CN117425660A

CN117425660A - Aromatic heterocyclic compound, intermediate thereof, pharmaceutical composition and application

Info

Publication number: CN117425660A
Application number: CN202380009114.XA
Authority: CN
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: Shanghai Yishi Pharmaceutical Technology Co ltd
Current assignee: Shanghai Yishi Pharmaceutical Technology Co ltd
Priority date: 2022-05-18
Filing date: 2023-05-17
Publication date: 2024-01-19
Also published as: WO2023222005A1

Abstract

The invention belongs to the technical field of medicines, and relates to an aromatic heterocyclic compound serving as an LRRK2 inhibitor. The invention provides a compound with a novel structure, which has a structure shown as a formula (K) and provides a novel direction for the development of LRRK2 inhibitor medicines. In vitro enzyme and cell activity inhibition activity researches show that the compounds have strong inhibition effect and can be used as a prospect compound for preventing or treating diseases mediated by LRRK 2.

Description

Aromatic heterocyclic compound, intermediate thereof, pharmaceutical composition and application

Citation of related application

The present invention claims priority from the application entitled "an aromatic heterocyclic compound and its preparation method" filed in China at 5.18 in 2022, application number 202210596201.7, and the application entitled "an aromatic heterocyclic compound and its preparation method" filed in China at 11.18 in 2022, application number 202211452918.0, the entire contents of which are incorporated herein by reference.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an aromatic heterocyclic compound, an intermediate for preparing the compound, a pharmaceutical composition containing the compound, and a preparation method and application of the compound.

Background

Parkinson's Disease (PD) is the second most common neurodegenerative disease next to alzheimer's disease, affecting approximately 2% of the population over 60 years. 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 of bradykinesia, resting tremor, myotonia, and postural gait impairment. Currently available treatments for parkinson's disease are symptomatic treatments, such as dopamine replacement therapy which can relieve symptoms, and there is still a lack of cure to prevent disease progression or reverse disease. Thus, the need for new therapeutic strategies for parkinson's disease is apparent. Furthermore, as the world population ages, this demand is obviously growing.

Only about 5-15% of PD cases have a family history, most of which are idiopathic. Epidemiological studies have shown that parkinson's disease has a strong genetic correlation. The genes related to PD autosomal dominant inheritance were found to be SNCA (alpha-synuclein) and LRRK2 (leucone-rich repeat kinase 2); genes related to the recessive inheritance of the PD autosomes are Parkin (Parkin) and PINK1 (PTEN-induced kinase 1), etc. Of all the defined risk genes, LRRK2 mutations are the most common cause of autosomal dominant inherited parkinson' S disease, with LRRK2G2019S mutations accounting for 5% of PD cases. Recent studies have found that patients with idiopathic PD without mutations also have conditions of overactivation of LRRK2 protein, increased autophosphorylation or expression. Therefore, LRRK2 has become an important role 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, belonging to the family of ROCO protein kinases. In contrast to other members of the ROCO family, LRRK2 comprises a diverse domain whose main functional domains are, in order from the N-terminus to the C-terminus: ARM (Armadillo repeats), ANK (ankyrin repeats), LRR (leucine rich repeat), ROC (Ras of complex proteins), COR (C-terminal of Roc), KIN (kinase) and WD40 (WD repeat domain). LRRK2 is widely expressed in heart, kidney, lung, liver and some immune cells and central nervous system, LRRK2 in neurons is distributed in cytoplasm, exists on various membrane structures such as mitochondria, golgi apparatus, lysosome and the like, and plays an important role in synaptic transmission, vesicle transport, mitochondrial function, autophagy regulation, microtubule stability regulation, inflammatory reaction and the like by mediating phosphorylation of downstream proteins. LRRK2 has both gtpase and kinase activities, with a mechanism of mutual regulation between the two. The kinase activity of LRRK2 depends on the formation of LRRK2 dimer, whereas gtpase is critical for dimer formation; conversely, kinase activation regulates the gtpase activity of LRRK2 by autophosphorylating the ROC domain.

Recent advances in the development of LRRK2 inhibitors are currently in the clinical stage. In terms of small molecule drugs, both DNL151 and DNL201 have completed phase I clinical trials, and WXWH0226 has obtained clinical trial batches. Various pharmaceutical enterprises have issued patents on LRRK2 inhibitors, the main structural types of compounds include pyrrolopyrimidines/pyridines/pyridazines (WO 2015113451, WO2016130920, WO2017106771, WO2018155916, WO 2015092592), aminopyrimidines (WO 2017087905, WO2017156493, WO2017218843, WO 2018217946), pyrimidinyl/pyridylisoindazoles (WO 2014137719, WO2014137723, WO2014134774, WO 2014137728) and macrocycles (e.g., WO2013046029, WO2014140235, WO2016042089, containing two ring systems of benzene and pyrazolopyrimidine or imidazopyridazine in the macrocyclic structure; e.g., WO2019012093, containing two ring systems of pyrazole and pyrimidine or pyridine in the macrocyclic structure), etc.

To date, no LRRK2 inhibitors have been marketed, and therefore it is still necessary to find more potent and safe LRRK2 inhibitors.

Disclosure of Invention

Technical problem to be solved by the invention

The object of the present invention is to provide a compound having a completely new structure as an LRRK2 inhibitor; also, the object of the present invention is to provide intermediates for preparing said compounds, a process for preparing said compounds, pharmaceutical compositions comprising said compounds and the use of said compounds for preventing and/or treating LRRK2 mediated diseases.

Technical proposal for solving the problems

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

wherein,

is a single bond or a double bond;

X ₁ 、X ₂ 、X ₃ and X ₄ Each independently CH or N;

Y ₁ 、Y ₂ and Y ₃ O, S or NR respectively and independently ^Y ；R ^Y Each occurrence is independently hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _3-8 Cycloalkyl or a 3-8 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 a 3-8 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

R ₃ is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, 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-C _3-8 Cycloalkyl, -C _1-3 alkyl-C _3-8 Cycloalkenyl, -C _1-3 An alkyl-3-12 membered heterocyclyl or-C (O) -3-12 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 membered heterocyclyl optionally being substituted with one or more groups 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 alkyl-O-C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and optionally C _1-3 Alkyl or halogen substituted 3-12 membered heterocyclyl substituents;

R ₄ each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxy, 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 A haloalkyl group;

R ₅ is 1, 2 or 3, each occurrence of which is independently hydrogen, deuterium, halogen, amino, hydroxy, mercapto, carboxyl, nitro, oxime, 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, -N (C) _1-6 Alkyl group ₂ 、-NH-C _3-6 Cycloalkyl, -N (C) _3-6 Cycloalkyl radicals) ₂ Or cyano;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2;

ring a is a 5-6 membered heteroaryl or ring a is absent.

In one embodiment of the present invention,is a single bond or a double bond, and the whole ring of the compound is aromatic.

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, X ₁ 、X ₃ And X ₄ Are all N.

In a specific embodiment of the invention, X ₁ And X ₂ Are all CH, X ₃ And X ₄ Are all N.

In one embodiment of the present invention,X ₁ 、X ₂ and X ₄ Are all CH, X ₃ Is N.

In one embodiment of the invention, Y ₂ Is O or S, Y ₁ And Y ₃ Are each independently NR ^Y 。

In one embodiment of the invention, Y ₂ Is O, Y ₁ And Y ₃ Are each independently NR ^Y 。

In one embodiment of the invention, Y ₁ Is O or S, Y ₂ And Y ₃ Are each independently NR ^Y 。

In one embodiment of the invention, Y ₁ Is O, Y ₂ And Y ₃ Are each independently NR ^Y 。

In one embodiment of the invention, Y ₁ Is O, Y ₂ Is O, Y ₃ Is NR (NR) ^Y 。

In one embodiment of the invention, R ^Y Each occurrence 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 a 3-8 membered heterocyclyl containing 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, hydroxy, nitro and amino.

In one embodiment of the invention, R ^Y Each occurrence is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropanyl or epoxybutanyl; the methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropyl or epoxybutynyl being optionally substituted with one or more of each Substituted with substituents independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro and amino.

In one embodiment of the invention, R ^Y Each occurrence is independently hydrogen.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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, alkynyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 The substituent of the haloalkoxy group is substituted.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Haloalkyl and C _1-3 The substituent of the haloalkoxy group is substituted.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, cyano,Hydroxy, amino and C _1-3 The substituent of the alkyl group is substituted.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, cyano, hydroxy, 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 or trifluoromethyl.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, -CH ₂ OCH ₃ Fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl.

In one embodiment of the invention, R ₃ Is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, 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 An alkyl-3-12 membered heterocyclyl or-C (O) -3-12 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally being substituted with one or more groups 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-O-C _1-6 Alkyl and optionally C _1-3 Substituted by substituents of alkyl-or halogen-substituted 3-to 12-membered heterocyclic groups containing 1 or 2 groups each independentlyA heteroatom selected from S, O and N.

In one embodiment of the invention, R ₃ Is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, amino, C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl, -C _1-2 alkyl-C _3-6 Cycloalkyl, -C _1-2 An alkyl-3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally being substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Haloalkyl, -C _1-3 alkyl-O-C _1-3 Alkyl and optionally C _1-3 The substituents of the alkyl-substituted 3-8 membered heterocyclic group containing 1 or 2 heteroatoms each independently selected from S, O and N.

In one embodiment of the invention, R ₃ Is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl, -C _1-2 alkyl-C _3-6 Cycloalkyl, -C _1-2 An alkyl-3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally being substituted with one or more groups each independently selected from deuterium, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, -CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₃ Substituted by substituents of 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl containing 1 or 2 substituents each independently selected from S, O and NA heteroatom.

In one embodiment of the invention, R ₃ Is 1 or 2, each occurrence of which is independently fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monocyclic heterocyclyl, 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH ₂ -6 membered mono-heterocyclyl, -CH ₂ CH ₂ -7-membered bridged heterocyclyl, -CH ₂ CH ₂ -a 6 membered mono-heterocyclyl, -a C (O) -7 membered bridged heterocyclyl, or-a C (O) -7 membered spiro heterocyclyl, said heterocyclyl containing 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 mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH ₂ -6 membered mono-heterocyclyl, -CH ₂ CH ₂ -7-membered bridged heterocyclyl, -CH ₂ CH ₂ -6 membered mono-heterocyclyl, -C (O) -7 membered bridged heterocyclyl or-C (O) -7 membered spiro heterocyclyl, optionally substituted with one or more groups each independently selected from cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, -CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₃ Substituted with substituents selected from the group consisting of 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, methyl-substituted 4-membered mono-heterocyclyl, methyl-substituted 5-membered mono-heterocyclyl, methyl-substituted 6-membered mono-heterocyclyl and 7-membered bridged heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N.

In one embodiment of the invention, R ₃ Each occurrence is independently Represents R ₃ Connection locations.

In one embodiment of the invention, R ₄ Each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxy, 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 A haloalkyl group.

In one embodiment of the invention, R ₄ Each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.

In one embodiment of the invention, R ₄ Each occurrence of which is independently hydrogen, fluorine or methyl.

In one embodiment of the invention, R ₅ Is 1, 2 or 3, each occurrence of which 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 group ₂ 、-NH-C _3-6 Cycloalkyl, -N (C) _3-6 Cycloalkyl radicals) ₂ Or cyano.

In one embodiment of the invention, R ₅ Is 1, 2 or 3, each occurrence of which 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 one embodiment of the invention, R ₅ Is 1, 2 or 3, each occurrence of which is independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, methylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, -NHCH ₃ 、-NHCH ₂ CH ₃ 、-N(CH ₃ ) ₂ -NH-cyclopropyl or cyano.

In one embodiment of the invention, R ₅ Is 1, 2 or 3, each occurrence of which is independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, 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, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl.

In a specific embodiment of the invention, ring a is a 5 membered heteroaryl ring.

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

In one embodiment of the invention, ring A is* Represents a condensed site.

Further, the present invention also provides a compound represented by any one of the formulae (K1) to (K11), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、Y ₁ 、Y ₂ 、Y ₃ N1 is as defined in formula (K).

Still further, the present invention provides a compound represented by formula (K1A) or formula (K1B), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ As defined in formula (K).

Still further, the present invention provides a compound represented by formula (K2A), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、Y ₁ As defined in formula (K).

Still further, the present invention provides a compound represented by formula (K3A) or formula (K3B), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ As defined in formula (K).

Still further, the present invention provides a compound represented by formula (K4A), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Still further, the present invention provides a compound represented by formula (K5A), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Still further, the present invention provides a compound represented by formula (K8A) or formula (K8B), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ As defined in formula (K).

In one embodiment of the invention, Y ₁ Is O or NH.

In one embodiment of the invention, Y ₁ Is NH.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence of which is independently hydrogen, deuterium, halogen or C _1-3 An alkyl group; the alkyl groups being optionally substituted by one or moreA plurality of substituents each independently selected from deuterium and halogen.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl.

In one embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine.

In one embodiment of the invention, R ₃ The number of (2) is 1 or 2, preferably 1.

In one embodiment of the invention, R ₃ Each occurrence is independently C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N.

In one embodiment of the invention, R ₃ Each occurrence is independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiro heterocyclyl, 8-membered spiro heterocyclyl, 9-membered spiro heterocyclyl, -C (O) -6-membered mono-heterocyclyl, -C (O) -7-membered bridged heterocyclyl, or-C (O) -7-membered spiro heterocyclyl, said heterocyclyl containing 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 single unit The heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiro heterocyclyl, 8-membered spiro heterocyclyl, 9-membered spiro heterocyclyl, -C (O) -6-membered mono-heterocyclyl, -C (O) -7-membered bridged heterocyclyl, or-C (O) -7-membered spiro heterocyclyl is optionally substituted with one or more substituents each independently selected from cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, methyl-substituted 4-membered mono-heterocyclyl, methyl-substituted 5-membered mono-heterocyclyl, methyl-substituted 6-membered mono-heterocyclyl, and 7-membered bridged heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N.

In one embodiment of the invention, R ₄ Each occurrence of which is independently hydrogen, deuterium, halogen or C _1-3 An alkyl group.

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

In one embodiment of the invention, R ₅ The number of (2) is 1, 2 or 3, preferably 1 or 2, more preferably 1.

In one embodiment of the invention, R ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-3 Alkyl, C _1-3 Haloalkyl or halogenoalkylC _3-6 Cycloalkyl groups.

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

In one embodiment of the invention, R ₅ Each occurrence is independently hydrogen, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₁ And R is ₂ Each occurrence of which is independently hydrogen, halogen or C _1-3 An alkyl group.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₁ And R is ₂ Each occurrence is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₁ And R is ₂ Each occurrence of which is independently hydrogen, methyl or fluoro.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₃ Is C _3-6 Cycloalkyl or a 3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N; the C is _3-6 Cycloalkyl or 3-9 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from fluoro, chloro, bromo and 3-6 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₃ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl or 6-membered mono-heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N; the cyclopropyl, cyclobutyl and cyclopentyl groupsOptionally substituted with one or more substituents each independently selected from fluorine, chlorine, bromine, 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl and 6-membered mono-heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₃ Is that Represents R ₃ Connection locations.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₄ Is C _1-3 An alkyl group.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₄ Is methyl or ethyl.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₄ Is methyl.

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₅ Is halogen, C _1-3 Haloalkyl or C _3-6 Cycloalkyl groups.

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

In one embodiment of the present invention, R in the compound represented by the formula (K1A) or (K1B) ₅ Is fluorine, chlorine, trifluoromethyl or cyclopropyl.

In one embodiment of the present invention, Y in the compound represented by the formula (K2A) ₁ Is O or NH.

In one embodiment of the present invention, Y in the compound represented by the formula (K2A) ₁ Is NH.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₁ And R is ₂ Each occurrence of which is independently hydrogen, halogen or C _1-3 An alkyl group.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₁ And R is ₂ Each occurrence is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₁ And R is ₂ Each occurrence of which is independently hydrogen, methyl or fluoro.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₃ Is a 3-9 membered heterocyclyl or a-C (O) -3-9 membered heterocyclyl containing 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 substituted with one or more substituents each independently selected from hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₃ Is 4-membered mono-heterocyclic group, 5-membered mono-heterocyclic group, 6-membered mono-heterocyclic group, 7-membered bridged heterocyclic group, 8-membered bridged heterocyclic group, 7-membered spiro heterocyclic group and 8-membered spiro heteroA cyclic group, a 9-membered spiroheterocyclyl group, -a C (O) -6-membered mono-heterocyclyl group, -a C (O) -7-membered bridged heterocyclyl group, or a C (O) -7-membered spiroheterocyclyl group, said heterocyclyl group containing 1 or 2 heteroatoms each independently selected from O and N; the 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 7-membered bridged heterocyclic group, 8-membered bridged heterocyclic group, 7-membered spiro heterocyclic group, 8-membered spiro heterocyclic group, 9-membered spiro heterocyclic group, -C (O) -6-membered monocyclic heterocyclic group, -C (O) -7-membered bridged heterocyclic group or-C (O) -7-membered spiro heterocyclic group is optionally substituted with one or more substituents each independently selected from the group consisting of hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 4-membered monocyclic heterocyclic group, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, methyl-substituted 4-membered monocyclic heterocyclic group, methyl-substituted 5-membered monocyclic heterocyclic group, methyl-substituted 6-membered monocyclic heterocyclic group and 7-membered bridged heterocyclic group, said heterocyclic group containing 1 or 2 heteroatoms each independently selected from the group consisting of O and N.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₃ Is that Represents R ₃ Connection locations.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₄ Each occurrence is independently hydrogen.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₅ Is halogen, C _1-3 Haloalkyl or C _3-6 Cycloalkyl groups.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₅ Is fluorine, chlorine, bromine or monofluorineMethyl, difluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl.

In one embodiment of the present invention, R in the compound represented by the formula (K2A) ₅ Is chloro, trifluoromethyl or cyclopropyl.

In addition, the invention also provides a compound shown as a formula (I), or a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein,

is a single bond or a double bond;

X ₁ 、X ₂ 、X ₃ and X ₄ Each independently CH or N;

Y ₁ 、Y ₂ and Y ₃ O, S or NR respectively and independently ^Y ；R ^Y Each occurrence is independently hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _3-8 Cycloalkyl or C _3-8 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 A heterocyclyl group containing 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 substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of 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 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl groups are optionally substituted with one or more groups 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 alkyl-O-C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _3-12 Substituents of the heterocyclic group are substituted;

R ₄ and R is ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio or C _1-6 A haloalkyl group;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2; when n2 is 1, ring A is a 5-6 membered heteroaryl; when n2 is 2, ring A is a 5-6 membered heteroaryl or ring A is absent.

In one embodiment of the present invention,is a single bond or a double bond, and the whole ring is aromaticSex ring.

In a specific embodiment of the invention, X ₁ 、X ₂ And X ₄ Are all CH, X ₃ Is N.

In one embodiment of the invention, R ^Y Each occurrence 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 A heterocyclyl group containing 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, hydroxy, nitro and amino.

In one embodiment of the invention, R ^Y Each occurrence of which is independently hydrogen, methyl, ethyl,Propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, glycidylyl or epoxybutanoyl; the methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropyl or epoxybutyl groups are optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro and amino.

In the present inventionIn a specific embodiment of the invention, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, amino and C _1-3 The substituent of the alkyl group is substituted.

In one embodiment of the invention, R ₃ Each occurrence 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 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl groups are optionally substituted with one or more groups 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-O-C _1-6 Alkyl and C _3-12 A substituent of a heterocyclic group, the heterocyclic group containing 1 or 2 heteroatoms each independently selected from S, O and N.

In one embodiment of the invention, R ₃ Each occurrence 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 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Haloalkyl, -C _1-3 alkyl-O-C _1-3 Alkyl and C _3-8 A substituent of a heterocyclic group, the heterocyclic group containing 1 or 2 heteroatoms each independently selected from S, O and N.

In one embodiment of the invention, R ₄ And R is ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio or C _1-3 A haloalkyl group.

In one embodiment of the invention, R ₄ And R is ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-3 Alkyl or C _1-3 A haloalkyl group.

In one embodiment of the invention, R ₄ Each occurrence of which is independently hydrogen, deuterium, or methyl.

In one embodiment of the invention, R ₅ Each occurrence is respectivelyIndependently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

In one embodiment of the invention, ring A is* Represents a condensed site.

In a specific embodiment of the invention, ring a is absent.

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

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 a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

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

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

wherein each substituent is as defined in formula (I).

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

wherein each substituent is as defined in formula (I).

Specifically, the compound in the present invention, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

in a second aspect, the present invention provides a process for the preparation of a compound of formula (I) or formula (K), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

The preparation method comprises the following steps:

the preparation method of the general formula I:

carrying out substitution reaction on (A1) and (B1) or (A2) and (B2) to obtain an intermediate (C), and carrying out intramolecular Buchwald-Hartwig coupling reaction on the intermediate (C) to obtain a compound shown as a formula (I) or a formula (K);

Wherein Y is _2’ is-OH, -SH or-NHR ^Y ；LG ^a Is a leaving group, preferably Cl, br, I or OTf, OMs; LG (light emitting diode) ^b Is a leaving group, preferably Cl, br, I or OTf, OMs; y is Y _3’ is-OH or-SH; y is Y ₃ Is O or S; the other substituents are as defined above.

Accordingly, the present invention also provides an intermediate (C) for preparing a compound represented by formula (I) or formula (K), or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein LG (glass fiber reinforced plastic) ^b Cl, br, I, OTf or OMs; y is Y _3’ is-OH or-SH; the other substituents are as defined in formula (I) or formula (K).

The preparation method of the general formula II:

carrying out substitution reaction on (A1) and (B1 ') or (A2) and (B2') to obtain an intermediate (C '), carrying out reduction reaction on (C') to obtain an intermediate (D), and carrying out intramolecular Buchwald-Hartwig coupling reaction on (D) to obtain a compound shown as a formula (I) or a formula (K);

wherein Y is _2’ is-OH, -SH or-NHR ^Y ；LG ^a Is a leaving group, preferably Cl, br, I or OTf, OMs; LG (light emitting diode) ^b Is a leaving group, preferably Cl, br, I or OTf, oms; the other substituents are as defined above.

Accordingly, the present invention also provides an intermediate (C') for preparing a compound of formula (I) or formula (K), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein LG (glass fiber reinforced plastic) ^b Cl, br, I, OTf or OMs; the other substituents are as defined in formula (I) or formula (K).

Accordingly, the present invention also provides an intermediate (D) for preparing a compound represented by formula (I) or formula (K), or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (particularly a compound of formula (K), a compound of any one of formulae (K1) to (K11), a compound of formula (I-a), formula (I-B), formula (II-a), formula (II-B), formula (III) or formula (IV), and a specific compound thereof, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, in the first aspect.

Further, the present invention also provides a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

In a fourth aspect, the present invention provides the use of a compound of the invention (particularly a compound of the first aspect as shown in formula (K), a compound of any one of formula (K1) to formula (K11), a compound of formula (I-a), formula (I-B), formula (II-a), formula (II-B), formula (III) or formula (IV), and a specific compound), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease mediated by LRRK2 kinase.

Specifically, the invention also provides application of the compound, or stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof in preparing medicines for treating or preventing Parkinsons Disease (PD).

In a fifth aspect, the present invention provides a compound of the invention, in particular a compound of the first aspect as shown in formula (K), a compound of any one of formula (K1) to formula (K11), a compound of formula (I-a), formula (I-B), formula (II-a), formula (II-B), formula (III) or formula (IV), and specific compounds), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular for the treatment or prophylaxis of a disease mediated by LRRK2 kinase.

In particular, the present invention also provides a compound of the present invention, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of parkinson's disease.

In a sixth aspect, the present invention provides a method for treating or preventing a disease mediated by LRRK2 kinase, comprising the steps of: a therapeutically or prophylactically effective amount of a compound of the invention, particularly a compound of the first aspect as shown in formula (K), a compound of any one of formula (K1) to formula (K11), a compound of formula (I-a), formula (I-B), formula (II-a), formula (II-B), formula (III) or formula (IV), and specific compounds, or stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, is administered to a subject in need thereof.

In particular, the present invention also provides a method for treating or preventing parkinson's disease, comprising the steps of: a therapeutically or prophylactically effective amount of a compound of the invention, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention designs a compound with a novel structure, and provides a novel direction for the development of LRRK2 inhibitor medicines. In vitro enzyme and cell inhibition activity studies show that the compounds have strong inhibition effect, so that the compounds can be used as the prospect compounds for treating LRRK2 mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has simple process and convenient operation, and is beneficial to large-scale industrial production and application.

Detailed Description

Definition of terms

The terms "optional," "any," "optionally," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "oxo" refers to the replacement of two hydrogen atoms at the same substitution position with the same oxygen atom to form a double bond.

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C _1-10 Alkyl groups), further preferably containing 1 to 8 carbon atoms (C _1-8 Alkyl groups), more preferably containing 1 to 6 carbon atoms (i.e. C _1-6 Alkyl), e.g. "C _1-6 Alkyl "means that the group is alkyl and the number of carbon atoms in 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C _2-10 Alkenyl groups), further preferably containing 2 to 8 carbon atoms (C _2-8 Alkenyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C _2-6 Alkenyl), 2 to 5 carbon atoms (i.e. C _2-5 Alkenyl), 2 to 4 carbon atoms (i.e. C _2-4 Alkenyl), 2 to 3 carbon atoms (i.e. C _2-3 Alkenyl), 2 carbon atoms (i.e. C ₂ Alkenyl), e.g. "C _2-6 Alkenyl "means that the group is alkenyl and the number of carbon atoms in the carbon chain 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.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, having at least one triple bond, unless otherwise specified. Alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C _2-10 Alkynyl groups), further preferably containing 2 to 8 carbon atoms (C _2-8 Alkynyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C _2-6 Alkynyl), 2 to 5 carbon atoms (i.e. C _2-5 Alkynyl), 2 to 4 carbon atoms (i.e. C _2-4 Alkynyl), 2 to 3 carbon atoms (i.e. C _2-3 Alkynyl), 2 carbon atoms (i.e. C ₂ Alkynyl groups), e.g. "C _2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain 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 radical having a specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C _3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C _3-10 Cycloalkyl), more preferably 3 to 6 carbon atoms (C _3-6 Cycloalkyl), 4-6 carbon atoms (C _4-6 Cycloalkyl), 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.

The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which is as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 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, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.

The term "alkylthio" refers to the substitution of-O-in the definition of "alkoxy" above for-S-unless otherwise specified.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine, iodine, unless otherwise specified. The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above 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 Etc.

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 a portion of the rings in the polycyclic ring being aromatic structures, containing 3 to 20 ring atoms, of which 1, 2, 3 or more are selected from N, O or S, the remaining ring atoms being C, preferably containing 3 to 12 ring atoms, further preferably containing 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, tetrahydropyranyl, morpholinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

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

The term "spirocycloalkyl", unless otherwise specified, refers to a saturated ring system of a specified number of carbon atoms formed by carbon atoms and hydrogen atoms sharing only one ring carbon atom. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Non-limiting examples of Shan Luohuan groups are Shan Luohuan groups 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, wherein the count of each ring includes a spiro atom. Non-limiting examples of Shan Luohuan bases include:etc.

Unless otherwise specified, the terms "heterospirocyclic group", "spiroheterocyclic group" refer to a cyclic structure having a specific number of carbon atoms and hetero atoms formed by two or more saturated rings sharing one ring carbon atom. 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 6 to 14 membered, more preferably 7 to 10 membered. Non-limiting examples of spiroheterocyclyl are 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 ring spiroheterocyclyl wherein the count of each ring includes a spiro atom. Non-limiting examples of hetero Shan Luohuan groups include:etc.

Unless otherwise specified, the term "bridged ring radical" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring having a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

unless otherwise specified, the terms "heterobridged cyclic group", "bridged heterocyclic group" refer to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two ring atoms that are not directly connected, which may contain one or more double bonds, but no ring has a fully conjugated pi electron system. The hetero atoms in the bridged heterocyclic group are one or more, preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3), and are independently selected from N, O or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. The bridged heterocyclic group is preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are 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 monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring group". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.

Unless otherwise specified, the term "heteroaryl", "arylheteroaryl" means an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 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, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.

The term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, unless otherwise specified, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or the free acid with a suitable reagent alone.

The terms "solvate", "solvate" and "solvates" mean, unless otherwise specified, the physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate," "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art. In general, the compounds of the present invention include solvates thereof.

Unless otherwise specified, the terms "isotopically-labeled analog," "isotopically-derivative," "stable isotopically-derivative" refer to isotopically-labeled molecules in compounds of the present invention, thereby providing isotopically-labeled analogs that may have improved pharmacological activity. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, ² h and ³ h is formed; carbon isotopes: ¹¹ C、 ¹³ c and C ¹⁴ C, performing operation; chlorine isotopes: ³⁵ cl and Cl ³⁷ Cl; fluorine isotopes: ¹⁸ f, performing the process; iodine isotopes: ¹²³ i and ¹²⁵ i, a step of I; nitrogen isotopes: ¹³ n and ¹⁵ n; oxygen isotopes: ¹⁵ O、 ¹⁷ o and ¹⁸ isotopes of O and sulfur ³⁵ S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. Especially deuterium ² H) And carbon% ¹³ C) The application is wider because they are easy to label and convenient to detect. Certain heavy isotopes, such as heavy hydrogen @, for example ² H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds. Typically, the compounds of the invention comprise isotopic derivatives (e.g., deuterated) thereof.

The term "stereoisomer" refers to compounds having the same chemical structure, but spatially different arrangements of atoms or groups, unless otherwise specified. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers and the like. The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers include interconversions by recombination of some of the bond-forming electrons.

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.

The term "co-crystal" is used to describe such situations, unless otherwise specified: wherein the neutral molecular component is present in a defined stoichiometric ratio within the crystalline compound. The preparation of pharmaceutical co-crystals enables changes to be made to the crystalline form of the active pharmaceutical ingredient, which in turn can change its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, J.Wobutes and L.Quere et al, RSC Publishing, 2012). Typically, the compounds of the invention comprise a co-crystal thereof.

The term "polymorphic form" refers to a different arrangement of chemical drug molecules, unless otherwise specified, generally expressed as the form in which the drug substance is present in a solid state. A drug may exist in a variety of crystalline forms, and different crystalline forms of the same drug may be differently dissolved and absorbed in the body, thereby affecting dissolution and release of the formulation. In general, the compounds of the present invention comprise polymorphs thereof.

The term "metabolite" refers to the product of a particular compound or salt thereof obtained in vivo by metabolism, unless otherwise specified. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient. Typically, the compounds of the invention comprise metabolites thereof.

The term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful because, in some instances, they may be easier to administer than the parent drug. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of the invention that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal an active moiety. Typically, the compounds of the invention comprise prodrugs thereof.

The term "optionally substituted" refers to the group unless otherwise specifiedThe hydrogen of the substitutable site is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, 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 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl and 5-10 membered heteroaryl ring groups, wherein said C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-10 Cycloalkyl, C _3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl or 5-to 10-membered heteroaryl ring groups optionally being selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl and C _1-6 One or more substituents of the alkoxy group are substituted.

The invention is further illustrated below in conjunction with specific examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials are presented herein for illustrative purposes only.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or/and liquid chromatography (HPLC). The NMR used instruments were Bruker 400MHz and/or Varian 400MHz; the LC-MS uses an instrument of Agilent 1260 informativity II-6120/6125MSD; the HPLC used instrument is Waters Acquity UPLC _2 or/and Shimadzu LC2030 or/and Agilent 1260 information II.

Preparative HPLC condition one (ammonia as additive): instrument: waters; and (3) a pump: 2545; a detector: 2489; wavelength: 214nm and 254nm; column model: welch xtime C18,21.2 x 250mm,10 μm; mobile phase: 0.1% ammonia water and acetonitrile; run time: 15min; flow rate: 25ml/min.

Preparative HPLC condition two (formic acid as additive): instrument: waters; and (3) a pump: 2545; a detector: 2489; wavelength: 214nm and 254nm; column model: welch Ultimate AQ-C18, 21.2X250 mm,10 μm; mobile phase: 0.1% formic acid, B acetonitrile; run time: 15min; flow rate: 25ml/min.

Preparative HPLC conditions tris (trifluoroacetic acid as additive): instrument: waters; and (3) a pump: 2545; a detector: 2489; wavelength: 214nm and 254nm; column model: welch Ultimate AQ-C18, 21.2X250 mm,10 μm; mobile phase: 0.1% of trifluoroacetic acid, and B of acetonitrile; run time: 15min; flow rate: 25ml/min.

The starting materials in the examples of the present invention are known and are commercially available or may be synthesized using or according to methods known in the art.

Description of terms or abbreviations

OTf: trifluoro methanesulfonic acid ester group

OMs: methanesulfonate ester group

DMF: n, N-dimethylformamide

DCM: dichloromethane (dichloromethane)

THF: tetrahydrofuran (THF)

DMSO: dimethyl sulfoxide

EDTA: ethylenediamine tetraacetic acid

HMDSLi: bis (trimethylsilyl) amide lithium (or hexamethyldisilazide lithium)

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

SEMCl: [2- (chloromethoxy) ethyl ] trimethylsilane (or 2- (trisilyl) 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: acetic acid ethyl ester

NIS: n-iodosuccinimide

DIPEA: diisopropylethylamine

DCE: dichloroethane (dichloroethane)

BTEAC: benzyl triethyl ammonium chloride

Preparation of the Compounds

Example 1

3-chloro-12-methyl-10- (tetrahydro-2H-pyran-3-yl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tetrahydro-2H-pyran-3-ylmethane sulfonate

tetrahydro-2H-pyran-3-ol (550 mg,5.39mmol,1.0 eq) and triethylamine (599.04 mg,5.92mmol,1.1 eq) are dissolved in dichloromethane (30 mL) and methanesulfonyl chloride (678.57 mg,5.92mmol,1.1 eq) is added under nitrogen at 0deg.C and stirred for 3 hours. TLC monitored the reaction was complete. To the reaction was added water quenching, extracted with dichloromethane (3×50 ml), and the organic phases were combined and concentrated directly to give the desired product (560 mg, 57.75% yield).

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)。

And a second step of: preparation of mixtures of 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole and 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole

tetrahydro-2H-pyran-3-ylmethylsulfonate (550 mg,3.05mmol,1.0 eq) and 3-methyl-4-nitro-1H-pyrazole (1.16 g,9.15mmol,3.0 eq) are dissolved in DMF (15 mL) and potassium carbonate (640 mg,4.63mmol,1.52 eq) is added under nitrogen protection at 90℃and stirred for 16 hours. LC-MS monitored the reaction for completion. The reaction mixture was quenched with water, extracted with dichloromethane (3×50 ml), the organic phases were combined, concentrated and purified by column chromatography to give the desired product (560 mg, 86.89%).

LC-MS(ESI)[M+H] ⁺ ＝212.0。

And a third step of: preparation of 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole

To a solution of 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole obtained in the second step and 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole in tetrahydrofuran (5 mL) at-78℃under nitrogen, a solution of lithium bis (trimethylsilyl) amide in THF (1M, 6.24mL,6.24mmol,3 eq) was added dropwise to a solution of tetrahydrofuran (3 mL) obtained in the second step after stirring and reacting at-78℃for 45 minutes, and then, hexachloroethane (1.47 g,6.24mmol,3 eq) was added dropwise under nitrogen at 15℃under stirring for 2 hours. LC-MS monitored the reaction for completion. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×20 ml), and the organic phases were combined, concentrated, and purified by column chromatography to give the desired 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)。

Fourth step: preparation of 2,4, 5-trichloro-7H-pyrrolo [2,3-d ] pyrimidine

2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (20.0 g,106.38mmol,1.0 eq) was dissolved in N, N-dimethylformamide (200 mL), and 1-chloropyrrolidine-2, 5-dione (17.05 g,127.65mmol,1.2 eq) was added to the reaction system and stirred at 50℃for 5 hours. LC-MS monitored reaction was complete. Water (200 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (3X 200 mL). The organic phases were combined, concentrated and purified by column chromatography to give the desired product (21.0 g, 88.74% yield).

LC-MS(ESI)[M+H] ⁺ ＝224.0； ¹ H NMR(400MHz，DMSO-d ₆ )：δ13.11(s，1H)，7.94(d，J＝13.2Hz，1H)。

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

2,4, 5-trichloro-7H-pyrrolo [2,3-d ] pyrimidine (4.1 g,18.43mmol,1.0 eq) was dissolved in dimethylformamide (40 mL), sodium hydrogen (810.8 mg,20.27mmol,1.1eq, 60%) was added to the reaction system at 0℃and stirred at 0℃for 0.5 hours, and [2- (chloromethoxy) ethyl ] trimethylsilane (3.69 g,22.12mmol,1.2 eq) was added to the reaction system and the reaction was continued at 0℃for 2 hours. LC-MS monitored the end of the reaction. Quench with 20mL of water and extract three times with ethyl acetate (3X 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the desired product (5.2 g, 79.99% yield).

LC-MS(ESI)[M+H] ⁺ ＝352.0。

Sixth step: preparation of 3- ((2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) propan-1-ol

2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (5.2 g,14.74mmol,1.0 eq) was dissolved in isopropanol (20 mL), 3-aminopropan-1-ol (1.22 g,16.22mmol,1.1 eq) and diisopropylethylamine (5.72 g,44.23mmol,3.0 eq) were added. The reaction was carried out at 85℃for 2 hours. LC-MS monitored reaction was complete. The desired product (5.4 g, 93.61% yield) was isolated and purified by column chromatography.

LC-MS(ESI)[M+H] ⁺ ＝391.0。

Seventh step: preparation of 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

3- ((2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) propan-1-ol (403.26 mg,1.03mmol,1.0 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydrogen (74.15 mg,3.09mmol,3.0 eq) was added to the reaction solution at 0deg.C. The reaction was continued at 0℃for 0.5 hours, 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole (255 mg,1.03mmol,1.0 eq) was added to the reaction system, and the reaction was continued at 0℃for 1 hour, followed by LC-MS monitoring for the completion of the reaction. Water (15 mL) was added to the reaction system, the mixture was quenched, extracted three times with ethyl acetate (3X 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the desired product (220 mg, 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)。

Eighth step: preparation of 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

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,0.33mmol,1.0 eq) was dissolved in a mixed solvent of ethanol (10 mL)/water (2 mL). Iron powder (92.98 mg,1.67mmol,5.0 eq) and ammonium chloride (106.88 mg,2mmol,6.0 eq) were added to the reaction system. The temperature was raised to 80℃and the reaction was carried out for 2 hours. LC-MS monitored the end of the reaction. Insoluble material was filtered, water (10 mL) was added to the filtrate, and extraction was performed three times with ethyl acetate (3×15 mL). The organic phases were combined, concentrated and purified by prep. plate to give the desired product (180 mg, 94.73% yield).

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)。

Ninth step: preparation of 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- (azobridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [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, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (50 mg,0.09mmol,1.0 eq) was dissolved in dioxane (4 mL), tris (dibenzylideneacetone) dipalladium (0) (8.02 mg,0.01mmol,0.1 eq), dicyclohexyl (2 ',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl) phosphine (8.35 mg,0.02mmol,0.2 eq), cesium carbonate (85.65 mg,0.26mmol,3.0 eq) were added to the reaction system, and the temperature was raised to 90℃under nitrogen atmosphere for 3 hours. The liquid monitoring reaction is complete. The reaction mixture was purified by column chromatography to give the desired product (25 mg, yield 53.41%).

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)。

Tenth step: preparation of 3-chloro-12-methyl-10- (tetrahydro-2H-pyran-3-yl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecanes

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- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (23 mg,0.04mmol,1.0 eq) was dissolved in 1mL of dichloromethane, trifluoroacetic acid (0.5 mL) was added, stirred at room temperature for 1 hour, TLC (DCM: meOH=10:1) was monitored for no starting material residue, the solvent was dried, tetrahydrofuran (1 mL) was added for redissolution, and aqueous ammonia (0.5 mL) was added to the reaction system. The reaction was continued at room temperature for 1 hour. LC-MS monitored reaction was complete. Concentrated, methanol (3 mL) was added, and the resultant was purified by preparative high performance liquid phase separation to give the objective product (5.2 mg, yield 25%).

LC-MS(ESI)[M+H] ⁺ ＝404.2； ¹ H NMR(400MHz，DMSO-d ₆ )：δ11.02(s，1H)，7.26(s，1H)，6.88(d，J＝2.4Hz，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- (azepine) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of a mixture of 5-methyl-4-nitro-1- (oxetan-3-yl) pyrazole and 3-methyl-4-nitro-1- (oxetan-3-yl) pyrazole

To DMF (20 mL) was added 3-methyl-4-nitro-1H-pyrazole (2.2 g,17.31mmol,1.0 eq) and cesium carbonate (11.28 g,34.62mmol,2.0 eq) and 3-iodooxetane (9.55 g,51.93mmol,3.0 eq) and reacted at 90℃for 3 hours under nitrogen. LC-MS monitored reaction was complete. The reaction mixture was extracted with methylene chloride (3X 30 mL), and the organic phase was concentrated and purified by column chromatography to give the desired product (1.8 g, yield 56.79%).

LC-MS(ESI)[M+H] ⁺ ＝184.0。

And a second step of: preparation of 5-chloro-3-methyl-4-nitro-1- (oxetan-3-yl) -1H-pyrazole

To a tetrahydrofuran (10 mL) mixture of 5-methyl-4-nitro-1- (oxetan-3-yl) pyrazole and 3-methyl-4-nitro-1- (oxetan-3-yl) pyrazole (1.7 g,9.28mmol,1.0 eq) was added dropwise a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 4.66mL,27.84mmol,3.0 eq) in dry ice/acetone bath, stirred at 78℃for 1h, at which temperature hexachloroethane (10.98 g,46.4mmol,5.0 eq) was added, slowly warmed to room temperature and stirred at 25℃for 4h. LC-MS monitored reaction was complete. Saturated ammonium chloride solution (20 mL) was added to quench, ethyl acetate (2×20 mL) was extracted, saturated brine (2×20 mL) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the desired product (800 mg, yield 39.66%).

LC-MS(ESI)[M+H] ⁺ ＝218.0。

And a third step of: preparation of 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 ] pyrimidin-4-amine

To 3- ((2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) propan-1-ol (1.98 g,5.05mmol,1.0 eq) in tetrahydrofuran (10 mL) was added sodium hydrogen (60%, 303mg,7.58mmol,1.5 eq) under ice-water bath, stirred for 1H, 5-chloro-3-methyl-4-nitro-1- (oxetan-3-yl) -1H-pyrazole (1.1 g,5.05mmol,1.0 eq) was added, the ice-water bath was removed, and stirred for 4H at 25 ℃. LC-MS monitored reaction was complete. The reaction mixture was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined, and purified by column chromatography to give the desired 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)。

Fourth step: preparation of 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

To ethanol (10 mL) and water (2 mL) were 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 ] pyrimidin-4-amine (500 mg,0.87mmol,1.0 eq) and ammonium chloride (280.3 mg,5.24mmol,6.0 eq) and iron powder (243.83 mg,4.37mmol,5.0 eq) were added and reacted at 80℃for 3 hours under nitrogen. LC-MS monitored reaction was complete. Dichloromethane (3×20 ml) was extracted, the organic phases were combined, concentrated, and purified by prep. plate to give the desired product (200 mg, 42.37% yield).

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)。

Fifth step: preparation of 3-chloro-12-methyl-10- (oxetan-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azepine) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

To a solvent of 1, 4-dioxane (3 mL) of 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,0.09mmol,1.0 eq) was added tris (dibenzylideneacetone) dipalladium (8 mg,0.01mmol,0.1 eq), dicyclohexyl (2 ',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl) phosphine (8.33 mg,0.02mmol,0.2 eq), cesium carbonate (85.36 mg,0.26mmol,3.0 eq) and nitrogen protection was stirred at 90℃for 3 hours. LC-MS monitored reaction was complete. The reaction solution was filtered, concentrated, and purified by preparative plate to give the objective product (10 mg, yield 21.96%).

LC-MS(ESI)[M+H] ⁺ ＝506.2。

Sixth step: preparation of 3-chloro-12-methyl-10- (oxetan-3-yl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azepine) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

To a solvent of 3-chloro-12-methyl-10- (oxetan-3-yl) -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] triazatridecane (20 mg,0.04mmol,1.0 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL,4.38mmol,109.6 eq) and the mixture was stirred at 25℃for 1 hour. TLC monitored reaction was complete. The reaction mixture was concentrated to give a crude product, which was dissolved in tetrahydrofuran (2 mL), then added with ammonia water (1 mL), and stirred at 25℃for 1 hour under nitrogen. LC-MS monitored reaction was complete. The reaction solution was concentrated, dissolved in methanol, and filtered, and the filtrate was separated and purified by preparative high-performance liquid chromatography to give the objective 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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 4 gave the compound of example 3, 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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3,4, 5-tribromo-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole

3,4, 5-tribromo-1H-pyrazole (4.8 g,15.75mmol,1 eq) was dissolved in tetrahydrofuran (100 mL), after nitrogen substitution, tetrahydro-2H-pyran-3-ol (1.93 g,18.9mmol,1.2 eq), triphenylphosphine (8.26 g,31.5mmol,2 eq) and diethyl azodicarboxylate (5.49 g,31.5mmol,2 eq) were added at 0deg.C and stirring was continued for 12 hours. TLC monitored the reaction was complete. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phases combined and purified by column chromatography to give the desired product (2.1 g, 34.29% yield).

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)。

And a second step of: preparation of 3, 4-dibromo-5-methyl-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole

3,4, 5-tribromo-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole (500 mg,1.29mmol,1 eq) was dissolved in tetrahydrofuran (5 mL), n-butyllithium (0.52 mL,1.29mmol,1 eq) was added at-78℃under nitrogen, stirred for half an hour, methyl iodide (365 mg,2.57mmol,2 eq) was added to the system, and stirred for 2 hours at-78 ℃. LC-MS monitored the end of the reaction. The reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (5 mL x 2), and the organic phases were combined, and purified by column chromatography to give the target product 3, 4-dibromo-5-methyl-1- (tetrahydro-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)。

And a third step of: preparation of 3-bromo-5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole

3, 4-dibromo-5-methyl-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole (850 mg,2.62mmol,1 eq) was dissolved in 98% concentrated sulfuric acid (10 mL), and 97% concentrated nitric acid (9 mL) was slowly added dropwise at 0deg.C in ice bath, and stirred at 0deg.C for 3 hours. LC-MS monitored the end of the reaction. The reaction was slowly added to ice water (30 mL), extracted with ethyl acetate (50 mL x 3), the organic phases combined and purified by column chromatography to give the desired product (760 mg, 99.99% yield).

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)。

Fourth step: preparation of 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-3-ol

3-bromo-5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole (360 mg,1.24mmol,1.0 eq) was dissolved in water (10 mL), followed by the addition of potassium hydroxide (1.46 g,26.02mmol,20.97 eq) under nitrogen protection at 120℃for 18 hours under reflux. LC-MS monitored reaction was complete. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), the aqueous phase was acidified (ph=3), extracted with dichloromethane (20 mL x 3), and the organic phase was concentrated to give the crude product (190 mg, 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)。

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

5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-3-ol (470 mg,2.07mmol,1.0 eq), tert-butyl (3-bromopropyl) carbamate (492.55 mg,2.07mmol,1.0 eq) were dissolved in N, N-dimethylformamide (10 mL), followed by addition of potassium carbonate (571.77 mg,4.14mmol,2 eq) under nitrogen protection at 60℃for 3 hours. LC-MS monitored reaction was complete. The reaction mixture was quenched with water (15 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and purified by column chromatography to give the desired product (570 mg, 96.85% yield).

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)。

Sixth step: preparation of 3- ((5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-3-yl-oxy) propan-1-amine

Tert-butyl (3- ((5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-3-yl) oxy) propyl) carbamate (500 mg,1.36mmol,1 eq) was dissolved in dioxane hydrochloride (4 m,8 ml) and stirred under nitrogen at 30 ℃ for 3 hours. LC-MS monitored reaction was complete. The reaction solution was concentrated to give the desired product (360 mg, yield 98.97%).

LC-MS(ESI)[M+H] ⁺ ＝285.2。

Seventh step: preparation of 2, 5-dichloro-N- (3- ((5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-3-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,1.0 eq) was dissolved in N, N-dimethylformamide (8 mL, 100.0%) and then sodium hydride (60%, 152mg,3.8mmol,3.0 eq) was added portionwise under ice-bath with stirring at 0℃for half an hour under nitrogen protection, then 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-eq ] pyrimidine (491.46 mg,1.39mmol,1.1 eq) was added to the system, after nitrogen displacement, stirring for 3 hours at 30℃LC-MS monitored reaction was complete, ice water (10 mL) was added dropwise, extracted with ethyl acetate (10 mL x 3), the organic phases were combined and the prepared plate was separated and purified (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)。

Eighth step: preparation of 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

2, 5-dichloro-N- (3- ((5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-3-yl) oxy) propyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (80 mg,0.13mmol,1 eq) was dissolved in ethanol (5 mL)/water (1 mL) mixed solvent. Iron powder (37.19 mg,0.67mmol,5 eq) and ammonium chloride (42.75 mg,0.8mmol,6 eq) were added to the reaction system. The temperature was raised to 80℃and the reaction was carried out for 2 hours. LC-MS monitored the end of the reaction. The filtrate was filtered, concentrated, washed with saturated brine, and the organic phases were combined and concentrated to give the crude product of interest (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)。

Ninth step: preparation of 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- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [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 (150 mg,0.26mmol,1 eq) was dissolved in dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (0) (24.07 mg,0.03mmol,0.1 eq), dicyclohexyl (2 ',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl) phosphine (25.06 mg,0.05mmol,0.2 eq), cesium carbonate (256.96 mg,0.79mmol,3 eq) was added to the reaction system. The temperature is raised to 90 ℃ in nitrogen atmosphere for reaction for 3 hours. LC-MS monitored reaction was complete. The resulting mixture was filtered through celite, and the filtrate was concentrated to give the desired product (80 mg, yield 45.58%) by plate separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝534.2。

Tenth step: preparation of 3-chloro-12-methyl-11- (tetrahydro-2H-pyran-3-yl) -5,6,7,8,11,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecanes

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- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (80 mg,0.15mmol,1 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and tetrahydrofuran (3 mL) was added thereto to redissolve the reaction mixture, and aqueous ammonia (2 mL) was added thereto. The reaction was continued at room temperature for 2 hours. LC-MS monitored reaction was complete. The reaction mixture was concentrated, 4mL of methanol was added, and the mixture was separated and purified to give the desired product (8 mg, yield 13.23%) by preparing a high performance liquid phase.

LC-MS(ESI)[M+H] ⁺ ＝404.2； ¹ H NMR(400MHz,DMSO-d6)δ10.96(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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: synthesis of a mixture of 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole and 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole

3-methyl-4-nitro-1H-pyrazole (20 g,157.36mmol,1 eq) and p-toluenesulfonic acid monohydrate (1.5 g,7.87mmol,0.05 eq) were dissolved in anhydrous ethyl acetate (200 mL) and 3, 4-dihydro-2H-pyran (19.86 g,236.03mmol,1.5 eq) was added dropwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours and TLC monitored the reaction was complete. The reaction mixture was washed with saturated brine (200 ml x 3), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give a mixture of the target product 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole and 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole, with a nuclear magnetic resonance display ratio of about 3:1 (30 g, yield 90.26%).

And a second step of: synthesis of 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole

To a solution of a mixture (15 g,71.02mmol,1 eq) of 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole and 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole in tetrahydrofuran (250 mL) under nitrogen protection was added a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 213.05mL,213.05mmol,3 eq) at-78 ℃. After stirring at-78℃for 45 minutes, a solution of hexachloroethane (50.44 g,213.05mmol,3 eq) in tetrahydrofuran (100 mL) was added dropwise and stirred at 15℃for 2 hours under nitrogen. TLC monitored reaction was complete. To the reaction solution was added saturated ammonium chloride solution (300 mL), which was quenched, extracted with ethyl acetate (200 ml×3), and purified by column chromatography to give the objective 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)。

And a third step of: synthesis of 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

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

LC-MS(ESI)[M+H] ⁺ ＝602.1。

Fourth step: synthesis of 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

Cuprous chloride (0.16 g,1.67mmol,0.2 eq) and sodium borohydride (1.26 g,33.3mmol,4 eq) were dissolved in tetrahydrofuran (50 mL), 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 (5 g,8.33mmol,1 eq) was dissolved in ethanol (50 mL) under nitrogen and the reaction system was added. Stirred at room temperature for 2 hours. LC-MS monitored reaction was complete. The filtrate was filtered and concentrated, and the desired product was isolated and purified by column chromatography (2 g, yield 42.08%).

LC-MS(ESI)[M+H] ⁺ ＝570.2。

Fifth step: synthesis of 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- (azobridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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 (2 g,3.51mmol,1 eq) was dissolved in dioxane (80 mL), tris (dibenzylideneacetone) dipalladium (0) (0.32 g,0.35mmol,0.1 eq), dicyclohexyl (2 ',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl) phosphine (0.33 g,0.7mmol,0.2 eq), cesium carbonate (3.43 g,10.52mmol,3 eq) was added to the reaction system, and the mixture was heated to 90℃under nitrogen atmosphere for 3 hours. LC-MS monitored reaction was complete. The resulting mixture was filtered through celite, and the filtrate was concentrated, and purified by column chromatography to give the desired product (1 g, yield 53.41%).

LC-MS(ESI)[M+H] ⁺ ＝534.1。

Sixth step: synthesis of 3-chloro-12-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azobridge) 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- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (1 g,1.87mmol,1 eq) was dissolved in acetic acid (20 mL) and water (5 mL) and stirred for 1 hour at 50 ℃. LC-MS monitoring reaction is complete, organic phase concentrated silica gel is directly stirred, and the target product is obtained through column chromatography separation and purification (400 mg, yield 47.53%).

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)。

Seventh step: synthesis of 3-chloro-12-methyl-11- (tetrahydrofuran-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -5,6,7,8,11,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazacyclotridecane

3-chloro-12-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazacyclotridecane (400 mg,0.89mmol,1 eq) was dissolved in DMF (4 mL), sodium hydrogen (42.67 mg,1.78mmol,2eq,60% content) was added at room temperature, stirred for 30 minutes, after which tetrahydrofuran-3-methylsulfonate (221.6 mg,1.33mmol,1.5 eq) was dissolved in DMF (1 mL) and stirred at room temperature for 16 hours. LC-MS monitored completion of the reaction, quenched by addition of water (20 mL), extracted with ethyl acetate (20 mL. 3), combined with the organic phase, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated filtrate, and purified by column chromatography to afford the desired product (80 mg, yield 17.3%).

LC-MS(ESI)[M+H] ⁺ ＝520.2。

Eighth step: synthesis of 3-chloro-12-methyl-11- (tetrahydrofuran-3-yl) -5,6,7,8,11,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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] triazacyclotridecane (80 mg,0.15mmol,1 eq) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, stirred at room temperature for 1 hour, the reaction was monitored to be complete by TLC, the reaction mixture was concentrated, tetrahydrofuran (1 mL) was added to be redissolved, and aqueous ammonia (0.5 mL) was added to the reaction system. The reaction was continued at room temperature for 1 hour. LC-MS monitored reaction was complete. The organic phase was concentrated, separated and purified by column chromatography to give crude product, which was then subjected to chiral column chromatography to give the desired 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＝2.4Hz,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)。

Examples 6 to 129

The compounds of examples 6-65 were prepared by reference to the preparation methods of examples 1-2 and 4-5; reference examples 194, 196 and 197, the compounds of examples 66-129 were prepared

Example 130

2- (5-chloro-7, 8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [2, 3-b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) -2-methylpropanenitrile

The first step: preparation of tert-butyl 2- (6-chloro-5-nitropyridin-2-yl) -2-cyanoacetate

2, 6-dichloro-3-nitropyridine (10.0 g,1.0 eq), potassium carbonate (18 g,2.5 eq) and THF (100 mL) were added to a 250mL three-port reaction flask at room temperature, tert-butyl cyanoacetate (11 g,1.5 eq) was added dropwise with stirring, and then the reaction system temperature was raised to 70℃and refluxed overnight. TLC monitored completion of the reaction, celite filtration, and the filtrate was concentrated and used directly in the next step (28.3 g).

And a second step of: preparation of tert-butyl 2- (6-chloro-5-nitropyridin-2-yl) -2-cyanopropionate

In a 250mL reaction flask at 25 ℃, the mixture of the previous step was dissolved in acetonitrile, then potassium carbonate (2.5 eq) was added, and after stirring for 10 minutes, meI (2.6 eq) was slowly added dropwise and the reaction system temperature was raised to 40 ℃, stirring overnight. TLC monitored completion of the reaction and the reaction solution was concentrated and used directly in the next step (9.2 g).

And a third step of: preparation of 2- (6-chloro-5-nitropyridin-2-yl) propionitrile

The mixture of the previous step was dissolved in DMSO (50 mL) and water (10 mL) at room temperature, then sodium chloride (2 w/w) was added, and the reaction system temperature was raised to 150℃and stirred for 2 hours. After completion of the reaction by TLC, it was cooled to room temperature, then water (100 mL) and ethyl acetate (50 mL) were added and stirred for 10 minutes; after 10 minutes, the mixture was allowed to stand for separation, the aqueous phase was extracted with ethyl acetate (50 mL) 2 times, the organic phases were combined, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and purified by column chromatography to give the objective product (5.0 g).

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

Fourth step: preparation of 2- (6-chloro-5-nitropyridin-2-yl) -2-methylpropanenitrile

2- (6-chloro-5-nitropyridin-2-yl) propionitrile (5.0 g,23.6mmol,1.0 eq) was dissolved in acetonitrile (125 mL) at 25℃and then potassium carbonate (8.16 g,59.1mmol,2.5 eq) was added and after stirring for 10 min MeI (8.72 g,61.4mmol,2.6 eq) was slowly added dropwise and the reaction temperature was raised to 40℃and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and water (100 mL) and ethyl acetate (125 mL) were added to the crude product and stirred for 10 minutes; after 10 minutes, the mixture was left to stand for separation, the aqueous phase was extracted with ethyl acetate (20 mL) 2 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the desired product was isolated and purified by column chromatography (4.82 g, yield 90.4%).

¹ H NMR(500MHz,CDCl ₃ ):δ8.11(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),1.93(s,6H)。

Fifth step: preparation of 2- (6- (3- ((2, 5-dichloropyrimidin-4-yl) amino) propoxy) -5-nitropyridin-2-yl) -2-methylpropanenitrile

NaH (425.5 mg,17.73mmol,2.0 eq) was dissolved in DMF (50 mL) in a 250mL three port reaction flask under nitrogen, then 3- ((2, 5-dichloropyrimidin-4-yl) amino) propan-1-ol (2.36 g,10.64mmol,1.2 eq) was slowly added and stirring was continued at 0deg.C for 0.5 hours followed by 2- (6-chloro-5-nitropyridin-2-yl) -2-methylpropanenitrile (2.0 g,8.86mmol,1.0 eq). The reaction was warmed to room temperature and stirred for 3 hours, then quenched with ice water at 0 ℃ in an ice bath, extracted with EA (50 ml,10 v/w), the organic phases were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the desired product was isolated and purified by column chromatography (2.1 g, yield 57.4%).

LC-MS(ESI)[M+H] ⁺ ＝411.2。

Sixth step: preparation of 2- (5-amino-6- (3- ((2, 5-dichloropyrimidin-4-yl) amino) propoxy) pyridin-2-yl) -2-methylpropanenitrile

2- (6- (3- ((2, 5-dichloropyrimidin-4-yl) amino) propoxy) -5-nitropyridin-2-yl) -2-methylpropanenitrile was reacted in a 50mL reaction flask at room temperature(2.1 g,5.11mmol,1.0 eq), iron powder (1.43 g,25.53mmol,5.0 eq) and ammonium chloride (1.36 g,25.53mmol,5.0 eq) were dissolved in EtOH/H ₂ O (20/2 mL), then the reaction system temperature was raised to 90℃and stirred for 2h. After completion of the TLC monitoring reaction, celite was used for filtration, and the filtrate was concentrated to give the objective product (1.9 g, yield 97.6%) by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝381.2。

Seventh step: preparation of 2- (5-chloro-7, 8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridec-13-yl) -2-methylpropanenitrile

Pd was introduced into a 20mL reaction flask under nitrogen protection ₂ (dba) ₃ (182.5 mg, 10%) and tBuXPhos (84.6 mg, 10%), 2- (5-amino-6- (3- ((2, 5-dichloropyrimidin-4-yl) amino) propoxy) pyridin-2-yl) -2-methylpropanenitrile (762 mg,1.99mmol,1.0 eq) and potassium carbonate (826.5 mg,5.98mmol,3.0 eq) were dissolved in anhydrous dioxane (10 mL) and then replaced with nitrogen. The reaction system temperature was raised to 100℃and stirring was continued for 2 hours under microwave conditions. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and crude products are obtained through column chromatography separation and purification. Then, the mixture was slurried with methanol and filtered to obtain the objective product (120 mg, yield 17.4%).

LC-MS(ESI)[M+H] ⁺ ＝345.4。

Examples 131 to 193

Referring to the procedure for the preparation of example 130, the compounds of examples 131-144 and 146-193 were prepared; referring to the procedure for the preparation 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 2,4, 5-trichloro-7H-pyrrolo [2,3-d ] pyrimidine

2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (20.0 g,106.38mmol,1.0 eq) was dissolved in N, N-dimethylformamide (200 mL), and 1-chloropyrrolidine-2, 5-dione (17.05 g,127.65mmol,1.2 eq) was added to the reaction system and stirred at 50℃for 5 hours. LC-MS monitored reaction was complete. 200mL of water was added to the reaction system, and the mixture was extracted three times with ethyl acetate (3X 200 mL). The organic phases were combined, concentrated, and purified by column chromatography to give the desired product (21.0 g, yield 88.74%).

And a second step of: preparation of 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine

2,4, 5-trichloro-7H-pyrrolo [2,3-d ] pyrimidine (4.1 g,18.43mmol,1.0 eq) was dissolved in dimethylformamide (40 mL), sodium hydrogen (810.8 mg,20.27mmol,1.1eq, 60%) was added to the reaction system at 0℃and stirred at 0℃for 0.5 hours, and [2- (chloromethoxy) ethyl ] trimethylsilane (3.69 g,22.12mmol,1.2 eq) was added to the reaction system and the reaction was continued at 0℃for 2 hours. LC-MS monitored the end of the reaction. Quench with 20mL of water and extract three times with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the desired product (5.2 g, yield 79.99%).

LC-MS(ESI)[M+H] ⁺ ＝352.0。

And a third step of: preparation of 3- ((2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) propan-1-ol

2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (5.2 g,14.74mmol,1.0 eq) was dissolved in 20mL of isopropanol, 3-aminopropan-1-ol (1.22 g,16.22mmol,1.1 eq) and diisopropylethylamine (5.72 g,44.23mmol,3.0 eq) were added. The reaction was carried out at 85℃for 2 hours. LC-MS monitored reaction was complete. The desired product (5.4 g, yield 93.61%) was isolated and purified by column chromatography.

LC-MS(ESI)[M+H] ⁺ ＝391.0。

Fourth step: preparation of 2, 5-dichloro-N- (3- ((6-chloro-3-nitropyridin-2-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 (4 g,10.22mmol,1 eq) was dissolved in THF (100 mL), sodium hydrogen (490 mg,20.44mmol,2 eq) was added, and after half an hour 2, 6-dichloro-3-nitropyridine (1.97 g,10.22mmol,1 eq) was reacted at 25℃for 2 hours. LC-MS monitored reaction was complete. To the reaction solution was added water (100 mL), extracted with ethyl acetate (500 ml×3), and the organic phase was washed with brine 2 times, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to give the objective product (4 g, yield 71.44%).

LC-MS(ESI)[M+H]+＝547.1。

Fifth step: preparation of N- (3- ((6- (2- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-nitropyridin-2-yl) oxy) propyl) -2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine

2, 5-dichloro-N- (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (1.2 g,2.19mmol,1 eq) was dissolved in isopropanol (100 mL), and 2-oxa-5-azabicyclo [2.2.1] heptane (217 mg,2.19mmol,1 eq) and N, N-diisopropylethylamine (849 mg,6.57mmol,3 eq) were added to react at 60℃for 16 hours. LC-MS monitoring reaction is complete, and the target product (1.2 g, yield 89.74%) is obtained by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝610.1。

Sixth step: preparation of 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

N- (3- ((6- (2- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-nitropyridin-2-yl) oxy) propyl) -2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (1.2 g,1.97mmol,1 eq) was dissolved in ethanol (100 mL), iron powder (1.1 g,19.7mmol,10 eq) and saturated aqueous ammonium chloride (1.05 g,19.7mmol,10 eq) were added, stirred at 60℃for 2 hours, LC-MS was monitored for reaction completion, the filtrate was concentrated, and column chromatography was isolated and purified to give the title product (600 mg, 52.46%).

LC-MS(ESI)[M+H] ⁺ ＝580.2。

Seventh step: preparation of 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- (azepine) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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 (600 mg,1.1mmol,1 eq) was dissolved in dioxane (50 mL), and tris (dibenzylideneacetone) dipalladium (95 mg,0.1mmol,0.1 eq), cesium carbonate (1.01 g,3.1mmol,3 eq) and X-Phos (49 mg,0.1mmol,0.1 eq) were added. The reaction was carried out at 90℃for 4 hours under nitrogen protection. LC-MS monitored reaction was complete. The desired product was isolated and purified by column chromatography (200 mg, yield 43.82%).

LC-MS(ESI)[M+H] ⁺ ＝544.2。

Eighth step: preparation of 11- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-chloro-1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) 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- (azepine) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (180 mg,0.33mmol,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. The reaction was completed as an intermediate by LC-MS monitoring, which was dried by spin, methanol (5 mL) was added, ammonia (10 mL) was added, stirring was continued at room temperature for 1 hour, and LC-MS monitoring was completed. The desired product (25 mg, yield 18.31%) was obtained by preparative high performance liquid phase separation 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＝8.2Hz,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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 197 gave the compound of example 195, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 2, 4-dichloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine

2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (10 g,53.19mmol,1.0 eq) was dissolved in dichloromethane (200 mL) under nitrogen, then N-iodosuccinimide (19.15 g,85.1mmol,1.6 eq) was slowly added at 0deg.C and the reaction mixture stirred at room temperature for 16 hours. LC-MS monitored reaction was complete. The mixture was filtered, and the cake was washed with distilled water and dried under reduced pressure to give the objective product (16 g, yield 96%).

LC-MS(ESI)[M+H] ⁺ ＝313.9。

And a second step of: preparation of 2, 4-dichloro-5-iodo-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine

2, 4-dichloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (16 g,50.97mmol,1.0 eq) was dissolved in tetrahydrofuran (200 mL), triethylamine (15.4 g,152mmol,3.0 eq) was added, and then [2- (chloromethoxy) ethyl ] trimethylsilane (17 g,102mmol,2.0 eq) was added dropwise and reacted at room temperature for 2 hours, and LC-MS monitored the reaction was complete. The reaction was quenched with water (100 mL), extracted with ethyl acetate (200 mL x 3), the organic phases were combined, concentrated, and purified by column chromatography to give the desired product (20 g, 88% yield).

LC-MS(ESI)[M+H] ⁺ ＝444.0。

And a third step of: preparation of 2, 4-dichloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine

Cuprous iodide (21.4 g,113mmol,5.0 eq) and potassium fluoride (6.5 g,113mmol,5.0 eq) were added to a three-necked flask, trimethyl (trifluoromethyl) silane (16 g,113mmol,5.0 eq) was dissolved in N-methylpyrrolidone (50 mL) under nitrogen and slowly added to the reaction flask via 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,23mmol,1.0 eq) was further dissolved in N-methylpyrrolidone (10 mL) under nitrogen and then added slowly via syringe. The resulting reaction mixture was stirred at 50℃for 12 hours. LC-MS monitored reaction was complete. The reaction was cooled to room temperature, quenched with distilled water, extracted with ethyl acetate (100 ml x 3), the organic phases were combined, concentrated, and purified by column chromatography to give the desired product (5 g, yield 57%).

LC-MS(ESI)[M+H] ⁺ ＝386.0。

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

2, 4-dichloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (5 g,12.94mmol,1.0 eq) was added to isopropanol (50 mL) and 3-aminopropan-1-ol (1.94 g,25.89 mmol) and the reaction was allowed to react at 85℃for 1 hour. LC-MS monitored reaction was complete. The desired product was isolated and purified by column chromatography (3 g, yield 54%).

LC-MS(ESI)[M+H] ⁺ ＝425.2。

Fifth step: preparation of tert-butyl 6-methoxy-2-azaspiro [3.3] hept-2-carboxylate

Tert-butyl 6-hydroxy-2-azaspiro [3.3] hept-2-carboxylate (6 g,28.13 mmol) was dissolved in tetrahydrofuran (5 mL), sodium tert-butoxide (5.41 g,56.26 mmol) and methyl iodide (5.99 g,42.19 mmol) were added at 0deg.C, and reacted at room temperature for 16 hours. LC-MS monitored reaction was complete. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases combined and concentrated to give the crude product of interest (6 g, 93% yield).

LC-MS(ESI)[M+Na] ⁺ ＝250.2。

Sixth step: preparation of 6-methoxy-2-azaspiro [3.3] heptane

Tert-butyl 6-methoxy-2-azaspiro [3.3] hept-2-carboxylate (6 g,26.4 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added to react at room temperature for 2 hours. LC-MS monitored reaction was complete. The reaction mixture was concentrated to give a crude product (3 g) of the objective product.

LC-MS(ESI)[M+H] ⁺ ＝128.3。

Seventh step: preparation of 2-chloro-N- (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) -7- ((2- (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 ] pyrimidin-4-yl) amino) propan-1-ol (2 g,4.71 mmol) was dissolved in dry tetrahydrofuran (20 mL), cooled to 0deg.C, sodium hydrogen (225 mg,9.41mmol, 60%) was added and the reaction stirred at 0deg.C for 0.5H, then 2, 6-dichloro-3-nitropyridine (328 mg,4.71 mmol) was added and the reaction continued for 2H. LC-MS monitored reaction was complete. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases combined, concentrated, and purified by column chromatography to give the desired product (1.2 g, 43% yield).

LC-MS(ESI)[M+H] ⁺ ＝581.1。

Eighth step: preparation of 2-chloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) -7- ((2- (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- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (1.2 g,2.06 mmol) was dissolved in isopropanol (10 mL), 6-methoxy-2-azaspiro [3.3] heptane (262 mg,2.06 mmol) and N, N-diisopropylethylamine (798 mg,6.18 mmol) were added and the reaction stirred at 60℃for 2 hours and LC-MS monitored for completion. The desired product (1.2 g, yield 86%) was obtained by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝672.2。

Ninth step: preparation of 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

2-chloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (1.2 g,1.79 mmol) was dissolved in ethanol (20 mL) and water (4 mL), iron powder (501 mg,8.95 mmol) and ammonium chloride (957 mg,17.9 mmol) were added and the reaction was reacted at 60℃for 3 hours. LC-MS monitored reaction was complete. The filtrate was filtered, concentrated, extracted with ethyl acetate (100 ml x 3) after adding water, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product of interest (1 g, 86% yield).

LC-MS(ESI)[M+H] ⁺ ＝642.2。

Tenth step: preparation of 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- (azepine) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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 (1 g,1.56 mmol) was dissolved in 1, 4-dioxane (20 mL), tris (dibenzylideneacetone) dipalladium (142 mg,0.16 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (148 mg,0.31 mmol) and cesium carbonate (1.52 g,4.67 mmol) were added and reacted at 90℃for 3 hours.

LC-MS(ESI)[M+H] ⁺ ＝606.3。

Eleventh step: preparation of 11- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3- (trifluoromethyl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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-bridged) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (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, concentrated under reduced pressure, methanol (5 mL) was added, aqueous ammonia (1 mL) was added, and the reaction was continued at room temperature for 1 hour. LC-MS detection reaction was complete. The reaction mixture was quenched with water, extracted with ethyl acetate (50 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the desired product (37.5 mg, yield 23.9%) by 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-amine

Crude 6-methoxy-2-azaspiro [3.3] heptane (3 g) was dissolved in anhydrous DMF at room temperature, followed by the sequential addition of potassium carbonate (4.15 g,30mmol,3 eq) and 6-chloro-3-nitropyridin-2-amine (2.38 g,10mmol,1 eq) and stirring of the reaction system at 60℃for 3 hours. TLC monitored reaction was complete. Cooled to room temperature, then water (50 mL) and ethyl acetate (30 mL) were added and stirred for 10 minutes. The mixture was allowed to stand for separation, the aqueous phase was extracted with ethyl acetate (30 ml×2), the organic phases were combined, washed with saturated brine for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the objective product (2.3 g, yield 87%) by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝265.1。

And a second step of: preparation of 2- (6-bromo-5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3] heptane

Under the protection of nitrogen, 6- (6-methoxy-2-azaspiro [3.3]]Hept-2-yl) -3-nitropyridin-2-amine (2 g,7.57 mmol) and tert-butyl nitrite (936.4 mg,9.08mmol,1.2 eq) were dissolved in CHBr ₃ (20 mL) of the reaction mixture was sealed at 90 ℃. LC-MS monitoring reaction is complete, and the target product (570 mg, yield 23%) is obtained by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝328.0。

And a third step of: preparation of 2, 5-dichloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-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 (286.2 mg,0.73mmol,1.2 eq) was dissolved in anhydrous tetrahydrofuran, then NaH (29.2 mg,0.73mmol,1.2eq,60% content) was added, after stirring for 10 minutes, 2- (6-bromo-5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3] heptane (200 mg,0.61 eq, 1 eq) was slowly added, the reaction temperature was raised to room temperature and stirring was continued for 2 hours. TLC monitored reaction was complete. Ice water was slowly added dropwise to the reaction solution to quench it, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the objective product (372 mg, yield 95%) by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝638.4。

Fourth step: preparation of 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

2, 5-dichloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (372 mg,0.58mmol,1.0 eq), iron powder (163.1 mg,2.91mmol,5.0 eq) and ammonium chloride (155.8 mg,2.91mmol,5.0 eq) were dissolved in ethanol/water (20/2 mL) at room temperature, and then the reaction system temperature was raised to 60℃and stirred for 1 hour. TLC monitoring reaction was complete, and column chromatography separation and purification gave the target product (300 m, yield 85%).

LC-MS(ESI)[M+H] ⁺ ＝608.3。

Fifth step: preparation of 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- (azobridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

Tris (dibenzylideneacetone) dipalladium (0) (45.1 mg, 10%) and 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (28.2 mg, 12%) were dissolved in anhydrous 1, 4-dioxane under nitrogen and stirred for 10 min. 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 (300 mg,0.49mmol,1.0 eq) and cesium carbonate (321.2 mg,0.98mmol,2.0 eq) were then added to the reaction system, replacing nitrogen. The reaction system temperature was raised to 100℃and stirring was continued for 16 hours. LC-MS monitored reaction was complete. The desired product was isolated and purified by column chromatography (160 mg, yield 57%).

LC-MS(ESI)[M+H] ⁺ ＝572.3。

Sixth step: preparation of 3-chloro-11- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azobridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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- (azoic bridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (160 mg,0.28mmol,1.0 eq) was dissolved in dichloromethane (5 mL) at 0deg.C, trifluoroacetic acid (0.5 mL) was slowly added dropwise, and after the addition, the reaction temperature was raised to room temperature and stirring was continued for 2 hours. The solvent and trifluoroacetic acid were then removed by concentration under reduced pressure, and ammonia-methanol solution (5 mL) was added and stirring was continued at room temperature for 1 hour. TLC monitored reaction was complete. The desired 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

Reference implementationExample 197A procedure for the preparation of the compound of example 198

Example 199

3-chloro-11- (2-oxa-7-azaspiro [3.5 ]]Non-7-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tert-butyl 3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) carbamate

Tert-butyl (3-hydroxypropyl) carbamate (7 g,39.95mmol,1 eq) was dissolved in toluene (60 mL), replaced with nitrogen three times, and sodium hydrogen (2.08 g,51.93mmol,1.3eq, purity 60%) was added to the reaction solution at 0 ℃.2, 6-dichloro-3-nitropyridine (9.25 g,47.94mmol,1.2 eq) was dissolved in toluene (10 mL) and slowly added dropwise to the reaction system at 25℃for a further 3.5 hours. After completion of the reaction by LC-MS, the reaction system was slowly poured into an aqueous ammonium chloride solution (500 mL), extracted with ethyl acetate (400 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=3:1) to give the objective compound (7.7 g, 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)。

And a second step of: preparation of tert-butyl 3- ((3-nitro-6- (2-oxa-7-azaspiro [3.5] non-7-yl) pyridin-2-yl) oxy) propyl) carbamate

Tert-butyl 3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl carbamate (1 g,3.01mmol,1.0 eq), 2-oxa-7-azaspiro [3.5] nonane (0.46 g,3.62mmol,1.2 eq), TEA (triethylamine) (0.76 g,7.54mmol,2.5 eq) were dissolved in DMF (10 mL) and reacted at 80℃for 16 h. After completion of the LC-MS detection reaction, water (50 mL) was added to the reaction system, extracted with ethyl acetate (50 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (0.84 g, yield 66%).

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)。

And a third step of: preparation of 3- ((3-nitro-6- (2-oxa-7-azaspiro [3.5] non-7-yl) pyridin-2-yl) oxy) propan-1-amine

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

LC-MS(ESI)[M+H] ⁺ ＝323.0.

Fourth step: preparation of 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 ] pyrimidin-4-amine

3- ((3-nitro-6- (2-oxa-7-azaspiro [3.5] non-7-yl) pyridin-2-yl) oxy) propan-1-amine (630 mg,1.95mmol,1.0 eq), 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (827.2 mg,2.35mmol,1.2 eq), DIPEA (N, N diisopropylethylamine) (1010.3 mg,7.82mmol,4 eq) was dissolved in 10mL isopropanol and reacted at 85℃for 4 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated, and purified by flash chromatography (silica gel, PE: ea=3:1) to give the objective 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)。

Fifth step: preparation of 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

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 ] pyrimidin-4-amine (750 mg,1.17mmol,1.0 eq), iron powder (327.8 mg,5.87mmol,5.0 eq), ammonium chloride (408.3 mg,7.63mmol,6.5 eq) were dissolved in 10mL ethanol and 2mL water at room temperature in a 50mL reaction bottle, and the system was then placed in an 80℃oil bath for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE: ea=1:2) to give the objective 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)。

Sixth step: preparation of 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- (azobridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

N- (3- ((3-amino-6- (2-oxa-7-azaspiro [3.5 ])]Non-7-yl) pyridin-2-yloxy) propyl) -2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ]Pyrimidine-4-amine (300 mg,0.49mmol,1.0 eq), pd ₂ (dba) ₃ (22.6 mg,0.02mmol,0.05 eq), xphos (35.2 mg,0.07mmol,0.15 eq) and cesium carbonate (482.0 mg,1.48mmol,3.0 eq) are dissolved in1, 4-Dioxa-hexacyclic ring (5 mL) was subjected to nitrogen exchange three times and then to oil bath reaction at 100deg.C for 1 hour. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated, and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (100 mg, yield 36%).

LC-MS(ESI)[M+H] ⁺ ＝572.1。

Seventh step: preparation of 3-chloro-11- (2-oxa-7-azaspiro [3.5] non-7-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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] triazatridecane (50 mg,0.09mmol,1.0 eq) was dissolved in tetrahydrofuran (1 mL), and a tetrahydrofuran solution (1 mL) of TBAF (tetrabutylammonium fluoride) was added and stirred at 65℃for 3 hours. After completion of the LC-MS detection reaction, the reaction mixture was dried by spin-drying, dissolved in 20mL of ethyl acetate, washed with saturated brine, and the organic phase was dried by spin-drying, and the crude product was isolated and purified by Prep-HPLC to give the objective 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference example 194, the compound of example 200, 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)。

Examples 201 to 202

Reference was made to the methods of preparation of examples 194 and 196-197 to give the compounds of examples 201-202.

Example 203

11- (6-methoxy-2-azaspiro [3.3 ]]Hept-2-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) imidazo [4,5-g]Pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

Reference example 194, preparation method, preparation of example 203, 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＝4.8Hz,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- (azoic bridge) pyrazolo [3,4-b][1]Oxa [4,6,10]Triazacyclotridec-7-amines

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

3-methyl-4-nitro-1H-pyrazole (6.22 g,48.96mmol,1 eq), 3-hydroxytetrahydropyran (5 g,48.96mmol,1 eq) and triphenylphosphine (15.4 g,58.75mmol,1.2 eq) were dissolved in tetrahydrofuran (100 mL) and stirred at 0deg.C for 30 min. Isopropyl azodicarboxylate (11.88 g,58.75mmol,1.2 eq) was then added dropwise, and the reaction temperature was slowly raised to 20℃for 12 hours. LC-MS monitored reaction was complete. The desired product was isolated and purified by column chromatography (4.75 g, yield 46%).

LC-MS(ESI)[M+H] ⁺ ＝212.2。

And a second step of: preparation of 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole

A mixture (1.5 g,7.1mmol,1 eq) of 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole and 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole obtained in the second step was dissolved in tetrahydrofuran (100 mL), 1M lithium hexamethyldisilazide solution (14.2 mL,14.2mmol,2 eq) was slowly added under nitrogen protection, and the mixture was reacted at-78℃for half an hour, and hexachloroethane (5.04 g,21.3mmol,3 eq) was added and reacted at room temperature under nitrogen protection for 2 hours. LC-MS monitored reaction was complete. 50mL of aqueous ammonia chloride was added to the reaction mixture, the mixture was concentrated, extracted with ethyl acetate (200 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the desired product (1 g, yield 57.33%).

LC-MS(ESI)[M+H] ⁺ ＝246.1。

And a third step of: synthesis of 2,5, 6-trichloro-N-methylpyrimidine-4-amine

Tetrachloropyrimidine (20 g,91.8mmol,1.0 eq) and methylamine hydrochloride (6.2 g,91.8mmol,1.0 eq) were dissolved in 300ml of DMSO, stirred under an ice bath for 10 minutes, then triethylamine (27.87 g,275.4mmol,3.0 eq) was slowly added dropwise to the above reaction solution, and the reaction system was stirred at room temperature for about 3 hours. LC-MS monitored reaction was complete. The reaction solution was slowly poured into a stirred ice-water bath, suction filtration was performed, the cake was dissolved in ethyl acetate (600 ml), and washed with a small amount of water (100 ml), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated, and the desired product was isolated and purified by column chromatography (14.5 g, yield 74.34%).

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

Fourth step: synthesis of 3- ((2, 5-dichloro-6- (methylamino) pyrimidin-4-yl) amino) propan-1-ol

2,5, 6-trichloro-N-methylpyrimidin-4-amine (3 g,14.2mmol,1.0 eq) was dissolved in isopropanol (30 mL), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (6.51 g,42.6mmol,3.0 eq) and 3-amino-1-propanol (1.11 g,14.9mmol,1.05 eq) were added and reacted at 90℃for 12 hours. LC-MS monitored reaction was complete. The crude product (2.51 g, purity 78.6%) of the target product was obtained by column chromatography separation and purification, and the target product (0.75 g, 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)。

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

3- ((2, 5-dichloro-6- (methylamino) pyrimidin-4-yl) amino) propan-1-ol (100 mg,0.4mmol,1 eq) was dissolved in tetrahydrofuran (4 mL), cooled to 0℃under nitrogen, and sodium hydrogen (35.04 mg,0.88mmol,60% content, 2.2 eq) was added and stirred for 0.5 h. Then, 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole (117.4 mg,0.48mmol,1.2 eq) was dissolved in tetrahydrofuran (2 mL), and the mixture was slowly dropped into the reaction system to react at 0℃for 2 hours. LC-MS monitored reaction was complete. Anhydrous methanol (2 mL) was added to the system, followed by filtration and concentration of the filtrate, followed by column chromatography separation and purification to give the objective product (140 mg, yield 76.03%).

LC-MS(ESI)[M+H] ⁺ ＝459.8。

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

Cuprous chloride (5.16 mg,0.05mmol,0.2 eq) and sodium borohydride (39.45 mg,1.04mmol,4 eq) were dissolved in tetrahydrofuran (5 mL), and 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,0.26mmol,1 eq) was dissolved in ethanol (5 mL), and then added to the reaction system. Stirred at room temperature for 2 hours. LC-MS monitored reaction was complete. The filtrate was filtered and concentrated, and the desired product was isolated and purified by column chromatography (60 mg, yield 53.48%).

LC-MS(ESI)[M+H] ⁺ ＝429.8。

Seventh step: synthesis of 8-chloro-N, 3-dimethyl-1- (tetrahydro-2H-pyran-3-yl) -1,4,10,11,12,13-hexahydro-5, 9- (azoic bridge) pyrazolo [3,4-b ] [1] oxa [4,6,10] triazatridec-7-amine

Will N ⁴ - (3- ((4-amino-3-methyl-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazol-5-yl) oxy) propyl) -2, 5-dichloro-N ⁶ Methyl pyrimidine-4, 6-diamine (50 mg,0.12mmol,1 eq), tris (dibenzylideneacetone) dipalladium (0) (10.64 mg,0.01mmol,0.1 eq), dicyclohexyl [2',4',6 '-tris (propan-2-yl) - [1,1' -biphenyl ]-2-yl]Phosphine (11.08 mg,0.02mmol,0.2 eq) and cesium carbonate (151.43 mg,0.46mmol,4 eq) were dissolved in dioxane (2 mL) and stirred for 1 hour at 100deg.C under nitrogen. LC-MS monitored reaction was complete. The mixture was filtered through celite, the filtrate was washed with ethyl acetate, the filtrate was concentrated, and the crude product was purified by column chromatography to give the desired product (3.75 mg, yield 7.93%) which was then prepared by high performance liquid chromatography.

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)。

Examples 205 to 341

Referring to the preparation 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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridec-4-amines

The first step: preparation of 4,5, 6-trichloropyrimidin-2-amine

4, 6-dichloropyrimidin-2-amine (5 g,30.5mmol,1 eq) was dissolved in chloroform (20 mL) under nitrogen, then NCS (6.11 g,45.7mmol,1.5 eq) was added at room temperature and the reaction temperature was raised to 60℃for 16 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (3 g, yield 50%).

LC-MS(ESI)[M+H] ⁺ ＝197.9。

And a second step of: 5, 6-dichloro-N ⁴ Preparation of-methylpyrimidine-2, 4-diamine

4,5, 6-trichloropyrimidin-2-amine (3 g,15.1mmol,1.0 eq) and methylamine hydrochloride (1.02 g,15.1mmol,1.0 eq) were dissolved in DMSO at room temperature, then triethylamine (2.3 mL,22.7mmol,1.5 eq) was slowly added dropwise and reacted at room temperature for 2 hours. After completion of the LC-MS detection reaction, water and ethyl acetate were added and stirred for 10 minutes, the mixture was left to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=5:1) to give the objective compound (2.1 g, yield 72%).

LC-MS(ESI)[M+H] ⁺ ＝193.0。

And a third step of: preparation of 3- ((2-amino-5-chloro-6- (methylamino) pyrimidin-4-yl) amino) propan-1-ol

At room temperature, 5, 6-dichloro-N ⁴ Methyl pyrimidine-2, 4-diamine (2 g,10.4mmol,1.0 eq) and amino alcohol (1.17 g,15.5mmol,1.5 eq) were dissolved in DMSO (20 mL), then triethylamine (2.1 g,20.8mmol,2.0 eq) was slowly added and the reaction temperature was raised to 130 ℃ for reaction overnight. After 16 hours, cool to room temperature, then add water and ethyl acetate and stir for 10 minutes, leave still to separate the liquid, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine in turn, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and then separate and purify by flash chromatography (silica gel, PE: ea=4:1, dcm: meoh=5:1) to give the title compound (1.5 g, yield 62%).

LC-MS(ESI)[M+H] ⁺ ＝232.3。

Fourth step: preparation of 3- ((2-bromo-5-chloro-6- (methylamino) pyrimidin-4-yl) amino) propan-1-ol

3- ((2-amino-5-chloro-6- (methylamino) pyrimidin-4-yl) amino) propan-1-ol (500 mg,2.15mmol,1.0 eq) was dissolved in CHBr under nitrogen ₃ (10 mL) and then sealed at 60 ℃. After LC-MS detection reaction is finished, decompressing and concentratingAfter the contraction, the objective compound was obtained (35 mg, yield 6%) by reverse phase column chromatography (75% mecn).

LC-MS(ESI)[M+H] ⁺ ＝295.0。

Fifth step: 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 Preparation of-methylpyrimidine-4, 6-diamine

3- ((2-bromo-5-chloro-6- (methylamino) pyrimidin-4-yl) amino) propan-1-ol (35 mg,0.11mmol,1.0 eq) was dissolved in anhydrous THF (10 mL) and NaH (3.8 mg,0.16mmol,1.2 eq) was then added and after 10 minutes of reaction, 2- (6-bromo-5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3] heptane (37.8 mg,0.13mmol,1.2 eq) was slowly added and the reaction was then raised to room temperature and stirred for a further 2 hours. After completion of LC-MS detection, the reaction was quenched by slowly dropping ice water, 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, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=20:1) to give the title compound (51 mg, yield 88%).

LC-MS(ESI)[M+H] ⁺ ＝542.2。

Sixth step: n (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 Preparation of-methylpyrimidine-4, 6-diamine

2-bromo-5-chloro-N was placed in a 25mL reaction flask at room temperature ⁴ - (3- ((6- (6-methoxy-2-azaspiro [3.3 ])]Hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) -N ⁶ Methyl pyrimidine-4, 6-diamine (51 mg,0.09mmol,1.0 eq), iron powder (26.2 mg,0.47mmol,5.0 eq) and ammonium chloride (25.1 mg,0.47mmol,5.0 eq) were dissolved in EtOH/H ₂ O mixed solvent (10/2 mL), then the reaction system temperature was raised to 80℃and stirred for 1 hour. After TLC monitoring the reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=10:1) to give the title compound (40 mg, 83% yield).

LC-MS(ESI)[M+H] ⁺ ＝512.2。

Seventh step: preparation of 5-chloro-13- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -N-methyl-7, 8,9, 10-tetrahydro-1H-2, 6- (azepine) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridec-4-amine

Pd was added to a 20mL three-port reaction flask under nitrogen protection ₂ (dba) ₃ (10%) and XPhos (12%) were dissolved in anhydrous 1, 4-dioxane (20 mL) and stirred for 10 min. Will 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 Methyl pyrimidine-4, 6-diamine (35 mg,0.07mmol,1.0 eq) and cesium carbonate (45.5 mmol,0.14mmol,2.0 eq) were added to the reaction system, then nitrogen was replaced, the temperature of the reaction system was raised to 90 ℃ and stirring was continued for 16 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE: ea=2:1, dcm: meoh=10:1) to give the objective 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 to 352

Reference to the preparation of examples 204, 342 and 354 gave the compounds of examples 343-352

Example 353

5-chloro-13- (6-methoxy-2-azaspiro [3.3]]Hept-2-yl) -7,8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 2, 5-dichloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) pyrimidin-4-amine

3- ((2, 5-dichloropyrimidin-4-yl) amino) propan-1-ol (162 mg,0.73mmol,1.2 eq) was dissolved in anhydrous THF, then NaH (18 mg,0.73mmol,1.2 eq) was added, after stirring for 10 min, 2- (6-bromo-5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3] heptane (200 mg,0.62mmol,1.0 eq) was slowly added, then warmed to room temperature and the reaction was continued for 2 h. After TLC monitored completion of the reaction, ice water was slowly added dropwise to quench the reaction, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=10:1) to give the title compound (260 mg, yield 80%).

LC-MS(ESI)[M+H] ⁺ ＝469.2。

And a second step of: preparation of N- (3- ((3-amino-6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) pyridin-2-yl) oxy) propyl) -2, 5-dichloropyrimidin-4-amine

2, 5-dichloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3 ]) was placed in a 50mL reaction flask at room temperature]Hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) pyrimidin-4-amine (260 mg,1.0 eq), iron powder (5.0 eq) and ammonium chloride (5.0 eq) were dissolved in EtOH/H ₂ O (20/2 mL) and then allowed to react at 60℃for 1 hour. After TLC monitoring the reaction was complete, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=10:1) to give the title compound (185 mg, 76% yield).

LC-MS(ESI)[M+H] ⁺ ＝438.2。

And a third step of: preparation of 5-chloro-13- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -7,8,9, 10-tetrahydro-1H-2, 6- (azepine) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecanes

Pd was introduced into a 20mL reaction flask under nitrogen protection ₂ (dba) ₃ (10%) and XPhos (12%) were dissolved in anhydrous 1, 4-dioxane and stirred 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)Cesium carbonate (2.0 eq) was added to the reaction system, followed by replacement of nitrogen. The temperature was raised to 100℃and the reaction was continued for 16 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE: ea=2:1, dcm: meoh=10:1) to give the objective 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＝6.1Hz,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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) propan-1-ol

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (2 g,9.22mmol,1 eq) was dissolved in isopropanol (20 mL) and 3-amino-1-propanol (830 mg,11.06mmol,1.2 eq) was added at 0deg.C. The reaction was carried out at 0℃for half an hour and at room temperature for 16 hours, and the target product was obtained by separation and purification by column chromatography (700 mg, yield 29%).

LC-MS(ESI)[M+H] ⁺ ＝256.0。

And a second step of: preparation of 2-chloro-N- (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) pyrimidin-4-amine

3- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) propan-1-ol (1.5 g,5.87mmol,1 eq) was dissolved in THF (20 mL), sodium hydrogen (60%) (211 mg,1.17mmol,1.5 eq) was added at 0deg.C, reacted at 0deg.C for 0.5 hours, and 2, 6-dichloro-3-nitropyridine (1.36 g,7.04mmol,1.2 eq) was added, reacted at room temperature for 0.5 hours, and LC-MS monitored reaction was complete. The reaction mixture was quenched with water, concentrated, extracted with ethyl acetate (100 ml×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the desired product (1.2 g, yield 49.6%) by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝412.0。

And a third step of: preparation of 2-chloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) pyrimidin-4-amine

2-chloro-N- (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) pyrimidin-4-amine (1.3 g,3.15mmol,1 eq) was dissolved in isopropanol (20 mL), N-diisopropylethylamine (1.22 g,9.46mmol,3 eq) was added, and 6-methoxy-2-azaspiro [3.3] heptane (401 mg,3.15mmol,1.2 eq) was reacted at 0℃for 2 hours. LC-MS monitored reaction was complete. The desired product was isolated and purified by column chromatography (260 mg, yield 16.39%).

LC-MS(ESI)[M+H] ⁺ ＝503.1。

Fourth step: preparation of 13- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -5- (trifluoromethyl) -7,8,9, 10-tetrahydro-1H-2, 6- (azepine) 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) propyl) -5- (trifluoromethyl) pyrimidin-4-amine (200 mg,0.4mmol,1 eq) was dissolved in ethanol (20 mL), and a saturated solution of iron powder (111 mg,1.99mmol,5 eq) and ammonium chloride (4 mL) was added and stirred at 100deg.C for 6 hours. LC-MS monitored reaction was complete. The filtrate was filtered, concentrated, added with water (50 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was washed 2 times with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative high performance liquid phase separation to give the desired 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＝5.8Hz,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 to 356

Reference example 354 preparation method, preparation implementationExamples 355-356 compounds:

example 357

13- (2-oxa-5-azabicyclo [ 2.2.1)]Hept-5-yl) -5-chloro-7, 8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 354 gave the compound of example 357, 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 to 426

Referring to the methods of preparation of examples 353 and 354, the compounds of examples 358-376 and 378-426 were prepared: referring to the procedure for the preparation 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- (azoic 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

Tert-butyl (3-hydroxypropyl) carbamate (1.77 g,10.1mmol,1.2 eq) was dissolved in anhydrous THF, then NaH (302 mg,12.6mmol,1.5 eq) was added and after 10 minutes of reaction, 1-bromo-2, 5-difluoro-4-nitrobenzene (2 g,8.4mmol,1.0 eq) was slowly added and then the reaction was continued at room temperature for 2 hours. After completion of the LC-MS detection reaction, the reaction was quenched by slowly dropping ice water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and after concentration of the filtrate, the filtrate was separated and purified by flash chromatography (silica gel, PE: ea=4:1) to give the objective compound (3 g, yield 91%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.09(d,J＝8.1Hz,1H),7.76(d,J＝5.8Hz,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)。

And a second step of: preparation of tert-butyl (3- (4-fluoro-5- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -2-nitrophenoxy) propyl) carbamate

In a 50mL three-port reaction flask, tert-butyl (3- (5-bromo-4-fluoro-2-nitrophenoxy) propyl) carbamate (2.5G, 6.4mmol,1.0 eq), 6-methoxy-2-azaspiro [3.3] heptane (970.3 mg,7.6mmol,1.2 eq), cesium carbonate (4.1G, 12.7mmol,2.0 eq) and Pd-XPhos-G3 (10%) were dissolved in anhydrous dioxane (50 mL) under nitrogen atmosphere, nitrogen was replaced, and the reaction system temperature was raised to 100℃and the reaction was continued for 16 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated and purified by flash chromatography (silica gel, PE: ea=4:1, dcm: meoh=20:1) to give the objective compound (1.5 g, yield 54%).

LC-MS(ESI)[M-99]＝340.2。

And a third step of: preparation of 2, 5-dichloro-N- (3- (4-fluoro-5- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -2-nitrophenoxy) propyl) pyrimidin-4-amine

Tert-butyl (3- (4-fluoro-5- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -2-nitrophenoxy) propyl) carbamate (480 mg,2mmol,1.0 eq) was dissolved in dichloromethane at room temperature in a 50mL reaction flask, TFA (3 v/w) was then slowly added dropwise and the reaction continued for 10 min. TFA and dichloromethane were removed by concentration under reduced pressure and used directly in the next step. The residue (678 mg) was dissolved in isopropyl alcohol (20 mL), and triethylamine (3.0 eq) was slowly added dropwise at 0℃to react for 10 minutes. 2,4, 5-trichloropyrimidine (603 mg,6mmol,1.2 eq) was added and the reaction was allowed to warm to 90℃and continued for 16 hours. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated and purified by flash chromatography (silica gel, PE: ea=4:1) to give the objective compound (610 mg, yield 63%).

LC-MS(ESI)[M+H] ⁺ ＝486.2。

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

2, 5-dichloro-N- (3- (4-fluoro-5- (6-methoxy-2-azaspiro [3.3 ]) was placed in a 50mL reaction flask at room temperature]Hept-2-yl) -2-nitrophenoxy) propyl) pyrimidin-4-amine (300 mg,0.62mmol,1.0 eq), iron powder (172 mg,3.1mmol,5.0 eq) and ammonium chloride (165 mg,3.1mmol,5.0 eq) were dissolved in EtOH/H ₂ O (10/2 mL) and then the system was warmed to 90℃and reacted for 2 hours. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=10:1) to give the title compound (254 mg, yield 90%).

LC-MS(ESI)[M+H] ⁺ ＝455.3。

Fifth step: preparation of 5-chloro-14-fluoro-13- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -7,8,9, 10-tetrahydro-1H-2, 6- (azepine) benzo [ b ] [1] oxa [4,6,10] triazatridecane:

n- (3- (2-amino-4-fluoro-5- (6-methoxy-2-azaspiro [3.3 ]) was placed in a 20mL microwave reaction flask under nitrogen protection]Hept-2-yl) benzeneOxy) propyl) -2, 5-dichloropyrimidin-4-amine (190 mg,0.42mmol,1 eq), pd ₂ (dba) ₃ (10%), XPhos (12%) and cesium carbonate (2793 mg,0.84mmol,2.0 eq) were added to anhydrous 1, 4-dioxane (10 mL) and nitrogen was replaced 3 times. The reaction system temperature was raised to 100℃and reacted under microwave reaction conditions for 4 hours. After completion of LC-MS detection, water and ethyl acetate were added to extract, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=4:1, dcm: meoh=10:1) to give the title compound (26.48 mg, yield 15%).

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＝6.0Hz,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 to 430

Referring to the methods of preparation of examples 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- (azepine) benzo [ b][1]Oxa [4,6,10]Triazacyclotridec-4-amines

Reference to the procedure for the preparation of example 427 gave the compound of example 431, 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 to 438

Referring to the methods of preparation of examples 342, 354 or 427, the compounds of examples 432-438 were prepared.

Example 439

12-methyl-10- (tetrahydro-2H-pyran-3-yl) -3- (trifluoromethyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azo-bridge) pyrazolo [2,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

LC-MS(ESI)[M+H] ⁺ ＝212.2。

A mixture (1.5 g,7.1mmol,1 eq) of 5-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole and 3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole obtained in the second step was dissolved in tetrahydrofuran (100 mL), 1M lithium hexamethyldisilazide solution (14.2 mL,14.2mmol,2 eq) was slowly added under nitrogen protection, and the mixture was reacted at-78℃for half an hour, and hexachloroethane (5.04 g,21.3mmol,3 eq) was added and reacted at room temperature under nitrogen protection for 2 hours. LC-MS monitored reaction was complete. 50mL of aqueous ammonia chloride was added to the reaction mixture, the mixture was concentrated, extracted with ethyl acetate (200 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the objective product (1 g, yield 57.33%) by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝246.1。

And a third step of: preparation of 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

3- ((2-chloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) propan-1-ol (800 mg,1.88mmol,1.0 eq) was dissolved in dry tetrahydrofuran (20 mL), cooled to 0deg.C, sodium hydrogen (68 mg,2.82mmol,1.5 eq) was added and reacted at 0deg.C for 0.5H. Then 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-3-yl) -1H-pyrazole (460 mg,1.88mmol,1.5 eq) was added and the reaction was continued for 2 hours. LC-MS monitored reaction was complete. The reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (100 mL x 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and purified by column chromatography to give the desired product (700 mg, yield 58%).

LC-MS(ESI)[M+H] ⁺ ＝634.2。

Fourth step: preparation of 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

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), and iron powder (330 mg,5.91 mmol) and ammonium chloride (632 mg,11.83 mmol) were added and reacted at 60℃for 3 hours. LC-MS monitored reaction was complete. Filtration, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, column chromatography separation and purification gave the objective product (400 mg, yield 66%).

LC-MS(ESI)[M+H] ⁺ ＝604.2。

Fifth step: preparation of 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- (azepine) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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), tris (dibenzylideneacetone) dipalladium (60 mg,0.07 mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (62 mg,0.13 mmol) and cesium carbonate (647 mg,1.99 mmol) were added and the reaction was monitored by LC-MS for completion at 90℃for 3 hours. The desired product was isolated and purified by column chromatography (150 mg, yield 40%).

LC-MS(ESI)[M+H] ⁺ ＝568.3。

Sixth step: preparation of 12-methyl-10- (tetrahydro-2H-pyran-3-yl) -3- (trifluoromethyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [2,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazacyclotridecane

In a 50mL single flask, 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- (azobridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (130 mg,0.23 mmol) was added, then concentrated hydrochloric acid (1 mL) was added, reacted at room temperature for 1 hour, concentrated under reduced pressure to remove hydrochloric acid, methanol (5 mL) was added, ammonia (1 mL) was further added, and the reaction was continued at room temperature for 1 hour. LC-MS monitored reaction was complete. The reaction solution was concentrated, and the desired product (22 mg, yield 21%) was obtained by separation and purification of the preparative high performance liquid phase.

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- (azoic bridge) pyrazolo [3, 4-b)]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridec-10-yl) -2-methylpropanenitrile

The first step: preparation of methyl 2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionate

3-methyl-4-nitro-1H-pyrazole (6 g,47.21mmol,1.0 eq) was dissolved in dimethylformamide (50 mL), and sodium hydrogen (3.4 g,85mmol, purity 60%,1.8 eq) was added at 0deg.C for 0.5 hours. Methyl 2-bromo-2-methylpropionate (12.82 g,70.81mmol,1.5 eq) was slowly added to the reaction system, and the reaction was continued at 10℃for 5 hours. After completion of the LC-MS detection reaction, water (20 mL) was added and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, concentrated, washed with lithium chloride solution (10%) and purified by flash chromatography (silica gel, PE: ea=2:1) to give the title compound (3.3 g, 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)。

And a second step of: preparation of 2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionic acid

Methyl 2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionate (6.1 g,26.85mmol,1.0 eq) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)/water (6 mL), and lithium hydroxide monohydrate (3.38 g,80.54mmol,3.0 eq) was added to the system to react at 10℃for 16 hours. After the LC-MS detection reaction is finished, water is added, and dilute hydrochloric acid (2 mol/L) is used for regulating the acidity to be 1-2. Extraction with ethyl acetate (50 ml x 3), combining the organic phases, drying over anhydrous sodium sulphate, filtration, concentration of the filtrate, and concentration gave crude title compound (5.3 g,24.86mmol, 92.6% yield).

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)。

And a third step of: preparation of 2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propanamide

2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionic acid (2.5 g,11.73mmol,1.0 eq) was dissolved in dichloromethane (10 mL), N-dimethylformamide (0.1 mL) was added dropwise, and oxalyl chloride (4.47 g,35.18mmol,3.0 eq) was added. After completion of the TLC detection, the reaction solution was concentrated, the residue was dissolved in tetrahydrofuran (10 ml), and aqueous ammonia (10 ml) was slowly added thereto, under nitrogen protection at 0℃for 3 hours. Stirring was continued for 1 hour. After completion of the reaction, LC-MS was used for extraction with methylene chloride, and the organic phase was concentrated to give the objective 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)。

Fourth step: preparation of 2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionitrile

2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propanamide (6.5 g,30.63mmol,1.0 eq) was dissolved in phosphorus oxychloride (15 mL). The reaction was carried out at 90℃for 1 hour. After completion of the LC-MS reaction, the reaction mixture was concentrated, water was slowly added to the reaction mixture, the mixture was extracted with ethyl acetate (100 ml. Times.3), and the organic phases were combined and concentrated to give a crude product of the objective 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)。

Fifth step: preparation of 2- (5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl) -2-methylpropanenitrile

2-methyl-2- (3-methyl-4-nitro-1H-pyrazol-1-yl) propionitrile (4.2 g,21.63mmol,1.0 eq) was dissolved in tetrahydrofuran (10 mL), and HMDSLi (108.1 mL,108.14mmol,5.0 eq) was added to the reaction system under a nitrogen atmosphere at-78 ℃. Hexachloroethane (15.36 g,64.88mmol,3.0 eq) was slowly added to the reaction system by reaction at-78℃for half an hour. The reaction was continued for two hours at 10 ℃. After completion of the LC-MS detection reaction, water (20 mL) was added and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, concentrated and purified by flash chromatography (silica gel, PE: ea=3:1) to give the title compound (3 g, yield 61%).

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

Sixth step: preparation of 2- (5- (3-aminopropoxy) -3-methyl-4-nitro-1H-pyrazol-1-yl) -2-methylpropanenitrile

Tert-butyl N- (3-hydroxypropyl) carbamate (337.32 mg,1.93mmol,1.1 eq) was dissolved in N, N-dimethylformamide (10 ml, 100.0%) and then sodium hydride (60%, 210mg,5.25mmol,3.0 eq) was added in portions under ice bath, reacted for half an hour under nitrogen protection, then 2- (5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl) -2-methylpropanenitrile (400 mg,1.75mmol,1.0 eq) was added, and after nitrogen substitution, the reaction was continued for 16 hours at 25 ℃. After completion of the LC-MS detection reaction, ice water (10 mL) was added dropwise to the reaction solution, followed by extraction with ethyl acetate (20 mL), saturated brine (20 ml×3), and the organic phase was concentrated, and the crude product was isolated by preparative TLC (PE: ea=2:1) to give the objective compound (90 mg, yield 19%).

LC-MS(ESI)[M+H] ⁺ ＝268.2。

Seventh step: preparation of 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-methylpropanenitrile

A single vial was taken, 2- (5- (3-aminopropoxy) -3-methyl-4-nitro-1H-pyrazol-1-yl) -2-methylpropanenitrile (200 mg,0.75mmol,1.1 eq) was dissolved in N, N-dimethylformamide (8 ml, 100.0%) and then sodium hydride (60%, 53.88mg,2.24mmol,3.0 eq) was added in portions under ice bath, the reaction was continued in ice bath under nitrogen for half an hour, and then 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (263.93 mg,0.75mmol,1 eq) was added, and after replacing nitrogen, the reaction was continued at 20℃for 3 hours. After the TLC detection was completed, ice water (10 mL) was added dropwise to the reaction solution, followed by extraction with ethyl acetate (15 ml×3), saturated brine (10 ml×2), and the organic phase was concentrated, and the crude product was separated by preparative TLC (PE: ea=2:1) to give the objective 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)。

Eighth step: preparation of 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-methylpropanenitrile

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-methylpropanenitrile (150 mg,0.25mmol,1.0 eq) was dissolved in ethanol (10 mL)/water (2 mL) mixed solvent. Iron powder (69.73 mg,1.25mmol,5.0 eq) and ammonium chloride (80.16 mg,1.5mmol,6.0 eq) were added to the reaction system, and the temperature was raised to 75℃for 2 hours. After the completion of the reaction by LC-MS, the reaction mixture was filtered, the filtrate was concentrated, saturated brine was applied, and the organic phases were combined and concentrated to give the crude title compound (130 mg, yield 91%).

LC-MS(ESI)[M+H] ⁺ ＝553.2。

Ninth step: preparation of 2- (3-chloro-12-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,13-hexahydro-10H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridec-10-yl) -2-methylpropanenitrile

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-methylpropanenitrile (130 mg,0.23mmol,1.0 eq) was dissolved in dioxane (5 mL), and tris (dibenzylideneacetone) dipalladium (0) (21.51 mg,0.02mmol,0.1 eq), dicyclohexyl [2',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl ] phosphine (22.39 mg,0.05mmol,0.2 eq), cesium carbonate (229.55 mg,0.7mmol,3.0 eq) was added to the reaction system. The temperature is raised to 90 ℃ in nitrogen atmosphere for reaction for 3 hours. After completion of LC-MS detection reaction, celite was filtered and the filtrate was concentrated, the crude product was isolated by preparative TLC (DCM: meoh=15:1) to give the title compound (40 mg, 33% yield).

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)。

Tenth step: preparation of 2- (3-chloro-12-methyl-1,5,6,7,8,13-hexahydro-10H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridec-10-yl) -2-methylpropanenitrile

2- (3-chloro-12-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,13-hexahydro-10H-4, 14- (azoic bridge) pyrazolo [3,4-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridec-10-yl) -2-methylpropanenitrile (40 mg,0.08mmol,1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. After the completion of the reaction, LC-MS was used to measure the reaction time, tetrahydrofuran (2 mL) was added to the reaction mixture to redissolve the reaction mixture, and ammonia (1.5 mL) was added to the reaction mixture, followed by further reaction at room temperature for 1 hour. After completion of the reaction, LC-MS was used to detect the presence of the solvent, and the solvent was dried by spin-drying, followed by separation and purification by Prep-HPLC to give the objective 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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of example 1 or 439 gave the compound of example 441, LC-MS (ESI) [ M+H ]] ⁺ ＝370.1； ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.73(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- (azoic bridge) pyrazolo [3,4-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 1 or 439 gave the compound of example 442, 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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3-fluoro-4- (3-methyl-4-nitro-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester

3-methyl-4-nitro-1H-pyrazole (0.99 g,7.8mmol,1.0 eq), 3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.71 g,7.8mmol,1.0 eq) and triphenylphosphine (2.25 g,8.68mmol,1.1 eq) were dissolved in anhydrous THF (30 mL) at 0deg.C, then diisopropyl azodicarboxylate (2.52 g,12.48mmol,1.6 eq) was slowly added, after which the reaction temperature was raised to room temperature and the reaction was continued overnight. TLC monitored incomplete substrate reaction, ice water was slowly added dropwise to quench the reaction, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, and after concentration of the filtrate, purified by flash chromatography (silica gel, PE: ea=10:1) to give the title compound (2.1 g, yield 82%).

LC-MS(ESI)[M-55]＝273.2。

And a second step of: preparation of 3-fluoro-4- (3-methyl-4-nitro-1H-pyrazol-1-yl) piperidine

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

And a third step of: preparation of 3-fluoro-4- (3-methyl-4-nitro-1H-pyrazol-1-yl) -1- (oxetan-3-yl) piperidine

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

LC-MS(ESI)[M+H] ⁺ ＝285.2。

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

3-fluoro-4- (3-methyl-4-nitro-1H-pyrazol-1-yl) -1- (oxetan-3-yl) piperidine (2.09 g,7.35mmol,1.0 eq) and THF (30 mL) were charged to a 100mL three-port reaction flask at-78deg.C under nitrogen. HMDSLi (8.82 mmol,1.2 eq) was then slowly added dropwise, the temperature of the system was maintained without significant increase, and the reaction was continued for 30 minutes. Then slowly add C ₂ Cl ₆ (3.48 g,14.7mmol,2.0 eq) and after the addition was complete, the system temperature was raised to room temperature and stirring continued. After TLC detection reaction is completed, slowly dropwise adding ice water to quench reaction, adding ethyl acetate, continuously stirring for 10 min, and standingAnd (5) placing a separating liquid. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.2 g, yield 51%) which was purified by flash chromatography (silica gel, PE: ea=2:1).

Fifth to eighth steps refer to the preparation method of example 1 or 439, and the compound of example 443 is prepared.

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＝2.4Hz,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- (azoic bridge) pyrazolo [3,4-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 1 or 439 gave the compound of example 444, 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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 1 or 439 gave the compound of example 445, 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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 1 or 439 gave the compound of example 446, 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-morpholinocyclobutyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azobridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3- (benzyloxy) cyclobutan-1-ol

3- (benzyloxy) cyclobutan-1-one (6.5 g,36.89mmol,1.0 eq) was dissolved in methanol (40 mL) and stirred at 0deg.C, sodium borohydride (2.79 g,73.78mmol,2.0 eq) was added slowly and reacted for 1 hour. After completion of the LC-MS detection reaction, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 ml×3), washed with saturated aqueous sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (6.5 g, yield 100%).

LC-MS(ESI)[M+H] ⁺ ＝179.1。

And a second step of: preparation of 1- (3- (benzyloxy) cyclobutyl) -3-methyl-4-nitro-1H-pyrazole

Triphenylphosphine (14.35 g,54.7mmol,1.5 eq) was dissolved in tetrahydrofuran (150 mL) and reacted at 0deg.C for 10 min. Isopropyl azodicarboxylate (11.06 g,54.7mmol,1.5 eq) was then added dropwise, the reaction mixture was reacted at 0℃for 15 minutes, 3-methyl-4-nitro-1H-pyrazole (4.64 g,36.47mmol,1.0 eq) was added, and after 15 minutes, 3- (benzyloxy) cyclobutan-1-ol (6.5 g,36.47mmol,1.0 eq) was added. The reaction solution was slowly heated to 25℃and reacted for 12 hours. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=5:1) to give the objective compound (10 g, yield 95%).

LC-MS(ESI)[M+H] ⁺ ＝288.1。

And a third step of: preparation of 1- (3- (benzyloxy) cyclobutyl) -5-chloro-3-methyl-4-nitro-1H-pyrazole

1- (3- (benzyloxy) cyclobutyl) -3-methyl-4-nitro-1H-pyrazole (6.0 g,20.88mmol,1.0 eq) was dissolved in tetrahydrofuran (150 mL), -reacted at 78℃for 15 min, then lithium bis (trimethylsilyl) amide (42 mL,42.0mmol,2.0 eq) was added and reacted for 30 min. Hexachloroethane (9.89 g,42.0mmol,2.0 eq) was further added, and the reaction mixture was reacted at-78℃for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, poured into water (100 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated aqueous sodium chloride, combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and then purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (4.48 g, yield 67%).

LC-MS(ESI)[M+H] ⁺ ＝322.0。

Fourth step: preparation of 3- (5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl) cyclobutan-1-ol

1- (3- (benzyloxy) cyclobutyl) -5-chloro-3-methyl-4-nitro-1H-pyrazole (4.23 g,13.15 mmol) was dissolved in anhydrous dichloromethane (50 mL). Boron trichloride (25 mL,25mmol,1M,1.9 eq) was added and reacted for 1 hour under nitrogen at 0deg.C. After completion of the LC-MS detection reaction, the reaction solution was washed with saturated aqueous sodium bicarbonate and saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=2:1) to give the objective compound (2.97 g, yield 98%).

LC-MS(ESI)[M+H] ⁺ ＝232.0。

Fifth step: preparation of 3- (5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl) cyclobutan-1-one

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

LC-MS(ESI)[M+H] ⁺ ＝230.1。

Sixth step: 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 (2.64 g,11.5 mmol), morpholine (3 g,34.49 mmol) and acetic acid (1.04 g,17.25 mmol) were dissolved in dichloromethane (30 mL) at 0deg.C. After 30 minutes of reaction at 0 ℃, sodium cyanoborohydride (1.42 g,22.99 mmol) was added and the reaction was continued for 1 hour. After completion of the LC-MS detection reaction, the mixture was washed with saturated aqueous sodium bicarbonate (20 mL) and brine (15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the title compound (2.81 g, yield 81%).

LC-MS(ESI)[M+H] ⁺ ＝301.1。

Seventh to tenth steps referring to the preparation method of example 1 or 439, the compound of example 447, LC-MS (ESI) [ M+H ], was prepared] ⁺ ＝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-morpholinocyclopentyl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azobridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 439 or 447 gave the compound of example 448, LC-MS (ESI) [ M+H ]] ⁺ ＝473.2； ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.02(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- (azoic bridge) pyrazolo [3,4-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 2, 6-dimethyltetrahydro-2H-pyran-4-ol

2, 6-dimethyl-4H-pyran-4-one (10 g,80.55 mmol) was dissolved in ethanol (100 mL), palladium on carbon (1.0 g) was added and reacted under 50psi of hydrogen at 40℃for 16 hours. After completion of the LC-MS detection reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product (10 g) of the objective compound.

LC-MS(ESI)[M+H] ⁺ ＝153.1。

And a second step of: preparation of 1- (2, 6-dimethyltetrahydro-2H-pyran-4-yl) -3-methyl-4-nitro-1H-pyrazole

Triphenylphosphine (30.9 g,118.02mmol,1.5 eq) was dissolved in tetrahydrofuran (150 mL), diisopropyl azodicarboxylate (23.8 g,118.02mmol,1.5 eq), 3-methyl-4-nitro-1H-pyrazole (10 g,78.68mmol,1.0 eq) and 2, 6-dimethyltetrahydro-2H-pyran-4-ol (10.2 g,78.68mmol,1.0 eq) were added sequentially at 0deg.C and reacted for 12 hours at room temperature. After completion of the LC-MS detection reaction, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (15 g).

LC-MS(ESI)[M+H] ⁺ ＝240.2。

And a third step of: preparation of 5-chloro-1- (2, 6-dimethyltetrahydro-2H-pyran-4-yl) -3-methyl-4-nitro-1H-pyrazole

1- (2, 6-Dimethyltetrahydro-2H-pyran-4-yl) -3-methyl-4-nitro-1H-pyrazole (15 g,62.69 mmol) was dissolved in tetrahydrofuran (100 mL), -lithium bis (trimethylsilyl) amide (1M, 94 mL) was added at 78℃and reacted at-78℃for 0.5 hours, hexachloroethane (22 g,94.03 mmol) was added and the reaction was continued at room temperature for 2 hours. After completion of the LC-MS detection reaction, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (200 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=5:1) to give the objective compound (3 g, three-step yield 13%).

LC-MS(ESI)[M+H] ⁺ ＝274.0。

Fourth to seventh steps reference 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

The compound of example 450 was prepared according to the methods described for preparation of examples 439 or 446.

Example 451

3, 7-trifluoro-12-methyl-10- (tetrahydro-2H-pyran-3-yl) -5,6,7,8,10,13-hexahydro-1H-4, 14- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 1 or 439 gave the compound of example 451, 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- (azobridge) pyrazolo [3,4-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3-methyl-4-nitro-1-vinyl-1H-pyrazole

3-methyl-4-nitro-1H-pyrazole (10 g,78.68mmol,1.0 eq) and benzyltriethylammonium chloride (1.79 g,7.87mmol,0.1 eq) were dissolved in dichloroethane (50 mL) and 50% aqueous NaOH (17.5 g,440 mmol) and the reaction was warmed to 80℃and maintained for 6 hours. After completion of the LC-MS detection reaction, the reaction solution was filtered, and after concentration of the filtrate, the reaction solution was purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (11.55 g, yield 96%).

LC-MS(ESI)[M+H] ⁺ ＝154.1。

And a second step of: preparation of 5-chloro-3-methyl-4-nitro-1-vinyl-1H-pyrazole

3-methyl-4-nitro-1-vinyl-1H-pyrazole (5 g,32.65mmol,1.0 eq) was dissolved in tetrahydrofuran (50 mL) and reacted at-78℃for 15 min. Then, lithium bis (trimethylsilyl) amide (65.3 mL,65.3mmol,2.0 eq) was added and reacted for 30 minutes, and hexachloroethane (15.46 g,65.3mmol,2.0 eq) was added and reacted at-78℃for 1 hour. After completion of the LC-MS detection reaction, the reaction solution was quenched with saturated aqueous ammonium chloride, poured into water (50 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (954 mg, yield 16%).

LC-MS(ESI)[M+H] ⁺ ＝188.0。

And a third step of: preparation of 5-chloro-1- (2, 2-difluorocyclopropyl) -3-methyl-4-nitro-1H-pyrazole

5-chloro-3-methyl-4-nitro-1-vinyl-1H-pyrazole (950 mg,5.06mmol,1.0 eq) and sodium fluoride (22 mg,0.51mmol,0.1 eq) were dissolved in methyl benzoate (5 mL) and heated to 110℃under nitrogen. Trimethylsilane 2, 2-difluoro-2- (fluorosulfonyl) acetate (5.07 g,20.24mmol,4.0 eq) was slowly added dropwise to the reaction solution and reacted for 20 minutes. After completion of the LC-MS detection reaction, the reaction solution was poured into water (30 mL), extracted with ethyl acetate (15 ml×3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (880 mg, yield 73%).

LC-MS(ESI)[M+H] ⁺ ＝238.0。

Fourth to seventh steps referring to the preparation method of example 1 or 439, the compound of example 452, LC-MS (ESI) [ M+H ], was prepared] ⁺ ＝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- (azoic bridge) pyrido [2,3-b][1,10]Dioxa [4,6]Diazacyclotridecane

The first step: preparation of 2, 5-dichloro-4- (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propoxy) pyrimidine:

3- ((2, 5-dichloropyrimidin-4-yl) oxy) propan-1-ol (2 g,8.97mmol,1.0 eq) was dissolved in anhydrous THF (50 mL) under nitrogen protection at 0deg.C, then NaH (322.8 mg,13.5mmol,1.5 eq) was added, after stirring for 10 min, 2, 6-dichloro-3-nitropyridine (2.25 g,11.7mmol,1.3 eq) was slowly added, then the reaction temperature was raised to room temperature and stirring continued for 2 h. After completion of the substrate reaction, the reaction was quenched by slowly dropping ice water, then the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the crude product, which was subjected to column chromatography (DCM: meoh=100:1) to give the objective compound (2.3 g, yield 68%).

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).

And a second step of: preparation of 2- (6- (3- ((2, 5-dichloropyrimidin-4-yl) oxy) propoxy) -5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3] heptane:

6-methoxy-2-azaspiro [3.3] heptane trifluoroacetate (330.7 mg,2.6mmol,1.3 eq) was dissolved in DMF (30 mL) at room temperature, followed by slow addition of potassium carbonate (8238 mg,6mmol,3 eq) and stirring for 20 min. After 20 minutes, 2, 5-dichloro-4- (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propoxy) pyrimidine (760 mg,2mmol,1 eq) was added and after the addition was completed, the reaction system temperature was raised to 50 ℃ and stirred for 16 hours. After completion of the substrate reaction, celite was filtered, the filtrate was extracted with ethyl acetate and water, the organic phases were combined, washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the crude product, which was chromatographed (DCM: meoh=100:1) to give the title compound (416 mg, yield 44%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.63(s,1H),8.15(d,J＝8.9Hz,1H),5.95(d,J＝9.0Hz,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).

And a third step of: preparation of 2- (3- ((2, 5-dichloropyrimidin-4-yl) oxy) propoxy) -6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) pyridin-3-amine:

2- (6- (3- ((2, 5-dichloropyrimidin-4-yl) oxy) propoxy) -5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3] in a 50mL reaction flask at room temperature ]Heptane (380 mg,0.81mmol,1.0 eq), ironPowder (0.23 g,4.1mmol,5.0 eq) and ammonium chloride (0.22 g,4.1mmol,5.0 eq) were dissolved in EtOH/H ₂ O (10/2 mL), then the reaction system temperature was raised to 80℃and stirred for 2h. After completion of the TLC monitoring reaction, celite was filtered and the organic phase was concentrated under reduced pressure to give the crude product. Crude column chromatography (DCM: meoh=10:1) afforded the title compound (355 mg, 100% yield).

LC-MS(ESI)[M+H] ⁺ ＝440.3.

Fourth step: preparation of 5-chloro-13- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -9, 10-dihydro-1 h,8h-2,6- (nitrogen bridge) pyrido [2,3-b ] [1,10] dioxa [4,6] diazacyclotridec:

pd was introduced into a 50mL three-port reaction flask under nitrogen protection ₂ (dba) ₃ (10%) and XPhos (12%) were dissolved in anhydrous dioxane (30 mL) and stirred at room temperature for 0.5 h. After 0.5 h, 2- (6- (3- ((2, 5-dichloropyrimidin-4-yl) oxy) propoxy) -5-nitropyridin-2-yl) -6-methoxy-2-azaspiro [3.3]Heptane (350 mg,0.79mmol,1 eq) and cesium carbonate (513.5 mg,1.58mmol,2.0 eq) were added to the reaction solution, followed by nitrogen substitution. The reaction system temperature was raised to 90℃and stirring was continued for 16 hours. After completion of the reaction, the organic phase was concentrated under reduced pressure using petroleum ether: ethyl acetate (8:1 to 4:1), DCM: meOH (10:1) column chromatography gave the title 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＝8.2Hz,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- (azoic bridge) benzo [ b ]]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: (E) Preparation of-N' - (dihydro-2H-pyran-3 (4H) -ylidene) -4-methoxybenzenesulfonyl hydrazide

dihydro-2H-pyran-3 (4H) -one (1.0 g,10mmol,1.0 eq) was dissolved in anhydrous MeOH (15 mL) at room temperature in a 50mL reaction flask, and then 4-methoxybenzenesulfonyl hydrazide (2.02 g,10mmol,1.0 eq) was added to react for 2 hours. After the completion of the LC-MS detection reaction, the reaction mixture was directly concentrated to give a crude product of the objective compound (2.8 g, yield 89%, purity 90%).

LC-MS(ESI)[M+H] ⁺ ＝284.7。

And a second step of: preparation of N- (3- (5-bromo-2-nitrophenoxy) propyl) -2, 5-dichloro-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 (4 g,10.22mmol,1.0 eq) was dissolved in anhydrous THF (60 mL) at 0deg.C in a 250mL reaction flask, then NaH (1.64 g,40.88mmol,4.0 eq) was added and reacted for 30 min. 4-bromo-2-fluoro-1-nitrobenzene (2.7 g,12.26mmol,1.2 eq) was added and reacted at 0℃for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was slowly dropped into methanol at 0 ℃ to quench, and the organic phase was concentrated under reduced pressure and separated and purified by flash chromatography (silica gel, PE: ea=9:1) to give the objective compound (5 g, yield 83%).

LC-MS(ESI)[M+H] ⁺ ＝592.0。

And a third step of: preparation of (3- (3- (2, 5-dichloro-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-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]Pyrimidine-4-amine (3 g,5.07mmol,1.0 eq), B ₂ Pin ₂ (pinacol diboronate) (1.5 g,6.09mmol,1.2 eq), pd (dppf) Cl ₂ ((1, 1' -bis (diphenylphosphino) ferrocene) palladium dichloride) (372 mg,0.5mmol,0.1 eq) and potassium acetate (1.5 g,15.22mmol,3 eq) were dissolved in 40mL of anhydrous 1, 4-dioxane, replaced with nitrogen, and reacted overnight at 80 ℃. After LC-MS detection reaction is finishedThe reaction mixture was diluted with water, extracted with ethyl acetate (50 ml 3), the organic phases combined, concentrated in vacuo and purified by a C18 reverse phase column (H ₂ O/CH ₃ Cn=75%) to give the objective compound (1.5 g, yield 53%).

LC-MS(ESI)[M+H] ⁺ ＝556.1。

Fourth step: preparation of 2, 5-dichloro-N- (3- (2-nitro-5- (tetrahydro-2H-pyran-3-yl) phenoxy) propyl) -7- (2- (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 ] pyrimidin-4-yl) amino) propoxy) -4-nitrophenyl) boronic acid (500 mg,0.9mmol,1 eq) and (E) -N' - (dihydro-2H-pyran-3 (4H) -ylidene) -4-methoxybenzenesulfonyl hydrazide (767 mg,2.7mmol,3 eq) were dissolved in 10mL of 1, 4-dioxane, cesium carbonate (878 mg,2.7mmol,3 eq) was added and reacted overnight at 100 ℃. After completion of the reaction by LC-MS, the reaction mixture was filtered, concentrated, and purified by flash chromatography (silica gel, PE: ea=5:1) to give the objective compound (150 mg, yield 30%).

LC-MS(ESI)[M+H] ⁺ ＝596.2。

Fifth step: preparation of N- (3- (2-amino-5- (tetrahydro-2H-pyran-3-yl) phenoxy) propyl) -2, 5-dichloro-7- (2- (trimethylsilyl) 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- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (200 mg,0.34mmol,1 eq) was dissolved in a mixed solution of ethanol (5 mL) and water (1 mL), iron powder (94 mg,1.68mmol,5 eq) and ammonium chloride (108 mg,2.01mmol,6 eq) were added in sequence and reacted at 80℃for 2 hours. After completion of the reaction by LC-MS, filtration, concentration of the filtrate, and purification by flash chromatography (silica gel, PE: ea=5:1) gave 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＝5.6Hz,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)。

Sixth step: preparation of 3-chloro-11- (tetrahydro-2H-pyran-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,14-hexahydro-4, 15- (azetidino) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazacyclotridecane

N- (3- (2-amino-5- (tetrahydro-2H-pyran-3-yl) phenoxy) propyl) -2, 5-dichloro-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (90 mg,0.16mmol,1 eq), xphos Pd G3 (14 mg,0.02mmol,0.1 eq) and cesium carbonate (155 mg,0.48mmol,3 eq) were dissolved in 1, 4-dioxane (4 mL), nitrogen was replaced, and the reaction was reacted in a microwave reactor at 100℃for 2 hours. After completion of the reaction, LC-MS was filtered, and the filtrate was concentrated and purified by preparative TLC to give the title compound (40 mg, 47.5%).

LC-MS(ESI)[M+H] ⁺ ＝530.2。

Seventh step: preparation of 3-chloro-11- (tetrahydro-2H-pyran-3-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azepine) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

3-chloro-11- (tetrahydro-2H-pyran-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazacyclotridecane (40 mg,0.08mmol,1 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 5 hours. After completion of the LC-MS detection, the reaction mixture was concentrated, redissolved in tetrahydrofuran (3 mL), and then reacted overnight at room temperature with aqueous ammonia (2 mL). After completion of the LC-MS detection reaction, the reaction mixture was concentrated and purified by Prep-HPLC to give the objective 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- (azoic bridge) benzo [ b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of N- (3- (5-bromo-4-fluoro-2-nitrophenoxy) propyl) -2, 5-dichloro-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 (4 g,10.22mmol,1.0 eq) was dissolved in tetrahydrofuran (40 mL) under nitrogen, the system was cooled to 0℃and then sodium hydride (1.23 g,30.66mmol,3.02 eq) was slowly added and reacted at 0℃for 0.5 hours. 1-bromo-2, 5-difluoro-4-nitrobenzene (2.92 g,12.26mmol,1.2 eq) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the reaction mixture, followed by reaction at 0deg.C for 2 hours. After completion of the LC-MS detection reaction, methanol (50 mL) was added dropwise to the system to quench, followed by filtration through celite, concentration of the filtrate, and separation and purification by flash chromatography (silica gel, PE: ea=9:1) gave the objective compound (5.5 g, yield 88%).

LC-MS(ESI)[M+H] ⁺ ＝607.9； ¹ H NMR(400MHz,DMSO-d ₆ ):δ8.16(d,J＝8.0Hz,1H),7.83(d,J＝6.0Hz,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)。

And a second step of: preparation of 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

N- (3- (5-bromo-4-fluoro-2-nitrophenoxy) propyl) -2, 5-dichloro-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (100 mg,0.16mmol,1.0 eq), trifluoroacetate of 6-methoxy-2-azaspiro [3.3] heptane (36.63 mg,0.16mmol,1.0 eq), xphos-Pd-G3 (methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)) (13.89 mg,0.02mmol,0.1 eq), cesium carbonate (213.88 mg,0.66mmol,4.0 eq) were dissolved in 1, 4-dioxane (4 mL) and reacted at 100℃for 18 hours. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=85:15) to give the objective 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)。

And a third step of: preparation of 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

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 (180 mg,0.27mmol,1.0 eq), reduced iron powder (76.65 mg,1.37mmol,5.0 eq), ammonium chloride (88.11 mg,1.65mmol,6.0 eq) were added to a mixed solvent (10 mL) of ethanol/water=5/1, and reacted at 80℃for 3 hours. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=72:28) to give the objective 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＝13.6Hz,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)。

Fourth step: preparation of 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- (azepine) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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 (140 mg,0.22mmol,1.0 eq), tris (dibenzylideneacetone) dipalladium (10.25 mg,0.01mmol,0.05 eq), dicyclohexyl [2',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl ] phosphine (16 mg,0.03mmol,0.15 eq), cesium carbonate (218.75 mg,0.67mmol,3.0 eq) were dissolved in 1, 4-dioxane (5 mL) and reacted at 90℃for 18 hours under nitrogen. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=65:35) to give the objective 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＝6.0Hz,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)。

Fifth step: preparation of 3-chloro-12-fluoro-11- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azepine) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatriene

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- (azoic bridge) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane (55 mg, 75% purity, 0.07mmol,1.0 eq) was dissolved in trifluoroacetic acid/dichloromethane=1/1 mixed solvent (4 mL) and reacted at room temperature for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated, and the crude product was dissolved in an aqueous ammonia/tetrahydrofuran=1/1 mixed solvent (4 mL) and stirred at room temperature for 1 hour. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by thin layer preparative chromatography (silica gel, DCM: meoh=20:1) to give the title 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＝2.4Hz,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- (azoic bridge) benzo [ b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 194 or 455, the compound of example 456, 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- (azoic bridge) benzo [ b ]]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 194 or 455, the compound of example 457, LC-MS (ESI) [ M+H ]] ⁺ ＝430.8； ¹ H NMR(400MHz,DMSO-d ₆ ):δ11.05(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- (azoic bridge) benzo [ b]Imidazo [4,5-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 or 427 gave the compound of example 457, LC-MS (ESI) [ M+H ]] ⁺ ＝425.9； ¹ H NMR(400MHz,DMSO-d ₆ ):δ12.19(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- (azoic bridge) benzo [ b)][1]Oxa [4,6,10]Triazacyclotridec 13-yl) -2-methylpropanenitrile

The first step: preparation of tert-butyl 2- (3-bromo-4-nitrophenyl) -2-cyanoacetate

2-bromo-4-fluoro-1-nitrobenzene (1 g,4.55mmol,1.0 eq) and potassium carbonate (1.88 g,13.65mmol,3.0 eq) were dissolved in THF (30 mL) at room temperature, then tert-butyl 2-cyanoacetate (0.96 g,6.82mmol,1.5 eq) was added and reacted at 60℃for 12 hours. After TLC detection was completed, diatomaceous earth was filtered, the filtrate was stirred with water and ethyl acetate, left to stand for separation, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (1.2 g, 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)。

And a second step of: preparation of 2- (3-bromo-4-nitrophenyl) acetonitrile

Tert-butyl 2- (3-bromo-4-nitrophenyl) -2-cyanoacetate (1.2 g,3.52mmol,1.0 eq) was dissolved in DMSO (10 mL) at room temperature, liCl (1.49 g,35.2mmol,10.0 eq) and water (1 mL) were added in sequence and reacted at 150 ℃. After completion of the TLC detection, the reaction mixture was cooled to room temperature, water and EA were then added, stirred for 0.5 hour, the mixture was left to stand to separate, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine successively for 2 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective 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)。

And a third step of: preparation of 2- (3-bromo-4-nitrophenyl) -2-methylpropanenitrile

2- (3-bromo-4-nitrophenyl) acetonitrile (800 mg,3.32mmol,1.0 eq) was dissolved in anhydrous THF (20 mL) at 25℃and then NaH (0.24 g,10mmol,3 eq) was added, after stirring for 10 min, meI (1.41 g,10mmol,3 eq) was slowly added dropwise and the reaction was allowed to proceed overnight at room temperature. After completion of the LC-MS detection reaction, water and ethyl acetate were added, stirred for 10 minutes, left to stand for separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=4:1) to give the objective compound (517 mg, yield 58%).

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

The fourth to sixth steps were carried out according to the method of reference example 130 or 354 to obtain 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- (azoic bridge) benzo [ b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (morpholinyl) methanones

The first step: preparation of 3- ((2, 5-dichloropyrimidin-4-yl) amino) butan-1-ol

2,4, 5-trichloropyrimidine (400 mg,4.36mol,1.0 eq) was dissolved in isopropanol (10 mL) and diisopropylethylamine (1.13 g,8.72mol,2.0 eq) was added. 3-Aminobutanol (428 mg,4.8mmol,1.1 eq) was added dropwise at 0deg.C and reacted for 0.5 hr. After completion of the LC-MS detection reaction, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=5:1) to give the objective compound (800 mg, yield 77%).

LC-MS(ESI)[M+H] ⁺ ＝236.1。

And a second step of: preparation of methyl 5- (3- ((2, 5-dichloropyrimidin-4-yl) amino) butoxy) -2-fluoro-4-nitrobenzoate

3- ((2, 5-dichloropyrimidin-4-yl) amino) butan-1-ol (1 g,4.2mmol,1.0 eq) was dissolved in tetrahydrofuran (50 mL) and sodium hydrogen (330 mg,8.4mmol,2.0eq, 60% purity) was added to the solution under ice water bath cooling for 30 minutes. Then, methyl 2, 5-difluoro-4-nitrobenzoate (910 mg,4.2mmol,1.0 eq) was added and reacted at 0℃for 1 hour. After completion of the LC-MS detection reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=4:1) to give the objective compound (900 mg, yield 70%).

LC-MS(ESI)[M+H] ⁺ ＝433.0。

And a third step of: preparation of methyl 4-amino-5- (3- ((2, 5-dichloropyrimidin-4-yl) amino) butoxy) -2-fluorobenzoate

Methyl 5- (3- ((2, 5-dichloropyrimidin-4-yl) amino) butoxy) -2-fluoro-4-nitrobenzoate (850 mg,1.96mmol,1.0 eq) was dissolved in ethanol (15 mL), saturated aqueous ammonium chloride solution (10 mL) and iron powder (268 mg,9.81mmol,5.0 eq) were added and reacted at 60 ℃ for 2 hours. After completion of the reaction by LC-MS detection, filtration, extraction of the filtrate with ethyl acetate, combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and separation and purification by flash chromatography gave the objective compound (560 mg, yield 70%).

LC-MS(ESI)[M+H] ⁺ ＝403.0。

Fourth step: preparation of methyl 5-chloro-14-fluoro-8-methyl-7, 8,9, 10-tetrahydro-1H-2, 6- (azepine) benzo [ b ] [1] oxa [4,6,10] triazatridec-13-carboxylate

Methyl 4-amino-5- (3- ((2, 5-dichloropyrimidin-4-yl) amino) butoxy) -2-fluorobenzoate (510 mg,1.26mmol,1.0 eq) was dissolved in dioxane (10 mL), dicyclohexyl [2',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl ] phosphine (121 mg,0.25mol,0.2 eq), tris (dibenzylideneacetone) dipalladium) (232 mg,0.25mol,0.2 eq) and cesium carbonate (284 mg,2.53mol,2.0 eq) were added. The reaction was carried out at 90℃under nitrogen for 3 hours. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=5:1) to give the objective compound (260 mg, yield 56%).

LC-MS(ESI)[M+H] ⁺ ＝367.1。

Fifth step: preparation of 5-chloro-14-fluoro-8-methyl-7, 8,9, 10-tetrahydro-1H-2, 6- (azepine) benzo [ b ] [1] oxa [4,6,10] triazatridec-13-carboxylic acid

Methyl 5-chloro-14-fluoro-8-methyl-7, 8,9, 10-tetrahydro-1H-2, 6- (nitrogen bridge) benzo [ b ] [1] oxa [4,6,10] triazatridec-13-carboxylate (240 mg,0.65mmol,1.0 eq) was dissolved in methanol (10 mL), and aqueous sodium hydroxide (4.0 mL, 2M) was added and reacted at 50℃for 1 hour. After completion of the LC-MS detection, the reaction mixture was concentrated, neutralized with dilute hydrochloric acid (1M), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product of the objective compound (200 mg, yield 87%).

LC-MS(ESI)[M+H] ⁺ ＝353.1。

Sixth step: preparation of (5-chloro-14-fluoro-8-methyl-7, 8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) benzo [ b ] [1] oxo [4,6,10] triazatridec-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] triazatridec-13-carboxylic acid (180 mg,0.51mmol,1.0 eq) was dissolved in N, N-dimethylformamide (5 mL), morpholine (58 mg,0.66mmol,1.3 eq), a carbomer (293 mg,0.66mmol,1.3 eq) and N, N-diisopropylethylamine (132 mg,1.02mmol,2 eq) were added and reacted at 25℃for 2 hours. After completion of the reaction by LC-MS, the reaction mixture was poured into water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then separated and purified by Prep-HPLC to give the objective 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＝6.4Hz,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＝7.2Hz,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- (azoic bridge) benzo [ b ]][1]Oxa [4,6,10]Triazacyclotridec-13-yl) methanones

Reference to the preparation of examples 354 or 460 gave the compound of example 461, 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- (azoic bridge) benzo [ b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (6-methoxy-2-azaspiro [3.3 ]]Hept-2-yl) methanones

Reference to the preparation of examples 354 or 460, the compound of example 462, 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- (azoic bridge) benzo [ b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (4- (oxetan-3-yl) piperazin-1-yl) methanone

Reference to the preparation of examples 354 or 460 gave the compound of example 463, 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- (azoic bridge) benzo [ b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (morpholinyl) methanones

Reference to the methods of preparation of examples 354 or 460, the compound of example 464, LC-MS (ESI) [ M+H ]] ⁺ ＝456.1； ¹ H NMR(400MHz,DMSO-d ₆ ):δ9.57(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-hexahydro-4, 15- (azepine) benzo [ b ]]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 455, the compound of example 465, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 gave the compound of example 466, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane formate salt

Reference to the procedure for the preparation of example 194 gave the compound of example 467, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3- ((5-bromo-2-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) propan-1-ol

5-bromo-2, 4-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (3.3 g,8.31mmol,1.0 eq) and 3-aminobutan-1-ol (936 mg,12.46mmol,1.5 eq) were added to isopropanol (30 mL) and reacted at 85℃for 1 hour. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=3:1) to give the objective compound (3.6 g, yield 99%).

LC-MS(ESI)[M+H] ⁺ ＝435.0。

And a second step of: preparation of 3- ((2-chloro-5-cyclopropyl-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] 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 (3.8 g,8.72mmol,1.0 eq), potassium cyclopropylfluoroborate (1.55 g,10.46mmol,1.2 eq), pd (PPh ₃ ) ₄ (400 mg,0.35mmol,0.04 eq) and potassium carbonate (2.41 g,17.44mmol,2.0 eq) were dissolved in toluene (40 mL) and water (4 mL). The reaction was carried out at 110℃for 12 hours under nitrogen. After the completion of the LC-MS detection reaction, the reaction solution was poured into water (30 mL), extracted with ethyl acetate (25 ml×3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography (silica gel, PE: ea=6:1) to give the objective Compound (1.2 g, yield 35%).

LC-MS(ESI)[M+H] ⁺ ＝397.2。

The third to seventh steps were carried out according to the method of reference example 194, to obtain 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1,10]Dioxa [4,6]Diazacyclotridecane

Reference to the procedure for the preparation of example 194 gave the compound of example 469, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane formate salt

Reference example 194, preparation method, preparation of example 470 compound, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 or 199 gave the compound of example 471, 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- (azoic bridge) pyrido [2,3-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 or 199 gave the compound of example 472, 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- (azepine) benzo [ b]Pyrrolo [2,3-g][1,10]Dioxa [4,6]Diazacyclotridecane

The first step: preparation of 3- (5-bromo-4-fluoro-2-nitrophenoxy) propan-1-ol

1, 3-propanediol (1.0 g,13.14mmol,1.0 eq) was dissolved in tetrahydrofuran (30 mL), sodium hydrogen (788.4 mg,19.71mmol,1.5eq, purity 60%) was added to the reaction system in an ice bath, and the reaction was continued for 30 minutes under an ice bath. 1-bromo-2, 5-difluoro-4-nitrobenzene (3.13 g,13.14mmol,1 eq) was dissolved in tetrahydrofuran (80 mL) and gradually added dropwise to the reaction solution, and the reaction was continued at room temperature for 2 hours. After completion of the LC-MS detection reaction, the reaction mixture was quenched with methanol, filtered through celite, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=10:1) to give the objective compound (2.5 g, yield 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＝6.0Hz,2H),3.53(dd,J＝11.2,6.0Hz,2H),1.84(p,J＝6.0Hz,2H)。

And a second step of: preparation of 2- (3- (5-bromo-4-fluoro-2-nitrophenoxy) propoxy) tetrahydro-2H-pyran

3- (5-bromo-4-fluoro-2-nitrophenoxy) propan-1-ol (2.5 g,8.5mmol,1.0 eq) was dissolved in dichloromethane (30 mL), stirred under an ice bath, 3, 4-dihydro-2H-pyran (1.07 g,12.75mmol,1.5 eq) was then added, stirred for two minutes, and 4-methylbenzenesulfonic acid pyridine (213.61 mg,0.85mmol,0.1 eq) was added and reacted at room temperature for 4 hours. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=20:1) to give the objective compound (2.96 g, yield 92%).

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.09(d,J＝8.0Hz,1H),7.81(d,J＝6.0Hz,1H),4.55(d,J＝3.6Hz,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)。

And a third step of: preparation of 5- (2-fluoro-4-nitro-5- (3- ((tetrahydro-2H-pyran-2-yl) oxy) propoxy) phenyl) -2-oxa-5-azabicyclo [2.2.1] heptane

2- (3- (5-bromo-4-fluoro-2-nitrophenoxy) propoxy) tetrahydro-2H-pyran (3.04 g,8.04mmol,1.0 eq), 2-oxa-5-azabicyclo [2.2.1] heptane (797.01 mg,8.04mmol,1.0 eq), cesium carbonate (7.86 g,24.12mmol,3.0 eq), tris (dibenzylideneacetone) dipalladium (0) (368.12 mg,0.4mmol,0.05 eq), and dicyclohexyl [2',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl ] phosphine (574.92 g,1.21mmol,0.15 eq) were dissolved in 1, 4-dioxane (80 mL) and reacted at 100℃under nitrogen protection for 6 hours. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (2.3 g, 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＝5.6Hz,1H),2.03-1.86(m,4H),1.75-1.55(m,2H),1.53-1.37(m,4H)。

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

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

LC-MS(ESI)[M+H] ⁺ ＝312.7。

Fifth step: preparation of 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

3- (5- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -4-fluoro-2-nitrophenoxy) propan-1-ol (640 mg,1.33mmol,1.0 eq) was dissolved in tetrahydrofuran (15 mL), nitrogen was replaced, and the temperature of the ice-salt bath was controlled at 0 ℃. Sodium hydride (47.96 mg,2mmol,1.5 eq) was added and reacted for 0.5 hour, and then a solution of 2,4, 5-trichloro-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (469.86 mg,1.33mmol,1.0 eq) in tetrahydrofuran (5 mL) was added dropwise and reacted for 2 hours at 25 ℃. After completion of the LC-MS detection reaction, saturated ammonium chloride solution (1.5 mL) and water (20 mL) were added, extraction was performed with dichloromethane (50 ml×3), the organic phases were washed with saturated aqueous sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and after concentration of the filtrate, purification was separated by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (600 mg, yield 72%).

LC-MS(ESI)[M+H] ⁺ ＝628.00。

Sixth step: preparation of 4- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -2- (3- ((2, 5-dichloro-7- ((2- (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 (500 mg,0.8mmol,1.0 eq) was dissolved in ethanol (50 mL) and water (10 mL), followed by ammonium chloride (276.58 mg,5.17mmol,6.5 eq) and iron powder (266.52 mg,4.77mmol,6.0 eq). The nitrogen was replaced and the reaction was carried out at 80℃for 3 hours. After LC-MS detection, the reaction mixture was filtered through celite, the cake was washed with dichloromethane (20 mL), and the filtrate was concentrated to give the crude title compound (460 mg, 89% yield).

LC-MS(ESI)[M+H] ⁺ ＝597.95。

Seventh step: preparation of 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- (azobridge) benzo [ b ] pyrrolo [2,3-g ] [1,10] dioxa [4,6] diazacyclotridecane

A solution of 4- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -2- (3- ((2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) oxy) propoxy) -5-fluoroaniline (460 mg,0.77mmol,1.0 eq) and cesium carbonate (375.59 mg,1.15mmol,4.0 eq) in dioxane (15 mL) was bubbled with nitrogen for 20 minutes, and tris (dibenzylideneacetone) dipalladium (70.37 mg,0.08mmol,0.1 eq) and 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (73.27 mg,0.15mmol,0.2 eq) were added and reacted for 1 hour at 90℃for 20 minutes. After completion of the LC-MS detection reaction, the reaction mixture was diluted with methylene chloride (50 mL), filtered through celite, and the cake was rinsed with methylene chloride (50 mL). After concentrating the filtrate, purification by flash chromatography (silica gel, PE: ea=1:1) afforded the title compound (290 mg, yield 62%).

LC-MS(ESI)[M+H] ⁺ ＝562.15。

Eighth step: preparation of 11- (2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-chloro-12-fluoro-1,7,8,14-tetrahydro-6H-4, 15- (azoic bridge) 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- (azoic bridge) benzo [ b ] pyrrolo [2,3-g ] [1,10] dioxa [4,6] diazacyclotridecane (150 mg,0.27mmol,1.0 eq) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added dropwise. The reaction was carried out at 25℃for 3 hours. After completion of the LC-MS detection reaction, ammonia (1 mL) was used to adjust the pH to about 8. The reaction mixture was concentrated, and tetrahydrofuran (3 mL) and aqueous ammonia (3 mL) were added thereto to react at 25℃for 2 hours. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated and purified by Prep-HPLC to give the objective 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- (azetidino) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the methods of preparation of examples 194 or 199, the compound of example 474, 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- (azepine) benzo [ b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 455, the compound of example 475, 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- (azoic bridge) pyrido [4, 3-b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (morpholinyl) methanones

The first step: preparation of tert-butyl (4-hydroxybut-2-yl) carbamate

3-Aminobutanol (1 g,11.22mmol,1.0 eq), 4-dimethylaminopyridine (274 mg,2.24mmol,0.2 eq) and triethylamine (1.7 g,16.83mmol,1.5 eq) were dissolved in tetrahydrofuran (15 mL), followed by the addition of di-tert-butyl dicarbonate (3.67 g,16.83mmol,1.5 eq) for 4 hours at room temperature. After completion of the reaction, the reaction mixture was poured into water (40 mL), extracted with ethyl acetate (15 ml×3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude title compound (2 g, 94%).

LC-MS(ESI)[M+Na] ⁺ ＝212.1。

And a second step of: preparation of tert-butyl (4- (2-chloro-5-nitropyridin-4-yl) oxy) butan-2-yl) carbamate

Tert-butyl (4-hydroxybut-2-yl) carbamate (2 g,10.57mmol,1.0 eq) is dissolved in anhydrous THF (30 mL) and stirred at 0deg.C for 10 min. Sodium hydrogen (634 mg,15.85mmol,1.5eq, 60% purity) was then added and reacted for 30 minutes. Then, 2, 4-dichloro-5-nitropyridine (2.04 g,10.57mmol,1.0 eq) was added thereto and reacted at 0℃for 1 hour. After completion of the LC-MS detection reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride, poured into water (25 mL) and extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, purification by flash chromatography (silica gel, PE: ea=5:1) afforded the title compound (1.9 g, yield 52%).

LC-MS(ESI)[M+Na] ⁺ ＝368.0。

And a third step of: preparation of tert-butyl (4- ((5-nitro-2-vinylpyridin-4-yl) oxy) butan-2-yl) carbamate

Tert-butyl (4- ((2-chloro-5-nitropyridin-4-yl) oxy) butan-2-yl) carbamate (1.9 g,5.49mmol,1.0 eq) potassium vinyltrifluoroborate (883 mg,6.59mmol,1.2 eq), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (403 mg,0.55mmol,0.1 eq) and sodium acetate (902 mg,10.99mmol,2.0 eq) were dissolved in toluene (30 mL) and reacted at 110℃for 4 hours under nitrogen. After completion of the LC-MS detection reaction, the reaction solution was poured into water (40 mL) and extracted with ethyl acetate (25 ml×3). The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=3:1) to give the title compound (911 mg, yield 49%).

LC-MS(ESI)[M+Na] ⁺ ＝360.1。

Fourth step: preparation of 4- (3- ((tert-butoxycarbonyl) amino) butoxy) -5-nitropyridine-2-carboxylic acid

Sodium periodate (2.88 g,13.49mmol,5 eq) and potassium permanganate (85 mg,0.54mmol,0.2 mmol) were dissolved in water (80 mL) and potassium carbonate (410 mg,2.97mmol,1.1 eq) was slowly added. Tert-butyl (4- ((5-nitro-2-vinylpyridin-4-yl) oxy) butan-2-yl) carbamate (910 mg,2.70mmol,1.0 eq) was then dissolved in tert-butanol (80 mL) and slowly added dropwise to the reaction solution for reaction at room temperature for 1 hour. Further, ethylene glycol (8 mL) was added to the reaction mixture, and the reaction was continued for 1 hour. Then, a saturated aqueous sodium bisulphite solution was added to the reaction solution, followed by extraction with ethyl acetate (40 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product of the objective compound (984 mg).

LC-MS(ESI)[M+Na] ⁺ ＝378.1。

Fifth step: preparation of tert-butyl (4- ((2- (morpholin-4-carbonyl) -5-nitropyridin-4-yl) oxy) butan-2-yl) carbamate

4- (3- (tert-Butoxycarbonyl) amino) butoxy) -5-nitropyridine-2-carboxylic acid (984 mg,2.77mmol,1.0 eq) and diisopropylethylamine (537 mg,4.15mmol,1.5 eq) were dissolved in dichloromethane (25 mL), HATU (N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro-urea phosphate) (1.60 g,4.15mmol,1.5 eq) was added and after 30 minutes the reaction was continued morpholine (290 mg,3.32mmol,1.0 eq) was added. After completion of the LC-MS detection reaction, the reaction solution was poured into water (30 mL) and extracted with dichloromethane (20 ml×3). The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the title compound (857 mg, 73%).

LC-MS(ESI)[M+Na] ⁺ ＝447.0。

Sixth step: preparation of (4- (3-aminobutoxy) -5-nitropyridin-2-yl) (morpholinyl) methanone

Tert-butyl (4- ((2- (morpholin-4-carbonyl) -5-nitropyridin-4-yl) oxy) butan-2-yl) carbamate (857 mg,2.02mmol,1.00 eq) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added dropwise and reacted at room temperature for 2 hours. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated to give the objective compound (654 mg, yield 100%).

LC-MS(ESI)[M+H] ⁺ ＝325.1。

Seventh step: preparation of (4- (3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) butoxy) -5-nitropyridin-2-yl) (morpholinyl) methanone

(4- (3-Aminobutoxy) -5-nitropyridin-2-yl) (morpholinyl) methanone (254 mg,2.02mmol,1.0 eq), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (525 mg,2.42mmol,1.20 eq) and diisopropylethylamine (521 mg,4.03mmol,2.0 eq) were added to isopropanol (20 mL) and reacted at 0℃for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was directly concentrated, and purified by preparative TLC (PE: ea=65%) to give the objective compound (180 mg, yield 18%).

LC-MS(ESI)[M+H] ⁺ ＝504.9。

Eighth step: preparation of (4- (3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) butoxy) -5-nitropyridin-2-yl) (morpholinyl) methanone

(4- (3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) butoxy) -5-nitropyridin-2-yl) (morpholinyl) methanone (170 mg,0.34mmol,1.0 eq), iron powder (188 mg,3.37mmol,10.0 eq) and saturated aqueous ammonium chloride solution (5 mL) were dissolved in ethanol (10 mL) and reacted at 80℃for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was filtered, the filtrate was poured into water (50 mL), extracted with ethyl acetate (25 ml×3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product of the objective compound (180 mg, yield 113%).

LC-MS(ESI)[M+H] ⁺ ＝475.1。

Ninth step: preparation of (8-methyl-5- (trifluoromethyl) -7,8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [4,3-b ] [1] oxa [4,6,10] triazatridec-13-yl) (morpholinyl) methanone

(5-amino-4- (3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) amino) butoxy) pyridin-2-yl) (morpholinyl) methanone (170 mg,0.36mmol,1.0 eq), tris (dibenzylideneacetone) dipalladium (66 mg,0.07mmol,0.2 eq), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (34 mg,0.07mmol,0.2 eq) and cesium carbonate (233 mg,0.72mmol,2.0 eq) were dissolved in 1, 4-dioxane (15 mL) and reacted at 90℃under nitrogen protection for 4 hours. After completion of the LC-MS reaction, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then separated and purified by Prep-HPLC to give the title compound (14.6 mg, yield 9%).

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- (azoic bridge) pyrido [2, 3-b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (morpholinyl) methanones

Reference example 476 was made to the procedure for the preparation of the compound of example 477, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 gave the compound of example 478, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 gave the compound of example 479, 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-Dimethylmorpholine) -5- (trifluoromethyl) -7,8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 353, the compound of example 480, 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- (azoic bridge) benzo [ b)]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridec-11-yl) (6-methoxy-2-azaspiro [3.3 ]]Hept-2-yl) methanones

Reference example 455, the compound of example 481, 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- (azoic bridge) pyrido [2, 3-b)]Pyrrolo [2,3-g ][1]Oxa [4,6,10]Triazacyclotridec-11-yl) (6-methoxy-2-azaspiro [3.3 ]]Hept-2-yl) methanones

Reference to the procedure for the preparation of example 194 or 199 gave the compound of example 482, 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- (azo) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 or 199 gave the compound of example 483, 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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tert-butyl (3- ((6- (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) -3-nitropyridin-2-yl) oxy) propyl) carbamate

Tert-butyl (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) carbamate (3.32 g,10mmol,1.0 eq) and 2-methyl-1- (oxetan-3-yl) piperazine (1.87 g,12mmol,1.2 eq) were dissolved in isopropanol (10 v/w) at room temperature, triethylamine (3.04 g,30mmol,3.0 eq) was slowly added and after 10 minutes the reaction was warmed to 80℃for 2 hours. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=4:1) to give the objective compound (3.8 g, yield 84%).

LC-MS(ESI)[M-55] ⁺ ＝396.3。

And a second step of: preparation of 3- ((6- (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) -3-nitropyridin-2-yl) oxy) propan-1-amine tert-butyl (3.8 g,8.4mmol,1.0 eq) carbamate (3.6- ((6-methyl-4- (oxetan-3-yl) piperazin-1-yl) -3-nitropyridin-2-yl) oxy) propyl) was dissolved in dichloromethane (10 mL), TFA (4.8 g,42mmol,5.0 eq) was slowly added, the reaction was warmed to room temperature and the reaction was continued for 1 hour. After the LC-MS detection reaction is finished, directly concentrating the reaction liquid to obtain a crude product of the target compound, and directly using the crude product in the next step.

LC-MS(ESI)[M+H] ⁺ ＝352.1。

And a third step of: preparation of 2-chloro-N- (3- (6- (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) -3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) pyrimidin-4-amine

3- ((6- (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) -3-nitropyridin-2-yl) oxy) propan-1-amine (3.1 g,8.8mmol,1.0 eq) and 2, 4-dichloro-5-trifluoromethylpyrimidine (2.11 g,9.7mmol,1.1 eq) were dissolved in isopropanol (10 v/w) at room temperature, then triethylamine (1.34 g,13.2mmol,1.5 eq) was slowly added and the reaction was warmed to 80℃for 2 hours. After completion of the LC-MS detection reaction, the organic phase was directly concentrated and subjected to reverse phase column chromatography to give the objective compound (2.1 g, yield 45%).

LC-MS(ESI)[M+H] ⁺ ＝532.3。

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

2-chloro-N- (3- (6- (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) -3-nitropyridin-2-yl) oxy) propyl) -5- (trifluoromethyl) pyrimidin-4-amine (500 mg,0.94mmol,1.0 eq), iron powder (0.26 g,4.7mmol,5.0 eq) and ammonium chloride (0.25 g,4.7mmol,5.0 eq) were dissolved in EtOH/H at room temperature ₂ O (20/5 mL), and then the reaction system was warmed to 100℃for 16 hours. After completion of LC-MS detection, the reaction mixture was filtered through celite, the filter cake was washed with dichloromethane/methanol (20:1), and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=20:1) to give the target compound (169.96 mg, 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-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 199, provided the compound of example 485, 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＝9.2Hz,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- (azoic bridge) pyrido [2,3-b ][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tert-butyl 5- (3-cyanooxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-carboxylate

Tert-butyl 2, 5-diazabicyclo [2.2.1] hept-2-carboxylate (5 g,25.22mmol,1.0 eq) was dissolved in 1, 2-dichloroethane (50 mL), nitrogen was replaced, oxetan-3-one (2.18 g,30.26mmol,1.2 eq), acetic acid (1.67 g,27.74mmol,1.1 eq) was added and reacted at 60℃for 0.5 hours. Trimethylcyanosilane (5.0 g,50.44mmol,2.0 eq) was then added and the reaction continued for 16 hours. The liquid phase monitoring reaction was completed. The reaction was concentrated and PH was adjusted to 7-8 with aqueous sodium bicarbonate, extracted with ethyl acetate (300 ml x 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by flash chromatography (silica gel, PE: ea=5:1) to give the title compound (4.5 g, yield 64%).

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)。

And a second step of: preparation of tert-butyl 5- (3-methyloxet-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-carboxylate

Tert-butyl 5- (3-cyanooxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-carboxylate (4.5 g,16.11mmol,1.0 eq) was dissolved in tetrahydrofuran (50 mL), replaced with nitrogen, and methylmagnesium bromide (9.6 g,80.55mmol,5.0eq,26.85 mL) was added and reacted at 60℃for 16 hours. After completion of the reaction, the reaction mixture was slowly poured into an aqueous ammonium chloride solution (200 mL) and extracted with dichloromethane (200 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, DCM: meoh=10:1) to give the title compound (1.45 g, yield 34%).

LC-MS(ESI)[M+H] ⁺ ＝269.0； ¹ H NMR(400MHz,DMSO-d ₆ ):δ4.48(t,J＝7.2Hz,2H),4.28(t,J＝6.4Hz,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＝11.2Hz,2H),1.44(s,3H),1.40(d,J＝11.2Hz,9H)。

And a third step of: preparation of 2- (3-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] heptane

Tert-butyl 5- (3-methyl-oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-carboxylate (1.95 g,7.27mmol,1.0 eq) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added and the reaction was carried out at room temperature for 16 hours. After completion of TLC detection, the reaction solution was directly concentrated to give a crude product of the objective compound (1.1 g), which was directly used in the next step.

¹ H NMR(400MHz,DMSO-d ₆ ):δ4.82(d,J＝7.6Hz,1H),4.67(d,J＝7.2Hz,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)。

Fourth step: preparation of 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

Tert-butyl 3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) carbamate (1.5 g,4.52mmol,1.0 eq), 2- (3-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] heptane (0.91 g,5.43mmol,1.2 eq) and triethylamine (1.83 g,18.09mmol,4.0 eq) were dissolved in N, N-dimethylformamide (15 mL) and the reaction was carried out at 100℃for 6 hours. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (1.2 g, 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)。

Fifth step: preparation of 3- ((6- (5- (3-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) -3-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 (1.5 g,3.24mmol,1.0 eq) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (5 mL) was added and reacted at room temperature for 2 hours. After completion of TLC detection, the reaction solution was directly concentrated to give a crude product of the target compound (1.15 g), which was directly used in the next step.

LC-MS(ESI)[M+H] ⁺ ＝364.0。

Sixth step: preparation of 2-chloro-N- (3- ((6- (5- (3-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-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-nitropyridin-2-yl) oxy) propan-1-amine (600 mg,1.65mmol,1.0 eq), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (429.8 mg,1.98mmol,1.2 eq) and N, N-diisopropylethylamine (853.5 mg,6.6mmol,4.0 eq) were dissolved in isopropanol (6 mL) and reacted at 80℃for 2 hours. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated and purified by flash chromatography (silica gel, PE: ea=2:1) to give the objective 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)。

Seventh step: preparation of 13- (5- (3-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1] hept-2-yl) -5- (trifluoromethyl) -7,8,9, 10-tetrahydro-1H-2, 6- (azepine) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecane

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 (120 mg,0.22mmol,1.0 eq), iron powder (61.6 mg,1.1mmol,5.0 eq), ammonium chloride (76.7 mg,1.43mmol,6.5 eq) were dissolved in ethanol (5 mL) and water (1 mL) at room temperature and reacted for 2 hours at 80 ℃. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated, and was separated and purified by Prep-HPLC to give the objective 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＝5.6Hz,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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 353, the compound of example 487, 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- (azoic bridge) benzo [ b)][1]Oxa [4,6,10]Triazacyclotridec-13-yl) (6-methoxy-2-azaspiro [3.3 ]]Hept-2-yl) methanones

Reference to the procedure for the preparation of example 460, the compound of example 488, 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- (azoic bridge) pyrido [2,3-b ][1]Oxa [4,6,10]Triazacyclotridec-13-yl) methanones

Reference example 476 was made to the procedure for the preparation of the compound of example 489, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridec-11 yl) methanones

Reference to the procedure for the preparation of example 199 gave the compound of example 490, 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- (azoic bridge) benzo [ b ]]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 455 gave the compound of example 491, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3- ((6-chloro-3-nitropyridin-2-yl) oxy) propan-1-amine

Tert-butyl (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) carbamate (10 g,30.14mmol,1.0 eq) was dissolved in dichloromethane/trifluoroacetic acid (3/1) (40 mL) and reacted at room temperature for 1 hour. After the LC-MS detection reaction was completed, the reaction solution was directly concentrated to obtain a crude product (6.98 g) of the objective compound, which was directly used in the next step.

LC-MS(ESI)[M+H] ⁺ ＝232.1。

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

3- [ (6-chloro-3-nitropyridin-2-yl) oxy ] propan-1-amine (6.9 g,29.79mmol,1.0 eq), 2, 4-dichloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (9.2 g,23.83mmol,0.8 eq) and diisopropylethylamine (15.4 g,119.15mmol,4.0 eq) were dissolved in isopropanol (150 mL) and reacted at 85℃for 1 hour. After completion of the LC-MS detection, the reaction mixture 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 purified by flash chromatography (silica gel, DCM: meoh=20:1) to give the title compound (3.95 g, yield 23%).

LC-MS(ESI)[M+H] ⁺ ＝581.1。

And a third step of: preparation of N- (3- ((3-amino-6-chloropyridin-2-yl) oxy) propyl) -2-chloro-5- (trifluoromethyl) -7- ((2- (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- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (1 g,1.72mmol,1.0 eq), iron powder (0.48 g,8.6mmol,5.0 eq) and ammonium chloride (0.46 g,8.6mmol,5.0 eq) were dissolved in a mixed solvent of ethanol/water (5/1) (18 mL) and reacted at 85℃for 1 hour. After completion of the LC-MS detection reaction, the reaction was concentrated directly and purified by flash chromatography (silica gel, DCM: meoh=40:1) to give the title compound (600 mg, yield 63%).

LC-MS(ESI)[M+H] ⁺ ＝551.1。

Fourth step: preparation of 11-chloro-3- (trifluoromethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) 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- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (600 mg,1.09mmol,1.0 eq), xphos Pd G3 (90 mg,0.11mmol,0.1 eq) and cesium carbonate (1.06G, 3.26mmol,3.0 eq) were dissolved in t-butanol (30 mL) and reacted at 80℃for 2 hours under nitrogen. LC-MS detected 50% of the product, celite filtration, concentration of the filtrate, and purification by flash chromatography (silica gel, PE: EA=5:1) afforded the title compound (100 mg, 18% yield).

LC-MS(ESI)[M+H] ⁺ ＝515.2。

Fifth step: preparation of 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- (azoic bridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

11-chloro-3- (trifluoromethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane (100 mg,0.19mmol,1.0 eq), 3-difluoro-1- (oxetan-3-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (87.71 mg,0.29mmol,1.5 eq), xphos Pd G ₃ (16.42 mg,0.02mmol,0.1 eq) and potassium phosphate (164.87 mg,0.78mmol,4.0 eq) were dissolved in dioxane/water (10/1) (3.3 mL) and reacted at 100℃for 1 hour under nitrogen. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective compound (35 mg, yield 28%).

LC-MS(ESI)[M+H] ⁺ ＝654.3。

Sixth step: preparation of 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- (azoic bridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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] triazatridecane (30 mg,0.05mmol,1.0 eq) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) was added and reacted at room temperature for 1 hour. The reaction mixture was concentrated, and tetrahydrofuran (1 mL) and aqueous ammonia (0.5 mL) were added thereto to continue the reaction for 0.5 hours. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated, and was separated and purified by Prep-HPLC to give the objective 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＝6.0Hz,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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 13- (3, 3-difluoro-1- (oxetan-3-yl) piperidin-4-yl) -5- (trifluoromethyl) -7,8,9, 10-tetrahydro-1H-2, 6- (azoic bridge) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecane

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- (azoic bridge) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecane (20 mg,0.04mmol,1.0 eq) was dissolved in ethanol (5 mL), 5% palladium on carbon (5 mg) was added and reacted under a hydrogen atmosphere at one atmosphere for 16 hours. After completion of the LC-MS detection reaction, palladium on carbon was filtered, and the filtrate was concentrated and purified by Prep-HPLC to give the objective 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＝7.6Hz,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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 1-benzyl-4- (3, 3-difluorocyclobutyl) piperazine

3, 3-Difluorocyclobutylamine hydrochloride (3 g,20.9mmol,1.0 eq) was dissolved in EtOH (60 mL) and N-benzyl-N, N-bis (2-chloroethyl) amine hydrochloride (6.74 g,25.08mmol,1.2 eq) and DIPEA (16.21 g,125.4mmol,6 eq) were added sequentially and reacted at 80℃for 16 hours under nitrogen. After completion of the reaction, the solvent was distilled off, quenched with water (100 mL) 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 then purified by flash chromatography (silica gel, PE: ea=2:1) to give the objective compound (2.5 g, 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)。

And a second step of: preparation of 1- (3, 3-difluorocyclobutyl) piperazine

1-benzyl-4- (3, 3-difluorocyclobutyl) piperazine (500 mg,1.88mmol,1.0 eq) was dissolved in ethyl acetate (15 mL), followed by the addition of HOAc (0.02 mL,0.33mmol,0.18 eq) and Pd (OH) ₂ Reaction at 25℃for 16 hours under hydrogen protection. After completion of the LC-MS detection reaction, filtration, concentration of the filtrate, and purification by flash chromatography (silica gel, DCM: meoh=10:1) gave the title 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)。

Third step to third stepEight steps of the preparation method of example 199, the compound of example 494, LC-MS (ESI) [ M+H ] was prepared] ⁺ ＝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＝6.0Hz,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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tert-butyl 3, 3-difluoro-4- (((trifluoromethyl) sulfonyl) oxy) -3, 6-dihydropyridine-1 (2H) -carboxylate

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

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)。

And a second step of: preparation of 3, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Tert-butyl 3, 3-difluoro-4- (((trifluoromethyl) sulfonyl) oxy) -3, 6-dihydropyridine-1 (2H) -carboxylate (9 g,24.5mmol,1.0 eq), pinacol diboronate (6.84 g,26.95mmol,1.1 eq), [1,1' -bis (diphenylphosphino) ferrocene ] palladium chloride (0.9 g,1.23mmol,0.05 eq) and potassium acetate (9.62 g,98.02mg,4.0 eq) were dissolved in dioxane (230 mL), displaced with nitrogen and reacted at 80℃for 7 hours. TLC detects the formation of product, filtration, washing of the filter cake with ethyl acetate, concentration of the filtrate, and purification by flash chromatography (silica gel, PE: ea=5:1) afforded the title compound (6 g, 59% yield).

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)。

And a third step of: preparation of 3, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine

3, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2 g,5.79mmol,1.0 eq) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added in an ice bath, and the reaction was carried out at room temperature for 6 hours. After the TLC detection was completed, the pH was adjusted to about 8 with triethylamine, and the reaction solution was directly concentrated to give a crude product (1.3 g) of the objective compound, which was directly used in the next step.

Fourth step: preparation of 3, 3-difluoro-1- (oxetan-3-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine

3, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (1.3 g,5.3mmol,1 eq) and oxetan-3-one (3.06 g,42.44mmol,8.0 eq) acetic acid (0.32 g,5.3mmol,1.0 eq) were dissolved in methanol (30 mL), and an appropriate amount of molecular sieve was added to react for 1 hour at 50 ℃. After cooling to room temperature, sodium cyanoborohydride (1.31 g,21.22mmol,4.0 eq) was added and reacted at room temperature for 16 hours. After completion of the LC-MS detection reaction, celite was filtered, washed with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=3:1) to give the title compound (780 mg, yield 49%).

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)。

Fifth step: preparation of 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- (azobridge) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecane

13-chloro-5- (trifluoromethyl) -7,8,9, 10-tetrahydro-1H-2, 6- (nitrogen-bridged) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecane (100 mg,0.29mmol,1 eq), 3-difluoro-1- (oxetan-3-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 6-tetrahydropyridine (130.66 mg,0.43mmol,1.5 eq), XPhos Pd G3 (24.46 mg,0.03mmol,0.1 eq) and potassium phosphate (245.6 mg,1.16mmol,4.0 eq) were dissolved in dioxane/water (10/1) (3.3 mL). The reaction was carried out at 100℃for 1 hour under nitrogen atmosphere. After completion of the LC-MS detection reaction, celite was filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the objective 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＝7.6Hz,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- (azoic bridge) pyrazolo [3,4-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the preparation of examples 1 or 443, the compound of example 496, LC-MS (ESI) [ M+H ], was prepared] ⁺ ＝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- (azoic bridge) benzo [ b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 455, provided the compound of example 497, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane formate salt

The first step: preparation of 4- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester

3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1 g,4.6mmol,1.0 eq) was dissolved in ethanol (20 mL), and (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride (624 mg,4.6mmol,1.0 eq) and acetic acid (0.5 mL) were added and sodium cyanoborohydride (853 mg,13.8mmol,3.0 eq) was slowly added to react at room temperature for 16 hours. After completion of LC-MS detection reaction, water (50 mL) was added, extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed 2 times with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and purified by flash chromatography (silica gel, DCM: ea=10:1) to give the title compound (600 mg, 43% yield).

LC-MS(ESI)[M+H] ⁺ ＝301.2。

And a second step of: 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,2mmol,1.0 eq) was dissolved in dichloromethane (5 mL), TFA (5 mL) was added and the reaction was carried out at room temperature for 2 hours. After the LC-MS detection reaction is finished, directly concentrating the reaction liquid to obtain a crude product of the target compound, and directly using the crude product in the next step.

LC-MS(ESI)[M+H] ⁺ ＝201.1。

The third to sixth steps were carried out according to the method of reference example 194 to obtain 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- (azoic bridge) benzo [ b)]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridec-11-yl) (6-methoxy-2-azaspiro [3.3]]Hept-2-yl) methanones

The first step: preparation of ((2, 5-difluoro-4-nitrophenyl) (6-methoxy-2-azaspiro [3.3] hept-2-yl) methanone

2, 5-difluoro-4-nitrobenzoic acid (1 g,4.92mmol,1.0 eq) and 6-methoxy-2-azaspiro [3.3] heptane (626 mg,4.92mmol,1.0 eq) were dissolved in N, N-dimethylformamide (5 mL), then urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (2.81 g,7.39mmol,1.5 eq) and diisopropylethylamine (1.91 g,14.77mmol,3.0 eq) were added and the reaction was reacted at room temperature for 16 hours. After completion of the LC-MS detection reaction, the reaction mixture was added with water, extracted with ethyl acetate (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and then purified by flash chromatography to give the title compound (1.0 g, yield 65%).

LC-MS(ESI)[M+H] ⁺ ＝313.1。

And a second step of: preparation of 3- ((2-chloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) butan-1-ol

2, 4-dichloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (2 g,5.18mmol,1.0 eq) was dissolved in isopropanol (50 mL), 3-aminobutanol (923 mg,10.36 mmol) was added and reacted at 85℃for 1 hour. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (PE: ea=3:1) to give the objective compound (1.5 g, yield 66%).

LC-MS(ESI)[M+H] ⁺ ＝439.2。

And a third step of: preparation of (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) methanone

3- ((2-chloro-5- (trifluoromethyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) butan-1-ol (1 g,2.28mmol,1.0 eq) was dissolved in THF (50 mL) and sodium hydrogen (182 mg,4.56mmol,2.0eq, 60% purity) was added at 0deg.C for half an hour. (2, 5-difluoro-4-nitrophenyl) (6-methoxy-2-azaspiro [3.3] hept-2-yl) methanone (710 mg,2.28mmol,1.0 eq) was added and reacted at room temperature for 2 hours. After completion of the LC-MS detection reaction, water quenching was added, the solvent was distilled off, extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=2:1) to give the title compound (1 g, yield 59%).

LC-MS(ESI)[M+H] ⁺ ＝731.2。

Fourth step: preparation of (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) methanone

(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) methanone (1 g,1.37mmol,1.0 eq) was added to ethanol (50 mL) and water (5 mL), iron powder (381 mg,6.84mmol,5.0 eq) and ammonium chloride (731 mg,13.68mmol,10.0 eq) were added and the reaction was reacted at 80℃for 16 hours. After the reaction was completed by LC-MS detection, the reaction solution was filtered, and after the filtrate was concentrated, water was added and extracted with ethyl acetate (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude title compound (800 mg, 83%).

LC-MS(ESI)[M+H] ⁺ ＝701.2。

Fifth step: preparation of (12-fluoro-6-methyl-3- (trifluoromethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1,5,6,7,8,14-hexahydro-4, 15- (azetidino) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridec-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-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) butoxy) -2-fluorophenyl) (6-methoxy-2-azaspiro [3.3] hept-2-yl) methanone (800 mg,1.14 mmol) was dissolved in 1, 4-dioxane (50 mL), tris (dibenzylideneacetone) dipalladium (104 mg, 104 mmol, 10%), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (108 mg,0.23mmol, 20%) and cesium carbonate (1.11 g,3.42mmol,3.0 eq) were added and the reaction was reacted at 90℃for 4 hours. After completion of the LC-MS detection reaction, the reaction solution was filtered, and after concentration of the filtrate, the reaction solution was purified by flash chromatography (silica gel, PE: ea=2:1) to give the objective compound (500 mg, yield 65%).

LC-MS(ESI)[M+H] ⁺ ＝665.3。

Sixth step: preparation of((12-fluoro-6-methyl-3- (trifluoromethyl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) benzo [ b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridec-11-yl) (6-methoxy-2-azaspiro [3.3] hept-2-yl) methanone

(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] triazatride-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 the reaction was carried out at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure, methanol (5 mL) and aqueous ammonia (2 mL) were added, and the reaction was continued at room temperature for 1 hour. After completion of the LC-MS detection reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (50 ml x 3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and purified by flash chromatography to give the title 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-methyl oxetan-3-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 199, the compound of example 500, 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- (azoic bridge) imidazo [4,5-g]Pyrido [2,3-b][1]Oxa [4,6,10]TriazacyclodecaTrialkanes

Reference to the procedure for the preparation of example 199, the compound of example 501, 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- (azoic bridge) benzo [ b ]][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 427 gave the compound of example 502, 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-morpholinpiperidin-1-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane formate salt

The first step: preparation of 3-fluoro-4- (morpholin-4-yl) piperidine-1-carboxylic acid tert-butyl ester

3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2 g,9.21mmol,1,0 eq) was dissolved in ethanol (20 mL), morpholine (803 mg,9.21mmol,1.0 eq) and acetic acid (0.5 mL) were added, and sodium cyanoborohydride (1.71 g,27.63mmol,3.0 eq) was slowly added and reacted at room temperature for 16 hours. After completion of LC-MS detection reaction, water (50 mL) was added, extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed 2 times with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and purified by flash chromatography (silica gel, DCM: ea=10:1) to give the title compound (2 g, yield 75%).

LC-MS(ESI)[M+H] ⁺ ＝289.2。

And a second step of: preparation of 4- (3-fluoropiperidin-4-yl) morpholine

3-fluoro-4- (morpholin-4-yl) piperidine-1-carboxylic acid tert-butyl ester (2 g,6.94mmol,1 eq) was dissolved in dichloromethane (5 mL), TFA (2 mL) was added and reacted at room temperature for 2 hours. After the LC-MS detection reaction is finished, directly concentrating the reaction liquid to obtain a crude product of the target compound, and directly using the crude product in the next step.

LC-MS(ESI)[M+H] ⁺ ＝189.1。

The third to sixth steps were carried out according to the method of reference example 194 to obtain 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- (azoic bridge) benzo [ b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane formate salt

Reference to the procedure for the preparation of example 455 gave the compound of example 504, 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- (azoic bridge) benzo [ b)]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridec-11-yl) (6-methoxy-2-azaspiro [3.3 ]]Hept-2-yl) methanones

Reference to the procedure for the preparation of example 499 gave the compound of example 505, 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- (azoic bridge) pyrido [2,3-b ]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference example 194, the compound of example 506, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 199, the compound of example 507, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tert-butyl 6- (difluoromethoxy) -2-azaspiro [3.3] hept-2-carboxylate

Tert-butyl 6-hydroxy-2-azaspiro [3.3] hept-2-carboxylate (3 g,14.07mmol,1.0 eq), 2-difluoro-2- (fluorosulfonyl) acetic acid (3.76 g,21.1mmol,1.5 eq) and cuprous iodide (0.54 g,2.81mmol,0.2 eq) were dissolved in acetonitrile (30 mL), and reacted at 50℃for 2 hours. After completion of the LC-MS reaction, the reaction mixture was concentrated and purified by flash chromatography (silica gel, PE: ea=3:1) to give the objective compound (1.7 g, 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)。

And a second step of: synthesis of 6- (difluoromethoxy) -2-azaspiro [3.3] heptane

Tert-butyl 6- (difluoromethoxy) -2-azaspiro [3.3] hept-2-carboxylate (1.7 g,6.46mmol,1.0 eq) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (6 mL) was added to react at room temperature for 2 hours. TLC detection was complete and the reaction solution was directly concentrated to give crude title compound (1 g) which was used directly in the next step.

LC-MS(ESI)[M+H] ⁺ ＝164.1。

The third to eighth steps 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-methyl oxetan-3-yl) piperazin-1-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azo) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 1- (3- (1H-1, 2, 3-triazol-1-yl) oxetan-3-yl) -4-benzylpiperazine

1-Benzylpiperazine (500 mg,2.84 mmol) was added to toluene (10 mL), followed by oxetan-3-one (225 mg,3.12 mmol) and 1H-1,2, 3-triazole (235 mg,3.41 mmol), and the reaction was reacted at 125℃for 2 hours. After the TLC detection was completed, the reaction mixture was cooled to room temperature, and the reaction mixture was used in the next step without any treatment.

And a second step of: preparation of 1-benzyl-4- (3-methyl oxetan-3-yl) piperazine

Methyl magnesium bromide solution (3M, 2.5 mL) was added to tetrahydrofuran (2.5 mL), and the toluene solution of the last step of 1- (3- (1H-1, 2, 3-triazol-1-yl) oxetan-3-yl) -4-benzylpiperazine (10 mL,800 mg) was added at 5℃and reacted at room temperature for 2 hours. After completion of the LC-MS detection reaction, the reaction mixture was quenched with ice water, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude title compound (0.2 g, yield 30%).

LC-MS(ESI)[M+H] ⁺ ＝247.2。

And a third step of: preparation of 1- (3-methyl oxetan-3-yl) piperazine

1-benzyl-4- (3-methyloxetan-3-yl) piperazine (200 mg,0.81 mmol) was dissolved in ethanol (10 mL), palladium on carbon (100 mg, 10%) was added, and the mixture was reacted at 60℃for 4 hours under a hydrogen atmosphere. LC-MS detection reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give the crude product of the objective compound (80 mg, yield 63%).

LC-MS(ESI)[M+H] ⁺ ＝157.2。

The fourth to seventh steps were carried out according to the method of reference example 194 to obtain 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- (azoic bridge) pyrido [2, 3-b)]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridec-11-yl) -6-methyl-2-azaspiro [3.3 ]Hept-6-ol

The first step: synthesis of tert-butyl 6-hydroxy-6-methyl-2-azaspiro [3.3] hept-2-carboxylate

Tert-butyl 6-oxo-2-azaspiro [3.3] hept-2-carboxylate (10 g,47.34mmol,1.0 eq) was dissolved in tetrahydrofuran (150 mL), and methylmagnesium bromide (47.3 mL,2mol/L,4.0 eq) was added dropwise to the ice bath under nitrogen protection, and the reaction was carried out for 2 hours. After completion of the reaction by TLC, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (150 mL), extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product of the objective compound (10 g).

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)。

And a second step of: synthesis of 6-methyl-2-azaspiro [3.3] hept-6-ol

6-hydroxy-6-methyl-2-azaspiro [3.3] heptyl-2-carboxylic acid tert-butyl ester (10 g,43.99mmol,1.0 eq) was dissolved in methanol hydrochloride (4M) (100 mL) and reacted at room temperature for 4 hours. After the LC-MS detection reaction, the reaction solution was directly concentrated to obtain a crude product (5 g) of the target compound.

LC-MS(ESI)[M+H] ⁺ ＝128.0。

The third to eighth steps 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-morpholinpiperidin-1-yl) -1,5,6,7,8,14-hexahydro-4, 15- (azepine) benzo [ b ]]Pyrrolo [2,3-g ][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 3-fluoro-4-morpholinopiperidine-1-carboxylic acid tert-butyl ester

3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (500 mg,2.3mmol,1.0 eq) was dissolved in DCM (5 mL) and morpholine (220.57 mg,2.53mmol,1.1 eq) was added and reacted at 25℃for 10 min. Sodium triethoxyborohydride (731.7 mg,3.45mmol,1.5 eq) was added in portions and reacted for 3 hours. After completion of the LC-MS detection reaction, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (20 ml×3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by flash chromatography (silica gel, DCM: meoh=10:1) to give the title compound (550 mg, yield 83%) as a white solid.

LC-MS(ESI)[M+H] ⁺ ＝288.80。

And a second step of: preparation of 4- (3-fluoropiperidin-4-yl) morpholine

3-fluoro-4-morpholinopiperidine-1-carboxylic acid tert-butyl ester (550 mg,1.91mmol,1.0 eq) was dissolved in dioxane (5 mL), and a solution of dioxane hydrochloride (5 mL, 4M) was added dropwise and reacted at 25℃for 16 hours. LC-MS detection reaction is complete, direct concentration and ethyl acetate beating for 20 minutes. Suction filtration gave crude hydrochloride of the target compound (450 mg). Without further purification, it was used directly in the next reaction.

LC-MS(ESI)[M+H] ⁺ ＝189.20。

The third to eighth steps 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- (azoic bridge) imidazo [4,5-g]Pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 or 199 gave the compound of example 512, 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 194 gave the compound of example 513, 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-bridged) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of tert-butyl (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) carbamate

Tert-butyl (3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl) carbamate (5 g,15.07mmol,1 eq), 6-methoxy-2-azaspiro [3.3] heptane (2.49 g,19.59mmol,1.3 eq) and triethylamine (6.1 g,60.29mmol,4 eq) were dissolved in DMF (70 mL) and reacted at 80℃for 2 hours under nitrogen protection and LC-MS detection was complete. The reaction solution was poured into 100mL of water. Ethyl acetate (100 ml x 2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by flash chromatography (silica gel, PE: ea=2:1) to give the title compound (6 g, yield 94%).

LC-MS(ESI)[M+H] ⁺ ＝367.2； ¹ H NMR(400MHz,CDCl ₃ ):δ8.22(d,J＝8.8Hz,1H),5.75(d,J＝8.8Hz,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)。

And a second step of: preparation of 3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propan-1-amine

Tert-butyl (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) oxy) propyl) carbamate (3.5 g,8.28mmol,1 eq) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added at room temperature and stirred for 2 hours, the reaction was complete by LC-MS detection, and the reaction solution was directly concentrated to give crude title compound (3 g).

LC-MS(ESI)[M+H] ⁺ ＝322.7。

And a third step of: preparation of 3, 6-dichloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yl) 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 (3 g, crude product from the previous step) 3,4, 6-trichloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine (4.37 g,12.42mmol,1.5 eq) and DIEA (8.56 g,66.26mmol,8 eq) were dissolved in azamethylpyrrolidone (40 mL), heated to 100 ℃ for 6 hours, the LC-MS detection reaction was completed, the reaction was poured into 100mL of water, ethyl acetate (100 mL x 3) was extracted, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (silica gel, PE: ea=1:1) to give the title compound (800 mg, 15%).

LC-MS(ESI)[M+H] ⁺ ＝637.1。

Fourth step: preparation of 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

3, 6-dichloro-N- (3- ((6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -3-nitropyridin-2-yloxy) propyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine (500 mg,0.78mmol,1 eq) was dissolved in ethanol/water (5/1) (12 mL), iron powder (218.94 mg,3.92mmol,5 eq) and ammonium chloride (209.72 mg,3.92mmol,5 eq) were added, warmed to 80℃and stirred for 1 hour, the reaction was completely detected by LC-MS, and the reaction solution was directly concentrated and purified by flash chromatography (silica gel, meOH=15:1) to give the title compound (250 mg, yield 52%).

LC-MS(ESI)[M+H] ⁺ ＝607.0。

Fifth step: preparation of 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-bridged) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

N- (3- ((3-amino-6- (6-methoxy-2-azaspiro [3.3] hept-2-yl) pyridin-2-yloxy) propyl) -3, 6-dichloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine (250 mg,0.41mmol,1 eq), tBuBrettPhos Pd G Br (cas: 2691807-28-8) (33.58 mg,0.1 eq) and cesium carbonate (536.2 mg,1.65mmol,3 eq) were dissolved in dioxane (10 mL), stirred for 2 hours under nitrogen protection at 100℃and the reaction was complete by LC-MS detection, the insoluble material was filtered off through celite, the ethyl acetate filter cake, the filtrate concentrated, and purified by flash chromatography (silica gel, meOH: 20:1) to give the title compound (84 mg, 36% yield).

LC-MS(ESI)[M+H] ⁺ ＝571.0。

Sixth step: preparation of 3-chloro-11- (6-methoxy-2-azaspiro [3.3] hept-2-yl) -1,5,6,7,8,14-hexahydro-4, 15- (methyl-bridged) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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-bridged) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane (84 mg,0.15mmol,1 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at room temperature and stirred for 1 hour, the reaction mixture was concentrated directly, tetrahydrofuran (4 mL) was diluted, 2mL of aqueous ammonia was added and stirred for 1 hour, LC-MS detection of completion of the reaction, the reaction mixture was concentrated, and purified by Prep-HPLC (C18, 0.05% NH) ₄ Aqueous OH, meCN) to afford the title 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＝8.0Hz,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- (azo) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of 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- (azobridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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 (40 mg,0.06mmol,1 eq) was dissolved in ethanol (5 mL), 5% palladium on carbon (6.51 mg,1 eq) was added and stirred at room temperature under an atmospheric pressure of hydrogen for 16 hours, the reaction was complete by LC-MS, the palladium on carbon was filtered off via celite, and the filtrate was concentrated to give the title compound (35 mg, 87%).

LC-MS(ESI)[M+H] ⁺ ＝656.3。

And a second step of: preparation of 11- (3, 3-difluoro-1- (oxetan-3-yl) piperidin-4-yl) -3- (trifluoromethyl) -1,5,6,7,8,14-hexahydro-4, 15- (azoic bridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazatridecane

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- (azabridge) pyrido [2,3-b ] pyrrolo [2,3-g ] [1] oxa [4,6,10] triazacyclotridecane (30 mg,0.05mmol,1 eq) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added, stirred at room temperature for 1 hour, the reaction was concentrated, 1mL of tetrahydrofuran and 0.5mL of aqueous ammonia were added and stirring continued for 0.5 hour, LC-MS detection was complete, the reaction was directly concentrated, and purification (C18, 0.1% aqueous FA, meCN) was isolated by Prep-HPLC to give the title 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- (azoic bridge) pyrido [2,3-b]Pyrrolo [2,3-g][1]Oxa [4,6,10]Triazacyclotridecane

Reference to the procedure for the preparation of example 510 gave the compound of example 516, 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- (azoic bridge) pyrido [2,3-b][1]Oxa [4,6,10]Triazacyclotridecane

The first step: preparation of (3R, 4S) -4- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester

3-fluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (4 g,18.41mmol,1.0 eq), bridged-ring morpholin hydrochloride (3 g,22.1mmol,1.2 eq), triethylamine (5.59 g,55.24mmol,3 eq) were dissolved in MeOH (40 mL) at room temperature, a few drops of acetic acid were added, stirring was performed at room temperature for 1 hour, sodium cyanoborohydride (2.28 g,36.83mmol,2 eq) was added to the reaction solution, the reaction was continued for one hour, LC-MS monitored the starting material was complete, dried by spin-on, and the desired product (4.87 g, 88% yield) was obtained by column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝301.1。

And a second step of: preparation of (1S, 4S) -5- ((3R, 4S) -3-fluoropiperidin-4-yl) -2-oxa-5-azabicyclo [2.2.1] heptane

(3R, 4S) -4- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (1.87 g,6.23mmol,1 eq) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (6 mL) was added and stirred at room temperature for 2 hours. TLC detection reaction was complete, and the reaction solution was directly concentrated to give the crude product of the objective product (1.2 g).

LC-MS(ESI)[M+H] ⁺ ＝201.0。

And a third step of: preparation of tert-butyl 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) carbamate

Tert-butyl 3- ((6-chloro-3-nitropyridin-2-yl) oxy) propyl carbamate (1.3 g,3.92mmol,1 eq), (1S, 4S) -5- ((3R, 4S) -3-fluoropiperidin-4-yl) -2-oxa-5-azabicyclo [2.2.1] heptane (0.94 g, crude product from the previous step) and triethylamine (1.59 g,15.68mmol,4 eq) were dissolved in DMF (15 mL) and the temperature was raised to 80℃for 2 hours. LC-MS detects that the raw materials are finished, spin-drying is carried out, and the target product (1.2 g, yield 61%) is obtained through column chromatography separation and purification.

LC-MS(ESI)[M+H] ⁺ ＝496.2。

Fourth step: preparation of 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) propan-1-amine

Tert-butyl 3- ((6- ((3R, 4S) -4- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-fluoropiperidin-1-yl) -3-nitropyridin-2-yloxy) propyl) carbamate (1.2 g,2.42mmol,1 eq) is dissolved in dichloromethane (20 mL) and trifluoroacetic acid (6 mL) is added and stirred at room temperature for 2 hours. TLC detection reaction was complete, and the reaction solution was directly concentrated to give the crude product of the objective compound (900 mg).

LC-MS(ESI)[M+H] ⁺ ＝396.2。

Fifth step: preparation of 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

3- ((6- ((3R, 4S) -4- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-halopiperidin-1-yl) -3-nitropyridin-2-yl) oxy) propan-1-amine (600 mg, crude product from the previous step), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (395.08 mg,1.82mmol,1.2 eq) and N, N-diisopropylethylamine (784.4 mg,6.07mmol,4 eq) were dissolved in DMF (6 mL) and reacted for 2 hours at room temperature, the reaction was complete by LC-MS detection, the reaction solution was spun dry, the crude product was isolated and purified by column chromatography to give the crude product, which was isolated and purified by preparative high performance liquid phase to give the desired 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＝8.8Hz,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)。

Sixth step: preparation of 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- (azepine) pyrido [2,3-b ] [1] oxa [4,6,10] triazatridecane

N- (3- ((6- ((3R, 4S) -4- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl) -3-halopiperidin-1-yl) -3-nitropyridin-2-yloxy) propyl) -2-chloro-5- (trifluoromethyl) pyrimidin-4-amine (200 mg,0.35mmol,1.0 eq), fe (96.95 mg,1.74mmol,5 eq), ammonium chloride (120.74 mg,2.26mmol,6.5 eq) were dissolved in 5mL of ethanol and 1mL of water at room temperature and then the system was placed in an oil bath at 85℃for 4 hours, the LC-MS monitored starting material was reacted completely, the spin-dried, the crude product was isolated and purified by preparative high performance liquid phase to give the desired 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) The reaction solution: 50mM HEPES (pH 7.5); 10mM MgCl ₂ ；1mM EDTA；0.01％Brij35；2mM DTT；

2) Detection solution: TR-FRET Dilution Buffer;

3) LRRK2 human recombinant protein: expression of recombinant full-length human LRRK2 protein in insect Sf9 cells using GST tags with baculovirus;

4) A substrate: 0.4. Mu.M Fluorescein-ERM (LRRKtide) peptide; 38. Mu.M ATP.

2. The detection method comprises the following steps:

time-resolved fluorescence energy resonance transfer (TR-FRET) the TR-FRET technique combines a time-resolved fluorescence detection technique with a fluorescence energy resonance transfer detection (FRET) technique. In experiments, when biomolecules interact, the distance of the acceptor fluorophore is pulled, and if the donor is excited, it will transfer its emitted light energy to the acceptor. The lanthanide fluorescent group is used as a donor, the emitted light has a long half-life, and the excitation and the emission of the acceptor fluorescent group can be detected after the background fluorescence with a short half-life disappears, so that the background is reduced and the signal to noise ratio is improved, and the sensitivity is improved.

1) Adding DMSO solution of a compound to be tested into a 384-micro-well plate through an Echo550 non-contact nano-upgrading sound wave liquid distribution system;

2) Preparing enzyme and polypeptide mixed solution (2 nM enzyme+0.4. Mu.M Fluorescein-ERM (LRRKtide) peptide) with freshly prepared reaction solution, adding 5. Mu.L 384 micro-well plate to the existing compound, centrifuging at 1000rpm/min for 1min, and incubating at room temperature for 15min;

3) Adding 5 mu L of 38 mu M ATP, centrifuging at 1000rpm/min for 1min, and reacting at room temperature for 120min;

4) Adding a detection reagent: purchased from Thermofisher (cat. PV 4900) 0.25nMTb-pERM (pLRRKtide) anti-body and 10mM EDTA,1000rpm/min are centrifuged for 1min, and reacted for 30min at room temperature;

5) Envison detected TR-TRET fluorescence signals, mirror 447 (D400/D505), filter 275 (520 nm) and 102 (485 nm);

6) Inhibition of enzyme activity by compounds was calculated by signal ratio (520 nm/485 nm) and IC was calculated by software XLfit5 fitting curve ₅₀ Values.

3. Experimental results:

TABLE 1 test results of LRRK2 kinase inhibitory Activity

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 compounds of the present invention have a significant inhibitory effect on LRRK2 kinase.

Experimental example 2: in vitro evaluation of Compounds for inhibition of p S935 LRRK2

1. Cell preparation:

1) Cell resuscitation:

HEK293T cells purchased by ATCC are taken out of liquid nitrogen and placed in a water bath at 37 ℃ and after ice melts, the cells are transferred to a centrifuge tube containing 10mL of complete medium and centrifuged at 1000rpm/min for 5min. The supernatant was discarded, resuspended in 15mL of fresh complete medium and transferred to a T75 flask, which was placed At 37℃with 5% CO ₂ Culturing in an incubator, and observing the growth state of cells in time.

2) Cell passage:

cell passage can be performed when the cells are cultured to 80-90% confluence. The supernatant was discarded, 20-25mL of PBS was added, and the flask was shaken several times. The PBS was discarded, 3-4mL of pancreatin was added to digest the cells, allowed to stand for 1-2min, 10mL of complete medium was added to terminate the digestion, and the cells were gently blown down until all cells were shed, forming a single cell suspension. The single cell suspension was transferred to a centrifuge tube and centrifuged at 1000rpm/min for 5min. The supernatant was discarded, resuspended in fresh complete medium and passaged 1:5 into T150 flasks. The flask was placed in 37℃and 5% CO ₂ Culturing in an incubator, and observing the growth state of cells in time.

3) Cell cryopreservation:

the cells with good growth state and cell activity rate reaching over 96 percent are frozen for seed preservation. The cell density was adjusted to 5 x 10 with cell cryopreservation ⁶ Per mL, then transferred to a cell cryopreservation tube, 1mL of cell suspension per tube. After the cell-containing cryopreservation tube was placed in the cryopreservation box, the cell-containing cryopreservation tube was stored in liquid nitrogen after being frozen overnight at-80 ℃.

2. The experimental steps are as follows:

1. the first day: HEK293T cell transfection

(1) 30mL of the cell suspension (containing 30X 10) ⁶ Individual cells) were inoculated in 150mm dishes.

(2) Preparing transfection reagent: the reagents were added in this order, 2mL opti-MEM+20. Mu.g DNA+60. Mu.L Tansit. Were gently mixed, and then left to stand at room temperature for 20min.

(3) Dripping the prepared transfection reagent into a 150mm culture dish inoculated with cells, mixing by gentle shaking, and adding into 37 ℃ and 5% CO ₂ The incubator cultures for 24 hours.

2. The following day: seed plate

The transfected cells were collected and the cell density was adjusted to 0.2X10 ⁶ /mL. The cell suspension was added to 384 microwell plates (10000 cells per well) at 50. Mu.L per well and centrifuged at 1000rpm/min for 1min. 384 microwell plates were placed at 37℃in 5% CO ₂ Incubator culture overnight。

3. Third day: compound treatment and HTRF detection

(1) Preparing a compound: the storage concentration of the compound is 10mM, and the compound is diluted to the required working concentration according to the requirement when the compound is used.

(2) Compounds were added to 384 microwell plates using TECAN according to Plate map, with final DMSO concentration adjusted to 0.2%.

(3) Centrifuging at 1000rpm/min for 1min, adding 37deg.C and 5% CO ₂ The incubator cultures for 2 hours.

(4) Preparation of HTRF cell lysates: 4mL Lysis buffer+12mL H ₂ O+160μL Blocking buffer。

(5) After 2h, 16. Mu.L of the cell lysate was added to each well, centrifuged at 1000rpm/min for 1min and the plate was shaken at 800rpm/min for 30min at room temperature.

(6) Preparing HTRF antibody mixed solution: 1600 μl=40 μl of Cryptate-anti+40 μ L d-anti+1520 μ L H ₂ O。

(7) After 30min, the mixture was centrifuged at 1000rpm/min for 2min.

(8) Adding the antibody mixed solution into 4 mu L of each well, centrifuging at 1000rpm/min for 1min, and incubating for 20-24h at room temperature.

(9) The plates were read on Envision.

3. Experimental results:

TABLE 2 test results of compounds for inhibition activity of 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 p S LRRK 2.

Claims

A compound represented by formula (K), or a stereoisomerism thereofA construct, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein,

is a single bond or a double bond;

X ₁ 、X ₂ 、X ₃ and X ₄ Each independently CH or N;

Y ₁ 、Y ₂ and Y ₃ O, S or NR respectively and independently ^Y ；R ^Y Each occurrence is independently hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _3-8 Cycloalkyl or a 3-8 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 a 3-8 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Alkyl hydroxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxyRadicals, nitro radicals, amino radicals, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

R ₃ is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, 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-C _3-8 Cycloalkyl, -C _1-3 alkyl-C _3-8 Cycloalkenyl, -C _1-3 An alkyl-3-12 membered heterocyclyl or-C (O) -3-12 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 membered heterocyclyl optionally being substituted with one or more groups 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 alkyl-O-C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and optionally C _1-3 Alkyl or halogen substituted 3-12 membered heterocyclyl substituents;

R ₄ each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxy, 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 A haloalkyl group;

R ₅ is 1, 2 or 3, each occurrence of which is independently hydrogen, deuterium, halogen, amino, hydroxy, mercapto, carboxyl, nitro, oxime, C _1-6 Alkenyl group,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, -N (C) _1-6 Alkyl group ₂ 、-NH-C _3-6 Cycloalkyl, -N (C) _3-6 Cycloalkyl radicals) ₂ Or cyano;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2;

ring a is a 5-6 membered heteroaryl or ring a is absent.
The compound of claim 1, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

X ₁ 、X ₂ 、X ₃ and X ₄ Are all N;

alternatively, X ₂ Is CH, X ₁ 、X ₃ And X ₄ Are all N;

alternatively, X ₁ And X ₂ Are all CH, X ₃ And X ₄ Are all N;

alternatively, X ₁ 、X ₂ And X ₄ Are all CH, X ₃ Is N.
A compound according to claim 1 or 2, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

Y ₂ is O or S, Y ₁ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₂ Is O, Y ₁ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₁ Is O or S, Y ₂ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₁ Is O, Y ₂ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₁ Is O, Y ₂ Is O, Y ₃ Is NR (NR) ^Y 。
A compound according to any one of claims 1-3, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ^Y each occurrence 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 a 3-8 membered heterocyclyl containing 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, hydroxy, nitro and amino;

Preferably, R ^Y Each occurrence is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropanyl or epoxybutanyl; the methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropyl or epoxybutyl groups are optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro and amino;

further preferably, R ^Y Each occurrence is independently hydrogen.
The compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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, alkynyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Haloalkyl and C _1-3 Substituted by a substituent of haloalkoxy;

more preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, amino and C _1-3 Substituted by alkyl;

further preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, cyano, hydroxy, 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 or trifluoromethyl;

still more preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, methyl, ethyl, n-propyl, isopropylCyclopropyl, methoxy, ethoxy, -CH ₂ OCH ₃ Fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl.
The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₃ is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, 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 An alkyl-3-12 membered heterocyclyl or-C (O) -3-12 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally being substituted with one or more groups 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-O-C _1-6 Alkyl and optionally C _1-3 An alkyl or halogen substituted 3-12 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N;

preferably, R ₃ Is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, amino, C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl, -C _1-2 alkyl-C _3-6 Cycloalkyl, -C _1-2 An alkyl-3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally being substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Haloalkyl, -C _1-3 alkyl-O-C _1-3 Alkyl and optionally C _1-3 A substituent substituted with an alkyl-substituted 3-8 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N;

more preferably, R ₃ Is 1 or 2, each occurrence of which is independently halogen, cyano, hydroxy, C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl, -C _1-2 alkyl-C _3-6 Cycloalkyl, -C _1-2 An alkyl-3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _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 optionally being substituted with one or more groups each independently selected from deuterium, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, -CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₃ A 3-6 membered heterocyclyl substituted with a methyl or ethyl substituted 3-6 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N;

further preferably, R ₃ Is 1 or 2, each occurrence of which is independently fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monocyclic heterocyclyl, 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH ₂ -6 membered mono-heterocyclyl, -CH ₂ CH ₂ -7-membered bridged heterocyclyl, CH ₂ CH ₂ -6-membered mono-heterocyclyl, -C (O) -6-membered mono-heterocycleA, -C (O) -7 membered bridged heterocyclyl or-C (O) -7 membered spiroheterocyclyl, said heterocyclyl containing 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 mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -CH ₂ -6 membered mono-heterocyclyl, -CH ₂ CH ₂ -7-membered bridged heterocyclyl, CH ₂ CH ₂ -6 membered mono-heterocyclyl, -C (O) -7 membered bridged heterocyclyl or-C (O) -7 membered spiro heterocyclyl, optionally substituted with one or more groups each independently selected from cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, -CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₃ Substituted with substituents selected from the group consisting of 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, methyl-substituted 4-membered mono-heterocyclyl, methyl-substituted 5-membered mono-heterocyclyl, methyl-substituted 6-membered mono-heterocyclyl and 7-membered bridged heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N;

still more preferably, R ₃ Each occurrence is independently Represents R ₃ Connection locations.
The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₄ each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxy, 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 A haloalkyl group;

preferably, R ₄ Each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl or trifluoromethyl;

more preferably, R ₄ Each occurrence of which is independently hydrogen, fluorine, methyl.
The compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₅ is 1, 2 or 3, each occurrence of which 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 group ₂ 、-NH-C _3-6 Cycloalkyl, -N (C) _3-6 Cycloalkyl radicals) ₂ Or cyano;

preferably, R ₅ Is 1, 2 or 3, each occurrence of which 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, R ₅ Is 1, 2 or 3, each occurrence of which is independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, methylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, -NHCH ₃ 、-NHCH ₂ CH ₃ 、-N(CH ₃ ) ₂ -NH-cyclopropyl or cyano;

further preferably, R ₅ Is 1, 2 or 3, each occurrence of which is independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl, -NHCH ₃ 、-NHCH ₂ CH ₃ -NH-cyclopropyl or cyano.
The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

n1 is 3.
The compound according to any one of claims 1 to 9, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

n2 is 1.
The compound according to any one of claims 1 to 9, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

n2 is 2.
The compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

Ring a is absent.
The compound according to any one of claims 1 to 11, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

ring A is a 5-6 membered heteroaromatic ring;

preferably, ring a is pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl.
The compound according to any one of claims 1-11 and 13, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

ring a is a 5 membered heteroaryl ring;

preferably, ring a is pyrrolyl, pyrazolyl or imidazolyl.
The compound of any one of claims 1-11 and 13-14, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

ring A is* Represents a condensed site;

alternatively, ring A is* Represents a condensed site.
A compound as shown in any one of formulas (K1) to (K11), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、Y ₁ 、Y ₂ 、Y ₃ N1 is as defined in claim 1.
A compound of formula (K1A) or (K1B), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ As defined in claim 1.
A compound of formula (K2A), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、Y ₁ As defined in claim 1.
The compound of claim 18, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

Y ₁ is O or NH;

preferably Y ₁ Is NH.
The compound of any one of claims 17-19, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₁ and R is ₂ Each occurrence of which is independently hydrogen, deuterium, halogen or C _1-3 An alkyl group; the alkyl group is optionally substituted with one or more substituents each independently selected from deuterium and halogen;

preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl;

more preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

alternatively, R ₁ And R is ₂ Each occurrence of which is independently hydrogen, halogen or C _1-3 An alkyl group;

preferably, R ₁ And R is ₂ Each occurrence of time divisionIndependently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine;

more preferably, R ₁ And R is ₂ Each occurrence of which is independently hydrogen, methyl or fluoro.
The compound of any one of claims 17-20, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₃ each occurrence is independently C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, 3-9 membered heterocyclyl or-C (O) -3-9 membered heterocyclyl optionally substituted with one or more substituents each independently selected from cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N;

preferably, R ₃ Each occurrence is independently methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiro heterocyclyl, 8-membered spiro heterocyclyl, 9-membered spiro heterocyclyl, -C (O) -6-membered mono-heterocyclyl, -C (O) -7-membered bridged heterocyclyl, or-C (O) -7-membered spiro heterocyclyl, said heterocyclyl containing 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 mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C (O) -6-membered mono-heterocyclyl, -C (O) -7-membered bridged heterocyclyl or-C (O) -7-membered spiroheterocyclyl optionally being selected from cyano, hydroxy, methyl, ethyl, cyano, hydroxy, and, Methoxy, ethoxy, fluoro, chloro, bromo, 4-membered mono-heterocyclyl, 5-membered mono-heterocyclyl, 6-membered mono-heterocyclyl, methyl-substituted 4-membered mono-heterocyclyl, methyl-substituted 5-membered mono-heterocyclyl, methyl-substituted 6-membered mono-heterocyclyl and 7-membered bridged heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N;

more preferably, R ₃ Each occurrence is independently Represents R ₃ A connection location;

alternatively, R ₃ Is a 3-9 membered heterocyclyl or a-C (O) -3-9 membered heterocyclyl containing 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 substituted with one or more substituents each independently selected from hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N;

preferably, R ₃ Is a 4-membered mono-heterocyclic group, a 5-membered mono-heterocyclic group, a 6-membered mono-heterocyclic group, a 7-membered bridged heterocyclic group, an 8-membered bridged heterocyclic group, a 7-membered spiro heterocyclic group, an 8-membered spiro heterocyclic group, a 9-membered spiro heterocyclic group, -C (O) -6-membered mono-heterocyclic group, -C (O) -7-membered bridged heterocyclic group, or-C (O) -7-membered spiro heterocyclic group, said heterocyclic group containing 1 or 2 heteroatoms each independently selected from O and N; the 4-membered mono-heterocyclic group, 5-membered mono-heterocyclic group, 6-membered mono-heterocyclic group, 7-membered bridged heterocyclic group, 8-membered bridged heterocyclic group, 7-membered spiro heterocyclic group, 8-membered spiro heterocyclic group, 9-membered spiro heterocyclic group, -C (O) -6-membered mono-heterocyclic group, -C (O) -7-membered bridged heterocyclic group The group or-C (O) -7 membered spiroheterocyclyl is optionally substituted with one or more substituents each independently selected from hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, 4 membered mono-heterocyclyl, 5 membered mono-heterocyclyl, 6 membered mono-heterocyclyl, methyl substituted 4 membered mono-heterocyclyl, methyl substituted 5 membered mono-heterocyclyl, methyl substituted 6 membered mono-heterocyclyl and 7 membered bridged heterocyclyl, said heterocyclyl containing 1 or 2 heteroatoms each independently selected from O and N;

more preferably, R ₃ Is that Represents R ₃ Connection locations.
The compound of any one of claims 17-21, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₄ each occurrence of which is independently hydrogen, deuterium, halogen or C _1-3 An alkyl group;

preferably, R ₄ Each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl;

more preferably, R ₄ Each occurrence of which is independently hydrogen, fluorine or methyl;

alternatively, R ₄ Each occurrence is independently hydrogen.
The compound of any one of claims 17-22, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₅ Is hydrogen, deuterium, halogen, C _1-3 Alkyl, C _1-3 Haloalkyl or C _3-6 Cycloalkyl;

preferably, R ₅ Hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl;

more preferably, R ₅ 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, R ₅ Is chloro, trifluoromethyl or cyclopropyl.
A compound of formula (I), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein,

is a single bond or a double bond;

X ₁ 、X ₂ 、X ₃ and X ₄ Each independently CH or N;

Y ₁ 、Y ₂ and Y ₃ O, S or NR respectively and independently ^Y ；R ^Y Each occurrence is independently hydrogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _3-8 Cycloalkyl or C _3-8 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 A heterocyclyl group containing 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 substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, phenyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of 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, -C _1-3 alkylene-C _3-12 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl are optionally substituted with one or more groups 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 alkyl-O-C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _3-12 Substituents of the heterocyclic group are substituted;

R ₄ and R is ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Alkylthio or C _1-6 A haloalkyl group;

n1 is 2, 3, 4 or 5;

n2 is 1 or 2; when n2 is 1, ring A is a 5-6 membered heteroaryl; when n2 is 2, ring A is a 5-6 membered heteroaryl or ring A is absent.
The compound of claim 24, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

X ₁ 、X ₂ 、X ₃ and X ₄ Are all N;

alternatively, X ₂ Is CH, X ₁ ，X ₃ And X ₄ Are all N;

alternatively, X ₁ And X ₂ Are all CH, X ₃ And X ₄ Are all N;

alternatively, X ₁ 、X ₂ And X ₄ Are all CH, X ₃ Is N.
The compound of claim 24 or 25, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

Y ₂ is O or S, Y ₁ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₂ Is O, Y ₁ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₁ Is O or S, Y ₂ And Y ₃ Are each independently NR ^Y ；

Alternatively, Y ₁ Is O, Y ₂ And Y ₃ Are each independently NR ^Y 。
The compound of any one of claims 24-26, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ^Y Each occurrence 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 A heterocyclyl group containing 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, hydroxy, nitro and amino;

preferably, R ^Y Each occurrence is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropanyl or epoxybutanyl; the methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropanyl, cyclohexenyl, epoxypropyl or epoxybutyl groups are optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro and amino;

more preferably, R ^Y Each occurrence is independently hydrogen.
The compound of any one of claims 24-27, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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, alkynyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Substituted by a substituent of haloalkoxy;

preferably, the method comprises the steps of,R ₁ and R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Haloalkyl and C _1-3 Substituted by a substituent of haloalkoxy;

More preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, halogen, cyano, hydroxy, 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 groups are optionally substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, amino and C _1-3 Substituted by alkyl;

further preferably, R ₁ And R is ₂ Each occurrence is independently hydrogen, deuterium, cyano, hydroxy, 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 or trifluoromethyl.
The compound of any one of claims 24-28, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₃ each occurrence 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 groupbase-C _3-8 Cycloalkenyl or-C _1-3 alkylene-C _3-12 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl groups are optionally substituted with one or more groups 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-O-C _1-6 Alkyl and C _3-12 Substituents of the heterocyclic group are substituted;

preferably, R ₃ Each occurrence 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 A heterocyclyl group containing 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more groups each independently selected from deuterium, halogen, cyano, hydroxy, nitro, amino, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Haloalkyl, -C _1-3 alkyl-O-C _1-3 Alkyl and C _3-8 Substituents of the heterocyclic group are substituted;

more preferably, R ₃ Each occurrence is independently Represents R ₃ Connection locations.
The compound of any one of claims 24-29, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

R ₄ and R is ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-3 Alkyl, C _1-3 Alkoxy, C _1-3 Alkylthio or C _1-3 A haloalkyl group;

preferably, R ₄ And R is ₅ Each occurrence is independently hydrogen, deuterium, halogen, C _1-3 Alkyl or C _1-3 A haloalkyl group;

More preferably, R ₄ Each occurrence of which is independently hydrogen, deuterium, or methyl;

more preferably, R ₅ Each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
The compound of any one of claims 24-30, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

ring a is pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl;

preferably, ring a is pyrrolyl, pyrazolyl or imidazolyl;

more preferably, ring A is* Represents a condensed site;

alternatively, ring a is absent.
A compound of formula (I-a) or formula (I-B), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein each substituent is as defined in claim 24.
A compound represented by the formula (II-A) or (II-B), or a stereoisomerism thereofA construct, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein each substituent is as defined in claim 24.
A compound of formula (III), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein each substituent is as defined in claim 24.
A compound of formula (IV), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein each substituent is as defined in claim 24.
The following compounds, or stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof:
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 (glass fiber reinforced plastic) ^b Cl, br, I, OTf or Oms; y is Y _3’ is-OH or-SH; the 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 (glass fiber reinforced plastic) ^b Cl, br, I, OTf or OMs, Y _3’ is-OH or-SH; the 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 (glass fiber reinforced plastic) ^b For Cl, br, I, OTf or OMs, the other substituents are as defined in claim 1.
An intermediate (C') for preparing a compound of formula (I), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein LG (glass fiber reinforced plastic) ^b For Cl, br, I, OTf or OMs, the 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 (glass fiber reinforced plastic) ^b For Cl, br, I, OTf or OMs, the other substituents are as defined in claim 1.
An intermediate (D) for preparing a compound of formula (I), or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein LG (glass fiber reinforced plastic) ^b For Cl, br, I, OTf or OMs, the other substituents are as defined in claim 24.
A pharmaceutical composition comprising a compound according to any one of claims 1-36, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
Use of a compound according to any one of claims 1-36, or a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43, for the manufacture of a medicament for the treatment or prophylaxis of a disease mediated by LRRK2 kinase, preferably parkinson's disease.