Aromatic heterocyclic compound and preparation method therefor

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

[0001] Citation of Related Applications

[0002] The present invention claims priority to the invention patent application entitled “A kind of aromatic heterocyclic compound and its preparation method” filed in China on September 7, 2023 with application number 202311150286.7 and the invention patent application entitled “A kind of aromatic heterocyclic compound and its preparation method” filed in China on June 5, 2024 with application number 202410721017.X. The entire contents of the above patent applications are incorporated herein by reference. Technical Field

[0003] 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

[0004] 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 a reduction in dopaminergic neurons in the substantia nigra of the brain, which leads to clinical manifestations such as 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. There is still no cure to prevent the progression of the disease or reverse the disease. The need for new treatment strategies for Parkinson's disease is obvious. In addition, this demand is obviously growing due to the continuous aging of the world's population.

[0005] Only approximately 5-15% of Parkinson's disease (PD) cases have a family history, and the majority of cases are idiopathic. Epidemiological studies have shown that Parkinson's disease has a strong genetic association. Studies have found that genes associated with autosomal dominant PD are SNCA (α-synuclein) and LRRK2 (Leucine-rich repeat kinase 2); genes associated with autosomal recessive PD are Parkin (Parkin) and PINK1 (PTEN-induced kinase 1). Among all identified risk genes, LRRK2 mutations are the most common cause of autosomal dominant Parkinson's disease, with the LRRK2G2019S mutation accounting for 5% of PD cases. Recent studies have found that patients with idiopathic PD without mutations also have overactivation, autophosphorylation, or increased expression of the LRRK2 protein. Therefore, LRRK2 has become a key player in the pathogenesis of Parkinson's disease, and LRRK2 inhibitors are promising therapeutic agents for Parkinson's disease.

[0006] LRRK2 is a large protein consisting of 2527 amino acids and belongs to the ROCO protein kinase family. Compared to other members of the ROCO family, LRRK2 contains diverse domains. Its main functional domains, from N-terminus to C-terminus, 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). LRRK2 is widely expressed in the brain, heart, kidney, lung, liver, some immune cells, and the central nervous system. In neurons, LRRK2 is distributed in the cytoplasm and is present on various membrane structures, including mitochondria, Golgi apparatus, and lysosomes. By mediating the phosphorylation of downstream proteins, LRRK2 plays an important role in synaptic transmission, vesicle trafficking, mitochondrial function, regulating autophagy, microtubule stability, and inflammatory responses. LRRK2 possesses both GTPase and kinase activities, and a mechanism of mutual regulation exists 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.

[0007] Currently, 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.

[0008] So far, there is still no LRRK2 inhibitor on the market, so it is still necessary to discover more effective and safe LRRK2 inhibitors.

[0009] Summary of the Invention

[0010] 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.

[0011] 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:

[0012] in,

[0013] X1, X2 and X3 are each independently CR X or N;

[0014] If present, each R X are each independently H, deuterium, halogen, -NR X1 R X2 OR 13 ;in,

[0015] If present, each R X1 and R X2 are 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 heterocyclic group; the C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thiaalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0016] Or, for each pair of R X1 and R X2 Together with the nitrogen atoms to which they are commonly attached, they independently form a 4-8 membered heterocyclic group; the 4-8 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl and C 1-3 substituted by an oxaalkyl substituent;

[0017] If present, each R 13 are independently H, deuterium, C 1-6 Alkyl, C1-6 Oxaalkyl, C 1-6 Thiaalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thiaalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0018] R1 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 with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2;

[0019] R2 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 radicals each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; wherein,

[0020] If present, R 21 and R 22 are 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; the C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thiaalkyl, C 2-6 Alkenyl, phenyl or 5-6 membered heteroaryl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, dimethylphosphino, phosphate, formamido, acetamido, methylsulfonamido, ethylsulfonamido, methylsulfonyl, ethylsulfonyl and C1-3 substituted by an alkyl substituent;

[0021] Alternatively, R1 and R2 together form a Q The substituted ring Q is phenyl or pyrrolyl;

[0022] If present, each R Q are independently deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Oxaalkyl, C 1-3 Halogenated alkyl, C 3-6 Substituted by cycloalkyl and 4-6 membered heterocyclic substituents; wherein the substituent C 1-3 Alkyl, C 1-3 Oxaalkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 substituted by a haloalkyl substituent;

[0023] R3 is deuterium, halogen, -CN, -OH, -NH2, C 3-10 Cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclic group; the C 3-10 Cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0024] If present, each R W are independently deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C1-3 Alkyl or C 3-6 Cycloalkyl is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 substituted by a haloalkyl substituent;

[0025] m is 0, 1, 2, or 3;

[0026] L does not exist or is in,

[0027] R4 and R5 are each independently H, deuterium, halogen, -CN, -OH, -SH, -NH2, 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 each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2;

[0028] Alternatively, R4 and R5 together with the C atom to which they are attached form a C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally substituted by one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0029] when for When R W is not optionally substituted C 3-6 Cycloalkyl or C optionally substituted by halogen 1-3 Alkyl, and R4 and R5 are not H or optionally substituted C 1-3 alkyl;

[0030] When L does not exist, for And R W is optionally substituted C 3-6 When it is a cycloalkyl group, R3 is not a heterocyclic group having an oxo group;

[0031] When L does not exist, for When R3 is not halogen, -CN or C 3-6 Cycloalkyl;

[0032] The heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from S, O and N.

[0033] 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:

[0034] in,

[0035] R X H, deuterium, -NR X1 R X2 OR 13 ;in,

[0036] If present, R X1 and R X2 are independently H, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0037] Or, R X1 and R X2 Together with the nitrogen atom to which they are commonly attached, they form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0038] If present, R 13 C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted by one or more groups independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0039] If present, each R Q are independently deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 substituted by a haloalkyl substituent;

[0040] R3 is deuterium, halogen, -CN, -OH, -NH2, C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; the C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 3-6 substituted by a cycloalkyl group or a 4-6 membered heterocyclic group;

[0041] Every R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted by one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0042] R4 and R5 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 with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2;

[0043] Alternatively, R4 and R5 together with the C atom to which they are attached form a C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally substituted by one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0044] m is 1 or 2;

[0045] n is 0, 1 or 2.

[0046] In a preferred embodiment of the present invention, R X is H or deuterium.

[0047] In a preferred embodiment of the present invention, R X -NR X1 R X2 ; Among them, R X1 and R X2 are independently H, deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted by one or more groups independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0048] Or, R X1 and R X2 Together with the nitrogen atom to which they are commonly attached, they form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent.

[0049] In a preferred embodiment of the present invention, R X1 and R X2 are each independently H, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl;

[0050] Or, R X1 and R X2 Together with the N atoms they are connected to form

[0051] In a preferred embodiment of the present invention, R X For-OR 13 ; Among them, R 13 It is a methyl group.

[0052] In a preferred embodiment of the present invention, R X For H, -NHCH3, Or -OCH3.

[0053] In a preferred embodiment of the present invention, each R Q are independently deuterium, halogen, -CN, -OH, -NO2, -NH2, 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 independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C1-3 Alkoxy and C 1-3 The alkyl group is substituted by a haloalkyl substituent.

[0054] In a preferred embodiment of the present invention, each R Q Each is independently deuterium, -F, -Cl, -Br, -CN, -OH, -NO2, -NH2, methyl, ethyl, cyclopropyl or cyclobutyl; the methyl, ethyl, cyclopropyl or cyclobutyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2 and -NH2.

[0055] In a preferred embodiment of the present invention, each R Q Each is independently -F, -Cl, -CN, methyl, trifluoromethyl or cyclopropyl.

[0056] In a preferred embodiment of the present invention, R3 is deuterium, halogen, -CN, -OH, -NH2, C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; the C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered heterocyclic group are substituted.

[0057] In a preferred embodiment of the present invention, R3 is -CN, C 4-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; the C 4-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from oxo, C 1-3 Alkyl, C 1-3 substituted by alkoxy and 4-6 membered heterocyclic substituents.

[0058] 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; and 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 is 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.

[0059] In a preferred embodiment of the present invention, in the formula (A1), R3 is -CN,

[0060] In a preferred embodiment of the present invention, in the formula (A1), R3 is -CN, Preferred

[0061] In a preferred embodiment of the present invention, in the formula (A1), R3 is

[0062] In a preferred embodiment of the present invention, in the formula (A2), R3 is

[0063] In a preferred embodiment of the present invention, in the general formula (A2), R3 is

[0064] In a preferred embodiment of the present invention, in the general formula (A2), R3 is

[0065] In a preferred embodiment of the present invention, each R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more substituents each independently selected from the group consisting of deuterium, halogen, -CN, -OH, -NO2, and -NH2.

[0066] In a preferred embodiment of the present invention, each R WEach is independently deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0067] In a preferred embodiment of the present invention, each R W Each is independently methyl, isopropyl or cyclopropyl.

[0068] In a preferred embodiment of the present invention, R4 and R5 are each independently H, deuterium or C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2;

[0069] Alternatively, R4 and R5 together with the C atom to which they are attached form a C 3-4 Cycloalkyl; the C 3-4 The cycloalkyl group is optionally substituted by one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent.

[0070] In a preferred embodiment of the present invention, R4 and R5 are each independently H, deuterium or methyl; the methyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen and -NH2;

[0071] Alternatively, R4 and R5 together with the C atom to which they are commonly attached form a cyclopropyl or cyclobutyl group; said cyclopropyl or cyclobutyl group is optionally substituted by one or more radicals independently selected from deuterium, halogen and C 1-3 substituted by an alkyl substituent.

[0072] 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.

[0073] In a preferred embodiment of the present invention, m is 1.

[0074] In a preferred embodiment of the present invention, n is 1 or 2.

[0075] In a preferred embodiment of the present invention, n is 1.

[0076] 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:

[0077] in,

[0078] R X H, deuterium or -NR X1 RX2 ;in,

[0079] R X1 and R X2 are independently H, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0080] If present, each R Q are independently deuterium, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 substituted by a cycloalkyl group and a 4-6 membered heterocyclic group; wherein the 4-6 membered heterocyclic group is optionally substituted by one or more of a methyl group, a hydroxyl group and a cyano group;

[0081] R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted by one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0082] n is 0, 1 or 2.

[0083] In a preferred embodiment of the present invention, R x For H.

[0084] In a preferred embodiment of the present invention, R x -NR X1 R X2 ; Among them, R X1 and R X2 are each independently H, deuterium or C 1-3 Alkyl; the C 1-3The alkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent.

[0085] In a preferred embodiment of the present invention, R X1 and R X2 Each is independently H, methyl, ethyl or isopropyl.

[0086] In a preferred embodiment of the present invention, R X It is H or -NHCH3.

[0087] In a preferred embodiment of the present invention, each R Q are independently deuterium, halogen, -CN, C 1-3 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group; the C 1-3 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-6 The 4-6 membered heterocyclic group is optionally substituted by one or more of a methyl group, a hydroxyl group and a cyano group.

[0088] In a preferred embodiment of the present invention, each R Q Each is independently -F, -Cl, cyclopropyl,

[0089] In a preferred embodiment of the present invention, R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0090] In a preferred embodiment of the present invention, R W is deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0091] In a preferred embodiment of the present invention, R W It is cyclopropyl.

[0092] In a preferred embodiment of the present invention, n is 2.

[0093] In a preferred embodiment of the present invention, n is 1.

[0094] In a preferred embodiment of the present invention, n is 0.

[0095] 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:

[0096] in,

[0097] X1, X2 and X3 are each independently CR X or N;

[0098] If present, each R X are each independently H, deuterium, halogen, -NR X1 R X2 OR 13 ;in,

[0099] If present, each R X1 and R X2 are each independently H, deuterium or C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent;

[0100] If present, each R 13 Each independently is 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, -NO2 and -NH2;

[0101] R1 is deuterium, halogen or C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2;

[0102] R 22 C 1-4 Alkyl or phenyl; the C 1-4 The alkyl or phenyl groups are optionally substituted with one or more groups independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, dimethylphosphoryl, phosphate, formamide, acetamide, methylsulfonamide, ethylsulfonamide, methylsulfonyl, ethylsulfonyl and C 1-3 substituted by an alkyl substituent;

[0103] Every R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C1-3 Alkyl or C 3-6 Cycloalkyl is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 substituted by a haloalkyl substituent;

[0104] R4 and R5 are each independently H, deuterium, halogen, -CN, 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 each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2;

[0105] Alternatively, R4 and R5 together with the C atom to which they are attached form a C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally substituted by one or more radicals each independently selected from deuterium, halogen, -CN and C 1-3 substituted by an alkyl substituent;

[0106] m is 1 or 2.

[0107] In a preferred embodiment of the present invention, X1 is CR X , X2 and X3 are both N.

[0108] In a preferred embodiment of the present invention, X1 and X2 are both CR X , X3 is N.

[0109] In a preferred embodiment of the present invention, X2 is CR X , X1 and X3 are both N.

[0110] In a preferred embodiment of the present invention, X3 is CR X , X1 and X2 are both N.

[0111] In a preferred embodiment of the present invention, X1 and X3 are both CR X , X2 is N.

[0112] In a preferred embodiment of the present invention, each R x Each is independently H, deuterium, F, Cl or Br.

[0113] In a preferred embodiment of the present invention, R x -NR X1 R X2 ; where each R X1 and RX2 Each is independently H, deuterium, methyl or ethyl.

[0114] In a preferred embodiment of the present invention, each R X1 and R X2 Each is independently H or ethyl.

[0115] In a preferred embodiment of the present invention, R x For-OR 13 ; where each R 13 Each independently is C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more substituents each independently selected from the group consisting of deuterium, halogen, -OH, and -NH2.

[0116] In a preferred embodiment of the present invention, R 13 It is a methyl group.

[0117] In a preferred embodiment of the present invention, R1 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, -NO2 and -NH2.

[0118] In a preferred embodiment of the present invention, R1 is -F, -Cl, -CH3, -CD3 or -CF3.

[0119] In a preferred embodiment of the present invention, R1 is -Cl, -CD3 or -CF3.

[0120] In a preferred embodiment of the present invention, R1 is -Cl.

[0121] In a preferred embodiment of the present invention, R 22 is methyl, ethyl or phenyl; the methyl, ethyl or phenyl group is optionally substituted by one or more groups independently selected from deuterium, -CN, -OH, -NO2, -NH2, dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethylsulfonamide, methanesulfonyl, ethylsulfonyl and C 1-3 substituted by an alkyl substituent.

[0122] In a preferred embodiment of the present invention, R 22 is ethyl, and the ethyl group is optionally substituted by one or more substituents each independently selected from deuterium, methyl, ethyl, F, Cl, Br, -CN, -OH, -NO2 and -NH2.

[0123] In a preferred embodiment of the present invention, R 22is phenyl, which is optionally substituted by one or more substituents independently selected from methyl, ethyl, F, Cl, Br, -CN, dimethylphosphinoyl, methylsulfonyl and ethylsulfonyl.

[0124] In a preferred embodiment of the present invention, R 22 -CH2CH3, -CH2CH2OH, -CD2CD3,

[0125] In a preferred embodiment of the present invention, R 22 -CH2CH3, -CD2CD3,

[0126] 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 independently selected from deuterium, halogen, -CN and C 1-3 substituted by an alkyl substituent.

[0127] In a preferred embodiment of the present invention, R W For deuterium, -CD3, cyclopropyl,

[0128] In a preferred embodiment of the present invention, R W For deuterium, cyclopropyl,

[0129] In a preferred embodiment of the present invention, R4 and R5 are each independently H, deuterium, -F, -Cl, -Br, -CN or C 1-3 alkyl;

[0130] Alternatively, R4 and R5 together with the C atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, wherein the cyclopropyl, cyclobutyl or cyclopentyl group is optionally substituted by one or more independently selected from deuterium, halogen, -CN and C 1-3 substituted by an alkyl substituent.

[0131] In a preferred embodiment of the present invention, R4 and R5 are each independently -F or methyl;

[0132] Alternatively, R4 and R5 together with the C atom to which they are attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more substituents independently selected from deuterium, -F and methyl.

[0133] In a preferred embodiment of the present invention, R4 and R5 are each independently -F, -CD3 or methyl;

[0134] Alternatively, R4 and R5 together with the C atom to which they are attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally substituted with one or more substituents each independently selected from -F and methyl.

[0135] In a preferred embodiment of the present invention, for Preferred

[0136] In a preferred embodiment of the present invention, m is 1.

[0137] 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:

[0138] Among them, R X 、R W , R1, R 22 , R4, R5 and m are as described in formula (A4).

[0139] In a preferred embodiment of the present invention, R x are each independently H or deuterium.

[0140] In a preferred embodiment of the present invention, R1 is -Cl or -CF3.

[0141] In a preferred embodiment of the present invention, R 22 is -CH2CH3, -CD2CD3 or

[0142] In a preferred embodiment of the present invention, R W It is cyclopropyl.

[0143] In a preferred embodiment of the present invention, R4 and R5 are each independently -CD3 or methyl; or, R4 and R5 together with the C atom to which they are commonly attached form a cyclopropyl group.

[0144] In a preferred embodiment of the present invention, for

[0145] In a preferred embodiment of the present invention, m is 1.

[0146] 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:

[0147] In a second aspect, the present invention provides a method for preparing compounds represented by formula (I), formula (A1) and formula (A4), stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof.

[0148] The present invention also provides a compound as shown in the general formula, and 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:

[0149] Preparation method of compound of general formula (I):

[0150] 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 X4 is a halogen, preferably Cl or Br; and the definitions of the other groups are as described above;

[0151] Preparation method of compound of general formula (A1):

[0152] 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; and the definitions of other groups are as described above; and

[0153] Preparation method of compound of general formula (A4):

[0154] The compound of formula (a1) is reacted (for example, a substitution reaction) to obtain the intermediate compound of formula (a2), the compound of formula (b1) is reacted (for example, a photocatalytic coupling reaction) to obtain the 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 the compound of formula (A4); wherein X4 is a halogen, preferably Cl or Br; and the definitions of other groups are as described above.

[0155] 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.

[0156] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0157] 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.

[0158] The present invention also provides the compound of the present invention, the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof, for use in treating and / or preventing diseases mediated by LRRK2 kinase.

[0159] The present invention also provides the compound of the present invention, the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof, for use in treating and / or preventing neurodegenerative diseases.

[0160] The present invention also provides the compound of the present invention, the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof, for use in treating and / or preventing Parkinson's disease.

[0161] In a fifth aspect, the present invention provides the compound of the present invention, and use of the stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts thereof in the preparation of drugs for treating and / or preventing diseases mediated by LRRK2 kinase.

[0162] 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.

[0163] 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 Parkinson's disease.

[0164] In a sixth aspect, the present invention provides a method for treating and / or preventing diseases mediated by LRRK2 kinase, comprising administering a compound of the present invention, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0165] The present invention also provides a method for treating and / or preventing neurodegenerative diseases, comprising administering the compound of the present invention, its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts to an individual in need thereof.

[0166] The present invention also provides a method for treating and / or preventing Parkinson's disease, comprising administering the compound of the present invention, its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts to an individual in need thereof.

[0167] Definition of terms

[0168] The terms "optional," "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0169] 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 as =0.

[0170] Unless otherwise specified, the term "alkyl" refers to a straight-chain or branched, saturated aliphatic hydrocarbon group. An alkyl group may contain 1 to 20 carbon atoms (i.e., C 1-20 alkyl), preferably containing 1 to 10 carbon atoms (i.e., C 1-10 alkyl), more preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), further preferably containing 1-6 carbon atoms (ie C 1-6 alkyl). For example, “C 1-6 The term "alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 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 and n-octyl.

[0171] Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond. 2-20 alkenyl), preferably containing 2 to 10 carbon atoms (ie, C 2-10 alkenyl), more preferably containing 2 to 8 carbon atoms (ie, C 2-8 alkenyl), further preferably containing 2 to 6 carbon atoms (ie, C 2-6alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 carbon atoms (ie C 2-4 alkenyl), 2-3 carbon atoms (ie C 2-3 alkenyl) or 2 carbon atoms (i.e. C2 alkenyl or vinyl). For example, "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0172] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic or polycyclic, saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (ie, C 3-10 Cycloalkyl), further preferably 3-6 carbon atoms (ie C 3-6 Cycloalkyl), 4-6 carbon atoms (ie C 4-6 Cycloalkyl) or 5-6 carbon atoms (ie C 5-6 Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, and dimethylcyclobutyl.

[0173] 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). A heteroalkyl group may contain 1 to 20 carbon atoms (i.e., C 1-20 heteroalkyl hetero), preferably containing 1 to 10 carbon atoms (ie, C 1-10 heteroalkyl), more preferably containing 1 to 8 carbon atoms (C 1-8 heteroalkyl), further preferably containing 1 to 6 carbon atoms (ie, 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 and 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, C 1-6 Non-limiting examples of oxaalkyl include, but are not limited to, methoxy, ethoxy, methoxymethyl, ethoxymethyl, and ethoxyethyl. Accordingly, when the heteroatom in the heteroalkyl group is a sulfur atom, the heteroalkyl group is a thiaalkyl group; for example, C 1-6Non-limiting examples of thioalkyl include, but are not limited to, methylthio, ethylthio, methylthiomethyl, ethylthiomethyl, ethylthioethyl, etc. When the only heteroatom or heteroatom group in a heteroalkyl group serves as the point of attachment to the parent core, the heteroalkyl group may also be referred to as an "alkheteroyl" (e.g., alkylamino, alkoxy, alkylthio, etc.).

[0174] 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 even more 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.

[0175] Unless otherwise specified, the term "alkylthio" refers to the above definition of "alkoxy" in which -O- is replaced by -S-.

[0176] 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 of the hydrogen atoms are replaced by halogen atoms. Representative examples of haloalkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0177] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic hydrocarbon group. A heterocyclyl group may be non-aromatic, or may include polycyclic rings in which some rings are aromatic. A heterocyclyl group may contain 3 to 20 ring atoms (i.e., a 3-20-membered heterocyclyl), wherein one, two, three, or more ring atoms are independently selected from N, O, and S, and the remaining ring atoms are C. A heterocyclyl group preferably contains 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclyl), more preferably 3 to 10 ring atoms (i.e., a 3-10-membered heterocyclyl), 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclyl), 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclyl), 4 to 6 ring atoms (i.e., a 4-6-membered heterocyclyl), or 5 to 6 ring atoms (i.e., a 5-6-membered heterocyclyl). 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, and the like. Polycyclic heterocyclic groups include spirocyclic, fused, and bridged heterocyclic groups.

[0178] Unless otherwise specified, the term "fused ring" refers to a non-aromatic, saturated or partially unsaturated bicyclic or polycyclic system formed by two or more cyclic structures sharing two adjacent atoms, 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.

[0179] Unless otherwise specified, the term "spiroalkyl" 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. Spiroalkyl is preferably a 6- to 14-membered spiroalkyl, more preferably a 7- to 10-membered spiroalkyl. Monospiroalkyl can be divided into monospiroalkyl of 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, and 5 / 6-membered rings, wherein the count of each ring includes the spiro atom. Non-limiting examples of monospiroalkyl include: wait.

[0180] Unless otherwise specified, the term "heterospirocyclyl" or "spiroheterocyclyl" 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 spiroheterocyclyl 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 spiroheterocyclyl is preferably a 6 to 14-membered spiroheterocyclyl, more preferably a 7 to 10-membered spiroheterocyclyl. The spiroheterocyclyl can be divided into 3 / 5-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered and 5 / 6-membered rings, wherein the count of each ring includes the spiro atom. Non-limiting examples of heteromonospirocyclyl include: wait.

[0181] Unless otherwise specified, the term "bridged cycloalkyl" refers to a polycyclic group containing 5 to 20 ring atoms, in which any two rings share two ring atoms that are not directly connected, and which is all carbon, and 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 bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:

[0182] Unless otherwise specified, the term "heterobridged ring group" or "bridged heterocyclic group" refers to a polycyclic group containing 5 to 14 ring atoms, wherein any two rings share two ring atoms that are not directly connected, and 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 heteroatoms, preferably 1-4 heteroatoms, more preferably 1-3 (i.e., 1, 2 or 3) heteroatoms, and each heteroatom is 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. Depending on 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:

[0183] 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.

[0184] Unless otherwise specified, the terms "heteroaryl" and "heteroaromatic group" refer to monocyclic or polycyclic aromatic heterocyclic ring systems having 5-12, 5-10, 5-8, or 5-6 membered rings, wherein one, two, three, or more ring atoms are heteroatoms and the remaining ring atoms are carbon atoms, each heteroatom independently selected from O, N, and S, preferably having 5-6 membered rings. 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, furyl, 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, benzothienyl, benzopyridinyl, benzopyrimid ... oxazine, benzimidazolyl, benzophthalazinyl, 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, etc.

[0185] Unless otherwise specified, the term "hydroxy" refers to an -OH group.

[0186] Unless otherwise specified, the term "mercapto" refers to a -SH group.

[0187] Unless otherwise specified, the term "amino" refers to a -NH2 group.

[0188] Unless otherwise specified, the term "nitro" refers to a -NO2 group.

[0189] Unless otherwise specified, the term "cyano" refers to a -CN group.

[0190] Unless otherwise specified, the term "carboxy" refers to a -C(=O)OH group.

[0191] 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 by replacing some or all of the hydroxyl groups in the above-mentioned phosphate group structure with other hydrocarbon groups (e.g., alkyl groups, cycloalkyl groups, aryl groups, etc.), such as dimethylphosphoryl (i.e., -P(=O)(CH3)2) as a non-limiting example of a dialkylphosphoryl group.

[0192] Unless otherwise specified, the term "amide group" refers to a group formed by replacing some or all of the hydrogen atoms in the above-mentioned amino structure with other acyl groups (for example, alkanoyl, cycloalkanoyl, aromatic acyl, etc.), such as formamide (i.e., -NHC(=O)H), acetamide (i.e., -NHC(=O)CH3), etc., which are non-limiting examples of alkanoyl groups.

[0193] Unless otherwise specified, the term "sulfoxide" refers to a -S(=O)- group and the term "sulfone" refers to a -S(=O)2- group.

[0194] Unless otherwise specified, the term "sulfonyl" refers to a group formed by connecting one segment of the above-mentioned sulfone group to other hydrocarbon groups (e.g., alkyl groups, cycloalkyl groups, aryl groups, etc.), such as methylsulfonyl (i.e., -S(=O)2CH3), ethylsulfonyl (i.e., -S(=O)2CH2CH3), etc., which are non-limiting examples of alkylsulfonyl groups.

[0195] Unless otherwise specified, the term "sulfonamide" refers to a group formed by replacing some or all of the hydrogen atoms in the above-mentioned amino structure with other sulfonyl groups (for example, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, etc.), such as methylsulfonamide (i.e., -NHS(=O)2CH3), ethylsulfonamide (i.e., -NHS(=O)2CH2CH3), etc. as non-limiting examples of alkylsulfonamide.

[0196] Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of mammals (particularly humans) without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent.

[0197] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, atropisomers, and the like based on the differences in the physical and chemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0198] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that are interconvertible across a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the 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 the reorganization of some of the bonding electrons.

[0199] Unless otherwise specified, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)), such as R and S configuration isomers containing asymmetric centers; (Z) and (E) configuration isomers of double bonds; and (Z) and (E) conformers. Therefore, single stereoisomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0200] Unless otherwise specified, the term "optionally substituted" or "optionally substituted by..." means that the hydrogen on the substitutable position of the group is not replaced or is replaced by one or more substituents, and the substituents are preferably selected from the following substituents: halogen, hydroxyl, thiol, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkanesulfonyl, 3-10 membered heterocycloalkyl, C 6-14Aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkanesulfonyl, 3-10 membered heterocycloalkyl, C 6-14 The aryl or 5-10 membered heteroaromatic ring group is optionally further independently selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted with one or more substituents.

[0201] The beneficial effects of the present invention are:

[0202] This invention designs a class of novel compounds, providing a new direction for the development of LRRK2 inhibitors. In vitro enzyme and cell inhibition studies demonstrate that these compounds possess potent inhibitory effects, making them promising candidates for the treatment and / or prevention of LRRK2-mediated diseases. Furthermore, the invention develops a specific synthesis method that is simple, easy to operate, and amenable to large-scale industrial production and application. DETAILED DESCRIPTION

[0203] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0204] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high performance liquid chromatography (HPLC). NMR measurements were performed using a Bruker 400 MHz and / or a Varian 400 MHz instrument; LC-MS measurements were performed using an Agilent 1260 Infinity II-6120 / 6125 MSD instrument; and HPLC measurements were performed using a Waters Acquity UPLC-2 and / or a Shimadzu LC2030 and / or an Agilent 1260 Infinity II instrument.

[0205] Preparative HPLC conditions 1 (ammonia as additive): instrument: Waters; pump: 2545; detector: 2489; wavelength: 214 nm & 254 nm; column model: Welch Xtimate C18, 21.2*250 mm, 10 μm; mobile phase: A: 0.1% v / v ammonia, B: acetonitrile; run time: 15 min; run time: 25 ml / min.

[0206] Preparation HPLC conditions 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.

[0207] Preparative HPLC conditions three (trifluoroacetic acid as additive): instrument: Waters; pump: 2545; detector: 2489; wavelength: 214 nm & 254 nm; column model: Welch Ultimate AQ-C18, 21.2*250 mm, 10 μm; mobile phase: A: 0.1% v / v trifluoroacetic acid, B: acetonitrile; running time: 15 min; running time: 25 ml / min.

[0208] 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.

[0209] Example 1

[0210] 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

[0211] Step 1: Synthesis of 2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0212] Under 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 allow to react at room temperature for 1 hour. After completion of the reaction as determined by LC-MS, the filter cake was filtered under reduced pressure to yield the crude title compound (840 mg, 92% yield). LC-MS (ESI) [M+H] + =279.45.

[0213] Step 2: Synthesis of 2-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0214] 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). The mixture was cooled to 0°C under nitrogen. Sodium hydride (89.31 mg, 3.72 mmol, 1.3 eq) was slowly added and stirred at 0°C for 0.5 hour. 2-(Trimethylsilyl)ethoxymethyl chloride (524.97 mg, 3.15 mmol, 1.1 eq) was then added and allowed to react at 0°C for 1.5 hours. After completion of the reaction as determined by LC-MS, the reaction mixture was quenched with ice 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, PE:EA = 10:1) to obtain the title compound (740 mg, 63% yield). LC-MS (ESI) [M+H] + =409.70.

[0215] Step 3: Synthesis of 2-chloro-5-(trifluoromethyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0216] 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 under nitrogen and heated to remove water. After 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 then added and the mixture was allowed to react at 50°C for 16 hours. After completion of the reaction, as determined by LC-MS, the reaction mixture was quenched with saturated ammonium chloride solution and diluted with dichloromethane. Filtered through celite, the filter cake was washed three times with dichloromethane. The filtrate was separated, and the organic phase was collected and washed 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 = 10:1) to obtain the title compound (400 mg, yield 78%). LC-MS (ESI) [M+H] + =351.70.

[0217] 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

[0218] 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) (for the synthesis method, see Steps 1 to 3 of Example 45) were dissolved in dioxane (10 mL), and chloro[(4,5-bis(diphenylphosphino)-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 sequentially. The reaction was carried out at 100°C under nitrogen for 12 hours. After completion of the reaction as determined by LC-MS, the mixture was diluted with water, extracted three times with dichloromethane, 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 = 1:1) to obtain the title compound (105 mg, 44% yield). LC-MS (ESI) [M+H] + =548.05.

[0219] 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

[0220] 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), and tetrabutylammonium fluoride (2 mL) was added dropwise. The mixture was reacted at 65°C for 12 hours. After completion of the reaction as determined by LC-MS, the reaction solution was concentrated, diluted with ethyl acetate, and washed five times with saturated brine to remove the tetrabutylammonium fluoride. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and analyzed by Pre-TLC (PE:EA = 2:1) to obtain the title compound (10.79 mg, 16% yield). LC-MS (ESI) [M+H] +=417.85; 1 H NMR(400MHz,DMSO-d6)δ12.36(s,1H),9.15(s,1H),8.75(s,1H),7.87(s,1H),7.76(s,2 H),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).

[0221] Example 2-3

[0222] Refer to Example 1, Synthesis Examples 2-3.

[0223] Example 4

[0224] 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

[0225] Step 1: Synthesis of 5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

[0226] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.02 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (15 mL), and 1-bromopyrrolidine-2,5-dione (3.48 g, 19.53 mmol, 1.5 eq) was added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction as determined by LC-MS, the reaction mixture was poured into water (300 mL) and stirred for 0.5 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude target compound (3.48 g, 90% yield). LC-MS (ESI) [M+H] + =231.9.

[0227] Step 2: Synthesis of 5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0228] 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. [2-(Chloromethoxy)ethyl]trimethylsilane (2.94 g, 17.62 mmol, 1.5 eq) was then added and allowed to react for 2 hours. After completion of the reaction as determined by LC-MS, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (30 mL x 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 = 20:1) to obtain the title compound (2.46 g, 58% yield). LC-MS (ESI) [M+H] + =362.0.

[0229] Step 3: Synthesis of 2-chloro-5-cyclopropyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0230] 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). Incubate at 110°C under nitrogen for 12 hours. After completion of the reaction, as determined by LC-MS, pour the reaction solution into water (30 mL), extract with ethyl acetate (15 mL x 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.

[0231] 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

[0232] 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 (10 mL) and reacted at 110 ° C under nitrogen protection for 18 hours. After the reaction was complete, the reaction solvent was directly dried and purified by flash chromatography (Silica gel, PE:EA=1:1) to obtain the target compound (203 mg, yield 95%). LC-MS (ESI) [M+H] + =520.3.

[0233] 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

[0234] 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 analysis indicates that the reaction is complete and the intermediate has been generated. The reaction solution is dried, and DMF (10 mL) and ethylenediamine (8 mL) are added, followed by reaction at room temperature for 1 hour. After completion of the reaction, as determined by LC-MS, the reaction solution is 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, filtered, and the filtrate was concentrated and purified using Prep-HPLC (C18, 0.05% NH4.H2O in water, MeCN) to obtain the target compound (25.8 mg, yield 26%). LC-MS (ESI) [M+H] + =390.2; 1H NMR (400MHz, DMSO-d6) 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).

[0235] Example 5

[0236] 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

[0237] Step 1: Synthesis of 2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine

[0238] 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 5.32 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), followed by the addition of 1-chloromethyl-4-fluoro-1,4-diazobicyclo-2.2.2-octane bis(tetrafluoroborate) salt (2.26 g, 6.38 mmol, 1.2 eq) and acetic acid (4 mL). The mixture was reacted at 85°C under nitrogen for 16 hours. After completion of the reaction, as determined by LC-MS, the reaction solution was concentrated under reduced pressure and purified by flash chromatography (Silica gel, PE:EA = 2:1) to obtain the title compound (500 mg, 46% yield). LC-MS (ESI) [M+H] + =204.0.

[0239] Step 2: Synthesis of 2,4-dichloro-5-fluoro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0240] 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 and sodium hydroxide (116.4 mg, 2.91 mmol, 1.2 eq) was slowly added. The mixture was allowed to react at 0°C for 0.5 hours. [2-(Chloromethoxy)ethyl]trimethylsilane (485.59 mg, 2.91 mmol, 1.2 eq) was then added and the mixture was allowed to react at 25°C for 2 hours. After completion of the reaction as determined by LC-MS, the reaction solution was quenched 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, PE:EA = 2:1) to obtain the title compound (540 mg, 66% yield). LC-MS (ESI) [M+H] + =335.65.

[0241] 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

[0242] 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. The mixture was reacted at 85°C for 2 hours. After completion of the reaction, the solvent was directly evaporated and the title compound was isolated and purified by flash chromatography (Silica gel, PE:EA = 1:1) to obtain the title compound (550 mg, 76% yield). LC-MS (ESI) [M+H] + =432.85.

[0243] Step 4: N 2 -{1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl}-5-fluoro-N 4 Synthesis of 7-[(4-methoxyphenyl)methyl]-N4-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0244] 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-butanol (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), and nitrogen was replaced three times. Dicyclohexyl[2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (105.7mg, 0.2mmol, 0.2eq) and tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (101.5mg, 0.1mmol, 0.1eq) were then added. The nitrogen was replaced three times, and the reaction was carried out at 80°C for 8 hours. After the reaction was completed as determined 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, PE:EA=1:1) to obtain the target compound (660mg, 92% yield). LC-MS (ESI) [M+H] + =629.20.

[0245] Step 5: N 2 -{1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl}-5-fluoro-N 4 Synthesis of methyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0246] 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 analysis indicated approximately 50% yield of the target intermediate. The reaction solution was concentrated, and N,N-dimethylformamide (3 mL) and ethylenediamine (2 mL) were added. The reaction was continued at 25°C for 1 hour. After completion of the reaction as determined 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 the crude target compound. Prep-HPLC and Prep-TLC were used to separate and purify the target compound (17.72 mg, 7% yield). LC-MS (ESI) [M+H] + =396.80; 1 H NMR (400MHz, DMSO-d6) 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).

[0247] Examples 6-15

[0248] Refer to Example 5, Synthesis Examples 6-15.

[0249] Example 16

[0250] 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

[0251] Step 1: Synthesis of 2,4,5-trichloropyrrolo[2,3-d]pyrimidine

[0252] 2,4-Dichloro-7H-pyrrolo[2,3-D]pyrimidine (10 g, 53.19 mmol, 1.0 eq) and NCS (1-chloropyridinylamino-2,5-dione) (7.1 g, 53.19 mmol, 1.1 eq) were dissolved in DMF (15 mL) and reacted at 50°C for 10 hours. After completion of the reaction as determined by LC-MS, the reaction solution was diluted with water, extracted with ethyl acetate (40 mL x 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 = 20:1) to obtain the title compound (9.4 g, 79% yield). LC-MS (ESI) [M+H] + =222.0.

[0253] Step 2: Synthesis of 2,4,5-trichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0254] 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). 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) were added and reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and purified by flash chromatography (Silica gel, PE:EA = 10:1) to obtain the title compound (10 g, 67% yield). LC-MS (ESI) [M+H] + =352.0.

[0255] Step 3: Synthesis of 2,5-dichloro-N-(propan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0256] 2,4,5-Trichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2 g, 5.67 mmol, 1.0 eq) and cyclobutylamine (0.48 g, 6.8 mmol, 1.2 eq) were dissolved in DMF, and N,N-diisopropylethylamine (1.45 g, 11.3 mmol, 2.0 eq) was added. The mixture was reacted at 120°C for 1 hour. After completion of the reaction, as determined by LC-MS, 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 purified by flash chromatography (Silica gel, PE:EA = 8:1) to obtain the title compound (1.4 g, 54% yield). LC-MS (ESI) [M+H] + =387.38.

[0257] Step 4: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N 4 Synthesis of cyclobutyl-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0258] 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, A mixture of 1,000 mmol (1.0 eq) and cesium carbonate (1.42 g, 4.31 mmol, 2.0 eq), tris(dibenzylideneacetone)dipalladium (394.23 mg, 0.43 mmol, 0.2 eq), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (205.24 mg, 0.43 mmol, 0.2 eq) was dissolved in DMF. The mixture was then added with microwaves at 120°C under nitrogen for 1 hour. After completion of the reaction, the solvent was dried and purified by Prep-HPLC to obtain the title compound (220 mg, 18% yield). LC-MS (ESI) [M+H] + =584.2.

[0259] Step 5: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N 4 Synthesis of cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0260] 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, and trifluoroacetic acid (193.83 mg, 1.7 mmol, 5.0 eq) was added and allowed to react for 1 hour. After the reaction was complete as determined by LC-MS, the reaction solution was concentrated and ammonia methanol (57.9 mg, 3.4 mmol, 10.0 eq) was added. The reaction was allowed to react at room temperature for 0.5 hour. After the reaction was complete as determined by LC-MS, the reaction solution was concentrated and purified by Prep-HPLC to obtain the title compound (50 mg, 34% yield). LC-MS (ESI) [M+H] + =453.94; 1 H NMR (400MHz, DMSO-d6) 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).

[0261] Example 17

[0262] 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

[0263] Step 1: Synthesis of 1-(2,5-dichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidine

[0264] 2,4,5-Trichloro-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.84 mmol, 1.0 eq) was dissolved in ethanol (30 mL). Azetidine (178 mg, 3.12 mmol, 1.1 eq) and N,N-diisopropylethylamine (367 mg, 2.84 mmol, 1.0 eq) were added and reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and purified by flash chromatography (Silica gel, PE:EA = 93:7) to obtain the title compound (320 mg, 30% yield). LC-MS (ESI) [M+H] + =373.1.

[0265] 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

[0266] 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) was added. , 1.0eq), X-phos ([1-(2-diphenylphosphinonaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphine) (41mg, 0.09mmol, 0.2eq), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium) (39mg, 0.04mol, 0.1eq) and cesium carbonate (281mg, 0.86mmol, 2.0eq) were reacted at 110°C under nitrogen for 10 hours. After completion of the reaction, the reaction solution was concentrated and purified by flash chromatography (Silica gel, PE:EA=45:55) to obtain the title compound (220mg, 90% yield). LC-MS (ESI) [M+H] + =569.2.

[0267] 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

[0268] 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, and the residue was dissolved in methanol (2 mL). Ammonia water (2 mL) was added and reacted at room temperature for 1 hour. After completion of the reaction, the solvent was directly evaporated and the product was purified by Prep-HPLC (C18, 10 mmol / L FA in water, MeCN) to obtain the title compound (34.2 mg, 22% yield). 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).

[0269] Examples 18-44

[0270] Refer to Examples 17 and 45, and synthesize Examples 18-44.

[0271] Example 45

[0272] N-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-8-cyclopropylquinazolin-2-amine

[0273] Step 1: Synthesis of ethyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propionate

[0274] 2H-1,2,3-triazole (20 g, 289.56 mmol, 1.0 eq) and potassium tert-butoxide (48.74 g, 434.34 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (200 mL). Ethyl 2-bromo-2-methylpropionate (84.72 g, 434.34 mmol, 1.5 eq) was added at 0°C under nitrogen protection. The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction as determined by LC-MS, water (300 mL) was added to the reaction system, which was then extracted with ethyl acetate (100 mL x 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 title compound (10.5 g, 20% yield). 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).

[0275] Step 2: Synthesis of 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)valeronitrile

[0276] To acetonitrile (1.34 g, 32.75 mmol, 2 eq) was added tetrahydrofuran (100 mL). Under nitrogen protection at -78°C, 2.4 M n-butyllithium (2.1 g, 32.75 mmol, 2.0 eq) was added. The reaction was incubated at -78°C for 30 minutes. Ethyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate (3 g, 16.37 mmol, 1.0 eq) was then added and the reaction was incubated at -78°C for 2 hours. After completion of the reaction as determined by LC-MS, water (100 mL) was added to the reaction system, and the pH was adjusted to 5-6 with 3 M hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL x 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, CDCl3) δ7.76(s,2H),3.10(s,2H),1.90(s,6H).

[0277] Step 3: Synthesis of 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine

[0278] 4-Methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)valeronitrile (6 g, 33.67 mmol, 1.0 eq) and cyclopropylhydrazine disalt (9.77 g, 67.34 mmol, 2.0 eq) were dissolved in ethanol (250 mL). 12 M hydrochloric acid (9.02 mL) was added under nitrogen and the mixture was allowed to react at 90°C for 5 hours. After completion of the reaction, the solvent was evaporated, saturated sodium carbonate solution (300 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3), followed by washing 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 = 100:1) to obtain the title compound (4.65 g, 59% yield). LC-MS (ESI) [M+H] + =233.1; 1 H NMR (400MHz, DMSO-d6) 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).

[0279] Step 4: Synthesis of 2-chloro-8-cyclopropylquinazoline

[0280] Dissolve 8-bromo-2-chloroquinazoline (500 mg, 2.05 mmol, 1.0 eq) in dioxane / H₂O (25 / 5 mL). Add cyclopropylboronic 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) sequentially. Incubate the reaction at 90°C under nitrogen for 16 hours. After completion of the reaction, as determined by LC-MS, quench the reaction with water (20 mL) and extract with ethyl acetate (100 mL x 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 33%). LC-MS (ESI) [M+H] + =205.1.

[0281] 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

[0282] 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)prop-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (181.59 mg, 0.78 mmol, 1.0 eq), Pd2(dba)3(tris(dibenzylidene)) The mixture was reacted with 1,2-dichloro-2-nitropropanol (1,1'-dipalladium) (71.59 mg, 0.08 mmol, 0.1 eq), XPhos (dicyclohexyl[2',4',6'-tri(propan-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) at 80°C under nitrogen for 16 hours. After completion of the reaction, as determined by LC-MS, the reaction solution was directly dried and purified by flash chromatography (silica gel, DCM:MeOH = 15:1) to obtain a crude product. The crude product was then separated and purified by Prep-HPLC (C18, 0.05% NH4.H2O in water, MeCN) to obtain the title compound (30.19 mg, 10% yield). LC-MS (ESI) [M+H] + =400.9; 1 H NMR(400MHz,DMSO-d6)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).

[0283] Examples 46-48

[0284] Refer to Example 45, Synthesis Examples 46-48.

[0285] Example 49

[0286] 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

[0287] Step 1: Synthesis of 2-chloro-N-ethyl-5-iodopyrimidin-4-amine

[0288] 2,4-Dichloro-5-iodo-pyrimidine (10 g, 36.38 mmol, 1.0 eq) was dissolved in acetonitrile (150 mL). Ethylamine (2 M in tetrahydrofuran) (19.1 mL, 38.2 mmol, 1.05 eq) and triethylamine (4.05 g, 40.02 mmol, 1.1 eq) were added sequentially. The reaction was allowed to react at 25°C for 16 hours. After completion of the reaction, the solvent was evaporated and the mixture was dissolved in ethyl acetate. The mixture was washed sequentially with saturated sodium chloride, 10% aqueous citric acid, and saturated sodium bicarbonate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography (Silica gel, PE:EA = 10:1) to obtain the title compound (7 g, 68% yield). LC-MS (ESI) [M+H] + =283.50.

[0289] Step 2: Synthesis of 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine

[0290] 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 under nitrogen and heated to remove water. After returning to room temperature, NMP (N-methylpyrrolidone) (200 mL) and TMSCF3 ((trifluoromethyl)trimethylsilane) (19.31 g, 135.8 mmol, 5.5 eq) were added and allowed to react at room temperature for 1 hour. 2-Chloro-N-ethyl-5-iodopyrimidin-4-amine (4.5 g, 15.87 mmol, 1 eq) was then added and allowed to react at 50°C for 16 hours. After completion of the reaction as determined by LC-MS, the reaction was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The reaction mixture was filtered through a pad of Celite, and 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 once with sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA = 10:1) to obtain the title compound (3.0 g, yield 54%). LC-MS (ESI) [M+H] + =225.95; 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 7.97 (s, 1H), 3.49-3.39 (m, 2H), 1.12 (t, J = 7.2Hz, 3H).

[0291] Step 3: Synthesis of ethyl 2-(2H-1,2,3-triazol-2-yl)acetate

[0292] Dissolve triazole (30 g, 434.34 mmol, 1.0 eq), ethyl bromoacetate (72.54 g, 434.34 mmol, 1 eq), and potassium carbonate (120.06 g, 868.68 mmol, 2.0 eq) in acetonitrile (350 mL) and heat to 80°C for 3 hours. After completion of the reaction, filter through celite, concentrate the filtrate, and purify it by flash chromatography (Silica gel, PE:EA = 5:1) to obtain the title compound (12.5 g, 18% yield). LC-MS (ESI) [M+H] + =156.1.

[0293] Step 4: Synthesis of ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylate

[0294] 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 temperature 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. Stirring was continued for 30 minutes. Finally, 1,3-dimethyl-1,3-diazide-2-one (10.45 g, 81.53 mmol, 1.1 eq) was added, and the temperature was slowly raised to room temperature. The reaction was allowed to proceed for 16 hours. After the reaction was complete, LC-MS analysis revealed that saturated aqueous ammonium chloride (500 mL) was added to the reaction solution, which was then extracted with ethyl acetate (100 mL x 3). The mixture was then 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) to obtain the title compound (780 mg, 6% yield). LC-MS (ESI) [M+H] + =181.6.

[0295] Step 5: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-3-oxopropionitrile

[0296] Acetonitrile (308.12 mg, 7.51 mmol, 2.0 eq) was dissolved in tetrahydrofuran (18 mL). The mixture was cooled to -78°C in a dry ice-ethanol bath under nitrogen. n-Butyllithium (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 ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylate (680 mg, 3.75 mmol, 1.0 eq) in tetrahydrofuran (2 mL) was added dropwise. The reaction was maintained at -78°C for 2 hours. After completion of the reaction as determined by LC-MS, 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 x 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.

[0297] Step 6: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-amine

[0298] 3-Oxo-3-[1-(2H-1,2,3-triazol-2-yl)cyclopropyl]propionitrile (600 mg, 3.41 mmol, 1.0 eq), cyclopropylhydrazine dihydrochloride (1.48 g, 10.22 mmol, 3.0 eq), and concentrated hydrochloric acid (0.87 mL) were dissolved in ethanol (36 mL) and reacted at 90°C for 2 hours. After completion of the reaction, as determined by LC-MS, the reaction solution was concentrated, and the residue was poured into saturated aqueous sodium bicarbonate (20 mL) and stirred for 5 minutes. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, DCM:MeOH = 20:1) to obtain the title compound (500 mg, 64% yield). LC-MS (ESI) [M+H] + =230.7.

[0299] Step 7: N 2 -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of 5-ethyl-(trifluoromethyl)pyrimidine-2,4-diamine

[0300] 2-Chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (100 mg, 0.44 mmol, 1 eq) was dissolved in dioxane (5 mL), and 1-cyclopropyl-3-[1-(2H-1,2,3-triazol-2-yl)cyclopropyl]-1H-pyrazol-5-amine (102.07 mg, 0.44 mmol, 1 eq) and p-toluenesulfonic acid monohydrate (42.16 mg, 0.22 mmol, 0.5 eq) were added. The reaction mixture was reacted at 90°C under nitrogen for 3 hours. LC-MS confirmed the reaction was complete. The product was concentrated and purified by flash chromatography (Silica gel, PE:EA = 1:1) to obtain 100 mg of the crude product, which was then purified by Prep-TLC (DCM:MeOH = 10:1) to obtain the title compound (18.33 mg, 10% yield). LC-MS (ESI) [M+H] + =419.85. 1 H NMR (400MHz, DMSO-d6) 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,1 H), 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).

[0301] Examples 50-51

[0302] Refer to Example 49, Synthesis Examples 50-51.

[0303] Example 52

[0304] 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

[0305] Step 1: Synthesis of di-tert-butyl 1-(2-methylcyclopropyl)hydrazine-1,2-dicarboxylate

[0306] In a single-necked flask, 2-methylcyclopropane-1-carboxylic acid (500 mg, 4.99 mmol, 1.0 eq), di-tert-butyl (E)-diazene-1,2-dicarboxylate (1.72 g, 7.49 mmol, 1.5 eq), cesium carbonate (325.43 mg, 1 mmol, 0.2 eq), and cerium trichloride (123.09 mg, 0.5 mmol, 0.1 eq) were dissolved in acetonitrile (15 mL). The flask was purged with nitrogen for 1 minute, then sealed and irradiated with 455 nm blue light. The reaction was allowed to react at room temperature for 24 hours. TLC analysis (PE / EA = 10 / 1, rf = 0.4) indicated the reaction was complete. The reaction solution was poured into saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by flash chromatography (Silica gel, PE:EA=10:1) to obtain the title 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).

[0307] Step 2: Synthesis of (2-methylcyclopropyl)hydrazine

[0308] In a single-necked flask, dissolve di-tert-butyl 1-(2-methylcyclopropyl)hydrazine-1,2-dicarboxylate (300 mg, 1.05 mmol, 1.0 eq) in 4 M dioxane hydrochloride solution (10 mL) and allow to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was directly spin-dried to obtain the crude target compound (150 mg). LC-MS (ESI) [M+H] + =87.1.

[0309] Step 3: Synthesis of ethyl 2-(2H-1,2,3-triazol-2-yl)acetate

[0310] In a single-necked flask, triazole (30 g, 434.34 mmol, 1.0 eq), ethyl bromoacetate (72.54 g, 434.34 mmol, 1.0 eq), and potassium carbonate (120.06 g, 868.68 mmol, 2.0 eq) were dissolved in acetonitrile (350 mL) and heated to 80°C for 3 hours. After completion of the reaction, the mixture was filtered through celite, the filtrate was concentrated, and then purified by flash chromatography (Silica gel, PE:EA = 5:1) to obtain the title compound (15.6 g, 23% yield). LC-MS (ESI) [M+H] +=156.1.

[0311] Step 4: Synthesis of ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylate

[0312] In a three-necked flask, ethyl 2-(2H-1,2,3-triazol-2-yl)acetate (15 g, 96.68 mmol, 1 eq) was dissolved in tetrahydrofuran (150 mL). An appropriate amount of molecular sieves was added and the mixture was cooled to -78°C in a dry ice-ethanol bath. LDA (lithium diisopropylamide) (120.8 mL, 241.7 mmol, 2 mmol / mL, 2.0 eq) was added and allowed to react for 1 hour. A solution of 1,3,2-dioxathiane 2,2-dioxide (13.2 g, 106.35 mmol, 1.1 eq) dissolved in tetrahydrofuran (50 mL) was added dropwise to the system and allowed to react for 30 minutes. Finally, 1,3-dimethyl-1,3-diazide-2-one (13.63 g, 106.35 mmol, 1.1 eq) was added and the temperature was slowly raised to room temperature for 16 hours. The reaction progress was monitored by LC-MS. 500 mL of saturated aqueous ammonium chloride was added to the reaction solution, which was then 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) to obtain the title compound (600 mg, 3% yield). LC-MS (ESI) [M+H] + =182.1.

[0313] Step 5: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-3-oxopropionitrile

[0314] In 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. Slowly add n-butyllithium (2.76 mL, 6.62 mmol, 2.4 mol / L, 2.0 eq) dropwise. Allow to react for 30 minutes. Then, add a solution of ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropane-1-carboxylate (600 mg, 3.31 mmol, 1.0 eq) in tetrahydrofuran (5 mL) dropwise. Maintain the reaction at -78°C for 2 hours. After completion of the reaction as determined by LC-MS, 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 x 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.

[0315] Step 6: Synthesis of 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-(2-methylcyclopropyl)-1H-pyrazol-5-amine

[0316] In a single-necked flask, 3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-3-oxopropionitrile (300 mg, 1.7 mmol, 1.0 eq), cyclopropylhydrazine dihydrochloride (0.54 g, 3.41 mmol, 2.0 eq), and concentrated hydrochloric acid (0.43 mL) were dissolved in ethanol (20 mL) and the mixture was heated to 90°C for 2 hours. After completion of the reaction, as determined by LC-MS, the reaction solution was concentrated, and the residue was poured into aqueous NaHCO₃ (20 mL) and stirred for 5 minutes. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, DCM:MeOH = 20:1) to obtain the title compound (100 mg, 24% yield). LC-MS (ESI) [M+H] + =245.2.

[0317] Step 7: N 2 -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-(2-methylcyclopropyl)-1H-pyrazol-5-yl)-N 4 Synthesis of 5-ethyl-(trifluoromethyl)pyrimidine-2,4-diamine

[0318] In a single-necked flask, 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) were dissolved in dioxane (4 mL) and the temperature was raised to 90 °C for 3 h. After the reaction was complete, the reaction solution was diluted with ethyl acetate to 20 mL and washed with saturated sodium bicarbonate aqueous solution and saturated brine, respectively. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by Prep-HPLC (C18, 10 mmol / L FA in water, MeCN) to obtain the title compound (15.5 mg, 10% yield). LC-MS (ESI) [M+H] + =434.2; 1H NMR(400MHz,DMSO-d6)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).

[0319] Examples 53-54

[0320] Refer to Examples 52 and 55, and synthesize Examples 53-54.

[0321] Example 55

[0322] 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

[0323] Step 1: Synthesis of 2-chloro-N-(ethyl-d5)-5-(trifluoromethyl)pyrimidin-4-amine

[0324] 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 at 0°C under nitrogen protection. The reaction was allowed to react for 30 minutes. Deuterated iodoethane (163 mg, 1.01 mmol, 2.0 eq) was then added, and the reaction mixture was allowed to react at 25°C for 16 hours. After completion of the reaction as determined by LC-MS, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by flash chromatography (Silica gel, PE:EA = 5:1) to obtain the title compound (65 mg, 55% yield). LC-MS (ESI) [M+H] + =230.6; 1 HNMR(400MHz,DMSO-d6)δ8.37(s,1H),7.96(s,1H).

[0325] Step 2: N 2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0326] 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 complete, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash chromatography (Silica gel, DCM:MeOH = 10:1) to obtain the crude product, which was then purified by Prep-HPLC (C18, 0.05% NH3.H2O in water, MeCN) to obtain the title compound (60 mg, 8% yield). LC-MS (ESI) [M+H] + =427.2.

[0327] Step 3: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine hydrochloride

[0328] 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). The reaction solution was reacted at 25°C for 0.5 hours. After completion of the reaction, the reaction solution was directly spin-dried and then lyophilized to obtain the title compound (37.82 mg, yield 87%). LC-MS (ESI) [M+H] + =427.3; 1HNMR (400MHz, DMSO-d6) δ9.73(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).

[0329] Example 56

[0330] Refer to Example 57, Synthesize Example 56.

[0331] Example 57

[0332] 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

[0333] Step 1: Synthesis of 4,6-dichloro-5-iodo-2-methylthiopyrimidine

[0334] 4,6-Dichloro-2-methylthiopyrimidine (6 g, 30.76 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 mL) at room temperature and the atmosphere was replaced with nitrogen three times. LDA (lithium diisopropylamide) (4.94 g, 46.14 mmol, 1.5 eq) was added at -78°C and allowed to react for 0.5 hour. Iodine (11.71 g, 46.14 mmol, 1.5 eq) was then added and allowed to react at room temperature for 1.5 hours. After completion of the reaction as determined by LC-MS, saturated aqueous sodium thiosulfate (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL x 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 = 12:1) to obtain the title compound (7 g, 70% yield). LC-MS (ESI) [M+H] + =320.1; 1 H NMR(400MHz,DMSO-d6)δ3.38 (s,3H).

[0335] Step 2: Synthesis of 6-chloro-N-ethyl-5-iodo-2-(methylthio)pyrimidin-4-amine

[0336] At room temperature, 4,6-dichloro-5-iodo-2-methylthiopyrimidine (7 g, 21.81 mmol, 1.0 eq) was dissolved in acetonitrile (70 mL). Ethylamine (0.98 g, 21.81 mmol, 1.0 eq) and triethylamine (3.31 g, 32.71 mmol, 1.5 eq) were added and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was directly dried and the product was purified by flash chromatography (Silica gel, PE:EA = 12:1) to obtain the title compound (7.1 g, 98% yield). LC-MS (ESI) [M+H] + =329.5.

[0337] Step 3: Synthesis of 6-chloro-N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-amine

[0338] 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 under nitrogen and heated to remove water. After returning to room temperature, NMP (N-methylpyrrolidone) (50 mL) and TMSCF3 ((trifluoromethyl)trimethylsilane) (8.54 g, 60.06 mmol, 10.0 eq) were added and allowed to react at room temperature for 1 hour. 6-Chloro-N-ethyl-5-iodo-2-(methylthio)pyrimidin-4-amine (3.6 g, 10.92 mmol, 1.0 eq) was then added and allowed to react at 50°C for 16 hours. After completion of the reaction as determined by LC-MS, the reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. Filtered through celite, 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 once 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 obtain the target compound (1.2 g, yield 40%). LC-MS (ESI) [M+H] + =272.0.

[0339] Step 4: Synthesis of N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-6-D-4-amine

[0340] 6-Chloro-N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-amine (1 g, 3.68 mmol, 1.0 eq) was dissolved in 10 mL of deuterated methanol at room temperature and allowed to react for 0.5 hour. Pd (0.2 g, 1.84 mmol, 0.5 eq), deuterated formic acid (0.51 g, 11.04 mmol, 3.0 eq), and triethylamine (1.12 g, 11.04 mmol, 3.0 eq) were then added and allowed to react at 95°C for 16 hours. After completion of the reaction, the mixture 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 title compound (300 mg, 19% yield). LC-MS (ESI) [M+H] + =239.1.

[0341] Step 5: Synthesis of tert-butylethyl 2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate

[0342] At room temperature, N-ethyl-2-(methylthio)-5-(trifluoromethyl)pyrimidin-6-D-4-amine (300 mg, 1.26 mmol, 1 eq) was dissolved in 3 mL of tetrahydrofuran. Di-tert-butyl dicarbonate (549.63 mg, 2.52 mmol, 2.0 eq), triethylamine (382.25 mg, 3.78 mmol, 3.0 eq), and 4-dimethylaminopyridine (76.92 mg, 0.63 mmol, 0.5 eq) were added. The mixture was reacted at 90°C for 4 hours. After completion of the reaction, the solvent was directly evaporated and the product was purified by flash chromatography (Silica gel, PE:EA = 12:1) to obtain the title compound (400 mg, 93% yield). LC-MS (ESI) [M+H] + =339.1.

[0343] Step 6: Synthesis of tert-butylethyl 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate

[0344] In a 50 mL single-necked vial at room temperature, tert-butylethyl 2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate (400 mg, 1.18 mmol, 1 eq) was dissolved in 4 mL of dichloromethane, and m-chloroperbenzoic acid (510 mg, 2.96 mmol, 2.5 eq) was added. The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the solvent was directly evaporated and the product was purified by flash chromatography (Silica gel, PE:EA = 1:1) to obtain the title compound (300 mg, 68% yield). LC-MS (ESI) [M+H] + =371.1.

[0345] 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

[0346] In a three-necked flask, 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (156.79 mg, 0.68 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). The nitrogen atmosphere was replaced three times with an appropriate amount of molecular sieves. Lithium bistrimethylsilylamide (225.9 mg, 1.35 mmol, 2.0 eq) was slowly added dropwise at -78°C. The mixture was allowed to react for 1 hour at -78°C. Subsequently, tert-butylethyl 2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl-6-(D)carbamate (250 mg, 0.68 mmol, 1.0 eq) was added to the reaction system and the reaction continued for 1 hour. After completion of the reaction, as determined by LC-MS, the reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL) under ice-cooling and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and 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.

[0347] Step 8: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of ethyl-5-(trifluoromethyl)pyrimidine-6d-2,4-diamine

[0348] In a 25 mL reaction vial at 0°C, 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). TFA (1 mL) was then slowly added, and the reaction system was warmed to room temperature and allowed to react for 2 hours. After completion of the reaction, as determined by LC-MS, the reaction solvent was evaporated, the pH was adjusted to 8-9 by adding saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (30 mL x 3). The mixture was then washed with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude target compound, which was then purified by reverse-phase column chromatography (25 mg, 32% yield). LC-MS (ESI) [M+H] + =423.4; 1 H NMR (400MHz, DMSO-d6) 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).

[0349] Example 58

[0350] 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

[0351] Step 1: Synthesis of lithium dichloro(2,2,6,6-tetramethylpiperidin-1-yl)zincate (II)

[0352] At room temperature, 2,2,6,6-tetramethylpiperidine (60 g, 424.78 mmol, 1.0 eq) was added to a reaction flask and dissolved in tetrahydrofuran (600 mL). The atmosphere was purged with nitrogen three times. n-Butyl lithium (27.21 g, 424.78 mmol, 1.0 eq) was added at -40°C, and the temperature was raised to -10°C for 1 hour. Zinc chloride (60.79 g, 446.02 mmol, 1.05 eq) was then added, and the reaction continued at -10°C for 0.5 hour, then returned to room temperature for 0.5 hour. The reaction solution was used directly in the next step.

[0353] Step 2: Synthesis of 2,4,6-trichloro-5-iodopyrimidine

[0354] In a three-necked flask, dissolve 2,4,6-trichloropyrimidine (20 g, 109.04 mmol, 1.0 eq) in tetrahydrofuran (200 mL) and slowly add dropwise to a solution of lithium dichloro(2,2,6,6-tetramethylpiperidin-1-yl)zincnate (II) (92.73 g, 327.12 mmol, 3.0 eq) in tetrahydrofuran (300 mL) at room temperature. Allow to react for 1 hour at room temperature. Then, dissolve iodine (55.35 g, 218.08 mmol, 2.0 eq) in tetrahydrofuran (100 mL) and add dropwise to the reaction system. Continue reacting for 1 hour. After completion of the reaction as determined by LC-MS, pour the reaction solution into a sodium thiosulfate solution (500 mL), extract with ethyl acetate (500 mL x 3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by flash chromatography (Silica gel, PE:EA=12:1) to obtain the target compound (20 g, yield 59%).

[0355] Step 3: Synthesis of 2,6-dichloro-N-ethyl-5-iodopyrimidin-4-amine

[0356] 2,4,6-Trichloro-5-iodopyrimidine (20 g, 64.66 mmol, 1.0 eq) was dissolved in acetonitrile (200 mL) at room temperature. Ethylamine (2.91 g, 64.66 mmol, 1.0 eq) and triethylamine (9.81 g, 96.99 mmol, 1.5 eq) were added and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was directly evaporated and the product was purified by flash chromatography (Silica gel, PE:EA = 12:1) to obtain the title compound (14 g, 68% yield). 1 H NMR (400MHz, DMSO-d6) δ7.67 (d, J = 5.2Hz, 1H), 3.45-3.35 (m, 2H), 1.12 (t, J = 7.2Hz, 3H).

[0357] Step 4: Synthesis of 2,6-dichloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine

[0358] Place cuprous iodide (4.94 g, 25.95 mmol, 5.5 eq) and potassium fluoride (1.51 g, 25.95 mmol, 5.5 eq) in a 100 mL three-necked flask. Heat to remove water under nitrogen. After returning to room temperature, add NMP (N-methylpyrrolidone) (15 mL) and TMSCF3 ((trifluoromethyl)trimethylsilane) (3.69 g, 25.95 mmol, 5.5 eq) and react at room temperature for 1 hour. Then add 2,6-dichloro-N-ethyl-5-iodopyrimidin-4-amine (1.5 g, 4.72 mmol, 1.0 eq) and react at 50°C for 16 hours. After completion of the reaction as determined by LC-MS, quench the reaction solution with saturated ammonium chloride solution and dilute with ethyl acetate. Filter through celite, and wash the filter cake three times with ethyl acetate. Separate the filtrate, and wash the organic phase once with saturated ammonium chloride solution and once 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 obtain the target compound (0.4 g, yield 32%). LC-MS (ESI) [M+H] + =260.0.

[0359] Step 5: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-6-chloro-N 4 Synthesis of 5-ethyl-(trifluoromethyl)pyrimidine-2,4-diamine

[0360] 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), and potassium acetate (185.2 mg, 1.89 mmol, 3.0 eq) were dissolved in dioxane (2 mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90°C for 1 hour. After the reaction was complete, the reaction solvent was dried and purified by flash chromatography (Silica gel, PE:EA = 2:1) to obtain the crude target compound, which was then purified by Prep-HPLC to obtain the target compound (65 mg, yield 23%). LC-MS (ESI) [M+H] + =456.1; 1H NMR(400MHz,DMSO-d6)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).

[0361] Examples 59-60

[0362] Refer to Examples 58 and 61, and Synthesize Examples 59-60.

[0363] Example 61

[0364] 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

[0365] Step 1: Synthesis of N-ethyl-6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-amine

[0366] 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. The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the solvent was directly dried and purified by flash chromatography (Silica gel, PE:EA = 10:1) to obtain the title compound (700 mg, 88% yield). LC-MS (ESI) [M+H] + =267.6; 1 H NMR (400MHz, DMSO-d6) 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).

[0367] Step 2: Synthesis of tert-butylethyl 6-methoxy-2-methylthio-5-trifluoromethylpyrimidin-4-ylcarbamate

[0368] 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). 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. The mixture was reacted at 90°C for 16 hours. LC-MS analysis confirmed the completion of the reaction. The solvent was then dried and the product was purified by flash chromatography (Silica gel, PE:EA = 12:1) to obtain the title compound (500 mg, 72% yield). LC-MS (ESI) [M+H] + =368.1.

[0369] Step 3: Synthesis of tert-butylethyl 6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-ylcarbamate

[0370] 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 m-chloroperbenzoic acid (562.59 mg, 3.26 mmol, 2.5 eq) was added. The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the solvent was directly dried and the product was purified by flash chromatography (Silica gel, PE:EA = 1:1) to obtain the title compound (370 mg, 71% yield). LC-MS (ESI) [M+H] + =400.2; 1 H NMR (400MHz, DMSO-d6) δ4.18(s,3H),3.83(d,J=6.8Hz,2H),3.46(s,3H),1.40(s,9H),1.18(t,J=6.8Hz,3H).

[0371] Step 4: N 2 -(3-(2-(4H-1,2,4-triazol-4-yl)propan-2-yl)-1-isopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of 5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0372] In a three-necked flask, 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-amine (320 mg, 1.38 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL). An appropriate amount of molecular sieves was added and the atmosphere was replaced with nitrogen three times. Lithium bistrimethylsilylamide (461.04 mg, 2.76 mmol, 2.0 eq) was slowly added dropwise at -78°C. The mixture was allowed to react for 1 hour at -78°C. Subsequently, tert-butylethyl 6-methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-ylcarbamate (550.22 mg, 1.38 mmol, 1.0 eq) was added to the reaction system and the reaction continued for 1 hour. After the reaction was complete as determined by LC-MS, saturated aqueous ammonium chloride (10 mL) was added dropwise to the reaction mixture under an ice bath to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated and purified by flash chromatography (Silica gel, PE:EA = 2:1) to obtain the title compound (170 mg, 38% yield). LC-MS (ESI) [M+H] + =552.0.

[0373] Step 5: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of 6-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0374] 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) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and allowed to react at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 8-10 with sodium bicarbonate in an ice bath and extracted with dichloromethane (50 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by Prep-HPLC (C18, 5 mmol / L NH3·H2O in water, MeCN) to obtain the title compound (16.95 mg, 20% yield). LC-MS (ESI) [M+H] + =452.2; 1H NMR(400MHz,DMSO-d6)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).

[0375] Example 62

[0376] 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

[0377] Step 1: Synthesis of 6-chloro-N-ethyl-3-iodopyrazin-2-amine

[0378] 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). Potassium fluoride (846mg, 14.6mmol, 2.0eq) was then added and reacted at 70°C for 16 hours. After completion of the reaction, ethyl acetate (50mL*3) was added 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 title compound (1.1g, 53% yield). LC-MS (ESI) [M+H] + =284.1.

[0379] Step 2: Synthesis of 6-chloro-N-ethyl-3-(trifluoromethyl)pyrazin-2-amine

[0380] At room temperature, 6-chloro-N-ethyl-3-iodopyrazin-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). Methyl fluorosulfonyldifluoroacetate (2.98 g, 15.5 mmol, 4.0 eq) was then slowly added dropwise. The mixture was allowed to react at 80°C for 16 hours. After completion of the reaction, as determined by LC-MS, water and ethyl acetate were added to the reaction system with stirring. The mixture was allowed to stand for separation. The aqueous phase was extracted with ethyl acetate (30 mL x 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 title compound (753 mg, 86% yield). LC-MS (ESI) [M+H] + =226.1.

[0381] Step 3: N 6 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 2 Synthesis of ethyl-3-(trifluoromethyl)pyrazine-2,6-diamine

[0382] In a 20 mL microwave reaction vial 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 eq), 6-chloro-N-ethyl-3-(trifluoromethyl)pyrazin-2-amine (338 mg, 1.5 mmol, 1.5 eq), Pd2(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 at 90 °C under microwave conditions for 16 h. After the reaction was completed, the reaction solvent was directly dried and purified by Prep-HPLC to obtain the target compound (59.7 mg, yield 14%). LC-MS (ESI) [M+H] + =422.4; 1H NMR(400MHz,DMSO-d6)δ7.91-7.86(m,1H),7.76(s,2H),7.69(s,1H),7.34(s,1H),5.88(s,1H),3.3 1(tt,J=7.1,3.5Hz,1H),3.12-3.01(m,2H),1.97(s,6H),1.02(t,J=7.1Hz,3H),0.99-0.85(m,4H).

[0383] Example 63

[0384] 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

[0385] Step 1: Synthesis of 6-chloro-N-ethyl-3-(trifluoromethyl)pyridin-2-amine

[0386] 6-Chloro-3-(trifluoromethyl)pyridin-2-amine (0.98 g, 5 mmol, 1.0 eq) was dissolved in DMF (10 mL) at 0°C. Potassium tert-butoxide (0.84 g, 7.5 mmol, 1.5 eq) was added portionwise. Ethyl iodide (1.17 g, 7.5 mmol, 1.5 eq) was then slowly added dropwise at 0°C. The reaction system was warmed to room temperature and the reaction was continued for 16 hours. After completion of the reaction as determined by LC-MS, water was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was then washed with water and then 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 title compound (960 mg, 85% yield). LC-MS (ESI) [M+H] + =225.1.

[0387] Step 2: N 6 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 2 Synthesis of ethyl-3-(trifluoromethyl)pyridine-2,6-diamine

[0388] In a 20 mL microwave reaction vial at room temperature, 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), Pd2(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-butanol (15 mL). The mixture was reacted in a microwave oven at 90°C under nitrogen for 3 hours. After completion of the reaction, the solvent was evaporated and the product was purified by Prep-HPLC to obtain the title compound (93 mg, 53% yield). LC-MS (ESI) [M+H] + =421.4; 1 H NMR (400MHz, DMSO-d6) 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,1H),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).

[0389] Example 64

[0390] Refer to Example 63, Synthesize Example 64.

[0391] Example 65

[0392] (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

[0393] Step 1: Synthesis of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0394] 2,4,5-Trichloropyrimidine (2.17 g, 11.82 mmol, 1.0 eq) was dissolved in isopropanol (20 mL), and (2-aminophenyl)dimethylphosphine oxide (1.0 g, 5.91 mmol, 0.5 eq) was added, followed by DIEA (N,N-diisopropylethylamine) (2.29 g, 17.73 mmol, 1.5 eq). The mixture was reacted at 60°C for 16 hours. LC-MS analysis confirmed that the reaction solvent was dried and the title compound was purified by flash chromatography (Silica gel, PE:EA = 1:1) to obtain the title compound (1.0 g, 53% yield). LC-MS (ESI) [M+H] + =316.0.

[0395] 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

[0396] (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 and extracted with ethyl acetate (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by Prep-HPLC (C18, 10 mmol / L NH3 in water, MeCN) to obtain the target compound (17 mg, 7% yield). LC-MS (ESI) [M+H] + =512.2; 1H NMR(400MHz,DMSO-d6)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).

[0397] Example 66

[0398] (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

[0399] Step 1: Synthesis of 2-chloro-N-[2-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine

[0400] 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (800 mg, 3.69 mmol, 1.0 eq) was dissolved in isopropanol (15 mL), and 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) were added. The mixture was allowed to react at 50°C for 2 hours. LC-MS analysis confirmed the reaction was complete, and the solvent was directly evaporated. The product was then purified by flash chromatography (Silica gel, PE:EA = 1:1) to obtain the title compound (400 mg, 31% yield). LC-MS (ESI) [M+H] + =350.1.

[0401] 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

[0402] 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(propyl-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), CS2CO3 (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-pyrazol-5-amine (66 mg, 0.29 mmol, 1.0 eq). The reaction was carried out at 60°C under nitrogen protection for 3 hours. After completion of the reaction, 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-d6) 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).

[0403] Example 67

[0404] 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

[0405] Step 1: Synthesis of 2,5-dichloro-N-(2-(methylsulfonyl)phenyl)pyrimidin-4-amine

[0406] Dissolve 2-methylsulfonylaniline (1.87 g, 10.9 mmol, 1.0 eq) in DMF (N,N-dimethylformamide) (20 mL). Carefully add NaH (sodium hydride) (360 mg, 9.26 mmol, 0.85 eq, 60% wt) under nitrogen at 0°C. Allow to react for 0.5 hours at 0°C. Add a solution of 2,4,5-trichloropyrimidine (2 g, 10.9 mmol, 1.0 eq) in DMF (N,N-dimethylformamide) (20 mL). Allow to react for 2 hours at 25°C under nitrogen. After completion of the reaction, as determined by LC-MS, quench the reaction with water (50 mL), extract with ethyl acetate (100 mL x 3), and wash with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then purified by flash chromatography (Silica gel, PE:EA=10:1) to obtain the title compound (0.15 g, yield 9%). 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 8.51 (s, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.9 7(d,J=7.8Hz,1H),7.82(t,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H),3.30(s,3H).

[0407] Step 2: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N 4 Synthesis of -(2-(methylsulfonyl)phenyl)pyrimidine-2,4-diamine

[0408] 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), Cs2CO3 (cesium carbonate) (368.64 mg, 1.13 mmol, 3.0 eq) was added, and the atmosphere was replaced with nitrogen. Xphos (dicyclohexyl[2',4',6'-tri(propyl-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) was reacted at 100°C under nitrogen for 16 hours. After completion of the reaction, 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 purified by Prep-HPLC (C18, 0.05% NH3H2O ​​in water, MeCN) to obtain the title compound (14.53 mg, 7% yield). LC-MS (ESI) [M+H] + =513.85. 1 H NMR (400MHz, DMSO-d6) 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=7.4 Hz,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).

[0409] Example 68

[0410] 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

[0411] Step 1: Synthesis of 6-chloro-N-ethyl-3-iodopyrazin-2-amine

[0412] At room temperature, 2,4,5-trichloropyrimidine (2 g, 10.9 mmol, 1.0 eq) and 4-fluoroaniline (1.33 g, 13 mmol, 1.1 eq) were dissolved in isopropanol (20 mL). DIPEA (1.69 g, 13 mmol, 1.2 eq) was then slowly added and allowed to react at 90°C for 0.5 h. After completion of the reaction, the solvent was directly evaporated and the product was purified by flash chromatography (Silica gel, PE:EA = 20:1) to obtain the title compound (2.4 g, 85% yield). LC-MS (ESI) [M+H] + =258.1.

[0413] Step 2: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-5-chloro-N 4 Synthesis of -(4-fluorophenyl)pyrimidine-2,4-diamine

[0414] In a 20 mL microwave reaction vial 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), Pd2(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-butanol (15 mL). The reaction was continued at 90°C under a nitrogen atmosphere in a microwave oven for 16 hours. After completion of the reaction, the solvent was evaporated and the product was purified by Prep-HPLC to obtain the title compound (98.2 mg, 22% yield). LC-MS (ESI) [M+H] = 454.3; 1 H NMR(400MHz,DMSO-d6)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).

[0415] Examples 69-74

[0416] Reference Examples 49, 52, 58, 61, Synthesis Examples 69-74.

[0417] Example 75

[0418] 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

[0419] Step 1: Synthesis of ethyl 2-(d3)methyl-2-(2H-1,2,3-triazol-2-yl)(d3)propionate

[0420] Ethyl 2-(2H-1,2,3-triazol-2-yl)acetate (1 g, 6.45 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (741.43 mg, 19.35 mmol, 3.0 eq) was added at 0°C. After 0.5 hour, deuterated iodomethane (1.18 ml, 19.35 mmol, 3.0 eq) was added and the reaction continued at 0°C for 0.5 hour. The reaction solution was quenched with saturated aqueous ammonium chloride (20 mL), water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried, concentrated in vacuo, and purified by column chromatography (Silica gel, PE:EA = 5:1) to obtain the desired product (500 mg, 41% yield). LC-MS (ESI) [M+H] + =190.5; 1 H NMR (400MHz, CDCl3) δ7.68-7.62(m,2H),4.20-4.13(m,2H),1.22-1.17(m,3H).

[0421] Step 2: Synthesis of 4-(d3)methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)(5,5,5-d3)valeronitrile

[0422] Acetonitrile (0.28 ml, 5.28 mmol, 2.0 eq) was dissolved in tetrahydrofuran (10 mL), and n-butyl lithium (2.11 mL, 5.28 mmol, 2.0 eq) 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 (500 mg, 2.64 mmol, 1.0 eq) was added and the reaction was continued at -78°C for 1 hour. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to quench, water (20 mL) was added, and the mixture was extracted with methyl tert-butyl ether (30 mL*2). The aqueous phase was adjusted to pH 4-5 with 1M hydrochloric acid and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried, concentrated in vacuo, and slurried with petroleum ether (5 mL) to obtain the desired product (400 mg, yield 82%). LC-MS (ESI) [M+H] + =185.1; 1 HNMR(400MHz,DMSO-d6)δ7.95(s,2H),3.92(s,2H).

[0423] Step 3: Synthesis of 1-cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)(1,1,1,3,3,3-d6)propan-2-yl]-1H-pyrazol-5-amine

[0424] 4-(d3)methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)(5,5,5-d3)valeronitrile (400 mg, 2.17 mmol, 1.0 eq) was dissolved in ethanol (5 mL), and cyclopropylhydrazine (313.13 mg, 4.34 mmol, 2.0 eq) and hydrogen chloride (0.4 mL, 10.86 mmol, 5.0 eq) were added. The reaction mixture was allowed to react at 70°C for 16 hours. The reaction mixture was concentrated in vacuo, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, concentrated in vacuo, and purified by column chromatography (Silica gel, PE:EA = 1:1) to obtain the desired product (200 mg, 38% yield). LC-MS (ESI) [M+H] + =239.3, 1 HNMR(400MHz,DMSO-d6)δ7.73(s,2H),5.11(s,2H),4.80(s,1H),3.15-3.07(m,1H),0.89-0.86(m,4H).

[0425] 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

[0426] 1-Cyclopropyl-3-[2-(2H-1,2,3-triazol-2-yl)(1,1,1,3,3,3-d6)propan-2-yl]-1H-pyrazol-5-amine (100 mg, 0.42 mmol, 1.0 eq) was dissolved in dioxane (3 mL), and 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. The mixture was reacted at 90°C for 2 hours. The reaction mixture was purified by reverse phase chromatography (0.1% aqueous ammonia solution, acetonitrile) to obtain the title compound (57.74 mg, 32% yield). LC-MS (ESI) [M+H] + =428.1; 1 HNMR(400MHz,DMSO-d6)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).

[0427] Examples 76-77

[0428] Refer to Example 17, Synthesis Examples 76-77.

[0429] Example 78

[0430] N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-N4-(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0431] Step 1: Synthesis of di-tert-butyl 1-(methyl-d3)hydrazine-1,2-dicarboxylate

[0432] Di-tert-butyl hydrazine-1,2-dicarboxylate (15.00 g, 64.58 mmol, 1.0 eq) was added to a solution of tetrahydrofuran (300 mL). Under nitrogen, sodium hydride (3.36 g, 83.95 mmol, 60%, 1.3 eq) was slowly added at 0°C. The mixture was allowed to react for 1 hour at 0°C. Deuterated iodomethane (6.55 g, 45.20 mmol, 0.7 eq) was then slowly added and allowed to react for 2 hours at 25°C. After completion of the reaction, as determined by LC-MS, the reaction solution was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (500 mL x 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 title compound (7.0 g, 43% yield). LC-MS (ESI) [M+23] + =272.2.

[0433] Step 2: Synthesis of (methyl-d3)hydrazine

[0434] Di-tert-butyl 1-(methyl-d3)hydrazine-1,2-dicarboxylate (10.00 g, 40.11 mmol, 1.0 eq) was added to a 4M dioxane hydrochloride solution (100 mL) and allowed to react at 25°C for 2 hours. After completion of the reaction as determined by TLC, the solvent was evaporated to afford the title compound (4.10 g, crude product). This product was used directly in the next step without further purification.

[0435] Step 3: Synthesis of 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d3)-1H-pyrazol-5-amine

[0436] (Methyl-d3)hydrazine (1.00 g, 6.11 mmol, 30%, 1.0 eq, crude product, obtained from the previous step) was added to an ethanol solution (10 mL), followed by 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)valeronitrile (0.36 g, 2.02 mmol, 0.3 eq). The mixture was reacted at 90°C for 3 hours. After completion of the reaction, the solvent was evaporated and the product was purified by reverse phase chromatography (1%-10% ACN in Water) to obtain the title compound (0.5 g, 12% yield). LC-MS (ESI) [M+H] + =210.2.

[0437] Step 4: N 2 Synthesis of -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-N4-(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0438] 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-(methyl-d3)-1H-pyrazol-5-amine (241 mg, 1.15 mmol, 1.0 eq) was added to 1,4-dioxane (1 mL), followed by 2-chloro-N-(ethyl-d5)-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). The mixture was reacted at 90°C for 12 hours. After completion of the reaction, the solvent was dried and the product was separated and purified by Prep-HPLC (C18, 0.1% FA in water, MeCN) to obtain the title compound (25.8 mg, 6% yield). LC-MS (ESI) [M+H] + =404.2; 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),8.14(s,1H),7.75(s,2H),7.14(s,1H),5.94(s,1H),1.97(s,6H).

[0439] Example 79

[0440] N 2 -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0441] Step 1: N 2 -(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0442] 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-pyrazol-5-amine (100 mg, 0.43 mmol, 1.0 eq) in 1,4-dioxane (2 mL). The mixture was reacted at 90°C under nitrogen for 3 h. LC-MS analysis confirmed the reaction was complete, and the solvent was dried and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to yield the title compound (25 mg, 13% yield). LC-MS (ESI) [M+H] + =425.0; 1 H NMR (400MHz, DMSO-d6) 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).

[0443] Example 80

[0444] 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-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0445] Step 1: Synthesis of 4-methyl-2H-1,2,3-triazole

[0446] 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). Acetic acid (4 mL), 10% palladium on carbon (0.40 g, 3.76 mmol, 0.16 eq), and 20% palladium hydroxide (0.40 g, 2.85 mmol, 0.12 eq) were then added. The mixture was allowed to react at 60°C for 48 hours. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was concentrated, and saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield the crude title compound (1.90 g, crude product) as a clear liquid. LC-MS (ESI) [M+H] +=84.1. It was used directly in the next reaction without further purification.

[0447] Step 2: Synthesis of methyl 2-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)propionate

[0448] 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 allowed to react at 25°C for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (100 mL x 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 title compound (0.20 g, 23% yield). LC-MS (ESI) [M+H] + =184.2.

[0449] Step 3: Synthesis of 4-methyl-4-(4-methyl-2H-1,2,3-triazol-2-yl)-3-oxopentanonitrile

[0450] Acetonitrile (89 mg, 2.18 mmol, 2.0 eq) was added to tetrahydrofuran (8 mL). n-Butyl lithium (139.6 mg, 2.18 mmol, 2.0 eq) was added at -78°C and the mixture was allowed to react for 1 hour. Methyl 2-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)propanoate (200 mg, 1.09 mmol, 1.0 eq) was then added and the reaction continued for 1 hour. After completion of the reaction as determined by LC-MS, the reaction solution was poured into saturated ammonium chloride solution and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield the title compound (200.0 mg, crude product). LC-MS (ESI) [M+H] + =193.0. It was used directly in the next reaction without further purification.

[0451] Step 4: Synthesis of 1-cyclopropyl-3-(2-(4-methyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-amine

[0452] 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). Cyclopropylhydrazine hydrochloride (170 mg, 1.56 mmol, 1.5 eq) was added at 25°C and reacted at 90°C for 2 hours. After completion of the reaction, the solvent was evaporated and the residue was dissolved in methanol. The residue was isolated and purified by flash chromatography (C18, 12% MeCN in water) to obtain the title compound (150 mg, 59% yield). LC-MS (ESI) [M+H] + =247.2.

[0453] Step 5: N 2 -(1-cyclopropyl-3-(2-(4-methyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-yl)-N 4 Synthesis of -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0454] 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), followed by 2-chloro-N-(ethyl-d5)-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). The reaction was allowed to react at 90°C for 3 hours. After completion of the reaction, LC-MS analysis was performed and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the title compound (24.6 mg, 20% yield). LC-MS (ESI) [M+H] + =434.2; 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.16(s,1H),7.77(s,2H),7.12-6.80(m,1H),5.98(s,1 H),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).

[0455] Example 81

[0456] 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

[0457] Step 1: Synthesis of 2-chloro-4-[(2-methoxyethyl)amino]-5-(trifluoromethyl)pyrimidine

[0458] 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. The mixture was allowed to react for 16 hours at 25°C. After completion of the reaction, the mixture was extracted with ethyl acetate (100 mL x 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 title compound (300 mg, 25% yield). LC-MS (ESI) [M+H] + =256.0.

[0459] 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

[0460] 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). 3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-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. The mixture was reacted at 90°C for 3 hours. After completion of the reaction, LC-MS analysis was performed and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the title compound (100.21 mg, 7% yield). LC-MS (ESI) [M+H] + =452.2; 1H NMR(400MHz,DMSO-d6)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).

[0461] Example 82

[0462] 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-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0463] Step 1: Synthesis of 1-benzyl-4,5-dimethyl-1H-1,2,3-triazole

[0464] 3,3-Dimethoxy-2-butanone (10.00 g, 75.67 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (20 mL), followed by the addition of p-toluenesulfonylhydrazide (14.09 g, 75.67 mmol, 1.0 eq). The reaction was allowed to react at room temperature for 1 hour. Benzylamine (8.51 g, 79.45 mmol, 1.05 eq) was then added and the reaction continued at 80°C for 4 hours. After completion of the reaction as determined by LC-MS, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reverse phase chromatography (C18, 0.1% TFA in water, MeCN) to obtain the title compound (6.00 g, 42% yield). LC-MS (ESI) [M+H] + =188.2.

[0465] Step 2: Synthesis of 4,5-dimethyl-2H-1,2,3-triazole

[0466] 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 on carbon (225 mg, 1.60 mmol, 0.1 eq) and palladium hydroxide (225 mmol, 1.60 mmol, 0.1 eq) were added under nitrogen. After hydrogen substitution, the reaction was continued at 60°C for 16 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to obtain the title compound (960 mg, 61% yield). LC-MS (ESI) [M+H]+ =98.1. It was used directly in the next reaction without further purification.

[0467] Step 3: Synthesis of methyl 2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-2-methylpropionate

[0468] 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-methylpropanoate (2.80 g, 15.44 mmol, 1.0 eq) in methanol (15 mL). The mixture was reacted at 80°C under nitrogen for 3 hours. After completion of the reaction, the filtrate was filtered, concentrated, and purified by reverse phase chromatography (C18, 15% MeCN in water) to obtain the title compound (525 mg, 17% yield). LC-MS (ESI) [M+H] + =198.1.

[0469] Step 4: Synthesis of 4-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-4-methyl-3-oxopentanonitrile

[0470] Acetonitrile (208 mg, 5.07 mmol, 2.0 eq) was added to a mixture of n-butyllithium (0.32 mL, 5.07 mmol, 2.0 eq) in tetrahydrofuran (5 mL) at -78°C under nitrogen. The mixture was stirred for 1 hour, followed by the addition of methyl 2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-2-methylpropanoate (500 mg, 2.54 mmol, 1.0 eq). The reaction was continued for 1 hour. After completion of the reaction as determined by LC-MS, the reaction solution was poured into ice water, adjusted to pH 6 with 1 M aqueous hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield the title compound (500 mg, 95% yield). LC-MS (ESI) [M+H] + =207.1. It was used directly in the next reaction without further purification.

[0471] Step 5: Synthesis of 1-cyclopropyl-3-(2-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)propan-2-yl)-1H-pyrazol-5-amine

[0472] Concentrated hydrochloric acid (0.2 mL, 2.40 mmol, 2.47 eq) was added to a mixture of 4-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)-4-methyl-3-oxopentanonitrile (200 mg, crude product, obtained from the previous step) and cyclopropylhydrazine hydrochloride (140 mg, 1.94 mmol, 2.0 eq) in ethanol (2 mL). The mixture was reacted at 90°C under nitrogen for 2 hours. After completion of the reaction, the solvent was evaporated, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (200 mg, 79% yield). LC-MS (ESI) [M+H] + =261.2, and was used directly in the next reaction without further purification.

[0473] Step 6: 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 Synthesis of -(ethyl-d5)-5-(trifluoromethyl)pyrimidine-2,4-diamine

[0474] 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-d5)-5-(trifluoromethyl)pyrimidin-4-amine (177 mg, 0.77 mmol, 1.0 eq) in 1,4-dioxane (2 mL). The mixture was reacted at 90°C under nitrogen for 3 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the title compound (17.58 mg, 5% yield). LC-MS (ESI) [M+H] + =425.0; 1 H NMR (400MHz, DMSO-d6) 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).

[0475] Example 83

[0476] 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

[0477] 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

[0478] 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. 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 purified by flash chromatography and 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(400MHz,CD3OD)δ8.12(s,1H),7.70(s,2H),5.99(s,1H),3.67(t,J=5.6Hz,2H), 3.52(t,J=5.6Hz,2H),3.35(dd,J=4.0,2.8Hz,1H),2.06(s,6H),1.09-1.00(m,4H).

[0479] Example 84

[0480] 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

[0481] Step 1: Synthesis of methyl 3-(2H-1,2,3-triazol-2-yl)cyclobutane-1-carboxylate

[0482] At 25°C under nitrogen, 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) for 2 hours. After completion of the reaction, as determined by LC-MS, the product was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to yield the title compound (1.00 g, 36% yield). LC-MS (ESI) [M+H] + =182.1.

[0483] Step 2: Synthesis of 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-3-oxopropionitrile

[0484] At -78°C, under nitrogen, n-butyllithium (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). The mixture was stirred for 1 hour, followed by the addition of methyl 3-(2H-1,2,3-triazol-2-yl)cyclobutane-1-carboxylate (1000mg, 5.52mmol, 1.0eq) and the reaction was allowed to proceed for 1 hour. After completion of the reaction, as determined by LC-MS, the reaction solution was poured into water, adjusted to pH 6 with 1M hydrochloric acid, and extracted with ethyl acetate (100mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to yield the title compound (1.00g, 95% yield). LC-MS (ESI) [M+H] + =191.1. It was used directly in the next reaction without further purification.

[0485] Step 3: Synthesis of 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-amine

[0486] Hydrochloric acid (0.35 mL, 9.46 mmol, 6 M in H2O, 2.0 eq) was added to a mixture of 3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-3-oxopropionitrile (900 mg, 4.73 mmol, 1.0 eq, crude product from the previous step) and cyclopropylhydrazine hydrochloride (341 mmol, 4.73 mmol, 1.0 eq) in ethanol (9 mL). The mixture was reacted at 90°C under nitrogen for 2 hours. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (1.00 g, 86% yield). LC-MS (ESI) [M+H] + =245.4. It was used directly in the next reaction without further purification.

[0487] Step 4: N 2 -(3-(3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 Synthesis of 5-ethyl-(trifluoromethyl)pyrimidine-2,4-diamine

[0488] 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 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). The mixture was reacted at 90°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was separated and purified by Prep-HPLC (C18, 0.5% FA in water, MeCN) to obtain the title compound (7.39 mg, 2% yield). LC-MS (ESI) [M+H] + =434.2; 1 H NMR(400MHz,DMSO-d6)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,4H),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).

[0489] The structure of reference compound 1 (DNL151) is as follows: (Compound 78 in CN109311857B);

[0490] The structure of reference compound 2 is as follows: (Compound 34 in CN109311857B).

[0491] Biology section

[0492] Experimental Example 1: In vitro evaluation of the inhibitory activity of compounds against LRRK2 kinase

[0493] 1. Experimental materials:

[0494] 1) Reaction solution: 50 mM HEPES (pH 7.5) (Manufacturer: GIBCO; Catalog No.: 15630-080); 10 mM MgCl2 (Manufacturer: Sigma; Catalog No.: 63069); 1 mM EDTA (Manufacturer: Invitrogen; Catalog No.: AM9260G); 0.01% Brij35 (Manufacturer: Millipore; Catalog No.: 203728); 2 mM DTT (Manufacturer: Sigma; Catalog No.: 43816).

[0495] 2) Detection solution: TR-FRET Dilution Buffer (Manufacturer: Thermo; Catalog No.: PV3574).

[0496] 3) LRRK2 human recombinant protein: The recombinant full-length human LRRK2 protein (Manufacturer: Thermo; Catalog No.: PR8604B) was expressed in insect Sf9 cells using baculovirus using a GST tag.

[0497] 4) Substrate: 0.4 μM Fluorescein-ERM (LRRKtide) peptide (Manufacturer: Thermo; Catalog No.: PV4901); 38 μM ATP (Manufacturer: Sigma; Catalog No.: A7699).

[0498] 2. Detection method:

[0499] Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET): TR-FRET combines time-resolved fluorescence detection with fluorescence resonance energy transfer (FRET). In the experiment, when biomolecules interact, the distance between the donor and acceptor fluorophores is shortened. When the donor is excited, it transfers its emitted light energy to the acceptor. Using lanthanide fluorophores as donors, whose emission light has a long half-life, both the excitation and emission of the donor and acceptor fluorophores can be detected after the short half-life background fluorescence disappears, reducing background and improving the signal-to-noise ratio, thereby increasing sensitivity.

[0500] 1) Add the DMSO solution of the test compound to a 384-well microplate using the Echo550 non-contact nanoliter acoustic dispensing system.

[0501] 2) Prepare a mixed enzyme and peptide solution (2 nM LRRK2 human recombinant protein + 0.4 μM Fluorescein-ERM (LRRKtide) peptide) using the freshly prepared reaction solution. Add 5 μL to the 384-well microplate containing the compound. Centrifuge at 1000 rpm / min for 1 minute. Incubate at room temperature for 15 minutes.

[0502] 3) Add 5 μL of 38 μM ATP, centrifuge at 1000 rpm / min for 1 min, and incubate at room temperature for 120 min.

[0503] 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 allowed to react at room temperature for 30 min.

[0504] 5) TR-TRET fluorescence signal was detected by Envison, mirror 447 (D400 / D505), filter 275 (520 nm) and 102 (485 nm).

[0505] 6) The inhibition of the compound on enzyme activity was calculated by the signal ratio (520 nm / 485 nm), and the IC was calculated using the XLfit5 software to fit the curve. 50 value.

[0506] Experimental results: The compound of the present invention has a strong inhibitory effect on LRRK2 kinase.

[0507] Table 1. Results of the inhibitory activity test of compounds on LRRK2 kinase

[0508] A:IC 50 ≤3nM; B: 3nM <IC 50 ≤20nM

[0509] Experimental Example 2: In vitro evaluation of the inhibitory activity of compounds against pS935

[0510] 1. Detection mechanism:

[0511] This experiment is designed to simply, quickly, and directly detect the phosphorylation level of LRRK2 (Ser935, i.e., pS935) in cells. After cell membrane lysis, the kit can be used to detect phosphorylated LRRK2 (Ser935).

[0512] Phosphorylated LRRK2 (Ser935) was detected using two different specific antibodies in a sandwich assay format, one with Eu 3+ - cryptate (donor) labeled, 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 emits fluorescence at a specific wavelength (665nm) at a specific location. The specific signal is proportional to phosphorylated LRRK2 (Ser935). Detection of phosphorylated LRRK2 (Ser935).

[0513] 2. Cell preparation:

[0514] 1) Cell recovery:

[0515] HEK293T cells purchased from ATCC were removed from 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 culture medium and centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded, the cells were resuspended in 15 mL of fresh complete culture medium, and the cells were transferred to a T75 culture flask. The flask was cultured in a 37°C, 5% CO2 incubator, and the cell growth status was monitored regularly.

[0516] 2) Cell passaging:

[0517] Cells can be passaged when they reach 80-90% confluence. Discard the supernatant, add 20-25 mL of PBS, and shake the culture flask several times. Discard the PBS, add 3-4 mL of trypsin to digest the cells, let them sit for 1-2 minutes, add 10 mL of complete culture medium to terminate the digestion, and gently pipette the cells until all cells are detached and a single-cell suspension is formed. Transfer the single-cell suspension to a centrifuge tube and centrifuge at 1000 rpm / min for 5 minutes. Discard the supernatant, resuspend the cells in fresh complete culture medium, and passage them at a 1:5 ratio into a T150 culture flask. Incubate the culture flask in a 37°C, 5% CO2 incubator and monitor the cell growth status promptly.

[0518] 3) Cell cryopreservation:

[0519] Cells with good growth status and cell viability of more than 96% were cryopreserved. The cell density of the collected cells was adjusted to 5x 10 6 / mL, and then transferred to cell cryovials, with 1 mL of cell suspension per tube. Place the cryovials containing cells in a freezing box and freeze at -80℃ overnight before transferring to liquid nitrogen for storage.

[0520] 3. Experimental steps:

[0521] 1. Day 1: HEK293T Cell Transfection

[0522] ⑴ 30 ml cell suspension (containing 30 x 10 6 cells) were seeded in 150 mm culture dishes.

[0523] (2) Prepare transfection reagents: Add 2 mL of opti-MEM (Gibco; Catalog No. 31985070) + 20 μg of DNA (AZENTA custom plasmid) + 60 μL of TansIT (MIRUS; Catalog No. MIR 2300) in the following order. Mix gently and let stand at room temperature for 20 minutes.

[0524] ⑶ Add the prepared transfection reagent evenly to the 150mm culture dish seeded with cells, shake gently to mix, and then place in a 37℃, 5% CO2 incubator for 24 hours.

[0525] 2. The next day: planting board

[0526] Collect the transfected cells and adjust the cell density to 0.2 x 10 6 / mL. Add 50 μL of the cell suspension to each well of a 384-well microplate (10,000 cells per well) and centrifuge at 1000 rpm / min for 1 minute. Place the 384-well microplate in a 37°C, 5% CO2 incubator and incubate overnight.

[0527] 3. Day 3: Compound Treatment and HTRF Detection

[0528] ⑴ Prepare compounds: The storage concentration of the compounds is 10mM. When using, dilute the compounds to the required working concentration as required.

[0529] ⑵ Add the compounds to a 384-well microplate using a TECAN instrument according to the plate map. After adding the compounds, add DMSO to adjust the final DMSO concentration to 0.2%.

[0530] (3) After centrifugation at 1000 rpm / min for 1 min, place in a 37°C, 5% CO2 incubator and culture for 2 h.

[0531] (4) Prepare HTRF cell lysis buffer (Manufacturer: Cisbio; Product No.: 6FLRKPEH): 4 mL Lysis buffer + 12 mL H2O + 160 μL Blocking buffer.

[0532] (5) After 2 h, add 16 μL of cell lysis buffer to each well and centrifuge at 1000 rpm / min for 1 min. Incubate the plate at 800 rpm / min and room temperature for 30 min.

[0533] ⑹ Prepare HTRF antibody mixed solution (manufacturer: Cisbio; catalog number: 6FLRKPEH): 1600 μL = 40 μL Cryptate-antibody + 40 μL d2-antibody + 1520 μL H2O.

[0534] ⑺After 30 minutes, centrifuge at 1000 rpm / min for 2 minutes.

[0535] ⑻Add 4 μL of the antibody mixture solution to each well and centrifuge at 1000 rpm / min for 1 min. Incubate at room temperature for 20-24 h.

[0536] ⑼Read the plate on Envision.

[0537] Experimental results: The compounds of the present invention have a strong inhibitory effect on p S935.

[0538] Table 2. Inhibitory activity test results of compounds against pS935 in HEK293 cells expressing G2019S LRRK2

[0539] A:IC 50 ≤5nM; B: 5 <IC 50 ≤20nM; C: 20 <IC 50 ≤50nM

[0540] Experimental Example 3: Pharmacokinetic Evaluation of Compounds

[0541] 1. Test objectives:

[0542] LC-MS / MS was used to test the pharmacokinetic characteristics of the compounds in C57BL / 6 mice.

[0543] 2. Experimental materials:

[0544] C57BL / 6 mice (male, 8 weeks old, body weight 25 g-30 g).

[0545] 3. Experimental operation:

[0546] The pharmacokinetic characteristics of the compounds following oral administration in rodents were tested using a standard protocol. Test and control compounds were prepared as 1 mg / mL suspensions and administered orally or intravenously to mice in a single dose. The vehicle was a 5% DMSO + 40% PEG400 + 55% CMC-Na (1%) aqueous solution.

[0547] This study used male C57BL / 6 mice, with intravenous (iv) administration at a dose of 1 mg / kg or 2 mg / kg and oral gavage (po) administration at a dose of 5 mg / kg. Plasma was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration in the intravenous group and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration in the po group.

[0548] Plasma samples were collected by centrifugation at approximately 4°C, 3000 g, for 15 min, and the supernatant was separated. Plasma samples were stored in polypropylene tubes, quickly frozen on dry ice, and kept at -80°C until LC-MS / MS analysis.

[0549] 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 drugs (Vss), etc.

[0550] The pharmacokinetic parameters of the compounds in the examples of the present invention in mice are shown in Table 3 below.

[0551] Table 3. Pharmacokinetic parameters of the compounds in mice

[0552] Experimental results: Compared with the control compound, the compound of the present invention has better in vivo pharmacokinetic properties and has drug potential.

Claims

1. A compound represented by the following formula (I), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: in, X1, X2 and X3 are each independently CR X or N; If present, each R X are each independently H, deuterium, halogen, -NR X1 R X2 OR 13 ;in, If present, each R X1 and R X2 Each independently is H, deuterium, C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thioalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thioalkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; Or, for each pair of R X1 and R X2 Together with the N atom to which they are commonly attached, they independently form a 4-8 membered heterocyclic group; the 4-8 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl and C 1-3 substituted by an oxaalkyl substituent; If present, each R 13 Each independently is H, deuterium, C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thioalkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thioalkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; R1 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 with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2; R2 is deuterium, halogen, -NR 21 R 22 , C 1-4 Alkyl, C 1-4 Oxaalkyl or C 1-4 Thioalkyl; the C 1-4 Alkyl, C 1-4 Oxaalkyl or C 1-4 The thiaalkyl group is optionally substituted with one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; wherein, If present, R 21 and R 22 Each independently is H, deuterium, C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thioalkyl, C 2-6 alkenyl, phenyl or 5-6 membered heteroaryl; the C 1-6 Alkyl, C 1-6 Oxaalkyl, C 1-6 Thioalkyl, C 2-6 The alkenyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted with one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethanesulfonamide, methanesulfonyl, ethanesulfonyl and C 1-3 substituted by an alkyl substituent; Alternatively, R1 and R2 together form a Q The substituted ring Q, wherein the ring Q is phenyl or pyrrolyl; If present, each R Q are independently deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Oxaalkyl, C 1-3 Haloalkyl, C 3-6 substituted by a cycloalkyl group and a 4-6 membered heterocyclic group; wherein the substituent C 1-3 Alkyl, C 1-3 Oxaalkyl, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Substituted by a haloalkyl substituent; R3 is deuterium, halogen, -CN, -OH, -NH2, C 3-10 Cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclic group; the C 3-10 Cycloalkyl, 5-12 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 Substituted by a cycloalkyl group and a 4-6-membered heterocyclic group; If present, each R W are independently deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Substituted by a haloalkyl substituent; m is 0, 1, 2 or 3; L does not exist or is in, R4 and R5 are each independently H, deuterium, halogen, -CN, -OH, -SH, -NH2, 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 each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2; Alternatively, R4 and R5 together with the C atom to which they are attached form a C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; when for When R W is not optionally substituted C 3-6 Cycloalkyl or C optionally substituted by halogen 1-3 alkyl, and R4 and R5 are not H or optionally substituted C 1-3 alkyl; When L does not exist, for And R W is an optionally substituted C 3-6 When it is a cycloalkyl group, R3 is not a heterocyclic group having an oxo group; When L does not exist, for When R3 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.

2. 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, R X H, deuterium, -NR X1 R X2 OR 13 ;in, If present, R X1 and R X2 Each independently is H, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; Or, R X1 and R X2 Together with the N atom to which they are commonly attached, they form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; If present, R 13 C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; If present, each R Q are independently deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Substituted by a haloalkyl substituent; R3 is deuterium, halogen, -CN, -OH, -NH2, C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; the C 3-10 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 Substituted by a cycloalkyl group and a 4-6-membered heterocyclic group; Every R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; R4 and R5 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 with 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 attached form a C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; m is 1 or 2; n is 0, 1 or 2.

3. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R X is H or deuterium.

4. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R X For-NR X1 R X2 ; Among them, R X1 and R X2 Each independently is H, deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; or, R X1 and R X2 Together with the N atom to which they are commonly attached, they form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; Preferably, R X1 and R X2 are each independently H, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl; or, R X1 and R X2 Together with the N atoms to which they are connected, they form 5. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R x For-OR 13 ; Among them, R 13 It is methyl.

6. The compound according to claim 2, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R X H, -NHCH3, Or -OCH3.

7. 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: Every R Q are independently deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Substituted by a haloalkyl substituent; Preferably, each R Q Each is independently deuterium, -F, -Cl, -Br, -CN, -OH, -NO2, -NH2, 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, -NO2 and -NH2; More preferably, each R Q Each is independently -F, -Cl, -CN, methyl, trifluoromethyl or cyclopropyl.

8. 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: R3 is deuterium, halogen, -CN, -OH, -NH2, C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; the C 3-8 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl are optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-6 Substituted by a cycloalkyl group and a 4-6-membered heterocyclic group; Preferably, R3 is -CN, C 4-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclic group; the C 4-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl may be substituted with one or more independently selected from oxo, C 1-3 Alkyl, C 1-3 Alkoxy and 4-6 membered heterocyclic substituents; 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), R3 is -CN, More preferably, in the formula (A1), R3 is -CN, Further preferably, in the formula (A1), R3 is Further preferably, in the formula (A2), R3 is Further preferably, in the formula (A2), R3 is Further preferably, in the formula (A2), R3 is 9. 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: Every R W 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 each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2; Preferably, each R W each independently is deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; More preferably, each R W Each is independently methyl, isopropyl or cyclopropyl.

10. The compound according to any one of claims 2 to 9, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R4 and R5 are each independently H, deuterium or C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with 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 attached form a C 3-4 Cycloalkyl; the C 3-4 The cycloalkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; 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 C 1-3 substituted by an alkyl substituent; 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.

11. 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.

12. A compound represented by the following formula (A3), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: in, R X H, deuterium or -NR X1 R X2 ;in, R X1 and R X2 Each independently is H, deuterium, C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; the C 1-3 Alkyl, C 3-6 The cycloalkyl or 4-6 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; If present, each R Q are independently deuterium, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group; the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group is substituted by a substituent of a 4-6 membered heterocyclic group; wherein the 4-6 membered heterocyclic group is optionally substituted by one or more of a methyl group, a hydroxyl group and a cyano group; R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; n is 0, 1 or 2.

13. The compound according to claim 12, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R X For-NR X1 R X2 ; Among them, R X1 and R X2 Each independently is H, deuterium or C 1-3 Alkyl; the C 1-3 Alkyl is selected from one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; Preferably, R X1 and R X2 Each is independently H, methyl, ethyl or isopropyl.

14. The compound according to claim 12, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: R X It is H or -NHCH3.

15. 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: Every R Q are independently deuterium, halogen, -CN, C 1-3 Alkyl, C 3-8 Cycloalkyl or 4-8 membered heterocyclic group; the C 1-3 Alkyl, C 3-8 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Oxaalkyl, C 3-6 The cycloalkyl group is substituted by a substituent of a 4-6 membered heterocyclic group; wherein the 4-6 membered heterocyclic group is optionally substituted by one or more of a methyl group, a hydroxyl group and a cyano group; Preferably, each R Q are independently -F, -Cl, cyclopropyl, 16. 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 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 It is cyclopropyl.

17. 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.

18. A compound represented by the following formula (A4), a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: in, X1, X2 and X3 are each independently CR X or N; If present, each R X are each independently H, deuterium, halogen, -NR X1 R X2 OR 13 ;in, If present, each R X1 and R X2 Each independently is H, deuterium or C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2 and C 1-3 substituted by an alkyl substituent; If present, each R 13 Each independently is C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2 and -NH2; R1 is deuterium, halogen or C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen, -CN, -OH, -NO2 and -NH2; R 22 C 1-4 Alkyl or phenyl; the C 1-4 The alkyl or phenyl radicals are optionally substituted with one or more radicals independently selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, dimethylphosphoryl, phosphate, formamide, acetamide, methylsulfonamide, ethylsulfonamide, methylsulfonyl, ethylsulfonyl and C 1-3 substituted by an alkyl substituent; Every R W Deuterium, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl or C 3-6 The cycloalkyl group is optionally substituted with one or more independently selected from deuterium, halogen, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Substituted by a haloalkyl substituent; R4 and R5 are each independently H, deuterium, halogen, -CN, C 1-3 Alkyl or C 3-6 Cycloalkyl; the C 1-3 Alkyl, C 3-6 Cycloalkyl is optionally substituted with 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 attached form a C 3-6 Cycloalkyl; the C 3-6 The cycloalkyl group is optionally substituted with one or more radicals each independently selected from deuterium, halogen, -CN and C 1-3 substituted by an alkyl substituent; m is 1 or 2.

19. The compound according to claim 18, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: X1 for CR X , X2 and X3 are both N; Alternatively, both X1 and X2 are CR X , X3 is N; Or, X2 is CR X , X1 and X3 are both N; Or, X3 for CR X , X1 and X2 are both N; Alternatively, both X1 and X3 are CR X , X2 is N.

20. The compound according to claim 18 or 19, a stereoisomer, a tautomer or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein: Every R X Each is independently H, deuterium, F, Cl or Br.

21. 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 For-NR X1 R X2 ; where each R X1 and R X2 are each independently H, deuterium, methyl or ethyl; Preferably, each R X1 and R X2 Each is independently H or ethyl.

22. The compound of claim 18 or 19, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R x For-OR 13 ; where each R 13 Each independently is C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more substituents each independently selected from deuterium, halogen, -OH and -NH2; Preferably, R 13 It is methyl.

23. 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: R1 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, -NO2 and -NH2; Preferably, R1 is -F, -Cl, -CH3, -CD3 or -CF3; More preferably, R1 is -Cl, -CD3 or -CF3.

24. 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 independently selected from deuterium, -CN, -OH, -NO2, -NH2, dimethylphosphoryl, phosphate, formamide, acetamide, methanesulfonamide, ethylsulfonamide, methanesulfonyl, ethylsulfonyl and C 1-3 substituted by an alkyl substituent; Preferably, R 22 is ethyl, wherein the ethyl is optionally substituted by one or more substituents independently selected from deuterium, methyl, ethyl, F, Cl, Br, -CN, -OH, -NO2 and -NH2; or, R 22 is phenyl, which 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 -CH2CH3, -CD2CD3, 25. 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 independently selected from deuterium, halogen, -CN and C 1-3 substituted by an alkyl substituent; Preferably, R W Deuterium, -CD3, cyclopropyl, More preferably, R W For deuterium, cyclopropyl, 26. 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 C 1-3 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 by one or more independently selected from deuterium, halogen, -CN and C 1-3 substituted by an alkyl substituent; 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 from deuterium, -F and substituted with a methyl substituent; Alternatively, preferably, R4 and R5 are each independently -F, -CD3 or methyl; or, R4 and R5 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 27. 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.

28. 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): in, R X , R W , R1, R 22 , R4, R5 and m are as described in formula (A4).

29. A compound, a stereoisomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

30. 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.

31. Use of the compound according to any one of claims 1 to 29, its stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts, 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.

32. 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.

33. Use of the compound according to any one of claims 1 to 29, its stereoisomers, tautomers or mixtures thereof or pharmaceutically acceptable salts or the pharmaceutical composition according to claim 30 in the preparation of a medicament for treating and / or preventing Parkinson's disease.

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