CN117247387A

CN117247387A - Aromatic heterocyclic compound and preparation method thereof

Info

Publication number: CN117247387A
Application number: CN202310703613.0A
Authority: CN
Inventors: 宋云龙; 刘天琪; 丁祥峰; 苗新园; 王克柱; 汪笛莎; 寇红艳; 居捷
Original assignee: Shanghai Yishi Pharmaceutical Technology Co ltd
Current assignee: Shanghai Yishi Pharmaceutical Technology Co ltd
Priority date: 2022-06-16
Filing date: 2023-06-14
Publication date: 2023-12-19

Abstract

The invention provides a compound with a new structure serving as an LRRK2 inhibitor, and stereoisomers, optical isomers and medicinal salts thereof. The invention designs an aromatic heterocycle substituted compound with a novel structure, and provides a new direction for the development of medicines of LRRK2 inhibitors. 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 treating LRRK2 mediated diseases.

Description

Aromatic heterocyclic compound and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to an aromatic heterocyclic compound, a preparation method and application thereof.

Background

Parkinson's Disease (PD) is the second most common progressive neurodegenerative disease next to alzheimer's disease, affecting about 2% of the population over 60 years old. The etiology of parkinson 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. The need for new therapeutic strategies for parkinson's disease is evident, and in addition, is clearly growing due to the ever-increasing progress in the aging world population.

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 (Leucine-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 LRRK 2G 2019S 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 of 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 N-terminus to C-terminus: ARM (Armadillo repeats), ANK (ankyrin repeats), LRR (leucine rich repeat, LRR), ROC (Ras of complex proteins), COR (C-terminal of Roc), KIN (kinase) and WD40 (WD repeat domain). LRRK2 is widely expressed in brain, 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.

The development of LRRK2 inhibitors has recently progressed to a clinical development stage, in terms of small molecule drugs, DNL151 and DNL201 have both completed clinical phase I experiments, and WXWH0226 has obtained clinical trial batches. Many pharmaceutical enterprises have issued patents on LRRK2 inhibitors, the main structural types of which include the pyrrolopyrimidine series (WO 2015113451, WO2016130920, WO2017106771, WO2018155916, WO2015092592, etc.), the aminopyrimidine series (WO 2017087905, WO2017156493, WO2017218843, WO 2018217946), the pyrimidinyl/pyridinyl-indazole series (WO 2014137719, WO2014137723, WO2014134774, WO 2014137728), and the macrocyclic series (WO 2013046029, WO2014140235, WO2016042089, WO 2019012093), 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

The invention aims to provide a compound with a brand new structure serving as an LRRK2 inhibitor, a pharmaceutical composition, a preparation method and application thereof in the aspect of treating diseases mediated by LRRK2 kinase.

In a first aspect of the invention, there is provided a compound of formula (I) as follows, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of said compound:

X ₁ Selected from CR _a And N;

X ₂ selected from CR _b And N;

X ₃ selected from CR _c And N;

R _a selected from H, deuterium, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted by one or more substituents each independently selected from deuterium, halogen, CN and OH;

R _b selected from H, deuterium, halogen, C _1-6 Alkyl, C _3-8 Cycloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 An alkoxy group; the alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy are optionally substituted with one or more groups selected from deuterium, halogen, CN, OH and NH ₂ Is substituted by a substituent of (2);

R _c selected from H, deuterium, C _1-6 Alkyl, C _1-6 A haloalkyl group;

R ₁ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-8 Cycloalkyl;

R ₂ selected from phenyl, naphthyl, 5-7 membered monocyclic heteroaryl, benzoC _4-8 Monocyclic cycloalkyl, benzo 4-8 membered monocyclic heterocyclyl, benzo 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heteroaryl and 4-8 membered monocyclic heterocyclyl; each of the above groups is optionally substituted with one or moreEach independently selected from deuterium, halogen, CN, -OR ₂₁ 、NO ₂ 、-NR ₂₂ R ₂₃ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Haloalkyl, C _1-6 Substituted by a substituent of haloalkoxy;

R ₂₁ selected from H, deuterium, C _1-6 Alkyl, C _1-6 A haloalkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, deuterium, C _1-6 Alkyl, C _3-8 Cycloalkyl, 3-12 membered heterocyclyl; the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents independently selected from deuterium, halogen and CN;

g is selected from O, S and NR _d ；R _d Selected from H, deuterium, C _1-6 Alkyl, C _1-6 A haloalkyl group;

ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl, benzo 5-6 membered monocyclic heterocyclyl, benzo C _5-9 Cycloalkyl, 5-6 membered monocyclic heteroaryl and 5-9 membered heterocyclyl;

R ₃ selected from H, halogen, deuterium, OH, CN, NO ₂ Methanesulfonyl, ethanesulfonyl, oxo, C _1-6 Alkyl, C ₂ - ₆ Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _1-6 Alkylthio, C _3-12 Cycloalkyl, -C _1-3 alkyl-C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -C _1-3 Alkyl-3-12 membered heterocyclyl, 5-12 membered heteroaryl, -C _1-3 Alkyl-5-12 membered heteroaryl, benzoC _3-6 Monocyclic cycloalkyl, benzo 3-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl, -OR ₃₁ ，-C(O)NR ₃₂ R ₃₃ ，-C(O)R ₃₄ ，-NR ₃₅ C(O)R ₃₆ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _1-6 An alkylthio group, which is a group having a hydroxyl group,C _3-12 cycloalkyl, -C _1-3 alkyl-C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -C _1-3 Alkyl-3-12 membered heterocyclyl, 5-12 membered heteroaryl, -C _1-3 Alkyl-5-12 membered heteroaryl, benzoC _3-6 Monocyclic cycloalkyl, benzo 3-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, CN, -CONH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -CH ₂ -3-12 membered heterocyclyl, optionally C _1-6 Alkyl or C ₁ - ₆ Haloalkyl substituted 5-12 membered heteroaryl, -C (O) -C _1-6 Alkyl, -NH-C _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ 、-NO ₂ Is substituted by a substituent of (2); when a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different;

R ₃₁ selected from H, deuterium, C _1-6 Alkyl, C _1-6 A haloalkyl group;

R ₃₂ and R is ₃₃ Independently selected from H, deuterium, C _1-6 Alkyl, C _3-8 Cycloalkyl, 3-12 membered heterocyclyl; the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents independently selected from deuterium, CN, OH and halogen;

R ₃₄ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl; the alkyl, alkoxy, cycloalkyl and heterocyclic groups are optionally selected from deuterium, CN, OH, halogen and C by one or more groups _1-6 Alkyl, C _1-6 Alkoxy, C _3-8 Cycloalkyl, optionally C _1-6 Alkyl substituted 3-12 membered heterocyclyl, -NH-C _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ Is substituted by a substituent of (2);

R ₃₅ selected from H, deuterium, C _1-6 Alkyl, C _3-8 Cycloalkyl;

R ₃₆ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl; the alkyl, alkoxy, cycloalkyl and heterocyclic groups are optionally selected from deuterium, CN, OH, halogen and C by one or more groups _1-6 Alkyl, C _1-6 Alkoxy, C _3-8 Cycloalkyl, optionally C _1-6 Alkyl substituted 3-12 membered heterocyclyl, -NH-C _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ Is substituted by a substituent of (2);

m is selected from 1,2,3,4 and 5;

unless otherwise indicated, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.

In a preferred embodiment of the invention, X ₁ Is N.

In a preferred embodiment of the invention, X ₁ Is CR (CR) _a Wherein R is _a Is H, deuterium, C _1-3 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted with one or more substituents each independently selected from deuterium, halogen, CN and OH.

In a preferred embodiment of the invention, X ₁ Is CR (CR) _a Wherein R is _a Is H, deuterium, C _1-3 An alkyl group; the alkyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, CN, OH.

In a preferred embodiment of the invention, X ₁ Is CR (CR) _a Wherein R is _a Is H, deuterium, methyl, ethyl, isopropyl.

In a preferred embodiment of the invention, X ₁ Is CR (CR) _a Wherein R is _a H, deuterium, methyl.

In a preferred embodiment of the invention, X ₂ Is N.

In a preferred embodiment of the invention, X ₂ Is CR (CR) _b Wherein R is _b Is H, deuterium, halogen, C _1-3 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-3 An alkoxy group; the alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy are optionally substituted with one or more groups selected from deuterium, halogen, CN, OH and NH ₂ Is substituted by a substituent of (2).

In a preferred embodiment of the invention, X ₂ Is CR (CR) _b Wherein R is _b Is H, deuterium, halogen, C _1-3 Alkyl, C _3-6 Cycloalkyl, C _1-3 An alkoxy group; the alkyl, cycloalkyl and alkoxy are optionally selected from deuterium, halogen, CN, OH and NH by one or more groups ₂ Is substituted by a substituent of (2).

In a preferred embodiment of the invention, X ₂ Selected from CR _b Wherein R is _b Is H, deuterium, F, cl, CF ₃ ，CHF ₂ ，CH ₂ F, methyl, ethyl, cyclopropyl.

In a preferred embodiment of the invention, X ₃ Is N.

In a preferred embodiment of the invention, X ₃ Is CR (CR) _c Wherein R is _c Is H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group.

In a preferred embodiment of the invention, X ₃ Is CR (CR) _c Wherein R is _c Is H, deuterium, methyl, CF ₃ ，CHF ₂ 。

In a preferred embodiment of the invention, X ₃ Is CR (CR) _c Wherein R is _c H.

In a preferred embodiment of the invention, R ₁ Selected from H, deuterium, C _1-3 Alkyl, C _1-3 Haloalkyl, C _3-6 Cycloalkyl groups.

In a preferred embodiment of the invention, R ₁ Selected from H, deuterium, methyl, ethyl, cyclopropyl, CF ₃ ，CHF ₂ ，CH ₂ F。

In a preferred embodiment of the invention, R ₁ Selected from H.

In a preferred embodiment of the invention, R ₂ Selected from phenyl, 5-6 membered monocyclic heteroaryl, benzoC _4-6 Monocyclic cycloalkyl, benzo 5-6 membered monocyclic heterocyclyl; the above groups are each optionally substituted with one OR more groups each independently selected from deuterium, halogen, -CN, -OR ₂₁ 、-NO ₂ 、-NR ₂₂ R ₂₃ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Haloalkyl, C _1-6 Substituted by a substituent of haloalkoxy;

R ₂₁ selected from H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, deuterium, C _1-3 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl; the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents each independently selected from deuterium, halogen and CN.

In a preferred embodiment of the invention, R ₂ Selected from phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, benzo 5-membered monocyclic heterocyclyl, benzo 6-membered monocyclic heterocyclyl; the above groups are each optionally substituted with one OR more groups each independently selected from deuterium, -OR ₂₁ 、-NR ₂₂ R ₂₃ 、C _1-3 Alkyl, C _3-6 Cycloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Haloalkyl, C _1-3 Substituted by a substituent of haloalkoxy;

R ₂₁ selected from H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, deuterium, C _1-3 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the alkyl, cycloalkyl, heterocycloalkyl are optionally substituted with one or more substituents each independently selected from deuterium, F, cl, br, CN.

In a preferred embodiment of the invention, R ₂ Selected from phenyl groupsA 6-membered monocyclic heteroaryl, a benzo 5-membered monocyclic heterocyclyl, a benzo 6-membered monocyclic heterocyclyl; the above groups are optionally selected from deuterium, C, and one or more of them _1-3 Alkyl, -OR ₂₁ 、-NR ₂₂ R ₂₃ Substituted by substituents;

R ₂₁ selected from H, C _1-3 An alkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, C _1-3 Alkyl, C _3-6 Cycloalkyl groups.

In a preferred embodiment of the invention, R ₂ Is selected from the group consisting of phenyl groups,the above groups are optionally selected from deuterium, C, and one or more of them _1-3 Alkyl, -OR ₂₁ 、-NR ₂₂ R ₂₃ Is substituted by a substituent of (2);

R ₂₁ selected from H, C _1-3 An alkyl group;

In a preferred embodiment of the invention, R ₂ Is selected from the group consisting of phenyl groups,the above groups are optionally substituted with one or more groups each independently selected from deuterium, methyl, OH, -OCH ₃ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、Is substituted by a substituent of (2).

In a preferred embodiment of the invention G is NR _d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is _d Is H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group.

In a preferred embodiment of the invention G is NR _d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is _d Is H, deuterium, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl.

In a preferred embodiment of the invention, G is NH.

In a preferred embodiment of the invention, ring a is 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, phenyl, benzo 5-membered monocyclic cycloalkyl, benzo 6-membered monocyclic cycloalkyl, benzo 5-membered monocyclic heterocyclyl, benzo 6-membered monocyclic heterocyclyl, 5-membered monocyclic heteroaryl-5-7-membered spiroheterocyclyl; 5 membered monocyclic heteroaryl and C _5-7 A spirocycloalkyl group.

In a preferred embodiment of the invention, ring A is pyrrolyl, furanyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, phenyl, indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl,

In a preferred embodiment of the invention, ring A is

In a preferred embodiment of the invention, ring A is Is the link between rings a and G.

In a preferred embodiment of the invention, R ₃ Selected from H, halogen, deuterium, OH, CN, NO ₂ Methanesulfonyl, oxo, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -CH ₂ -5-12 membered heteroaryl, 5-6 membered heteroarylMonocyclic heteroaryl radical C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl, -OR ₃₁ ，-C(O)NR ₃₂ R ₃₃ ，-C(O)R ₃₄ ，-NR ₃₅ C(O)R ₃₆ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -CH ₂ -5-12 membered heteroaryl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, -CN, -CONH ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -CH ₂ -3-6 membered heterocyclyl, optionally C _1-6 Alkyl or C _1-6 Haloalkyl substituted 5-6 membered heteroaryl, -C (O) -C _1-3 Alkyl, -NH-C _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ 、-NO ₂ Is substituted by a substituent of (2);

R ₃₁ Selected from H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group;

R ₃₂ and R is ₃₃ Independently selected from H, deuterium, C _1-4 An alkyl group; the alkyl is optionally substituted with one or more substituents each independently selected from deuterium, CN, OH, halogen;

R ₃₄ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-9 Cycloalkyl, 3-9 membered heterocyclyl; said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, -CN, -OH, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl, optionally C _1-3 Alkyl substituted 3-6 membered heterocyclyl, -NH-C _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Is substituted by a substituent of (2);

R ₃₅ selected from H, deuterium, C _1-6 An alkyl group;

R ₃₆ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl; the alkyl, alkoxy and cycloalkyl are optionally selected from deuterium, CN, OH, halogen and C by one or more groups _1-3 The substituent of the alkyl group is substituted.

In a preferred embodiment of the invention, R ₃ Selected from H, halogen, deuterium, OH, CN, methanesulfonyl, oxo, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Hydroxyalkyl group, C _3-6 Monocyclic cycloalkyl, C _5-7 Condensed ring cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-8 membered spirocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, -CH ₂ -5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heteroaryl and C _4-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 4-6 membered monocyclic heterocyclyl, -OR ₃₁ ，-C(O)NR ₃₂ R ₃₃ ，-C(O)R ₃₄ ，-NR ₃₅ C(O)R ₃₆ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Hydroxyalkyl group, C _3-6 Monocyclic cycloalkyl, C _5-7 Condensed ring cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-8 membered spirocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, -CH ₂ -5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heteroaryl and C _4-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 4-6 membered monocyclic heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, -CN, -CONH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-6 Monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl, -CH ₂ -3-6 membered monocyclic heterocyclyl, optionally C _1-3 Alkyl or C _1-3 Haloalkyl-substituted 5-6 membered monocyclic heteroaryl, -C (O) -C _1-3 Alkyl, -NH-C _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Is substituted by a substituent of (2);

R ₃₁ selected from H, deuterium, C _1-3 An alkyl group;

R ₃₄ selected from C _3-6 Monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-8 membered spiro heterocyclyl; the C is _3-6 Monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-8 membered spirocyclic heterocyclyl optionally substituted with one or more groups each independently selected from deuterium, CN, OH, halogen, C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Monocyclic cycloalkyl, optionally C _1-3 Alkyl substituted 3-6 membered monocyclic heterocyclyl, -NH-C _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Is substituted by a substituent of (2);

R ₃₅ selected from H, deuterium, C _1-3 An alkyl group;

R ₃₆ selected from H, deuterium, C _1-3 Alkyl, C _1-3 An alkoxy group; the alkyl and alkoxy are optionally substituted by one or more substituents each independently selected from deuterium, CN, OH, and halogen.

In a preferred embodiment of the invention, R ₃ Selected from H, F, cl, oxo, methyl, methylsulfonyl, -OCH ₃ ，-CH ₂ OH， When a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different.

In a preferred embodiment of the invention, m is 1,2 and 3.

The invention also provides a compound shown in the following formula (II), wherein the stereoisomer, tautomer or mixture thereof and pharmaceutically acceptable salt of the compound are shown in the specification:

wherein each substituent is defined as the compound of formula (I).

The invention also provides a compound shown in the following formula (III), wherein the stereoisomer, tautomer or mixture thereof, and pharmaceutically acceptable salt of the compound are shown in the specification:

Wherein Y is ₁ And Y ₂ Independently selected from CH or N; the other substituents are defined as in the compounds of formula (I);

in a preferred embodiment of the invention, Y ₁ Is N, Y ₂ CH;

in a preferred embodiment of the invention, Y ₁ Is CH, Y ₂ Is N;

in a preferred embodiment of the invention, Y ₁ And Y ₂ Are CH.

In a preferred embodiment of the invention, R ₃ Selected from H, F, cl, oxo, methyl, methylsulfonyl, -OCH ₃ ，-CH ₂ OH，

When a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different.

The invention also provides a compound shown in the following formula (IV), wherein the stereoisomer, tautomer or mixture thereof and pharmaceutically acceptable salt of the compound are shown in the specification:

wherein W is ₁ And W is ₂ Independently selected from the group consisting of N,represents a single bond or a double bond; the other substituents are defined as in the compounds of formula (I).

In a preferred embodiment of the invention, R ₃ Selected from H, F, cl, methyl, methanesulfonyl, -OCH ₃ ，-CH ₂ OH， When a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different.

The invention also provides a compound represented by the following formula (v-a), a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt thereof:

Wherein each substituent is defined as the compound of formula (IV).

The invention also provides a compound represented by the following formula (v-b), wherein the stereoisomer, tautomer or mixture thereof, pharmaceutically acceptable salt of the compound:

wherein each substituent is defined as the compound of formula (IV).

The compound of the invention, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of the compound are selected from the group consisting of:

/>

the invention also provides a method for preparing the compound shown in the formula (I), a stereoisomer, a tautomer or a mixture of the stereoisomer and the tautomer and pharmaceutically acceptable salt of the compound. The preparation method comprises the following steps:

obtaining an intermediate (B) through Suzuki coupling reaction of the (A) and the (B); and (B) andthe compound shown in the formula I is obtained through Buchwald-Hartwig coupling reaction, wherein LG ^a Is a leaving group, preferably Cl, br, I or OTf, more preferably I; m is a borate or a boric acid group. />

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

The invention also provides a pharmaceutical composition which comprises the compound shown in the invention, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts and pharmaceutically acceptable auxiliary materials.

The invention also provides a compound shown in the invention, a stereoisomer, a tautomer or a mixture of the stereoisomers and the tautomers and pharmaceutically acceptable salts of the compound, and application of the stereoisomer and the tautomer or the mixture of the stereoisomers and the pharmaceutically acceptable salts of the compound in preparation of medicines for treating or preventing diseases mediated by LRRK2 kinase.

The invention also aims at providing the application of the compound shown in the invention, the stereoisomer, the tautomer or the mixture thereof and the pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing the degenerative diseases of the nervous system.

The invention also provides the application of the compound shown in the invention, the stereoisomer, the tautomer or the mixture thereof and the pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing Parkinson's Disease (PD).

Definition of the definition

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 carbonsAn atom, preferably containing 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 of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.Polycyclic cycloalkyl includes spiro cycloalkyl, fused ring cycloalkyl, and bridged ring cycloalkyl.

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 above definition by-S-unless otherwise specified.

The term "halogen" or "halo" refers to F, cl, br, I 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 hydrocarbon substituent that is not aromatic in structure, but also includes a portion of the rings in the polycyclic ring being aromatic in structure. Comprising 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S and the remaining ring atoms are C. Preferably 3 to 12 ring atoms, more preferably 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.

Unless otherwise specified, the terms "spirocycloalkyl" and "spirocycloalkyl" refer to saturated ring systems of a specified number of carbon atoms formed by sharing only one ring carbon atom consisting of carbon atoms and hydrogen atoms. 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.

The terms "heterospirocyclic group", "spiroheterocyclic group" and "spiroheterocyclic group" refer to a cyclic structure having a specific number of carbon atoms and hetero atoms, formed by two or more rings sharing one ring carbon atom, unless otherwise specified. 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. PreferablyFrom 6 to 14, more preferably from 7 to 10. 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 heteroatoms in the bridged heterocyclic group are one or more, preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3), and the heteroatoms are independently selected from N, O or S (O) m (where m is an integer from 0 to 2 and the remaining ring atoms are carbon.

Etc.

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" 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 the compounds of formula I to formula II, 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. In particular deuterium ³ H and carbon ¹³ C, because they are easily labeled and conveniently detected, the application is wider. 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 formula I that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but once inside the cell is beneficial, it is then metabolically hydrolyzed to the carboxylic acid, the active entity. 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" means, unless otherwise specified, that the hydrogen of the substitutable site of the group 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 or 5-10 membered heteroaryl ring group, wherein the 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 may optionally be selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl or C _1-6 Alkoxy is substituted by one or more of the substituents, which means that two H's in the same substitution position are replaced by the same O to form a double bond.

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 inhibitor-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

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present 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 measurements were performed using either Bruker 400MHz or/and Varian 400MHz; the LC-MS uses an instrument of Agilent,1260 Infinicity II-6120/6125MSD; the instrument used for HPLC is Waters Acquity UPLC _2 or/and Shimadzu LC2030 or/and Agilent,1260 Infinicity II.

Preparation of HPLC Condition one (ammonia as additive) instrumentation: waters; a pump 2545; detector 2489; wavelength 214nm &254nm; column model Welch ximate C18,21.2 x 250mm,10um; mobile phase A is 0.1% ammonia water and B is acetonitrile; the running time is 15min; the flow rate was 25ml/min.

Preparation of HPLC condition II (formic acid as additive) instrumentation of Waters; a pump 2545; detector 2489; wavelength 214nm &254nm; column model Welch Ultimate AQ-C18,21.2 x 250mm,10um; mobile phase A is 0.1% formic acid, B is acetonitrile; the running time is 15min; the flow rate was 25ml/min.

Preparation of HPLC conditions tris (trifluoroacetic acid) as additive: instrumentation: waters; a pump 2545; detector 2489; wavelength 214nm &254nm; column model Welch Ultimate AQ-C18,21.2 x 250mm,10um; mobile phase A is 0.1% trifluoroacetic acid, B is acetonitrile; the running time is 15min; the flow rate was 25ml/min.

The starting materials in the examples of the present invention are known and 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: methanesulfonyl group

DMF: n, N-dimethylformamide

DCM: dichloromethane (dichloromethane)

THF: tetrahydrofuran (THF)

DMSO: dimethyl sulfoxide

EDTA: ethylenediamine tetraacetic acid

NCS: 1-chloropyrrolidine-2, 5-dione

SEMCl: [2- (chloromethoxy) ethyl ] trimethylsilane

TFA: trifluoroacetic acid

PD ₂ (DBA) ₃ : tris (dibenzylideneacetone) dipalladium

Xphos: dicyclohexyl [2',4',6 '-tris (propan-2-yl) - [1,1' -biphenyl ] -2-yl ] phosphine

Xanphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene

Example 1

(4- ((5-chloro-4- (3- (methylamino) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

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

To DMF (200 mL) was added 2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (18.7 g,100mmol,1.0 eq) and N-chlorosuccinimide (26.6 g,200mmol,2 eq) and reacted at 20℃for 16 hours. LCMS monitored completion of the reaction. Water (100 mL) was added to the reaction mixture, the resulting mixture was extracted with methylene chloride (200 mL), the organic phases were combined, and the resultant was separated and purified by column chromatography to give the objective 2,4, 5-trichloro-7H-pyrrolo [2,3-d ] pyrimidine (13.9 g, yield 62.90%).

LCMS(ESI)[M+H] ⁺ ＝224.0； ¹ H NMR(400MHz，DMSO-d ₆ )δ13.11(s，1H)，7.94

(d，J＝13.2Hz，1H).

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

To DMF (200 mL) of 2,4, 5-trichloro-7H-pyrrolo [2,3-d ] pyrimidine (13.9 g,62.9mmol,1.0 eq) was added sodium hydride (1.8 g,75.5mmol,1.2 eq) in portions under ice-water bath and stirred for 1H, at which temperature 2- (trimethylsilyl) ethoxymethyl chloride (20.88 g,125.8mmol,2.0 eq) was added, slowly warmed to room temperature and stirred for 4H at 25 ℃. LCMS monitored completion of the reaction. To the reaction solution was added water (100 mL), extracted with ethyl acetate (2X 100 mL), the organic phases were combined, washed with saturated brine (2X 100 mL), dried over anhydrous sodium sulfate, filtered, the solvent was removed by spin-drying the filtrate, and the target product 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (14.5 g, yield 65.9%) was isolated and purified by column chromatography.

LCMS(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) -N-methylaniline

To a solvent of dioxane and water (20 mL, 1:1) was added 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (2 g,5.7mmol,1.0 eq) and N-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (1.3 g,5.7mmol,1.0 eq), tetrakis triphenylphosphine palladium (0.65 g,0.57mmol,0.11 eq), cesium carbonate (3.7 g,11.4mmol,2.0 eq) and microwaved at 90℃for 1 hour under nitrogen. LCMS monitored completion of the reaction, water (100 mL) was added, extraction with ethyl acetate (20 mL), and the organic phases combined, column chromatography separation and purification afforded the target product 3- (2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -N-methylaniline (0.8 g, 33.3% yield).

LCMS(ESI)[M+H] ⁺ ＝423.1。

Fourth step: preparation of (4- ((5-chloro-4- (3- (methylamino) phenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl)) amino) -3-methoxyphenyl) (morpholino) methanone

3- (2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -N-methylaniline (0.8 g,1.89mmol,1.0 eq), (4-amino-3-methoxyphenyl) (morpholinyl) methanone (0.45 g,1.89mmol,1.0 eq) was added cesium carbonate (1.23 g,3.79mmol,2.0 eq), tris (dibenzylideneacetone) dipalladium (180 mg,0.2mmol,0.1 eq), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (94 mg,0.2mmol,0.1 eq) dissolved in DMF (20 mL) and reacted under a microwave at 120℃for 2 hours under nitrogen protection. LCMS monitored completion of the reaction and column chromatography separation and purification afforded the target product (4- ((5-chloro-4- (3- (methylamino) phenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl)) amino) -3-methoxyphenyl) (morpholino) methanone (400 mg, 34.2% yield).

LCMS(ESI)[M+H] ⁺ ＝623.2.

Fifth step: preparation of (4- ((5-chloro-4- (3- (methylamino) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

(4- ((5-chloro-4- (3- (methylamino) phenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl)) amino) -3-methoxyphenyl) (morpholino) methanone (400 mg,0.64mmol,1.0 eq) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added and stirred at 90℃for 3 hours. The reaction mixture was dried under reduced pressure, and then ammonia methanol solution (10 mL) was added thereto, followed by stirring at room temperature for 1 hour. LCMS monitored completion of the reaction and column chromatography gave the desired product (80 mg, 25.3% yield).

¹ H NMR(400MHz,DMSO-d ₆ )δ12.06(d,J＝2.5Hz,1H),8.59(d,J＝8.2Hz,1H),7.96(s,1H),7.44(d,J＝2.5Hz,1H),7.25–7.18(m,1H),7.09(d,J＝1.8Hz,1H),7.04(dd,J＝8.3,1.8Hz,1H),6.95–6.88(m,2H),6.73–6.65(m,1H),5.82(s,1H),3.93(s,3H),3.68–3.47(m,8H),2.74(d,J＝3.2Hz,3H).

Examples 2 to 15

Reference to the procedure for the preparation of example 1, the compounds of examples 2-15 were prepared

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Example 16

(4- ((5-chloro-4- (1, 2,3, 4-tetrahydroquinolin-7-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

The first step: preparation of 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydroquinoline

To a dioxane (20 mL) solvent was added 7-bromo-1, 2,3, 4-tetrahydroquinoline (1.0 g,4.7mmol,1.0 eq), pinacol biborate (1.8 g,7.1mmol,1.5 eq), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (0.3 g,0.47mmol,0.1 eq), potassium acetate (0.92 g,9.4mmol,2 eq) and the mixture was reacted by microwave at 90℃for 2 hours under nitrogen. LCMS monitored completion of the reaction, water (100 mL) was added, extracted with ethyl acetate (20 mL), the organic phases combined and purified by column chromatography to give the desired product 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydroquinoline (0.8 g, 65.5% yield).

LCMS(ESI)[M+H] ⁺ ＝260.2。

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

To a solvent of dioxane and water (30 mL, 1:1) under nitrogen was added 7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,2,3, 4-tetrahydroquinoline (0.8 g,3.1mmol,1.0 eq) and 2,4, 5-trichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (1.1 g,3.1mmol,1.0 eq) (synthesis method same as example 1), tetrakis triphenylphosphine palladium (0.35 g,0.31mmol,0.1 eq), cesium carbonate (2.1 g,6.2mmol,2.0 eq) and microwaves were reacted at 90℃for 1 hour. LCMS monitored completion of the reaction, water (100 mL) was added, extraction with ethyl acetate (20 mL), and the organic phases combined, and column chromatography separation and purification afforded the desired product 7- (2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1,2,3, 4-tetrahydroquinoline (0.6 g, 43.4% yield).

LCMS(ESI)[M+H] ⁺ ＝449.1。

And a third step of: preparation of (4- ((5-chloro-4- (1, 2,3, 4-tetrahydroquinolin-7-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)) ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

7- (2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1,2,3, 4-tetrahydroquinoline (0.6 g,1.33mmol,1.0 eq), (4-amino-3-methoxyphenyl) (morpholinyl) methanone (0.31 g,1.33mmol,1.0 eq) was added to cesium carbonate (0.86 g,2.66mmol,2.0 eq), tris (dibenzylideneacetone) dipalladium (90 mg,0.1mmol,0.1 eq), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (47 mg,0.1mmol,0.1 eq) in DMF (20 mL) and reacted under nitrogen at 120℃for 2 hours under microwave. LCMS monitored completion of the reaction and column chromatography separation and purification gave the target product (4- ((5-chloro-4- (1, 2,3, 4-tetrahydroquinolin-7-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)) ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone (0.5 g, 58.1% yield).

LCMS(ESI)[M+H] ⁺ ＝649.3。

Fourth step: preparation of (4- ((5-chloro-4- (1, 2,3, 4-tetrahydroquinolin-7-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone

(4- ((5-chloro-4- (1, 2,3, 4-tetrahydroquinolin-7-yl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)) ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone (500 mg,0.77mmol,1.0 eq) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added and stirred at 90℃for 3 hours. The reaction mixture was dried under reduced pressure, and then ammonia methanol solution (10 mL) was added thereto, followed by stirring at room temperature for 1 hour. LCMS monitored reaction was complete. The target product (4- ((5-chloro-4- (1, 2,3, 4-tetrahydroquinolin-7-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone (100 mg, 25.1% yield) was obtained by column chromatography separation and purification.

LCMS(ESI)[M+H] ⁺ ＝519.2。

Examples 17 to 20

Reference to the preparation of examples 1 and 16 gave the compounds of examples 17-20

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Example 21

(4- ((5-chloro-4-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholinyl) methanone

The first step: preparation of 3-methoxy-4-nitrobenzoyl chloride

3-methoxy-4-nitrobenzoic acid (CAS: 5081-36-7) (1.5 g,7.61mmol,1.0 eq) was dissolved in thionyl chloride (CAS: 7719-09-7) (1.81 g,15.22mmol,1.0 eq) and reacted at 85℃for 6 hours. After completion of the reaction by TLC and LC-MS detection, the reaction solution was directly concentrated to give a crude product of the objective compound (1.5 g, yield 91%).

LC-MS(ESI)[M-4+H] ⁺ ＝212.1.

And a second step of: preparation of (3-methoxy-4-nitrophenyl) (morpholinyl) methanone

Crude 3-methoxy-4-nitrobenzoyl chloride (1.5 g,6.11mmol,1.0 eq) was dissolved in dry tetrahydrofuran (100 mL), N-diisopropylethylamine (1.8 mL,9.78mmol,1.6 eq) and morpholine (CAS: 110-91-8) (2.58 mL,30.55mmol,5 eq) were added sequentially to the solution under nitrogen at 0deg.C, and the mixture was stirred at 0deg.C for 1 hour. After completion of the LC-MS reaction, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 ml×3), washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, purification by flash chromatography (silica gel, PE: ea=1:1) afforded the title compound (1.5 g, yield 81%).

LCMS(ESI)[M+H] ⁺ ＝267.1.

And a third step of: preparation of 4-amino-3-methoxyphenyl (morpholino) methanone

3-methoxy-4-nitrophenyl (morpholino) methanone (1.5 g,5.63mmol,1.0 eq) was dissolved in methanol (200 mL), palladium on carbon (CAS: 7440-05-3) (59.6 mg,0.56mmol,0.1 eq) was added and reacted at room temperature under hydrogen atmosphere for 2 hours. After completion of the LC-MS detection reaction, the reaction mixture was filtered, and the filtrate was concentrated to give a crude product of the objective compound (1.5 g, yield 87%).

LCMS(ESI)[M+H] ⁺ ＝237.1.

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

2, 4-dichloro-7H-pyrrolo [2,3-d ] pyrimidine (CAS: 90213-66-4) (2 g,10.64mmol,1.0 eq) was dissolved in DMF (50 mL), N-chlorosuccinimide (CAS: 128-09-6) (1.7 g,12.77mmol,1.2 eq) was added and reacted at 50℃for 2 hours under nitrogen. After completion of the LC-MS detection reaction, the reaction solution was poured into water (500 mL), extracted with ethyl acetate (200 ml×5), washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate, purification by flash chromatography (silica gel, PE: ea=20:1) afforded the title compound (1.6 g, yield 68%).

LCMS(ESI)[M+H] ⁺ ＝223.0.

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 (1 g,4.5mmol,1.0 eq) and triethylamine (CAS: 121-44-8) (1.3 g,13.5mmol,3.0 eq) were added to tetrahydrofuran (20 mL), and 2- (trimethylsilyl) ethoxymethyl chloride (754 mg,9.0mmol,1.0 eq) was added dropwise and reacted at room temperature for 1 hour. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated and purified by flash chromatography (silica gel, PE: ea=20:1) to give the objective compound (1 g, yield 63%).

LCMS(ESI)[M+H] ⁺ ＝352.0.

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

2,4, 5-trichloro-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (240 mg,0.68mmol,1.0 eq), phenylboronic acid (CAS: 98-80-6) (124 mg,1.02mol,1.5 eq), palladium acetate (CAS: 3375-31-3) (31 mg,0.14mol,0.2 eq) and sodium carbonate (CAS: 497-19-8) (222 mg,2.04mmol,3.0 eq), triphenylphosphine-3, 3',3 "-trisulphonate trisodium salt (CAS: 63995-70-0) (40 mg,0.07mmol,0.1 eq) were dissolved in acetonitrile (20 mL) and water (2 mL). The reaction was carried out at 100℃for 4 hours under nitrogen protection. After completion of the LC-MS detection reaction, the reaction mixture was directly concentrated and purified by flash chromatography (silica gel, PE: ea=10:3) to give the objective compound (170 mg, yield 63%).

LCMS(ESI)[M+H] ⁺ ＝394.1.

Seventh step: preparation of (4- ((5-chloro-4-phenyl-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholinyl) methanone

2, 5-dichloro-4-phenyl-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine (150 mg,0.38mmol,1.0 eq), 4-amino-3-methoxyphenyl (morpholino) methanone (98.9 mg,0.42mmol,1.1 eq), pd ₂ (dba) ₃ (CAS: 51364-51-3) (34.8 mg,0.04mmol,0.1 eq), X-Phos (CAS: 564483-18-7) (18.1 mg,0.04mmol,0.1 eq) and K ₂ CO ₃ (CAS: 584-08-7) (105 mg,0.76mmol,2.0 eq) was dissolved in sec-butanol (10 mL). Under the protection of nitrogen, the reaction is carried out for 2 hours at 90 ℃. After completion of the LC-MS detection reaction, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 ml×3), washed with saturated brine solution, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and purification by flash chromatography (silica gel, PE: ea=10:3) gave the title compound (204 mg, yield 90%).

LCMS(ESI)[M+H] ⁺ ＝594.3.

Eighth step: preparation of (4- ((5-chloro-4-phenyl-7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholinyl) methanone

(4- ((5-chloro-4-phenyl-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholinyl) methanone (204 mg,0.34mmol,1.0 eq) was dissolved in hydrochloric acid (10 mL, 7N) and refluxed for 1 hour. After removing hydrochloric acid by rotary evaporation, the crude product was dissolved in methanol (5 mL), ammonia water (5 mL) was added to the system pH >8, and the reaction was stirred for 0.5 hour. 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 (46 mg, yield 29%).

LCMS(ESI)[M+H] ⁺ ＝464.1.

¹ H NMR(400MHz,DMSO)δ12.15(s,1H),8.56(d,J＝8.2Hz,1H),8.03(s,1H),7.78–7.75(m,2H),7.58–7.51(m,3H),7.49(s,1H),7.09(d,J＝1.6Hz,1H),7.05(dd,J＝8.2,1.6Hz,1H),3.93(s,3H),3.58–3.44(m,8H).

Examples 22 to 43

Reference to the preparation of examples 1, 16 and 21 gave the compounds of examples 22-43

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Example 44

2- (4- ((5-chloro-4- (3- (methylamino) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile

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

To a solution of 3- (2, 5-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -N-methylaniline (800 mg,1.89mmol,1.0 eq) (synthesis as in example 1) in 1, 4-dioxane (3 mL) was added 2- (4-amino-3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (310 mg,1.89mmol,1.0 eq), tris (dibenzylideneacetone) dipalladium (16 mg,0.02mmol,0.1 eq), dicyclohexyl [2',4',6 '-tris (propan-2-yl) - [1,1' -biphenyl ] -2-yl ] phosphine (16.6 mg,0.04mmol,0.2 eq), cesium carbonate (1.84 g,5.67mmol,3.0 eq) and stirred under nitrogen for 3 hours at 90 ℃. LCMS monitored completion of the reaction and column chromatography separation and purification afforded the target product 2- (4- ((5-chloro-4- (3- (methylamino) phenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (400 mg, yield 38.50%).

LCMS(ESI)[M+H] ⁺ ＝551.2。

And a second step of: preparation of 2- (4- ((5-chloro-4- (3- (methylamino) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile

To a solution of 2- (4- ((5-chloro-4- (3- (methylamino) phenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (400 mg,0.72mmol,1.0 eq) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL), followed by stirring at 25 ℃ for 1 hour. TLC detection was complete, and the reaction mixture was concentrated to give a crude product, which was dissolved in methanol (10 mL) with ammonia and stirred at 25℃for 1 hour. LCMS detected completion of the reaction, the reaction was concentrated, and 3mL of methanol was added to the concentrated solution to afford the desired product, 2- (4- ((5-chloro-4- (3- (methylamino) phenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methyl-1H-pyrazol-1-yl) -2-methylpropanenitrile (100 mg, yield 32.79%) by preparative high-performance liquid phase separation purification.

LCMS(ESI)[M+H] ⁺ ＝421.2。

Examples 45 to 125

Referring to the procedure for the preparation of example 44, the compounds of examples 45-124 were prepared; reference to the procedure for the preparation of example 1, the compound of example 125 was prepared

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Example 126

(4- ((5-chloro-4- (3-methoxyphenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxybenzene) (morpholinyl) methanone

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The first step: preparation of 2, 5-dichloro-4- (3-methoxyphenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine

2,4, 5-trichloro-7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (400 mg,1.13mmol,1.0 eq) was dissolved in acetonitrile (20 mL) and water (4 mL), and (3-methoxyphenyl) boric acid (207 mg,1.36mmol,1.2 eq) (CAS: 10365-98-7), palladium acetate (51 mg,0.23mmol,0.2 eq) (CAS: 3375-31-3), sodium carbonate (240 mg,2.26mmol,2.0 eq) (CAS: 497-19-8) and triphenylphosphine-3, 3' -trisulfonic acid trisodium salt (129 mg,0.23mmol,0.2 eq) (CAS: 63995-70-0) were added. The reaction was carried out at 90℃under nitrogen for 4 hours. LCMS detected completion of the reaction, directly concentrated the reaction, and purified by flash chromatography (silica gel, DCM: meoh=20:1) to give the title compound (320 mg, 66% yield) as a pale yellow solid. LCMS (ESI) [ m+h ] +=424.1, tr=1.55 min.

And a second step of: preparation of (4- ((5-chloro-4- (3-methoxyphenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxybenzene) (morpholinyl) methanone

2, 5-dichloro-4- (3-methoxyphenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ]Pyrimidine (300 mg,0.71mmol,1.0 eq) was dissolved in 2-butanol (10 mL) and 2-methoxy-4 was added- (morpholine-4-carbonyl) aniline (184 mg,0.78mmol,1.1 eq), tris (dibenzylideneacetone) dipalladium (129 mg,0.14mmol,0.2 eq) (CAS: 51364-51-3), dicyclohexyl [2',4',6 '-tris (propan-2-yl) - [1,1' -biphenyl)]-2-yl]Phosphine (67 mg,0.14mmol,0.2 eq) (CAS: 564483-18-7) and cesium carbonate (463mg, 1.41mmol,2.0 eq) (CAS: 534-17-8). The reaction was carried out at 100℃under nitrogen for 6 hours. LCMS detected completion of the reaction, directly concentrated the reaction, and purified by flash chromatography (silica gel, PE: ea=5:1) to give the title compound (180 mg, 41% yield). LCMS (ESI) [ M+H ]] ⁺ ＝624.3.

And a third step of: preparation of (4- ((5-chloro-4- (3-methoxyphenyl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-methoxybenzene) (morpholinyl) methanone

(4- ((5-chloro-4- (3-methoxyphenyl) -7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-2-yl) amino) -3-methoxybenzene) (morpholinyl) methanone (160 mg,0.26mmol,1.0 eq) was dissolved in hydrochloric acid (10 mL, 7N) and reacted at 50℃for 1 hour. After removing hydrochloric acid by rotary evaporation, the crude product is dissolved in methanol (5 mL), and ammonia water (5 mL) is added to the pH of the system>8, stirring and reacting for 0.5 hour. After completion of the LC-MS detection reaction, the reaction was directly concentrated, purified with Prep plate (MeOH: dcm=1:20), and then isolated and purified using Prep-HPLC to give the title compound (20 mg, 16%). LCMS (ESI) [ M+H ] ] ⁺ ＝494.2； ¹ H NMR (400 mhz, dmso) δ12.14 (s, 1H), 8.55 (d, j=8.2 hz, 1H), 8.04 (s, 1H), 7.49 (s, 1H), 7.45 (t, j=7.8 hz, 1H), 7.34-7.32 (m, 1H), 7.31-7.27 (m, 1H), 7.12-7.09 (m, 2H), 7.04 (dd, j=8.2, 1.6hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.57-3.50 (m, 8H)

Experiment 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；2mMDTT.

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: 0.4uM Fluorescein-ERM (LRRKtide) peptide;38uM 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) The enzyme and polypeptide mixture was prepared with freshly prepared reaction solution (2 nM enzyme+0.4 uM Fluorescein-ERM

(LRRKtide) peptides), 5uL to 384 microwell plates of the existing compounds were added and centrifuged at 1000rpm/min for 1min. Incubating for 15min at room temperature;

3) Adding 5uL 38uM ATP,1000rpm/min, and centrifuging for 1min. Reacting for 120min at room temperature;

4) Adding a detection reagent: 0.25nMTb-pERM (pLRRKtide) anti-body and 10mM EDTA,1000rpm/min for 1min. Reacting 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 the compounds was calculated by signal ratio (520 nm/485 nm) and IC50 values were calculated using software XLfit5 fitted curve.

Experimental results:

TABLE 1LRRK2 kinase inhibition Activity test results

Example Compounds	LRRK2 kinase Activity IC ₅₀ (nM)
		1	A
16	B
		44	A

Wherein A is IC ₅₀ Less than 5nM; b is IC ₅₀ Greater than 5nM and less than 10nM

Experiment 2 in vitro evaluation of LRRK2 cell (pS 935) inhibitory Activity

1. Cell resuscitation

HEK293T cells were removed from the liquid nitrogen and placed in a 37℃water bath, after ice was thawed, the cells were 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 in 37℃and 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, the mixture was 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 at 37℃with 5% CO ₂ Culturing in incubator, and observing cells in timeGrowth state.

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 5x 10 with cell cryopreservation ⁶ Per mL, then transferred to a cell cryopreservation tube, per tube l mL cell suspension. The frozen tube with the cells is placed in a frozen box and transferred to liquid nitrogen for preservation after being frozen at-80 ℃ for overnight.

4. The experimental steps are as follows:

1) HEK293T cell transfection (first day)

The preparation method comprises the steps of preparing 30ml of cell suspension (30 x 10 ⁶ Individual cells) were inoculated in 150mm dishes.

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

Thirdly, uniformly dripping the prepared transfection reagent into a 150mm culture dish inoculated with cells, slightly shaking and uniformly mixing, and then putting into 37 ℃ and 5% CO ₂ The incubator cultures for 24 hours.

2) (the next day) seed plates

Transfected cells were collected and cell density was adjusted to 0.2X106/mL. The cell suspension was added to 384 microwell plates (10000 cells per well) at 50ul per well and centrifuged at 1000rpm/min for 1min. 384 microwells were incubated overnight at 37℃in a 5% CO2 incubator.

3) (third day) Compound treatment and HTRF detection

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.

The compound is added into 384 micro-pore plates by using TECAN, and the final concentration of DMSO is adjusted to 0.2%.

After centrifugation at 1000rpm/min for 1min, the mixture was placed in a 5% CO2 incubator at 37℃for 2h.

Preparing HTRF cell lysate: 4mL Lysis buffer+12mL H2O+160 mu L Blocking buffer.

After 2h, adding 16 mu L of cell lysate into each hole, and centrifuging at 1000rpm/min for 1min. The plate was shaken for 30min at room temperature at 800 rpm/min.

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

After 30min, centrifugation is carried out at 1000rpm/min for 2min.

Add 4. Mu.L of antibody mixture solution per well and centrifuge at 1000rpm/min for 1min. Incubating for 4-48h at room temperature.

Read the board on Envision.

Test results:

TABLE 2 results of pS935 cell inhibitory Activity test

Wherein A is IC ₅₀ Less than 10nM; b is IC ₅₀ Greater than 10nM and less than 20nM

Experiment 3 evaluation of the pharmacokinetics of the Compounds

1. Purpose of test

Study of the pharmacokinetics of Compounds in C57BL/6 mice- -brain tissue and plasma drug concentration ratio

2. Experimental materials:

CD-1 mice (Male, 8 weeks old, weight 25g-30 g)

3. Experimental operation:

the rodent drug substitution profile of the compounds after oral administration was tested in a standard protocol, in which the candidate compounds were formulated as a 1mg/mL suspension and administered to mice in a single oral administration. The oral vehicle was 5% dmso/40% peg400/55% aqueous solution. The project uses male CD-1 mice, and the administration dosage is 2mg/kg and the oral administration is 10mg/kg. The whole brain will be collected 0.25 and 1 hour after administration of the intravenous set.

Tissue samples were buffered with 15mM fetal bovine serum [ fetal bovine serum (ph=7.4): methanol (volume ratio, 2:1)]Homogenates were homogenized at 1:5 (w: v) and split into 2 aliquots, one for analysis and the other for backup. In addition, the intravenous group collected plasma for 0.083,0.25,0.5,1,2,4,8, 24 hours after administration, the oral group collected plasma for 0.25,0.5,1,2,4 after administration, 8,24h plasma, plasma samples the supernatant was separated by centrifugation at about 4 degrees celsius, 3000g,15 minutes within half an hour of collection. Plasma samples were stored in polypropylene tubes, flash frozen on dry ice and kept at-80 degrees celsius until LC/MS analysis. Adding acetonitrile solution containing internal standard to precipitate protein, mixing, centrifuging to obtain supernatant, introducing sample, quantitatively analyzing blood concentration by LC-MS/MS analysis method, and calculating drug substitution parameters such as peak concentration (C) _max ) Half-life (T) _1/2 ) Peak time (T) _max ) Drug concentration (AUC) of different tissues _o-last ) Brain tissue and plasma drug concentration ratio (B/P), etc. Experimental results show that the compound has good in vivo pharmacokinetics and has a potential of patent medicine.

Claims

1. A compound of formula (I) as follows, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of said compound:

X ₁ selected from CR _a And N;

X ₂ selected from CR _b And N;

X ₃ selected from CR _c And N;

R _c selected from the group consisting of H, deuterium,C _1-6 alkyl, C _1-6 A haloalkyl group;

R ₂ selected from phenyl, naphthyl, 5-7 membered monocyclic heteroaryl, benzoC _4-8 Monocyclic cycloalkyl, benzo 4-8 membered monocyclic heterocyclyl, benzo 5-7 membered monocyclic heteroaryl, 5-7 membered monocyclic heteroaryl and 4-8 membered monocyclic heterocyclyl; the above groups are each optionally substituted with one OR more groups each independently selected from deuterium, halogen, CN, -OR ₂₁ 、NO ₂ 、-NR ₂₂ R ₂₃ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Haloalkyl, C _1-6 Substituted by a substituent of haloalkoxy;

R ₂₁ selected from H, deuterium, C _1-6 Alkyl, C _1-6 A haloalkyl group;

R ₃ selected from H, halogen, deuterium, OH, CN, NO ₂ Methanesulfonyl, ethanesulfonyl, oxo, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _1-6 Alkylthio, C _3-12 Cycloalkyl, -C _1-3 alkyl-C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -C _1-3 Alkyl-3-12 membered heterocyclyl, 5-12 membered heteroaryl, -C _1-3 Alkyl-5-12 membered heteroarylRadical, benzo C _3-6 Monocyclic cycloalkyl, benzo 3-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl, -OR ₃₁ ，-C(O)NR ₃₂ R ₃₃ ，-C(O)R ₃₄ ，-NR ₃₅ C(O)R ₃₆ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _1-6 Alkylthio, C _3-12 Cycloalkyl, -C _1-3 alkyl-C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -C _1-3 Alkyl-3-12 membered heterocyclyl, 5-12 membered heteroaryl, -C _1-3 Alkyl-5-12 membered heteroaryl, benzoC _3-6 Monocyclic cycloalkyl, benzo 3-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, CN, -CONH ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -CH ₂ -3-12 membered heterocyclyl, optionally C _1-6 Alkyl or C _1-6 Haloalkyl substituted 5-12 membered heteroaryl, -C (O) -C _1-6 Alkyl, -NH-C _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ 、-NO ₂ Is substituted by a substituent of (2); when a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different;

R ₃₁ selected from H, deuterium, C _1-6 Alkyl, C _1-6 A haloalkyl group;

R ₃₄ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl;the alkyl, alkoxy, cycloalkyl and heterocyclic groups are optionally selected from deuterium, CN, OH, halogen and C by one or more groups _1-6 Alkyl, C _1-6 Alkoxy, C _3-8 Cycloalkyl, optionally C _1-6 Alkyl substituted 3-12 membered heterocyclyl, -NH-C _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ Is substituted by a substituent of (2);

R ₃₅ selected from H, deuterium, C _1-6 Alkyl, C _3-8 Cycloalkyl;

m is selected from 1,2,3,4 and 5;

2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt thereof, wherein X ₁ Is N;

preferably, X ₁ Is CR (CR) _a Wherein R is _a Is H, deuterium, C _1-3 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted by one or more substituents each independently selected from deuterium, halogen, CN and OH;

preferably, X ₁ Is CR (CR) _a Wherein R is _a Is H, deuterium, C _1-3 An alkyl group; the alkyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, CN, OH;

preferably, X ₁ Is CR (CR) _a Wherein R is _a H, deuterium, methyl, ethyl, isopropyl;

preferably, X ₁ Is CR (CR) _a Wherein R is _a H, deuterium, methyl.

3. The compound of claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt thereof, wherein X ₂ Is N;

preferably, X ₂ Is CR (CR) _b Wherein R is _b Is H, deuterium, halogen, C _1-3 Alkyl, C _3-6 Cycloalkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-3 An alkoxy group; the alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy are optionally substituted with one or more groups selected from deuterium, halogen, CN, OH and NH ₂ Is substituted by a substituent of (2);

preferably, X ₂ Is CR (CR) _b Wherein R is _b Is H, deuterium, halogen, C _1-3 Alkyl, C _3-6 Cycloalkyl, C _1-3 An alkoxy group; the alkyl, cycloalkyl and alkoxy are optionally selected from deuterium, halogen, CN, OH and NH by one or more groups ₂ Is substituted by a substituent of (2);

preferably, X ₂ Selected from CR _b Wherein R is _b Is H, deuterium, F, cl, CF ₃ ，CHF ₂ ，CH ₂ F, methyl, ethyl, cyclopropyl.

4. A compound according to any one of claims 1 to 3, which is a stereoisomer, tautomer, or mixture thereof, pharmaceutically acceptable salt, wherein X ₃ Is N;

preferably, X ₃ Is CR (CR) _c Wherein R is _c Is H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group;

preferably, X ₃ Is CR (CR) _c Wherein R is _c Is H, deuterium, methyl, CF ₃ ，CHF ₂ ；

Preferably, X ₃ Is CR (CR) _c Wherein R is _c H.

5. The compound of any one of claims 1-4, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt thereof, wherein R ₁ Selected from H, deuterium, C _1-3 Alkyl, C _1-3 Haloalkyl, C _3-6 Cycloalkyl;

preferably, R ₁ Selected from H, deuterium, methyl, ethyl, cyclopropyl, CF ₃ ，CHF ₂ ，CH ₂ F；

Preferably, R ₁ Selected from H.

6. The compound of any one of claims 1-5, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt thereof, wherein R ₂ Selected from phenyl, 5-6 membered monocyclic heteroaryl, benzoC _4-6 Monocyclic cycloalkyl, benzo 5-6 membered monocyclic heterocyclyl; the above groups are each optionally substituted with one OR more groups each independently selected from deuterium, halogen, -CN, -OR ₂₁ 、-NO ₂ 、-NR ₂₂ R ₂₃ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, C _1-6 Alkoxy, C _1-6 Alkylthio, C _1-6 Haloalkyl, C _1-6 Substituted by a substituent of haloalkoxy;

R ₂₁ selected from H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, deuterium, C _1-3 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl; the alkyl, cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents independently selected from deuterium, halogen and CN;

preferably, R ₂ Selected from phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, benzo 5-membered monocyclic heterocyclyl, benzo 6-membered monocyclic heterocyclyl; the above groups are each optionally substituted with one OR more groups each independently selected from deuterium, -OR ₂₁ 、-NR ₂₂ R ₂₃ 、C _1-3 Alkyl, C _3-6 Cycloalkyl, C _1-3 Alkoxy, C _1-3 Alkylthio, C _1-3 Haloalkyl, C _1-3 Substituted by a substituent of haloalkoxy;

R ₂₁ selected from H, deuterium, C _1-3 Alkyl, C _1-3 A haloalkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, deuterium, C _1-3 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents each independently selected from deuterium and F, cl, br, CN;

preferably, R ₂ Selected from phenyl, 6 membered monocyclic heteroaryl, benzo 5 membered monocyclic heterocyclyl, benzo 6 membered monocyclic heterocyclyl; the above groups are optionally selected from deuterium, C, and one or more of them _1-3 Alkyl, -OR ₂₁ 、-NR ₂₂ R ₂₃ Substituted by substituents;

R ₂₁ selected from H, C _1-3 An alkyl group;

R ₂₂ and R is ₂₃ Independently selected from H, C _1-3 Alkyl, C _3-6 Cycloalkyl;

preferably, R ₂ Is selected from the group consisting of phenyl groups,the above groups are optionally selected from deuterium, C, and one or more of them _1-3 Alkyl, -OR ₂₁ 、-NR ₂₂ R ₂₃ Is substituted by a substituent of (2);

R ₂₁ selected from H, C _1-3 An alkyl group;

preferably, R ₂ Is selected from the group consisting of phenyl groups,the above groups are optionally substituted with one or more groups each independently selected from deuterium, methyl, OH, -OCH ₃ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、/>Is substituted by a substituent of (2).

7. The compound of any one of claims 1-6, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt thereof, wherein G is NR _d The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is _d H, deuterium, methyl, ethyl, trifluoromethyl, difluoromethyl, monofluoromethyl;

preferably, G is NH.

8. The compound of any one of claims 1-7, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt thereof, wherein ring a is 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, phenyl, benzo 5-membered monocyclic cycloalkyl, benzo 6-membered monocyclic cycloalkyl, benzo 5-membered monocyclic heterocyclyl, benzo 6-membered monocyclic heterocyclyl, 5-membered monocyclic heteroaryl-5-membered spiroheterocyclyl; 5 membered monocyclic heteroaryl and C _5-7 A spirocycloalkyl group;

preferably, ring A is pyrrolyl, furanyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, phenyl, indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl,

preferably, ring A is

Preferably, ring A is Is the link between rings a and G.

9. The compound of any one of claims 1-8, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt thereof, wherein R ₃ Selected from H, halogen, deuterium, OH, CN, NO ₂ Methanesulfonyl, oxo, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -CH ₂ -5-12 membered heteroaryl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl, -OR ₃₁ ，-C(O)NR ₃₂ R ₃₃ ，-C(O)R ₃₄ ，-NR ₃₅ C(O)R ₃₆ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Hydroxyalkyl group, C _3-12 Cycloalkyl, -CH ₂ -C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -CH ₂ -5-12 membered heteroaryl, 5-6 membered monocyclic heteroaryl and C _3-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 3-6 membered monocyclic heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, -CN, -CONH ₂ 、C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, -CH ₂ -3-6 membered heterocyclyl, optionally C _1-6 Alkyl or C _1-6 Haloalkyl substituted 5-6 membered heteroaryl, -C (O) -C _1-3 Alkyl, -NH-C _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ 、-NO ₂ Is substituted by a substituent of (2);

R ₃₁ selected from H, deuterium, C _1-3 Alkyl, C _1-3 HaloalkanesA base;

R ₃₅ selected from H, deuterium, C _1-6 An alkyl group;

R ₃₆ selected from H, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl; the alkyl, alkoxy and cycloalkyl are optionally selected from deuterium, CN, OH, halogen and C by one or more groups _1-3 Substituted by alkyl;

preferably, R ₃ Selected from H, halogen, deuterium, OH, CN, methanesulfonyl, oxo, C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Hydroxyalkyl group, C _3-6 Monocyclic cycloalkyl, C _5-7 Condensed ring cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-8 membered spirocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, -CH ₂ -5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heteroaryl and C _4-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 4-6 membered monocyclic heterocyclyl, -OR ₃₁ ，-C(O)NR ₃₂ R ₃₃ ，-C(O)R ₃₄ ，-NR ₃₅ C(O)R ₃₆ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Hydroxyalkyl group, C _3-6 Monocyclic cycloalkyl, C _5-7 Condensed ring cycloalkyl, -CH ₂ -C _3-6 Cycloalkyl, 3-6 membered monocyclic heterocyclyl, 5-8 membered spirocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, -CH ₂ -5-6 membered singleCycloheteroaryl, 5-6 membered monocyclic heteroaryl and C _4-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl and 4-6 membered monocyclic heterocyclyl are optionally substituted with one or more groups each independently selected from deuterium, halogen, oxo, -CN, -CONH ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-6 Monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl, -CH ₂ -3-6 membered monocyclic heterocyclyl, optionally C _1-3 Alkyl or C _1-3 Haloalkyl-substituted 5-6 membered monocyclic heteroaryl, -C (O) -C _1-3 Alkyl, -NH-C _1-3 Alkyl, -N (C) _1-3 Alkyl group ₂ Is substituted by a substituent of (2);

R ₃₁ selected from H, deuterium, C _1-3 An alkyl group;

R ₃₅ selected from H, deuterium, C _1-3 An alkyl group;

R ₃₆ selected from H, deuterium, C _1-3 Alkyl, C _1-3 An alkoxy group; the alkyl and alkoxy are optionally substituted by one or more substituents independently selected from deuterium, CN, OH and halogen;

preferably, R ₃ Selected from H, F, cl, oxo, methyl, methylsulfonyl, -OCH ₃ ，-CH ₂ OH， When a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different.

10. A compound according to any one of claims 1 to 9, which is a stereoisomer, tautomer or mixture thereof, pharmaceutically acceptable salt thereof, wherein m is 1,2 and 3.

11. A compound of formula (ii) as follows, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of said compound:

wherein each substituent is defined as the compound of formula (I).

12. A compound of formula (iii) as follows, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of said compound:

preferably, Y ₁ Is N, Y ₂ CH;

preferably, Y ₁ Is CH, Y ₂ Is N;

preferably, Y ₁ And Y ₂ Are CH;

preferably, R ₃ Selected from H, F, cl, oxo, methyl, methylsulfonyl, -OCH ₃ ，-CH ₂ OH，

13. A compound of formula (iv) as follows, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of said compound:

wherein W is ₁ And W is ₂ Independently selected from the group consisting of N,represents a single bond or a double bond; the definition of other substituents is as described in the compound of formula (I);

preferably, R ₃ Selected from H, F, cl, methyl, methanesulfonyl, -OCH ₃ ，-CH ₂ OH， When a plurality of R ₃ When simultaneously occurring, each R ₃ May be the same or different.

14. A compound of formula (v-a) as follows, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts of said compound:

wherein each substituent is defined as the compound of formula (IV).

15. A compound of formula (v-b) as shown below, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of the compound:

wherein each substituent is defined as the compound of formula (IV).

16. A compound, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt thereof, selected from the group consisting of:

/>

17. a pharmaceutical composition comprising a compound according to any one of claims 1-16, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of the compound.

18. Use of a compound according to any one of claims 1-16, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt of a compound, or a composition of claim 17, in the manufacture of a medicament for use in treating a disease mediated by LRRK2 kinase.

19. Use of a compound according to any one of claims 1 to 16, a stereoisomer, a tautomer, or a mixture thereof, a pharmaceutically acceptable salt, or a composition according to claim 17, for the manufacture of a medicament for the treatment or prophylaxis of a neurodegenerative disease of the nervous system.

20. Use of a compound according to any one of claims 1 to 16, a stereoisomer, a tautomer of a compound or a mixture of same, a pharmaceutically acceptable salt or a composition of claim 17, for the manufacture of a medicament for the treatment or prophylaxis of parkinson's disease.