Pyridinopyrrole derivative and application thereof in preparation of leucine-rich repeat kinase 2 inhibitor

Abstract

The invention discloses a pyridinopyrrole derivative and application thereof in preparation of a leucine-rich repeat kinase 2 inhibitor, the pyridinopyrrole derivative has a good inhibition effect on LRRK2 activity, and the pyridinopyrrole derivative is a potential therapeutic drug for treating central nervous degenerative diseases (such as Parkinson's disease).

Description

Technical Field

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

[0002] Parkinson's disease (PD) is a chronic neurodegenerative disease that mainly affects the elderly. Its incidence rate is second only to Alzheimer's disease. Since it was first discovered and named in 1817, humans have been fighting against it for more than two centuries. At present, the awareness, consultation and diagnosis rates of Parkinson's disease are low, and there is no cure. Patients suffer from motor nervous system disorders such as tremor, limb stiffness, motor dysfunction and gait abnormalities throughout their lives, as well as non-motor symptoms such as hyposmia, sleep disorders and constipation. Existing drug treatments can only relieve symptoms to a certain extent, but cannot prevent the progression of the disease. Commonly used drugs in clinical practice have great deficiencies in meeting the needs of patients with Parkinson's disease in the middle and late stages. There is an urgent need to develop a class of drugs that can prevent Parkinson's pathology and biochemical degeneration. Disease-modifying therapy is the mainstream direction of the current development of drugs for the treatment of Parkinson's disease. It can affect the initial triggering factors of neuronal degeneration and promote neuronal compensatory responses or reduce pathological propagation and progression. 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, resulting in the inability to degrade α-syn and causing toxicity. LRRK2 is involved in α-syn-mediated neurotoxicity. LRRK2 induces mitochondrial damage and endolysosomal dysfunction through oxidative mechanisms, inducing the progression of Parkinson's disease. LRRK2 kinase inhibitors can reduce pathological damage in Parkinson's disease models and improve patients' motor dysfunction. The safety and tolerability of two new LRRK2 kinase inhibitors, DNL201 and DNL151, were successfully tested in Phase IB clinical trials, and DNL151 has been launched into Phase IIb / III registration clinical studies. Therefore, the development of LRRK2 small molecule inhibitors is one of the most promising research directions for the development of Parkinson's treatment drugs.

[0004] Therefore, developing effective inhibitors of LRRK2 kinase and mutant LRRK2 kinase has become an important approach to treat 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 pyrido-pyrrole compounds are a class of LRRK2 inhibitors, and the general chemical structure formula is shown below.

[0006]

[0007] Although 148 in the patent has good LRRK2 inhibitory activity, with an IC50 activity of <0.5μM, experiments have found that this type of compound has low blood-brain barrier permeability and poor pharmacokinetic properties, so it has stopped at the preclinical research stage. This indicates that it is necessary to find better blood-brain barrier permeable compounds for this target in order to ensure effective drug administration to the brain while reducing drug concentration 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, R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, methylcarbamoyl;

[0015] X is selected from an aromatic ring and an aromatic heterocyclic ring.

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

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

[0018] R2, R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, 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) ketone, 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 the activity of LRRK2 and are potential therapeutic drugs for treating central nervous system degenerative diseases (such as Parkinson's disease).

[0048] Other advantages, objectives and features of the present invention will be described in the following description to some extent, and to some extent, will be obvious to those skilled in the art based on the following examination and study, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can 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 in conjunction with the accompanying drawings, wherein:

[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 of Example 2;

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

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

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

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

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

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

[0058] Fig. 9 This is the synthetic route of the target compound F009 of Example 9;

[0059] Fig.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 implementation modes.

[0061] Definition and Description

[0062] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its 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 are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans 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 compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention with relatively non-toxic acids or bases. 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 a pure 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 a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain 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, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0066] The term "therapeutically effective dose" refers to an amount of a compound of the formula sufficient to be effective for treatment 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 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 the 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 the therapeutic composition is contemplated. Supplementary active ingredients may also be incorporated into the composition.

[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 (1,4-dioxane); 30% H2O2 (30% hydrogen peroxide); 4.0M HCl in Dioxane (4.0M hydrogen chloride in dioxane); 4.0M HCl in EA (4.0M hydrogen chloride in ethyl acetate); 7.0M NH3 in MeOH (7.0M 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 (biboronic acid pinacol ester); 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(dichlorothionyl); 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 known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. Any intermediate or compound in the synthetic route that can be obtained by other reaction conditions is considered an alternative to the 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] First, AlCl3 (54.1 g, 405.6 mmol) was dissolved in DCM (950 ml), and then 5-bromo-7-azaindole (CAS No.: 183208-35-7, source: Shanghai Titan Technology Co., Ltd., 10 g, 50.7 mmol) was added, stirred at room temperature (25 ° C) for 1 h, and finally cyclopropylcarbonyl chloride (7.43 g, 71.0 mmol) was added, and the reaction was allowed to proceed overnight at 45 ° C. The reaction was monitored by TLC plate. After the reaction was completed, the unreacted AlCl3 was first filtered out with diatomaceous earth, 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 was ethyl acetate / petroleum ether volume fraction = 0-30%) to obtain intermediate 3 (8.44 g, yield 62%) 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), K2CO3 (120.80 mg, 0.87 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (2 ml) / water (400 ul) was added, nitrogen protection, 100 ° C for 2 hours, and the reaction process was monitored by TLC. After the reaction was completed, the reaction product was extracted with ethyl acetate, and the obtained crude product was purified by silica gel column chromatography (elution gradient was 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., 2g, 11.62mmol) was added to concentrated hydrochloric acid (33ml) (white solid was precipitated), and NaNO2 (1.2g, 16.27mmol) was added dropwise at 0℃ in an ice bath to obtain H2O (2.3ml) solution, and stirred at room temperature (25℃) for 0.5h to obtain a mixture (the system turned yellow with a small amount of solid). At 0℃ in an ice bath, it was added dropwise to a mixed aqueous solution of SOCl2 (4.65ml, 63.95mmol) and CuCl (1.2g, 11.62mmol), and stirred at room temperature (25℃) for 1.5h, and the system was clear green. The reaction was monitored by TLC plate during the reaction. After the reaction was completed, the reaction solution was extracted with dichloromethane, and the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product intermediate 6 (2.4g, yield 80.80%) as a yellow liquid, which was directly used for the next step 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 violent, the system turned yellow, and solid precipitated (turbid). Stir for 1 h. The reaction was monitored by TLC plate. After the reaction was completed, the reaction solution was extracted with ethyl acetate, 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 was 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), K2CO3 (1.03 g, 7.46 mmol) were added to a 15 ml sealed tube, and 1,4-Dioxane (10 ml) / water (2 ml) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100 ° C for 2 hours. The reaction process 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 was 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), AcOK (4.44 g, 45.26 mmol) were added to a 150 ml sealed tube, and 1,4-Dioxane (60 ml) was added. Nitrogen was protected and the reaction was carried out in an oil bath at 110 ° C for 2 hours. 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 was methanol / dichloromethane volume fraction = 0-10%) to obtain intermediate 8 (2.61 g, yield 36%) as a white solid. [M+H] + =313 (boronic acid); [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., 2.0g, 7.2mmol) was dissolved in THF (20ml), N2 protected, cooled to -78°C, n-BuLi (2.9ml, 7.2mmol) was added dropwise, and reacted at -78°C for 2h after the addition was complete. Finally, dimethyl disulfide (640ul, 7.2mmol) was added dropwise, and after the addition was completed, it was transferred to room temperature (25°C) for 1h, and the reaction process was monitored by TLC plate. After the reaction was completed, the reaction solution was extracted with ethyl acetate, the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 11 (1.8g, 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, and stirred at room temperature (25°C) for 1 h. The reaction process was monitored by TLC plate. After the reaction was completed, the crude product was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether volume fraction = 0-20%) to obtain intermediate 12-1 (1.5 g) as an oil.

[0098] AcOH (7.5 ml) and 30% H2O2 (600 ul) were added to the intermediate 12-1 (1.5 g), and the mixture was stirred at 90°C for 2 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (elution gradient: ethyl acetate / petroleum ether volume fraction = 0-20%) to obtain the intermediate 12 (1.38 g, yield 67.98%) 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), K2CO3 (427 mg, 3.09 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (4 ml) / water (800 ul) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100°C for 2 hours. The reaction process 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 was 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] First, AlCl3 (16.25 g, 121.84 mmol) was dissolved in DCM (300 ml), and then 5-bromo-7-azaindole (CAS: 183208-35-7, source: Shanghai Titan Technology Co., Ltd., 3 g, 15.23 mmol) was added. 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 an oil bath at 45 ° C for overnight reaction. The reaction was monitored by TLC plate. After the reaction was completed, the unreacted AlCl3 was first filtered out with diatomaceous earth, 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 a crude product. The crude product was purified by silica gel column chromatography (elution gradient was 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 (1g, 4.2mmol), BPD (1.6g, 6.2mmol), Pd (dppf) Cl2 (150mg, 0.42mmol), AcOK (1.03g, 10.4mmol) were added to a 15ml sealed tube, and 1,4-Dioxane (10ml) was added. Nitrogen protection was applied and the reaction was carried out in an oil bath at 110°C for 2h. 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 was methanol / dichloromethane volume fraction = 0-10%) to obtain intermediate 15 (500mg, yield 41.66%) as a white solid. [M+H] + =287 (boronic acid); [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., 5g, 17.99mmol), benzyl mercaptan (3.35g, 26.98mmol), DIPEA (4.65g, 35.98mmol), xantphos (1.04g, 1.80mmol), Pd2(dpa)3 (822.5mg, 0.90mmol) were added to a 150ml sealed tube, and toluene (50ml) was added, nitrogen protection, 100℃ oil bath pot reaction for 3h, and the reaction process was monitored by TLC plate. After the reaction was completed, the reaction solution was extracted with ethyl acetate, 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: 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, stirred for 10 min, and the ice bath was removed to naturally warm up to room temperature (25 ° C) and stirred for 3 h. The reaction process 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 dissolved in DCM (15 ml), cooled to 0 ° C in an ice bath, and ammonia (15 ml) was added, stirred for 10 min, and the ice bath was removed to naturally warm up 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 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 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), K2CO3 (250 mg, 1.8 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (2 ml) / water (400 ul) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100°C for 2 hours. The reaction process 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 was 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), K2CO3 (260 mg, 1.89 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (4 ml) / water (800 ul) was added, nitrogen protection, 100 ° C oil bath pot reaction for 2 hours, and the reaction process was monitored by TLC plate. After the reaction was completed, the reaction solution was extracted with ethyl acetate, 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 was methanol / dichloromethane volume fraction = 0-10%) to obtain compound F005 as a white solid. Compound F005 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 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 operation 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] Dissolve 5-bromo-1H-pyrrolo[2,3-B]pyridine-3-carboxaldehyde (CAS No.: 757978-33-9, source: Shanghai Haohong Biopharmaceutical Technology Co., Ltd., 2g, 8.88mmol) in pyridine (6ml), add hydroxylamine hydrochloride (741mg, 10.66mmol), stir at room temperature (25℃) for 2h, and monitor the reaction process by TLC plate. After the reaction is completed, concentrate under reduced pressure to obtain the crude product intermediate 25 (2.53g, 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 the reaction was completed, the mixture was concentrated under reduced pressure and toluene was removed to obtain the crude product intermediate 26 (2.18 g, crude yield 98%) 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), AcOK (744.40 mg, 7.59 mmol) were added to a 15 ml sealed tube, and 1,4-Dioxane (10 ml) was added. The mixture was protected by nitrogen and reacted in an oil bath at 110 ° C for 2 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 was methanol / dichloromethane volume fraction = 0-10%) to obtain intermediate 27 (734.8 mg, yield 72%) as a white solid. [M+H] + =270 (borax); [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), K2CO3 (149.02 mg, 1.08 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (2 ml) / water (400 ul) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100°C for 2 hours. The reaction process 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 was 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 50mL round-bottom flask, 3-bromo-5-isopropylbenzoic acid (CAS No.: 112930-39-9, source: Shanghai Titan Technology Co., Ltd., 500mg, 2.05mmol), methylamine hydrochloride (153mg, 2.25mmol), NMI (523mg, 6.38mmol) and acetonitrile (10ml) were added and dissolved and stirred for 15 minutes, and then TCFH (575mg, 2.05mmol) was added to continue the reaction for 2 hours, and the reaction was detected by TLC. After the reaction was completed, the acetonitrile was dried and extracted with ethyl acetate, the organic phases were combined and 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 was ethyl acetate / petroleum ether volume fraction = 0-30%) to obtain intermediate 29 (541mg, yield 83%) 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), K2CO3 (106 mg, 0.72 mmol) were added to a 15 ml sealed tube, and 1,4-Dioxane (2 ml) / water (400 ul) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100°C for 2 hours. The reaction process 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 was 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 Fig. 9 shown.

[0144] The specific steps are as follows:

[0145] Step 1: Preparation of intermediate 30

[0146] The 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 completed, the mixture was stirred at room temperature (25 ° C) for 2 hours, and then ammonia water (5.52 ml, 23 ml / g) was added. After the addition was completed, the mixture was stirred at room temperature (25 ° C) for 2 hours. 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 was methanol / dichloromethane volume fraction = 0-10%) to obtain the 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), K2CO3 (85.6 mg, 0.62 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (2 ml) / water (400 ul) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100°C for 2 hours. The reaction process 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 was 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 Fig.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), K2CO3 (36.5 mg, 0.26 mmol) were added to a 15 ml sealed tube, and then 1,4-Dioxane (2 ml) / water (400 ul) was added, and nitrogen was protected, and the reaction was carried out in an oil bath at 100 ° C for 2 hours. The reaction process 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 preparing a silica gel plate (elution gradient was ethyl acetate / petroleum ether volume fraction = 0-30%) to obtain compound F010 as a white solid. Compound F010 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 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 positive compound (structural formula is shown in Table 1, similar structural compounds disclosed by Arrien in patent US8791112B2, and synthesized with reference to the document) solution, 35 μL of test compound solution, and 35 μL of blank solution were added to a 384-well plate, and the plate was centrifuged at 2500 rpm for 1 minute. With 1 mM as the initial concentration, 3-fold gradient dilution was performed for 10 points, and 100 nL of positive compound, test compound, and blank well solution were added to another 384-well assay plate, 3 replicates, and the plate was centrifuged at 2500 rpm for 1 minute and sealed in foil for standby use.

[0160] Enzyme reaction: Dilute the LRRKtide substrate and LRRK2G2019S kinase mixed working solution (final concentration of LRRKtide substrate: 400nM and LRRK2 G2019S kinase: 580ng / mL) with assay buffer (Thermo Fisher TR-FRET Dilution buffer) and add it to all sample wells of the above 384 assay plate, 5μL per well, and incubate the 384 assay plate at 23°C for 20 minutes. After incubation, dilute the 2×ATP working solution (134μM) with assay buffer and add it to each well, 5mL per well, and incubate the 384 assay plate at 23°C for 60 minutes.

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

[0162] Method reference: J. DeBicente 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 new compounds provided in the embodiments of the present invention have an inhibitory effect on the kinase LRRK2 G2019S. Compared with the inhibitory activity of the positive structure on LRRK2 G2019S, all the compounds in the embodiments showed an inhibitory effect equivalent to or better than that on the mutant kinase LRRK2G2019S, with F010 being the best, F003 and F006 being the second best, F001, F002, F004, F007 and F009 being the third best, and F005 and F008 being equivalent to the positive control. The compounds have potential application value in the preparation of drugs for preventing and / or treating diseases related to increased gene LRRK2 activity in vivo.

[0168] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. 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 solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution, which should 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 the general formula (1), R1 is selected from cyano, C 1-7 Alkylcarbonyl; R2, R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, methylcarbamoyl; X is selected from an aromatic ring and an aromatic heterocyclic ring.

2. The pyridopyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the general formula (1), R1 is selected from cyano, methylcarbonyl or cyclopropylcarbonyl; R2, R3 are selected from hydrogen, methyl, isopropyl, tert-butyl, aminosulfonyl, methylaminosulfonyl, methylsulfonyl, carbamoyl, methylcarbamoyl; X is a benzene ring or a pyridine ring.

3. Use of the pyridopyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a leucine-rich repeat kinase 2 inhibitor.

4. Use of the pyridopyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a drug for preventing and / or treating diseases by inhibiting the activity of leucine-rich repeat kinase 2.

5. Use of the pyridopyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a drug for treating or preventing chronic neurodegenerative diseases.

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

7. A pharmaceutical composition or preparation, characterized in that: It comprises the pyridopyrrole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2.

8. A pharmaceutical composition or preparation according to claim 7, characterized in that: It also contains pharmaceutically acceptable excipients, adjuvants or carriers.

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