Pyridopyrrole derivatives and their use in preparing leucine-rich repeat kinase 2 inhibitors

Abstract

The present invention discloses pyridopyrrole derivatives and their use in the preparation of leucine-rich repeat kinase 2 inhibitors, which have a good inhibitory effect on LRRK2 activity and are potential therapeutic drugs for treating central nervous system degenerative diseases (such as Parkinson's disease).

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs and provides a pyridopyrrole derivative and an application thereof in the preparation of a leucine-rich repeat kinase 2 inhibitor. Background Art

[0002] Parkinson's disease (PD) is a chronic neurodegenerative disorder that primarily affects middle-aged and elderly people, ranking second in incidence after Alzheimer's disease. Since its initial discovery and naming in 1817, humanity has been battling this disease for over two centuries. Currently, awareness, consultation, and diagnosis rates for Parkinson's disease are low, and there is no cure. Patients suffer lifelong motor neurological disorders such as tremor, limb stiffness, decreased motor function, and gait abnormalities, as well as non-motor symptoms such as hyposmia, sleep disturbances, and constipation. Existing drug treatments can only provide limited symptom relief but cannot halt disease progression. Commonly used clinical medications fall short in meeting the needs of patients with mid- to late-stage Parkinson's disease, necessitating the development of drugs that can prevent Parkinson's pathology and biochemical degeneration. Disease-modifying therapies are currently the mainstream approach in the development of Parkinson's disease treatments, aiming to influence the initial triggers of neuronal degeneration, promote compensatory responses, or mitigate the spread and progression of the disease. Current mainstream research believes 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 treating Parkinson's disease.

[0003] Leucine-rich repeat kinase 2 (LRRK2) blocks chaperone-mediated autophagy, preventing α-syn degradation and leading to toxicity. LRRK2 is involved in α-syn-mediated neurotoxicity. LRRK2 induces mitochondrial damage and endolysosomal dysfunction through oxidative mechanisms, triggering the progression of Parkinson's disease. LRRK2 kinase inhibitors can alleviate pathological damage in Parkinson's disease models and improve patients' motor dysfunction. Two new LRRK2 kinase inhibitors, DNL201 and DNL151, have successfully completed Phase IB safety and tolerability clinical trials, and DNL151 has entered Phase IIb / III registration clinical trials. Therefore, the development of small molecule LRRK2 inhibitors is one of the most promising research directions for the development of Parkinson's disease treatment drugs.

[0004] Therefore, developing effective inhibitors of LRRK2 kinase and mutant LRRK2 kinases has become an important approach for treating neurodegenerative diseases. The present invention aims to invent a compound that can highly inhibit LRRK2 kinase, thereby further inventing a drug that can effectively treat neurodegenerative diseases.

[0005] Patent US8791112B2 discloses that Arrien's pyridopyrrole compounds are a class of LRRK2 inhibitors, and their general chemical structure is shown below.

[0006]

[0007] While patent 148 exhibits strong LRRK2 inhibitory activity, with an IC50 of <0.5μM, experiments have shown that this type of compound has low blood-brain barrier permeability and poor pharmacokinetic properties, halting its development at the preclinical stage. This suggests that the search for higher-quality blood-brain barrier-permeable compounds targeting this target is needed to ensure effective drug delivery to the brain while minimizing drug concentrations and toxic side effects in peripheral tissues. Summary of the Invention

[0008] In view of this, the object of the present invention is to provide a pyridopyrrole derivative and its use in the preparation of leucine-rich repeat kinase 2 inhibitors.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] 1. A pyridopyrrole derivative or a pharmaceutically acceptable salt thereof, wherein the structure of the derivative is shown in the general formula (1):

[0011]

[0012] In the general formula (1),

[0013] R1 is selected from cyano, C 1-7 alkylcarbonyl;

[0014] R2 and R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, and methylcarbamoyl;

[0015] X is selected from aromatic rings and aromatic heterocyclic rings.

[0016] Preferably, in the general formula (1),

[0017] R1 is selected from cyano, methylcarbonyl or cyclopropylcarbonyl;

[0018] R2 and R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, and methylcarbamoyl;

[0019] X is a benzene ring or a pyridine ring.

[0020] Preferably, the derivative is cyclopropyl (5-(3-isopropylphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone, and its chemical structure is as follows:

[0021]

[0022] Preferably, the derivative is 3-(3-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide, and its chemical structure is as follows:

[0023]

[0024] Preferably, the derivative is cyclopropyl (5-(3-isopropyl-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone, and its chemical structure is as follows:

[0025]

[0026] Preferably, the derivative is 3-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-isopropylbenzenesulfonamide, and its chemical structure is as follows:

[0027]

[0028] Preferably, the derivative is cyclopropyl (5-(5,6-dimethylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methanone, and its chemical structure is as follows:

[0029]

[0030] Preferably, the derivative is (5-(6-(tert-butyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(cyclopropyl)methanone, and its chemical structure is as follows:

[0031]

[0032] Preferably, the derivative is 3-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-isopropylbenzenesulfonamide, and its chemical structure is as follows:

[0033]

[0034] Preferably, the derivative is 3-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-isopropyl-N-methylbenzamide, and its chemical structure is as follows:

[0035]

[0036] Preferably, the derivative is 3-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-isopropylbenzamide, and its chemical structure is as follows:

[0037]

[0038] Preferably, the derivative is 3-(3-(cyclopropanecarbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-isopropylbenzenesulfonamide, and its chemical structure is as follows:

[0039]

[0040] 2. Use of the aforementioned pyridopyrrole derivatives or pharmaceutically acceptable salts thereof in the preparation of leucine-rich repeat kinase 2 inhibitors.

[0041] 3. Use of the aforementioned pyridopyrrole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for inhibiting the activity of leucine-rich repeat kinase 2 to prevent and / or treat diseases.

[0042] 4. Use of the aforementioned pyridopyrrole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating or preventing chronic neurodegenerative diseases.

[0043] 5. Use of the aforementioned pyridopyrrole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating or preventing Parkinson's disease.

[0044] 6. A pharmaceutical composition or preparation comprising the aforementioned pyridopyrrole derivative or a pharmaceutically acceptable salt thereof.

[0045] Preferably, it further comprises pharmaceutically acceptable excipients, adjuvants or carriers.

[0046] The beneficial effects of the present invention are:

[0047] The novel pyridopyrrole derivatives obtained by screening in the present invention have a good inhibitory effect on LRRK2 activity and are potential therapeutic drugs for treating central nervous system degenerative diseases (such as Parkinson's disease).

[0048] Other advantages, objects, and features of the present invention will be described in part in the following description and, in part, will be apparent to those skilled in the art upon examination of the following description or may be learned from practice of the present invention. The objects and other advantages of the present invention may be realized and obtained through the following description. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention will be described in detail below with reference to the accompanying drawings, in which:

[0050] Figure 1 This is the synthetic route of the target compound F001 in Example 1;

[0051] Figure 2 This is the synthetic route of the target compound F002 in Example 2;

[0052] Figure 3 This is the synthetic route of the target compound F003 in Example 3;

[0053] Figure 4 This is the synthetic route of the target compound F004 in Example 4;

[0054] Figure 5 This is the synthetic route of the target compound F005 in Example 5;

[0055] Figure 6 This is the synthetic route of the target compound F006 in Example 6;

[0056] Figure 7 This is the synthetic route of the target compound F007 in Example 7;

[0057] Figure 8 This is the synthetic route of the target compound F008 in Example 8;

[0058] Figure 9 This is the synthetic route of the target compound F009 in Example 9;

[0059] Figure 10 This is the synthetic route of the target compound F010 in Example 10. DETAILED DESCRIPTION

[0060] The present invention will be further described below in conjunction with specific embodiments.

[0061] Definition and Description

[0062] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0063] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0064] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the 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 in neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the 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 a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0065] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0066] The term "therapeutically effective dose" refers to an amount of a compound of the formula sufficient to provide therapeutic effect when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the specific activity of the therapeutic agent used, the patient's age, physical condition, the presence of other disease states, and nutritional status. In addition, other medications that the patient may be receiving will affect the determination of a therapeutically effective amount of the therapeutic agent to be administered.

[0067] The term "treat" means any treatment of a disease in a mammal, including: (i) preventing the disease, i.e., causing clinical symptoms of the disease not to develop; (ii) inhibiting the disease, i.e., arresting the development of clinical symptoms; and / or (iii) palliating the disease, i.e., causing regression of clinical symptoms.

[0068] The term "pharmaceutically acceptable excipient, adjuvant, or carrier" 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 agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0069] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification:

[0070] 1,4-Dioxane; 30% H2O2 (30% hydrogen peroxide); 4.0 M HCl in Dioxane (4.0 M hydrogen chloride in dioxane); 4.0 M HCl in EA (4.0 M hydrogen chloride in ethyl acetate); 7.0 M NH3 in MeOH (7.0 M ammonia in methanol); AcCl (acetyl chloride); ACN (acetonitrile); AcOH (acetic acid); AcOK (potassium acetate, anhydrous); Ag2SO4 (silver sulfate, anhydrous); AlCl3 (aluminum chloride); aq. (aqueous solution); (Boc)2O (di-tert-butyl dicarbonate); BPD (pinacol borate); CuCl (cuprous chloride); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); EA (ethyl acetate); FA (formic acid); g (gram); h (hour);

[0071] H2O (water); HCl (hydrogen chloride); Hz (hertz); I2 (iodine); L (liter); L (microliter); LiOH (lithium hydroxide, anhydrous); m (milliliter); M (mole); mg (milligram); MHz (megahertz); min (minute); mM (millimole); mmol (millimole); mol (mole); N2 (nitrogen); Na2S2O3 (sodium thiosulfate, anhydrous); NaHCO3 (sodium bicarbonate, anhydrous); NaNO2 (sodium nitrite); n-BuLi (n-butyllithium); NH4HCO3 (ammonium bicarbonate); NMI (N- methylimidazole); Pd(dppf)Cl2 ([1,1-bis(diphenylphosphino)ferrocene]dichloropalladium); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium); Na2CO3 (sodium carbonate, anhydrous); Pd2(dpa)3 (tris(dibenzylideneacetone)dipalladium); Py (pyridine); rt (room temperature); SOCl2 (thionyl chloride); TCFH (N,N,N,N-tetramethylchloroformamidine hexafluorophosphate); THF (tetrahydrofuran); TLC (thin layer chromatography); xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

[0072] 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, embodiments formed by combining these with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Any intermediates or compounds in the synthetic route that can be obtained by alternative reaction conditions are considered alternatives to the present invention.

[0073] Example 1: Synthesis of target compound F001

[0074] Synthesis route such as Figure 1 shown.

[0075] The specific steps are as follows:

[0076] Step 1: Preparation of intermediate 3

[0077] AlCl₃ (54.1 g, 405.6 mmol) was dissolved in DCM (950 ml), followed by the addition of 5-bromo-7-azaindole (CAS No. 183208-35-7, source: Shanghai Titan Technology Co., Ltd., 10 g, 50.7 mmol). The mixture was stirred at room temperature (25°C) for 1 h. Finally, cyclopropylcarbonyl chloride (7.43 g, 71.0 mmol) was added and the mixture was allowed to react overnight at 45°C. The reaction was monitored by TLC. After completion of the reaction, unreacted AlCl₃ was filtered through celite, and the filter cake was rinsed with DCM. The filtrate was poured into water, and the product was extracted with ethyl acetate. The crude product was purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether (volume fraction = 0-30%)) to afford Intermediate 3 (8.44 g, 62% yield) as a white solid. [M+H] + =265; [M+H] + =267.

[0078] Step 2: Preparation of compound F001

[0079] Intermediate 3 (230 mg, 0.87 mmol), 3-isopropylphenylboronic acid (CAS No. 216019-28-2, source: Shanghai Titan Technology Co., Ltd., 142.28 mg, 0.87 mmol), Pd(dppf)Cl2 (63.94 mg, 0.087 mmol), and K2CO3 (120.80 mg, 0.87 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (2 ml) in water (400 μl) was then added. The mixture was reacted at 100° C. for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction product was extracted with ethyl acetate, and the crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F001 as a white solid. Compound F001 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F001 (50.4 mg, yield 19.08%) as a white solid. [M+H] + =305; HPLC=96.65%; 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),8.74(s,1H),8.64(d,J=19.0Hz,2H),7.69 –7.45(m,2H),7.45–7.19(m,2H),2.99(s,1H),2.81(s,1H),1.32–0.87(m,10H).

[0080] Example 2: Synthesis of target compound F002

[0081] Synthesis route such as Figure 2 shown.

[0082] The specific steps are as follows:

[0083] Step 1: Preparation of intermediate 6

[0084] 3-Bromoaniline (CAS No. 591-19-5, source: Shanghai Titan Technology Co., Ltd., 2 g, 11.62 mmol) was added to concentrated hydrochloric acid (33 ml) (white solid precipitated). NaNO2 (1.2 g, 16.27 mmol) was added dropwise in an ice bath at 0°C to obtain a H2O (2.3 ml) solution. The mixture was stirred at room temperature (25°C) for 0.5 h to obtain a mixture (the system turned yellow with a small amount of solid). The mixture was then added dropwise to a mixed aqueous solution of SOCl2 (4.65 ml, 63.95 mmol) and CuCl (1.2 g, 11.62 mmol) in an ice bath at 0°C. The mixture was stirred at room temperature (25°C) for 1.5 h, and the system turned clear green. The reaction was monitored by TLC. Upon completion, the reaction solution was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, Intermediate 6 (2.4 g, 80.80% yield), as a yellow liquid, which was directly used in the next reaction.

[0085] Step 2: Preparation of Intermediate 7

[0086] Intermediate 6 (2.4 g, 9.39 mmol) was dissolved in pyridine (5 ml) and 7.0 M NH3 in MeOH (2 ml) was added. The reaction was vigorous, the system turned yellow, and solid precipitated (turbid). The mixture was stirred for 1 h. The reaction was monitored by TLC plate. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane volume fraction = 0-10%) to obtain intermediate 7 (880 mg, yield 39.63%) as a yellow solid. [M+H] + =236,238.

[0087] Step 3: Preparation of compound F002

[0088] Intermediate 7 (880 mg, 3.73 mmol), intermediate 8 (1.03 g, 4.47 mmol), Pd(dppf)Cl2 (176 mg, 0.22 mmol), and K2CO3 (1.03 g, 7.46 mmol) were added to a 15 ml sealed tube, followed by the addition of 1,4-Dioxane (10 ml) / water (2 ml). The mixture was reacted in an oil bath at 100°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F002 as a white solid. Compound F002 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F002 (60 mg, yield 23.40%) as a white solid. [M+H] + =342; HPLC = 95.06%; 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.80–8.73(m,2H),8.67(d,J=2.3Hz,1H),8.15(s,1H),7.97(d,J=7.7Hz,1H),7.82(d,J= 7.7Hz, 1H), 7.69 (t, J = 7.8Hz, 1H), 7.46 (s, 2H), 2.82 (tt, J = 8.1, 4.4Hz, 1H), 1.00 (t, J = 3.9Hz, 2H), 0.92 (dd, J = 7.4, 4.2Hz, 2H).

[0089] Example 3: Synthesis of target compound F003

[0090] Synthesis route such as Figure 3 shown.

[0091] The specific steps are as follows:

[0092] Step 1: Preparation of Intermediate 8

[0093] Intermediate 3 (6 g, 22.63 mmol), BPD (5.75 g, 22.63 mmol), Pd (dppf) Cl2 (828 mg, 1.13 mmol), and AcOK (4.44 g, 45.26 mmol) were added to a 150 ml sealed tube, followed by 1,4-Dioxane (60 ml). Under nitrogen protection, the mixture was reacted in an oil bath at 110 ° C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane volume fraction = 0-10%) to obtain Intermediate 8 (2.61 g, yield 36%) as a white solid. [M+H] + =313 (boronic acid ester); [M+H] + =231 (boric acid).

[0094] Step 2: Preparation of Intermediate 11

[0095] 1,3-Dibromo-5-isopropylbenzene (CAS No. 62655-20-3, source: Shanghai Titan Technology Co., Ltd., 2.0 g, 7.2 mmol) was dissolved in THF (20 ml) under N2 protection. The temperature was cooled to -78°C, and n-BuLi (2.9 ml, 7.2 mmol) was added dropwise. After completion, the mixture was allowed to react at -78°C for 2 h. Finally, dimethyl disulfide (640 μl, 7.2 mmol) was added dropwise. After addition, the mixture was allowed to react at room temperature (25°C) for 1 h, monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 11 (1.8 g, crude yield 102.27%).

[0096] Step 3: Preparation of intermediate 12

[0097] The crude product 11 (1.8 g, 7.34 mmol) was dissolved in AcOH (10 ml), and 30% H₂O₂ (1.47 ml) was added. The mixture was stirred at room temperature (25°C) for 1 h, with the reaction monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether (volume fraction = 0-20%)) to afford intermediate 12-1 (1.5 g) as an oil.

[0098] To Intermediate 12-1 (1.5 g) was added AcOH (7.5 ml) and 30% H₂O₂ (600 μl). The mixture was stirred at 90°C for 2 h, with TLC monitoring. After completion, the reaction was concentrated under reduced pressure to afford a crude product, which was then purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether (volume fraction = 0-20%)) to afford Intermediate 12 (1.38 g, 67.98% yield) as an oil.

[0099] Step 4: Preparation of compound F003

[0100] Intermediate 12 (428 mg, 1.54 mmol), intermediate 8 (355 mg, 1.54 mmol), Pd(dppf)Cl2 (112 mg, 0.154 mmol), and K2CO3 (427 mg, 3.09 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (4 ml) in water (800 μl) was then added. The mixture was reacted in an oil bath at 100°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F003 as a white solid. Compound F003 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F003 (65 mg, yield 11.00%) as a white solid. [M+H] + =383; HPLC=96.60%; 1 H NMR (400MHz, DMSO-d6) δ12.69(d,J=3.2Hz,1H),8.80–8.70(m,3H),8.01(t,J=1.7Hz,1H),7.94(s,1H),7.78(d,J=1.8Hz,1H),3.33(s,3H) ,3.15(h,J=6.8Hz,1H),2.82(tt,J=7.9,4.5Hz,1H),1.31(d,J=6.9Hz,6H),1.01(dd,J=7.4,4.1Hz,2H),0.93(dq,J=10.0,3.8,3.4Hz,2H).

[0101] Example 4: Synthesis of target compound F004

[0102] Synthesis route such as Figure 4 shown.

[0103] The specific steps are as follows:

[0104] Step 1: Preparation of intermediate 14

[0105] AlCl₃ (16.25 g, 121.84 mmol) was dissolved in DCM (300 ml), followed by the addition of 5-bromo-7-azaindole (CAS: 183208-35-7, source: Shanghai Titan Technology Co., Ltd., 3 g, 15.23 mmol). After addition, the mixture was stirred at room temperature (25°C) for 1 h. Finally, AcCl (1.67 g, 21.32 mmol) was added. After addition, the mixture was moved to a 45°C oil bath and allowed to react overnight. The reaction was monitored by TLC. After completion of the reaction, unreacted AlCl₃ was filtered through celite, and the filter cake was rinsed with DCM. The filtrate was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether (volume fraction) = 0-30%) to obtain Intermediate 14 (3.04 g, yield 83.51%) as a white solid. [M+H] + =239; [M+H] + =241.

[0106] Step 2: Preparation of Intermediate 15

[0107] Intermediate 14 (1 g, 4.2 mmol), BPD (1.6 g, 6.2 mmol), Pd(dppf)Cl2 (150 mg, 0.42 mmol), and AcOK (1.03 g, 10.4 mmol) were added to a 15 ml sealed tube, followed by 1,4-Dioxane (10 ml). Under nitrogen protection, the mixture was reacted in an oil bath at 110°C for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain Intermediate 15 (500 mg, yield 41.66%) as a white solid. [M+H] + =287 (boronic acid ester); [M+H] + =205 (boric acid).

[0108] Step 3: Preparation of Intermediate 18

[0109] 1,3-Dibromo-5-isopropylbenzene (CAS No. 62655-20-3, source: Shanghai Titan Technology Co., Ltd., 5 g, 17.99 mmol), benzyl mercaptan (3.35 g, 26.98 mmol), DIPEA (4.65 g, 35.98 mmol), xantphos (1.04 g, 1.80 mmol), and Pd2(dpa)3 (822.5 mg, 0.90 mmol) were added to a 150 ml sealed tube. Toluene (50 ml) was then added. Under nitrogen protection, the mixture was reacted in an oil bath at 100°C for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether, volume fraction = 0-2%) to obtain intermediate 18 (2.53 g, yield 43.7%) as a yellow solid.

[0110] Step 4: Preparation of Intermediate 20

[0111] Intermediate 18 (1.5 g, 4.69 mmol) was dissolved in acetic acid (10 ml) / water (5 ml), cooled to 0°C in an ice bath, and N-chlorosuccinimide (1.88 g, 14.06 mmol) was added. The mixture was stirred for 10 min, the ice bath was removed, and the temperature was naturally raised to room temperature (25°C) and stirred for 3 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in DCM (15 ml), cooled to 0°C in an ice bath, and aqueous ammonia (15 ml) was added. The mixture was stirred for 10 min, the ice bath was removed, and the temperature was naturally raised to room temperature (25°C) and stirred for 3 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by C18 column chromatography (elution gradient: ACN / 0.1% NH4HCO3 volume fraction = 0-100%) to obtain intermediate 20 (1.18 g, yield 90.0%) as a white solid. [M+H] + =278; [M+H] + =280.

[0112] Step 3: Preparation of compound F004

[0113] Intermediate 20 (200 mg, 0.72 mmol), Intermediate 15 (310 mg, 1.08 mmol), Pd(dppf)Cl2 (52.68 mg, 0.072 mmol), and K2CO3 (250 mg, 1.8 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (2 ml) in water (400 μl) was then added. The mixture was reacted in an oil bath at 100°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F004 as a white solid. Compound F004 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F004 (88 mg, yield 34.24%) as a white solid. [M+H] + =358; HPLC=95.60%; 1 H NMR(400MHz,DMSO-d6)δ8.65(d,J=19.1Hz,2H),8.51(s,1H),7.96(s,1H),7.81 (s,1H),7.70(s,1H),3.10(p,J=7.0Hz,1H),2.47(s,3H),1.30(d,J=6.9Hz,6H).

[0114] Example 5: Synthesis of target compound F005

[0115] Synthesis route such as Figure 5 shown.

[0116] The specific steps are as follows:

[0117] Step 1: Preparation of compound F005

[0118] Intermediate 8 (235 mg, 0.75 mmol), 2,3-dimethyl-5-bromopyridine (CAS No. 27063-90-7, source: Shanghai Titan Technology Co., Ltd., 191 mg, 0.75 mmol), Pd(dppf)Cl2 (56 mg, 0.075 mmol), and K2CO3 (260 mg, 1.89 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (4 ml) in water (800 μl) was then added. The mixture was reacted in an oil bath at 100°C under nitrogen for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F005 as a white solid. Compound F005 was further purified using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F005 (10.2 mg, yield 4.6%) as a white solid. [M+H] + =292; HPLC = 98.68%; 1 H NMR (400MHz, DMSO-d6) δ12.65(s,1H),8.75(d,J=3.0Hz,1H),8.68(d,J=2.3Hz,1H),8.63(d,J=2.3Hz,1H),8.59( d,J=2.3Hz,1H),2.87–2.76(m,1H),2.47(s,3H),2.34(s,3H),1.00(p,J=3.6Hz,2H),0.92(dq,J=7.3,3.3Hz,2H).

[0119] Example 6: Synthesis of target compound F006

[0120] Synthesis route such as Figure 6 shown.

[0121] The specific steps are as follows:

[0122] Step 1: Preparation of compound F006

[0123] The experimental procedure refers to the synthetic route of compound F005; compound F006 (48.0 mg, yield 21.9%) is a white solid. [M+H] + =320; HPLC=97.02%; 1H NMR(400MHz, CDCl3)δ12.62(s,1H),9.43–9.18(m,2H),8.30–8.14(m,1H),7.77–7.63(m,2H),7.36–7.2 7(m,1H),2.59–2.46(m,1H),2.02(d,J=6.9Hz,1H),1.47(s,9H),1.37–1.17(m,2H),1.05–0.95(m,1H).

[0124] Example 7: Synthesis of target compound F007

[0125] Synthesis route such as Figure 7 shown.

[0126] The specific steps are as follows:

[0127] Step 1: Preparation of intermediate 25

[0128] 5-Bromo-1H-pyrrolo[2,3-B]pyridine-3-carbaldehyde (CAS No. 757978-33-9, Source: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., 2 g, 8.88 mmol) was dissolved in pyridine (6 ml), and hydroxylamine hydrochloride (741 mg, 10.66 mmol) was added. The mixture was stirred at room temperature (25°C) for 2 h, and the reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, Intermediate 25 (2.53 g, crude yield 118%), as a colorless oil. [M+H] + =240; [M+H] + =242.

[0129] Step 2: Preparation of intermediate 26

[0130] Intermediate 25 (2.4 g, 9.99 mmol) was dissolved in SOCl2 (24 ml, 10 ml / g) and reacted in an oil bath at 75°C for 1.5 h. The reaction was monitored by TLC. After completion, the reaction was concentrated under reduced pressure and the toluene was removed to afford the crude product, Intermediate 26 (2.18 g, 98% crude yield), as a white solid. [M+H] + =222; [M+H] + =224.

[0131] Step 3: Preparation of intermediate 27

[0132] Intermediate 26 (842.1 mg, 3.79 mmol), BPD (963.08 mg, 3.79 mmol), Pd(dppf)Cl2 (138.75 mg, 0.19 mmol), and AcOK (744.40 mg, 7.59 mmol) were added to a 15 ml sealed tube, followed by 1,4-Dioxane (10 ml). The mixture was reacted in an oil bath at 110°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain Intermediate 27 (734.8 mg, yield 72%) as a white solid. [M+H] + =270 (boronic acid ester); [M+H] + =188 (boric acid).

[0133] Step 4: Preparation of compound F007

[0134] Intermediate 20 (200 mg, 0.72 mmol), intermediate 27 (232 mg, 0.86 mmol), Pd(dppf)Cl2 (52.68 mg, 0.072 mmol), and K2CO3 (149.02 mg, 1.08 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (2 ml) in water (400 μl) was then added. The mixture was reacted in an oil bath at 100°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F007 as a white solid. Compound F007 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and lyophilized to obtain compound F007 (38.4 mg, yield 15%) as a white solid. [M+H] + =341; HPLC=96.19%; 1 H NMR (600MHz, DMSO-d6) δ12.96(s,1H),8.75(d,J=2.2Hz,1H),8.51(s,1H),8.42(d,J=2.1Hz,1H),8.03(d,J =1.9Hz,1H),7.93(s,1H),7.70(s,1H),7.36(d,J=2.3Hz,1H),3.09(p,J=7.0Hz,1H),1.29(d,J=6.9Hz,6H).

[0135] Example 8: Synthesis of target compound F008

[0136] Synthesis route such as Figure 8 shown.

[0137] The specific steps are as follows:

[0138] Step 1: Preparation of intermediate 29

[0139] In a 50 mL round-bottom flask, 3-bromo-5-isopropylbenzoic acid (CAS No. 112930-39-9, source: Shanghai Titan Technology Co., Ltd., 500 mg, 2.05 mmol), methylamine hydrochloride (153 mg, 2.25 mmol), NMI (523 mg, 6.38 mmol), and acetonitrile (10 ml) were added and dissolved and stirred for 15 minutes. TCFH (575 mg, 2.05 mmol) was then added and the reaction continued for 2 hours. The reaction was monitored by TLC. After the reaction, the acetonitrile was dried and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether (volume fraction) = 0-30%) to obtain intermediate 29 (541 mg, 83% yield) as a light yellow oil. [M+H] + =256; [M+H] + =258.

[0140] Step 2: Preparation of compound F008

[0141] Intermediate 29 (150 mg, 0.51 mmol), Intermediate 27 (210 mg, 0.72 mmol), Pd(dppf)Cl2 (37.5 mg, 0.051 mmol), and K2CO3 (106 mg, 0.72 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (2 ml) in water (400 μl) was then added. The mixture was reacted in an oil bath at 100°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F008 as a white solid. Compound F008 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F008 (102.5 mg, yield 63%) as a white solid. [M+H] + =319; HPLC=98.93%; 1H NMR (600MHz, DMSO-d6) δ8.79(d,J=2.1Hz,1H),8.58–8.54(m,1H),8.51(s,1H),8.45(d,J=2.1Hz,1H),8.02(t,J=1.7Hz ,1H),7.83(t,J=1.8Hz,1H),7.74(d,J=1.7Hz,1H),3.06(p,J=7.0Hz,1H),2.83(d,J=4.5Hz,3H),1.30(d,J=6.9Hz,6H).

[0142] Example 9: Synthesis of target compound F009

[0143] Synthesis route such as Figure 9 shown.

[0144] The specific steps are as follows:

[0145] Step 1: Preparation of intermediate 30

[0146] Intermediate 28 (240 mg, 0.98 mmol) was dissolved in THF (3 ml), and N,N'-carbonyldiimidazole (175.44 mg, 1.08 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature (25°C) for 2 hours. Ammonia water (5.52 ml, 23 ml / g) was added. After the addition was complete, the mixture was stirred at room temperature (25°C) for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane volume fraction = 0-10%) to obtain Intermediate 30 (125.7 mg, yield 52%) as a white solid. [M+H] + =242; [M+H] + =244.

[0147] Step 2: Preparation of compound F009

[0148] Intermediate 30 (100 mg, 0.41 mmol), intermediate 27 (166.75 mg, 0.62 mmol), Pd(dppf)Cl2 (30.2 mg, 0.041 mmol), and K2CO3 (85.6 mg, 0.62 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (2 ml) in water (400 μl) was then added. The mixture was reacted in an oil bath at 100°C for 2 h under nitrogen protection. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (elution gradient: methanol / dichloromethane (volume fraction = 0-10%)) to obtain compound F009 as a white solid. Compound F009 was purified again using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F009 (78.9 mg, yield 63%) as a white solid. [M+H] + =305; HPLC=98.19%; 1 H NMR (600MHz, DMSO-d6) δ12.91(s,1H),8.77(d,J=2.2Hz,1H),8.49(s,1H),8.45(d,J=2.2Hz,1H),8.10(s,1H),8.06(t, J=1.7Hz,1H),7.82(t,J=1.8Hz,1H),7.76(t,J=1.7Hz,1H),7.41(s,1H),3.04(p,J=6.9Hz,1H),1.28(d,J=6.9Hz,6H).

[0149] Example 10: Synthesis of target compound F010

[0150] Synthesis route such as Figure 10 shown.

[0151] The specific steps are as follows:

[0152] Step 1: Preparation of compound F010

[0153] Intermediate 8 (53 mg, 0.17 mmol), intermediate 20 (47 mg, 0.17 mmol), Pd(dppf)Cl2 (12.8 mg, 0.017 mmol), and K2CO3 (36.5 mg, 0.26 mmol) were added to a 15 ml sealed tube. 1,4-Dioxane (2 ml) / water (400 μl) was then added. The mixture was protected by nitrogen and reacted in an oil bath at 100°C for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative silica gel (elution gradient: ethyl acetate / petroleum ether, volume fraction = 0-30%) to obtain compound F010 as a white solid. Compound F010 was further purified using a preparative chromatography column (elution gradient: ACN / 0.1% FA, volume fraction = 30% to 70%), and freeze-dried to obtain compound F010 (22 mg, yield 32%) as a white solid. [M+H] + =413; HPLC=98.07%; 1 H NMR (600MHz, DMSO-d6) δ11.67(d,J=2.1Hz,1H),8.77(d,J=2.2Hz,1H),7.71( d,J=1.7Hz,1H),7.68(d,J=1.8Hz,1H),7.60(s,1H),7.51(s,1H),7.33(d,J= 2.0Hz,1H),7.32(s,2H),3.05(dt,J=13.8,6.5Hz,1H),2.76–2.71(m,1H),1. 28(d,J=6.9Hz,6H), 0.97(dt,J=4.9,2.8Hz,2H), 0.94(dt,J=8.1,3.0Hz,2H).

[0154] Biological activity test

[0155] Protein binding assay:

[0156] Reagents and consumables:

[0157] 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 (Solarbio)

[0158] Experimental process:

[0159] All test compounds (including positive controls and test samples) were diluted to 1 mM with DMSO to obtain the corresponding test compound solutions. 35 μL of the positive compound solution (structural formula shown in Table 1, similar structural compounds disclosed by Arrien in US Patent No. 8791112B2 and synthesized with reference thereto), 35 μL of the test compound solution, and 35 μL of the blank solution were added to a 384-well plate. The plate was centrifuged at 2500 rpm for 1 minute. A 3-fold serial dilution was performed with a starting concentration of 1 mM for 10 points. 100 nL of the positive compound, test compound, and blank solution were added to another 384-well assay plate in triplicate. The plate was centrifuged at 2500 rpm for 1 minute and sealed in foil until ready for use.

[0160] Enzyme reaction: LRRKtide substrate and LRRK2 G2019S kinase working solution diluted in assay buffer (Thermo Fisher TR-FRET Dilution buffer) (final concentrations of LRRKtide substrate: 400 nM and LRRK2 G2019S kinase: 580 ng / mL) were added to all sample wells of the above 384 assay plate, 5 μL per well, and the 384 assay plate was incubated at 23°C for 20 minutes. After incubation, 2× ATP working solution (134 μM) diluted in assay buffer was added to each well, 5 mL per well, and the 384 assay plate was incubated at 23°C for 60 minutes.

[0161] Detection: Dilute EDTA and pLRRKtide antibody in assay buffer (TR-FRET Dilution buffer) to prepare a mixed working solution (final concentrations: 10 mM EDTA, 2 nM pLRRKtide antibody). Add 10 μL of this antibody mixture to each well of the 384-well assay plate and incubate at 23°C for 60 minutes. Read the plate in TE-FRET mode using 340 nm excitation, 520 nm fluorescence emission, and 490 nm terbium emission.

[0162] Method reference: J. de Bicente Fidalgo et al. Compounds, compositions and methods: CN113939294A[P]. 2022-01-14.

[0163] The activity data of each compound are shown in Table 1.

[0164] Table 1. Compound activity data

[0165]

[0166]

[0167] As shown in Table 1, the series of novel compounds provided in the Examples of the present invention have inhibitory effects on the kinase LRRK2 G2019S. Compared to the inhibitory activity of the positive control against LRRK2 G2019S, all of the Example compounds exhibited comparable or superior inhibitory activity against the mutant kinase LRRK2 G2019S, with F010 being the most effective, F003 and F006 being the second most effective, F001, F002, F004, F007, and F009 being the third most effective, and F005 and F008 being comparable to the positive control. These compounds have potential applications in the preparation of medicaments for the prevention and / or treatment of diseases associated with elevated LRRK2 gene activity.

[0168] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions, which should all be included in the scope of the claims of the present invention.

Claims

1. A pyridopyrrole derivative or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the derivative is shown in the general formula (1): In general formula (1), R1 is selected from cyano, methylcarbonyl or cyclopropylcarbonyl; R2 and R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, and methylcarbamoyl; X is a benzene ring or a pyridine ring; Furthermore, the combination in which R1 is a cyano group, R2 and R3 are hydrogen, and X is a benzene ring is excluded; Excluding the combination in which R1 is cyclopropylcarbonyl, R2 and R3 are selected from isopropyl and aminosulfonyl, and X is a benzene ring.

2. Use of the pyridopyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating or preventing Parkinson's disease.

3. A pharmaceutical composition, characterized in that Comprising the pyridopyrrole derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition according to claim 3, characterized in that It also contains pharmaceutically acceptable excipients or carriers.

5. A preparation, characterized in that Comprising the pyridopyrrole derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

6. A preparation according to claim 5, characterized in that It also contains pharmaceutically acceptable excipients or carriers.

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