CN115819405A - Pyrimidinylaminopyrazole derivatives and their use as leucine-rich repeat kinase 2 inhibitors - Google Patents

Abstract

The invention discloses a pyrimidine aminopyrazole derivative and its application as an inhibitor of leucine-rich repeat kinase 2. On the basis of pyrimidine aminopyrazole as a skeleton, a class of nitrogen-containing heterocyclic derivatives is further discovered. Compared with the existing similar skeleton structure compounds, the derivative shows a stronger inhibitory effect on LRRK2 activity. It is a class of compounds with potential therapeutic effects on central nervous diseases (such as: Parkinson's disease).

Description

Pyrimidine aminopyrazole derivatives and their usefulness as leucine-rich repeat kinase 2 inhibitors application

technical field

The invention belongs to the technical field of chemical medicines, and relates to pyrimidine aminopyrazole derivatives and their application as leucine-rich repeat kinase 2 inhibitors.

Background technique

Parkinson's disease (PD) is the second most common chronic neurodegenerative disease in middle-aged and elderly people, second only to Alzheimer's disease. Since it was discovered and named in 1817, human beings have fought against it for more than two hundred years. At present, people's awareness of this disease is low, the rate of visits is low, the rate of diagnosis is low, and it is incurable. The patient's lifelong manifestations are tremor, limb stiffness, hypokinesia, abnormal gait and other motor nervous system disorders, as well as hyposmia and sleep disorders. , constipation and other non-motor symptoms. Existing drugs can only alleviate the symptoms themselves to varying degrees, but cannot control the progression of the disease. The current commonly used clinical drugs are far from meeting the needs of the existing Parkinson's patients in the middle and advanced stages, and there is an urgent need for a class of drugs that can prevent Parkinson's pathological and biochemical degeneration. Disease-modifying therapy is currently the mainstream direction of drug development for Parkinson's disease, which can affect the initial triggers of neuronal degeneration and promote neuronal compensatory responses or reduce pathological spread and progression. Current mainstream studies believe that the aggregation of α-Syn in Lewy bodies (LB) is an important cause of Parkinson's disease, and reducing the aggregation of α-Syn is a potential method for the treatment of Parkinson's disease.

However, leucine-rich repeat kinase 2 (Leucine-rich repeat kinase 2, LRRK2) blocks chaperone-mediated autophagy, resulting in the inability of α-syn to be degraded and causing toxicity. LRRK2 is involved in α-syn-mediated neurotoxicity, and LRRK2 induces mitochondrial damage and endolysosomal dysfunction through an oxidative mechanism, which induces the progression of Parkinson's disease. LRRK2 kinase inhibitors can alleviate the pathological damage in Parkinson's disease models and improve the motor dysfunction of patients. The safety and tolerability of two novel LRRK2 kinase inhibitors, DNL201 and DNL151, have been successfully tested in phase IB clinical trials, and phase IIb/III registration clinical trials of DNL151 have been carried out. Therefore, the development of small molecule inhibitors of LRRK2 is currently one of the most promising research directions for the development of Parkinson's drugs.

Therefore, developing effective LRRK2 kinase inhibitors and mutant LRRK2 kinase inhibitors has become an important way to treat neurodegenerative diseases. The present invention aims to invent a compound that can highly inhibit LRRK2 kinase, so as to further invent a drug that can well treat neurodegenerative diseases.

Patent US8802674B2 discloses that the pyrimidine aminobenzamide compound of Gentech Company is a class of LRRK2 inhibitors, and its chemical structural formula is as follows:

US09212173B2 discloses that the pyrimidine aminopyrazole compound of Gentech Company is a class of LRRK2 inhibitors, and its chemical structural formula is as follows:

In the company's later research, it was found that the above-mentioned types of compounds had potential toxic side effects on peripheral tissues (such as kidney and lung) in animal experiments. In view of the fact that Parkinson's disease has not had a successful drug research in recent years, there is only one new drug in clinical research. Therefore, more highly active new structural small molecule LRRK2 kinase inhibitors are yet to be discovered.

Contents of the invention

In view of this, the object of the present invention is to provide a pyrimidine aminopyrazole derivative and its application as a leucine-rich repeat kinase 2 inhibitor.

To achieve the above object, the present invention provides the following technical solutions:

1. Pyrimidineaminopyrazole derivatives, or optical isomers thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, or hydrates, solvates, N-oxides, deuterated compounds thereof, the derivatives The general structure of is as follows:

Wherein, R _is selected from H, F, Cl, Br or I;

R _is selected from H, F, Cl, Br or I;

And n and m are selected from 1,2,3 respectively.

R ₃ is selected from H, C _1-6 alkyl, oxo C _1-6 alkyl or halogenated C _1-6 alkyl, respectively. .

Preferably, the derivative is

N ² -(5-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N ⁴ -methyl-5-(trifluoro Methyl)pyrazol-2,4-hydrazine, N ² -(5-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N ⁴ -methyl -5-(trifluoromethyl)py rimidine-2,4-diamine, its chemical structure is as follows:

Preferably, the derivative is

N ² -(3-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N ⁴ -methyl-5-(trifluoro Methyl)pyrazol-2,4-hydrazine, N ² -(3-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N ⁴ -methyl -5-(trifluoromethyl)py rimidine-2,4-diamine, its chemical structure is as follows:

2. Pyrimidineaminopyrazole derivatives, or their optical isomers, or their prodrugs, or their pharmaceutically acceptable salts, or their hydrates, solvates, N-oxides, and deuterated substances as leucine-rich Use of acid repeat kinase 2 inhibitors.

3. Pyrimidineaminopyrazole derivatives, or their optical isomers, or their prodrugs, or their pharmaceutically acceptable salts, or their hydrates, solvates, N-oxides, and deuterated substances in the preparation of therapeutic or Application of drugs in the prevention of Parkinson's disease.

4. Pyrimidineaminopyrazole derivatives, or their optical isomers, or their prodrugs, or their pharmaceutically acceptable salts, or their hydrates, solvates, N-oxides, and deuterated substances in the preparation of therapeutic or Application of drugs in the prevention of chronic neurodegenerative diseases.

5. Pyrimidine aminopyrazole derivatives, or their optical isomers, or their prodrugs, or their pharmaceutically acceptable salts, or their hydrates, solvates, N-oxides, deuterated The application of leucine repeat kinase 2 activity in medicines for preventing and/or treating diseases.

6. A pharmaceutical composition or preparation, comprising the aforementioned pyrimidineaminopyrazole derivative, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate, solvate, N - oxides, deuterides.

Preferably, pharmaceutically acceptable adjuvants, adjuvants or carriers are also included.

The beneficial effects of the present invention are:

The applicant has further discovered a class of nitrogen-containing heterocyclic derivatives based on pyrimidine aminopyrazole as the skeleton. Compared with existing compounds with similar skeleton structures, the derivatives show stronger inhibitory effect on LRRK2 activity. It is a class of compounds with potential therapeutic effects on central nervous diseases (such as Parkinson's).

Description of drawings

In order to make the purpose, technical solution and beneficial effect of the present invention clearer, the present invention provides the following drawings for illustration.

FIG. 1 is the synthesis route of F101 and F102 in Example 1.

Detailed ways

The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The term "therapeutically effective dose" refers to that amount of a compound of formula sufficient to be therapeutically effective when administered to a mammal in need of such treatment. A therapeutically effective amount will vary depending on the particular activity of the therapeutic agent employed, the age, physiological condition, presence of other disease states and nutritional status of the patient. In addition, other drug treatments that the patient may be receiving will affect the determination of a therapeutically effective amount of the therapeutic agent to be administered.

The term "treatment" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease to not develop; (ii) inhibiting the disease, that is, preventing the development of clinical symptoms; and/or (iii) ) to alleviate the disease, that is, to cause the regression of clinical symptoms.

The term "pharmaceutically acceptable excipients, adjuvants or carriers" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention. Any intermediate or compound 1 in the synthetic route that can be obtained through other reaction conditions is regarded as an alternative to the invention.

Embodiment 1: the synthesis of target compound F-101 and F-102

The synthetic route is shown in Figure 1.

Specific steps are as follows:

Step 1: Preparation of Intermediate 2

Add 2,4-dichloro-5-trifluoromethylpyrimidine (5.00g, 23.04mmol) and triethylamine (4.66g, 46.08mmol) into 50.0mL of methanol and cool down to -80°C. After cooling down, methylamine hydrochloride (1.56 g, 23.04 mmol) was added to the reaction system in batches, and the reaction was carried out at -80° C. for 2 h after the addition was complete. The progress of the reaction was monitored by TLC, and the temperature was raised to room temperature after the completion of the reaction. The solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1, volume ratio) to obtain intermediate 2 (1.34 g, 27.5%, white solid), [M+H] ⁺ =212.

Step 2: The preparation of intermediate 5

Add intermediate 3 (2.26g, 20.00mmol), intermediate 4 (4.83g, 24.00mmol) and triphenylphosphine (9.44g, 36.00mmol) into 20.0mL tetrahydrofuran, stir to dissolve, cool down to below - 10°C. Diisopropyl azodicarboxylate (7.28 g, 36.00 mmol) was weighed and dissolved in 10 mL of tetrahydrofuran, and slowly dropped into the above-mentioned reaction flask. After the drop was completed, it was slowly raised to room temperature and reacted for 17 hours. LC-MS and TLC monitoring showed that the reaction of raw materials was complete. Add 200.0 mL of water to the reaction solution, extract twice with ethyl acetate, combine the ethyl acetate phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product Intermediate 5 (2.50 g, 43.0%, yellow oil) , [M+H] ⁺ =297, [M-Boc+H] ⁺ =197. Jump straight into the next step.

Step 3: The preparation of intermediate 6

Intermediate 5 (25.50 g, 86.10 mmol) was dissolved in ethyl acetate, 2M hydrochloric acid ethyl acetate solution (50.0 mL) was added, and the mixture was stirred at room temperature for 3 h. LC-MS detected that the raw materials were not completely reacted, and 2M hydrochloric acid ethyl acetate solution (20.0 mL) was added and stirred at room temperature for 1 h, and LC-MS detected that the raw materials were completely reacted. After filtration, the filter cake was pumped cold to dryness to obtain intermediate 6 (3.26 g, 16.3%, off-white solid), [M+H] ⁺ =197.

Step 4: Preparation of intermediate 7

To a solution of Intermediate 6 (1.62 g, 8.25 mmol) and cesium carbonate (10.70 g, 33.00 mmol) in N,N-dimethylformamide (20.0 mL) was added 1-fluoro-2-iodoethane (1.72 g ,9.90mmol), after the addition was completed, the temperature was raised to 50°C for 2.5h. LC-MS monitoring showed that the reaction of raw materials was complete. Add 150.0 mL of water, extract with ethyl acetate, wash the extracted organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product intermediate 7 (2.03 g, 120.0%, yellow oil), [ M+H] ⁺ = 243. Jump straight into the next step.

Step 5: The preparation of intermediate 8

Take the reaction test tube, add intermediate 7 (2.03g, 8.30mmol), ethanol 10.0mL, iron powder (1.40g, 25.00mmol) and saturated ammonium chloride aqueous solution 10.0mL, react at room temperature for 0.5h. LC-MS detected that most of the raw materials were unreacted, and iron powder (1.00 g, 17.80 mmol) was added, and stirred at room temperature for 45 min. LC-MS monitored the completion of the raw material reaction. Filter through diatomaceous earth, rinse the filter cake with ethanol, concentrate the ethanol to dryness, add dichloromethane to the residue for extraction, dry the extracted organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain intermediate 8 (1.93g, 108.5%, brown-black oil), [M+H] ⁺ =213. Jump straight into the next step.

Step 6: The preparation of intermediate 9

To a mixture of Intermediate 8 (1.93g, 9.10mmol) in tetrahydrofuran (10.0mL) and water (10.0mL), cesium carbonate (5.54g, 17.00mmol) and Boc ₂ O (2.10g, 9.60mmol) were successively added, Reaction at room temperature for 1h. LC-MS monitored the completion of the raw material reaction, and the reaction solution was extracted with ethyl acetate. The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.20 g of a purple oily substance. The crude product was purified by silica gel column chromatography to obtain intermediate 9 (970.0 mg, 34.1%, solid), [M+H] ⁺ =313, [M+H-100] ⁺ =213, [M+H-56] ⁺ =257.

Step 7: Preparation of intermediates 10A and 10B

Take the reaction test tube, add intermediate 9 (800.0mg, 2.56mmol), NCS (376.0mg, 2.82mmol), dichloromethane 16.0mL, and react at room temperature for 18h. LC-MS and TLC monitored that about half of the raw material reacted, and the reaction was stopped. The reaction solution was washed with sodium thiosulfate, washed with water, anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain intermediates 10A and 10B (10A: 174.0 mg, 19.6%; 10B: 154.0 mg, 17.3%), which were respectively concentrated and put into the next step directly. [M+H] ⁺ =347, [M+H-100] ⁺ =247, [M+H-56] ⁺ =291.

Step 8: Preparation of intermediates 11A and 11B

Intermediate 10A (174.0mg, 0.50mmol) was added to 4.0mL ethyl acetate hydrochloride solution (2M) and reacted at room temperature for 14h. LC-MS monitored the completion of the reaction. The reaction solution was filtered, rinsed with ethyl acetate, and the solid was collected quickly (the solid is easy to absorb moisture), and the oil pump was cold pumped to dryness to obtain intermediate 11A (134.0 mg, 94.3%, off-white solid), [M+H] ⁺ =247 . 11B was obtained by the same method.

Step 9: Preparation of Compounds F-101 and F-102

Take the reaction test tube, add Intermediate 11A (134.0mg, 0.47mmol), Intermediate 2 (150.0mg, 0.71mmol), acetic acid (14.0mg, 0.24mmol) and t-BuOH (7.0mL), heat up to 50°C and react overnight . LC-MS monitored that a small amount of raw materials were not completely reacted, so the reaction was stopped. The reaction solution was filtered and rinsed with ethyl acetate to obtain a solid product. Dissolve the solid with dichloromethane, add saturated sodium bicarbonate to wash, separate the layers, extract the aqueous phase with dichloromethane twice, and combine the dichloromethane phases. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=10/1, volume ratio), and dried to obtain the final product (F-101: 102.0mg, 51.1%, off-white solid, [M+H] ⁺ =422 ); 1H NMR (400MHz, DMSO-d6) δ9.00(s, 1H), 8.08(s, 1H), 7.84(s, 1H), 7.03(s, 1H), 4.60(t, J=4.9Hz, 1H), 4.48(t, J=4.9Hz, 1H), 4.28–4.15(m, 1H), 3.00(d, J=11.8Hz, 2H), 2.82(s, 3H), 2.69(t, J=4.9 Hz,1H),2.62(t,J＝4.9Hz,1H),2.26–2.15(m,2H),2.08–1.93(m,2H),1.89–

1.77(m,2H). By the same method, F-102 was obtained from intermediate 11B: 97.0 mg, 42.2%, off-white solid), [M+H] ⁺ =422. 1H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H ),8.08(s,1H),7.84(s,1H),7.03(s,1H),4.60(t,J=4.9Hz,1H),4.48(t,J=4.9Hz,1H),4.28–4.15 (m,1H),3.00(d,J=12.2,2H),2.82(s,3H),2.69(t,J=4.9Hz,1H),2.62(t,J=4.9Hz,1H),2.20( td, J = 11.9, 2.3 Hz, 2H), 2.01 (qd, J = 12.2, 3.8 Hz, 2H), 1.87–1.78 (m, 2H).

Biological activity test

Protein binding experiments:

Reagent consumables:

LRRK2 G2019S enzyme (Thermo Fisher), substrate (LRRKtide) (Thermo Fisher), ATP (Thermo Fisher) TR-FRET diluent (Thermo Fisher), pLRRKtide antibody (Thermo Fisher), 384-well plate (PE ) DMSO (Solebao)

experiment procedure:

All test compounds (including positive controls and test samples) were diluted to 1 mM with DMSO to obtain corresponding test compound solutions. 35 μL positive compound (see Table 1 for structural formula, Genentech company in the literature (Bryan K, Chan, Anthony A, et al. Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor. [J]. (1): Compounds with similar structures disclosed in 85-90., and synthesized with reference to this document) solution, 35 μL test compound solution, and 35 μL blank solution were added to a 384-well plate at a time, and the plate was centrifuged at 2500 rpm for 1 minute with 1 mM as the initial Concentration, 3-fold gradient dilution 10 points, and according to each hole 100nL positive compound, test compound, blank hole solution were added to another 384 assay plate, 3 duplicate holes, the plate was centrifuged at 2500rpm for 1 minute and placed on a foil Sealed for use.

Enzyme reaction: Dilute LRRKtide substrate and LRRK2G2019S kinase mixed working solution with assay buffer (Thermo Fisher TR-FRET Dilution buffer) (final concentration is LRRKtide substrate: 400nM and LRRK2 G2019S kinase: 580ng/mL) and add it to the above 384 assay Plate 5 μL per well of all sample wells in the 384 assay plate and incubate at 23 °C for 20 min. After incubation, dilute 2×ATP working solution (134 μM) with assay buffer and add to each well, 5 mL per well, and incubate 384 assay plate at 23° C. for 60 minutes.

Detection: Dilute EDTA and pLRRKtide antibody with assay buffer (TR-FRET Dilution buffer) to obtain a mixed working solution (final concentration: EDTA: 10mM, pLRRKtide antibody: 2nM). Then, 10 μL of the antibody mixed working solution was added to each well of the above-mentioned 384 assay plate, and incubated at 23° C. for 60 minutes. The plate was read on a microplate reader in TE-FRET mode with 340nm excitation light, 520nm fluorescence emission light and 490nm terbium emission light.

Method reference: J de Bicente Fidalgo et al. Compounds, compositions and methods: CN113939294A[P].2022-01-14.

The activity data of each compound are shown in Table 1.

Table 1. Compound Activity Data Sheet

As can be seen from Table 1, the series of new compounds provided by the embodiments of the present invention have a stronger inhibitory effect on the kinase LRRK2 G2019S, which is obviously stronger than the positive control (Genentech company in the literature (Bryan K, Chan, Anthony A, et al. Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2Inhibitor.[J].ACS Med Chem Lett.2012Nov 23; 4(1):85-90. The inhibitory activity of LRRK2 G2019S. In the preparation of prevention and/or Or it has potential application value in medicines for treating diseases related to increased activity of gene LRRK2 in vivo.

Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that it can be described in terms of form and Various changes may be made in the details without departing from the scope of the invention defined by the claims.

Claims (8)

1. Pyrimidineaminopyrazole derivatives, or optical isomers thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, or hydrates, solvates, N-oxides, deuterated compounds thereof, characterized in that , the general structure of the derivative is as follows:

in, R _is selected from H, F, Cl, Br or I; R _is selected from H, F, Cl, Br or I; And n and m are selected from 1,2,3 respectively. R ₃ is selected from H, C _1-6 alkyl, oxo C _1-6 alkyl or halogenated C _1-6 alkyl, respectively. 2. The pyrimidine aminopyrazole derivative according to claim 1, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate, solvate, N-oxide , Deuterium, characterized in that the derivative is N ² -(5-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl )-N ⁴ -methyl-5-(trifluoromethyl)pyrimidine-2,4-hydrazine, its chemical structural formula is as follows:

3. The pyrimidine aminopyrazole derivative according to claim 1, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate, solvate, N-oxide , Deuterium, characterized in that the derivative is N ² -(3-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl )-N ⁴ -methyl-5-(trifluoromethyl)pyrimidine-2,4-hydrazine, its chemical structure is as follows:

4. The pyrimidine aminopyrazole derivative according to any one of claims 1 to 3, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate or solvate , N-oxides, and deuterated substances as leucine-rich repeat kinase 2 inhibitors. 5. The pyrimidine aminopyrazole derivative according to any one of claims 1 to 3, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate or solvate Application of , N-oxide and deuterium in the preparation of medicines for treating or preventing Parkinson's disease. 6. The pyrimidine aminopyrazole derivative according to any one of claims 1 to 3, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate or solvate Application of , N-oxide and deuterium in the preparation of medicines for treating or preventing chronic neurodegenerative diseases. 7. The pyrimidine aminopyrazole derivative according to any one of claims 1 to 3, or its optical isomer, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate or solvate Application of , N-oxide and deuterated substances in the preparation of medicines for preventing and/or treating diseases by inhibiting the activity of leucine-rich repeat kinase 2. 8. A pharmaceutical composition or preparation, comprising the pyrimidine aminopyrazole derivative according to any one of claims 1 to 3, or its optical isomer, or its prodrug, or its pharmaceutically acceptable Salts, or hydrates, solvates, N-oxides, and deuteriums thereof.

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