol, 1.0eq) in N,N-dimethylformamide (5mL), add morpholine (58mg, 0.66mmol, 1.3eq) , Carter condensation agent (293mg, 0.66mmol, 1.3eq) and N,N-diisopropylethylamine (132mg, 1.02mmol, 2eq), react at 25°C for 2 hours. After the LC-MS detection reaction is completed, the reaction solution is poured into water, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated, separated and purified by Prep-HPLC to obtain the target compound (27 mg , yield 12%).

LC-MS (ESI) [M+H] ⁺ =422.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.18 (s, 1H), 7.90 (s, 1H), 7.00 (t, J = 6.4 Hz,2H),6.93(d,J＝10.8Hz,1H),4.37(dd,J＝11.6,4.0Hz,1H),4.02(t,J＝11.2Hz,1H),3.86-3.74(m,1H ),3.72-3.51(m,6H),3.26(s,1H),2.54(s,1H),1.84-1.70(m,1H),1.68-1.51(m,1H),1.27(d,J＝7.2 Hz,3H).

Example 461

(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)(5-chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2 ,6-(Nitrogen-bridged)benzo[b][1]oxa[4,6,10]triazacyclotridecane-13-yl)methanone

Referring to the preparation method of Example 354 or 460, the compound of Example 461 was prepared, LC-MS (ESI) [M+H] ⁺ =434.1; ¹ H NMR (400MHz, CD ₃ OD): δ7.81 (d, J ＝2.0Hz,1H),7.15-7.03(m,1H),6.92(t,J＝10.8Hz,1H),4.68(d,J＝36.4Hz,1H),4.44-4.38(m,2H),4.17 -4.10(m,1H),3.99-3.75(m,3H),3.63-3.40(m,2H),2.02-1.67(m,4H),1.33(d,J＝6.8Hz,3H).

Example 462

(5-Chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4,6, 10]Triazacyclotridecane-13-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone

Referring to the preparation method of Example 354 or 460, the compound of Example 462 was prepared, LC-MS (ESI) [M+H] ⁺ =462.1; ¹ H NMR (400MHz, CD ₃ OD): δ7.81 (s, 1H ),7.12(d,J＝6.0Hz,1H),6.89(d,J＝11.2Hz,1H),4.44(dd,J＝11.2,3.6Hz,1H),4.24-4.05(m,5H),3.97 -3.70(m,2H),3.21(s,3H),2.61-2.42(m,2H),2.23-2.02(m,2H),1.91-1.84(m,1H),1.81-1.65(m,1H) ,1.33(d,J=6.8Hz,3H).

Example 463

(5-Chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa[4,6, 10]Triazacyclotridecane-13-yl)(4-(oxetan-3-yl)piperazin-1-yl)methanone

Referring to the preparation method of Example 354 or 460, the compound of Example 463 was prepared, LC-MS (ESI) [M+H] ⁺ =477.2; ¹ H NMR (400MHz, CD ₃ OD): δ7.81 (s, 1H ),7.04(d,J＝6.4Hz,1H),6.91(d,J＝10.4Hz,1H),4.69(t,J＝6.4Hz,2H),4.60(t,J＝6.0Hz,2H), 4.43(dd,J＝11.2,3.2Hz,1H),4.12(t,J＝10.4Hz,1H),3.96-3.70(m,3H),3.59-3.42(m,3H),2.52-2.27(m, 4H), 1.91-1.82 (m, 1H), 1.80-1.66 (m, 1H), 1.33 (d, J = 7.2Hz, 3H).

Example 464

(14-Fluoro-8-methyl-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa [4,6,10]Triazacyclotrideca-13-yl)(morpholinyl)methanone

Referring to the preparation method of Example 354 or 460, the compound of Example 464 was prepared, LC-MS (ESI) [M+H] ⁺ = 456.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.57 (s, 1H),8.50(s,1H),7.06(d,J＝6.4Hz,1H),6.96(d,J＝10.6Hz,1H),6.83(d,J＝6.8Hz,1H),4.36(d, J＝11.0Hz,1H),4.07(t,J＝11.2Hz,1H),3.93-3.91(m,1H),3.75-3.62(m 4H),3.55(s,2H),3.29-3.28(m, 1H), 1.80-1.70 (m, 1H), 1.68-1.51 (m, 1H), 1.27 (d, J = 7.2Hz, 3H), 1.23 (s, 1H).

Example 465

12-Fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1,5,6,7,8,14-hexa Hydrogen-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 455, the compound of Example 465 was prepared, LC-MS (ESI) [M+H] ⁺ =493.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.62 (d, J= 2.4Hz,1H),8.24(s,1H),7.40(s,1H),6.74(d,J＝13.2Hz,1H),6.24-6.07(m,2H),4.16(s,2H),3.79- 3.75(m,5H),3.41(d,J＝5.2Hz,2H),3.12(s,3H),2.47-2.44(m,2H),2.07-1.98(m,2H),1.72(s,2H) .

Example 466

11-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro-4 ,15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 466 was prepared, LC-MS (ESI) [M+H] ⁺ =462.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.63 (s, 1H) ,8.24(s,1H),7.38(s,1H),7.22(d,J＝8.4Hz,1H),6.14(d,J＝8.4Hz,1H),6.10(t,J＝6.0Hz,1H) ,4.46-4.41(m,4H),3.70-3.67(m,2H),3.35-3.33(m,2H),2.88-2.85(m,2H),1.82-1.72(m,6H).

Example 467

11-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro-4 ,15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecanecarboxylate

Referring to the preparation method of Example 194, the compound of Example 467 was prepared, LC-MS (ESI) [M+H] ⁺ =532.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.64 (s, 1H) ,8.21(s,1H),7.39(s,1H),7.22(d,J＝8.4Hz,1H),6.27(d,J＝8.4Hz,1H),6.12(t,J＝6.0Hz,1H) ,4.47(br s,2H),4.18-4.15(m,2H),3.37-3.35(m,2H),2.71(t,J＝11.6Hz,2H),2.60-2.43(m,4H),2.38- 2.35(m,5H),2.17(s,3H),1.82-1.74(m,4H),1.44-1.36(m,2H).

Example 468

3-Cyclopropyl-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15-( Nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: 3-((5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 4-yl)amino)propan-1-ol

5-Bromo-2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3.3g, 8.31 mmol, 1.0eq) and 3-aminobutan-1-ol (936mg, 12.46mmol, 1.5eq) were added to isopropanol (30mL) and reacted at 85°C for 1 hour. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the target compound (3.6 g, yield 99%).

LC-MS (ESI) [M+H] ⁺ =435.0.

Step 2: 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Preparation of pyrimidin-4-yl)amino)propan-1-ol

3-((5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )Amino)propan-1-ol (3.8g, 8.72mmol, 1.0eq), potassium cyclopropylfluoroborate (1.55g, 10.46mmol, 1.2eq), Pd(PPh ₃ ) ₄ (400mg, 0.35mmol, 0.04eq ) and potassium carbonate (2.41g, 17.44mmol, 2.0eq) were dissolved in toluene (40mL) and water (4mL). React under nitrogen protection at 110°C for 12 hours. After the reaction is detected by LC-MS, pour the reaction solution into water (30 mL) and extract with ethyl acetate (25 mL*3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. Use flash chromatography to separate and purify (silica gel, PE:EA=6:1) to obtain the target compound (1.2g, yield 35%).

LC-MS (ESI) [M+H] ⁺ =397.2.

From the third step to the seventh step, refer to the preparation method of Example 194 to prepare the compound of Example 468, LC-MS (ESI) [M+H] ⁺ = 448.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10 .44(s,1H),8.21(s,0H),7.87(s,1H),7.19(d,J＝8.0Hz,1H),6.50(t,J＝6.2Hz,1H),6.34(s, 1H),5.83(d,J＝8.0Hz,1H),4.48(s,2H),3.85(s,2H),3.82-3.74(m,3H),3.12(s,3H),2.48-2.41(m ,4H),2.08-1.99(m,2H),1.97-1.87(m,1H),1.75(s,2H),0.85-0.70(m,2H),0.47-0.43(m,2H).

Example 469

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-(trifluoromethyl)-1,7,8,14-tetrahydro-6H-4,15 -(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1,10]dioxa[4,6]diazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 469 was prepared, LC-MS (ESI) [M+H] ⁺ =449.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.91(d,J＝2.2Hz,1H),8.70(s,1H),7.53(s,1H),7.26(d,J＝8.2Hz,1H ),6.06(d,J＝8.2Hz,1H),4.76(s,1H),4.63(s,1H),4.54(s,1H),4.45(t,J＝5.0Hz,2H),3.78(d ,J＝6.4Hz,1H),3.68(d,J＝7.2Hz,1H),3.43(d,J＝8.6Hz,1H),3.20(d,J＝9.8Hz,1H),2.51(s,2H ), 1.90 (d, J = 9.4Hz, 2H), 1.83 (d, J = 9.4Hz, 1H).

Example 470

3-Chloro-11-(4-(oxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge) Pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecanecarboxylate

Referring to the preparation method of Example 194, the compound of Example 470 was prepared, LC-MS (ESI) [M+H] ⁺ =457.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.06 (d, J= 1.6Hz,1H),8.15(s,1H),7.23(d,J＝8.4Hz,1H),6.83(d,J＝2.2Hz,1H),6.73(t,J＝6.2Hz,1H),6.27 (d,J＝8.4Hz,1H),4.57(t,J＝6.2Hz,2H),4.48(t,J＝6.0Hz,4H),3.44(d,J＝6.2Hz,1H),3.33-3.31 (m,6H),2.38-2.33(m,4H),1.75(s,2H).

Example 471

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro-4 ,15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 199, the compound of Example 471 was prepared, LC-MS (ESI) [M+H] ⁺ =448.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.62 (s, 1H),8.20(s,1H),7.39(s,1H),7.22(d,J＝8.4Hz,1H),6.11(t,J＝6.0Hz,1H),6.00(d,J＝8.4Hz, 1H),4.73(s,1H),4.62(s,1H),4.49(s,2H),3.77(d,J＝6.4Hz,1H),3.67(d,J＝7.2Hz,1H),3.42( d,J＝9.2Hz,1H),3.36(d,J＝5.6Hz,2H),3.18(d,J＝9.6Hz,1H),1.90(d,J＝7.6Hz,1H),1.82(d, J＝9.2Hz,1H),1.73(s,2H).

Example 472

3-Chloro-11-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge )pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 199, the compound of Example 472 was prepared, LC-MS (ESI) [M+H] ⁺ =413.80; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (s, 1H),8.11(s,1H),7.21(d,J＝8.0Hz,1H),6.82(d,J＝2.4Hz,1H),6.71(t,J＝6.0Hz,1H),5.88(d, J＝8.0Hz,1H),4.71(s,4H),4.48(s,2H),4.03(s,4H),3.31-3.28(m,2H),1.74(s,2H).

Example 473

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1,7,8,14-tetrahydro-6H-4,15- (nitrogen bridge) benzo[b]pyrrolo[2,3-g][1,10]dioxa[4,6]diazacyclotridecane

Step 1: Preparation of 3-(5-bromo-4-fluoro-2-nitrophenoxy)propan-1-ol

Dissolve 1,3-propanediol (1.0g, 13.14mmol, 1.0eq) in tetrahydrofuran (30mL), add sodium hydrogen (788.4mg, 19.71mmol, 1.5eq, purity 60%) to the reaction system in an ice bath. Continue the reaction under the bath for 30 minutes. Dissolve 1-bromo-2,5-difluoro-4-nitrobenzene (3.13g, 13.14mmol, 1eq) in tetrahydrofuran (80mL), gradually add it dropwise to the reaction solution, and continue the reaction at room temperature for 2 hours. . After the LC-MS detection reaction is completed, the reaction solution is quenched with methanol, filtered through diatomaceous earth, and the filtrate is concentrated and separated and purified by flash chromatography (silica gel, PE:EA=10:1) to obtain the target compound (2.5g, collected rate 65%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.09 (d, J = 8.0Hz, 1H), 7.79 (d, J = 5.6Hz, 1H), 4.56 (t, J = 5.2Hz, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.53 (dd, J = 11.2, 6.0 Hz, 2H), 1.84 (p, J = 6.0 Hz, 2H).

Step 2: Preparation of 2-(3-(5-bromo-4-fluoro-2-nitrophenoxy)propoxy)tetrahydro-2H-pyran

Dissolve 3-(5-bromo-4-fluoro-2-nitrophenoxy)propan-1-ol (2.5g, 8.5mmol, 1.0eq) in dichloromethane (30mL), stir in an ice bath, Then add 3,4-dihydro-2H-pyran (1.07g, 12.75mmol, 1.5eq), stir for two minutes, then add 4-methylbenzenesulfonate pyridine (213.61mg, 0.85mmol, 0.1eq), stir at room temperature The reaction was carried out for 4 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=20:1) to obtain the target compound (2.96g, yield 92%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.09 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 6.0 Hz, 1H), 4.55 (d, J = 3.6 Hz, 1H), 4.27(t,J＝6.0Hz,2H),3.83-3.63(m,2H),3.52-3.35(m,2H),1.96(p,J＝6.0Hz,2H),1.77-1.56(m,2H) ,1.51-1.39(m,4H).

Step 3: 5-(2-fluoro-4-nitro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-2-oxa -Preparation of 5-azabicyclo[2.2.1]heptane

2-(3-(5-Bromo-4-fluoro-2-nitrophenoxy)propoxy)tetrahydro-2H-pyran (3.04g, 8.04mmol, 1.0eq), 2-oxa- 5-Azabicyclo[2.2.1]heptane (797.01mg, 8.04mmol, 1.0eq), cesium carbonate (7.86g, 24.12mmol, 3.0eq), tris(dibenzylideneacetone)dipalladium(0)( 368.12mg, 0.4mmol, 0.05eq), and dicyclohexyl[2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl]phosphine (574.92g, 1.21mmol ,0.15eq) was dissolved in 1,4-dioxane (80mL), and reacted at 100°C for 6 hours under nitrogen protection. After the reaction was detected by LC-MS, it was filtered and the filtrate was concentrated and then separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (2.3g, yield 72%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.82 (d, J = 14.0Hz, 1H), 6.36 (d, J = 8.0Hz, 1H), 4.87 (s, 1H), 4.70-4.50 (m ,2H),4.28-4.16(m,2H),3.92-3.75(m,3H),3.75-3.66(m,2H),3.53(d,J＝10.0Hz,1H),3.43-3.36(m,1H ), 3.17 (d, J = 5.6 Hz, 1H), 2.03-1.86 (m, 4H), 1.75-1.55 (m, 2H), 1.53-1.37 (m, 4H).

Step 4: 3-(5-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-fluoro-2-nitrophenoxy)propan-1-ol preparation

5-(2-fluoro-4-nitro-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)phenyl)-2-oxa-5- Azabicyclo[2.2.1]heptane (1g, 2.5mmol, 1.0eq) was dissolved in a mixed solution of acetic acid/water (12/4mL), and reacted at 70°C for 3 hours. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated, diluted with dichloromethane (100 mL), and washed with water (30 mL) and saturated sodium chloride solution (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (700 mg, yield 58%).

LC-MS (ESI) [M+H] ⁺ =312.7.

Step 5: 5-(5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)oxy)propoxy)-2-fluoro-4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

3-(5-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-fluoro-2-nitrophenoxy)propan-1-ol (640 mg, 1.33 mmol, 1.0eq) was dissolved in tetrahydrofuran (15mL), replaced with nitrogen, and the temperature was controlled at 0°C in an ice-salt bath. Add sodium hydride (47.96mg, 2mmol, 1.5eq), react for 0.5 hours, and then add 2,4,5-trichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H dropwise - A solution of pyrrolo[2,3-d]pyrimidine (469.86 mg, 1.33 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was reacted at 25°C for 2 hours. After the reaction is detected by LC-MS, add saturated ammonium chloride solution (1.5mL) and water (20mL), extract with dichloromethane (50mL*3), wash the organic phase with saturated sodium chloride aqueous solution, combine the organic phases, and use Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, then separate and purify using flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (600 mg, yield 72%).

LC-MS(ESI)[M+H] ⁺ =628.00.

Step 6: 4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-(3-((2,5-dichloro-7-((2-( Preparation of trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)propoxy)-5-fluoroaniline

5-(5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)oxy)propoxy)-2-fluoro-4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (500mg, 0.8mmol, 1.0 eq) was dissolved in ethanol (50mL) and water (10mL), and ammonium chloride (276.58mg, 5.17mmol, 6.5eq) and iron powder (266.52mg, 4.77mmol, 6.0eq) were added in sequence. Replace nitrogen gas and react at 80°C for 3 hours. After the reaction was detected by LC-MS, filter through diatomaceous earth with suction, rinse the filter cake with dichloromethane (20 mL), and concentrate the filtrate to obtain the crude target compound (460 mg, yield 89%).

LC-MS (ESI) [M+H] ⁺ =597.95.

Step 7: 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1-((2-(trimethylsilyl)) Ethoxy)methyl)-1,7,8,14-tetrahydro-6H-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1,10]dioxo Preparation of hetero[4,6]diazacyclotridecane

4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-(3-((2,5-dichloro-7-((2-(trimethyl) Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)propoxy)-5-fluoroaniline (460mg, 0.77mmol, 1.0eq) and A solution of cesium carbonate (375.59 mg, 1.15 mmol, 4.0 eq) in dioxane (15 mL) was bubbled with nitrogen for 20 minutes, and then tris(dibenzylideneacetone) dipalladium (70.37 mg, 0.08 mmol, 0.1 eq) and 2-Dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl (73.27 mg, 0.15 mmol, 0.2 eq), bubble for 20 minutes, react at 90°C for 1 hour. After the reaction was detected by LC-MS, the reaction solution was diluted with dichloromethane (50 mL), filtered through diatomaceous earth, and the filter cake was rinsed with dichloromethane (50 mL). After concentrating the filtrate, it was separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (290 mg, yield 62%).

LC-MS (ESI) [M+H] ⁺ =562.15.

Step 8: 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1,7,8,14-tetrahydro-6H- Preparation of 4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1,10]dioxa[4,6]diazacyclotridecane

11-(2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1-(2-(trimethylsilyl)ethoxy )methyl)-1,7,8,14-tetrahydro-6H-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1,10]dioxa[4 ,6] Diazacyclotridecane (150 mg, 0.27 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. React at 25°C for 3 hours. After the LC-MS detection reaction was completed, ammonia solution (1 mL) was used to adjust the pH to about 8. The reaction solution was concentrated, tetrahydrofuran (3 mL) and ammonia water (3 mL) were added, and the reaction was carried out at 25°C for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by Prep-HPLC to obtain the target compound (32.1 mg, yield 27%).

LC-MS(ESI)[M+H] ⁺ =431.80; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.42(s,1H),8.63(s,1H),7.03(s,1H), 6.80(d,J＝14.4Hz,1H),6.40(d,J＝8.8Hz,1H),4.50(t,J＝15.8Hz,4H),4.33-4.19(m,2H),3.85(d,J ＝7.6Hz,1H),3.75(d,J＝6.8Hz,1H),3.58(dd,J＝9.6,2.2Hz,1H),3.05(dd,J＝9.6,3.0Hz,1H),1.90(d ,J＝9.2Hz,3H),1.81(d,J＝9.6Hz,1H).

Example 474

13-(4-(oxetan-3-yl)piperazin-1-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-( Nitrogen bridge)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 199, the compound of Example 474 was prepared, LC-MS (ESI) [M+H] ⁺ =452.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.07 (s, 1H),8.06(s,1H),7.32(t,J＝5.7Hz,1H),7.27(d,J＝8.4Hz,1H),6.32(d,J＝8.3Hz,1H),4.57(t, J＝6.5Hz,2H),4.47(t,J＝6.0Hz,3H),3.43(t,J＝4.4Hz,4H),3.29-3.21(m,4H),2.35(t,J＝5.0Hz, 4H),1.75(s,2H).

Example 475

11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-12-fluoro-3-(trifluoromethyl)-1,5,6,7,8,14- Hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 455, the compound of Example 475 was prepared, LC-MS (ESI) [M+H] ⁺ =465.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.62 (d, J= 2.4Hz,1H),8.25(s,1H),7.40(s,1H),6.79(d,J＝14.4Hz,1H),6.36(d,J＝8.8Hz,1H),6.16(s,1H) ,4.51(d,J＝28.0Hz,2H),4.17(d,J＝5.6Hz,2H),3.80-3.78(m,2H),3.43(d,J＝5.5Hz,3H),3.12-2.99( m,1H),1.98-1.69(m,4H).

Example 476

(8-Methyl-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[4,3-b][1]oxa [4,6,10]Triazacyclotrideca-13-yl)(morpholinyl)methanone

Step 1: Preparation of tert-butyl (4-hydroxybut-2-yl) carbamate

Dissolve 3-aminobutanol (1g, 11.22mmol, 1.0eq), 4-dimethylaminopyridine (274mg, 2.24mmol, 0.2eq) and triethylamine (1.7g, 16.83mmol, 1.5eq) in tetrahydrofuran (15mL ), then add di-tert-butyl dicarbonate (3.67g, 16.83mmol, 1.5eq) and react at room temperature for 4 hours. After the LC-MS detection reaction is completed, pour the reaction solution into water (40 mL), extract with ethyl acetate (15 mL*3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude target compound (2 g, 94%).

LC-MS (ESI) [M+Na] ⁺ =212.1.

Second step: Preparation of (4-(2-chloro-5-nitropyridin-4-yl)oxy)but-2-yl)carbamic acid tert-butyl ester

(4-hydroxybut-2-yl)carbamic acid tert-butyl ester (2g, 10.57mmol, 1.0eq) was dissolved in anhydrous THF (30mL), and stirred at 0°C for 10 minutes. Then sodium hydrogen (634 mg, 15.85 mmol, 1.5 eq, purity 60%) was added and the reaction was carried out for 30 minutes. Then 2,4-dichloro-5-nitropyridine (2.04g, 10.57mmol, 1.0eq) was added, and the reaction was carried out at 0°C for 1 hour. After the LC-MS detection reaction is completed, add saturated aqueous ammonium chloride solution to quench, pour the reaction solution into water (25mL), and extract with ethyl acetate (20mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and then separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (1.9g, yield 52%).

LC-MS (ESI) [M+Na] ⁺ =368.0.

Step 3: Preparation of (4-((5-nitro-2-vinylpyridin-4-yl)oxy)but-2-yl)carbamic acid tert-butyl ester

(4-((2-Chloro-5-nitropyridin-4-yl)oxy)but-2-yl)carbamic acid tert-butyl ester (1.9g, 5.49mmol, 1.0eq), potassium ethylene trifluoroborate (883mg, 6.59mmol, 1.2eq), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (403mg, 0.55mmol, 0.1eq) and sodium acetate (902mg, 10.99mmol, 2.0eq) Dissolve in toluene (30 mL) and react at 110°C for 4 hours under nitrogen protection. After the LC-MS detection reaction is completed, pour the reaction solution into water (40mL) and extract with ethyl acetate (25mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the target compound (911 mg, yield 49 %).

LC-MS (ESI) [M+Na] ⁺ =360.1.

Step 4: Preparation of 4-(3-((tert-butoxycarbonyl)amino)butoxy)-5-nitropyridine-2-carboxylic acid

Dissolve sodium periodate (2.88g, 13.49mmol, 5eq) and potassium permanganate (85mg, 0.54mmol, 0.2mmol) in water (80mL), and slowly add potassium carbonate (410mg, 2.97mmol, 1.1eq). Then (4-((5-nitro-2-vinylpyridin-4-yl)oxy)but-2-yl)carbamic acid tert-butyl ester (910 mg, 2.70 mmol, 1.0 eq) was dissolved in tert-butanol (80 mL), and slowly added dropwise to the reaction solution, and reacted at room temperature for 1 hour. Ethylene glycol (8 mL) was then added to the reaction solution, and the reaction was continued for 1 hour. Then, a saturated sodium bisulfite aqueous solution was added to the reaction liquid, and the mixture was extracted with ethyl acetate (40 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude target compound (984 mg).

LC-MS (ESI) [M+Na] ⁺ =378.1.

Step 5: Preparation of tert-butyl (4-((2-(morpholine-4-carbonyl)-5-nitropyridin-4-yl)oxy)butan-2-yl)carbamate

4-(3-(tert-butoxycarbonyl)amino)butoxy)-5-nitropyridine-2-carboxylic acid (984mg, 2.77mmol, 1.0eq) and diisopropylethylamine (537mg, 4.15mmol ,1.5eq) was dissolved in dichloromethane (25mL), and HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphoric acid was added Urea) (1.60g, 4.15mmol, 1.5eq), after reacting for 30 minutes, add morpholine (290mg, 3.32mmol, 1.0eq) and continue the reaction for 1.5 hours. After the LC-MS detection reaction is completed, pour the reaction solution into water (30 mL) and extract with dichloromethane (20 mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (857 mg, 73%) .

LC-MS (ESI) [M+Na] ⁺ =447.0.

Step 6: Preparation of: (4-(3-aminobutoxy)-5-nitropyridin-2-yl)(morpholinyl)methanone

Tert-butyl (4-((2-(morpholine-4-carbonyl)-5-nitropyridin-4-yl)oxy)butan-2-yl)carbamate (857 mg, 2.02 mmol, 1.00 eq) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated to obtain the target compound (654 mg, yield 100%).

LC-MS (ESI) [M+H] ⁺ =325.1.

Step 7: (4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)butoxy)-5-nitropyridin-2-yl)(morpholinyl ) Preparation of Methyl Ketone

(4-(3-Aminobutoxy)-5-nitropyridin-2-yl)(morpholinyl)methanone (654 mg, 2.02 mmol, 1.0 eq), 2,4-dichloro-5-( Trifluoromethyl)pyrimidine (525 mg, 2.42 mmol, 1.20 eq) and diisopropylethylamine (521 mg, 4.03 mmol, 2.0 eq) were added to isopropanol (20 mL) and reacted at 0°C for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by preparative TLC (PE:EA=65%) to obtain the target compound (180 mg, yield 18%).

LC-MS (ESI) [M+H] ⁺ =504.9.

Step 8: (4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)butoxy)-5-nitropyridin-2-yl)(morpholinyl ) Preparation of Methyl Ketone

(4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)butoxy)-5-nitropyridin-2-yl)(morpholinyl)methanone (170mg, 0.34mmol, 1.0eq), iron powder (188mg, 3.37mmol, 10.0eq) and saturated aqueous ammonium chloride solution (5mL) were dissolved in ethanol (10mL) and reacted at 80°C for 2 hours. After the LC-MS detection reaction is completed, filter the reaction solution, pour the filtrate into water (50mL), extract with ethyl acetate (25mL*3), combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, and filter. After the filtrate was concentrated, the crude target compound (180 mg, yield 113%) was obtained.

LC-MS (ESI) [M+H] ⁺ =475.1.

Step 9: (8-methyl-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[4,3-b][ Preparation of 1]oxa[4,6,10]triazacyclotridecane-13-yl)(morpholinyl)methanone

(5-Amino-4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)butoxy)pyridin-2-yl)(morpholinyl)methanone ( 170 mg, 0.36 mmol, 1.0 eq), tris(dibenzylideneacetone) dipalladium (66 mg, 0.07 mmol, 0.2 eq), 2-dicyclohexylphosphine-2',4',6'-triisopropyl linkage Benzene (34 mg, 0.07 mmol, 0.2 eq) and cesium carbonate (233 mg, 0.72 mmol, 2.0 eq) were dissolved in 1,4-dioxane (15 mL) and reacted at 90°C for 4 hours under nitrogen protection. After the LC-MS detection reaction is completed, pour the reaction solution into water (30mL), extract with ethyl acetate (15mL*3), combine the organic phases, wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate Afterwards, the target compound (14.6 mg, yield 9%) was separated and purified by Prep-HPLC.

LC-MS (ESI) [M+H] ⁺ = 439.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.68 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.36(s,1H),6.85(d,J＝7.0Hz,1H),4.40(d,J＝11.6Hz,1H),4.30(t,J＝11.2Hz,1H),3.91(dd,J＝12.2 ,5.6Hz,1H),3.66-3.56(m,8H),1.87-1.77(m,1H),1.72-1.59(m,1H),1.27(d,J=7.0Hz,3H).

Example 477

(8-Methyl-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa [4,6,10]Triazacyclotrideca-13-yl)(morpholinyl)methanone

Referring to the preparation method of Example 476, the compound of Example 477 was prepared, LC-MS (ESI) [M+H] ⁺ =439.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.70 (s, 1H) ,8.18(s,1H),7.56(d,J＝7.6Hz,1H),7.21(d,J＝7.6Hz,1H),6.87(d,J＝7.2Hz,1H),5.01(t,J＝ 11.2Hz,1H),4.08(d,J＝12.0Hz,1H),3.93-3.80(m,1H),3.70-3.45(m,8H),1.87-1.58(m,2H),1.26(d,J =7.2Hz,3H).

Example 478

3-Chloro-11-(7-oxa-2-azaspiro[3.5]non-2-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge) Pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 478 was prepared, LC-MS (ESI) [M+H] ⁺ =442.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.08 (s, 1H) ,8.13(s,1H),7.23(d,J＝8.4Hz,1H),6.85(d,J＝0.2Hz,1H),6.75(t,J＝6.0Hz,1H),5.89(d,J＝ 8.4Hz,1H),4.50(br s,2H),3.67(s,4H),3.59-3.56(m,4H),3.35-3.33(m,2H),1.77-1.74(m,6H).

Example 479

3-Chloro-11-(2,6-dimethylmorpholinyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b ]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 479 was prepared, LC-MS (ESI) [M+H] ⁺ =430.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.07 (s, 1H) ,8.17(s,1H),7.24(d,J＝8.2Hz,1H),6.83(d,J＝2.2Hz,1H),6.74(s,1H),6.27(d,J＝8.2Hz,1H) ,4.49(s,2H),3.98(d,J＝11.2Hz,2H),3.65-3.62(m 3H),2.33-2.28(m,3H),1.76(s,2H),1.16(d,J＝ 6.2Hz, 6H).

Example 480

13-(2,6-dimethylmorpholinyl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen-bridged)pyrido[2, 3-b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 353, the compound of Example 480 was prepared, LC-MS (ESI) [M+H] ⁺ =425.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.09 (s, 1H) ,8.07(s,1H),7.34(t,J＝5.6Hz,1H),7.27(d,J＝8.4Hz,1H),6.32(d,J＝8.0Hz,1H),4.45(br s,2H ),4.01-3.98(m,2H),3.62-3.60(m,2H),3.30-3.26(m,2H),3.36-3.30(m,2H),1.75(br s,2H),1.15(d, J=6.0Hz,6H).

Example 481

(3-Chloro-12-fluoro-6-methyl-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g ][1]oxa[4,6,10]triazacyclotridec-11-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone

Referring to the preparation method of Example 455, the compound of Example 481 was prepared, LC-MS (ESI) [M+H] ⁺ =501.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.28 (s, 1H) ,8.86(s,1H),7.06(dd,J＝6.2,3.4Hz,1H),6.96(d,J＝2.4Hz,1H),6.90(d,J＝11.4Hz,1H),6.07(d, J＝7.0Hz,1H),4.37(dd,J＝11.2,2.4Hz,1H),4.16-3.86(m,6H),3.82-3.65(m,1H),3.09(s,3H),2.47-2.44 (m,2H),2.05-1.98(m,2H),1.83-1.61(m,2H),1.30(d,J＝6.8Hz,3H).

Example 482

(3-Chloro-6-methyl-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g ][1]oxa[4,6,10]triazacyclotridecan-11-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone

Referring to the preparation method of Example 194 or 199, the compound of Example 482 was prepared, LC-MS (ESI) [M+H] ⁺ =484.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.30 (s, 1H),8.96(s,1H),7.52-7.46(m,2H),6.96(d,J＝2.4Hz,1H),6.05(d,J＝7.6Hz,1H),5.13-5.02(m,1H ),4.70-4.55(m,2H),4.10(d,J＝11.8Hz,1H),4.02(d,J＝22.8Hz,2H),3.91(s,1H),3.77(dd,J＝16.2, 6.8Hz,1H),3.12(s,3H),2.47-2.45(m,2H),2.08-2.01(m,2H),1.85-1.70(m,2H),1.32(d,J＝6.8Hz,3H ).

Example 483

3-Chloro-11-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15 -(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194 or 199, the compound of Example 483 was prepared, LC-MS (ESI) [M+H] ⁺ =471.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.05 (d, J＝2.4Hz,1H),8.13(s,1H),7.22(d,J＝8.3Hz,1H),6.83(d,J＝2.4Hz,1H),6.72(t,J＝6.2Hz,1H) ,6.26(d,J＝8.4Hz,1H),4.59-4.53(m,2H),4.52-4.45(m,3H),3.82-3.74(m,1H),3.74-3.64(m,2H),3.31 -3.30(m,2H),3.06-2.95(m,1H),2.77-2.63(m,2H),2.39-2.31(m,1H),2.13-2.03(m,1H),2.05-1.93(m, 1H), 1.75 (s, 2H), 0.89 (d, J = 6.3Hz, 3H).

Example 484

13-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H- 2,6-(Nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Step 1: (3-((6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-nitropyridin-2-yl)oxy) Preparation of tert-butyl propyl carbamate

At room temperature, (3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester (3.32g, 10mmol, 1.0eq) and 2-methyl-1 -(Oxan-3-yl)piperazine (1.87g, 12mmol, 1.2eq) was dissolved in isopropyl alcohol (10v/w), and triethylamine (3.04g, 30mmol, 3.0eq) was slowly added. After reacting for 10 minutes, the reaction system was heated to 80°C and reacted for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=4:1) to obtain the target compound (3.8g, yield 84%).

LC-MS(ESI)[M-55] ⁺ =396.3.

Step 2: 3-((6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-nitropyridin-2-yl)oxy)propanyl -Preparation of 1-amine: (3-((6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-nitropyridine- 2-yl)oxy)propyl)carbamic acid tert-butyl ester (3.8g, 8.4mmol, 1.0eq) was dissolved in dichloromethane (10mL), TFA (4.8g, 42mmol, 5.0eq) was slowly added, and the reaction The system was raised to room temperature and the reaction was continued for 1 hour. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated to obtain the crude target compound, which is directly used in the next step.

LC-MS (ESI) [M+H] ⁺ =352.1.

Step 3: 2-Chloro-N-(3-(6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-nitropyridine-2- Preparation of methyl)oxy)propyl)-5-(trifluoromethyl)pyrimidin-4-amine

At room temperature, 3-((6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-nitropyridin-2-yl)oxy)propanyl -1-amine (3.1g, 8.8mmol, 1.0eq) and 2,4-dichloro-5-trifluoromethylpyrimidine (2.11g, 9.7mmol, 1.1eq) were dissolved in isopropyl alcohol (10v/w) , then slowly add triethylamine (1.34g, 13.2mmol, 1.5eq), and heat the reaction system to 80°C for 2 hours. After the reaction was detected by LC-MS, the organic phase was directly concentrated and reversed-phase column chromatography was used to obtain the target compound (2.1 g, yield 45%).

LC-MS (ESI) [M+H] ⁺ =532.3.

Step 4: N-(3-((3-amino-6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)oxy group Preparation of )propyl)-2-chloro-5-(trifluoromethyl)pyrimidin-4-amine

At room temperature, 2-chloro-N-(3-(6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-3-nitropyridine-2 -(yl)oxy)propyl)-5-(trifluoromethyl)pyrimidin-4-amine (500mg, 0.94mmol, 1.0eq), iron powder (0.26g, 4.7mmol, 5.0eq) and ammonium chloride ( 0.25g, 4.7mmol, 5.0eq) was dissolved in EtOH/H ₂ O (20/5mL), and then the reaction system was heated to 100°C for 16 hours. After the LC-MS detection reaction is completed, filter through diatomaceous earth, wash the filter cake with dichloromethane/methanol (20:1), concentrate the filtrate, and use flash chromatography to separate and purify (silica gel, DCM:MeOH=20:1) to obtain Target compound (169.96mg, yield 39%).

LC-MS (ESI) [M+H] ⁺ = 466.3; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.07 (s, 1H), 8.07 (s, 1H), 7.33 (s, 1H), 7.27(d,J＝8.3Hz,1H),6.31(d,J＝8.1Hz,1H),4.67-4.35(m,6H),3.80(d,J＝12.1Hz,1H),3.70(q,J ＝10.3,7.0Hz,2H),3.26(d,J＝23.2Hz,2H),3.04(t,J＝9.9Hz,1H),2.81-2.72(m,1H),2.68(d,J＝10.4Hz ,1H),2.35(s,1H),2.08(s,1H),1.76(s,2H),0.89(d,J＝6.2Hz,3H).

Example 485

3-Chloro-11-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-1,5,6, 7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triaza cyclotridecane

Referring to the preparation method of Example 199, the compound of Example 485 was prepared, LC-MS (ESI) [M+H] ⁺ =483.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.03 (d, J= 2.0Hz,1H),8.05(s,1H),7.21(d,J＝8.0Hz,1H),6.82(d,J＝2.4Hz,1H),6.70(t,J＝6.4Hz,1H),5.99 (d,J＝8.0Hz,1H),4.63(s,1H),4.55(s,1H),4.47(d,J＝6.0Hz,1H),4.35(s,1H),4.25(d,J＝ 6.0Hz,1H),4.19-4.12(m,2H),3.72(s,1H),3.31-3.22(m,3H),3.14(d,J＝9.2Hz,1H),3.02(m,J＝9.2 Hz,2H),1.83(s,3H),1.68(s,1H),1.48(s,3H).

Example 486

13-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-(trifluoromethyl)-7 ,8,9,10-tetrahydro-1H-2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 5-(3-cyanooxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-carboxylic acid tert-butyl ester

Dissolve 2,5-diazabicyclo[2.2.1]hept-2-carboxylic acid tert-butyl ester (5g, 25.22mmol, 1.0eq) in 1,2-dichloroethane (50mL), replace with nitrogen, Add oxetan-3-one (2.18g, 30.26mmol, 1.2eq) and acetic acid (1.67g, 27.74mmol, 1.1eq), and react at 60°C for 0.5 hours. Then trimethylsilyl cyanide (5.0g, 50.44mmol, 2.0eq) was added, and the reaction was continued for 16 hours. Liquid phase monitors reaction completion. Concentrate the reaction solution, adjust the pH to 7-8 with sodium bicarbonate aqueous solution, extract with ethyl acetate (300ml*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate, then separate and purify using flash chromatography. (silica gel, PE:EA=5:1), the target compound (4.5g, yield 64%) was obtained.

LC-MS (ESI) [M+H] ⁺ =280.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ4.86-4.77 (m, 1H), 4.71 (t, J = 7.2Hz, 1H), 4.58-4.45(m,2H),4.29(d,J＝13.6Hz,1H),3.70(d,J＝8.4Hz,1H),3.31-3.20(m,1H),3.13(t,J＝8.0Hz ,1H),2.97(m,J＝9.2Hz,1H),2.66(m,J＝8.8Hz,1H),1.87(t,J＝ 8.4Hz, 1H), 1.69 (t, J = 8.8Hz, 1H), 1.40 (d, J = 6.0Hz, 9H).

Step 2: Preparation of 5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-carboxylic acid tert-butyl ester

5-(3-cyanooxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-carboxylic acid tert-butyl ester (4.5g, 16.11mmol, 1.0eq) dissolved In tetrahydrofuran (50 mL), nitrogen was replaced, methylmagnesium bromide (9.6 g, 80.55 mmol, 5.0 eq, 26.85 mL) was added, and the reaction was carried out at 60°C for 16 hours. After the reaction is detected by LC-MS, slowly pour the reaction solution into ammonium chloride aqueous solution (200mL), and extract with dichloromethane (200mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1) to obtain the target compound (1.45g, yield 34%).

LC-MS (ESI) [M+H] ⁺ =269.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ4.48 (t, J = 7.2 Hz, 2H), 4.28 (t, J = 6.4 Hz, 1H),4.19(m,J＝9.2Hz,2H),3.63(s,1H),3.08(m,J＝18.0Hz,2H),2.96-2.81(m,2H),1.68(d,J＝11.2 Hz, 2H), 1.44 (s, 3H), 1.40 (d, J = 11.2Hz, 9H).

Step 3: Preparation of 2-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptane

5-(3-Methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-carboxylic acid tert-butyl ester (1.95g, 7.27mmol, 1.0eq) Dissolve in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and react at room temperature for 16 hours. After TLC detects that the reaction is complete, the reaction solution is directly concentrated to obtain the crude target compound (1.1g), which is directly used in the next step.

¹ H NMR (400MHz, DMSO-d ₆ ): δ4.82 (d, J = 7.6 Hz, 1H), 4.67 (d, J = 7.2 Hz, 1H), 4.47 (s, 1H), 4.41 (d, J ＝7.6Hz,2H),4.34(d,J＝7.2Hz,1H),3.60(d,J＝12.0Hz,1H),3.46-3.33(m,2H),3.27(d,J＝11.6Hz,1H ), 2.11 (d, J = 12.0Hz, 1H), 1.94 (d, J = 12.0Hz, 1H), 1.61 (s, 3H).

Step 4: tert-butyl (3-((6-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl) Preparation of )-3-nitropyridin-2-yl)oxy)propyl)carbamate

3-((6-Chloro-3-nitropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester (1.5g, 4.52mmol, 1.0eq), 2-(3-methyloxa Cyclbut-3-yl)-2,5-diazabicyclo[2.2.1]heptane (0.91g, 5.43mmol, 1.2eq) and triethylamine (1.83g, 18.09mmol, 4.0eq) were dissolved in N , N-dimethylformamide (15mL), heat to 100°C and react for 6 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (1.2g, yield 57%).

LC-MS (ESI) [M+H] ⁺ =464.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.20 (d, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.24 ( m,J＝8.8Hz,1H),4.86(d,J＝108.0Hz,1H),4.48(d,J＝6.0Hz,1H),4.45-4.28(m,3H),4.21(dd,J＝25.6 ,5.6Hz,2H),3.83(d,J＝26.0Hz,1H),3.44-3.27(m,2H),3.16-3.01(m,4H),1.87(m,J＝14.8Hz,4H),1.46 (s, 3H), 1.38 (d, J = 15.2Hz, 9H).

Step 5: 3-((6-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-3- Preparation of nitropyridin-2-yl)oxy)propan-1-amine

Tert-butyl(3-((6-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-3 -Nitropyridin-2-yl)oxy)propyl)carbamate (1.5g, 3.24mmol, 1.0eq) was dissolved in dichloromethane (20mL), added trifluoroacetic acid (5mL), and reacted at room temperature 2 Hour. After TLC detects that the reaction is complete, the reaction solution is directly concentrated to obtain the crude target compound (1.15g), which is directly used in the next step.

LC-MS (ESI) [M+H] ⁺ =364.0.

Step 6: 2-Chloro-N-(3-((6-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept- Preparation of 2-yl)-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)pyrimidin-4-amine

3-((6-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-nitropyridine -2-yl)oxy)propan-1-amine (600mg, 1.65mmol, 1.0eq), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (429.8mg, 1.98mmol, 1.2eq) and N,N-diisopropylethylamine (853.5 mg, 6.6 mmol, 4.0 eq) was dissolved in isopropyl alcohol (6 mL), and the temperature was raised to 80°C for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=2:1) to obtain the target compound (300 mg, yield 33%).

LC-MS (ESI) [M+H] ⁺ =544.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.37 (d, J = 0.8Hz, 1H), 8.20 (d, J = 9.2Hz, 1H),8.05(s,1H),6.23(m,J＝9.2Hz,1H),4.81(d,J＝70.8Hz,1H),4.53-4.35(m,3H),4.34-4.12(m,3H ),3.80(d,J＝38.4Hz,1H),3.62(d,J＝5.6Hz,2H),3.38(d,J＝10.0Hz,1H),3.28-2.91(m,3H),2.16-1.96 (m,2H),1.93-1.75(m,2H),1.45(s,3H).

Step 7: 13-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-(trifluoromethyl base)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[4,6,10]triazacyclodeca Preparation of trioxane

At room temperature, 2-chloro-N-(3-((6-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept- 2-yl)-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)pyrimidin-4-amine (120mg, 0.22mmol, 1.0eq), iron powder (61.6mg ,1.1mmol, 5.0eq), ammonium chloride (76.7mg, 1.43mmol, 6.5eq), dissolved in ethanol (5mL) and water (1mL), reacted at 80°C for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by Prep-HPLC to obtain the target compound (60 mg, yield 57%).

LC-MS (ESI) [M+H] ⁺ =478.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.99 (s, 1H), 8.06 (s, 1H), 7.31 (t, J = 5.6 Hz,1H),7.24(d,J＝8.4Hz,1H),6.03(d,J＝8.4Hz,1H),4.57(s,2H),4.46(d,J＝6.0Hz,1H),4.34( s,1H),4.23(d,J＝6.0Hz,1H),4.15(m,J＝6.0Hz,2H),3.73(s,1H),3.27(d,J＝7.2Hz,3H),3.12( d, J＝9.2Hz, 1H), 3.02 (m, J＝8.8Hz, 2H), 1.82 (s, 3H), 1.66 (s, 1H), 1.47 (s, 3H).

Example 487

13-(7-oxa-2-azaspiro[3.5]non-2-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-( Nitrogen bridge)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 353, the compound of Example 487 was prepared, LC-MS (ESI) [M+H] ⁺ =437.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.04 (s, 1H) ,8.06(s,1H),7.32(d,J＝5.6Hz,1H),7.24(d,J＝8.4Hz,1H),5.90(d,J＝8.0Hz,1H),4.45(br s,2H ),3.66(s,4H),3.64-3.53(m,4H),3.28-3.27(m,2H),1.74-1.71(m,6H).

Example 488

(14-Fluoro-8-methyl-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxa [4,6,10]triazacyclotridec-13-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone

Referring to the preparation method of Example 460, the compound of Example 488 was prepared, LC-MS (ESI) [M+H] ⁺ =496.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.59 (s, 1H) ,8.17(s,1H),7.14-7.07(m,1H),6.94(d,J＝11.2Hz,1H),6.83(d,J＝6.8Hz,1H),4.40-4.32(m,1H), 4.12-3.91(m,6H),3.78-3.65(m,1H),3.09(s,3H),2.47-2.42(m,2H),2.06-1.95(m,2H),1.83-1.72(m,1H ),1.68-1.53(m,1H),1.27(d,J＝7.2Hz,3H).

Example 489

(6-Methoxy-2-azaspiro[3.3]hept-2-yl)(8-methyl-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2 ,6-(Nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazatridecane-13-yl)methanone

Referring to the preparation method of Example 476, the compound of Example 489 was prepared, LC-MS (ESI) [M+H] ⁺ =479.2; ¹ H NMR (400MHz, CD ₃ OD): δ8.26 (s, 1H), 7.79-7.58 (m, 2H), 5.16 (t, J = 11.6Hz, 1H), 4.85-4.76 (m, 2H), 4.37-4.23(m,1H),4.23-4.07(m,3H),3.96-3.81(m,1H),3.26(d,J＝1.2Hz,3H),2.64-2.57(m,2H),2.25- 2.11(m,2H),2.11-1.85(m,2H),1.42(d,J＝6.8Hz,3H).

Example 490

(6-methoxy-2-azaspiro[3.3]hept-2-yl)(6-methyl-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro -4,15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane-11 base) Methyl ketone

Referring to the preparation method of Example 199, the compound of Example 490 was prepared, LC-MS (ESI) [M+H] ⁺ =518.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.92 (s, 1H) ,9.12(s,1H),7.55(s,1H),7.51(s,2H),5.24-5.23(m,1H),5.15-5.07(m,1H),4.70-4.57(m,2H),4.12 -4.09(m,1H),4.05-3.99(m,2H),3.91(br s,1H),3.81-3.72(m,1H),3.11(s,3H),2.55-2.46(m,2H), 2.06-2.01(m,2H),1.87-1.8.3(m,1H),1.74-1.67(m,1H),1.31(d,J＝6.4Hz,3H).

Example 491

3-Chloro-12-fluoro-11-(4-(oxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15- (nitrogen bridge)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 455, the compound of Example 491 was prepared, LC-MS (ESI) [M+H] ⁺ =474.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.08 (d, J= 2.2Hz,1H),8.28(s,1H),6.85(d,J＝2.4Hz,1H),6.84-6.77(m,2H),6.61(d,J＝8.4Hz,1H),4.56(t, J＝6.4Hz,2H),4.46(t,J＝6.0Hz,2H),4.23-4.14(m,2H),3.51-3.44(m,1H),3.41-3.37(m,2H),3.03-3.01 (m,4H),2.45-2.38(m,4H),1.79-1.72(m,2H).

Example 492

11-(3,3-difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)-1 ,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6, 10]Triazacyclotridecane

Step 1: Preparation of 3-((6-chloro-3-nitropyridin-2-yl)oxy)propan-1-amine

Dissolve (3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester (10g, 30.14mmol, 1.0eq) in dichloromethane/trifluoroacetic acid ( 3/1) (40mL), react at room temperature for 1 hour. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated to obtain the crude target compound (6.98g), which is directly used in the next step.

LC-MS (ESI) [M+H] ⁺ =232.1.

Step 2: 2-chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)-7-((2 Preparation of -(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

3-[(6-Chloro-3-nitropyridin-2-yl)oxy]propan-1-amine (6.9g, 29.79mmol, 1.0eq), 2,4-dichloro-5-(trifluoro Methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (9.2g, 23.83mmol, 0.8eq) and diiso Propylethylamine (15.4g, 119.15mmol, 4.0eq) was dissolved in isopropyl alcohol (150mL) and reacted at 85°C for 1 hour. After the reaction was detected by LC-MS, the reaction solution was diluted with ethyl acetate (150 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, DCM:MeOH=20:1) to obtain the target compound (3.95g, yield 23% ).

LC-MS (ESI) [M+H] ⁺ =581.1.

Step 3: N-(3-((3-amino-6-chloropyridin-2-yl)oxy)propyl)-2-chloro-5-(trifluoromethyl)-7-((2- Preparation of (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2-Chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)-7-((2-(trifluoromethyl) Methylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1g, 1.72mmol, 1.0eq), iron powder (0.48g, 8.6mmol, 5.0eq) ) and ammonium chloride (0.46g, 8.6mmol, 5.0eq) were dissolved in ethanol/water (5/1) (18mL) mixed solvent, and reacted at 85°C for 1 hour. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, DCM:MeOH=40:1) to obtain the target compound (600 mg, yield 63%).

LC-MS (ESI) [M+H] ⁺ =551.1.

Step 4: 11-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,14- Preparation of hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

N-(3-((3-Amino-6-chloropyridin-2-yl)oxy)propyl)-2-chloro-5-(trifluoromethyl)-7-((2-(trimethyl) Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (600mg, 1.09mmol, 1.0eq), Xphos Pd G3 (90mg, 0.11mmol, 0.1eq) Dissolve cesium carbonate (1.06g, 3.26mmol, 3.0eq) in tert-butanol (30mL) and react at 80°C for 2 hours under nitrogen protection. LC-MS detected ~50% of the product. After diatomaceous earth filtration, the filtrate was concentrated and then separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (100 mg, yield 18%).

LC-MS (ESI) [M+H] ⁺ =515.2.

Step 5: 11-(3,3-difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl base)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[ 2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10] Preparation of triazacyclotridecane

11-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,14-hexahydro- 4,15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane (100mg, 0.19mmol ,1.0eq), 3,3-difluoro-1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxabora Cyclopent-2-yl)-1,2,3,6-tetrahydropyridine (87.71mg, 0.29mmol, 1.5eq), Xphos Pd G ₃ (16.42mg, 0.02mmol, 0.1eq) and potassium phosphate (164.87mg ,0.78mmol, 4.0eq) was dissolved in dioxane/water (10/1) (3.3mL), and reacted at 100°C for 1 hour under nitrogen protection. After the LC-MS detection reaction is completed, filter through diatomaceous earth, and the filtrate is concentrated and separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (35 mg, yield 28%).

LC-MS (ESI) [M+H] ⁺ =654.3.

Step 6: 11-(3,3-difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl base)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane

11-(3,3-Difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)- 1-((2-(Trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3 -b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane (30mg, 0.05mmol, 1.0eq) was dissolved in dichloromethane (1.5mL), Add trifluoroacetic acid (0.5 mL) and react at room temperature for 1 hour. The reaction solution was concentrated, tetrahydrofuran (1 mL) and ammonia water (0.5 mL) were added, and the reaction was continued for 0.5 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by Prep-HPLC to obtain the target compound (2.3 mg, yield 9%).

LC-MS (ESI) [M+H] ⁺ =523.9; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.78 (s, 1H), 8.84 (s, 1H),, 7.49-7.40 (m, 2H),7.20(s,1H),7.09(d,J＝7.6Hz,1H),6.29-6.19(m,1H),4.61(t,J＝6.4Hz,4H),4.50(t,J＝6.0 Hz, 2H), 3.82-3.74 (m, 1H), 3.34-3.23 (m, 4H), 2.97 (t, J = 12.0Hz, 2H), 1.85-1.72 (m, 2H).

Example 493

13-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro- 1H-2,6-(Nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Step 1: 13-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(trifluoromethyl)-7,8,9,10 - Preparation of tetrahydro-1H-2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

13-(3,3-Difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)- 7,8,9,10-tetrahydro-1H-2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane ( 20 mg, 0.04 mmol, 1.0 eq) was dissolved in ethanol (5 mL), 5% palladium on carbon (5 mg) was added, and the reaction was carried out under a hydrogen atmosphere of one atmosphere for 16 hours. After the reaction was detected by LC-MS, the palladium carbon was filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC to obtain the target compound (5.87 mg, yield 30%).

LC-MS (ESI) [M+H] ⁺ =487.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.48 (s, 1H), 8.13 (s, 1H), 7.43 (d, J = 7.6 Hz,2H),6.94(d,J=7.6Hz,1H),4.66-4.37(m,6H),3.66-3.55(m,1H),3.29-3.15(m,3H),3.08-2.97(m, 1H), 2.86 (d, J = 10.8Hz, 1H), 2.35 (d, J = 16.4Hz, 1H), 2.24-2.06 (m, 2H), 1.96-1.72 (m, 3H).

Example 494

3-Chloro-11-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge )pyrido[2,3-b]pyrrolo [2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 1-benzyl-4-(3,3-difluorocyclobutyl)piperazine

Dissolve 3,3-difluorocyclobutylamine hydrochloride (3g, 20.9mmol, 1.0eq) in EtOH (ethanol) (60mL), and then add N-benzyl-N,N-bis(2-chloro Ethyl)amine hydrochloride (6.74g, 25.08mmol, 1.2eq) and DIPEA (16.21g, 125.4mmol, 6eq) were reacted at 80°C for 16 hours under nitrogen protection. After the reaction was detected by LC-MS, the solvent was evaporated, water (100 mL) was added to quench, and extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=2:1) to obtain the target compound (2.5g, yield 45%).

LC-MS (ESI) [M+H] ⁺ =267.2; ¹ H NMR (400MHz, CDCl ₃ ): δ7.73 (s, 2H), 7.44 (s, 3H), 4.47 (s, 1H), 4.01 ( d,J＝14.4Hz,4H),3.60-3.53(m,4H),3.33(s,4H).

Step 2: Preparation of 1-(3,3-difluorocyclobutyl)piperazine

Dissolve 1-benzyl-4-(3,3-difluorocyclobutyl)piperazine (500mg, 1.88mmol, 1.0eq) in ethyl acetate (15mL), then add HOAc (0.02mL, 0.33mmol) ,0.18eq) and Pd(OH) ₂ /C (200mg, 1.42mmol, 0.76eq), reacted at 25°C for 16 hours under hydrogen protection. After the reaction was detected by LC-MS, it was filtered, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, DCM:MeOH=10:1) to obtain the target compound (300 mg, yield 91%).

LC-MS (ESI) [M+H] ⁺ =177.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ2.75-2.52 (m, 7H), 2.32-2.30 (m, 3H), 1.89 (s ,2H).

The preparation method of Example 199 from the third step to the eighth step was used to prepare the compound of Example 494, LC-MS (ESI) [M+H] ⁺ = 491.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11. 06(d,J＝2.0Hz,1H),8.15(s,1H),7.23(d,J＝8.4Hz,1H),6.83(d,J＝2.4Hz,1H),6.73(t,J＝6.0 Hz,1H),6.27(d,J＝8.4Hz,1H),4.47(s,2H),3.39(s,4H),3.30(s,4H),2.70(s,3H),2.41(s,4H ),1.75(s,2H).

Example 495

13-(3,3-difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-7 ,8,9,10-tetrahydro-1H-2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

Dissolve 3,3-difluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (30g, 127.53mmol, 1.0eq) in anhydrous dichloromethane (300mL), add triethylamine (64.53g, 637.67mmol, 5.0eq), add trifluoromethanesulfonic anhydride (71.97g, 255.07mmol, 2.0eq) dropwise under ice bath conditions, slowly warm to room temperature and react for 16 hours. Product formation was detected by TLC. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by flash chromatography. After purification (silica gel, PE:EA=5:1), the target compound (10.9g, 29.68mmol, yield 23%) was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ6.57 (s, 1H), 4.26 (q, J = 4.0Hz, 2H), 4.04 (t, J = 10.8Hz, 2H), 1.51 (s, 9H) .

Step 2: 3,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydrogen Preparation of pyridine-1(2H)-carboxylic acid tert-butyl ester

3,3-Difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (9g, 24.5mmol, 1.0 eq), pinacol diborate (6.84g, 26.95mmol, 1.1eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (0.9g, 1.23mmol, 0.05eq) ) and potassium acetate (9.62g, 98.02mg, 4.0eq) were dissolved in dioxane (230mL), replaced with nitrogen, and reacted at 80°C for 7 hours. TLC detected product formation, filtered, and washed the filter cake with ethyl acetate. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=5:1) to obtain the target compound (6g, yield 59%).

¹ H NMR (400MHz, CDCl ₃ ): δ6.88 (s, 1H), 4.06 (s, 2H), 3.78 (t, J = 10.8Hz, 2H), 1.47 (s, 9H), 1.30 (s, 12H) ).

Step 3: 3,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3, Preparation of 6-tetrahydropyridine

3,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-tert-butylcarboxylate (2g, 5.79mmol, 1.0eq) was dissolved in dichloromethane (6mL), trifluoroacetic acid (2mL) was added under ice bath, and the reaction was carried out at room temperature for 6 hours. After the TLC detection reaction is completed, use triethylamine to adjust the pH to about 8, and directly concentrate the reaction solution to obtain a crude target compound (1.3g), which is directly used in the next step.

Step 4: 3,3-difluoro-1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle Preparation of pent-2-yl)-1,2,3,6-tetrahydropyridine

3,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetramethyl Hydropyridine (1.3g, 5.3mmol, 1eq), oxetan-3-one (3.06g, 42.44mmol, 8.0eq) and acetic acid (0.32g, 5.3mmol, 1.0eq) were dissolved in methanol (30mL) and added Add an appropriate amount of molecular sieve and react at 50°C for 1 hour. After cooling to room temperature, sodium cyanoborohydride (1.31g, 21.22mmol, 4.0eq) was added and reacted at room temperature for 16 hours. After the reaction is detected by LC-MS, filter through diatomaceous earth, wash with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate with After separation and purification by flash chromatography (silica gel, PE:EA=3:1), the target compound (780 mg, yield 49%) was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ6.91 (t, J = 3.2Hz, 1H), 4.68 (d, J = 6.4Hz, 4H), 3.88-3.75 (m, 1H), 3.14 (dd, J =8.8,5.6Hz,2H),2.85(t,J=11.2Hz,2H),1.29(s,12H).

Step 5: 13-(3,3-difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl base)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[4,6,10]triazacyclodeca Preparation of trioxane

13-Chloro-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[ 4,6,10]triazacyclotridecane (100mg, 0.29mmol, 1eq), 3,3-difluoro-1-(oxetan-3-yl)-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (130.66mg, 0.43mmol, 1.5eq), XPhos Pd G3 (24.46mg, 0.03mmol, 0.1eq) and potassium phosphate (245.6mg, 1.16mmol, 4.0eq) were dissolved in dioxane/water (10/1) (3.3mL). React at 100°C for 1 hour under nitrogen protection. After the reaction was detected by LC-MS, filter through diatomaceous earth, and the filtrate was concentrated and separated and purified by flash chromatography (silica gel, PE:EA=1:1) to obtain the target compound (24 mg, yield 17%).

LC-MS (ESI) [M+H] ⁺ =484.9; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.58 (s, 1H), 8.14 (s, 1H), 7.48 (d, J = 7.6 Hz,2H),7.22(s,1H),7.13(d,J＝7.6Hz,1H),4.55(dt,J＝12.4,6.4Hz,6H),3.83-3.73(m,1H),3.31-3.26 (m, 4H), 2.97 (t, J = 12.0Hz, 2H), 1.80 (s, 2H).

Example 496

10-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-12-methyl-3-(trifluoromethyl)-5,6,7,8,10 ,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triaza cyclotridecane

Referring to the preparation method of Example 1 or 443, the compound of Example 496 was prepared, LC-MS (ESI) [M+H] ⁺ =511.4; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.60 (s, 1H),7.44(d,J＝5.2Hz,2H),6.17(t,J＝5.7Hz,1H),4.97-4.74(m,1H),4.62-4.52(m,2H),4.51-4.39(m ,2H),4.29-4.12(m,3H),3.62-3.55(m,3H),3.18-3.13(m,1H),2.77-2.70(m,1H),2.15(s,3H),2.04-1.97 (m,3H),1.92-1.79(m,3H).

Example 497

3-Chloro-12-fluoro-11-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro -4,15-(Nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 455, the compound of Example 497 was prepared, LC-MS (ESI) [M+H] ⁺ =488.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.08 (s, 1H) ,8.28(s,1H),6.89-6.76(m,3H),6.59(d,J＝8.6Hz,1H),4.57-4.47(m,4H),4.26-4.13(m,2H),3.81-3.63 (m,1H),3.39(dd,J＝10.6,5.2Hz,2H),3.13(d,J＝11.2Hz,1H),3.06(d,J＝9.2Hz,1H),2.86(t,J＝ 9.4Hz, 1H), 2.73-2.56 (m, 2H), 2.21 (t, J = 10.2Hz, 1H), 1.75 (s, 2H), 0.89 (d, J = 5.4Hz, 3H).

Example 498

11-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidin-1-yl)-3-chloro-1 ,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6, 10]Triazacyclotridecanecarboxylate

Step 1: Preparation of 4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester

Dissolve 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1g, 4.6mmol, 1.0eq) in ethanol (20mL), add (1S,4S)-2-oxa-5- Azabicyclo[2.2.1]heptane hydrochloride (624mg, 4.6mmol, 1.0eq) and acetic acid (0.5mL), slowly add sodium cyanoborohydride (853mg, 13.8mmol, 3.0eq) and react at room temperature 16 hours. After the reaction is detected by LC-MS, add water (50mL), extract with dichloromethane (100mL*3), combine the organic phases, wash with brine twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, use flash chromatography The target compound (600 mg, yield 43%) was obtained by separation and purification (silica gel, DCM:EA=10:1).

LC-MS (ESI) [M+H] ⁺ =301.2.

Step 2: Preparation of: (1S,4S)-5-(3-fluoropiperidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (600 mg, 2 mmol, 1.0eq) was dissolved in dichloromethane (5mL), TFA (5mL) was added, and the reaction was carried out at room temperature for 2 hours. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated to obtain the crude target compound, which is directly used in the next step.

LC-MS (ESI) [M+H] ⁺ =201.1.

From the third step to the sixth step, refer to the preparation method of Example 194 to prepare the compound of Example 498, LC-MS (ESI) [M+H] ⁺ =515.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11 .05(s,1H),8.12(s,1H),7.22(d,J＝8.4Hz,1H),6.82(d,J＝1.8Hz,1H),6.71(t,J＝6.4Hz,1H) ,6.28(d,J＝8.4Hz,1H),4.85(d,J＝49.2Hz,1H),4.58-4.50(m,2H),4.44-4.31(m,2H),4.10(s,1H), 3.93-3.88(m,1H),3.71(d,J＝18.7Hz,1H),3.57-3.49(m,1H),3.38-3.31(m,2H),3.15-2.71(m,4H),2.45- 2.38(m,1H),1.83-1.67(m,5H),1.62(d,J=8.8Hz,1H).

Example 499

(12-Fluoro-6-methyl-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[ 2,3-g][1]oxa[4,6,10]triazatridecane-11-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl )methyl ketone

The first step: Preparation of ((2,5-difluoro-4-nitrophenyl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone

Dissolve 2,5-difluoro-4-nitrobenzoic acid (1g, 4.92mmol, 1.0eq) and 6-methoxy-2-azaspiro[3.3]heptane (626mg, 4.92mmol, 1.0eq) To N,N-dimethylformamide (5 mL), add N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphoric acid Urea (2.81g, 7.39mmol, 1.5eq) and diisopropylethylamine (1.91g, 14.77mmol, 3.0eq) were reacted at room temperature for 16 hours. After the reaction is detected by LC-MS, water is added to the reaction solution, extracted with ethyl acetate (50mL*3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography to obtain the target compound. (1.0g, yield 65%).

LC-MS (ESI) [M+H] ⁺ =313.1.

Step 2: 3-((2-chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)amino)butan-1-ol

2,4-Dichloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2g, 5.18mmol, 1.0eq) was dissolved in isopropanol (50mL), 3-aminobutanol (923mg, 10.36mmol) was added, and the reaction was carried out at 85°C for 1 hour. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (PE:EA=3:1) to obtain the target compound (1.5g, yield 66%).

LC-MS (ESI) [M+H] ⁺ =439.2.

Step 3: (5-(3-((2-chloro-5-(trifluoromethyl))-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)butoxy)-2-fluoro-4-nitrophenyl)(6-methoxy-2-azaspiro[3.3]hept-2- Preparation of methyl ketone

3-((2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino)butan-1-ol (1g, 2.28mmol, 1.0eq) was dissolved in THF (50mL), and sodium hydrogen (182mg, 4.56mmol, 2.0eq, purity 60%) was added at 0°C. , react at 0°C for half an hour. Add (2,5-difluoro-4-nitrophenyl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone (712mg, 2.28mmol, 1.0eq), and add React at room temperature for 2 hours. After the reaction is detected by LC-MS, add water to quench, evaporate the solvent, extract with ethyl acetate (100mL*3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate with Separate and purify by flash chromatography (silica gel, PE:EA=2:1) to obtain the target compound (1g, yield 59%).

LC-MS (ESI) [M+H] ⁺ =731.2.

Step 4: (4-amino-5-(3-((2-chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)butoxy)-2-fluorophenyl)(6-methoxy-2-azaspiro[3.3]hept-2-yl ) Preparation of Methyl Ketone

(5-(3-((2-chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)butoxy)-2-fluoro-4-nitrophenyl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methyl Ketone (1g, 1.37mmol, 1.0eq) was added to ethanol (50mL) and water (5mL), iron powder (381mg, 6.84mmol, 5.0eq) and ammonium chloride (731mg, 13.68mmol, 10.0eq) were added, and the reaction React at 80°C for 16 hours. After the LC-MS detection reaction is completed, filter the reaction solution. After the filtrate was concentrated, water was added and extracted with ethyl acetate (50mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude target compound (800 mg, 83%).

LC-MS (ESI) [M+H] ⁺ =701.2.

Step 5: (12-fluoro-6-methyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6, 7,8,14-hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane Preparation of -11-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl]methanone

(4-Amino-5-(3-((2-chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrole And[2,3-d]pyrimidin-4-yl)amino)butoxy)-2-fluorophenyl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone (800mg, 1.14mmol) was dissolved in 1,4-dioxane (50mL), and tris(dibenzylideneacetone)dipalladium (104mg, 011mmol, 10%), 2-bicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl (108 mg, 0.23 mmol, 20%) and cesium carbonate (1.11 g, 3.42 mmol, 3.0 eq) were reacted at 90°C for 4 hours. After the reaction was detected by LC-MS, the reaction solution was filtered. After the filtrate was concentrated, it was separated and purified by flash chromatography (silica gel, PE:EA=2:1) to obtain the target compound (500 mg, yield 65%).

LC-MS (ESI) [M+H] ⁺ =665.3.

Step 6: ((12-fluoro-6-methyl-3-(trifluoromethyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[ b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecan-11-yl)(6-methoxy-2-azaspiro[3.3] Preparation of hept-2-yl)methanone

(12-Fluoro-6-methyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7,8 ,14hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane-11-yl )(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone (200 mg, 0.3 mmol) was added to dichloromethane (5 mL), then trifluoroacetic acid (2 mL) was added, and React at room temperature for 1 hour. Then the reaction solution was concentrated under reduced pressure, methanol (5 mL) was added, and ammonia water (2 mL) was added, and the reaction was continued at room temperature for 1 hour. After the LC-MS detection reaction is completed, the reaction solution is diluted with water, extracted with ethyl acetate (50mL*3), the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated, separated and purified by flash chromatography to obtain the target product Compound (41 mg, yield 25%).

LC-MS (ESI) [M+H] ⁺ =535.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.89 (s, 1H), 8.98 (s, 1H), 7.55 (s, 1H), 7.08-7.06(m,1H),6.92(d,J＝11.6Hz,1H),5.24(d,J＝7.2Hz,1H),4.38-4.35(m,1H),4.14-4.07(m,2H) ,4.01(s,2H),4.12-4.09(m,2H),3.77-3.68(m,1H),3.09(s,3H),2.48-2.44(m,2H),2.05-1.98(m,2H) ,1.80-1.76(m,1H),1.68-1.61(m,1H),6.92(d,J＝6.8Hz,3H).

Example 500

3-Cyclopropyl-11-(5-(3-methyloxetan-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)-1,5, 6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]tri Azacyclotridecane

Referring to the preparation method of Example 199, the compound of Example 500 was prepared, LC-MS (ESI) [M+H] ⁺ =489.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.43 (s, 1H) ,7.82(s,1H),7.20(d,J＝8.0Hz,1H),6.49(s,1H),6.34(s,1H),5.98(d,J＝8.0Hz,1H),4.64(s, 1H),4.54(s,1H),4.47(d,J＝6.0Hz,1H),4.37(s,1H),4.25(d,J＝6.0Hz,1H),4.21-4.10(m,2H), 3.72(s,1H),3.26(s,3H),3.15(d,J＝8.8Hz,1H),3.02(m,J＝9.6Hz,2H),1.93(s,1H),1.83(s,3H ), 1.69 (s, 1H), 1.48 (s, 3H), 0.77 (d, J = 6.8Hz, 2H), 0.52-0.38 (m, 2H).

Example 501

11-(4-(oxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)imidazo[4 ,5-g]pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 199, the compound of Example 501 was prepared, LC-MS (ESI) [M+H] ⁺ =423.90; ¹ H NMR (400MHz, DMSO-d ₆ ): δ12.18 (s, 1H) ,8.19(s,1H),7.70(s,1H),7.53(s,1H),7.24(d,J＝8.4Hz,1H),6.27(d,J＝8.4Hz,1H),4.57(t, J＝6.4Hz,2H),4.48(t,J＝6.0Hz,4H),3.41(s,4H),3.30-3.19(m,3H),2.38(s,4H),1.73(s,2H).

Example 502

14-fluoro-13-(4-(oxetan-3-yl)piperazin-1-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2 ,6-(Nitrogen-bridged)benzo[b][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 427, the compound of Example 502 was prepared, LC-MS (ESI) [M+H] ⁺ =469.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ9.67 (s, 1H) ,8.25(s,1H),8.00(s,1H),7.01(d,J＝13.4Hz,1H),6.77(d,J＝8.2Hz,1H),4.94(d,J＝6.2Hz,2H) ,4.78(t,J＝7.6Hz,2H),4.57(s,1H),4.29(s,2H),4.04(s,5H),3.42(d,J＝4.6Hz,2H),3.21(d, J＝31.4Hz,3H),1.84(s,2H).

Example 503

3-Chloro-11-(3-fluoro-4-morpholinopiperidin-1-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2 ,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecanecarboxylate

Step 1: Preparation of tert-butyl 3-fluoro-4-(morpholin-4-yl)piperidine-1-carboxylate

Dissolve 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2g, 9.21mmol, 1.0eq) in ethanol (20mL), add morpholine (802mg, 9.21mmol, 1.0eq) and Acetic acid (0.5mL), slowly add sodium cyanoborohydride (1.71g, 27.63mmol, 3.0eq), and react at room temperature for 16 hours. After the reaction is detected by LC-MS, add water (50mL), extract with dichloromethane (100mL*3), combine the organic phases, wash with brine twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate, use flash chromatography The target compound was separated and purified (silica gel, DCM:EA=10:1) to obtain the target compound (2g, yield 75%).

LC-MS (ESI) [M+H] ⁺ =289.2.

Step 2: Preparation of 4-(3-fluoropiperidin-4-yl)morpholine

Dissolve 3-fluoro-4-(morpholin-4-yl)piperidine-1-carboxylic acid tert-butyl ester (2g, 6.94mmol, 1eq) in dichloromethane (5mL), add TFA (2mL), and add React at room temperature for 2 hours. After the LC-MS detection reaction is completed, the reaction solution is directly concentrated to obtain the crude target compound, which is directly used in the next step.

LC-MS (ESI) [M+H] ⁺ =189.1.

From the third step to the sixth step, refer to the preparation method of Example 194 to prepare the compound of Example 503, LC-MS (ESI) [M+H] ⁺ =503.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11 .06(d,J＝1.8Hz,1H),8.15(s,1H),7.21(d,J＝8.4Hz,1H),6.83(d,J＝2.2Hz,1H),6.73(t,J＝ 6.2Hz,1H),6.28(d,J＝8.4Hz,1H),5.08(d,J＝49.2Hz,1H),4.51-4.47(m,3H),4.27(d,J＝12.6Hz,1H) ,3.34-3.30(m,3H),3.03-2.68(m,3H),2.58-2.49(m,5H),2.46-2.42(m,1H),1.85-1.69(m,5H).

Example 504

11-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidin-1-yl)-3-chloro-12 -Fluoro-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1]oxa[4,6, 10]Triazacyclotridecanecarboxylate

Referring to the preparation method of Example 455, the compound of Example 504 was prepared, LC-MS (ESI) [M+H] ⁺ =532.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.08 (d, J= 2.4Hz,1H),8.29(s,1H),6.86(d,J＝2.4Hz,1H),6.81(d,J＝13.8Hz,2H),6.61(d,J＝8.6Hz,1H),4.82 (d,J＝50.3Hz,1H),4.35(s,1H),4.19(s,2H),3.92-3.89(m,1H),3.73(d,J＝20.2Hz,1H),3.59-3.49( m,2H),3.39(d,J＝5.4Hz,2H),3.08-2.89(m,,2H),2.92-2.72(m,2H),2.67(s,1H),2.61(s,1H), 1.82(d,J=10.4Hz,1H), 1.74(d,J=8.4Hz,4H), 1.63(d,J=9.4Hz,1H).

Example 505

(3,12-difluoro-6-methyl-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g] [1]oxa[4,6,10]triazacyclodecane-11-yl)(6-methoxy-2-azaspiro[3.3]hept-2-yl)methanone

Referring to the preparation method of Example 499, the compound of Example 505 was prepared, LC-MS (ESI) [M+H] ⁺ =485.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.71 (s, 1H) ,8.77(s,1H),7.15-6.99(m,1H),6.89(d,J＝11.6Hz,1H),6.77-6.59(m,2H),4.36(d,J＝10.8Hz,1H), 4.09-3.90(m,6H),3.82-3.64(m,1H),3.09(s,3H),2.47-2.42(m,2H),2.09-1.96(m,2H),1.80-1.60(m,2H ), 1.27 (d, J = 6.8Hz, 3H).

Example 506

3-Cyclopropyl-11-(4-(oxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen Bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 506 was prepared, LC-MS (ESI) [M+H] ⁺ =463.5; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.70 (s, 1H) ,8.28(s,1H),7.27(d,J＝8.2Hz,1H),6.88(s,1H),6.41(s,1H),6.31(d,J＝7.4Hz,1H),4.60(t, J＝5.8Hz,7H),4.57-4.38(m,4H),3.66-3.35(m,10H),2.46-2.41(m,1H),2.02-1.92(m,1H),1.79(s,2H) ,0.82-0.77(m,2H),0.49-0.46(m,2H).

Example 507

11-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidin-1-yl)-3-cyclopropyl -1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4, 6,10]Triazacyclotridecane

Referring to the preparation method of Example 199, the compound of Example 507 was prepared, LC-MS (ESI) [M+H] ⁺ =521.2; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.44 (s, 1H) ,7.90(s,1H),7.21(d,J＝8.4Hz,1H),6.51(t,J＝5.6Hz,1H),6.34(s,1H),6.27(d,J＝8.4Hz,1H) ,4.85(d,J＝48.4Hz,1H),4.49(s,2H),4.42-4.32(m,2H),4.08(s,1H),3.91(m,J＝12.0Hz,1H),3.72( d,J＝18.8Hz,1H),3.52(d,J＝6.4Hz,1H),3.09-2.95(m,2H),2.85(s,1H),2.70(d,J＝20.8Hz,2H), 2.42(m,J＝16.0Hz,2H),1.94(s,1H),1.82-1.66(m,5H),1.62(d,J＝8.8Hz,1H),0.78(m,J＝8.0Hz,2H ),0.46(d,J=3.2Hz,2H).

Example 508

3-Chloro-11-(6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15 -(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester

6-Hydroxy-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (3g, 14.07mmol, 1.0eq), 2,2-difluoro-2-(fluorosulfonyl)acetic acid (3.76g , 21.1mmol, 1.5eq) and copper iodide (0.54g, 2.81mmol, 0.2eq) were dissolved in acetonitrile (30mL), heated to 50°C and reacted for 2 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated and separated and purified by flash chromatography (silica gel, PE:EA=3:1) to obtain the target compound (1.7g, yield 46%).

LC-MS (ESI) [M+H] ⁺ =264.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ6.59 (t, J = 75.6Hz, 1H), 4.54-4.41 (m, 1H), 3.81(d,J＝20.0Hz,4H),2.54(d,J＝3.2Hz,2H),2.29-2.16(m,2H),1.36(s,9H).

Step 2: Synthesis of 6-(difluoromethoxy)-2-azaspiro[3.3]heptane

Dissolve 6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (1.7g, 6.46mmol, 1.0eq) in dichloromethane (20mL), add trifluoro Acetic acid (6 mL), react at room temperature for 2 hours. TLC detects that the reaction is complete, and the reaction solution is directly concentrated to obtain the crude target compound (1g), which is directly used in the next step.

LC-MS (ESI) [M+H] ⁺ =164.1.

From the third step to the eighth step, refer to the preparation method of Example 199 to prepare the compound of Example 508, LC-MS (ESI) [M+H] ⁺ = 478.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11 .04(s,1H),8.10(s,1H),7.20(d,J＝8.0Hz,1H),6.83-6.78(m,1H),6.71(t,J＝6.0Hz,1H),6.53( d,J＝75.6Hz,1H),5.84(d,J＝8.0Hz,1H),4.53(m,J＝16.4Hz,3H),3.88(s,2H),3.84(s,2H),3.30- 3.28(m,1H),2.62-2.54(m,2H),2.35-2.19(m,3H),1.74(s,2H).

Example 509

3-Chloro-11-(4-(3-methyloxetan-3-yl)piperazin-1-yl)-1,5,6,7,8,14-hexahydro-4,15- (nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of 1-(3-(1H-1,2,3-triazol-1-yl)oxetan-3-yl)-4-benzylpiperazine

1-Benzylpiperazine (500mg, 2.84mmol) was added to toluene (10mL), followed by oxetan-3-one (225mg, 3.12mmol) and 1H-1,2,3-triazole (235mg ,3.41mmol), the reaction was carried out at 125°C for 2 hours. After the TLC detection reaction is completed, it is cooled to room temperature, and the reaction solution is used directly in the next step without treatment.

Step 2: Preparation of 1-benzyl-4-(3-methyloxetan-3-yl)piperazine

Add methylmagnesium bromide solution (3M, 2.5mL) to tetrahydrofuran (2.5mL), and add 1-(3-(1H-1,2,3-triazol-1-yl)oxygen from the previous step at 5°C Heterocycline-3-yl)-4-benzylpiperazine in toluene solution (10 mL, 800 mg), react at room temperature for 2 hours. After the reaction is detected by LC-MS, the reaction solution is quenched with ice water, extracted with ethyl acetate (50mL*3), the organic phases are combined, washed with saturated sodium chloride aqueous solution (10mL), dried over anhydrous sodium sulfate, and filtered. , after the filtrate is concentrated, the target is obtained The crude compound (0.2g, yield 30%).

LC-MS (ESI) [M+H] ⁺ =247.2.

Step 3: Preparation of 1-(3-methyloxetan-3-yl)piperazine

Dissolve 1-benzyl-4-(3-methyloxetan-3-yl)piperazine (200 mg, 0.81 mmol) in ethanol (10 mL), add palladium on carbon (100 mg, 10%), and mix under hydrogen Under the atmosphere, the reaction was carried out at 60°C for 4 hours. LC-MS detected that the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude target compound (80 mg, yield 63%).

LC-MS (ESI) [M+H] ⁺ =157.2.

The fourth to seventh steps refer to the preparation method of Example 194 to prepare the compound of Example 509. LC-MS (ESI) [M+H] ⁺ =471.2; ¹ H NMR (400MHz, CD ₃ OD): δ7. 28(d,J＝8.0Hz,1H),6.68(s,1H),6.28(d,J＝8.4Hz,1H),4.65-4.58(m,4H),4.29-4.28(m,2H),3.51 -3.49(m,4H),3.45-3.42(m,2H),2.53-2.50(m,4H),1.88-1.87(m,2H),1.40(s,3H).

Example 510

2-(3-Chloro-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1 ]oxa[4,6,10]triazacyclotridecan-11-yl)-6-methyl-2-azaspiro[3.3]heptan-6-ol

Step 1: Synthesis of 6-hydroxy-6-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester

Dissolve 6-oxo-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (10g, 47.34mmol, 1.0eq) in tetrahydrofuran (150mL), add methyl bromide dropwise in an ice bath under nitrogen protection Magnesium chloride (47.3mL, 2mol/L, 4.0eq), react for 2 hours. After TLC detects that the reaction is complete, pour the reaction solution into saturated ammonium chloride aqueous solution (150mL), extract with ethyl acetate (100mL*3), combine the organic phases, wash twice with saturated brine, dry with anhydrous sodium sulfate, and filter , after the filtrate was concentrated, the crude target compound (10 g) was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ3.91 (d, J=10.8Hz, 4H), 2.26 (s, 4H), 1.43 (s, 9H), 1.32 (s, 3H).

Step 2: Synthesis of 6-methyl-2-azaspiro[3.3]heptan-6-ol

Dissolve 6-hydroxy-6-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (10g, 43.99mmol, 1.0eq) in methanol hydrochloride (4M) (100mL), and react at room temperature 4 hours. After the reaction was detected by LC-MS, the reaction solution was directly concentrated to obtain the crude target compound (5g).

LC-MS (ESI) [M+H] ⁺ =128.0.

From the third step to the eighth step, refer to the preparation method of Example 199 to prepare the compound of Example 510. LC-MS (ESI) [M+H] ⁺ = 442.1; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11 .04(d,J＝2.0Hz,1H),8.08(s,1H),7.19(d,J＝8.0Hz,1H),6.82(d,J＝2.4Hz,1H),6.70(t,J＝ 6.0Hz,1H),5.83(d,J＝8.0Hz,1H),4.89(s, 1H),4.47(s,2H),3.84(d,J＝28.4Hz,4H),3.31-3.28(m,2H),2.27-2.14(m,4H),1.74(s,2H),1.20(s ,3H).

Example 511

3-Chloro-12-fluoro-11-((3R,4S)-3-fluoro-4-morpholinepiperidin-1-yl)-1,5,6,7,8,14-hexahydro-4, 15-(Nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: Preparation of tert-butyl 3-fluoro-4-morpholinepiperidine-1-carboxylate

Dissolve 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (500mg, 2.3mmol, 1.0eq) in DCM (5mL), add morpholine (220.57mg, 2.53mmol, 1.1eq), React at 25°C for 10 minutes. Add sodium triethoxyborohydride (731.7mg, 3.45mmol, 1.5eq) in batches and react for 3 hours. After the reaction is detected by LC-MS, the reaction solution is quenched with water (10 mL), extracted with dichloromethane (20 mL*3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated by flash chromatography. After purification (silica gel, DCM:MeOH=10:1), the target compound (550 mg, yield 83%) was obtained as a white solid.

LC-MS (ESI) [M+H] ⁺ =288.80.

Step 2: Preparation of 4-(3-fluoropiperidin-4-yl)morpholine

Dissolve 3-fluoro-4-morpholinepiperidine-1-carboxylic acid tert-butyl ester (550mg, 1.91mmol, 1.0eq) in dioxane (5mL), and add dioxane hydrochloride solution (5mL, 4M), react at 25°C for 16 hours. LC-MS detected that the reaction was complete, concentrated directly, and slurried with ethyl acetate for 20 minutes. After suction filtration, the crude hydrochloride salt of the target compound (450 mg) was obtained. It was used directly in the next reaction without further purification.

LC-MS (ESI) [M+H] ⁺ =189.20.

From the third step to the eighth step, refer to the preparation method of Example 455 to prepare the compound of Example 511, LC-MS (ESI) [M+H] ⁺ =519.85; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11 .08(s,1H),8.29(s,1H),6.85(d,J＝2.4Hz,1H),6.83-6.78(m,2H),6.60(d,J＝8.4Hz,1H),5.04( d,J＝50.0Hz,1H),4.18(s,2H),3.59(s,5H),3.40(t,J＝10.8Hz,3H),2.96-2.70(m,2H),2.59(s,4H ), 2.39-2.36 (m, 1H), 1.93 (d, J = 8.8Hz, 1H), 1.75 (s, 3H).

Example 512

11-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidin-1-yl)-1,5,6 ,7,8,14-hexahydro-4,15-(nitrogen bridge)imidazo[4,5-g]pyrido[2,3-b][1]oxa[4,6,10]triazo heterocyclotridecane

Referring to the preparation method of Example 194 or 199, the compound of Example 512 was prepared, LC-MS (ESI) [M+H] ⁺ =482.2; ¹ H NMR (400MHz, CD ₃ OD): δ12.18 (s, 1H ),8.13(s,1H),7.70(s,1H),7.58(br s,1H),7.23(d,J＝8.4Hz,1H),6.33-6.29(m,1H),4.68-4.47(m ,3H),4.32(s,1H),4.17-4.06(m,1H),3.92-3.86(m,1H),3.74-3.61(m,2H),3.54-3.51(m,1H),3.28-3.26 (m,2H),3.19-3.10(m,1H),3.03-2.96(m,2H),2.87-2.72(m,1H),2.49-2.46(m,1H),2.03-1.87(m,1H) ,1.73-1.68(m,3H),1.60-1.58(m,1H),1.54-1.38(m,1H).

Example 513

3-Chloro-7,7-difluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro- 4,15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 194, the compound of Example 513 was prepared, LC-MS (ESI) [M+H] ⁺ =478.0; ¹ H NMR (400MHz, DMSO-d ₆ ): δ11.16 (d, J= 2.2Hz,1H),8.30(s,1H),7.27(d,J＝8.2Hz,1H),7.01(t,J＝6.4Hz,1H),6.89(d,J＝2.4Hz,1H),5.94 (d,J＝8.0Hz,1H),4.71(s,2H),3.90(s,2H),3.85(s,2H),3.82-3.75(m,2H),3.12(s,3H),2.47- 2.45(m,2H),2.11-1.97(m,2H).

Example 514

3-Chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15-(methyl Bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

The first step: tert-butyl(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy)propyl Preparation of carbamate

tert-Butyl (3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)carbamate (5g, 15.07mmol, 1eq), 6-methoxy-2- Azaspiro[3.3]heptane (2.49g, 19.59mmol, 1.3eq) and triethylamine (6.1g, 60.29mmol, 4eq) were dissolved in DMF (70mL), reacted at 80°C for 2 hours under nitrogen protection, LC- MS detection reaction was complete. Pour the reaction solution into 100 mL of water. Extract with ethyl acetate (100mL*2), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and mix the sample, and use flash chromatography to separate and purify (silica gel, PE:EA=2:1) to obtain Target compound (6g, yield 94%).

LC-MS (ESI) [M+H] ⁺ =367.2; ¹ H NMR (400MHz, CDCl ₃ ): δ8.22 (d, J = 8.8 Hz, 1H), 5.75 (d, J = 8.8 Hz, 1H) ,5.30(s,1H),4.49(t,J＝6.0Hz,2H),4.11(d,J＝10.8Hz,4H),3.84(t,J＝6.8Hz,1H),3.35(t,J＝ 6.0Hz,2H),3.25(s,3H),2.61-2.46(m,2H),2.28-2.11(m,2H),2.06-1.92(m,2H),1.45(s,9H).

Step 2: 3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy)propan-1-amine Preparation

tert-Butyl(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy)propyl)amino Formate (3.5g, 8.28mmol, 1eq) was dissolved in dichloromethane (15mL), trifluoroacetic acid (5mL) was added at room temperature and stirred for 2 hours. LC-MS detected that the reaction was complete, and the reaction solution was directly concentrated to obtain the crude target compound ( 3g).

LC-MS (ESI) [M+H] ⁺ =322.7.

Step 3: 3,6-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine-2- Preparation of methyl)oxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy)propan-1-amine (3g, Crude product, obtained from the reaction in the previous step), 3,4,6-trichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b] Pyridine (4.37g, 12.42mmol, 1.5eq) and DIEA (8.56g, 66.26mmol, 8eq) were dissolved in nitrogen methylpyrrolidone (40mL), heated to 100°C and reacted for 6 hours. LC-MS detected that the reaction was complete, and the reaction solution was Pour into 100mL of water, extract with ethyl acetate (100mL*3), combine the organic phases and wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and use flash chromatography to separate and purify (silica gel, PE:EA=1: 1), the target compound (800 mg, yield 15%) was obtained.

LC-MS (ESI) [M+H] ⁺ =637.1.

Step 4: N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl) Preparation of -3,6-dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

3,6-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy methyl)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (500mg, 0.78mmol, 1eq ) dissolve To ethanol/water (5/1) (12mL), add iron powder (218.94mg, 3.92mmol, 5eq) and ammonium chloride (209.72mg, 3.92mmol, 5eq), heat to 80°C and stir for 1 hour, LC-MS After checking that the reaction is complete, the reaction solution is directly concentrated and mixed, and separated and purified by flash chromatography (silica gel, DCM:MeOH=15:1) to obtain the target compound (250 mg, yield 52%).

LC-MS (ESI) [M+H] ⁺ =607.0.

Step 5: 3-chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1,5,6,7,8,14-hexahydro-4,15-(methyl bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxy Preparation of hetero[4,6,10]triazacyclotridecane

N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl)-3, 6-Dichloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (250mg, 0.41mmol, 1eq) , tBuBrettPhos Pd G6Br (cas: 2691807-28-8) (33.58mg, 0.1eq) and cesium carbonate (536.2mg, 1.65mmol, 3eq) were dissolved in dioxane (10mL), stirred at 100°C for 2 hours under nitrogen protection , LC-MS detects that the reaction is complete, filter out the insoluble matter through diatomaceous earth, rinse the filter cake with ethyl acetate, concentrate the filtrate and mix the sample, and use flash chromatography to separate and purify (silica gel, DCM:MeOH=20:1) to obtain the target Compound (84 mg, yield 36%).

LC-MS (ESI) [M+H] ⁺ =571.0.

Step 6: 3-Chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15 Preparation of -(methyl-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

3-Chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1,5,6,7,8,14-hexahydro-4,15-(methyl bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4 ,6,10] triazacyclotridecane (84mg, 0.15mmol, 1eq) was dissolved in dichloromethane (3mL), trifluoroacetic acid (1mL) was added at room temperature and stirred for 1 hour, the reaction solution was directly concentrated, tetrahydrofuran (4mL) ), add 2 mL ammonia and stir for 1 hour. LC-MS detects that the reaction is complete. The reaction solution is concentrated and separated and purified by Prep-HPLC (C18, 0.05% NH ₄ OH aqueous solution, MeCN) to obtain the target compound (17.52 mg, yield 27 %).

LC-MS (ESI) [M+H] ⁺ =440.9; ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.83 (s, 1H), 7.97 (s, 1H), 7.30 (d, J = 8.0 Hz,1H),6.82(d,J＝2.4Hz,1H),5.96(d,J＝8.0Hz,1H),5.80(s,1H),5.10(s,1H),4.30(s,2H), 3.85(d,J＝21.2Hz,4H),3.80-3.74(m,1H),3.44-3.36(m,2H),3.12(s,3H),2.47-2.45(m,2H),2.09-1.98( m,2H),1.84-1.74(m,2H).

Example 515

11-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-3-(trifluoromethyl)-1,5,6,7,8,14 -Hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Step 1: 11-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-3-(trifluoromethyl)-1-((2-( Trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2 , Preparation of 3-g][1]oxa[4,6,10]triazacyclotridecane

11-(3,3-Difluoro-1-(oxetan-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)- 1-((2-(Trimethylsilyl)ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3 -b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane (40mg, 0.06mmol, 1eq) was dissolved in ethanol (5mL), and 5% of Palladium on carbon (6.51mg,1eq), in an atmosphere Stir at room temperature for 16 hours under a pressurized hydrogen atmosphere. LC-MS detects that the reaction is complete. The palladium carbon is filtered through diatomaceous earth and the filtrate is concentrated to obtain the target compound (35 mg, yield 87%).

LC-MS (ESI) [M+H] ⁺ =656.3.

Step 2: 11-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-3-(trifluoromethyl)-1,5,6,7 ,8,14-hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacycle Preparation of tridecane

11-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-3-(trifluoromethyl)-1-((2-(trimethyl) Silyl)ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3- g][1]oxa[4,6,10]triazacyclotridecane (30mg, 0.05mmol, 1eq) was dissolved in dichloromethane (1.5mL), added trifluoroacetic acid (0.5mL), and kept at room temperature Stir for 1 hour, concentrate the reaction solution, add 1 mL of tetrahydrofuran and 0.5 mL of ammonia water and continue stirring for 0.5 hours. LC-MS detects that the reaction is complete. The reaction solution is directly concentrated and separated and purified by Prep-HPLC (C18, 0.1% FA aqueous solution, MeCN) to obtain Target compound (11.26 mg, yield 47%).

LC-MS (ESI) [M+H] ⁺ =526.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.75 (s, 1H), 8.71 (s, 1H), 7.49-7.33 (m, 2H) ,6.88(d,J＝7.6Hz,1H),6.21(t,J＝6.0Hz,1H),4.62-4.40(m,6H),3.61(dd,J＝12.4,6.0Hz,1H),3.36( d,J＝5.6Hz,2H),3.24-3.13(m,1H),3.08-2.97(m,1H),2.86(d,J＝10.0Hz,1H),2.40-2.31(m,1H),2.24 -2.07(m,2H),1.95-1.71(m,3H).

Example 516

3-Chloro-11-(6-methoxy-6-methyl-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4, 15-(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane

Referring to the preparation method of Example 510, the compound of Example 516 was prepared, LC-MS (ESI) [M+H] ⁺ =456.2.

Example 517

13-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidin-1-yl) -5-(Trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[4,6, 10]Triazacyclotridecane

Step 1: (3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine-1-carboxy Preparation of acid tert-butyl ester

At room temperature, 3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (4g, 18.41mmol, 1.0eq), bridged morpholine hydrochloride (3g, 22.1mmol, 1.2eq), triethyl Dissolve amine (5.59g, 55.24mmol, 3eq) in MeOH (40mL), add a few drops of acetic acid, stir at room temperature for 1 hour, add sodium cyanoborohydride (2.28g, 36.83mmol, 2eq) to the reaction solution, and continue the reaction. After one hour, LC-MS monitored the complete reaction of the raw material, spin it to dryness, and separate and purify it by column chromatography to obtain the target product (4.87 g, yield 88%).

LC-MS (ESI) [M+H] ⁺ =301.1.

Step 2: Preparation of: (1S,4S)-5-((3R,4S)-3-fluoropiperidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

Tert-butyl (3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine-1-carboxylate The ester (1.87g, 6.23mmol, 1eq) was dissolved in dichloromethane (20mL), trifluoroacetic acid (6mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction solution was directly concentrated to obtain the crude target product (1.2g).

LC-MS (ESI) [M+H] ⁺ =201.0.

Step 3: 3-((6-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3- Preparation of tert-butyl fluoropiperidin-1-yl)-3-nitropyridin-2-yl)oxy)propyl)carbamate

3-((6-Chloro-3-nitropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester (1.3g, 3.92mmol, 1eq), (1S,4S)-5-(( 3R,4S)-3-fluoropiperidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (0.94g, crude product obtained from the previous step) and triethylamine (1.59g , 15.68mmol, 4eq) was dissolved in DMF (15mL), and the temperature was raised to 80°C for 2 hours. The raw materials were detected by LC-MS, spun to dryness, and separated and purified by column chromatography to obtain the target product (1.2 g, yield 61%).

LC-MS (ESI) [M+H] ⁺ =496.2.

Step 4: 3-((6-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3- Preparation of fluoropiperidin-1-yl)-3-nitropyridin-2-yl)oxy)propan-1-amine

3-((6-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine -1-yl)-3-nitropyridin-2-yl)oxy)propyl)carbamic acid tert-butyl ester (1.2g, 2.42mmol, 1eq) was dissolved in dichloromethane (20mL), and trifluoroacetic acid ( 6 mL) and stir at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction solution was directly concentrated to obtain the crude target compound (900 mg).

LC-MS (ESI) [M+H] ⁺ =396.2.

Step 5: N-(3-((6-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl) -3-fluoropiperidin-1-yl)-3- Preparation of nitropyridin-2-yl)oxy)propyl)-2-chloro-5-(trifluoromethyl)pyrimidin-4-amine

3-((6-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine -1-yl)-3-nitropyridin-2-yl)oxy)propan-1-amine (600 mg, crude product, obtained from the previous step), 2,4-dichloro-5-(trifluoromethyl) Pyrimidine (395.08mg, 1.82mmol, 1.2eq) and N,N-diisopropylethylamine (784.4mg, 6.07mmol, 4eq) were dissolved in DMF (6mL) and reacted at room temperature for 2 hours. LC-MS detected that the reaction was complete. , spin the reaction solution to dryness, and obtain the crude target product through column chromatography separation and purification. The crude product is separated and purified by preparative high-performance liquid phase to obtain the target product (240 mg, yield 27%).

LC-MS (ESI) [M+H] ⁺ =576.2; ¹ H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 8.20 (t, J = 7.2Hz, 1H), 8.04 (t, J＝5.4Hz,1H),6.55(m,J＝4.4Hz,1H),4.77-4.50(m,1H),4.48-4.37(m,2H),4.35(s,1H),4.10-3.93(m ,1H),3.87(m,J＝9.2Hz,2H),3.80-3.70(m,2H),3.68-3.51(m,4H),3.04-2.78(m,2H),2.43(t,J＝8.8 Hz, 1H), 2.06 (p, J = 6.4Hz, 2H), 1.87 (m, J = 13.2Hz, 1H), 1.71 (d, J = 9.2Hz, 1H), 1.65-1.42 (m, 2H).

Step 6: 13-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-fluoropiperidine- 1-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[ Preparation of 4,6,10]triazacyclotridecane

At room temperature, N-(3-((6-((3R,4S)-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl) -3-fluoropiperidin-1-yl)-3-nitropyridin-2-yl)oxy)propyl)-2-chloro-5-(trifluoromethyl)pyrimidin-4-amine (200 mg, 0.35 mmol, 1.0eq), Fe (96.95mg, 1.74mmol, 5eq), ammonium chloride (120.74mg, 2.26mmol, 6.5eq), dissolved in 5mL ethanol and 1mL water, and then placed the system in an 85°C oil bath for reaction After 4 hours, LC-MS monitored that the reaction of the raw material was complete, and the raw material was spun to dryness. The crude product was separated and purified by preparative high-performance liquid phase to obtain the target product (41.27 mg, yield 23%).

LC-MS (ESI) [M+H] ⁺ =510.2; ¹ H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 8.07 (s, 1H), 7.33 (t, J = 5.6Hz, 1H),7.27(d,J＝8.4Hz,1H),6.36(d,J＝8.4Hz,1H),4.64(d,J＝35.2Hz,1H),4.45(s,2H),4.32(s, 1H),4.09(d,J＝16.0Hz,1H),3.98-3.83(m,2H),3.68(d,J＝50.8Hz,2H),3.53(d,J＝6.4Hz,1H),3.27- 3.16(m,2H),3.15-2.91(m,2H),2.82(s,1H),2.42(d,J＝9.6Hz,2H),1.94(s,1H),1.75(s,2H),1.69 (d, J=9.6Hz, 1H), 1.60 (d, J=9.2Hz, 1H).

Determination of biological activity

Experimental Example 1: In vitro evaluation of LRRK2 kinase inhibitory activity

1. Experimental materials:

1) Reaction solution: 50mM HEPES (PH7.5); 10mM MgCl ₂ ; 1mM EDTA; 0.01% Brij35; 2mM DTT;

2) Detection solution: TR-FRET Dilution Buffer;

3) LRRK2 human recombinant protein: Use GST tag and baculovirus to express recombinant full-length human LRRK2 protein in insect Sf9 cells;

4) Substrate: 0.4μM Fluorescein-ERM(LRRKtide)peptide; 38μM ATP.

2. Detection method:

Time-resolved fluorescence resonance energy transfer technology (TR-FRET): TR-FRET combines time-resolved fluorescence detection technology and fluorescence resonance energy transfer detection (FRET) technology. In experiments, when biomolecules interact with each other, the distance between the donor and acceptor fluorophores is shortened. If the donor is excited, it will transfer its emitted light energy to the acceptor. Using lanthanide element fluorophores as donors, the emitted light has a long half-life. Both the excitation and emission of the donor-acceptor fluorophores can be detected after the short half-life background fluorescence disappears, reducing the background and improving the signal-to-noise ratio. Therefore, Can improve sensitivity.

1) Add the DMSO solution of the compound to be tested to the 384 microwell plate through the Echo550 non-contact nanoliter sonic dispensing system;

2) Use the freshly prepared reaction solution to prepare a mixed solution of enzyme and peptide (2nM enzyme + 0.4μM Fluorescein-ERM (LRRKtide) peptide), add 5μL to the 384 microwell plate with existing compounds, centrifuge at 1000rpm/min for 1 minute, and incubate at room temperature 15min;

3) Add 5μL 38μM ATP, centrifuge at 1000rpm/min for 1min, and react at room temperature for 120min;

4) Add detection reagent: purchased from Thermofisher (Cat. No. PV4900) 0.25nM Tb-pERM (pLRRKtide) Antibody and 10mM EDTA, centrifuge at 1000rpm/min for 1 minute, react at room temperature for 30 minutes;

5) Envison detects TR-TRET fluorescence signal, mirror 447 (D400/D505), filter 275 (520nm) and 102 (485nm);

6) Calculate the compound’s inhibition of enzyme activity through the signal ratio (520nm/485nm), and use the software XLfit5 to fit the curve to calculate the IC ₅₀ value.

3. Experimental results:

Table 1. LRRK2 kinase inhibitory activity test results

A: IC ₅₀ ≤5nM; B: 5<IC ₅₀ ≤20nM; C: 20<IC ₅₀ ≤50nM; D: 50<IC ₅₀ ≤100nM

As can be seen from Table 1, the compound of the present invention has a significant inhibitory effect on LRRK2 kinase.

Experimental Example 2: In vitro evaluation of the inhibitory activity of compounds against p S935 LRRK2

1. Cell preparation:

1) Cell recovery:

Remove the HEK293T cells purchased from ATCC from the liquid nitrogen and place them in a water bath at 37°C. After the ice melts, transfer the cells to a centrifuge tube containing 10 mL of complete culture medium and centrifuge at 1000 rpm/min for 5 min. Discard the supernatant, resuspend with 15 mL of fresh complete culture medium and transfer to a T75 culture bottle. Place the culture bottle into a 37°C, 5% _CO2 incubator for culture, and observe the cell growth status in time.

2) Cell passage:

Cells can be passaged when the cells are cultured to 80-90% confluence. Discard the supernatant, add 20-25mL PBS, and shake the culture bottle several times. Discard the PBS, add 3-4 mL of trypsin to digest the cells, let stand for 1-2 min, add 10 mL of complete culture medium to terminate digestion, and gently pipet the cells until all cells fall off to form a single cell suspension. Transfer the single cell suspension to a centrifuge tube and centrifuge at 1000 rpm/min for 5 min. Discard the supernatant, resuspend in fresh complete culture medium, and subculture it into T150 culture flask at a ratio of 1:5. Place the culture bottle into a 37°C, 5% _CO2 incubator for culture, and observe the cell growth status in time.

3) Cell cryopreservation:

Cells that are in good growth status and have a cell viability rate of over 96% are cryopreserved for seed preservation. Use cell cryopreservation solution to adjust the density of the collected cells to 5 x 10 ⁶ /mL, and then transfer them to cell cryopreservation tubes, with 1 mL of cell suspension in each tube. Place the cryopreservation tube containing the cells in the cryopreservation box, store it in a -80°C refrigerator overnight, and then transfer it to liquid nitrogen for storage.

2. Experimental steps:

1. Day 1: HEK293T cell transfection

(1) Inoculate 30 mL of cell suspension (containing 30 x 10 ⁶ cells) in a 150 mm culture dish.

(2) Prepare transfection reagents: Add reagents in order, 2mL opti-MEM+20μg DNA+60μL TansIT. Mix gently and let stand at room temperature for 20 minutes.

(3) Evenly drop the prepared transfection reagent into the 150mm culture dish seeded with cells, shake gently to mix, and then place it in a 37°C, 5% CO ₂ incubator for 24 hours.

2. The second day: seed board

Collect the transfected cells and adjust the cell density to 0.2 x 10 ⁶ /mL. Add 50 μL of cell suspension per well to a 384 microwell plate (10,000 cells per well), and centrifuge at 1,000 rpm/min for 1 min. Place the 384 microwell plate into a 37°C, 5% _CO2 incubator overnight.

3. Day 3: Compound processing and HTRF detection

(1) Prepare compounds: The storage concentration of compounds is 10mM. When using, dilute the compounds to the required working concentration as required.

(2) Add the compounds to the 384 microwell plate using TECAN according to the Plate map, and adjust the final concentration of DMSO to 0.2%.

(3) After centrifugation at 1000 rpm/min for 1 minute, place it in a 37°C, 5% CO ₂ incubator for 2 hours.

(4) Prepare HTRF cell lysis solution: 4mL Lysis buffer+12mL H ₂ O+160 μL Blocking buffer.

(5) After 2 hours, add 16 μL of cell lysis solution to each well, centrifuge at 1000 rpm/min for 1 min, and shake the plate at 800 rpm/min for 30 min at room temperature.

(6) Prepare HTRF antibody mixed solution: 1600 μL = 40 μL Cryptate-antibody + 40 μL d2-antibody + 1520 μL H ₂ O.

(7) After 30 minutes, centrifuge at 1000 rpm/min for 2 minutes.

(8) Add 4 μL of antibody mixed solution to each well, centrifuge at 1000 rpm/min for 1 min, and incubate at room temperature for 20-24 h.

(9) Read the plate on Envision.

3. Experimental results:

Table 2. Test results of inhibitory activity of compounds against p S935 in HEK293 cells expressing G2019S LRRK2

As can be seen from Table 2, the compounds of the present invention have a significant inhibitory effect on pS935LRRK2.

Claims

A compound represented by formula (K), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

in,

Is a single bond or a double bond;

X 1 , X 2 , X 3 and X 4 are independently CH or N;

Y 1 , Y 2 and Y 3 are independently O, S or N R Y ; each occurrence of R Y is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclic group contains 1 or 2 members independently selected from S , O and N heteroatoms; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally one or more independently selected from deuterium, halogen, The substituents of oxo, cyano, hydroxy, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy replace;

Each occurrence of R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkyl hydroxyl group, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, Substituted with substituents of hydroxyl, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

The number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-12 membered heterocyclyl, -C 1-3 alkyl Base-C 3-8 cycloalkyl, -C 1-3 alkyl-C 3-8 cycloalkenyl, -C 1-3 alkyl-3-12-membered heterocyclyl or -C(O)-3- 12-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-12 membered heterocyclyl , -C 1-3 alkyl -C 3-8 cycloalkyl, -C 1-3 alkyl-C 3-8 cycloalkenyl, -C 1-3 alkyl-3-12 membered heterocyclyl or -C(O)-3-12 The heterocyclic group is optionally composed of one or more members independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, -C 1-6 alkyl-OC 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy and optionally substituted by C 1-3 alkyl or halogen Substituted by substituents of 3-12 membered heterocyclyl;

Each occurrence of R 4 is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, cyano, nitro, oxime, C 1-6 alkenyl, C 1-6 alkynyl, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 haloalkyl;

The number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, nitro, oxime group, C 1-6 alkenyl, C 1- 6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio , C 1-6 haloalkyl, C 3-6 cycloalkyl , -NH-C 1-6 alkyl base, -N(C 1-6 alkyl) 2 , -NH-C 3-6 cycloalkyl, -N(C 3-6 cycloalkyl) 2 or cyano group;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2;

Ring A is a 5-6 membered heteroaryl group or Ring A does not exist.
The compound according to claim 1, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

X 1 , X 2 , X 3 and X 4 are all N;

Or, X 2 is CH, X 1 , X 3 and X 4 are all N;

Or, X 1 and X 2 are both CH, X 3 and X 4 are both N;

Alternatively, X 1 , X 2 and X 4 are all CH, and X 3 is N.
The compound according to claim 1 or 2, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Y 2 is O or S, Y 1 and Y 3 are independently NR Y ;

Or, Y 2 is O, Y 1 and Y 3 are independently N R Y ;

Or, Y 1 is O or S, Y 2 and Y 3 are independently NR Y ;

Or, Y 1 is O, Y 2 and Y 3 are independently NR Y ;

Alternatively, Y 1 is O, Y 2 is O, and Y 3 is NR Y .
The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R Y is independently hydrogen, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino;

Preferably, each occurrence of R Y is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methyl thio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butyl oxide; the methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl , propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butylene oxide are optionally substituted by one or more independently Substituted with substituents selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino;

Further preferably, each occurrence of R Y is independently hydrogen.
The compound according to any one of claims 1 to 4, or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts, wherein,

Each occurrence of R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 hydroxyalkyl group or C 3-8 cycloalkyl group; the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkyl group, The thio group, hydroxyalkyl group or cycloalkyl group is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, hydroxyl, nitro, amino, C 1-6 alkyl, C 1- Substituted with substituents of 6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

Preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally replaced by one or more Each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkyl Substituted by an oxygen substituent;

More preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1- 3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally replaced by one or more independently Substituted with substituents selected from deuterium, halogen, cyano, hydroxyl, amino and C 1-3 alkyl;

Further preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, cyano, hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl base, methoxy, ethoxy, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoro methyl;

More preferably, each occurrence of R 1 and R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, -CH 2 OCH 3. Fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl.
The compound according to any one of claims 1-5, or its stereoisomer, tautomer or mixture, or Its pharmaceutically acceptable salt, wherein,

The number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylthio, C 3-8 cycloalkyl, 3-12-membered heterocyclyl, -C 1-3 alkyl-C 3-8 cycloalkyl, -C 1-3 alkyl-3-12-membered Heterocyclyl or -C(O)-3-12-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, -C 1-3 alkyl-C 3-8 cycloalkyl, - C 1-3 alkyl-3-12-membered heterocyclyl or -C(O)-3-12-membered heterocyclyl is optionally selected from one or more groups, each independently selected from deuterium, halogen, oxo group, and cyano group , hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C 1- 6 alkyl-OC 1-6 alkyl and optionally substituted by C 1-3 alkyl or halogen substituted 3-12 membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 each independently heteroatoms selected from S, O and N;

Preferably, the number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, amino, C 1-4 alkyl, C 3-6 cycloalkyl, 3-9 yuan Heterocyclyl, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl, The heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-4 alkyl group, C 3-6 cycloalkyl group, 3-9 membered heterocyclyl group, - C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl is optionally substituted by one or more Each is independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkyl, -C 1-3 alkyl-OC 1-3 alkyl and a substituent of a 3-8 membered heterocyclyl optionally substituted by C 1-3 alkyl, the heterocyclyl containing 1 or 2 each heteroatoms independently selected from S, O and N;

More preferably, the number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-9 yuan hetero. Cyclic group, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl, so The heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-4 alkyl group, C 3-6 cycloalkyl group, 3-9 membered heterocyclyl group, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9 membered heterocyclyl or -C(O)-3-9 membered heterocyclyl is optionally replaced by one or more Each is independently selected from deuterium, cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , 3-6 yuan Heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N;

Further preferably, the number of R 3 is 1 or 2, and each occurrence is independently fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocycle base, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH 2 -6-membered monoheterocyclyl, -CH 2 CH 2 -7-membered bridge Heterocyclyl, CH 2 CH 2 -6-membered monoheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C(O)-7-membered Spiroheterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridge Heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH 2 -6-membered monoheterocyclyl, -CH 2 CH 2 -7 One-membered bridged heterocyclyl, CH 2 CH 2 -6-membered monoheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C(O)- The 7-membered spiroheterocyclyl group is optionally selected from one or more groups, each independently selected from cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, -CH 2 OCH 3 , - CH 2 CH 2 OCH 3 , 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, methyl-substituted 4-membered monoheterocyclyl, methyl-substituted 5-membered monoheterocyclyl, Substituted with methyl-substituted 6-membered monoheterocyclyl and 7-membered bridged heterocyclyl substituents, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N;

Further preferably, each occurrence of R 3 is independently Represents the R 3 connection location.
The compound according to any one of claims 1 to 6, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R 4 is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, cyano, nitro, oxime, C 1-3 alkenyl, C 1-3 alkynyl, C 1- 3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkyl;

Preferably, each occurrence of R 4 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl or trifluoromethyl. base;

More preferably, each occurrence of R 4 is independently hydrogen, fluorine, or methyl.
The compound according to any one of claims 1 to 7, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

The number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkyl, C 3-6 cycloalkyl, -NH-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NH-C 3-6 cycloalkyl, -N( C 3-6 cycloalkyl) 2 or cyano;

Preferably, the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy , ethoxy, methylthio, ethylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -NH-cyclopropyl, -N(cyclopropyl) 2 or cyano;

More preferably, the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, methylthio, monofluoromethyl , difluoromethyl, trifluoromethyl, cyclopropyl, -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -NH-cyclopropyl or cyano group;

Further preferably, the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl , -NHCH 3 , -NHCH 2 CH 3 , -NH-cyclopropyl or cyano group.
The compound according to any one of claims 1 to 8, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

n1 is 3.
The compound according to any one of claims 1 to 9, or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts, wherein,

n2 is 1.
The compound according to any one of claims 1 to 9, or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts, wherein,

n2 is 2.
The compound according to any one of claims 1-11, or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts, wherein,

Ring A does not exist.
The compound according to any one of claims 1-11, or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts, wherein,

Ring A is a 5-6 membered heteroaromatic ring;

Preferably, Ring A is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl.
The compound according to any one of claims 1-11 and 13, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Ring A is a 5-membered heteroaromatic ring;

Preferably, Ring A is pyrrolyl, pyrazolyl or imidazolyl.
The compound according to any one of claims 1-11 and 13-14, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Ring A is ** represents the fusion site;

Or, ring A is ** represents the fusion site.
A compound represented by any one of formulas (K1) to formula (K11), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

Among them, R 1 , R 2 , R 3 , R 4 , R 5 , Y 1 , Y 2 , Y 3 and n1 are as defined in claim 1.
A compound represented by formula (K1A) or formula (K1B), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1.
A compound represented by formula (K2A), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

Wherein, R 1 , R 2 , R 3 , R 4 , R 5 and Y 1 are as defined in claim 1.
The compound according to claim 18, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Y 1 is O or NH;

Preferably, Y 1 is NH.
The compound according to any one of claims 17-19, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, or C 1-3 alkyl; the alkyl is optionally substituted with one or more substituents each independently selected from deuterium and halogen. ;

Preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl;

More preferably, each occurrence of R 1 and R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

Alternatively, each occurrence of R 1 and R 2 is independently hydrogen, halogen or C 1-3 alkyl;

Preferably, each occurrence of R 1 and R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

More preferably, each occurrence of R1 and R2 is independently hydrogen, methyl or fluorine.
The compound according to any one of claims 17-20, or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts, wherein,

Each occurrence of R 3 is independently C 1-4 alkyl, C 3-6 cycloalkyl, 3-9 membered heterocyclyl or -C(O)-3-9 membered heterocyclyl, and the heterocyclyl The cyclic group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-4 alkyl, C 3-6 cycloalkyl, 3-9 membered heterocyclyl or -C(O )-3-9-membered heterocyclic group is optionally composed of one or more members independently selected from cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, 3-6-membered Heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N;

Preferably, each occurrence of R3 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl Cyclic group, the heterocyclic group contains 1 or 2 heteroatoms each independently selected from S, O and N; the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocycle base, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7 The one-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl is optionally selected from one or more groups, each independently selected from cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine , chlorine, bromine, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, methyl-substituted 4-membered monoheterocyclyl, methyl-substituted 5-membered monoheterocyclyl, methyl Substituted with substituents of substituted 6-membered monoheterocyclyl and 7-membered bridged heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N;

More preferably, each occurrence of R 3 is independently Represents the R 3 connection position;

Alternatively, R 3 is a 3-9 membered heterocyclyl group or -C(O)-3-9 membered heterocyclyl group, which contains 1 or 2 heteroatoms each independently selected from O and N; so The 3-9-membered heterocyclic group or -C(O)-3-9-membered heterocyclic group is optionally selected from one or more groups independently selected from hydroxyl, methyl, ethyl, methoxy, ethoxy, Substituted with fluorine, chlorine, bromine, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 each independently selected from O and N heteroatoms;

Preferably, R 3 is a 4-membered monoheterocyclyl, a 5-membered monoheterocyclyl, a 6-membered monoheterocyclyl, a 7-membered bridged heterocyclyl, an 8-membered bridged heterocyclyl, a 7-membered spiroheterocyclyl, an 8-membered Spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl , the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from O and N; the 4-membered monoheterocyclyl group, 5-membered monoheterocyclyl group, 6-membered monoheterocyclyl group, 7-membered bridged heterocyclic group Cyclic group, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)- The 7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl is optionally selected from one or more groups, each independently selected from hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine , bromine, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, methyl-substituted 4-membered monoheterocyclyl, methyl-substituted 5-membered monoheterocyclyl, methyl-substituted Substituted with substituents of 6-membered monoheterocyclyl and 7-membered bridged heterocyclyl, the heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N;

More preferably, R 3 is Represents the R 3 connection location.
The compound according to any one of claims 17-21, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R 4 is independently hydrogen, deuterium, halogen or C 1-3 alkyl;

Preferably, each occurrence of R 4 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl;

More preferably, each occurrence of R 4 is independently hydrogen, fluorine or methyl;

Alternatively, each occurrence of R 4 may independently be hydrogen.
The compound according to any one of claims 17-22, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

R 5 is hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

Preferably, R5 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl or cyclopropyl Butyl;

More preferably, R 5 is hydrogen, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl;

Alternatively, R 5 is halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl;

Preferably, R 5 is fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl;

More preferably, R5 is chlorine, trifluoromethyl or cyclopropyl.
A compound represented by formula (I), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

in,

Is a single bond or a double bond;

X 1 , X 2 , X 3 and X 4 are independently CH or N;

Y 1 , Y 2 and Y 3 are independently O, S or N R Y ; each occurrence of R Y is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkyl group or C 3-8 heterocyclyl group, the heterocyclyl group contains 1 or 2 groups each independently selected from S , O and N heteroatoms; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally one or more independently selected from deuterium, halogen, The substituents of oxo, cyano, hydroxy, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy replace;

Each occurrence of R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or C 3-8 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, hydroxyalkyl, cycloalkyl or heterocyclyl groups are optionally replaced by a or more are independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy, C 1-6 haloalkyl Substituted with C 1-6 haloalkoxy substituents;

R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, C 3 -8 cycloalkenyl, C 3-12 heterocyclyl, -C 1-3 alkylene -C 3-8 cycloalkyl, -C 1-3 alkylene -C 3-8 cycloalkenyl, -C 1-3 alkylene-C 3-12 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, cycloalkyl, cycloalkenyl and heterocyclyl are optionally selected from one or more groups independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, -C 1-6 alkyl-OC 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy Substituted with substituents of base and C 3-12 heterocyclyl;

Each occurrence of R 4 and R 5 is independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 haloalkyl;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2; when n2 is 1, ring A is a 5-6 membered heteroaryl group; when n2 is 2, ring A is a 5-6 membered heteroaryl group or ring A does not exist.
The compound according to claim 24, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

X 1 , X 2 , X 3 and X 4 are all N;

Or, X 2 is CH, X 1 , X 3 and X 4 are all N;

Or, X 1 and X 2 are both CH, X 3 and X 4 are both N;

Alternatively, X 1 , X 2 and X 4 are all CH, and X 3 is N.
The compound according to claim 24 or 25, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Y 2 is O or S, Y 1 and Y 3 are independently NR Y ;

Or, Y 2 is O, Y 1 and Y 3 are independently N R Y ;

Or, Y 1 is O or S, Y 2 and Y 3 are independently NR Y ;

Alternatively, Y 1 is O, and Y 2 and Y 3 are each independently N R Y .
The compound according to any one of claims 24-26, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R Y is independently hydrogen, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, C 3-8 cycloalkyl or C 3-8 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, cycloalkyl or heterocyclyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino;

Preferably, each occurrence of R Y is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methyl thio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butyl oxide; the methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl , propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butylene oxide are optionally substituted by one or more independently Substituted with substituents selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino;

More preferably, each occurrence of R Y is independently hydrogen.
The compound according to any one of claims 24-27, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 hydroxyalkyl group or C 3-8 cycloalkyl group; the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkyl group, The thio group, hydroxyalkyl group or cycloalkyl group is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, hydroxyl, nitro, amino, C 1-6 alkyl, C 1- Substituted with substituents of 6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

Preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally replaced by one or more Each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkyl Substituted by an oxygen substituent;

More preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1- 3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally replaced by one or more independently Substituted with substituents selected from deuterium, halogen, cyano, hydroxyl, amino and C 1-3 alkyl;

Further preferably, each occurrence of R 1 and R 2 is independently hydrogen, deuterium, cyano, hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl base, methoxy, ethoxy, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoro methyl.
The compound according to any one of claims 24-28, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R 3 is independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-12 heterocyclyl, -C 1-3 alkylene-C 3-8 cycloalkyl, -C 1-3 alkylene-C 3-8 cycloalkenyl or -C 1-3 alkylene- C 3-12 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkoxy, alkylthio, cycloalkyl, cyclic Alkenyl or heterocyclyl is optionally selected from one or more groups, each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C 1-6 alkyl-OC 1-6 alkyl and C 3-12 heterocyclyl substituents replace;

Preferably, each occurrence of R 3 is independently C 1-4 alkyl, C 3-8 cycloalkyl, C 3-9 heterocyclyl, -C 1-2 alkylene-C 3-8 cyclo Alkyl or -C 1-2 alkylene-C 3-9 heterocyclyl, the heterocyclyl contains 1 or 2 heterocyclic groups each independently selected from S, O and N Atom; the alkyl, cycloalkyl or heterocyclyl group is optionally composed of one or more independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1- Substituted with substituents of 3 alkoxy, C 1-3 alkylthio, C 1-3 haloalkyl, -C 1-3 alkyl-OC 1-3 alkyl and C 3-8 heterocyclyl;

More preferably, each occurrence of R 3 is independently Represents the R 3 connection location.
The compound according to any one of claims 24-29, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Each occurrence of R 4 and R 5 is independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkyl;

Preferably, each occurrence of R 4 and R 5 is independently hydrogen, deuterium, halogen, C 1-3 alkyl or C 1-3 haloalkyl;

More preferably, each occurrence of R 4 is independently hydrogen, deuterium or methyl;

More preferably, each occurrence of R 5 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
The compound according to any one of claims 24-30, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt, wherein,

Ring A is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl;

Preferably, Ring A is pyrrolyl, pyrazolyl or imidazolyl;

More preferably, ring A is ** represents the fusion site;

Alternatively, ring A does not exist.
A compound represented by formula (IA) or formula (IB), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salt:

Wherein, each substituent is as defined in claim 24.
A compound represented by formula (II-A) or formula (II-B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:

Wherein, each substituent is as defined in claim 24.
A compound represented by formula (III), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

Wherein, each substituent is as defined in claim 24.
A compound represented by formula (IV), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable salts:

Wherein, each substituent is as defined in claim 24.
The following compounds, or their stereoisomers, tautomers or mixtures, or their pharmaceutically acceptable salts:
An intermediate (C) for preparing a compound represented by formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein, LG b is Cl, Br, I, OTf or Oms; Y 3' is -OH or -SH; other substituents are as defined in claim 1.
An intermediate (C) for preparing a compound represented by formula (I), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein, LG b is Cl, Br, I, OTf or OMs, Y 3' is -OH or -SH; other substituents are as defined in claim 24.
An intermediate (C') for preparing a compound represented by formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein, LG b is Cl, Br, I, OTf or OMs, and other substituents are as defined in claim 1.
An intermediate (C') for preparing a compound represented by formula (I), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein, LG b is Cl, Br, I, OTf or OMs, and other substituents are as defined in claim 24.
An intermediate (D) for preparing a compound represented by formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein, LG b is Cl, Br, I, OTf or OMs, and other substituents are as defined in claim 1.
An intermediate (D) for preparing a compound represented by formula (I), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein, LG b is Cl, Br, I, OTf or OMs, and other substituents are as defined in claim 24.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

Preferably, the pharmaceutical composition further contains pharmaceutically acceptable excipients.
The compound according to any one of claims 1-36, or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 43 in Use in the preparation of medicines for treating or preventing diseases mediated by LRRK2 kinase, preferably Parkinson's disease.