WO2025051214A1 - Aromatic heterocyclic compound and preparation method therefor - Google Patents

Abstract

Provided are a compound having a new structure and serving as an LRRK2 inhibitor, and a stereoisomer, optical isomer, and pharmaceutically acceptable salt thereof. A new direction is provided for the development of LRRK2 inhibitor drugs. In vitro enzyme and cell activity inhibition studies show that these compounds all have a strong inhibitory effect, and can be used as promising compounds for treating and/or preventing LRRK2-mediated diseases (such as neurodegenerative diseases, especially Parkinson's disease).

Description

Aromatic heterocyclic compound and preparation method thereof

Citation of Related Applications

The present invention claims priority to the invention patent application entitled “A kind of aromatic heterocyclic compound and its preparation method” and application number 202311150286.7 filed in China on September 7, 2023 and the invention patent application entitled “A kind of aromatic heterocyclic compound and its preparation method” and application number 202410721017.X filed in China on June 5, 2024, and the entire contents of the above patent applications are incorporated herein by reference.

Technical Field

The present invention relates to the field of medical technology, and in particular to a class of aromatic heterocyclic compounds and a preparation method and use of the compounds.

Background Art

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease after Alzheimer’s disease, affecting approximately 2% of the population over 60 years old. The etiology of Parkinson’s disease is very complex, and the typical manifestation is the reduction of dopaminergic neurons in the substantia nigra of the brain, which leads to clinical manifestations of bradykinesia, resting tremor, muscle rigidity and postural gait disorders. Currently available treatments for Parkinson’s disease are only symptomatic treatments, such as dopamine replacement therapy, which can relieve symptoms, and there is still a lack of cure to stop the progression of the disease or reverse the disease. The need for new treatment strategies for Parkinson’s disease is obvious. In addition, this need is obviously growing due to the continuous aging of the world’s population.

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

LRRK2 is a large protein containing 2527 amino acids and belongs to the ROCO protein kinase family. Compared with other members of the ROCO family, LRRK2 contains diverse structural domains. Its main functional domains are: 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) from N-terminus to C-terminus. LRRK2 is widely expressed in the brain, heart, kidney, lung, liver and some immune cells and central nervous system. LRRK2 in neurons is distributed in the cytoplasm and exists in various membrane structures such as mitochondria, Golgi bodies, and lysosomes. It plays an important role in synaptic transmission, vesicle transport, mitochondrial function, regulation of autophagy, regulation of microtubule stability, and inflammatory response by mediating phosphorylation of downstream proteins. LRRK2 has both GTPase and kinase activities, and there is a mechanism of mutual regulation between the two. The kinase activity of LRRK2 depends on the formation of LRRK2 dimers, and GTPase is essential for the formation of dimers; conversely, after kinase activation, it regulates the GTPase activity of LRRK2 by autophosphorylating the ROC domain.

At present, the latest progress in the development of LRRK2 inhibitors is in the clinical development stage. In terms of small molecule drugs, Denali Therapeutics' DNL151 and DNL201 have completed Phase I clinical trials. Many pharmaceutical companies have applied for patents on LRRK2 inhibitors. The main structural types of compounds include pyrrolopyrimidine/pyridine series (WO2015113451, WO2016130920, WO2017106771, WO2018155916, WO2015092592), aminopyrimidine series (WO2017087905, WO2017156493, WO2017106771, WO2018155916, WO2015092592), 17218843, WO2018217946), pyrimidinyl/pyridinyl-indazole series (WO2014137719, WO2014137723, WO2014134774, WO2014137728) and macrocyclic series (WO2013046029, WO2014140235, WO2016042089, WO2019012093), etc.

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

Summary of the invention

The object of the present invention is to provide a compound with a novel structure as an LRRK2 inhibitor, a preparation method thereof and use thereof in preventing and/or treating diseases mediated by LRRK2.

The first aspect of the present invention provides a compound represented by the following formula (I), a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof:

in,

X ₁ , X ₂ and X ₃ are each independently CR _X or N;

If present, each _RX is independently H, deuterium, halogen, ^{-NRX1RX2 or -OR13} ; wherein,

If present, each of ^RX1 and ^RX2 is independently H, deuterium, _C1-6 alkyl, C1-6 oxaalkyl, _C1-6 thiaalkyl, _C2-6 alkenyl, _C3-6 cycloalkyl or 4-6 membered heterocyclyl; said _C1-6 alkyl, _C1-6 oxaalkyl, _C1-6 thiaalkyl, _C2-6 alkenyl, _C3-6 cycloalkyl or _4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, _-NO2 , _-NH2 and _C1-3 alkyl;

Alternatively, each pair of ^RX1 and ^RX2 together with the N atom to which they are commonly attached independently form a 4-8 membered heterocyclic group; the 4-8 membered heterocyclic group is optionally substituted by one or more substituents independently selected from deuterium, _halogen , -CN, -OH, -NO2, _-NH2 , _C1-3 alkyl and _C1-3 oxaalkyl;

If present, each R ¹³ is independently H, deuterium, C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; said C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

R ₁ is deuterium, halogen, C _1-4 alkyl, C _2-6 alkenyl or C _3-6 cycloalkyl; the C _1-4 alkyl, C _2-6 alkenyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ;

R ₂ is deuterium, halogen, -NR ²¹ R ²² , C _1-4 alkyl, C _1-4 oxaalkyl or C _1-4 thiaalkyl; the C _1-4 alkyl, C _1-4 oxaalkyl or C _1-4 thiaalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; wherein,

If present, R ²¹ and R ²² are each independently H, deuterium, C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, phenyl or 5-6 membered heteroaryl; said C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, phenyl or 5-6 membered heteroaryl being optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , dimethylphosphoryl, phosphate, formamido, acetamido, methanesulfonamido, ethanesulfonamido, methanesulfonyl, ethanesulfonyl and C _1-3 alkyl;

Alternatively, _R1 and _R2 together form a ring Q optionally substituted by one or more _RQ , wherein the ring Q is phenyl or pyrrolyl;

If present, each R _Q is independently deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 oxaalkyl, C _3-10 cycloalkyl or 4-10 membered heterocyclyl; said C _1-3 alkyl, C _1-3 oxaalkyl, C _3-10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 oxaalkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; wherein said substituents are C _1-3 alkyl, C _1-3 oxaalkyl, C 1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl. _3-6 -membered cycloalkyl or 4-6-membered heterocyclyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl;

R ₃ is deuterium, halogen, -CN, -OH, -NH ₂ , C _3-10 cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclyl; the C _3-10 cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl;

If present, each R _W is independently deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl or C _3-6 cycloalkyl; said C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl;

m is 0, 1, 2 or 3;

L does not exist or is in,

R ₄ and R ₅ are each independently H, deuterium, halogen, -CN, -OH, -SH, -NH ₂ , C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ;

Alternatively, R ₄ and R ₅ together with the C atom to which they are commonly attached form a C _3-6 cycloalkyl group; the C _3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

when for When R _W is not an optionally substituted C _3-6 cycloalkyl group or a C _1-3 alkyl group optionally substituted by a halogen group, and R ₄ and R ₅ are not H or an optionally substituted C _1-3 alkyl group;

When L does not exist, for When R _W is an optionally substituted C _3-6 cycloalkyl group, R ₃ is not a heterocyclic group having an oxo group;

When L does not exist, for When R ₃ is not halogen, -CN or C _3-6 Cycloalkyl;

The heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from S, O and N.

The present invention also provides a compound represented by the following formula (A1) or (A2), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

_RX is H ^, deuterium, ^-NRX1RX2 or ^-OR13 ; wherein,

If present, ^RX1 and ^RX2 are each independently H, deuterium, C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; said C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

Alternatively, ^RX1 and ^RX2 together with the N atom to which they are commonly attached form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, _-NO2 , _-NH2 and _C1-3 alkyl;

If present, R ¹³ is C _1-3 alkyl or C _3-6 cycloalkyl; said C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

If present, each R _Q is independently deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; said C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl;

R ₃ is deuterium, halogen, -CN, -OH, -NH ₂ , C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; the C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl;

Each R _W is independently deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

_R4 and _R5 are each independently H, deuterium, _C1-3 alkyl or _C3-6 cycloalkyl; the _C1-3 alkyl or _C3-6 cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, _-OH , -NO2 and _-NH2 ;

Alternatively, R ₄ and R ₅ together with the C atom to which they are commonly attached form a C _3-6 cycloalkyl group; the C _3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

m is 1 or 2;

n is 0, 1 or 2.

In a preferred embodiment of the present invention, _RX is H or deuterium.

In a preferred embodiment of the present invention, _RX is ^-NRX1RX2 ; ^{wherein RX1} and ^RX2 are each independently H, Deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

Alternatively, ^RX1 and ^RX2 together with the N atom to which they are commonly attached form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, _-NO2 , _-NH2 and _C1-3 alkyl.

In a preferred embodiment of the present invention, ^RX1 and ^RX2 are each independently H, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl;

Alternatively, ^RX1 and ^RX2 together with the N atom to which they are commonly attached form

In a preferred embodiment of the present invention, R _X is -OR ¹³ ; wherein R ¹³ is methyl.

In a preferred embodiment of the present invention, _RX is H, _-NHCH3 , or -OCH ₃ .

In a preferred embodiment of the present invention, each R _Q is independently deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl.

In a preferred embodiment of the present invention, each R _Q is independently deuterium, -F, -Cl, -Br, -CN, -OH, -NO ₂ , -NH ₂ , methyl, ethyl, cyclopropyl or cyclobutyl; the methyl, ethyl, cyclopropyl or cyclobutyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ and -NH ₂ .

In a preferred embodiment of the present invention, each R _Q is independently -F, -Cl, -CN, methyl, trifluoromethyl or cyclopropyl.

In a preferred embodiment of the present invention, R ₃ is deuterium, halogen, -CN, -OH, -NH ₂ , C _3-8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; the C _3-8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl.

In a preferred embodiment of the present invention, R ₃ is -CN, C _4-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; the C _4-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from oxo, C _1-3 alkyl, C _1-3 alkoxy and 4-6 membered heterocyclyl.

In a preferred embodiment of the present invention, _R3 is -CN, a 5-membered heteroaryl, a 6-membered heteroaryl, a 9-membered fused ring heteroaryl, a 10-membered fused ring heteroaryl, a 4-membered monoheterocyclic radical, a 5-membered monoheterocyclic radical, a 6-membered monoheterocyclic radical, a 7-membered bridged heterocyclic radical, an 8-membered bridged heterocyclic radical, a 7-membered spiro heterocyclic radical, an 8-membered spiro heterocyclic radical or a 9-membered spiro heterocyclic radical; the 5-membered heteroaryl, 6-membered heteroaryl, 9-membered fused ring heteroaryl, a 10-membered fused ring heteroaryl, a 4-membered monoheterocyclic radical, a 5-membered monoheterocyclic radical, a 6-membered monoheterocyclic radical, a 7-membered bridged heterocyclic radical, an 8-membered bridged heterocyclic radical, a 7-membered spiro heterocyclic radical, an 8-membered spiro heterocyclic radical or a 9-membered spiro heterocyclic radical are optionally substituted by one or more substituents each independently selected from oxo, methyl, ethyl, methoxy, a 4-membered monoheterocyclic radical, a 5-membered monoheterocyclic radical and a 6-membered monoheterocyclic radical.

In a preferred embodiment of the present invention, in the formula (A1), R ₃ is -CN,

In a preferred embodiment of the present invention, in the formula (A1), R ₃ is -CN, Best

In a preferred embodiment of the present invention, in the formula (A1), R ₃ is

In a preferred embodiment of the present invention, in the formula (A2), R ₃ is

In a preferred embodiment of the present invention, in the general formula (A2), R ₃ is

In a preferred embodiment of the present invention, in the general formula (A2), R ₃ is

In a preferred embodiment of the present invention, each R _W is independently deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ .

In a preferred embodiment of the present invention, each R _W is independently deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

In a preferred embodiment of the present invention, each R _W is independently methyl, isopropyl or cyclopropyl.

In a preferred embodiment of the present invention, R ₄ and R ₅ are each independently H, deuterium or C _1-3 alkyl; the C _1-3 alkyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ;

Alternatively, R ₄ and R ₅ together with the C atom to which they are attached form a C _3-4 cycloalkyl group; the C _3-4 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl.

In a preferred embodiment of the present invention, _R4 and _R5 are each independently H, deuterium or methyl; the methyl group is optionally substituted by one or more substituents each independently selected from deuterium, halogen and _-NH2 ;

Alternatively, R ₄ and R ₅ together with the C atom to which they are commonly attached form a cyclopropyl or cyclobutyl group; the cyclopropyl or cyclobutyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen and C _1-3 alkyl.

In a preferred embodiment of the present invention, _R4 and _R5 are methyl; or, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl group.

In a preferred embodiment of the present invention, m is 1.

In a preferred embodiment of the present invention, n is 1 or 2.

In a preferred embodiment of the present invention, n is 1.

The present invention also provides a compound represented by the following formula (A3), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

_RX is H, deuterium or ^-NRX1RX2 ; ^wherein ,

R ^X1 and R ^X2 are each independently H, deuterium, C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; the C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

If present, each R _Q is independently deuterium, halogen, -CN, C _1-3 alkyl, C _1-3 alkoxy, C _3-10 cycloalkyl or 4-10 membered heterocyclyl; said C _1-3 alkyl, C _1-3 alkoxy, C _3-10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; wherein said 4-6 membered heterocyclyl is optionally substituted with one or more of methyl, hydroxyl and cyano;

R _W is deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

n is 0, 1 or 2.

In a preferred embodiment of the present invention, _Rx is H.

In a preferred embodiment of the present invention, R _x is -NR ^{X1 RX2} ; wherein ^RX1 and ^RX2 are each independently H, deuterium or C _1-3 alkyl; the C _1-3 alkyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl.

In a preferred embodiment of the present invention, ^RX1 and ^RX2 are each independently H, methyl, ethyl or isopropyl.

In a preferred embodiment of the present invention, _RX is H or _-NHCH3 .

In a preferred embodiment of the present invention, each R _Q is independently deuterium, halogen, -CN, C _1-3 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl; the C _1-3 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more The alkylene group is substituted with substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 oxaalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclic group; wherein the 4-6 membered heterocyclic group is optionally substituted with one or more of methyl, hydroxyl and cyano.

In a preferred embodiment of the present invention, each R _Q is independently -F, -Cl, cyclopropyl,

In a preferred embodiment of the present invention, R _W is deuterium, C _1-3 alkyl or C _3-6 cycloalkyl.

In a preferred embodiment of the invention, R _W is deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

In a preferred embodiment of the invention, R _W is cyclopropyl.

In a preferred embodiment of the present invention, n is 2.

In a preferred embodiment of the present invention, n is 1.

In a preferred embodiment of the present invention, n is zero.

The present invention also provides a compound represented by the following formula (A4), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

in,

X ₁ , X ₂ and X ₃ are each independently CR _X or N;

If present, each _RX is independently H, deuterium, halogen, ^{-NRX1RX2 or -OR13} ; wherein,

If present, each of ^RX1 and ^RX2 is independently H, deuterium or C _1-3 alkyl; said C _1-3 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl;

If present, each R ¹³ is independently C _1-3 alkyl; said C _1-3 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ and -NH ₂ ;

R ₁ is deuterium, halogen or C _1-4 alkyl; the C _1-4 alkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ;

R ²² is C _1-4 alkyl or phenyl; the C _1-4 alkyl or phenyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethanesulfonamide, methanesulfonyl, ethanesulfonyl and C _1-3 alkyl;

Each R _W is independently deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl;

_R4 and _R5 are each independently H, deuterium, halogen, -CN, _C1-3 alkyl or _C3-6 cycloalkyl; the _C1-3 alkyl or _C3-6 cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, -OH, _-NO2 and _-NH2 ;

Alternatively, _R4 and _R5 together with the C atom to which they are commonly attached form a _C3-6 cycloalkyl group; the _C3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN and _C1-3 alkyl;

m is 1 or 2.

In a preferred embodiment of the present invention, _X1 is _CRx , and _X2 and _X3 are both N.

In a preferred embodiment of the present invention, _X1 and _X2 are both _CRx , and _X3 is N.

In a preferred embodiment of the present invention, _X2 is _CRx , and _X1 and _X3 are both N.

In a preferred embodiment of the present invention, _X3 is _CRx , and _X1 and _X2 are both N.

In a preferred embodiment of the present invention, _X1 and _X3 are both _CRx , and _X2 is N.

In a preferred embodiment of the present invention, each R _x is independently H, deuterium, F, Cl or Br.

In a preferred embodiment of the present invention, R _x is -NR ^{X1 RX2} ; wherein each of ^RX1 and ^RX2 is independently H, deuterium, methyl or ethyl.

In a preferred embodiment of the present invention, each of ^RX1 and ^RX2 is independently H or ethyl.

In a preferred embodiment of the present invention, R _x is -OR ¹³ ; wherein each R ¹³ is independently C _1-3 alkyl; said C _1-3 alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -OH and -NH ₂ .

In a preferred embodiment of the present invention, R ¹³ is methyl.

In a preferred embodiment of the present invention, R ₁ is deuterium, halogen, methyl or ethyl; the methyl or ethyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ .

In a preferred embodiment of the present invention, R ₁ is -F, -Cl, -CH ₃ , -CD ₃ or -CF ₃ .

In a preferred embodiment of the present invention, R ₁ is -Cl, -CD ₃ or -CF ₃ .

In a preferred embodiment of the present invention, R ₁ is -Cl.

In a preferred embodiment of the present invention, R ²² is methyl, ethyl or phenyl; the methyl, ethyl or phenyl is optionally substituted by one or more substituents independently selected from deuterium, -CN, -OH, -NO ₂ , -NH ₂ , dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethanesulfonamide, methanesulfonyl, ethanesulfonyl and C _1-3 alkyl.

In a preferred embodiment of the present invention, R ²² is ethyl, which is optionally substituted with one or more substituents each independently selected from deuterium, methyl, ethyl, F, Cl, Br, -CN, -OH, -NO ₂ and -NH ₂ .

In a preferred embodiment of the present invention, R ²² is phenyl, which is optionally substituted with one or more substituents each independently selected from methyl, ethyl, F, Cl, Br, -CN, dimethylphosphinoyl, methylsulfonyl and ethylsulfonyl.

In a preferred embodiment of the present invention, R ²² is -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, -CD ₂ CD ₃ ,

In a preferred embodiment of the present invention, R ²² is -CH ₂ CH ₃ , -CD ₂ CD ₃ ,

In a preferred embodiment of the present invention, R _W is deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN and C _1-3 alkyl.

In a preferred embodiment of the present invention, R _W is deuterium, -CD ₃ , cyclopropyl,

In a preferred embodiment of the present invention, R _W is deuterium, cyclopropyl,

In a preferred embodiment of the present invention, R ₄ and R ₅ are each independently H, deuterium, -F, -Cl, -Br, -CN or C _1-3 alkyl;

Alternatively, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl, cyclobutyl or cyclopentyl group, wherein the cyclopropyl, cyclobutyl or cyclopentyl group is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN and _C1-3 alkyl.

In a preferred embodiment of the present invention, R ₄ and R ₅ are each independently -F or methyl;

Alternatively, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more substituents independently selected from deuterium, -F and methyl.

In a preferred embodiment of the present invention, R ₄ and R ₅ are each independently -F, -CD ₃ or methyl;

Alternatively, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more substituents independently selected from -F and methyl.

In a preferred embodiment of the present invention, for Best

In a preferred embodiment of the present invention, m is 1.

The present invention further provides a compound represented by the following formula (A5), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R _X , R _W , R ₁ , R ₂₂ , R ₄ , R ₅ and m are as described in formula (A4).

In a preferred embodiment of the present invention, each R _x is independently H or deuterium.

In a preferred embodiment of the present invention, R ₁ is -Cl or -CF ₃ .

In a preferred embodiment of the present invention, R ²² is -CH ₂ CH ₃ , -CD ₂ CD ₃ or

In a preferred embodiment of the invention, R _W is cyclopropyl.

In a preferred embodiment of the present invention, R ₄ and R ₅ are each independently -CD ₃ or methyl; or, R ₄ and R ₅ together with the C atom to which they are commonly attached form a cyclopropyl group.

In a preferred embodiment of the present invention, for

In a preferred embodiment of the present invention, m is 1.

The present invention also provides a compound, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

The second aspect of the present invention provides a method for preparing the compounds represented by formula (I), formula (A1) and formula (A4), stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof.

The present invention also provides a compound as shown in the general formula, a method for preparing a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt of the compound, the preparation method including but not limited to the following method:

Preparation method of compound of general formula (I):

The compound of formula (a) and the compound of formula (b) are reacted (for example, a substitution reaction or a Buchwald-Hartwig coupling reaction) to obtain a compound of formula (I); wherein X ₄ is a halogen, preferably Cl or Br; and the definitions of other groups are as described above;

Preparation method of compound of general formula (A1):

The compound of formula (a1) is reacted (e.g., a substitution reaction) to obtain an intermediate compound of formula (b1), and the compound of formula (b1) and the compound of formula (c1) are reacted (e.g., a substitution reaction or a Buchwald-Hartwig coupling reaction) to obtain a compound of formula (A1); wherein X is a halogen, preferably Cl or Br; the definitions of other groups are as described above; and,

Preparation method of compound of general formula (A4):

The compound of formula (a1) is reacted (for example, a substitution reaction) to obtain an intermediate compound of formula (a2), the compound of formula (b1) is reacted (for example, a photocatalytic coupling reaction) to obtain an intermediate compound of formula (b2), and the compound of formula (a2) and the compound of formula (b2) are reacted (for example, a substitution reaction or a Buchwald-Hartwig coupling reaction) to obtain a compound of formula (A4); wherein _X4 is a halogen, preferably Cl or Br; and the definitions of other groups are as described above.

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

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

In a fourth aspect, the present invention provides a compound of the present invention, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.

The present invention also provides the compound of the present invention, the stereoisomer, tautomer or mixture thereof or pharmaceutically acceptable salt thereof, for use in treating and/or preventing diseases mediated by LRRK2 kinase.

The present invention also provides the compound of the present invention, the stereoisomer, tautomer or mixture thereof or pharmaceutically acceptable salt of the compound, for use in treating and/or preventing neurodegenerative diseases.

The present invention also provides the compound of the present invention, the stereoisomer, tautomer or mixture thereof or pharmaceutically acceptable salt of the compound, for use in treating and/or preventing Parkinson's disease.

The fifth aspect of the present invention provides the compound of the present invention, and use of the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts of the compound in the preparation of drugs for treating and/or preventing diseases mediated by LRRK2 kinase.

The present invention also provides the compound of the present invention, and use of the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts of the compound in the preparation of drugs for treating and/or preventing neurodegenerative diseases.

The present invention also provides the compound of the present invention, and use of the stereoisomer, tautomer or mixture thereof or pharmaceutically acceptable salt of the compound in preparing a drug for treating and/or preventing Parkinson's disease.

The sixth aspect of the present invention provides a method for treating and/or preventing diseases mediated by LRRK2 kinase, comprising: administering the compound of the present invention, the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof to an individual in need thereof.

The present invention also provides a method for treating and/or preventing neurodegenerative diseases, comprising: administering the compound of the present invention, the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof to an individual in need thereof.

The present invention also provides a method for treating and/or preventing Parkinson's disease, comprising: administering the compound of the present invention, the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof to an individual in need thereof.

Definition of terms

The terms "optional", "optionally", "optionally" or "arbitrarily" 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.

Unless otherwise specified, the term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond, which can be represented by =0.

Unless otherwise specified, the term "alkyl" refers to a straight or branched, saturated aliphatic hydrocarbon group. The alkyl group may contain 1-20 carbon atoms (i.e., C _1-20 alkyl), preferably 1-10 carbon atoms (i.e., C _1-10 alkyl), more preferably 1-8 carbon atoms (i.e., C _1-8 alkyl), and further preferably 1-6 carbon atoms (i.e., C _1-6 alkyl). For example, "C _1-6 alkyl" means that the group is an alkyl group, and the number of carbon atoms in the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5 or 6). Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

Unless otherwise specified, the term "alkenyl" refers to a straight or branched, unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond. The alkenyl group may contain 2-20 carbon atoms (i.e., _C2-20 alkenyl), preferably 2-10 carbon atoms (i.e., _C2-10 alkenyl), more preferably 2-8 carbon atoms (i.e., _C2-8 alkenyl), further preferably 2-6 carbon atoms (i.e., _C2-6 alkenyl), 2-5 carbon atoms (i.e., _C2-5 alkenyl), 2-4 carbon atoms (i.e., _C2-4 alkenyl), 2-3 carbon atoms (i.e., _C2-3 alkenyl) or 2 carbon atoms (i.e., C2 _alkenyl or vinyl). For example, " _C2-6 alkenyl" means that the group is an alkenyl group, and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic or polycyclic, saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C _3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (i.e., C _3-10 cycloalkyl), further preferably 3-6 carbon atoms (i.e., C _3-6 cycloalkyl), 4-6 carbon atoms (i.e., C _4-6 cycloalkyl) or 5-6 carbon atoms (i.e., C _5-6 cycloalkyl). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, and dimethylcyclobutyl.

Unless otherwise specified, the term "heteroalkyl" refers to a group formed by replacing a non-terminal carbon atom (e.g., a secondary, tertiary or quaternary carbon atom) in an alkyl group with a heteroatom (e.g., a tetravalent Si atom) or a heteroatom group (e.g., a trivalent N atom, a P atom; a divalent NH fragment, a PH fragment, an O atom or a S atom). The heteroalkyl group may contain 1-20 carbon atoms (i.e., C _1-20 heteroalkyl), preferably 1-10 carbon atoms (i.e., C _1-10 heteroalkyl), more preferably 1-8 carbon atoms (C _1-8 heteroalkyl), and further preferably 1-6 carbon atoms (i.e., C _1-6 heteroalkyl). For example, "C _1-6 heteroalkyl" means that the group is a heteroalkyl group, and the number of carbon atoms in the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5 or 6). When the heteroatom in the heteroalkyl group is an oxygen atom, the heteroalkyl group is an oxoalkyl group; for example, non-limiting examples of C _1-6 oxoalkyl groups include, but are not limited to, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and ethoxyethyl, etc. Correspondingly, when the heteroatom in the heteroalkyl group is a sulfur atom, the heteroalkyl group is a thioalkyl group; for example, non-limiting examples of C _1-6 thioalkyl groups include, but are not limited to, methylthio, ethylthio, methylthiomethyl, ethylthiomethyl, and ethylthioethyl, etc. When the only heteroatom or heteroatom group in the heteroalkyl group is the site of attachment to the parent nucleus, the heteroalkyl group may also be referred to as an "alkoxy" group (e.g., alkylamino, alkoxy, alkylthio, etc.).

Unless otherwise specified, the term "alkoxy" refers to an "-O-alkyl" group, wherein the alkyl group is as defined above, i.e., may contain 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and further preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy and 1-ethylpropoxy, etc.

Unless otherwise specified, the term "alkylthio" means that -O- in the above definition of "alkoxy" is replaced by -S-.

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

Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated, monocyclic, bicyclic or polycyclic cyclic hydrocarbon group. The heterocyclyl group may be a non-aromatic structure, and may also include the case where some of the rings in the polycyclic ring are aromatic structures. The heterocyclyl group may contain 3-20 ring atoms (i.e., a 3-20-membered heterocyclyl group), wherein 1, 2, 3 or more ring atoms are each independently selected from N, O and S, and the remaining ring atoms are C. The heterocyclyl group preferably contains 3-12 ring atoms (i.e., a 3-12-membered heterocyclyl group), and more preferably contains 3-10 ring atoms (i.e., a 3-10-membered heterocyclyl group), 3-8 ring atoms (i.e., a 3-8-membered heterocyclyl group), 3-6 ring atoms (i.e., a 3-6-membered heterocyclyl group), 4-6 ring atoms (i.e., a 4-6-membered heterocyclyl group) or 5-6 ring atoms (i.e., a 5-6-membered heterocyclyl group). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Representative examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, tetrahydropyranyl, morpholinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged ring heterocyclic groups.

Unless otherwise specified, the term "fused ring" refers to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic system formed by two or more ring structures sharing two adjacent atoms, including fused carbocyclic groups and fused heterocyclic groups, wherein the "fused heterocyclic group" contains one or more heteroatoms independently selected from oxygen, nitrogen and sulfur.

Unless otherwise specified, the term "spirocycloalkyl" refers to a saturated ring system consisting of carbon atoms and hydrogen atoms, sharing only one ring carbon atom, and having a specific number of carbon atoms. Spirocycloalkyl is preferably a 6- to 14-membered spirocycloalkyl, more preferably a 7- to 10-membered spirocycloalkyl. Monospirocyclic radicals can be divided into monospirocyclic radicals of 3-, 5-, 4-, 4-, 5-, 4-, 6-, 5-, and 5-membered rings, wherein the count of each ring includes the spiral atom. Non-limiting examples of monospirocyclic radicals include: wait.

Unless otherwise specified, the term "heterospirocyclic group", "spiroheterocyclic group" refers to a ring system formed by two or more saturated rings, sharing only one ring carbon atom, and having a specific number of carbon atoms and heteroatoms. The heteroatoms in the spiroheterocyclic group are preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3), and the heteroatoms are each independently selected from N, O and S. The spiroheterocyclic group is preferably a 6- to 14-membered spiroheterocyclic group, more preferably a 7- to 10-membered spiroheterocyclic group. The spiroheterocyclic group can be divided into 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 spiroheterocyclic groups, wherein the count of each ring includes the spiro atom. Non-limiting examples of heteromonospirocyclic groups include: wait.

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

Unless otherwise specified, the term "heterobridged ring group" or "bridged heterocyclic group" refers to a polycyclic group containing 5 to 14 ring atoms, any two rings sharing two ring atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. The bridged heterocyclic group contains one or more heterocyclic atoms, preferably 1-4 heterocyclic atoms, more preferably 1-3 (i.e., 1, 2 or 3) heterocyclic atoms, and the heteroatoms are each independently selected from N, O and S(O) _m (wherein, m is any integer from 0 to 2), and the remaining ring atoms are carbon atoms. The bridged heterocyclic group is preferably a 6- to 14-membered bridged heterocyclic group, more preferably a 7- to 10-membered bridged heterocyclic group. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Non-limiting examples of bridged heterocyclic groups include:

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

Unless otherwise specified, the term "heteroaryl" or "aromatic heteroyl" refers to a monocyclic or polycyclic aromatic heterocyclic ring system containing a 5-12-membered structure, a 5-10-membered structure, a 5-8-membered structure or a 5-6-membered structure, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining ring atoms are carbon atoms, and the heteroatoms are each independently selected from O, N and S, preferably containing a 5-6-membered structure. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring group". Non-limiting examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimid ... oxazine, benzimidazolyl, benzophthalazine, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

Unless otherwise specified, the term "hydroxy" refers to an -OH group.

Unless otherwise specified, the term "mercapto" refers to a -SH group.

Unless otherwise specified, the term "amino" refers to a _-NH2 group.

Unless otherwise specified, the term "nitro" refers to a _-NO2 group.

Unless otherwise specified, the term "cyano" refers to a -CN group.

Unless otherwise specified, the term "carboxy" refers to a -C(=O)OH group.

Unless otherwise specified, the term "phosphate group" refers to a -P(=O)(OH) ₂ group, and the term "phosphoryl group" refers to a group formed after some or all of the hydroxyl groups in the above-mentioned phosphate group structure are replaced by other hydrocarbon groups (e.g., alkyl, cycloalkyl, aryl, etc.), such as dimethylphosphoryl (i.e., -P(=O)(CH ₃ ) ₂ ) as a non-limiting example of a dialkylphosphoryl group.

Unless otherwise specified, the term "amide group" refers to a group in which some or all of the hydrogen atoms in the above amino structure are replaced by other acyl groups (e.g., alkanoyl, cycloalkanoyl, aromatic acyl, etc.), such as formamide (i.e., -NHC(=O)H), acetamide (i.e., -NHC(=O)CH ₃ ) and the like as non-limiting examples of alkanoyl groups.

Unless otherwise specified, the term "sulfoxide" refers to a -S(=O)- group and the term "sulfone" refers to a -S(=O) _2- group.

Unless otherwise specified, the term "sulfonyl" refers to a group formed by connecting one segment of the above sulfone group to another hydrocarbon group (e.g., alkyl, cycloalkyl, aryl, etc.), such as methylsulfonyl _{(i.e., -S(=O)2CH3 )} and ethylsulfonyl (i.e., -S(=O) _2CH2CH3 ) as non- _limiting examples of _{alkylsulfonyl} .

Unless otherwise specified, the term "sulfonylamide" refers to a group formed by replacing some or all of the hydrogen atoms in the above amino structure with other sulfonyl groups (e.g., alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, etc.). Non-limiting examples are methanesulfonylamide (ie, -NHS(=O) _2CH3 ), ethanesulfonylamide (ie, -NHS(=O) _2CH2CH3 ) _, and _{the like} .

Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for contact with mammalian (especially human) tissues without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit/risk ratio within the scope of reasonable medical judgment. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

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

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

Unless otherwise specified, the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)), such as R and S configuration isomers containing asymmetric centers; (Z) and (E) configuration isomers of double bonds; and (Z) and (E) conformational isomers. Therefore, single stereoisomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) all fall within the scope of the present invention.

Unless otherwise specified, the terms "optionally substituted" and "optionally substituted by..." mean that the hydrogen on the substitutable position of the group is not substituted or is substituted by one or more substituents, and the substituents are preferably selected from the following substituents: halogen, hydroxyl, thiol, cyano, nitro, amino, azido, oxo, carboxyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-10 cycloalkyl, C3-10 cycloalkylsulfonyl, _3-10 membered heterocycloalkyl, _C6-14 aryl or 5-10 membered heteroaryl ring group, wherein the _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkyl, C1-6 alkoxy, _C3-10 cycloalkyl, C3-10 cycloalkylsulfonyl, _3-10 membered heterocycloalkyl, C6-14 aryl or _5-10 membered heteroaryl ring group _{The 6-14} membered aryl or 5-10 membered heteroaromatic ring group is optionally further substituted by one or more substituents each independently selected from halogen, hydroxy, amino, cyano, C _1-6 alkyl and C _1-6 alkoxy.

The beneficial effects of the present invention are:

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

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to professionals in the field. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

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

Preparation HPLC condition 1 (ammonia as additive): instrument: Waters; pump: 2545; detector: 2489; wavelength: 214nm &254nm; column model: Welch Xtimate C18, 21.2*250mm, 10μm; mobile phase: A: 0.1% v/v ammonia, B: acetonitrile; running time: 15min; running time: 25ml/min.

Preparation HPLC condition two (formic acid as additive): instrument: Waters; pump: 2545; detector: 2489; wavelength: 214nm&254nm; column model: Welch Ultimate AQ-C18, 21.2*250mm, 10μm; mobile phase: A: 0.1% v/v formic acid, B: acetonitrile; running time: 15min; running time: 25ml/min.

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

The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

Example 1

N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Step 1: Synthesis of 2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

In an ice-water bath, add N-iodosuccinimide (769.12 mg, 3.42 mmol, 1.05 eq) to a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 3.26 mmol, 1.0 eq) in acetonitrile (5 mL) and react at room temperature for 1 hour. After the reaction is completed as detected by LC-MS, the mixture is filtered under reduced pressure, and the filter cake is the crude target compound (840 mg, yield 92%). LC-MS (ESI) [M+H] ⁺ = 279.45.

Step 2: Synthesis of 2-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

2-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 2.86 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0°C under nitrogen protection, and sodium hydride (89.31 mg, 3.72 mmol, 1.3 eq) was slowly added, and stirred at 0°C for 0.5 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (524.97 mg, 3.15 mmol, 1.1 eq) was then added, and the mixture was reacted at 0°C for 1.5 hours. After the reaction was completed by LC-MS detection, ice water was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA=10:1) to obtain the target compound (740 mg, yield 63%). LC-MS (ESI) [M+H] ⁺ = 409.70.

Step 3: Synthesis of 2-chloro-5-(trifluoromethyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

Cuprous iodide (1394.45 mg, 7.32 mmol, 5.0 eq) and potassium fluoride (425.4 mg, 7.32 mmol, 5.0 eq) were placed in a 100 mL three-necked flask, protected by nitrogen, and heated to remove water. When the temperature returned to room temperature, N-methylpyrrolidone (5 mL) and (trifluoromethyl)trimethylsilane (1041.1 mg, 7.32 mmol, 5.0 eq) were added and stirred at room temperature for 1 hour. 2-Chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (600 mg, 1.46 mmol, 1.0 eq) was added and reacted at 50 °C for 16 hours. After the reaction was completed by LC-MS detection, the reaction solution was quenched with saturated ammonium chloride solution and dichloromethane was added. Dilute. Filter through diatomaceous earth, and wash the filter cake three times with dichloromethane. Separate the filtrate, take the organic phase, and wash it with saturated ammonium chloride solution and saturated brine. Combine the organic phases, dry them with anhydrous sodium sulfate, filter them, concentrate the filtrate, and separate and purify it by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (400mg, yield 78%). LC-MS(ESI)[M+H] ⁺ ＝351.70.

Step 4: Synthesis of 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-N-[5-(trifluoromethyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-1H-pyrazol-5-amine

2-Chloro-5-(trifluoromethyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.43 mmol, 1.0 eq) and 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine (99.03 mg, 0.43 mmol, 1 eq) (the synthesis method can be seen in steps 1 to 3 of Example 45) were dissolved in dioxane (10 mL), and chloro[(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2-aminobiphenyl)]palladium(II) (75.78 mg, 0.09 mmol, 0.2 eq) and cesium carbonate (416.73 mg, 1.28 mmol, 3.0 eq) were added in sequence. React at 100°C for 12 hours under nitrogen protection. After the reaction is completed, dilute with water, extract with dichloromethane three times, and wash with saturated brine. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain the target compound (105 mg, yield 44%). LC-MS(ESI)[M+H] ⁺ ＝548.05.

Step 5: Synthesis of 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-N-[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-1H-pyrazol-5-amine

1-Cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-N-[5-(trifluoromethyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-1H-pyrazol-5-amine (85 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (2 mL) was added dropwise, and the mixture was reacted at 65°C for 12 hours. After the reaction was completed by LC-MS, the reaction solution was concentrated, diluted with ethyl acetate, and washed 5 times with saturated brine to remove tetrabutylammonium fluoride. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and analyzed by Pre-TLC (PE:EA=2:1) to obtain the target compound (10.79 mg, yield 16%). LC-MS(ESI)[M+H] ⁺ =417.85; ¹ H NMR (400MHz, DMSO-d ₆ )δ12.36(s,1H),9.15(s,1H),8.75(s,1H),7.87(s,1H),7.76(s,2H),5.93(s ,1H),3.41-3.35(m,1H),1.98(s,6H),0.96-0.90(m,2H),0.85-0.80(m,2H).

Example 2-3

Refer to Example 1, Synthesis Examples 2-3.

Example 4

N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Step 1: Synthesis of 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2g, 13.02mmol, 1.0eq) in N,N-dimethylformamide (15mL), add 1-bromopyrrolidine-2,5-dione (3.48g, 19.53mmol, 1.5eq), and react at room temperature for 2 hours. After the reaction is completed by LC-MS detection, pour the reaction solution into water (300mL) and stir for 0.5 hours. Filter the reaction solution, wash the filter cake with ethyl acetate, dry the filtrate with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude target compound (3.48g, yield 90%). LC-MS (ESI) [M+H] ⁺ = 231.9.

Step 2: Synthesis of 5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

5-Bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2.73 g, 11.74 mmol, 1.0 eq) and triethylamine (2.14 g, 21.14 mmol, 1.8 eq) were dissolved in tetrahydrofuran (40 mL) and stirred at 0°C for 15 minutes. Then [2-(chloromethoxy)ethyl]trimethylsilane (2.94 g, 17.62 mmol, 1.5 eq) was added and reacted for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (30 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝20:1) to obtain the target compound (2.46 g, yield 58%). LC-MS(ESI)[M+H] ⁺ ＝362.0.

Step 3: Synthesis of 2-chloro-5-cyclopropyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

Dissolve 5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.38 mmol, 1.0 eq), potassium cyclopropylfluoroborate (245 mg, 1.65 mmol, 1.2 eq), tetrakis(triphenylphosphine)palladium (159 mg, 0.14 mmol, 0.1 eq) and potassium carbonate (381 mg, 2.76 mmol, 2.0 eq) in toluene (15 mL) and water (2 mL). React at 110 ° C for 12 hours under nitrogen protection. After the reaction is completed by LC-MS detection, pour the reaction solution into water (30 mL), extract with ethyl acetate (15 mL*3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=3:1) to obtain the target compound (219 mg, yield 49%). LC-MS (ESI) [M+H] ⁺ = 362.0.

Step 4: Synthesis of N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

2-Chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (146 mg, 0.45 mmol, 1.1 eq), 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (95 mg, 0.41 mmol, 1.0 eq), tris(dibenzylidene-BASE acetone)dipalladium (75 mg, 0.08 mmol, 0.2 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (39 mg, 0.08 mmol, 0.2 eq) and potassium phosphate (261 mg, 1.23 mmol, 2.0 eq) were dissolved in toluene. (10mL), react at 110°C for 18 hours under nitrogen protection. After the reaction is completed by LC-MS detection, the reaction solvent is directly dried, and the target compound is separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain the target compound (203mg, yield 95%). LC-MS(ESI)[M+H] ⁺ ＝520.3.

Step 5: Synthesis of N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Dissolve N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (190 mg, 0.37 mmol, 1.0 eq) in dichloromethane (10 mL), add trifluoroacetic acid (6 mL) dropwise, and react at room temperature for 1 hour. LC-MS detected that the reaction was completely generated intermediate. After the reaction solution was dried, DMF (10 mL) and ethylenediamine (8 mL) were added and reacted at room temperature for 1 hour. After the reaction was completed by LC-MS detection, the reaction solution was poured into water (60 mL), extracted with ethyl acetate (15 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then separated and purified by Prep-HPLC (C18, 0.05% NH ₄ .H ₂ O in water, MeCN) to obtain the target compound (25.8 mg, yield 26%). LC-MS(ESI)[M+H] ⁺ =390.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ11.22(s,1H),8.76(s,1H),8.64(s,1H),7.75(s,2H),6.86(d,J=1.5Hz,1H),5.94(s,1H),3.42-3. 36(m,1H),1.97(s,6H),1.94-1.85(m,1H),0.96-0.92(m,2H),0.86-0.81(m,4H),0.67-0.60(m,2H).

Example 5

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoro- ^N 4 -methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

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

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1g, 5.32mmol, 1.0eq) was dissolved in acetonitrile (20mL), and then 1-chloromethyl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis(tetrafluoroborate) salt (2.26g, 6.38mmol, 1.2eq) and acetic acid (4mL) were added in sequence, and the mixture was reacted at 85°C for 16 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solution was concentrated under reduced pressure and separated and purified by flash chromatography (Silica gel, PE:EA＝2:1) to obtain the target compound (500mg, yield 46%). LC-MS(ESI)[M+H] ⁺ ＝204.0.

Step 2: Synthesis of 2,4-dichloro-5-fluoro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.43 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), the reaction system was cooled to 0°C, sodium hydrogen (116.4 mg, 2.91 mmol, 1.2 eq) was slowly added, and the reaction was carried out at 0°C for 0.5 hours, and then [2-(chloromethoxy)ethyl]trimethylsilane (485.59 mg, 2.91 mmol, 1.2 eq) was added and the reaction was carried out at 25°C for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was quenched with water, extracted with ethyl acetate, and washed with saturated brine. Wash. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=2:1) to obtain the target compound (540 mg, yield 66%). LC-MS (ESI) [M+H] ⁺ = 335.65.

Step 3: Synthesis of 2-chloro-5-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,4-dichloro-5-fluoro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (540 mg, 1.61 mmol, 1.0 eq) was dissolved in isopropanol (2 mL), and [(4-methoxyphenyl)methyl](methyl)amine (254.97 mg, 1.69 mmol, 1.05 eq) and N,N-diisopropylethylamine (415.09 mg, 3.21 mmol, 2.0 eq) were added, and the mixture was reacted at 85°C for 2 hours. After the reaction was completed, the reaction solvent was directly dried, and the target compound was separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain the target compound (550 mg, yield 76%). LC-MS(ESI)[M+H] ⁺ ＝432.85.

Step 4: Synthesis of N ² -{1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl}-5-fluoro-N ⁴ -[(4-methoxyphenyl)methyl]-N 4 -methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

2-Chloro-5-fluoro-N-[(4-methoxyphenyl)methyl]-N-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (500 mg, 1.1 mmol, 1.0 eq) was dissolved in tert-butyl alcohol (20 mL), and 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine (283.3 mg, 1.2 mmol, 1 .1eq), potassium phosphate (588.3mg, 2.8mmol, 2.5eq), replace nitrogen three times, then add dicyclohexyl [2', 4', 6'-tri (propan-2-yl) - [1, 1'-biphenyl] -2-yl] phosphine (105.7mg, 0.2mmol, 0.2eq) and tri (1, 5-diphenylpenta-1, 4-diene-3-one) dipalladium (101.5mg, 0.1mmol, 0.1eq), replace nitrogen three times, and react at 80 ° C for 8 hours. After the reaction is completed by LC-MS detection, the reaction solution is diluted with water, extracted with ethyl acetate, and washed with saturated brine. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (Silica gel, PE: EA = 1: 1) to obtain the target compound (660mg, yield 92%). LC-MS (ESI) [M+H] ⁺ = 629.20.

Step 5: Synthesis of N ² -{1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl}-5-fluoro-N ⁴ -methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

N2-{1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl}-5-fluoro-N4-[(4-methoxyphenyl)methyl]-N4-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (400 mg, 0.62 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25°C for 2.5 hours. LC-MS detected about 50% of the target compound intermediate, concentrated the reaction solution, then added N,N-dimethylformamide (3 mL) and ethylenediamine (2 mL), and reacted at 25°C for 1 hour. After the reaction was completed by LC-MS, the reaction solution was diluted with water, extracted with ethyl acetate, and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, DCM:MeOH=10:1) to obtain a crude target compound, which was then separated and purified by Prep-HPLC and Prep-TLC to obtain the target compound (17.72 mg, yield 7%). LC-MS(ESI)[M+H] ⁺ =396.80; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(s,1H),8.30(s,1H),7.75(s,2H),6.81(d,J＝4.4Hz,1H),6.65(t,J＝2.0Hz,1H),5.93(s, 1H),3.47-3.41(m,1H),2.85(d,J＝4.4Hz,3H),1.96(s,6H),0.97-0.92(m,2H),0.91-0.86(m,2H).

Embodiment 6-15

Refer to Example 5, Synthesis Examples 6-15.

Example 16

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

Step 1: Synthesis of 2,4,5-trichloropyrrolo[2,3-d]pyrimidine

2,4-Dichloro-7H-pyrrole[2,3-D]pyrimidine (10g, 53.19mmol, 1.0eq) and NCS (1-chloropyridinic acid-2,5-dione) (7.1g, 53.19mmol, 1.1eq) were dissolved in DMF (15mL) and reacted at 50°C for 10 hours. After the reaction was completed by LC-MS detection, the reaction solution was diluted with water, extracted with ethyl acetate (40mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝20:1) to obtain the target compound (9.4g, yield 79%). LC-MS(ESI)[M+H] ⁺ ＝222.0.

Step 2: Synthesis 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 (9.4 g, 42.25 mmol, 1.0 eq) was dissolved in THF (60 mL) and added Add SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride) (7.75 g, 46.48 mmol, 1.1 eq) and triethylamine (4.28 g, 42.25 mmol, 1.0 eq) and react at room temperature for 2 hours. After the reaction is completed by LC-MS detection, the reaction solution is directly concentrated and separated and purified by flash chromatography (Silica gel, PE: EA = 10: 1) to obtain the target compound (10 g, yield 67%). LC-MS (ESI) [M + H] ⁺ = 352.0.

Step 3: Synthesis of 2,5-dichloro-N-(propan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

2,4,5-trichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2g, 5.67mmol, 1.0eq) and cyclobutylamine (0.48g, 6.8mmol, 1.2eq) were dissolved in DMF, N,N-diisopropylethylamine (1.45g, 11.3mmol, 2.0eq) was added, and the mixture was reacted at 120°C for 1 hour. After the reaction was completed by LC-MS detection, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝8:1) to obtain the target compound (1.4g, yield 54%). LC-MS(ESI)[M+H] ⁺ ＝387.38.

Step 4: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -cyclobutyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

1-Cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine (500 mg, 2.15 mmol, 1.0 eq), 2,5-dichloro-N-(propan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (833.86 mg, 2.15 mmol, 1.0eq) was dissolved in DMF, and then cesium carbonate (1.42g, 4.31mmol, 2.0eq), tris(dibenzylideneacetone)dipalladium (394.23mg, 0.43mmol, 0.2eq) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (205.24mg, 0.43mmol, 0.2eq) were added, and microwave reaction was carried out at 120°C for 1 hour under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried, and Prep-HPLC was used for separation and purification to obtain the target compound (220mg, yield 18%). LC-MS (ESI) [M+H] ⁺ = 584.2.

Step 5: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N4-cyclobutyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (200 mg, 0.34 mmol, 1.0 eq) was dissolved in methanol, trifluoroacetic acid (193.83 mg, 1.7 mmol, 5.0 eq) was added, and the reaction was allowed to proceed for 1 hour. After the reaction was completed by LC-MS, the reaction solution was concentrated, ammonia methanol (57.9 mg, 3.4 mmol, 10.0 eq) solution was added, and the reaction was allowed to proceed at room temperature for 0.5 hour. After the reaction was completed by LC-MS, the reaction solution was concentrated, and the target compound (50 mg, yield 34%) was obtained by separation and purification by Prep-HPLC. LC-MS(ESI)[M+H] ⁺ =453.94; ¹ H NMR (400MHz, DMSO-d ₆ )δ11.33(s,1H),8.39(s,1H),7.75(s,2H),6.95(d,J＝2.3Hz,1H),6.26(d,J＝7.7Hz,1H),6.00(s,1H),4.55(q,J＝8.0Hz,1H),3.43( dq,J＝7.3,3.7Hz,1H),2.25(d,J＝8.5Hz,2H),2.06(p,J＝9.8Hz,2H),1.97(s,6H),1.67(dt,J＝17.9,9.0Hz,2H),0.99-0.84(m,4H).

Embodiment 17

N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-4-(azetidin-1-yl)-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Step 1: Synthesis of 1-(2,5-dichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidine

Dissolve 2,4,5-trichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.84 mmol, 1.0 eq) in ethanol (30 mL), add azetidine (178 mg, 3.12 mmol, 1.1 eq) and N,N-diisopropylethylamine (367 mg, 2.84 mmol, 1.0 eq), and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝93:7) to obtain the target compound (320 mg, yield 30%). LC-MS(ESI)[M+H] ⁺ ＝373.1.

Step 2: Synthesis of N-[(4-azetidin-1-yl)-5-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propyl-2-yl]-1H-pyrazol-5-amine

1-(2,5-dichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidine (177 mg, 0.47 mmol, 1.1 eq) was dissolved in toluene (15 mL), and 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propyl-2-yl]-1H-pyrazol-5-amine (100 mg, 0.43 mmol, 1.0 eq), X-phos ([1-(2-diphenylphosphinonaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphine) (41 mg, 0.09 mmol, 0.2 eq), Pd ₂ (dba) ₃ (Tris(dibenzylideneacetone)dipalladium) (39 mg, 0.04 mol, 0.1 eq) and cesium carbonate (281 mg, 0.86 mmol, 2.0 eq) were reacted at 110°C for 10 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solution was concentrated and purified by flash chromatography (Silica gel, PE:EA＝45:55) to obtain the target compound (220 mg, yield 90%). LC-MS(ESI)[M+H] ⁺ ＝569.2.

Step 3: Synthesis of N-[(4-azetidin-1-yl)-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propyl-2-yl]-1H-pyrazol-5-amine

N-[(4-azetidin-1-yl)-5-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propyl-2-yl]-1H-pyrazol-5-amine (200 mg, 0.35 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (4 mL) was added. After reacting at room temperature for 2 hours, the reaction solution was concentrated, the residue was dissolved in methanol (2 mL), ammonia water (2 mL) was added, and the reaction was allowed to react at room temperature for 1 hour. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried and separated and purified by Prep-HPLC (C18, 10 mmol/L FA in water, MeCN) to obtain the target compound (34.2 mg, yield 22%). LC-MS(ESI)[M+H] ⁺ =439.1; ¹ H NMR (400MHz, DMSO) δ11.49(s,1H),8.45(s,1H),7.75(s,2H),7.03(d,J＝2.8Hz,1H),5.95(s,1H),4.26(t ,J＝7.4Hz,4H),3.44-3.41(m,1H),2.40-2.32(m,2H),1.96(s,6H),0.97-0.92(m,2H),0.91-0.86(m,2H).

Embodiment 18-44

Refer to Examples 17, 45, Synthetic Examples 18-44.

Embodiment 45

N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-8-cyclopropylquinazolin-2-amine

Step 1: Synthesis of ethyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propionate

2H-1,2,3-triazole (20g, 289.56mmol, 1.0eq) and potassium tert-butoxide (48.74g, 434.34mmol, 1.5eq) were dissolved in N,N-dimethylformamide (200mL), and ethyl 2-bromo-2-methylpropionate (84.72g, 434.34mmol, 1.5eq) was added under nitrogen protection at 0℃, and reacted at 25℃ for 16 hours. After the reaction was completed by LC-MS detection, water (300mL) was added to the reaction system, extracted with ethyl acetate (100mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝100:1) to obtain the target compound (10.5g, yield 20%). LC-MS (ESI) [M+H] ⁺ =184.1; ¹ H NMR (400MHz, CDCl3) δ7.65 (s, 2H), 4.16-4.15 (m, 2H), 1.97 (d, J = 1.2Hz, 6H), 1.23-1.17 (m, 3H).

Step 2: Synthesis of 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile

Tetrahydrofuran (100 mL) was added to acetonitrile (1.34 g, 32.75 mmol, 2 eq), and 2.4 M n-butyl lithium (2.1 g, 32.75 mmol, 2.0 eq) was added under nitrogen protection at -78 ° C, and the mixture was reacted at -78 ° C for 30 minutes, and then 2-methyl-2-(2H-1,2,3-triazol-2-yl) propionic acid ethyl ester (3 g, 16.37 mmol, 1.0 eq) was added, and the mixture was reacted at -78 ° C for 2 hours. After the reaction was completed by LC-MS detection, water (100 mL) was added to the reaction system, and the pH was adjusted to 5-6 with 3 M hydrochloric acid, and then extracted with ethyl acetate (200 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=100:1) to obtain the target compound (2.91 g, yield 100%). LC-MS (ESI) [M+H] ⁺ = 179.1; ¹ H NMR (400MHz, CDCl ₃ ) δ7.76 (s, 2H), 3.10 (s, 2H), 1.90 (s, 6H).

Step 3: Synthesis of 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazole-5-amine

Dissolve 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile (6g, 33.67mmol, 1.0eq) and cyclopropylhydrazine disalt (9.77g, 67.34mmol, 2.0eq) in ethanol (250mL), add 12M hydrochloric acid (9.02mL) under nitrogen protection, and react at 90°C for 5 hours. After the reaction is completed by LC-MS detection, the reaction solvent is dried, saturated sodium carbonate solution (300mL) is added, extracted with ethyl acetate (150mL*3), and washed with saturated brine. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (Silica gel, DCM:MeOH＝100:1) to obtain the target compound (4.65g, yield 59%). LC-MS (ESI) [M+H] ⁺ =233.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.72 (s, 2H), 5.11 (s, 2H), 4.79 (s, 1H), 3.14-3.08 (m, 1H), 1.88 (s, 6H), 0.88-0.85 (m, 4H).

Step 4: Synthesis of 2-chloro-8-cyclopropylquinazoline

8-Bromo-2-chloroquinazoline (500 mg, 2.05 mmol, 1.0 eq) was dissolved in Dioxane/H ₂ O (25/5 mL), and then cyclopropylboric acid (176.39 mg, 2.05 mmol, 1.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (150.67 mg, 0.21 mmol, 0.1 eq), and anhydrous sodium carbonate (652.94 mg, 6.16 mmol, 3.0 eq) were added in sequence. The reaction solution was reacted at 90°C under nitrogen protection for 16 hours. After the reaction was completed as detected by LC-MS, water (20 mL) was added to the reaction solution to quench, and the solution was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA = 5:1) to obtain the target compound (140 mg, yield Yield: 33%). LC-MS (ESI) [M+H] ⁺ = 205.1.

Step 5: Synthesis of N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-8-cyclopropylquinazolin-2-amine

2-Chloro-8-cyclopropylquinazoline (160 mg, 0.78 mmol, 1.0 eq) was dissolved in t-BuOH (tert-butyl alcohol) (10 mL), and then 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (181.59 mg, 0.78 mmol, 1.0 eq), Pd ₂ (dba) ₃ (Tris(dibenzylideneacetone)dipalladium) (71.59 mg, 0.08 mmol, 0.1 eq), XPhos (dicyclohexyl[2',4',6'-tri(propane-2-yl)-[1,1'-biphenyl]-2-yl]phosphine) (111.81 mg, 0.23 mmol, 0.3 eq) and potassium phosphate (497.85 mg, 2.35 mmol, 3.0 eq) were reacted at 80°C under nitrogen protection for 16 hours. After the reaction was completed as determined by LC-MS, the reaction solution was directly spin-dried and purified by flash chromatography (Silica gel, DCM:MeOH=15:1) to obtain a crude product, which was then separated and purified by Prep-HPLC (C18, 0.05% NH ₄ .H ₂ O in water, MeCN) to obtain the target compound (30.19 mg, yield 10%). LC-MS(ESI)[M+H] ⁺ =400.9; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.66(s,1H),9.30(s,1H),7.86-7.62(m,3H),7.41-7.25(m,2H),6.30(s,1H),3.58(d, J＝3.6Hz,1H),2.51-2.50(m,1H),1.98(s,6H),1.08-0.93(m,6H),0.76(d,J＝4.0Hz,2H).

Examples 46-48

Refer to Example 45, Synthetic Examples 46-48.

Embodiment 49

N ² -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 2-chloro-N-ethyl-5-iodopyrimidin-4-amine

2,4-Dichloro-5-iodo-pyrimidine (10g, 36.38mmol, 1.0eq) was dissolved in acetonitrile (150mL), and ethylamine (2M in tetrahydrofuran) (19.1mL, 38.2mmol, 1.05eq) and triethylamine (4.05g, 40.02mmol, 1.1eq) were added in sequence, and the reaction was reacted at 25°C for 16 hours. After the reaction was completed by LC-MS detection, the reaction solvent was dried, the mixture was dissolved in ethyl acetate, and washed once with saturated sodium chloride, 10% citric acid aqueous solution and saturated sodium bicarbonate solution in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (7g, yield 68%). LC-MS(ESI)[M+H] ⁺ ＝283.50.

Step 2: Synthesis of 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine

Cuprous iodide (25.86 g, 135.8 mmol, 5.5 eq) and potassium fluoride (7.89 g, 87.3 mmol, 5.5 eq) were added to a 250 mL three-necked flask, and the mixture was heated to remove water under nitrogen protection. After returning to room temperature, NMP (N-methylpyrrolidone) (200 mL) and TMSCF ₃ ((trifluoromethyl)trimethylsilane) (19.31 g, 135.8 mmol, 5.5 eq) were added, and the mixture was reacted at room temperature for 1 hour. 2-Chloro-N-ethyl-5-iodopyrimidine-4-amine (4.5 g, 15.87 mmol, 1 eq) was added, and the mixture was reacted at 50°C for 16 hours. After the reaction was completed by LC-MS detection, the reaction was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed three times with ethyl acetate. The filtrate was separated, and the organic phase was washed once with a saturated ammonium chloride solution and a sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (3.0 g, yield 54%). LC-MS (ESI) [M+H] ⁺ ＝225.95; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.36 (s, 1H), 7.97 (s, 1H), 3.49-3.39 (m, 2H), 1.12 (t, J＝7.2Hz, 3H).

Step 3: Synthesis of ethyl 2-(2H-1,2,3-triazol-2-yl)acetate

Dissolve triazole (30g, 434.34mmol, 1.0eq), ethyl bromoacetate (72.54g, 434.34mmol, 1eq) and potassium carbonate (120.06g, 868.68mmol, 2.0eq) in acetonitrile (350mL) and heat to 80°C for 3 hours. After the reaction is completed, filter with diatomaceous earth, concentrate the filtrate, and separate and purify by flash chromatography (Silica gel, PE:EA＝5:1) to obtain the target compound (12.5g, yield 18%). LC-MS(ESI)[M+H] ⁺ ＝156.1.

Step 4: Synthesis of 1-(2H-1,2,3-triazole-2-yl)cyclopropane-1-carboxylic acid ethyl ester

Ethyl 2-(2H-1,2,3-triazol-2-yl)acetate (11.5 g, 74.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (250 mL), and an appropriate amount of molecular sieves was added. The mixture was cooled to -78°C in a dry ice ethanol bath, and lithium (1+) bis(propan-2-yl) nitrogen oxide (92.7 mL, 185.3 mmol, 2 mmol/mL, 2.5 eq) was added dropwise. After stirring for 1 hour, 1,3,2-dioxathiazole 2,2-dioxide (10.12 g, 81.53 mmol, 1.1 eq) was dissolved in tetrahydrofuran (50 mL) and added dropwise to the system. The mixture was stirred for 30 minutes, and finally 1,3-dimethyl-1,3-diazide-2-one (10.45 g, 81.53 mmol, 1.1 eq) was added. The temperature was slowly raised to room temperature and the reaction was carried out for 16 hours. After the reaction was completed by LC-MS detection, saturated aqueous ammonium chloride solution (500 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, DCM) to obtain the target compound (780 mg, yield 6%). LC-MS (ESI) [M+H] ⁺ =181.6.

Step 5: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-3-oxopropionitrile

Acetonitrile (308.12 mg, 7.51 mmol, 2.0 eq) was dissolved in tetrahydrofuran (18 mL), cooled to -78 °C in a dry ice ethanol bath under nitrogen protection, and n-butyl lithium (3.2 mL, 7.51 mmol, 2.4 mol/L, 2.0 eq) was slowly added dropwise. After stirring for 30 minutes, a solution of 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylic acid ethyl ester (680 mg, 3.75 mmol, 1.0 eq) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was maintained at -78 °C for 2 hours. After the reaction was completed by LC-MS detection, the reaction mixture was poured into ice water (50 mL), adjusted to pH = 5-6 with hydrochloric acid (1 mol/L), extracted with ethyl acetate (30 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (700 mg), which was used directly in the next step. LC-MS (ESI) [M+H] ⁺ = 177.1.

Step 6: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazole-5-amine

3-Oxo-3-[1-(2H-1,2,3-triazol-2-yl)cyclopropyl]propionitrile (600mg, 3.41mmol, 1.0eq), cyclopropylhydrazine dihydrochloride (1.48g, 10.22mmol, 3.0eq) and concentrated hydrochloric acid (0.87mL) were dissolved in ethanol (36mL) and reacted at 90°C for 2 hours. After the reaction was completed by LC-MS detection, the reaction solution was concentrated, and the residue was poured into a saturated sodium bicarbonate aqueous solution (20mL) and stirred for 5 minutes. It was extracted with ethyl acetate (20mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, DCM:MeOH＝20:1) to obtain the target compound (500mg, yield 64%). LC-MS(ESI)[M+H] ⁺ ＝230.7.

Step 7: Synthesis of N ² -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

2-Chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (100 mg, 0.44 mmol, 1 eq) was dissolved in dioxane (5 mL), 1-cyclopropyl-3-[1-(2H-1,2,3-triazol-2-yl)cyclopropyl]-1H-pyrazol-5-amine (102.07 mg, 0.44 mmol, 1 eq), p-toluenesulfonic acid monohydrate) (42.16 mg, 0.22 mmol, 0.5 eq) were added, and the reaction solution was reacted at 90°C for 3 hours under nitrogen protection. LC-MS detected that the reaction was complete. Direct concentration was performed, and the crude product was separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain 100 mg, which was then separated and purified by Prep-TLC (DCM:MeOH＝10:1) to obtain the target compound (18.33 mg, yield 10%). LC-MS(ESI)[M+H] ⁺ =419.85. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.35(s,1H),8.14(s,1H),7.82(s,2H),7.15(t,J＝5.2Hz,1H),5.77(s,1H),3.44(dd,J＝9.0,5.2Hz,1H),3.27(d ,J＝6.0Hz,2H),1.63(dd,J＝7.4,5.0Hz,2H),1.56(dd,J＝7.8,5.0Hz,2H),1.01(t,J＝7.0Hz,3H),0.94-0.88(m,4H).

Examples 50-51

Refer to Example 49, Synthetic Examples 50-51.

Embodiment 52

N ² -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-(2-methylcyclopropyl)-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of di-tert-butyl 1-(2-methylcyclopropyl)hydrazine-1,2-dicarboxylate

Take a single-mouth bottle, dissolve 2-methylcyclopropane-1-carboxylic acid (500mg, 4.99mmol, 1.0eq), (E)-diazene-1,2-dicarboxylic acid di-tert-butyl ester (1.72g, 7.49mmol, 1.5eq), cesium carbonate (325.43mg, 1mmol, 0.2eq) and cerium trichloride (123.09mg, 0.5mmol, 0.1eq) in acetonitrile (15mL), pass nitrogen for 1 minute, then seal and irradiate with 455nm blue light, react at room temperature for 24 hours. TLC detection (PE/EA＝10/1, rf＝0.4) The reaction is complete. Pour the reaction solution into saturated ammonium chloride aqueous solution (100mL), extract with ethyl acetate (50mL*3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=10:1) to obtain the target compound (158 mg, yield 11%). ¹ H NMR (400MHz, CDCl3) δ6.39-5.91 (m, 1H), 2.69-2.40 (m, 1H), 1.47 (s, 18H), 1.15-1.07 (m, 1H), 1.05 (s, 3H), 0.87-0.79 (m, 1H), 0.54-0.42 (m, 1H).

Step 2: Synthesis of (2-methylcyclopropyl)hydrazine

Take a single-mouth bottle, dissolve 1-(2-methylcyclopropyl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester (300 mg, 1.05 mmol, 1.0 eq) in 4M hydrochloric acid dioxane solution (10 mL), and react at room temperature for 16 hours. After the reaction is completed by TLC detection, the reaction solution is directly spin-dried to obtain the crude product of the target compound (150 mg). LC-MS (ESI) [M+H] ⁺ = 87.1.

Step 3: Synthesis of ethyl 2-(2H-1,2,3-triazol-2-yl)acetate

Take a single-mouth bottle, dissolve triazole (30g, 434.34mmol, 1.0eq), ethyl bromoacetate (72.54g, 434.34mmol, 1.0eq) and potassium carbonate (120.06g, 868.68mmol, 2.0eq) in acetonitrile (350mL), and heat to 80℃ for 3 hours. After the reaction is completed, filter with diatomaceous earth, concentrate the filtrate, and separate and purify it by flash chromatography (Silica gel, PE:EA＝5:1) to obtain the target compound (15.6g, yield 23%). LC-MS(ESI)[M+H] ⁺ ＝156.1.

Step 4: Synthesis of ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylate

Take a three-necked flask, dissolve ethyl 2-(2H-1,2,3-triazol-2-yl)acetate (15 g, 96.68 mmol, 1 eq) in tetrahydrofuran (150 mL), add an appropriate amount of molecular sieves, cool to -78 °C in a dry ice ethanol bath, and add LDA (lithium diisopropylamide) (120.8 mL, 241.7mmol, 2mmol/mL, 2.0eq), after 1 hour of reaction, a solution of 1,3,2-dioxathiacyclohexane 2,2-dioxide (13.2g, 106.35mmol, 1.1eq) dissolved in tetrahydrofuran (50mL) was added dropwise to the system, reacted for 30 minutes, and finally 1,3-dimethyl-1,3-diazide-2-one (13.63g, 106.35mmol, 1.1eq) was added, and the temperature was slowly raised to room temperature for 16 hours. LC-MS was used to detect the progress of the reaction, 500mL of saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, DCM) to obtain the target compound (600mg, yield 3%). LC-MS (ESI) [M+H] ⁺ = 182.1.

Step 5: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-3-oxopropionitrile

Take a three-necked flask, dissolve acetonitrile (271.87 mg, 6.62 mmol, 2.0 eq) in tetrahydrofuran (15 mL), cool to -78 ° C in a dry ice ethanol bath under nitrogen protection, slowly add n-butyl lithium (2.76 mL, 6.62 mmol, 2.4 mol/L, 2.0 eq) dropwise and react for 30 minutes, then add a solution of 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylic acid ethyl ester (600 mg, 3.31 mmol, 1.0 eq) in tetrahydrofuran (5 mL), keep -78 ° C for 2 hours. After the reaction is completed by LC-MS detection, pour the reaction solution into ice water (20 mL), adjust the pH to 5-6 with HCl (1 mol/L), extract with ethyl acetate (20 mL*3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (400 mg). LC-MS (ESI) [M+H] ⁺ = 177.1.

Step 6: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-(2-methylcyclopropyl)-1H-pyrazole-5-amine

Take a single-mouth bottle, dissolve 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-3-oxopropionitrile (300mg, 1.7mmol, 1.0eq), cyclopropylhydrazine dihydrochloride (0.54g, 3.41mmol, 2.0eq) and concentrated hydrochloric acid (0.43mL) in ethanol (20mL), and heat to 90℃ for 2 hours. After the reaction is completed by LC-MS detection, the reaction solution is concentrated, and the residue is poured into NaHCO ₃ aqueous solution (20mL) and stirred for 5 minutes. Extract with ethyl acetate (20mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify it by flash chromatography (Silica gel, DCM:MeOH＝20:1) to obtain the target compound (100mg, yield 24%). LC-MS(ESI)[M+H] ⁺ ＝245.2.

Step 7: Synthesis of N ² -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-(2-methylcyclopropyl)-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

Take a single-necked bottle, dissolve 1-(2-methylcyclopropyl)-3-[1-(2H-1,2,3-triazol-2-yl)cyclopropyl]-1H-pyrazol-5-amine (90 mg, 0.37 mmol, 1.0 eq), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (83.11 mg, 0.37 mmol, 1.0 eq) and 4-methylbenzene-1-sulfonic acid hydrate (35.04 mg, 0.18 mmol, 0.5 eq) in dioxane (4 mL), and heat to 90 ° C for 3 hours. After the reaction was completed by LC-MS detection, the reaction solution was diluted with ethyl acetate to 20 mL, washed with saturated sodium bicarbonate aqueous solution and saturated brine respectively, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC (C18, 10 mmol/L FA in water, MeCN) to obtain the target compound (15.5 mg, yield 10%). LC-MS(ESI)[M+H] ⁺ =434.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.26(s,1H),8.13(s,1H),7.82(s,2H),7.13(s,1H),5.71(s,1H),3.30-3.25(m,2H),3.18-3.09(m,1H) ,1.67-1.51(m,4H),1.23(s,1H),1.13-1.07(m,1H),1.02(d,J＝6.1Hz,6H),0.71(dd,J＝12.4,6.2Hz,1H).

Examples 53-54

Refer to Examples 52 and 55, and Synthesize Examples 53-54.

Embodiment 55

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine hydrochloride

Step 1: Synthesis of 2-chloro-N-(ethyl-d5)-5-(trifluoromethyl)pyrimidin-4-amine

2-Chloro-5-(trifluoromethyl)pyrimidin-4-amine (100 mg, 0.51 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (DMF) (2 mL), potassium tert-butoxide (85.2 mg, 0.76 mmol, 1.5 eq) was added under nitrogen protection at 0°C, and the reaction was allowed to react for 30 minutes, and then deuterated iodoethane (163 mg, 1.01 mmol, 2.0 eq) was added, and the reaction solution was allowed to react at 25°C for 16 hours. After the reaction was completed as detected by LC-MS, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA=5:1) to obtain the target compound (65 mg, yield 55%). LC-MS (ESI) [M+H] ⁺ =230.6; ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.37 (s, 1H), 7.96 (s, 1H).

Step 2: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (400 mg, 1.73 mmol, 1.0 eq) and 2-chloro-N-(ethyl-d5)-5-(trifluoromethyl)pyrimidin-4-amine (402.86 mg, 1.73 mmol, 1.0 eq) were dissolved in dioxane (17 mL), and p-toluenesulfonic acid monohydrate (164.96 mg, 0.87 mmol, 0.5 eq) was added, and the reaction solution was reacted at 90 ° C under nitrogen protection for 3 hours. After the reaction was completed by LC-MS detection, the reaction solution was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (50mL*3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, DCM:MeOH=10:1) to obtain a crude product, which was separated and purified by Prep-HPLC (C18, 0.05% NH ₃ .H ₂ O in water, MeCN) to obtain the target compound (60 mg, yield 8%). LC-MS (ESI) [M+H] ⁺ = 427.2.

Step 3: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine hydrochloride

N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine (40 mg, 0.09 mmol, 1 eq) was dissolved in 4 M dioxane hydrochloride (5 mL), and the reaction solution was reacted at 25° C. for 0.5 hours. After the reaction was completed by LC-MS detection, the reaction solution was directly spin-dried and then freeze-dried. The target compound (37.82 mg, yield 87%) was obtained. LC-MS (ESI) [M+H] ⁺ = 427.3; ¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.27 (s, 1H), 7.76 (s, 3H), 5.95 (s, 1H), 3.49-3.41 (m, 1H), 1.96 (s, 6H), 0.96 (s, 4H).

Embodiment 56

Refer to Example 57, Synthesize Example 56.

Embodiment 57

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-6d-2,4-diamine

Step 1: Synthesis of 4,6-dichloro-5-iodo-2-methylthiopyrimidine

At room temperature, 4,6-dichloro-2-methylthiopyrimidine (6 g, 30.76 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 mL), replaced with nitrogen three times, and LDA (lithium diisopropylamide) (4.94 g, 46.14 mmol, 1.5 eq) was added at -78 ° C to react for 0.5 hours, and then iodine (11.71 g, 46.14 mmol, 1.5 eq) was added and reacted at room temperature for 1.5 hours. After the reaction was completed by LC-MS detection, saturated sodium thiosulfate aqueous solution (200 mL) was added and extracted with ethyl acetate (200 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝12:1) to obtain the target compound (7 g, yield 70%). LC-MS (ESI) [M+H] ⁺ =320.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ3.38 (s,3H).

Step 2: Synthesis of 6-chloro-N-ethyl-5-iodo-2-(methylthio)pyrimidin-4-amine

At room temperature, 4,6-dichloro-5-iodo-2-methylthiopyrimidine (7g, 21.81mmol, 1.0eq) was dissolved in acetonitrile (70mL), and then ethylamine (0.98g, 21.81mmol, 1.0eq) and triethylamine (3.31g, 32.71mmol, 1.5eq) were added, and the reaction was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction solvent was directly dried, and the target compound was separated and purified by flash chromatography (Silica gel, PE:EA＝12:1) to obtain the target compound (7.1g, yield 98%). LC-MS(ESI)[M+H] ⁺ ＝329.5.

Step 3: Synthesis of 6-chloro-N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-amine

Cuprous iodide (11.44 g, 60.06 mmol, 5.5 eq) and potassium fluoride (3.49 g, 60.06 mmol, 5.5 eq) were added to a 100 mL three-necked flask, protected by nitrogen, and heated to remove water. After returning to room temperature, NMP (N-methylpyrrolidone) (50 mL) and TMSCF ₃ ((trifluoromethyl)trimethylsilane) (8.54 g, 60.06 mmol, 10.0 eq) were added, and the reaction was carried out at room temperature for 1 hour. 6-Chloro-N-ethyl-5-iodo-2-(methylthio)pyrimidine-4-amine (3.6 g, 10.92 mmol, 1.0 eq) was added, and the reaction was carried out at 50°C for 16 hours. After the reaction was completed by LC-MS detection, the reaction solution was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. Filtered with diatomaceous earth, the filter cake was washed three times with ethyl acetate. The filtrate was separated, and the organic phase was taken and washed once with saturated ammonium chloride solution and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=12:1) to obtain the target compound (1.2 g, yield 40%). LC-MS (ESI) [M+H] ⁺ = 272.0.

Step 4: Synthesis of N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidine-6-D-4-amine

At room temperature, 6-chloro-N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-amine (1g, 3.68mmol, 1.0eq) was dissolved in 10mL of deuterated methanol and reacted for 0.5 hours. Then Pd (0.2g, 1.84mmol, 0.5eq) and deuterated formic acid (0.51g, 11.04mmol, 3.0eq) and triethylamine (1.12g, 11.04mmol, 3.0eq) were added and reacted at 95°C for 16 hours. After the reaction was completed by LC-MS detection, it was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA＝12:1) to obtain the target compound (300mg, yield 19%). LC-MS(ESI)[M+H] ⁺ ＝239.1.

Step 5: Synthesis of tert-butylethyl 2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate

At room temperature, N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidine-6-D-4-amine (300 mg, 1.26 mmol, 1 eq) was dissolved in 3 mL of tetrahydrofuran, and then di-tert-butyl dicarbonate (549.63 mg, 2.52 mmol, 2.0 eq) and triethylamine (382.25 mg, 3.78 mmol, 3.0 eq) and 4-dimethylaminopyridine (76.92 mg, 0.63 mmol, 0.5 eq) were added, and the mixture was reacted at 90°C for 4 hours. After the reaction was completed, the reaction solvent was directly dried and purified by flash chromatography (Silica gel, PE:EA=12:1) to obtain the target compound (400 mg, yield 93%). LC-MS (ESI) [M+H] ⁺ = 339.1.

Step 6: Synthesis of tert-butylethyl 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate

At room temperature, in a 50mL single-mouth bottle, tert-butylethyl 2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate (400mg, 1.18mmol, 1eq) was dissolved in 4mL dichloromethane, and then m-chloroperbenzoic acid (510mg, 2.96mmol, 2.5eq) was added and reacted at room temperature for 4 hours. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried and separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain the target compound (300mg, yield 68%). LC-MS(ESI)[M+H] ⁺ ＝371.1.

Step 7: Synthesis of tert-butyl (2-((3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl-6-D)(ethyl)carbamate

Take a three-necked flask, dissolve 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazole-5-amine (156.79 mg, 0.68 mmol, 1.0 eq) in tetrahydrofuran (3 mL), add appropriate molecular sieves to replace nitrogen 3 times, slowly add bistrimethylsilyl lithium amide (225.9 mg, 1.35 mmol, 2.0 eq) at -78 ° C, and react at -78 ° C for 1 hour, then add tert-butyl ethyl 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate (250 mg, 0.68 mmol, 1.0 eq) to the reaction system, and continue to react for 1 hour. After the reaction is completed by LC-MS detection, add saturated ammonium chloride aqueous solution (10 mL) under ice bath to quench, and extract with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=2:1) to obtain the target compound (200 mg, yield 56%). LC-MS (ESI) [M+H] ⁺ = 523.2.

Step 8: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-6d-2,4-diamine

At 0°C, in a 25 mL reaction bottle, tert-butyl (2-((3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl-6-D)(ethyl)carbamate (100 mg, 0.19 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), then TFA (1 mL) was slowly added, and the temperature of the reaction system was raised to room temperature, and the reaction was continued for 2 hours. After the reaction was completed by LC-MS detection, the reaction solvent was dried, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8-9, dichloromethane was added for extraction (30 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude target compound, which was obtained by reverse phase column chromatography (25 mg, yield 32%). LC-MS(ESI)[M+H] ⁺ =423.4; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.34(s,1H),7.75(s,2H),7.22-7.14(m,1H),5.92(s,1H),3.45(tt,J＝7.3,4.0Hz ,1H),3.30(d,J＝5.4Hz,2H),1.96(s,6H),1.04(t,J＝7.0Hz,3H),0.96-0.89(m,4H).

Embodiment 58

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-6-chloro-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of lithium dichloro(2,2,6,6-tetramethylpiperidin-1-yl)zinc oxide (II)

At room temperature, 2,2,6,6-tetramethylpiperidine (60 g, 424.78 mmol, 1.0 eq) was added to the reaction bottle, dissolved in tetrahydrofuran (600 mL), replaced with nitrogen three times, and n-butyl lithium (27.21 g, 424.78 mmol, 1.0 eq) was added at -40°C, and then the temperature was raised to -10°C for reaction for 1 hour. Zinc chloride (60.79 g, 446.02 mmol, 1.05 eq) was added, and the reaction continued at -10°C for 0.5 hour, and then the temperature was returned to room temperature for reaction for 0.5 hour. The reaction solution was directly used for the next step.

Step 2: Synthesis of 2,4,6-trichloro-5-iodopyrimidine

Take a three-necked flask, dissolve 2,4,6-trichloropyrimidine (20g, 109.04mmol, 1.0eq) in tetrahydrofuran (200mL), slowly add it dropwise to a tetrahydrofuran solution (300mL) of lithium dichloro (2,2,6,6-tetramethylpiperidin-1-yl) zincate (II) (92.73g, 327.12mmol, 3.0eq) at room temperature, and react at room temperature for 1 hour. Then, dissolve iodine (55.35g, 218.08mmol, 2.0eq) in tetrahydrofuran (100mL), add it dropwise to the reaction system, and continue to react for 1 hour. After the reaction is completed by LC-MS detection, pour the reaction solution into a sodium thiosulfate solution (500mL), extract with ethyl acetate (500mL*3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA＝12:1) to give the target compound (20 g, yield 59%).

Step 3: Synthesis of 2,6-dichloro-N-ethyl-5-iodopyrimidin-4-amine

At room temperature, 2,4,6-trichloro-5-iodopyrimidine (20 g, 64.66 mmol, 1.0 eq) was dissolved in acetonitrile (200 mL), and then ethylamine (2.91 g, 64.66 mmol, 1.0 eq) and triethylamine (9.81 g, 96.99 mmol, 1.5 eq) were added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solvent was directly dried, and the target compound was separated and purified by flash chromatography (Silica gel, PE:EA＝12:1) to obtain the target compound (14 g, yield 68%). ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.67(d,J＝5.2 Hz,1H),3.45-3.35(m,2H),1.12(t,J＝7.2 Hz,3H).

Step 4: Synthesis of 2,6-dichloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine

Cuprous iodide (4.94 g, 25.95 mmol, 5.5 eq) and potassium fluoride (1.51 g, 25.95 mmol, 5.5 eq) were placed in a 100 mL three-necked flask. Nitrogen protection, heating to remove water. After returning to room temperature, NMP (N-methylpyrrolidone) (15 mL) and TMSCF ₃ ((trifluoromethyl)trimethylsilane) (3.69 g, 25.95 mmol, 5.5 eq) were added, and the reaction was carried out at room temperature for 1 hour. 2,6-dichloro-N-ethyl-5-iodopyrimidine-4-amine (1.5 g, 4.72 mmol, 1.0 eq) was added, and the reaction was carried out at 50°C for 16 hours. After the reaction was completed by LC-MS detection, the reaction solution was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. Filtered with diatomaceous earth, the filter cake was washed three times with ethyl acetate. The filtrate was separated, and the organic phase was washed once with saturated ammonium chloride solution and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=12:1) to obtain the target compound (0.4 g, yield 32%). LC-MS (ESI) [M+H] ⁺ = 260.0.

Step 5: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-6-chloro-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

2,6-Dichloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (200 mg, 0.63 mmol, 1.0 eq), 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (175.34 mg, 0.75 mmol, 1.2 eq), sodium acetate (14.12 mg, 0.06 mmol, 0.1 eq), Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthine) (72.8 mg, 0.13 mmol, 0.2 eq), potassium acetate (185.2 mg, 1.89 mmol, 3.0 eq) were dissolved in dioxane (2 mL), replaced with nitrogen three times, and reacted at 90 ° C for 1 hour. After the reaction was completed, the reaction solvent was directly dried by spin drying, and the crude target compound was separated and purified by flash chromatography (Silica gel, PE:EA＝2:1), and then separated and purified by Prep-HPLC to obtain the target compound (65 mg, yield 23%). LC-MS (ESI) [M+H] ⁺ ＝456.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.86 (s, 1H), 7.75 (s, 2H), 7.43 (s, 1H), 5.93 (s, 1H), 3.45 (s, 1H), 3.29-3.19 (m, 2H), 1.95 (s, 6H), 0.99 (d, J＝7.7Hz, 3H), 0.96-0.91 (m, 4H).

Examples 59-60

Refer to Examples 58 and 61, and Synthesize Examples 59-60.

Embodiment 61

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-6-methoxy-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of N-ethyl-6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-amine

6-Chloro-N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-amine (800 mg, 2.94 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and sodium methoxide (477.19 mg, 8.83 mmol, 3 eq) was added, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried, and the target compound (700 mg, yield 88%) was obtained by flash chromatography separation and purification (Silica gel, PE:EA=10:1). LC-MS (ESI) [M+H] ⁺ =267.6; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.19 (s, 1H), 3.88 (s, 3H), 3.48-3.40 (m, 2H), 2.47 (s, 3H), 1.11 (t, J = 7.2Hz, 3H).

Step 2: Synthesis of tert-butylethyl 6-methoxy-2-methylthio-5-trifluoromethylpyrimidin-4-ylcarbamate

At room temperature, N-ethyl-6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-amine (500 mg, 1.87 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and then di-tert-butyl dicarbonate (816.59 mg, 3.74 mmol, 2.0 eq), triethylamine (567.91 mg, 5.61 mmol, 3.0 eq) and 4-dimethylaminopyridine (114.28 mg, 0.94 mmol, 0.5 eq) were added, and the mixture was reacted at 90°C for 16 hours. After the reaction was completed, the reaction solvent was directly dried, and the target compound was separated and purified by flash chromatography (Silica gel, PE:EA＝12:1) to obtain the target compound (500 mg, yield 72%). LC-MS(ESI)[M+H] ⁺ ＝368.1.

Step 3: Synthesis of tert-butylethyl 6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-ylcarbamate

At room temperature, tert-butylethyl 6-methoxy-2-methylthio-5-trifluoromethylpyrimidin-4-ylcarbamate (500 mg, 1.3 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and then m-chloroperbenzoic acid (562.59 mg, 3.26 mmol, 2.5 eq) was added, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried, and the target compound (370 mg, yield 71%) was obtained by flash chromatography separation and purification (Silica gel, PE: EA = 1: 1). LC-MS (ESI) [M+H] ⁺ = 400.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 4.18 (s, 3H), 3.83 (d, J = 6.8 Hz, 2H), 3.46 (s, 3H), 1.40 (s, 9H), 1.18 (t, J = 6.8 Hz, 3H).

Step 4: Synthesis of N ² -(3-(2-(4H-1,2,4-triazol-4-yl)propan-2-yl)-1-isopropyl-1H-pyrazol-5-yl)-N ⁴ -isopropyl-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

Take a three-necked flask and add 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazole-5-amine (320 mg, 1.38 mmol, 1.0eq) was dissolved in tetrahydrofuran (5mL), and an appropriate amount of molecular sieves was added. The nitrogen was replaced 3 times, and bis(trimethylsilyl)amide lithium (461.04mg, 2.76mmol, 2.0eq) was slowly added dropwise at -78°C, and the reaction was carried out at -78°C for 1 hour. Then, tert-butylethyl 6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-ylcarbamate (550.22mg, 1.38mmol, 1.0eq) was added to the reaction system, and the reaction was continued for 1 hour. After the reaction was completed by LC-MS detection, saturated aqueous ammonium chloride solution (10mL) was added dropwise to the reaction solution under ice bath to quench, and extracted with ethyl acetate (50mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝2:1) to obtain the target compound (170mg, yield 38%). LC-MS (ESI) [M+H] ⁺ = 552.0.

Step 5: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-6-methoxy-5-(trifluoromethyl)pyrimidine-2,4-diamine

Dissolve tert-butyl 2-((3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-6-methoxy-5-(trifluoromethyl)pyrimidin-4-yl)(ethyl)carbamate (100 mg, 0.18 mmol, 1.0 eq) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and react at room temperature for 1 hour. After the reaction is completed by LC-MS detection, adjust the pH to 8-10 with sodium bicarbonate under ice bath, and extract with dichloromethane (50 mL*3). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify with Prep-HPLC (C18, 5 mmol/L NH ₃ ·H ₂ O in water, MeCN) to obtain the target compound (16.95 mg, yield 20%). LC-MS(ESI)[M+H] ⁺ =452.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(s,1H),7.74(s,2H),6.82(s,1H),5.90(s,1H),3.81(s,3H),3.49(m,J ＝3.6Hz,1H),3.29-3.20(m,2H),1.95(s,6H),1.01(s,3H),0.96-0.90(m,4H).

Embodiment 62

N ⁶ -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ² -ethyl-3-(trifluoromethyl)pyrazine-2,6-diamine

Step 1: Synthesis of 6-chloro-N-ethyl-3-iodopyrazin-2-amine

At room temperature, 3,5-dichloro-2-iodopyrazine (2g, 7.3mmol, 1.0eq) and ethylamine hydrochloride (653mg, 8mmol, 1.1eq) were dissolved in dimethyl sulfoxide (20mL), and potassium fluoride (846mg, 14.6mmo, 2.0eq) was added, and the mixture was reacted at 70°C for 16 hours. After the reaction was completed by LC-MS detection, ethyl acetate was added for extraction (50mL*3), and the mixture was washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (1.1g, yield 53%). LC-MS(ESI)[M+H] ⁺ ＝284.1.

Step 2: Synthesis of 6-chloro-N-ethyl-3-(trifluoromethyl)pyrazine-2-amine

At room temperature, 6-chloro-N-ethyl-3-iodopyrazine-2-amine (1.1 g, 3.9 mmol, 1.0 eq) and CuI (148 mg, 0.78 mmol, 0.2 eq) were dissolved in anhydrous DMF (N,N-dimethylformamide) (10 mL), and then methyl fluorosulfonyl difluoroacetate (2.98 g, 15.5 mmol, 4.0 eq) was slowly added dropwise, and the mixture was reacted at 80 ° C for 16 hours. After the reaction was completed by LC-MS detection, water and ethyl acetate were added to the reaction system and stirred, and the mixture was allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL*3) and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (753 mg, yield 86%). LC-MS(ESI)[M+H] ⁺ ＝226.1.

Step 3: Synthesis of N ⁶ -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ² -ethyl-3-(trifluoromethyl)pyrazine-2,6-diamine

At room temperature, in a 20 mL microwave reaction vial, 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine (232 mg, 1.0 mmol, 1 eq), 6-chloro-N-ethyl-3-(trifluoromethyl)pyrazin-2-amine (338 mg, 1.5 mmol, 1.5 eq), Pd ₂ (dba) ₃ (92 mg, 0.1 mmol, 10%), potassium phosphate (637 mg, 3.0 mmol, 3 eq) and XPhos (dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) (57 mg, 0.12 mmol, 12%) were dissolved in anhydrous tert-butanol (15 mL) and reacted under nitrogen protection at 90 °C under microwave conditions for 16 hours. After the reaction was completed, the reaction solvent was directly dried by spun-drying, and the target compound (59.7 mg, yield 14%) was obtained by Prep-HPLC separation and purification. LC-MS (ESI) [M+H] ⁺ = 422.4; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.91-7.86 (m, 1H), 7.76 (s, 2H), 7.69 (s, 1H), 7.34 (s, 1H), 5.88 (s, 1H), 3.31 (tt, J = 7.1, 3.5 Hz, 1H), 3.12-3.01 (m, 2H), 1.97 (s, 6H), 1.02 (t, J = 7.1 Hz, 3H), 0.99-0.85 (m, 4H).

Embodiment 63

N ⁶ -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ² -ethyl-3-(trifluoromethyl)pyridine-2,6-diamine

Step 1: Synthesis of 6-chloro-N-ethyl-3-(trifluoromethyl)pyridin-2-amine

At 0°C, 6-chloro-3-(trifluoromethyl)pyridin-2-amine (0.98g, 5mmol, 1.0eq) was dissolved in DMF (10mL), potassium tert-butoxide (0.84g, 7.5mmol, 1.5eq) was added in batches, and then iodoethane (1.17g, 7.5mmol, 1.5eq) was slowly added dropwise at 0°C, and the temperature of the reaction system was raised to room temperature, and the reaction was continued for 16 hours. After the reaction was completed by LC-MS detection, water was added to the reaction system, extracted with ethyl acetate (30mL*3), and washed with water and saturated brine respectively. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (960mg, yield 85%). LC-MS(ESI)[M+H] ⁺ ＝225.1.

Step 2: Synthesis of N ⁶ -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ² -ethyl-3-(trifluoromethyl)pyridine-2,6-diamine

At room temperature, in a 20 mL microwave reaction bottle, 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine (697 mg, 3.0 mmol, 1.5 eq), 6-chloro-N-ethyl-3-(trifluoromethyl)pyridin-2-amine (450 mg, 2 mmol, 1.0 eq), Pd ₂ (dba) ₃ (183 mg, 0.2 mmol, 10%), potassium phosphate (1.27 g, 6.0 mmol, 3 eq) and XPhos (114 mg, 0.24 mmol, 12%) were dissolved in anhydrous tert-butyl alcohol (15 mL), and reacted at 90°C under a nitrogen atmosphere for 3 hours under microwave conditions. After the reaction was completed, the reaction solvent was directly dried by LC-MS, and the target compound (93 mg, yield 53%) was obtained by separation and purification by Prep-HPLC. LC-MS(ESI)[M+H] ⁺ =421.4; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.95(s,1H),7.75(s,2H),7.49(d,J＝8.4Hz,1H),6.17(t,J＝5.5Hz,1H),6.12(d,J＝8.4Hz,1H),6.05(s,1 H), 3.42 (d, J = 5.5Hz, 1H), 3.25 (t, J = 6.6Hz, 2H), 1.96 (s, 6H), 1.03 (t, J = 7.0Hz, 3H), 0.97 (d, J = 5.6Hz, 4H).

Embodiment 64

Reference Example 63, Synthesis Example 64.

Embodiment 65

(2-((2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-chloropyrimidin-4-yl)aminophenyl)dimethylphosphine oxide

Step 1: Synthesis of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Dissolve 2,4,5-trichloropyrimidine (2.17 g, 11.82 mmol, 1.0 eq) in isopropanol (20 mL), add (2-aminophenyl) dimethylphosphine oxide (1.0 g, 5.91 mmol, 0.5 eq), then add DIEA (N,N-diisopropylethylamine) (2.29 g, 17.73 mmol, 1.5 eq), and react at 60°C for 16 hours. After the reaction is completed, the reaction solvent is directly dried, and the target compound is separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain the target compound (1.0 g, yield 53%). LC-MS(ESI)[M+H] ⁺ ＝316.0.

Step 2: Synthesis of (2-((2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-chloropyrimidin-4-yl)aminophenyl)dimethylphosphine oxide

(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (136 mg, 0.43 mmol, 1.0 eq) and 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (100 mg, 0.43 mmol, 1.0 eq) were dissolved in toluene (10 mL), and _Pd2 (dba) ₃ (tris(dibenzylideneacetone)dipalladium) (39 mg, 0.04 mmol, 10%), xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) (41 mg, 0.09 mmol, 0.2 eq) and _Cs2CO3 (cesium carbonate) (420 mg, 1.29 mmol, 3.0 eq) were _added and reacted at 110°C for 16 hours. The product was detected by LC-MS, water was added to the reaction system, extracted with ethyl acetate (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC (C18, 10 mmol/L NH ₃ in water, MeCN) to obtain the target compound (17 mg, yield 7%). LC-MS (ESI) [M+H] ⁺ =512.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.35 (br s, 1H), 9.08 (br s,1H),8.34(s,1H),8.15(s,1H),7.73(s,2H),7.58-7.52(m,1H),7.34-7.30(m,1H),7.14-7.10( m,1H),5.81(s,1H),3.49-3.37(m,1H),1.96(s,6H),1.79(s,3H),1.75(s,3H),0.96-0.78(m,4H).

Embodiment 66

(2-((2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidine (4-pyridin-4-yl)amino)phenyl)dimethylphosphine oxide

Step 1: Synthesis of 2-chloro-N-[2-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine

Dissolve 2,4-dichloro-5-(trifluoromethyl)pyrimidine (800 mg, 3.69 mmol, 1.0 eq) in isopropanol (15 mL), add DIEA (N,N-diisopropylethylamine) (1.43 g, 11.07 mmol, 3.0 eq) and 2-(dimethylphosphoryl)aniline (624 mg, 3.69 mmol, 1.0 eq), and react at 50°C for 2 hours. After the reaction is completed, the reaction solvent is directly dried, and the target compound is separated and purified by flash chromatography (Silica gel, PE:EA＝1:1) to obtain the target compound (400 mg, yield 31%). LC-MS(ESI)[M+H] ⁺ ＝350.1.

Step 2: Synthesis of (2-((2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

2-Chloro-N-[2-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine (100 mg, 0.29 mmol, 1.0 eq) was dissolved in toluene (10 mL), and Xphos (dicyclohexyl[2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine) (CAS: 564483-18-7) (27 mg, 0.06 mmol, 0.2 eq), _Pd2 (dba) ₃ (tris(dibenzylideneacetone)dipalladium) (CAS: 51364-51-3) (52 mg, 0.06 mol, 0.2 eq) and _CS2CO3 were added _. (Cesium carbonate) (CAS: 534-17-8) (186 mg, 0.57 mmol, 2.0 eq) and 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazole-5-amine (66 mg, 0.29 mmol, 1.0 eq). The reaction was carried out at 60 ° C for 3 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried and separated by Prep-HPLC (C18, 30 mmol/L FA in water, MeCN) to obtain the target compound (17.7 mg, yield 11%). LC-MS (ESI) [M+H] ⁺ =546.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.93(s,1H),9.49(s,1H),8.41(s,1H),8.07(s,1H),7.74(s,2H),7.56(dd,J＝14.0,8.0Hz,1H),7.30(s,1H) ,7.16(t,J＝7.2Hz,1H),5.81(s,1H),3.31-2.78(m,1H),1.95(s,6H),1.74(d,J＝13.6Hz,6H),0.93-0.74(m,4H).

Embodiment 67

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -(2-(methylsulfonyl)phenyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 2,5-dichloro-N-(2-(methylsulfonyl)phenyl)pyrimidin-4-amine

Dissolve 2-methylsulfonylaniline (1.87 g, 10.9 mmol, 1.0 eq) in DMF (N, N-dimethylformamide) (20 mL), carefully add NaH (sodium hydrogen) (360 mg, 9.26 mmol, 0.85 eq, 60% wt) under nitrogen protection at 0°C, and react for 0.5 hours under nitrogen protection at 0°C. Then add 2,4,5-trichloropyrimidine (2 g, 10.9 mmol, 1.0 eq) in DMF (N, N-dimethylformamide) (20 mL), and react for 2 hours under nitrogen protection at 25°C. After the reaction is completed by LC-MS detection, the reaction solution is quenched with water (50 mL), extracted with ethyl acetate (100 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA=10:1) to obtain the target compound (0.15 g, yield 9%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.70(s,1H),8.51(s,1H),8.16(d,J=8.2Hz,1H),7.97(d,J=7.8Hz,1H),7.82(t,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H),3.30(s,3H).

Step 2: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -(2-(methylsulfonyl)phenyl)pyrimidine-2,4-diamine

1-Cyclopropyl-3-[1-(2H-1,2,3-triazol-2-yl)cyclopropyl]-1H-pyrazol-5-amine (87.6 mg, 0.38 mmol, 1.0 eq) and 2,5-dichloro-N-(2-methylsulfonylphenyl)pyrimidin-4-amine (120 mg, 0.38 mmol, 1.0 eq) were dissolved in dioxane (6 mL), Cs ₂ CO ₃ (cesium carbonate) (368.64 mg, 1.13 mmol, 3.0 eq) was added, and nitrogen was replaced. Xphos (dicyclohexyl[2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine) (35.96 mg, 0.08 mmol, 0.2 eq) and Xphos Pd G3 ((2-dicyclohexylphosphino--2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)] methanesulfonate palladium) (31.89 mg, 0.04 mmol, 0.1 eq), reacted at 100°C for 16 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (30 mL*3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC (C18, 0.05% NH ₃ H ₂ O in water, MeCN) to obtain the target compound (14.53 mg, yield 7%). LC-MS(ESI)[M+H] ⁺ =513.85. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.47(s,1H),9.23(s,1H),8.33(s,1H),8.26(s,1H),7.89(d,J＝7.8Hz,1H),7.74(s,2H),7.56(t,J＝7.4Hz,1H),7. 33(t,J＝7.6Hz,1H),5.79(s,1H),3.39-3.35(m,1H),3.27(s,3H),1.95(s,6H),0.93-0.86(m,2H),0.86-0.80(m,2H).

Embodiment 68

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -(4-fluorophenyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 6-chloro-N-ethyl-3-iodopyrazin-2-amine

At room temperature, 2,4,5-trichloropyrimidine (2g, 10.9mmol, 1.0eq) and 4-fluoroaniline (1.33g, 13mmol, 1.1eq) were dissolved in isopropanol (20mL), and then DIPEA (1.69g, 13mmol, 1.2eq) was slowly added and reacted at 90°C for 0.5 hours. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried and separated and purified by flash chromatography (Silica gel, PE:EA＝20:1) to obtain the target compound (2.4g, yield 85%). LC-MS(ESI)[M+H] ⁺ ＝258.1.

Step 2: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N ⁴ -(4-fluorophenyl)pyrimidine-2,4-diamine

At room temperature, 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine (232 mg, 1.0 mmol, 1.0 eq), 2,5-dichloro-N-(4-fluorophenyl)pyrimidin-4-amine (310 mg, 1.2 mmol, 1.2 eq), Pd ₂ (dba) ₃ (92 mg, 0.1 mmol, 10%), potassium phosphate (637 mg, 3.0 mmol, 3.0 eq) and XPhos (57 mg, 0.12 mmol, 12%) were dissolved in anhydrous tert-butyl alcohol (15 mL) in a 20 mL microwave reaction bottle, and the reaction was continued at 90°C under the protection of nitrogen for 16 hours. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried and separated and purified by Prep-HPLC to obtain the target compound (98.2 mg, yield 22%). LC-MS (ESI) [M+H]=454.3; ¹ H NMR (400MHz, DMSO-d ₆ )δ8.99(s,1H),8.88(s,1H),8.11(s,1H),7.72(s,2H),7.58-7.51(m,2H),7.07( t,J＝8.8Hz,2H),5.76(s,1H),3.32-3.29(m,1H),1.92(s,6H),0.89-0.78(m,4H).

Examples 69-74

Reference Examples 49, 52, 58, 61, Synthesis Examples 69-74.

Embodiment 75

N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl-1,1,1,3,3,3-d ₆ )-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of ethyl 2-(d ₃ )methyl-2-(2H-1,2,3-triazol-2-yl)(d ₃ )propionate

Dissolve ethyl 2-(2H-1,2,3-triazol-2-yl)acetate (1g, 6.45mmol, 1.0eq) in N,N-dimethylformamide (10mL), add sodium hydride (741.43mg, 19.35mmol, 3.0eq) at 0°C, react for 0.5 hours, add deuterated iodomethane (1.18ml, 19.35mmol, 3.0eq), and continue to react at 0°C for 0.5 hours. Add saturated aqueous ammonium chloride solution (20mL) to the reaction solution to quench, add water (20mL), extract with ethyl acetate (30mL*2), combine the organic phases, The organic phase was dried, concentrated in vacuo, and then purified by column chromatography (Silica gel, PE:EA=5:1) to obtain the target product (500 mg, yield 41%). LC-MS (ESI) [M+H] ⁺ = 190.5; ¹ H NMR (400MHz, CDCl ₃ ) δ7.68-7.62 (m, 2H), 4.20-4.13 (m, 2H), 1.22-1.17 (m, 3H).

Step 2: Synthesis of 4-(d ₃ )methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)(5,5,5-d ₃ )valeronitrile

Acetonitrile (0.28ml, 5.28mmol, 2.0eq) was dissolved in tetrahydrofuran (10mL), and n-butyl lithium (2.11mL, 5.28mmol, 2.0eq) was added under nitrogen protection at -78°C. After reacting for 1 hour, 2-( ^2H3 )methyl- _2- (2H-1,2,3-triazol-2-yl)( _d3 )propionic acid ethyl ester (500mg, 2.64mmol, 1.0eq) was added, and the reaction was continued at -78°C for 1 hour. Saturated aqueous ammonium chloride solution (20mL) was added to the reaction solution to quench, water (20mL) was added, and methyl tert-butyl ether (30mL*2) was extracted. The aqueous phase was adjusted to pH 4-5 with 1M hydrochloric acid, extracted with ethyl acetate (30mL*3), and the organic phases were combined, dried, concentrated in vacuo, and slurried with petroleum ether (5mL) to obtain the target product (400mg, yield 82%). LC-MS (ESI) [M+H] ⁺ =185.1; ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.95 (s, 2H), 3.92 (s, 2H).

Step 3: Synthesis of 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)(1,1,1,3,3,3-d ₆ )propan-2-yl]-1H-pyrazole-5-amine

4-(d ₃ )methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)(5,5,5-d ₃ )pentanenitrile (400 mg, 2.17 mmol, 1.0 eq) was dissolved in ethanol (5 mL), cyclopropylhydrazine (313.13 mg, 4.34 mmol, 2.0 eq) and hydrogen chloride (0.4 mL, 10.86 mmol, 5.0 eq) were added, and the mixture was reacted at 70° C. for 16 hours. The reaction solution was concentrated in vacuo, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried, concentrated in vacuo, and then purified by column chromatography (Silica gel, PE:EA=1:1) to obtain the target product (200 mg, yield 38%). LC-MS (ESI) [M+H] ⁺ =239.3, ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.73 (s, 2H), 5.11 (s, 2H), 4.80 (s, 1H), 3.15-3.07 (m, 1H), 0.89-0.86 (m, 4H).

Step 4: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl-1,1,1,3,3,3- _d6 )-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

1-Cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)(1,1,1,3,3,3-d ₆ )propan-2-yl]-1H-pyrazol-5-amine (100 mg, 0.42 mmol, 1.0 eq) was dissolved in dioxane (3 mL), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (94.66 mg, 0.42 mmol, 1.0 eq) and 4-methylbenzene-1-sulfonic acid (36.13 mg, 0.21 mmol, 0.5 eq) were added, and the mixture was reacted at 90° C. for 2 hours. The reaction solution was prepared by reverse phase (0.1% ammonia solution, acetonitrile) to obtain the target compound (57.74 mg, yield 32%). LC-MS(ESI)[M+H] ⁺ =428.1; ¹ HNMR (400MHz, DMSO-d ₆ )δ8.14(s,1H),7.75(s,2H),7.21-7.09(m,1H),5.92(s,1H),3.47-3.41(m,1H),3.30-3.26(m,2H),1.04(t,J=7.0Hz,3H),0.96-0.89(m,4H).

Examples 76-77

Refer to Example 17, Synthetic Examples 76-77.

Embodiment 78

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d ₃ )-1H-pyrazol-5-yl)-N 4-(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of di-tert-butyl 1-(methyl-d ₃ )hydrazine-1,2-dicarboxylate

Add di-tert-butyl hydrazine-1,2-dicarboxylate (15.00g, 64.58mmol, 1.0eq) to a solution of tetrahydrofuran (300mL), slowly add sodium hydride (3.36g, 83.95mmol, 60%, 1.3eq) at 0℃ under nitrogen protection, react at 0℃ for 1 hour, then slowly add deuterated iodomethane (6.55g, 45.20mmol, 0.7eq), and react at 25℃ for 2 hours. After the reaction is completed by LC-MS detection, the reaction solution is quenched with saturated ammonium chloride solution (300mL) and extracted with ethyl acetate (500mL*3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (7.0g, yield 43%). LC-MS(ESI)[M+23] ⁺ ＝272.2.

Step 2: Synthesis of (methyl-d ₃ )hydrazine

Add di-tert-butyl 1-(methyl-d ₃ )hydrazine-1,2-dicarboxylate (10.00 g, 40.11 mmol, 1.0 eq) to dioxane hydrochloride solution (100 mL, 4 M) and react at 25°C for 2 hours. After the reaction was completed by TLC, the reaction solvent was dried to obtain the target compound (4.10 g, crude product). It was used directly in the next step without further purification.

Step 3: Synthesis of 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d ₃ )-1H-pyrazol-5-amine

(Methyl-d ₃ )hydrazine (1.00 g, 6.11 mmol, 30%, 1.0 eq, crude product, obtained from the previous step) was added to an ethanol (10 mL) solution, and 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile (0.36 g, 2.02 mmol, 0.3 eq) was added, and the mixture was reacted at 90°C for 3 hours. After the reaction was completed, the reaction solvent was dried by spin drying, and the target compound was separated and purified by reverse phase chromatography (1%-10% ACN in Water) to obtain the target compound (0.5 g, yield 12%). LC-MS (ESI) [M+H] ⁺ = 210.2.

Step 4: Synthesis of N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d ₃ )-1H-pyrazol-5-yl)-N 4 -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d ₃ )-1H-pyrazol-5-amine (241 mg, 1.15 mmol, 1.0 eq) was added to 1,4-dioxane (1 mL), and then 2-chloro-N-(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidin-4-amine (265 mg, 1.15 mmol, 1.0 eq) and p-toluenesulfonic acid (109 mg, 0.58 mmol, 0.5 eq) were added, and the reaction was carried out at 90° C. for 12 hours. After the reaction was completed by LC-MS detection, the reaction solvent was dried and separated and purified by Prep-HPLC (C18, 0.1% FA in water, MeCN) to obtain the target compound (25.8 mg, yield 6%). LC-MS (ESI) [M+H] ⁺ = 404.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.14 (s, 1H), 7.75 (s, 2H), 7.14 (s, 1H), 5.94 (s, 1H), 1.97 (s, 6H).

Embodiment 79

N ² -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of N ² -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

4-Methylbenzene-1-sulfonic acid hydrate (82 mg, 0.43 mmol, 1.0 eq) was added to a mixture of 2-chloro-N-(ethyl-d5)-5-(trifluoromethyl)pyrimidin-4-amine (100 mg, 0.43 mmol, 1.0 eq) and 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazole-5-amine (100 mg, 0.43 mmol, 1.0 eq) in 1,4-dioxane (2 mL), and the mixture was reacted at 90° C. for 3 h under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solvent was directly dried and separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the target compound (25 mg, yield 13%). LC-MS(ESI)[M+H] ⁺ =425.0; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.34(s,1H),8.14(s,1H),7.82(s,2H),7.12(s,1H),5.77(s,1H),3.48-3.43(m,1H),1.65-1.54(m,4H),0.97-0.87(m,4H).

Embodiment 80

N ² -(1-cyclopropyl-3-(2-(4-methyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 4-methyl-2H-1,2,3-triazole

2-Benzyl-4-methyl-2H-1,2,3-triazole (4.00 g, 23.09 mmol, 1.0 eq) was added to a mixture of methanol (40 mL) and water (40 mL), and acetic acid (4 mL), 10% palladium carbon (0.40 g, 3.76 mmol, 0.16 eq) and 20% palladium hydroxide (0.40 g, 2.85 mmol, 0.12 eq) were added, and the mixture was reacted at 60°C for 48 hours. After the reaction was completed by LC-MS detection, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, saturated sodium bicarbonate solution was added to adjust the pH to 9, and the mixture was extracted with ethyl acetate (300 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (1.90 g, crude product), a transparent liquid. LC-MS (ESI) [M+H] ⁺ = 84.1. It was used directly in the next step without further purification.

Step 2: Synthesis of methyl 2-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl) propionate

4-Methyl-2H-1,2,3-triazole (0.40 g, crude product, obtained from the previous step) was added to N,N-dimethylformamide (4 mL), potassium tert-butoxide (0.80 g, 7.40 mmol, 1.5 eq) and methyl 2-bromo-2-methylpropionate (1.10 g, 5.92 mmol, 1.2 eq) were added at 0°C, and the mixture was reacted at 25°C for 12 hours. After the reaction was completed by LC-MS detection, it was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA＝5:1) to obtain the target compound (0.20 g, yield 23%). LC-MS(ESI)[M+H] ⁺ ＝184.2.

Step 3: Synthesis of 4-methyl-4-(4-methyl-2H-1,2,3-triazol-2-yl)-3-oxopentanonitrile

Acetonitrile (89 mg, 2.18 mmol, 2.0 eq) was added to tetrahydrofuran (8 mL), and n-butyl lithium (139.6 mg, 2.18 mmol, 2.0 eq) was added at -78 ° C. The mixture was reacted for 1 hour at -78 ° C. Then methyl 2-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl) propionate (200 mg, 1.09 mmol, 1.0 eq) was added and the reaction was continued for 1 hour. After the reaction was completed by LC-MS detection, the reaction solution was poured into a saturated ammonium chloride solution and extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (200.0 mg, crude product). LC-MS (ESI) [M+H] ⁺ = 193.0. It was used directly in the next step without further purification.

Step 4: Synthesis of 1-cyclopropyl-3-(2-(4-methyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazole-5-amine

4-Methyl-4-(4-methyl-2H-1,2,3-triazol-2-yl)-3-oxopentanonitrile (200 mg, crude product, obtained from the previous step) was added to ethanol (10 mL), and cyclopropylhydrazine hydrochloride (170 mg, 1.56 mmol, 1.5 eq) was added at 25°C, and the reaction was carried out at 90°C for 2 hours. After the reaction was completed by LC-MS detection, the reaction solvent was dried, and the residue was dissolved in methanol, and separated and purified by flash chromatography (C18, 12% MeCN in water) to obtain the target compound (150 mg, yield 59%). LC-MS (ESI) [M+H] ⁺ = 247.2.

Step 5: Synthesis of N ² -(1-cyclopropyl-3-(2-(4-methyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

1-Cyclopropyl-3-(2-(4-methyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-amine (140 mg, 0.57 mmol, 1.0 eq) was added to 1,4-dioxane (3 mL), and then 2-chloro-N-(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidin-4-amine (131 mg, 0.57 mmol, 1.0 eq) and p-toluenesulfonic acid (32 mg, 0.17 mmol, 0.3 eq) were added, and the mixture was reacted at 90°C for 3 hours. After the reaction was completed by LC-MS, the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the target compound (24.6 mg, yield 20%). LC-MS(ESI)[M+H] ⁺ =434.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.95(s,1H),8.16(s,1H),7.77(s,2H),7.12-6.80(m,1H),5.98(s,1H),3.46-3 .42(m,2H),3.35-3.28(m,2H),1.97(s,6H),1.08-1.05(m,3H),0.99-0.96(m,4H).

Embodiment 81

N ² -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -(2-methoxyethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 2-chloro-4-[(2-methoxyethyl)amino]-5-(trifluoromethyl)pyrimidine

2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.0 g, 4.61 mmol, 1.0 eq) was added to a solution of dichloromethane (10 mL). N,N-diisopropylethylamine (1.19 g, 9.2 mmol, 2.0 eq) and 2-methoxyethylamine (0.31 g, 4.15 mmol, 0.9 eq) were slowly added at 25°C under nitrogen protection. The mixture was reacted for 16 hours at 25°C. After the reaction was completed by LC-MS detection, the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA＝10:1) to obtain the target compound (300 mg, yield 25%). LC-MS(ESI)[M+H] ⁺ ＝256.0.

Step 2: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-(2-methoxyethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

2-Chloro-4-[(2-methoxyethyl)amino]-5-(trifluoromethyl)pyrimidine (200 mg, 0.78 mmoL, 1.0 eq) was added to 1,4-dioxane (4 mL), and 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazole-5-amine (182 mg, 0.78 mmoL, 1.0 eq) and p-toluenesulfonic acid (40 mg, 0.23 mmoL, 0.3 eq) were added at 25°C, and the mixture was reacted at 90°C for 3 hours. After the reaction was completed by LC-MS, the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the target compound (100.21 mg, yield 7%). LC-MS(ESI)[M+H] ⁺ =452.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.26(s,1H),8.16(s,1H),7.75(s,2H),7.02(s,1H),5.89(s,1H),3.46-3.32(m,5H),3.18(s,3H),1.95(s,6H),0.96-0.87(m,4H).

Embodiment 82

N ² -(1-cyclopropyl-3-(2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of 1-benzyl-4,5-dimethyl-1H-1,2,3-triazole

Dissolve 3,3-dimethoxy-2-butanone (10.00 g, 75.67 mmol, 1.0 eq) in dimethyl sulfoxide (20 mL), then add p-methylbenzenesulfonyl hydrazide (14.09 g, 75.67 mmol, 1.0 eq), react at room temperature for 1 hour, then add benzylamine (8.51 g, 79.45 mmol, 1.05 eq), and continue to react at 80°C for 4 hours. After the reaction is completed by LC-MS detection, water (100 mL) is added to the reaction solution, and extracted with ethyl acetate (50 mL*3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and separated and purified by reverse phase chromatography (C18, 0.1% TFA in water, MeCN) to obtain the target compound (6.00 g, yield 42%). LC-MS (ESI) [M+H] ⁺ = 188.2.

Step 2: Synthesis of 4,5-dimethyl-2H-1,2,3-triazole

1-Benzyl-4,5-dimethyl-1H-1,2,3-triazole (3.00 g, 16.02 mmol, 1.0 eq) was added to a mixture of methanol (5 mL), water (5 mL), and acetic acid (1 mL). Palladium carbon (225 mg, 1.60 mmol, 0.1 eq) and palladium hydroxide (225 mmol, 1.60 mmol, 0.1 eq) were added under nitrogen protection. After hydrogen replacement, the mixture was reacted at 60 ° C for 16 hours. After the reaction was completed by LC-MS detection, the reaction solution was filtered and the filtrate was concentrated to obtain the target compound (960 mg, yield 61%). LC-MS (ESI) [M+H] ⁺ = 98.1. It was used directly in the next step without further purification.

Step 3: Synthesis of methyl 2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-2-methylpropanoate

Potassium carbonate (4.27 g, 30.89 mmol, 2.0 eq) was added to a mixture of 4,5-dimethyl-2H-1,2,3-triazole (1.5 g, 15.44 mmol, 1.0 eq) and methyl 2-bromo-2-methylpropionate (2.80 g, 15.44 mmol, 1.0 eq) in methanol (15 mL), and the mixture was reacted at 80°C for 3 hours under nitrogen protection. After the reaction was completed, the filtrate was filtered, concentrated, and separated and purified by reverse phase chromatography (C18, 15% MeCN in water) to obtain the target compound (525 mg, yield 17%). LC-MS (ESI) [M+H] ⁺ = 198.1.

Step 4: Synthesis of 4-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-4-methyl-3-oxopentanonitrile

At -78 ° C, under nitrogen protection, acetonitrile (208 mg, 5.07 mmol, 2.0 eq) was added to a mixture of n-butyl lithium (0.32 mL, 5.07 mmol, 2.0 eq) in tetrahydrofuran (5 mL), stirred for 1 hour, and then 2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-2-methylpropionic acid methyl ester (500 mg, 2.54 mmol, 1.0 eq) was added, and the reaction was continued for 1 hour. After the reaction was completed by LC-MS detection, the reaction solution was poured into ice water, the pH was adjusted to 6 with 1M hydrochloric acid aqueous solution, and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (500 mg, yield 95%). LC-MS (ESI) [M+H] ⁺ = 207.1. It was used directly in the next step without further purification.

Step 5: Synthesis of 1-cyclopropyl-3-(2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazole-5-amine

Concentrated hydrochloric acid (0.2mL, 2.40mmol, 2.47eq) was added to a mixture of 4-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-4-methyl-3-oxopentanonitrile (200mg, crude product, obtained from the previous step) and cyclopropylhydrazine hydrochloride (140mg, 1.94mmol, 2.0eq) in ethanol (2mL), and reacted at 90°C for 2 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solvent was dried, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (30mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (200mg, yield 79%). LC-MS (ESI) [M+H] ⁺ = 261.2, without further purification, it was directly used in the next reaction.

Step 6: Synthesis of N ² -(1-cyclopropyl-3-(2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-yl)-N ⁴ -(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidine-2,4-diamine

p-Toluenesulfonic acid (132 mg, 0.77 mmol, 1.0 eq) was added to a mixture of 1-cyclopropyl-3-(2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-amine (200 mg, crude product, obtained from the previous step) and 2-chloro-N-(ethyl-d ₅ )-5-(trifluoromethyl)pyrimidin-4-amine (177 mg, 0.77 mmol, 1.0 eq) in 1,4-dioxane (2 mL), and reacted at 90° C. for 3 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the mixture was filtered, the filtrate was concentrated, and then separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the target compound (17.58 mg, yield 5%). LC-MS (ESI) [M+H] ⁺ = 425.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.30 (s, 1H), 8.14 (s, 1H), 7.16 (s, 1H), 5.92 (s, 1H), 3.46-3.40 (m 1H),2.12(s,6H),1.87(s,6H),0.95-0.90(m,4H).

Embodiment 83

2-((2-((3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)ethanol

Step 1: Synthesis of 2-((2-((3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)ethanol

N-(2-((tert-butyldimethylsilyloxy)ethyl)-2-chloro-5-(trifluoromethyl)pyrimidin-4-amine (500 mg, 1.41 mmol, 1.0 eq) was added to 1,4-dioxane (5 mL), and 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (326 mg, 1.41 mmol, 1.50 eq) and p-toluenesulfonic acid (242 mg, 1.41 mmol, 1.0 eq) were added, and the mixture was reacted at 90°C for 12 hours. After the reaction was completed by LC-MS, the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by flash chromatography and separated and purified by Prep-HPLC (C18, 0.1% FA in water, MeCN) to obtain the target compound (60 mg, yield 10%). LC-MS (ESI) [M+H] ⁺ = 438.2; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (s, 1H), 7.70 (s, 2H), 5.99 (s, 1H), 3.67 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.35 (dd, J = 4.0, 2.8 Hz, 1H), 2.06 (s, 6H), 1.09-1.00 (m, 4H).

Embodiment 84

N ² -(3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

Step 1: Synthesis of methyl 3-(2H-1,2,3-triazol-2-yl)cyclobutane-1-carboxylate

At 25°C, under nitrogen protection, diisopropyl azodicarboxylate (3.11 g, 15.37 mmol, 1.0 eq) was added to a mixture of triphenylphosphine (4.03 g, 15.37 mmol, 1.0 eq), methyl 3-hydroxycyclobutane-1-carboxylate (2.00 g, 15.37 mmol, 1.0 eq) and 2H-1,2,3-triazole (1.06 g, 15.37 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and reacted for 2 hours. After the reaction was completed by LC-MS detection, it was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the target compound (1.00 g, yield 36%). LC-MS (ESI) [M+H] ⁺ = 182.1.

Step 2: Synthesis of 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-3-oxopropionitrile

At -78 ° C, under nitrogen protection, n-butyl lithium (2.5M in hexane, 4.42mL, 11.04mmol, 2.0eq) was added to a mixture of acetonitrile (543mg, 11.04mmol, 2.0eq) in tetrahydrofuran (10mL), stirred for 1 hour, and then 3-(2H-1,2,3-triazol-2-yl) cyclobutane-1-carboxylic acid methyl ester (1000mg, 5.52mmol, 1.0eq) was added and reacted for 1 hour. After the reaction was completed by LC-MS detection, the reaction solution was poured into water, 1M hydrochloric acid was added to adjust the pH to 6, and extracted with ethyl acetate (100mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (1.00g, yield 95%). LC-MS (ESI) [M+H] ⁺ = 191.1. It was used directly in the next step without further purification.

Step 3: Synthesis of 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazole-5-amine

Hydrochloric acid (0.35 mL, 9.46 mmol, 6 M in H ₂ O, 2.0 eq) was added to 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutane In a mixture of ethanol (9 mL), cyclopropylhydrazine hydrochloride (341 mmol, 4.73 mmol, 1.0 eq) and ethanol (9 mL) were reacted at 90 ° C for 2 hours under nitrogen protection. After the reaction was completed by LC-MS detection, saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8, and extracted with ethyl acetate (40 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (1.00 g, yield 86%). LC-MS (ESI) [M + H] ⁺ = 245.4. It was used directly in the next reaction without further purification.

Step 4: Synthesis of N ² -(3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

p-Toluenesulfonic acid (70 mg, 0.41 mmol, 0.5 eq) was added to a mixture of 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-amine (200 mg, 0.82 mmol, 1.0 eq, crude product, obtained from the previous step) and 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (184 mg, 0.82 mmol, 1.0 eq) in dioxane (2 mL), and the mixture was reacted at 90° C. for 16 hours under nitrogen protection. After the reaction was completed by LC-MS detection, the reaction solution was separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the target compound (7.39 mg, yield 2%). LC-MS(ESI)[M+H] ⁺ =434.2; ¹ H NMR (400MHz, DMSO-d ₆ )δ9.31(s,1H),8.16(s,1H),7.83(s,2H),7.15(s,1H),6.30(s,1H),5.34-5.26(m,1H),3.54-3.41(m,4 H),2.93-2.86(m,2H),2.67-2.61(m,2H),1.12(t,J＝7.2Hz,3H),1.01–0.97(m,2H),0.92-0.87(m,2H).

The structure of reference compound 1 (DNL151) is as follows: (Compound 78 in CN109311857B);

The structure of reference compound 2 is as follows: (Compound 34 in CN109311857B).

Biology Section

Experimental Example 1: In vitro evaluation of the inhibitory activity of compounds against LRRK2 kinase

1. Experimental materials:

1) Reaction solution: 50 mM HEPES (PH 7.5) (manufacturer: GIBCO; catalog number: 15630-080); 10 mM MgCl ₂ (manufacturer: Sigma; catalog number: 63069); 1 mM EDTA (manufacturer: Invitrogen; catalog number: AM9260G); 0.01% Brij35 (manufacturer: Millipore; catalog number: 203728); 2 mM DTT (manufacturer: Sigma; catalog number: 43816).

2) Detection solution: TR-FRET Dilution Buffer (Manufacturer: Thermo; Product No.: PV3574).

3) LRRK2 human recombinant protein: The recombinant full-length human LRRK2 protein was expressed in insect Sf9 cells using baculovirus using a GST tag (manufacturer: Thermo; catalog number: PR8604B).

4) Substrate: 0.4μm Fluorescein-ERM (LRRKtide) peptide (Manufacturer: Thermo; Catalog Number: PV4901); 38μm ATP (Manufacturer: Sigma; Catalog Number: A7699).

2. Detection method:

Time-resolved fluorescence resonance energy transfer (TR-FRET): TR-FRET combines time-resolved fluorescence detection technology and fluorescence resonance energy transfer (FRET) detection technology. In the experiment, when biological molecules interact with each other, the distance between the donor and acceptor fluorescent groups is shortened. If the donor is excited, it will transfer its emission light energy to the acceptor. Using lanthanide fluorescent groups as donors, the emission light has a long half-life. The excitation and emission of the donor and acceptor fluorescent groups can be detected after the short half-life background fluorescence disappears, reducing the background and improving the signal-to-noise ratio, thereby improving the sensitivity.

1) Add the DMSO solution of the test compound to a 384-well microplate using the Echo550 non-contact nanoliter acoustic dispensing system.

2) Prepare the enzyme and peptide mixed solution (2nM LRRK2 human recombinant protein + 0.4μm Fluorescein-ERM (LRRKtide) peptide) with the freshly prepared reaction solution, add 5μL to the 384 microplate containing the existing compound, and centrifuge at 1000rpm/min for 1min. Incubate at room temperature for 15min.

3) Add 5 μL 38 μM ATP and centrifuge at 1000 rpm/min for 1 min. Incubate at room temperature for 120 min.

4) Add detection reagent: purchased from Thermofisher (Cat. No. PV4900) 0.25nM Tb-pERM (pLRRKtide) Antibody and 10 mM EDTA were centrifuged at 1000 rpm/min for 1 min and reacted at room temperature for 30 min.

5) Envison was used to detect the TR-TRET fluorescence signal, mirror 447 (D400/D505), filter 275 (520nm) and 102 (485nm).

6) The inhibition of the compound on enzyme activity was calculated by the signal ratio (520 nm/485 nm), and the IC ₅₀ value was calculated by fitting the curve using the software XLfit5.

Experimental results: The compounds of the present invention have a strong inhibitory effect on LRRK2 kinase.

Table 1. Results of the inhibitory activity test of the compounds on LRRK2 kinase

A: IC ₅₀ ≤3nM; B: 3nM<IC ₅₀ ≤20nM

Experimental Example 2: In vitro evaluation of the inhibitory activity of compounds against p S935

1. Detection mechanism:

This experiment is designed to simply, quickly and directly detect the phosphorylation level of LRRK2 (Ser935, i.e. p S935) in cells. After cell membrane lysis, the kit can be used to detect phosphorylated LRRK2 (Ser935).

Phosphorylated LRRK2 (Ser935) was detected in a sandwich assay format using 2 different specific antibodies, one labeled with Eu ³⁺ -cryptate (donor) and the second labeled with d2 (acceptor). When the dyes are in close proximity, excitation of the donor with a light source (laser or flashlight) triggers fluorescence resonance energy transfer (FRET) to the acceptor, which in turn fluoresces at a specific location. Light wavelength (665nm). The specific signal is proportional to phosphorylated LRRK2 (Ser935). Detection of phosphorylated LRRK2 (Ser935).

2. Cell preparation:

1) Cell recovery:

HEK293T cells purchased from ATCC were taken out of liquid nitrogen and placed in a 37°C water bath. After the ice melted, the cells were transferred to a centrifuge tube containing 10 mL of complete medium and centrifuged at 1000 rpm/min for 5 min. The supernatant was discarded, resuspended with 15 mL of fresh complete medium and transferred to a T75 culture flask. The culture flask was placed in a 37°C, 5% CO ₂ incubator for culture, and the cell growth status was observed in time.

2) Cell passaging:

Cells can be passaged when they reach 80-90% confluence. Discard the supernatant, add 20-25mL PBS, and shake the culture flask several times. Discard the PBS, add 3-4mL trypsin to digest the cells, let stand for 1-2 minutes, add 10ml complete medium to terminate the digestion, and gently blow the cells until all cells fall off to form a single cell suspension. Transfer the single cell suspension to a centrifuge tube and centrifuge at 1000rpm/min for 5 minutes. Discard the supernatant, resuspend with fresh complete medium, and passage to a T150 culture flask at 1:5. Place the culture flask in a 37°C, 5% CO ₂ incubator and observe the cell growth status in time.

3) Cell cryopreservation:

Cryopreservation of cells with good cell growth and cell viability of more than 96% was performed. The collected cells were adjusted to a density of 5 x 10 ⁶ /mL with cell freezing solution, and then transferred to cell cryopreservation tubes, with 1 mL of cell suspension in each tube. The cryopreservation tubes containing cells were placed in a cryopreservation box and stored in a -80°C refrigerator overnight, and then transferred to liquid nitrogen for storage.

3. Experimental steps:

1. Day 1: HEK293T cell transfection

(1) Inoculate 30 ml of cell suspension (containing 30 x 10 ⁶ cells) in a 150 mm culture dish.

⑵Prepare transfection reagent: Add reagents in order: 2mL opti-MEM (manufacturer: Gibco; item number: 31985070) + 20μg DNA (manufacturer: AZENTA custom plasmid) + 60μL TansIT (manufacturer: MIRUS; item number: MIR 2300). Mix gently and let stand at room temperature for 20 minutes.

⑶ Add the prepared transfection reagent evenly into the 150 mm culture dish inoculated with cells, shake gently to mix, and place in a 37°C, 5% CO ₂ incubator for 24 hours.

2. The next day: Seeding the board

Collect the transfected cells and adjust the cell density to 0.2x 10 ⁶ /mL. Add 50 μL of the cell suspension to each well of a 384-well microplate (10,000 cells per well), centrifuge at 1000 rpm/min for 1 min. Place the 384-well microplate in a 37°C, 5% CO ₂ incubator and culture overnight.

3. Day 3: Compound Treatment and HTRF Detection

⑴ Prepare compounds: The storage concentration of the compounds is 10mM. When using, dilute the compounds to the required working concentration as required.

⑵ Add the compounds into the 384-well microplate using the TECAN instrument according to the Plate map. After adding the compounds, add DMSO and adjust the final DMSO concentration to 0.2%.

(3) After centrifugation at 1000 rpm/min for 1 min, place in a 37°C, 5% CO ₂ incubator and culture for 2 h.

(4) Prepare HTRF cell lysis buffer (manufacturer: Cisbio; catalog number: 6FLRKPEH): 4 mL Lysis buffer + 12 mL H ₂ O + 160 μL Blocking buffer.

⑸After 2 hours, add 16 μL of cell lysis buffer to each well and centrifuge at 1000 rpm/min for 1 min. Vibrate the plate at 800 rpm/min and room temperature for 30 min.

(6) Prepare HTRF antibody mixed solution (manufacturer: Cisbio; catalog number: 6FLRKPEH): 1600 μL = 40 μL Cryptate-antibody + 40 μL d2-antibody + 1520 μL H ₂ O.

⑺After 30 minutes, centrifuge at 1000 rpm/min for 2 minutes.

⑻Add 4 μL of antibody mixed solution to each well, centrifuge at 1000 rpm/min for 1 min, and incubate at room temperature for 20-24 h.

⑼Read the plate on Envision.

Experimental results: The compounds of the present invention have a strong inhibitory effect on p S935.

Table 2. Results of the inhibitory activity test of the compounds on pS935 in HEK293 cells expressing G2019S LRRK2

A: IC ₅₀ ≤5nM; B: 5<IC ₅₀ ≤20nM; C: 20<IC ₅₀ ≤50nM

Experimental Example 3: Pharmacokinetic Evaluation of Compounds

1. Test purpose:

LC-MS/MS was used to test the pharmacokinetic characteristics of the compounds in C57BL/6 mice.

2. Experimental materials:

C57BL/6 mice (male, 8 weeks old, body weight 25 g-30 g).

3. Experimental operation:

The pharmacokinetic characteristics of the compounds in rodents after oral administration were tested using a standard protocol. The test compounds and control compounds were prepared into 1 mg/mL suspensions and given to mice orally or intravenously. The solvent was 5% DMSO + 40% PEG400 + 55% CMC-Na (1%) aqueous solution.

Male C57BL/6 mice were used for this project. The intravenous (iv) dose was 1 mg/kg or 2 mg/kg; the oral gavage (po) dose was 5 mg/kg. The plasma of the intravenous group was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, and the plasma of the oral group was collected at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration.

Plasma samples were collected by centrifugation at about 4°C, 3000g, 15 min, and the supernatant was separated to obtain plasma samples within half an hour of collection. Plasma samples were stored in polypropylene tubes, quickly frozen on dry ice and kept at -80°C until LC-MS/MS analysis.

Add acetonitrile solution containing internal standard to precipitate protein, mix thoroughly, centrifuge and take supernatant for sampling, quantitatively analyze blood drug concentration by LC-MS/MS analysis method, and calculate pharmacokinetic parameters, such as peak time (T _max ), area under the drug-time curve (AUC), elimination half-life (T _1/2 ), clearance rate (CL), apparent tissue distribution of drug (Vss), etc.

The pharmacokinetic parameters of the compounds in the examples of the present invention in mice are shown in Table 3 below.

Table 3. Pharmacokinetic parameters of the compounds in mice

Experimental results: Compared with the control compound, the compound of the present invention has better in vivo pharmacokinetic properties and has drug potential.

Claims (33)

A compound represented by the following formula (I), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
in, X ₁ , X ₂ and X ₃ are each independently CR _X or N; If present, each _RX is independently H, deuterium, halogen, ^{-NRX1RX2 or -OR13} ; wherein, If present, each of ^RX1 and ^RX2 is independently H, deuterium, _C1-6 alkyl, C1-6 oxaalkyl, _C1-6 thiaalkyl, _C2-6 alkenyl, _C3-6 cycloalkyl or 4-6 membered heterocyclyl; said _C1-6 alkyl, _C1-6 oxaalkyl, _C1-6 thiaalkyl, _C2-6 alkenyl, _C3-6 cycloalkyl or _4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, _-NO2 , _-NH2 and _C1-3 alkyl; Alternatively, each pair of ^RX1 and ^RX2 together with the N atom to which they are commonly attached independently form a 4-8 membered heterocyclic group; the 4-8 membered heterocyclic group is optionally substituted by one or more substituents independently selected from deuterium, _halogen , -CN, -OH, -NO2, _-NH2 , _C1-3 alkyl and _C1-3 oxaalkyl; If present, each R ¹³ is independently H, deuterium, C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; said C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; R ₁ is deuterium, halogen, C _1-4 alkyl, C _2-6 alkenyl or C _3-6 cycloalkyl; the C _1-4 alkyl, C _2-6 alkenyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ; R ₂ is deuterium, halogen, -NR ²¹ R ²² , C _1-4 alkyl, C _1-4 oxaalkyl or C _1-4 thiaalkyl; the C _1-4 alkyl, C _1-4 oxaalkyl or C _1-4 thiaalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; wherein, If present, R ²¹ and R ²² are each independently H, deuterium, C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, phenyl or 5-6 membered heteroaryl; said C _1-6 alkyl, C _1-6 oxaalkyl, C _1-6 thiaalkyl, C _2-6 alkenyl, phenyl or 5-6 membered heteroaryl being optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , dimethylphosphoryl, phosphate, formamido, acetamido, methanesulfonamido, ethanesulfonamido, methanesulfonyl, ethanesulfonyl and C _1-3 alkyl; Alternatively, _R1 and _R2 together form a ring Q optionally substituted by one or more _RQ , wherein the ring Q is phenyl or pyrrolyl; If present, each R _Q is independently deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 oxaalkyl, C _3-10 cycloalkyl or 4-10 membered heterocyclyl; said C _1-3 alkyl, C _1-3 oxaalkyl, C _3-10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 oxaalkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; wherein said substituents are C _1-3 alkyl, C _1-3 oxaalkyl, C 1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl. _{The 3-6-} membered cycloalkyl or 4-6-membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , Substituted with a C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl substituent; R ₃ is deuterium, halogen, -CN, -OH, -NH ₂ , C _3-10 cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclyl; the C _3-10 cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; If present, each R _W is independently deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl or C _3-6 cycloalkyl; said C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl; m is 0, 1, 2 or 3; L does not exist or is in, R ₄ and R ₅ are each independently H, deuterium, halogen, -CN, -OH, -SH, -NH ₂ , C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ; Alternatively, R ₄ and R ₅ together with the C atom to which they are commonly attached form a C _3-6 cycloalkyl group; the C _3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; when for When R _W is not an optionally substituted C _3-6 cycloalkyl group or a C _1-3 alkyl group optionally substituted by a halogen group, and R ₄ and R ₅ are not H or an optionally substituted C _1-3 alkyl group; When L does not exist, for When R _W is an optionally substituted C _3-6 cycloalkyl group, R ₃ is not a heterocyclic group having an oxo group; When L does not exist, for When R ₃ is not halogen, -CN or C _3-6 cycloalkyl; The heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from S, O and N. A compound represented by the following formula (A1) or (A2), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
in, _RX is H ^, deuterium, ^-NRX1RX2 or ^-OR13 ; wherein, If present, ^RX1 and ^RX2 are each independently H, deuterium, C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; said C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; Alternatively, ^RX1 and ^RX2 together with the N atom to which they are commonly attached form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, _-NO2 , _-NH2 and _C1-3 alkyl; If present, R ¹³ is C _1-3 alkyl or C _3-6 cycloalkyl; said C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; If present, each R _Q is independently deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; said C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl; R ₃ is deuterium, halogen, -CN, -OH, -NH ₂ , C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; the C _3-10 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; Each R _W is independently deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; _R4 and _R5 are each independently H, deuterium, _C1-3 alkyl or _C3-6 cycloalkyl; the _C1-3 alkyl or _C3-6 cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, _-OH , -NO2 and _-NH2 ; Alternatively, R ₄ and R ₅ together with the C atom to which they are commonly attached form a C _3-6 cycloalkyl group; the C _3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; m is 1 or 2; n is 0, 1 or 2. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: _RX is H or deuterium. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof; or or a pharmaceutically acceptable salt thereof, wherein R _X is -NR ^X1 R ^X2 ; wherein R ^X1 and R ^X2 are each independently H, deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; or, R ^X1 and R ^X2 together with the N atom to which they are commonly attached form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; Preferably, ^RX1 and ^RX2 are each independently H, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl; or, ^RX1 and ^RX2 together with the N atom to which they are commonly attached form The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R _x is -OR ¹³ ; wherein R ¹³ is methyl. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: _RX is H, -NHCH ₃ , or -OCH ₃ . The compound according to any one of claims 2 to 6, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R _Q is independently deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl; Preferably, each R _Q is independently deuterium, -F, -Cl, -Br, -CN, -OH, -NO ₂ , -NH ₂ , methyl, ethyl, cyclopropyl or cyclobutyl; the methyl, ethyl, cyclopropyl or cyclobutyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ and -NH ₂ ; More preferably, each R _Q is independently -F, -Cl, -CN, methyl, trifluoromethyl or cyclopropyl. The compound according to any one of claims 2 to 7, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ₃ is deuterium, halogen, -CN, -OH, -NH ₂ , C _3-8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; the C _3-8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; Preferably, _R3 is -CN, _C4-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; the _C4-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted by one or more substituents independently selected from oxo, _C1-3 alkyl, _C1-3 alkoxy and 4-6 membered heterocyclyl; More preferably, _R3 is -CN, a 5-membered heteroaryl, a 6-membered heteroaryl, a 9-membered fused heteroaryl, a 10-membered fused heteroaryl, a 4-membered monoheterocyclic group, a 5-membered monoheterocyclic group, a 6-membered monoheterocyclic group, a 7-membered bridged heterocyclic group, an 8-membered bridged heterocyclic group, a 7-membered spiro heterocyclic group, 8-membered spiro heterocyclic group or 9-membered spiro heterocyclic group; the 5-membered heteroaryl, 6-membered heteroaryl, 9-membered fused ring heteroaryl, 10-membered fused ring heteroaryl, 4-membered monoheterocyclic group, 5-membered monoheterocyclic group, 6-membered monoheterocyclic group, 7-membered bridged heterocyclic group, 8-membered bridged heterocyclic group, 7-membered spiro heterocyclic group, 8-membered spiro heterocyclic group or 9-membered spiro heterocyclic group is optionally substituted by one or more substituents independently selected from oxo, methyl, ethyl, methoxy, 4-membered monoheterocyclic group, 5-membered monoheterocyclic group and 6-membered monoheterocyclic group; More preferably, in the formula (A1), R ₃ is -CN, More preferably, in the formula (A1), R ₃ is -CN, More preferably, in the formula (A1), R ₃ is Further preferably, in the formula (A2), R ₃ is Further preferably, in the formula (A2), R ₃ is Further preferably, in the formula (A2), R ₃ is The compound according to any one of claims 2 to 8, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R _W is independently deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ; Preferably, each R _W is independently deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; More preferably, each R _W is independently methyl, isopropyl or cyclopropyl. The compound according to any one of claims 2 to 9, a stereoisomer, a tautomer or a A mixture or a pharmaceutically acceptable salt, wherein _R4 and _R5 are each independently H, deuterium or _C1-3 alkyl; the _C1-3 alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, _-NO2 and _-NH2 ; or, _R4 and _R5 together with the C atom to which they are commonly attached form a _C3-4 cycloalkyl; the _C3-4 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, _-NO2 , _-NH2 and _C1-3 alkyl; Preferably, _R4 and _R5 are each independently H, deuterium or methyl; the methyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen and _-NH2 ; or, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl or cyclobutyl group; the cyclopropyl or cyclobutyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen and _C1-3 alkyl; More preferably, _R4 and _R5 are methyl; or, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl group. The compound according to any one of claims 2 to 10, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: m is 1; n is 1 or 2, preferably 1. A compound represented by the following formula (A3), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
in, _RX is H, deuterium or ^-NRX1RX2 ; ^wherein , R ^X1 and R ^X2 are each independently H, deuterium, C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl; the C _1-3 alkyl, C _3-6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; If present, each R _Q is independently deuterium, halogen, -CN, C _1-3 alkyl, C _1-3 alkoxy, C _3-10 cycloalkyl or 4-10 membered heterocyclyl; said C _1-3 alkyl, C _1-3 alkoxy, C _3-10 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; wherein said 4-6 membered heterocyclyl is optionally substituted with one or more of methyl, hydroxyl and cyano; R _W is deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; n is 0, 1 or 2. The compound according to claim 12, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: _RX is ^-NRX1RX2 ; wherein ^{RX1 and RX2} are each independently H, deuterium or _C1-3 alkyl; the _C1-3 alkyl is any is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; Preferably, ^RX1 and ^RX2 are each independently H, methyl, ethyl or isopropyl. The compound according to claim 12, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: _RX is H or _-NHCH3 . The compound according to any one of claims 12 to 14, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each R _Q is independently deuterium, halogen, -CN, C _1-3 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl; the C _1-3 alkyl, C _3-8 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 oxaalkyl, C _3-6 cycloalkyl and 4-6 membered heterocyclyl; wherein the 4-6 membered heterocyclyl is optionally substituted by one or more of methyl, hydroxyl and cyano; Preferably, each R _Q is independently -F, -Cl, cyclopropyl, The compound according to any one of claims 12 to 15, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R _W is deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; Preferably, R _W is deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; More preferably, R _W is cyclopropyl. The compound according to any one of claims 12 to 16, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 1 or 2. A compound represented by the following formula (A4), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
in, X ₁ , X ₂ and X ₃ are each independently CR _X or N; If present, each _RX is independently H, deuterium, halogen, ^{-NRX1RX2 or -OR13} ; wherein, If present, each of ^RX1 and ^RX2 is independently H, deuterium or C _1-3 alkyl; said C _1-3 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ and C _1-3 alkyl; If present, each R ¹³ is independently C _1-3 alkyl; said C _1-3 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ and -NH ₂ ; R ₁ is deuterium, halogen or C _1-4 alkyl; the C _1-4 alkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ; R ²² is C _1-4 alkyl or phenyl; the C _1-4 alkyl or phenyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, -CN, -OH, -NO ₂ , -NH ₂ , dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethanesulfonamide, methanesulfonyl, ethanesulfonyl and C _1-3 alkyl; Each R _W is independently deuterium, C _1-3 alkyl or C _3-6 cycloalkyl; the C _1-3 alkyl or C _3-6 cycloalkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ , -NH ₂ , C _1-3 alkyl, C _1-3 alkoxy and C _1-3 haloalkyl; _R4 and _R5 are each independently H, deuterium, halogen, -CN, _C1-3 alkyl or _C3-6 cycloalkyl; the _C1-3 alkyl and _C3-6 cycloalkyl are optionally substituted by one or more substituents each independently selected from deuterium, halogen, -CN, -OH, _-NO2 and _-NH2 ; Alternatively, _R4 and _R5 together with the C atom to which they are commonly attached form a _C3-6 cycloalkyl group; the _C3-6 cycloalkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN and _C1-3 alkyl; m is 1 or 2. The compound according to claim 18, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: _X1 is CR _X , _X2 and _X3 are both N; Alternatively, _X1 and _X2 are both CR _X , and _X3 is N; Alternatively, _X2 is CR _X , and _X1 and _X3 are both N; Alternatively, _X3 is CR _X , and _X1 and _X2 are both N; Alternatively, _X1 and _X3 are both CR _X , and _X2 is N. The compound according to claim 18 or 19, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Each _RX is independently H, deuterium, F, Cl or Br. The compound according to claim 18 or 19, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R _x is -NR ^X1 R ^X2 ; wherein each R ^X1 and R ^X2 are independently H, deuterium, methyl or ethyl; Preferably, each of ^RX1 and ^RX2 is independently H or ethyl. The compound according to claim 18 or 19, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R _x is -OR ¹³ ; wherein each R ¹³ is independently a C _1-3 alkyl group; the C _1-3 alkyl group is optionally substituted by one or more substituents independently selected from deuterium, halogen, -OH and -NH ₂ ; Preferably, R ¹³ is methyl. The compound according to any one of claims 18 to 22, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ₁ is deuterium, halogen, methyl or ethyl; the methyl or ethyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN, -OH, -NO ₂ and -NH ₂ ; Preferably, R ₁ is -F, -Cl, -CH ₃ , -CD ₃ or -CF ₃ ; More preferably, R ₁ is -Cl, -CD ₃ or -CF ₃ . The compound according to any one of claims 18 to 23, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ²² is methyl, ethyl or phenyl; the methyl, ethyl or phenyl is optionally substituted by one or more substituents independently selected from deuterium, -CN, -OH, -NO ₂ , -NH ₂ , dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethanesulfonamide, methanesulfonyl, ethanesulfonyl and C _1-3 alkyl; Preferably, R ²² is ethyl, the ethyl group is optionally substituted by one or more substituents independently selected from deuterium, methyl, ethyl, F, Cl, Br, -CN, -OH, -NO ₂ and -NH ₂ ; or, R ²² is phenyl, the phenyl group is optionally substituted by one or more substituents independently selected from methyl, ethyl, F, Cl, Br, -CN, dimethylphosphoryl, methylsulfonyl and ethylsulfonyl; More preferably, R ²² is -CH ₂ CH ₃ , -CD ₂ CD ₃ , The compound according to any one of claims 18 to 24, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R _W is deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, -CN and C _1-3 alkyl; Preferably, R _W is deuterium, -CD ₃ , cyclopropyl, More preferably, R _W is deuterium, cyclopropyl, The compound according to any one of claims 18 to 25, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: _R4 and _R5 are each independently H, deuterium, -F, -Cl, -Br, -CN and _C1-3 alkyl; or, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl, cyclobutyl or cyclopentyl group, wherein the cyclopropyl, cyclobutyl or cyclopentyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen, -CN and _C1-3 alkyl; Preferably, _R4 and _R5 are each independently -F or methyl; or, _R4 and _R5 together with the C atom to which they are commonly attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more independently selected deuterium, -F, and methyl substituents; Alternatively, preferably, R ₄ and R ₅ are each independently -F, -CD ₃ or methyl; or, R ₄ and R ₅ together with the C atom to which they are commonly connected form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted by one or more substituents each independently selected from -F and methyl; More preferably, for The compound according to any one of claims 18 to 26, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: m is 1. The compound according to any one of claims 18 to 27, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (A5):
wherein R _X , R _W , R ₁ , R ₂₂ , R ₄ , R ₅ and m are as described in formula (A4). A compound, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:






A pharmaceutical composition comprising the compound according to any one of claims 1 to 29, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Use of the compound according to any one of claims 1 to 29, the stereoisomer, tautomer or mixture thereof or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 30 in the preparation of a medicament for treating and/or preventing a disease mediated by LRRK2 kinase. Use of a compound according to any one of claims 1 to 29, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating and/or preventing a degenerative disease of the nervous system. Use of the compound according to any one of claims 1 to 29, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 30 in the preparation of a medicament for treating and/or preventing Parkinson's disease.