CN115819405A

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

Info

Publication number: CN115819405A
Application number: CN202211643320.XA
Authority: CN
Inventors: 雷皇书; 洪亮; 刘才平; 刘灏; 柯颂
Original assignee: Chongqing Feiyinke Biotechnology Co ltd; Shanghai Tiandu Technology Co ltd; Shanghai Chongqing Artificial Intelligence Research Institute; Shanghai Jiaotong University
Current assignee: Chongqing Feiyinke Biotechnology Co ltd; Shanghai Tiandu Technology Co ltd; Shanghai Chongqing Artificial Intelligence Research Institute; Shanghai Jiaotong University
Priority date: 2022-12-20
Filing date: 2022-12-20
Publication date: 2023-03-21

Abstract

The invention discloses a pyrimidine aminopyrazole derivative and application thereof as a leucine-rich repeat kinase 2 inhibitor, further discovers a class of nitrogen-containing heterocyclic derivatives on the basis of taking pyrimidine aminopyrazole as a framework, and shows stronger inhibition effect on LRRK2 activity compared with the existing compound with a similar framework structure. Is a potential compound for treating central nervous diseases (such as Parkinson).

Description

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

Technical Field

The invention belongs to the technical field of chemical drugs, and relates to a pyrimidine aminopyrazole derivative and application thereof as a leucine-rich repeat kinase 2 inhibitor.

Background

Parkinson's Disease (PD) is the second largest chronic neurodegenerative disease that occurs in the middle-aged and elderly, second only to alzheimer's disease. Since its discovery and naming in 1817, the history of human fight against it has been more than two hundred years. At present, people have low cognition, low diagnosis rate and low diagnosis rate on the disease and can not cure the disease, and the patient presents with motor nervous system disorders such as tremor, limb stiffness, hypokinesia, gait abnormality and the like and non-motor symptoms such as hyposmia, sleep disorder, constipation and the like for life. The existing medicines can only relieve symptoms to different degrees and cannot control the disease progress. The current clinical commonly used medicines can not meet the requirements of the existing Parkinson patients in middle and late stages, and a medicine capable of preventing physiological and biochemical degeneration of the Parkinson disease is urgently needed. Disease modification therapy is the mainstream direction for the current development of drugs for treating parkinson's disease, and can affect the initial trigger of neuronal degeneration and promote neuronal compensation responses or reduce the spread and progression of pathology. At present, mainstream research considers that alpha-Syn aggregation in Lewy Bodies (LB) is an important reason for the pathogenesis of the Parkinson's disease, and reducing the alpha-Syn aggregation is a potential method for treating the Parkinson's disease.

And Leucine-rich repeat kinase 2 (LRRK2) blocks chaperone mediated autophagy, so that alpha-syn cannot be degraded and toxicity is generated. LRRK2 is involved in alpha-syn-mediated neurotoxicity, and LRRK2 induces mitochondrial damage and endolysosomal dysfunction through an oxidation mechanism to induce the progression of Parkinson's disease. The LRRK2 kinase inhibitor can relieve pathological damage of a Parkinson disease model and improve motor dysfunction of a patient. Phase IB clinical trials for the safety and tolerability of two novel LRRK2 kinase inhibitors, DNL201 and DNL151, were successful, and DNL151 has carried out phase IIb/III registration clinical studies. Therefore, the development of LRRK2 small-molecule inhibitors is one of the current research directions with the most potential for developing Parkinson therapeutic drugs.

Therefore, the development of potent inhibitors of LRRK2 kinase as well as mutant LRRK2 kinase is an important approach to the treatment of neurodegenerative diseases. The invention aims to invent a compound capable of highly inhibiting LRRK2 kinase, so that a medicament capable of well treating neurodegenerative diseases can be further invented.

Patent US8802674B2 discloses pyrimidine aminobenzamides of Gentech as a class of LRRK2 inhibitors, having the following chemical formula:

US09212173B2 discloses that pyrimidine amino pyrazoles of Gentech are inhibitors of LRRK2, and the chemical structural formula is as follows:

in later studies in the company, the compounds of the above classes were found to have potential toxic side effects on peripheral tissues (such as kidney and lung) in animal experiments. In view of the fact that the Parkinson disease has not been successfully researched by 1 medicament in recent years, only 1 new medicament is clinically researched. Therefore, more highly active new-structure small molecule LRRK2 kinase inhibitors are yet to be discovered.

Disclosure of Invention

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

In order to achieve the purpose, the invention provides the following technical scheme:

1. the pyrimidine aminopyrazole derivative, or an optical isomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an N-oxide and a deuteron thereof has the following general structure:

wherein R is ₁ Selected from H, F, cl, br or I;

R ₂ selected from H, F, cl, br or I;

and n and m are each selected from 1,2,3.

R ₃ Selected from H and C _1-6 Alkyl, oxo C _1-6 Alkyl or halogenated C _1-6 An alkyl group. .

Preferably, 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-diamine, N ² -(5-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N ⁴ -methyl-5- (trifluoromethylphenyl) pyrimidine-2, 4-diamine, having the following chemical formula:

preferably, 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-diamine, N ² -(3-chloro-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)-N ⁴ -methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine, having the chemical formula:

2. use of a pyrimidinylaminopyrazole derivative, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deutero-derivative thereof as a leucine-rich repeat kinase 2 inhibitor.

3. The application of the pyrimidine aminopyrazole derivative, or the optical isomer, the prodrug, the pharmaceutically acceptable salt, the hydrate, the solvate, the N-oxide and the deuteron thereof in preparing the medicine for treating or preventing the Parkinson disease.

4. The application of the pyrimidine aminopyrazole derivative, or the optical isomer, the prodrug, the pharmaceutically acceptable salt, the hydrate, the solvate, the N-oxide and the deuteron thereof in preparing the medicine for treating or preventing chronic neurodegenerative diseases.

5. The application of the pyrimidine aminopyrazole derivative, or the optical isomer, the prodrug, the pharmaceutically acceptable salt, the hydrate, the solvate, the N-oxide and the deuteron thereof in preparing the medicine for inhibiting the activity of the leucine-rich repeat kinase 2 to prevent and/or treat diseases.

6. A pharmaceutical composition or formulation comprising a pyrimidinylaminopyrazole derivative as hereinbefore described, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteride thereof.

Preferably, the composition also comprises pharmaceutically acceptable auxiliary materials, auxiliary materials or carriers.

The invention has the beneficial effects that:

the applicant further discovers a class of nitrogen-containing heterocyclic derivatives on the basis of taking pyrimidine aminopyrazole as a framework, and compared with the existing compounds with similar framework structures, the derivatives show stronger inhibition effect on LRRK2 activity. Is a compound with potential therapeutic effect on central nervous diseases (such as Parkinson).

Drawings

In order to make the object, technical solution and advantages of the present invention more clear, the present invention provides the following drawings for illustration.

FIG. 1 shows the synthesis routes of F101 and F102 in example 1.

Detailed Description

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

Definitions and explanations

As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. 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 a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amines or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

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

The term "therapeutically effective amount" refers to an amount of a compound of formula (la) sufficient to effect treatment when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the particular activity of the therapeutic agent used, the age, physiological condition of the patient, the presence of other disease states, and nutritional status. In addition, other medications that the patient may be receiving will affect the determination of the 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, i.e., causing the clinical symptoms of the disease not to develop; (ii) inhibition of disease, i.e., arresting the development of clinical symptoms; and/or (iii) relieving the disease, i.e., causing regression of clinical symptoms.

The term "pharmaceutically acceptable adjuvant, adjuvant or carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Such media and agents for pharmaceutically active substances are well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the composition.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention. All intermediates in the synthetic route or compound 1 that are accessible by other reaction conditions are considered alternatives to the invention.

Example 1: synthesis of target Compounds F-101 and F-102

The synthetic route is shown in figure 1.

The method comprises the following specific steps:

preparation of intermediate 2 in Step 1

2, 4-dichloro-5-trifluoromethylpyrimidine (5.00g, 23.04mmol) and triethylamine (4.66g, 46.08mmol) were added to 50.0mL of methanol and the temperature was reduced to-80 ℃. After the temperature is reduced, methylamine hydrochloric acid is addedThe salt (1.56g, 23.04mmol) was added in portions to the reaction system, and after the addition was completed, the reaction was carried out at-80 ℃ for 2 hours. The reaction progress was monitored by TLC and after completion of the reaction, the temperature was raised to room temperature. 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 give intermediate 2 (1.34g, 27.5%, white solid), [ M + H%] ⁺ ＝212。

Step 2 preparation of intermediate 5

Intermediate 3 (2.26g, 20.00mmol), intermediate 4 (4.83g, 24.00mmol) and triphenylphosphine (9.44g, 36.00mmol) were added to 20.0mL tetrahydrofuran, stirred to dissolve the supernatant and cooled to below-10 ℃. Diisopropyl azodicarboxylate (7.28g, 36.00mmol) was weighed and dissolved in 10mL tetrahydrofuran, and slowly dropped into the reaction flask, and after dropping, the temperature was slowly raised to room temperature for reaction for 17h. The starting material was completely reacted as monitored by LC-MS and TLC. Adding 200.0mL of water into the reaction solution, extracting twice with ethyl acetate, combining ethyl acetate phases, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 5 (2.50g, 43.0%, yellow oil), [ M + H%] ⁺ ＝297，[M-Boc+H] ⁺ =197. Directly put into the next step.

Preparation of intermediate 6 of Step 3

Intermediate 5 (25.50g, 86.10 mmol) was dissolved in ethyl acetate, and 2M ethyl acetate hydrochloride solution (50.0 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. The raw materials are not reacted completely through LC-MS monitoring, 2M ethyl acetate hydrochloride solution (20.0 mL) is added and stirred at room temperature for 1h, and the raw materials are reacted completely through LC-MS monitoring. Filtering, and pumping the filter cake to dryness to obtain intermediate 6 (3.26g, 16.3%, white solid), [ M + H%] ⁺ ＝197。

Step 4 preparation of intermediate 7

To a solution of intermediate 6 (1.62g, 8.25mmol) and cesium carbonate (10.70g, 33.00mmol) in N, N-dimethylformamide (20.0 mL) was added 1-fluoro-2-iodoethane (1.72g, 9.90mmol), and after addition, the temperature was raised to 50 ℃ for reaction for 2.5h. And (5) monitoring by LC-MS, and completely reacting the raw materials. Adding 150.0mL of water, extracting with ethyl acetate, washing the extracted organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain crude intermediate 7 (2.03g, 120.0%, yellow oily substance) [ M + H ]] ⁺ =243. Directly put into the next step.

Step 5 preparation of intermediate 8

A reaction tube was taken, and intermediate 7 (2.03g, 8.30mmol), ethanol 10.0mL, iron powder (1.40g, 25.00mmol) and saturated aqueous ammonium chloride solution 10.0mL were added and reacted at room temperature for 0.5h. LC-MS monitors that most of the raw materials are not reacted, and iron powder (1.00g, 17.80mmol) is supplemented, and stirring is carried out for 45min at room temperature. The completion of the reaction of the starting materials was monitored by LC-MS. Filtering with diatomaceous earth, washing the filter cake with ethanol, concentrating the ethanol to dryness, extracting the residue with dichloromethane, drying the extracted organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain intermediate 8 (1.93g, 108.5%, brown and black oil) [ M + H ]] ⁺ =213. Directly put into the next step.

Step 6 preparation of intermediate 9

To a mixture of intermediate 8 (1.93g, 9.10 mmol) in tetrahydrofuran (10.0 mL) and water (10.0 mL) were added cesium carbonate (5.54g, 17.00mmol) and Boc in this order ₂ O (2.10 g, 9.60mmol) was reacted at room temperature for 1 hour. LC-MS monitors the reaction of the raw materials, and the reaction solution is extracted by ethyl acetate. The extracted organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.20g of a purple oil, and the crude product was purified by silica gel column chromatography to give 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

The reaction tube was charged with intermediate 9 (800.0 mg, 2.56mmol), NCS (376.0 mg, 2.82mmol) and dichloromethane (16.0 mL) and reacted at room temperature for 18 hours. And monitoring about half of the reaction of the raw materials by LC-MS and TLC, stopping the reaction, washing the reaction solution by sodium thiosulfate, washing by water, filtering by anhydrous sodium sulfate, and concentrating to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain

intermediates

10A and 10B (10a, 174.0mg,19.6%;10b, 154.0mg, 17.3%), which were concentrated respectively and directly put to the next step. [ M + H ]] ⁺ ＝347，[M+H-100] ⁺ ＝247，[M+H-56] ⁺ ＝291。

Step 8 preparation of

intermediates

11A and 11B

Intermediate 10A (174.0 mg, 0.50mmol) was added to 4.0mL ethyl acetate hydrochlorideSolution (2M), room temperature reaction 14h, LC-MS monitor the completion of the raw material reaction. Filtering the reaction solution, leaching with ethyl acetate, rapidly collecting solid (the solid is easy to absorb moisture), and cold pumping to dryness with oil pump to obtain intermediate 11A (134.0 mg,94.3%, white solid), [ M + H ]] ⁺ =247. In the same manner, 11B was obtained.

Step 9 preparation of Compounds F-101 and F-102

Intermediate 11A (134.0 mg, 0.47mmol), intermediate 2 (150.0 mg, 0.71mmol), acetic acid (14.0 mg, 0.24mmol) and t-BuOH (7.0 mL) were added to the reaction tube, and the reaction was allowed to warm to 50 ℃ overnight. And (5) monitoring that a small amount of raw materials are not reacted by LC-MS, and stopping the reaction. And filtering the reaction liquid, and leaching with ethyl acetate to obtain a solid product. The solid was dissolved with dichloromethane, washed with saturated sodium bicarbonate, separated, the aqueous phase extracted twice with dichloromethane and the dichloromethane phases combined. 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 give 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＝4.9Hz,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). In the same manner, from intermediate 11B, 97.0mg,42.2% as a 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＝11.9,2.3Hz,2H),2.01(qd,J＝12.2,3.8Hz,2H),1.87–1.78(m,2H)。

Biological activity assay

Protein binding assay:

reagent consumables:

LRRK2G2019S enzyme (sereifei), substrate (LRRKtide) (sereifei), ATP (sereifei) TR-FRET diluent (sereifei), plrrrktide antibody (sereifei), 384-well Plate (PE) DMSO (solilebao)

The experimental process comprises the following steps:

all test compounds (including positive controls and test samples) were diluted to 1mM in DMSO to give the corresponding test compound solutions. 35 μ L of a positive compound (formula shown in Table 1, genentech company in the literature (Bryan K, chan, anthony A, et al, discovery of a high selectivity, brain-peptide Aminopyrazole LRRK2 Inhibitor [ J ]. ACS Med Chem Lett.2012Nov 23 (1): 85-90. The synthesis of which reference) solution, 35 μ L of test compound solution, 35 μ L of blank solution were added in portions to 384 well plates, plates were centrifuged at 2500rpm for 1 minute at 1mM initial concentration, 3-fold gradient diluted for 10 points, and 100nL of positive compound per well, test compound, blank well solution were added to another 384 assay plate, 3 duplicate wells, plates were centrifuged at 2500rpm for 1 minute and sealed in foil until needed.

Enzyme reaction: a mixed working solution of LRRKtide substrate and LRRK2G2019S kinase (final concentration of LRRKtide substrate: 400nM and LRRK2G2019S kinase: 580 ng/mL) diluted with assay buffer (Samerfei TR-FRET Dilution buffer) was added to all sample wells of the 384 assay plates described above, 5. Mu.L per well, and the 384 assay plates were incubated at 23 ℃ for 20 min. After incubation, 2 × ATP working solution (134 μ M) diluted with assay buffer was added to each well, 5mL per well, and 384 assay plates were incubated for 60 minutes at 23 ℃.

And (3) detection: EDTA and pLRRKtide antibody were diluted with an assay buffer (TR-FRET Dilution buffer) to give a mixed working solution (final concentration: EDTA:10mM, pLRRKtide antibody: 2 nM). Then, 10. Mu.L of the antibody mixed working solution was added to each well of the 384 assay plate and incubated at 23 ℃ for 60 minutes. The plate was read in a microplate reader in TE-FRET mode with excitation light at 340nm, fluorescence emission at 520nm and terbium emission at 490 nm.

The method refers to: compounds, compositions and methods of J debisentfeldag and the like CN113939294A [ P ].2022-01-14.

The activity data for each compound are shown in table 1.

TABLE 1 table of compound activity data

As can be seen from Table 1, the series of novel compounds provided by the embodiment of the invention have stronger inhibitory effect on the kinase LRRK2G2019S, which is obviously stronger than that of a positive control (the similar structural compounds disclosed in the paper of Genentech company (Bryan K, chan, anthony A, et al. Discovery of a high choice, brain-peptide amino pyrazoles LRRK2 Inhibitor [ J ]. ACS Med Chem Lett.2012Nov 23 (1): 85-90.) have potential application value in preparing medicines for preventing and/or treating diseases related to the increase of the activity of the gene LRRK2G2019S in vivo.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. A pyrimidine aminopyrazole derivative, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, a solvate, an N-oxide, a deuteron thereof, wherein the general structure of the derivative is as follows:

wherein the content of the first and second substances,

R ₁ selected from H, F, cl, br or I;

R ₂ selected from H, F, cl, br or I;

and n and m are each selected from 1,2,3.

R ₃ Selected from H and C _1-6 Alkyl, oxo C _1-6 Alkyl or halogenated C _1-6 An alkyl group.

2. The pyrimidine aminopyrazole derivative according to claim 1, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteron thereof, wherein 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-diamine having the following chemical formula:

3. the pyrimidine aminopyrazole derivative according to claim 1, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteron thereof, wherein 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-diamine having the following chemical formula:

4. use of a pyrimidinylaminopyrazole derivative of any one of claims 1 to 3, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deutero-derivative thereof as a leucine-rich repeat kinase 2 inhibitor.

5. Use of a pyrimidinylaminopyrazole derivative of any one of claims 1 to 3, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteron thereof for the manufacture of a medicament for the treatment or prevention of Parkinson's disease.

6. Use of the pyrimidinylaminopyrazole derivative of any one of claims 1 to 3, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteride thereof for the manufacture of a medicament for the treatment or prevention of chronic neurodegenerative disease.

7. Use of the pyrimidinylaminopyrazole derivative of any one of claims 1 to 3, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteron-oxide thereof for the manufacture of a medicament for inhibiting the activity of leucine-rich repeat kinase 2 for the prevention and/or treatment of diseases.

8. A pharmaceutical composition or formulation comprising a pyrimidinylaminopyrazole derivative of any one of claims 1 to 3, or an optical isomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate, solvate, N-oxide, deuteride thereof.