Sulfoximine compound and use thereof

Abstract

The present application provides a sulfoximine compound and a use thereof. The sulfoximine compound has the structure as represented by formula (I). The compound provided by the present application shows good inhibitory activity, oral absorption and brain permeability for the LRRK2 protein kinase, and meets the requirements of drug development of neurodegenerative diseases.

Description

A sulfoximine compound and its application Technical Field

[0001] The present application belongs to the field of medicinal chemistry, and specifically relates to a sulfoximine compound and its application, and in particular to a sulfoximine compound with good inhibitory effect and its application. Background Art

[0002] Leucine-rich repeat kinase 2 (LRRK2), the protein product of the LRRK2 gene, is a serine / threonine protein kinase. Although the function of LRRK2 protein is not fully understood, LRRK2 gene mutations were found to be associated with Parkinson's disease (PD) as early as 2004. Common LRRK2 gene mutations include G2019S and I2020T in the kinase active domain, and R1441G / C / H and Y1699C in the GTPase domain. These mutations can lead to increased LRRK2 protein kinase activity, triggering various pathological changes, including increased synuclein and TAU protein phosphorylation, neurological inflammation, and neuronal mitochondrial dysfunction.

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, with more than 10 million patients worldwide, but no effective treatment has been found to date. 10% of PD patients have a clear family history, with LRRK2 mutation being the most common cause. This mutation occurs in approximately 5% of familial PD and 1% of non-familial PD, and the clinical manifestations caused by these mutations are no different from those of sporadic PD. In addition, LRRK2 mutations can also lead to pathological changes in the TAU protein, which is a major feature of Alzheimer's disease. LRRK2 is believed to be at the upstream stage of the pathogenesis of neurodegenerative diseases and also plays an important role in other neurodegenerative diseases. Therefore, the development of LRRK2-specific inhibitors has become one of the effective ways to treat PD and other neurodegenerative diseases.

[0004] Existing LRRK2 protein kinase compounds have unsatisfactory enzyme inhibitory activity or poor brain penetration, failing to meet the requirements of drug development. Therefore, there is an urgent need in the art for compounds with good protein kinase inhibitory activity and / or good brain penetration.

[0005] Summary of the Invention

[0006] The present application provides a sulfoximine compound and its application, particularly a sulfoximine compound with good inhibitory effect and its application. The compound provided in the present application exhibits excellent inhibitory activity, oral absorption, and brain penetration against LRRK2 protein kinase, meeting the requirements for drug development for neurodegenerative diseases.

[0007] In a first aspect, the present application provides a sulfoximine compound or a stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt thereof, wherein the structure of the sulfoximine compound is shown in Formula I:

[0008] Wherein, A is selected from hydrogen, substituted or unsubstituted any one of the following groups: C 1～6 Alkyl, C 3～8 Cycloalkyl, C 6～14 aryl, 5-12 membered heteroaryl, 3-8 membered heterocyclic group, 5-10 membered bridged ring group or 5-12 membered spirocyclic group, wherein the substituents substituted are selected from C 1～4 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3-8 membered heterocyclic group, C 1～3 Alkylphosphoryl, C 1～3 alkylsulfonyl, oxo, cyano or halogen;

[0009] L is selected from -H, -O-, -NH-, -S- or -N(C 1～4 alkyl)-, when L is -H, A does not exist;

[0010] R1 is selected from hydrogen, cyano, hydroxyl, C 3～6 Cycloalkyl, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 1～6 Alkoxy, wherein the substituted substituent is selected from hydroxy, methylamino, dimethylamino, methoxy, carboxyl, oxo, cyano or halogen;

[0011] R2 is selected from C 1～4 Alkyl, C 1～6 Alkoxy, C 3～6 cycloalkyl, cyano or halogen;

[0012] m is selected from 0, 1 or 2, when m is 0, the substituent is absent; when m is 2, the two R2 are the same or different;

[0013] X is selected from CH or N; Y and Z are independently selected from C or N;

[0014] R a is selected from hydrogen, cyano, halogen, C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 Alkylphosphoryl or C 1～3 alkylsulfonyl;

[0015] R b Selected from hydrogen, amino or C 1～3 Alkylamino; and

[0016] R a and R b It exists independently or is linked together with the carbon atoms to form a 5- to 12-membered heteroaromatic ring or a 5- to 8-membered heterocyclic ring.

[0017] The above-mentioned sulfoximine compounds with specific structures exhibit excellent inhibitory activity, oral absorption and brain permeability against LRRK2 protein kinase, and can achieve effective treatment of LRRK2 protein kinase-related diseases.

[0018] Preferably, the structure of the sulfoximine compound is as shown in Formula II:

[0019] Among them, A, L, R1, R2, m, X, Y, Z and R a The same limitations as above apply.

[0020] Preferably, the structure of the sulfoximine compound is as shown in Formula III:

[0021] Wherein, A, L, R1, R2, m, X, Y and Z have the same defined ranges as above;

[0022] M is selected from C or N. When M is selected from C, R3 is selected from hydrogen or halogen; when M is selected from N, R3 is absent.

[0023] Preferably, the structure of the sulfoximine compound is as shown in Formula IV:

[0024] Wherein, A, L, R1, R2, m, X, Y and Z have the same defined ranges as above;

[0025] R4, R5 are independently selected from hydrogen or fluorine, R6 is selected from hydrogen or C 1～3 alkyl.

[0026] Preferably, A is selected from the following structures:

[0027] Preferably, said L is selected from -O- or -NH-.

[0028] Preferably, the sulfoximine compound is selected from any one of the following structures:

[0029] In a second aspect, the present application provides use of the above-mentioned sulfoximine compound or its stereoisomers, tautomers, isotope-labeled substances or pharmaceutically acceptable salts in the preparation of LRRK2 protein kinase inhibitors.

[0030] The above-mentioned LRRK2 protein kinase inhibitor can be used as a drug for LRRK2 protein kinase-related diseases, and can also be used as an inhibitor in scientific research, such as research on related signaling pathways.

[0031] In a third aspect, the present application provides a pharmaceutical composition comprising at least one sulfoximine compound as described above or a stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt thereof.

[0032] In a fourth aspect, the present application further provides the use of the above-mentioned sulfoximine compound or its stereoisomers, tautomers, isotope-labeled substances or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing LRRK2 protein kinase-related diseases.

[0033] Preferably, the disease comprises a neurodegenerative disease, an immune-related disease or a cancer, specifically comprising Parkinson's disease, Alzheimer's disease, Huntington's disease, Crohn's disease, inflammatory bowel disease, colitis, tuberculosis, leprosy, melanoma, non-melanoma skin cancer or breast cancer.

[0034] Compared with the prior art, this application has the following beneficial effects:

[0035] The present application provides a sulfoximine compound with a specific structure, which exhibits excellent inhibitory activity, oral absorption and brain permeability against LRRK2 protein kinase, and can achieve effective treatment of LRRK2 protein kinase-related diseases. DETAILED DESCRIPTION

[0036] In order to further illustrate the technical means and effects adopted by this application, the technical solution of this application is further explained below in combination with the preferred embodiments of this application, but this application is not limited to the scope of the embodiments.

[0037] The term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, for example, C 1～3 Alkyl refers to a saturated hydrocarbon group containing 1 to 3 carbon atoms. 1～4 Alkyl refers to a saturated hydrocarbon group containing 1 to 4 carbon atoms. 1～6 The alkyl group is a saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight-chain, branched or cyclic alkyl groups. The alkyl group herein is preferably C 1～10 Alkyl, C 1～8 Alkyl, C 1～6 Alkyl or C 1～4 alkyl.

[0038] The term "alkoxy" refers to an alkyl-O-. 1～6"Alkoxy" is intended to include C1, C2, C3, C4, C5, C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy and cyclopropoxy), tert-butoxy and the like. Preferred alkoxy groups herein include C 1～10 Alkoxy, C 1～8 Alkoxy, C 1～6 Alkoxy and C 1～4 Alkoxy.

[0039] The term "cycloalkyl" refers to a cyclized alkyl group based on a non-aromatic carbocyclic ring. Cycloalkyl groups may include monocyclic, bicyclic, or polycyclic ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. 3～8 Cycloalkyl refers to a cycloalkyl group containing 3 to 8 carbon atoms. The preferred cycloalkyl group herein is C 3～8 Cycloalkyl, C 3～6 Cycloalkyl.

[0040] The term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic heterocycloalkyl group in which one or two or three of the ring carbon atoms are replaced by heteroatoms selected from O, N and S atoms. The heterocycloalkyl group preferably has 3, 4, 5, 6, 7 or 8 ring atoms. Preferred heterocyclyl groups herein are C 3～8 Heterocyclic or C 3～6 Heterocyclic group.

[0041] The term "aryl" refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, etc. The aryl group is preferably a monocyclic, bicyclic or tricyclic ring system having 6 to 14 or 6 to 12 ring members. Preferably, at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. "Substituted aryl" means that at least one hydrogen atom on the phenyl ring of the aryl group is replaced by a non-hydrogen moiety. The substituents of the aryl group can be halogen, C 1～10 Alkoxy, -CN, -OH, -SH, -NH2, C 1～6 Alkyl. Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring.

[0042] The term "heteroaromatic ring" or "heteroaryl" refers to a 5-12 membered aromatic monocyclic, bicyclic, or polycyclic heterocyclic ring that is fully unsaturated, partially unsaturated, and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. The heteroaryl group herein is preferably a 5- to 12-membered heteroaryl group. The heteroaryl group herein preferably has 1, 2, or 3 heteroatoms independently selected from N, O, and S. Preferably, the heteroaryl group herein includes a 5-, 6-, or 7-membered aromatic monocyclic ring or an 8-, 9-, 10-, 11-, or 12-membered aromatic bicyclic or polycyclic heterocyclic ring; preferably, any of the heterocyclic rings defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocyclic ring may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, the heteroatoms are not adjacent to each other.Examples of aromatic heteroyl groups include, but are not limited to, acridinyl, azetidinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiopyranyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, quinolinyl, decahydroquinolinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolinyl, indolizinyl, indolyl, 3H -indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perylene diazepine, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl, phthalazinyl, Piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinazolinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2 ,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiapyranyl, thiazolopyridyl, thiapyranothiazolyl, thiapyranoxazolyl, thiapyranoimidazolyl, thiapyranyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinazolinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", and "-pyrimidylbiphenyl-".

[0043] The term "C1～3 "Alkylphosphoryl" refers to C 1～3 In the alkyl-substituted phosphoryl group, the two alkyl groups on the phosphoryl group may be the same or different.

[0044] The term "C 1～3 "Alkylsulfonyl" refers to C 1～3 Alkyl-substituted sulfonyl.

[0045] The term "halogen" includes fluorine, chlorine, bromine and iodine.

[0046] The term "bridged cyclic group" refers to a polycyclic group of 5 to 18 members, preferably 5 to 10 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other. More preferably, it is a 6 to 10 membered, and even more preferably a 7 to 10 membered bridged cyclic group. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or pyridone, more preferably a bicyclic or tricyclic. The bridged cyclic group herein allows one, two or three ring atoms to be selected from N, O, S, SO and / or S(O)2 heteroatoms.

[0047] The term "spirocyclyl" refers to a 5 to 18-membered, preferably 6 to 12-membered, polycyclic group containing two or more cyclic structures that share one carbon atom. Depending on the number of rings, spirocyclyl can be divided into bicyclic and tricyclic groups, preferably bicyclic. Spirocyclyl herein allows one, two or three of the ring atoms to be heteroatoms selected from N, O, S, SO and / or S(O) 2.

[0048] As used herein, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that enable the compounds of the present application to maintain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by Formula I can be a salt formed by a carboxyl group or an amine group (mainly an amine group) with a suitable base or acid, such as a salt (including a metal salt, an ammonium salt) formed with a suitable base or a salt formed with a suitable acid. The compound of the present application preferably forms a salt with a suitable acid, and the acid may be selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid, preferably methanesulfonic acid or hydrochloric acid.

[0049] As used herein, the term "treating" includes any effect that results in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, modulation, improvement, or elimination, or amelioration of the symptoms thereof.

[0050] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0051] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e., adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.

[0052] The term “TLC” refers to thin-layer chromatography;

[0053] In order to better illustrate the technical means and effects thereof adopted in the present application, the present application is further described below in conjunction with non-limiting examples. The examples of the present application, including the description provided in the examples, are intended to illustrate the embodiments of the present application and are not intended to limit the scope of any protection of the present application. According to the present application, it will be understood by those skilled in the art that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of the present application and still the same or similar results can be obtained.

[0054] Unless otherwise stated, all materials / reagents were obtained from commercial suppliers and used without further purification. The structures of the compounds in the following examples were characterized and confirmed by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0055] 1 H NMR spectra were recorded at room temperature on a Bruker Avance 400 MHz spectrometer using deuterated dimethyl sulfoxide (d-DMSO), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or deuterated water (D2O). Chemical shift values ​​(δ) are in ppm using tetramethylsilane (TMS) or the residual solvent peak as the internal standard. Coupling constants (J) are in Hertz (Hz). 1 The multiplicity of peaks in HNMR spectra is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet), and br (broad).

[0056] The instrument used for liquid chromatography-mass spectrometry (LC-MS) was a Shimadzu LCMS-2020, and the instrument used for preparative high-performance liquid chromatography (Prep-HPLC) was a Bonna-Agela FLEXA FL-H100G. The thin-layer chromatography silica gel plates used for thin-layer chromatography (TLC) were Yantai Huanghai HSGF254 thin-layer chromatography silica gel plates. The specifications used for reaction monitoring were 2.5×8 cm, with a coating thickness of 0.2±0.03 mm, and the specifications used for separation and purification were 20×20 cm, with a coating thickness of 0.4-0.5 mm. Silica gel column chromatography used Qingdao Marine 100-200 mesh or 200-300 mesh silica gel as the carrier.

[0057] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention.

[0058] Example 1

[0059] (1s,4s)-4-(4-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-(methylimino)hexahydro-1λ 6 -Thiopyran 1-oxide

[0060] Implementation steps (implementation method 1):

[0061] Step 1: Synthesis of Intermediate 1-c: 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran

[0062] To a solution of 1-iodo-4-nitrobenzene (1-a, 1.05 g, 4.21 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1-b, 1.0 g, 4.42 mmol), and sodium carbonate (894 mg, 8.42 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was added tetrakis(triphenylphosphine)palladium (487 mg, 0.42 mmol). The mixture was reacted at 90°C under a nitrogen atmosphere for 16 hours. Stirring was stopped after monitoring the reaction progress by TLC. The mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and water (10 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether as eluent) to give the intermediate 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran as a yellow solid (1-c, 590 mg, 60%).

[0063] 1 HNMR (400MHz, CDCl3): δ 8.20-8.17 (m, 2H), 7.50-7.47 (m, 2H), 6.37-6.34 (m, 1H), 3.40-3.37 (m, 2H), 2.91 (t, J = 5.8Hz, 2H), 2.74-2.70 (m, 2H).

[0064] Step 2: Synthesis of Intermediate 1-d: 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1-oxide

[0065] To a solution of methanol (12 mL) and water (3 mL) containing 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran (1-c, 590 mg, 2.67 mmol) was added sodium periodate (572 mg, 2.67 mmol) in portions under ice bath conditions. The mixture was gradually warmed to room temperature and reacted for 8 hours. Stirring was stopped after monitoring the reaction progress by TLC. The mixture was filtered through celite and the filtrate was collected. The filter cake was washed with methanol (10 mL × 2) and the filtrate was combined. After concentration under reduced pressure, the mixture was diluted with water (10 mL) and dichloromethane (10 mL × 2). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with a petroleum ether solution containing 10% ethyl acetate to obtain the intermediate 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1-oxide as a light yellow solid (1-d, 540 mg, 85%).

[0066] LC-MS:(ES + ):m / z 238.10[M+H] + .

[0067] 1 HNMR (400MHz, CDCl3): δ8.22 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 6.12-6.10 (m , 1H), 3.64-3.51(m, 2H), 3.33-3.17(m, 2H), 2.95-2.88(m, 1H), 2.79-2.72(m, 1H).

[0068] Step 3: Synthesis of Intermediate 1-e: (1s,4s)-4-(4-aminophenyl)tetrahydro-2H-thiopyran 1-oxide

[0069] Platinum dioxide (100%, 300 mg) was added to a solution of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1-oxide (1-d, 300 mg, 1.26 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction progress was monitored by TLC, and stirring was discontinued. The reaction mixture was filtered through celite, and the filtrate was collected. The filter cake was washed with methanol (10 mL x 2), and the combined filtrates were concentrated under reduced pressure to obtain the crude product (1s,4s)-4-(4-aminophenyl)tetrahydro-2H-thiopyran 1-oxide as a yellow solid (1-e, 200 mg, 75%).

[0070] 1 HNMR (400MHz, d-DMSO): δ6.88 (d, J=8.4Hz, 2H), 6.51 (d, J=8.4Hz, 2H), 4.87 (s, 2H), 2.93- 2.87 (m, 2H), 2.76-2.68 (m, 2H), 2.59-2.54 (m, 1H), 2.25-2.14 (m, 2H), 1.66-1.62 (m, 2H).

[0071] Step 4: Synthesis of Intermediate 1-f: tert-Butyl (4-((1s,4s)-1-oxytetrahydro-2H-thiopyran-4-yl)phenyl)carbamate

[0072] To a solution of (1s,4s)-4-(4-aminophenyl)tetrahydro-2H-thiopyran-1-oxide (1-e, 200 mg, 0.95 mmol) and sodium carbonate (304 mg, 2.87 mmol) in tetrahydrofuran (3 mL) and water (2 mL) was added di-tert-butyl dicarbonate (521 mg, 2.39 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 6 hours. Stirring was discontinued after monitoring the reaction progress by TLC. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction solution for dilution. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude tert-butyl (4-((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl)carbamate as a pale yellow solid (1-f, 175 mg, 59%).

[0073] 1 HNMR (400MHz, d-DMSO): δ9.26 (s, 1H), 7.38 (d, J=8.4Hz, 2H), 7.12 (d, J=8.8Hz, 2H), 2. 98-2.88(m, 2H), 2.79-2.65(m, 3H), 2.33-2.20(m, 2H), 1.73-1.62(m, 2H), 1.47(s, 9H).

[0074] Step 5: Intermediate 1-g: (4-((1s,4s)-1-Iminyl-1-oxyhexahydro-1λ 6 Synthesis of tert-butyl (4-thiopyran-4-yl)phenyl)carbamate

[0075] To a methanol (1 mL) solution containing tert-butyl (4-((1s,4s)-1-oxytetrahydro-2H-thiopyran-4-yl)phenyl)carbamate (1-f, 120 mg, 0.39 mmol) and ammonium carbamate (121 mg, 1.55 mmol) was added iodobenzene diacetate (375 mg, 1.15 mmol). The mixture was reacted at room temperature for 0.5 hours. After monitoring the reaction progress by TLC, stirring was stopped. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent containing 5% methanol in dichloromethane) to obtain (4-((1s,4s)-1-imino-1-oxyhexahydro-1λ 6 tert-Butyl-thiopyran-4-yl)phenyl)carbamate was obtained as a white solid (1-g, 82 mg, 65%).

[0076] 1HNMR (400MHz, d-DMSO): δ9.27 (s, 1H), 7.37 (d, J=8.4Hz, 2H), 7.11 (d, J=8.4Hz, 2H), 3.72 (s, 1 H), 3.17-3.10(m, 2H), 3.01-2.97(m, 2H), 2.82-2.75(m, 1H), 2.08-1.90(m, 4H), 1.46(s, 9H).

[0077] Step 6: Intermediate 1-h: (4-((1s,4s)-1-(methylimino)-1-oxohexahydro-1λ 6 Synthesis of tert-butyl (4-thiopyran-4-yl)phenyl)carbamate

[0078] To the containing (4-((1s,4s)-1-imino-1-oxyhexahydro-1λ 6 To a solution of tert-butyl (1-thiopyran-4-yl)phenyl)carbamate (1-g, 80 mg, 0.24 mmol), paraformaldehyde (59 mg, 1.97 mmol), and triethylsilane (86 mg, 0.74 mmol) in acetonitrile (5 mL) was added trifluoroacetic acid (87 mg, 0.76 mmol), and the reaction solution was stirred at room temperature for 16 hours. Stirring was stopped after monitoring the reaction progress by TLC. The mixture was partitioned between ethyl acetate (10 mL) and saturated sodium carbonate solution (10 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 5% methanol in dichloromethane) to obtain (4-((1s,4s)-1-(methylimino)-1-oxohexahydro-1λ) 6 tert-Butyl-thiopyran-4-yl)phenyl)carbamate was obtained as a white solid (1-h, 53 mg, 63%).

[0079] LC-MS:(ES + ):m / z 339.15[M+H] + .

[0080] 1 HNMR (400MHz, d-DMSO): δ9.27 (s, 1H), 7.38 (d, J=8.4Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 3.24-3.1 4(m, 2H), 3.07-3.00(m, 2H), 2.87-2.77(m, 1H), 2.67(s, 3H), 2.07-1.94(m, 4H), 1.46(s, 9H).

[0081] Step 7: Fragment 1-i: (1s,4s)-4-(4-aminophenyl)-1-(methylimino)hexahydro-1λ 6 -Synthesis of Thiopyran 1-Oxide

[0082] To the containing (4-((1s,4s)-1-imino-1-oxyhexahydro-1λ 6 To a solution of tert-butyl (1-h, 50 mg, 0.15 mmol) (4-thiopyran-4-yl)phenyl)carbamate (1-h, 50 mg, 0.15 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL), and the mixture was reacted at room temperature for 0.5 hours. Stirring was stopped after monitoring the reaction progress by TLC. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 10% methanol) to obtain (1s,4s)-4-(4-aminophenyl)-1-(methylimino)hexahydro-1λ 6 -Thiopyran 1-oxide was obtained as a white solid (1-i, 33 mg, 94%).

[0083] LC-MS:(ES + ):m / z 239.15[M+H] + .

[0084] Step 8: Compound 1: (1s,4s)-4-(4-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-(methylimino)hexahydro-1λ 6 -Synthesis of Thiopyran 1-Oxide

[0085] To the intermediate (1s,4s)-4-(4-aminophenyl)-1-(methylimino)hexahydro-1λ 6To a solution of 1-thiopyran 1-oxide (1-i, 30 mg, 0.12 mmol) and a fragment of (1r,4r)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexyl-1-ol (1-j, 47 mg, 0.15 mmol), 1,1'-bis(diphenylphosphino)ferrocene (14 mg, 0.025 mmol), and cesium carbonate (163 mg, 0.5 mmol) in 1,4-dioxane (1 mL) was added tetrakis(triphenylphosphine)palladium (14.5 mg, 0.012 mmol). The reaction solution was purged with nitrogen three times and heated to 110°C with stirring for 16 hours. Stirring was stopped after monitoring the reaction progress by TLC. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (10 mL) and saturated water (10 mL). The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 5% methanol in dichloromethane) to give (1s,4s)-4-(4-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-(methylimino)hexahydro-1λ 6 -Thiopyran 1-oxide was obtained as a white solid (Compound 1, 26 mg, 60%).

[0086] LC-MS:(ES + ):m / z 513.20[M+H] + .

[0087] 1 HNMR (400MHz, CD3OD): δ8.35 (s, 1H), 7.61 (d, J = 8.8Hz, 2H), 7.25 (d, J = 8.4Hz, 2H), 5.43 (brs, 1H), 3.37-3.31 (m, 2H), 3.20-3.12 ( m, 2H), 2.94-2.87 (m, 1H), 2.81 (s, 3H), 2.31-2.17 (m, 4H), 2.06-1.99 (m, 2H), 1.86-1.71 (m, 4H), 1.56-1.51 (m, 2H), 1.22 (s, 3H).

[0088] Example 2

[0089] 1-(ethylimino)-4-(5-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)-1λ 6 -Thiomorpholine 1-oxide

[0090] Implementation steps (implementation method 2):

[0091] Step 1: Synthesis of Intermediate 2-b: 4-(5-nitropyridin-2-yl)thiomorpholine 1-oxide

[0092] Sodium periodate (323 mg, 1.51 mmol) was added to a solution of 4-(5-nitropyridin-2-yl)thiomorpholine (2-a, 285 mg, 1.26 mmol) in anhydrous methanol (10 mL). The mixture was stirred at room temperature for 5 hours. Stirring was stopped after monitoring the reaction progress by TLC. The reaction mixture was filtered through celite and the filtrate was collected. The filter cake was washed with methanol (10 mL x 2), and the combined filtrates were concentrated under reduced pressure to obtain crude 4-(5-nitropyridin-2-yl)thiomorpholine 1-oxide as a yellow solid (2-b, 300 mg, 98%).

[0093] LC-MS:(ES + ):m / z 242.25[M+H] + .

[0094] 1 HNMR (400MHz, CDCl3) δ9.09 (d, J=2.5Hz, 1H), 8.31 (dd, J=9.4, 2.8Hz, 1H), 6.72 (d, J=9.4 Hz, 1H), 4.46 (d, J=14.8Hz, 2H), 4.32–4.19 (m, 2H), 3.02–2.86 (m, 2H), 2.85–2.69 (m, 2H).

[0095] Step 2: Intermediate 2-c: 1-imino-4-(5-nitropyridin-2-yl)-1λ 6 -Synthesis of Thiomorpholine 1-Oxide

[0096] To a solution of 4-(5-nitropyridin-2-yl)thiomorpholine 1-oxide (2-b, 300 mg, 1.24 mmol) and ammonium carbamate (290 mg, 3.72 mmol) in methanol (10 mL) was added iodobenzene diacetate (1.2 g, 3.72 mmol). The mixture was reacted at room temperature for 2.5 hours. Stirring was stopped after monitoring the reaction progress by TLC. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent containing 5% methanol in dichloromethane) to obtain 1-imino-4-(5-nitropyridin-2-yl)-1λ 6 -Thiomorpholine 1-oxide was obtained as a yellow solid (2-c, 256 mg, 81%).

[0097] LC-MS:(ES + ):m / z 257.00[M+H]+ .

[0098] 1 HNMR (400MHz, CDCl3): δ8.44 (d, J=5.4Hz, 1H), 7.43 (d, J=1.4Hz, 1H), 7.40 (dd, J=5.4, 1.7Hz, 1H), 4.31 (ddd, J=14.4, 9.6, 4.8Hz, 2H), 4.18 (dt, J=11.0, 5.2Hz, 2H), 3.12 (d, J=5.2Hz, 4H).

[0099] Step 3: Intermediate 2-d: 1-(ethylimino)-4-(5-nitropyridin-2-yl)-1λ 6 -Synthesis of Thiomorpholine 1-Oxide

[0100] To contain 1-imino-4-(5-nitropyridin-2-yl)-1λ 6 -Thiomorpholine 1-oxide as a yellow solid (2-c, 256 mg, 1.00 mmol), acetaldehyde (220 mg, 5.00 mmol), triethylsilane (348 mg, 3.00 mmol) in acetonitrile (10 mL) was added with trifluoroacetic acid (342 mg, 3.00 mmol), and the reaction solution was stirred at room temperature for 16 hours. After monitoring the progress of the reaction by TLC, stirring was stopped. The mixture was partitioned between ethyl acetate (10 mL) and saturated sodium carbonate solution (10 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 5% methanol in dichloromethane) to obtain 1-(ethylimino)-4-(5-nitropyridin-2-yl)-1λ 6 -Thiomorpholine 1-oxide was obtained as a yellow solid (2-d, 260 mg, 91%).

[0101] LC-MS:(ES + ):m / z 285.10[M+H] + .

[0102] 1HNMR (400MHz, CDCl3) δ8.37 (d, J=5.4Hz, 1H), 7.36 (d, J=1.4Hz, 1H), 7.33 (dd, J=5.4, 1.7Hz, 1H), 4.22 (ddd, J=14.4, 7.1, 2.9Hz, 2 H), 4.09 (ddd, J=14.6, 7.8, 2.5Hz, 2H), 3.23 (dd, J=15.1, 4.6Hz, 2H), 3.14 (q, J=7.2Hz, 2H), 3.10–3.01 (m, 2H), 1.22–1.18 (m, 3H).

[0103] Step 4: Intermediate 2-e: 4-(5-aminopyridin-2-yl)-1-(ethylimino)-1λ 6 -Synthesis of Thiomorpholine 1-Oxide

[0104] To contain 1-(ethylimino)-4-(5-nitropyridin-2-yl)-1λ 6 To a solution of 1-thiomorpholine 1-oxide (2-d, 50 mg, 0.18 mmol) in methanol (4 mL) was added Pd / C (10%, 50 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. Stirring was stopped after monitoring the reaction progress by TLC. The reaction mixture was filtered through celite and the filtrate was collected. The filter cake was washed with methanol (10 mL x 2) and the filtrates were combined and concentrated under reduced pressure to obtain the crude product 4-(5-aminopyridin-2-yl)-1-(ethylimino)-1λ 6 -Thiomorpholine 1-oxide was obtained as a yellow solid (2-e, 13 mg, 29%).

[0105] LC-MS:(ES + ):m / z 255.05[M+H] + .

[0106] Step 5: Compound 2: 1-(ethylimino)-4-(5-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)-1λ 6 -Synthesis of Thiomorpholine 1-Oxide

[0107] To the intermediate 4-(5-aminopyridin-2-yl)-1-(ethylimino)-1λ 6To a solution of 1,4-dioxane (1 mL) containing 1-thiomorpholine 1-oxide (2-e, 12.8 mg, 0.05 mmol), a fragment of (1r,4r)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexyl-1-ol (1-j, 15.5 mg, 0.05 mmol), 1,1'-bis(diphenylphosphino)ferrocene (5.6 mg, 12 μmol), and potassium carbonate (13.8 mg, 0.10 mmol) was added tetrakis(triphenylphosphine)palladium (5.8 mg, 5 μmol). The reaction mixture was purged with nitrogen three times and heated to 100°C with stirring for 12 hours. Stirring was stopped after monitoring the reaction progress by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (10 mL) and saturated water (10 mL). The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 5% methanol in dichloromethane) to give 1-(ethylimino)-4-(5-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)-1λ 6 -Thiomorpholine 1-oxide was obtained as a pale yellow solid (compound 2, 26 mg, 60%).

[0108] LC-MS:(ES + ):m / z 529.25[M+H] + .

[0109] 1 H NMR (400MHz, CDCl3) δ8.54 (d, J=0.8Hz, 1H), 8.37 (d, J=5.4Hz, 1H), 7.36 (d, J=1.4Hz, 1H), 7.33 (dd, J=5.4, 1.7Hz, 1H), 5.59-5.53 (m, 1H), 4.22 (ddd, J=14.4, 7.1, 2.9Hz, 2H), 4.09 (ddd, J=14.6, 7.8, 2. 5Hz, 2H), 3.23 (dd, J=15.1, 4.6Hz, 2H), 3.14 (q, J=7.2Hz, 2H), 3.10-3.01 (m, 2H), 2.10-1.99 (m, 2H), 1.89 (dd, J=14.0, 4.2Hz, 2H), 1.80-1.71 (m, 2H), 1.56-1.54 (m, 2H), 1.30 (s, 3H), 1.22-1.18 (m, 3H).

[0110] The following compounds in Table 1 were synthesized using a method similar to the above:

[0111] Table 1

[0112] Biological activity test example:

[0113] Biological test example-1: LRRK2 kinase activity inhibition experiment:

[0114] The ADP-Glo ​​assay was used to detect the inhibitory activity of compounds against LRRK2 kinase activity. Compounds were diluted in 1× kinase buffer. 3 μL of the 1 mM compound DMSO stock solution was added to 57 μL of 1× kinase buffer D, and the compound was diluted 5-fold in 1× kinase buffer. 1 μL of the compound diluted in kinase buffer was added to a Greiner 384-well plate, and a DMSO blank control and a buffer background control were set up. Kinase solution (kinase concentration titration and S / N = 10 were used to determine the kinase dilution ratio) was added to 2 μL of the kinase solution at 2.5 times the final concentration. The plate was centrifuged at 1000 g for 30 seconds and allowed to stand at room temperature for 15 minutes. A mixture of ATP and kinase substrate at 2.5 times the final concentration was prepared in 1× kinase buffer. 2 μL of the mixture at 2.5 times the final concentration of ATP and kinase substrate was added to initiate the reaction. The plate was centrifuged at 1000 g for 30 seconds, sealed, and allowed to stand at room temperature for 1 hour. Add 5 μL of ADP-Glo ​​reagent and incubate at room temperature for 40 minutes; then add 10 μL of detection reagent and incubate at room temperature for 40 minutes. Luminescence signals were measured on a Biotek Synergy H1 microplate reader. Inhibition rate (%) = 100 - (compound signal value - background signal value) / (blank control signal value - background signal value) × 100. The dose-response ratio (IC) was calculated by fitting the log[inhibitor] vs. response-variable slope curve. 50 value.

[0115] The IC values ​​of some compounds in the LRRK2 kinase activity assay are provided in Table 2 below. 50 Range:

[0116] (IC 50 Range: A: <0.1 μM; B: 0.1-0.5 μM; C: >0.5 μM):

[0117] Table 2 IC values ​​of compounds in LRRK2 kinase activity assay 50

[0118] Biological test example-2: Detection of the inhibition rate of mutant phosphorylated LRRK2 (S935) in transfected cells:

[0119] Cell transfection

[0120] HEK293T cells were seeded at 1×10^6 cells per well in a 12-well plate filled with DMEM medium and incubated overnight at 37°C in a 5% CO2 cell culture incubator. After 24 hours of culture, the cells were replaced with OPTI-MEM medium, which facilitates transfection. Each well was transfected with 2.5 μg of the pCMV-LRRK2-G2019S plasmid at a 3:1 ratio of PEI to plasmid. After thorough mixing and allowing to stand for approximately 15 minutes, the mixture was added dropwise to the 12-well plate. Six to eight hours after transfection, the OPTI-MEM medium was aspirated and replaced with DMEM medium. The cells were then incubated in a cell culture incubator for approximately 24 hours. Two microliters of the compound in DMSO stock solution or 0.1% DMSO (volume ratio) were then added, mixed, and cultured for an additional 16 to 18 hours.

[0121] Protein extraction

[0122] Add 50 μL of AlphaLISA 1x lysis buffer to each sample, lyse the cells on ice for 20 minutes, centrifuge at 12000 rpm at 4°C for 30 minutes, collect the supernatant, measure the concentration of the cell lysate by BCA, and normalize the concentrations of all samples.

[0123] Determination of pS935

[0124] Add 10 μL of sample of the same concentration to a 384-well plate, then add 5 μL of Acceptor Mix, seal the plate with sealing film and cover with tin foil, mix well, incubate at room temperature for 2 hours, then add 5 μL of Donor Mix, mix well, incubate in the dark for 16-18 hours, and read with a PE microplate reader for data analysis.

[0125] Table 3 below provides the inhibitory activity IC values ​​of some compounds on LRRK2 (S935) in cells. 50 Range:

[0126] (IC 50 Range: A: <0.1μM; B: 0.1-0.5μM; C: >0.5μM)

[0127] Table 3 Inhibitory activity IC of compounds against LRRK2 (S935) in cells 50

[0128] Biological test example-3: oral blood drug concentration test and brain penetration test in mice

[0129] C57BL / 6JNifdc mice used in this experiment were provided by Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd. The compound was dissolved in DMSO / Solutol / Saline (v / v / v = 10 / 10 / 80) as a stock solution (3 mg / mL). The stock solution was orally administered to three C57BL / 6JNifdc mice at a dose of 20 mg / kg. Blood was collected from the orbital venous plexus 0.5 and 1 hour after oral administration. One hour after blood collection, the mice were euthanized, and whole brain tissue was collected.

[0130] Plasma processing:

[0131] About 200 μL of blood sample was collected into EDTAK2 blood collection tube, and then immediately centrifuged at 10,000 rpm for 5 minutes. 66 μL of supernatant plasma was collected, 198 μL of acetonitrile (from Anage) was added, and vortexed for 5 minutes. Then, it was immediately centrifuged at 13,000 rpm for 8 minutes, and 200 μL of supernatant was collected to detect blood drug concentration.

[0132] Brain tissue processing:

[0133] The collected whole brain tissue samples were weighed and placed in a pre-cooled grinding tube. 1 mL of acetonitrile was added and the samples were ground evenly using a freezer grinder. The samples were then ultrasonicated for 20 minutes and centrifuged at 13,000 rpm for 20 minutes. 200 μL of the supernatant was collected and placed in a sample vial for testing.

[0134] Standard sample preparation:

[0135] Accurately weigh the drug and dissolve it in acetonitrile to 100 μg / mL. Use a pipette to draw 50 μL of the solution into 4.95 mL of acetonitrile / water (v / v = 3 / 1) to obtain a 1000 ng / mL stock solution. Take 650 μL of the stock solution and sequentially dilute it 2-fold with acetonitrile / water (v / v = 3 / 1) to obtain standard samples with concentrations of 500 ng / mL, 250 ng / mL, 125 ng / mL, 62.5 ng / mL, and 31.25 ng / mL, respectively.

[0136] Sample concentration monitoring:

[0137] Standard solutions with concentrations of 1000 ng / mL, 500 ng / mL, 250 ng / mL, 125 ng / mL, 62.5 ng / mL, and 31.25 ng / mL were analyzed using LC-MS (Shimadzu LC-MS2020 and LC-2030 Plus) in SIM mode to generate calibration curves. Treated blood samples were also analyzed using this method and quantitatively analyzed using the calibration curves to obtain drug concentration data for each treated blood sample.

[0138] Data processing:

[0139] Export the data and calculate the average blood drug concentration at each sampling time point:

[0140] Plasma drug concentration = drug concentration in treated blood sample × 4 / drug molecular weight; average blood drug concentration is the average of the drug concentration in the blood at each sampling time point.

[0141] Drug concentration in brain = drug concentration in treated brain tissue sample / brain tissue weight; average blood drug concentration is the average of blood drug concentrations at each sampling time point.

[0142] Table 4 below provides the plasma and brain drug concentrations of some compounds after oral administration to mice:

[0143] Table 4 Drug concentrations of the compounds in mice after oral administration

[0144] From the above results, it can be seen that the compound of the present application has good oral plasma drug concentration and brain drug concentration, and can be used as an oral drug to treat neurodegenerative diseases.

[0145] The applicant declares that while the above-mentioned examples are used to illustrate the sulfoximine compounds and their applications, the present application is not limited to these examples. This does not imply that the present application must rely on these examples in order to be implemented. Persons skilled in the art should understand that any improvements to the present application, equivalent replacements for raw materials in the present product, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present application.

[0146] The preferred embodiments of the present application are described in detail above. However, the present application is not limited to the specific details of the above embodiments. Within the technical concept of the present application, various simple modifications can be made to the technical solution of the present application, and these simple modifications all fall within the scope of protection of the present application.

[0147] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner unless there is any contradiction. In order to avoid unnecessary repetition, this application will not further describe various possible combinations.

Claims

1. A sulfoximine compound or a stereoisomer, tautomer, isotope-labeled substance or a pharmaceutically acceptable salt thereof, wherein: The structure of the sulfoximine compound is shown in Formula I: Wherein, A is selected from hydrogen, substituted or unsubstituted any one of the following groups: C 1～6 Alkyl, C 3～8 Cycloalkyl, C 6～14 aryl, 5-12 membered heteroaryl, 3-8 membered heterocyclic group, 5-10 membered bridged ring group or 5-12 membered spirocyclic group, wherein the substituents substituted are selected from C 1～4 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, 3- to 8-membered heterocyclic group, C 1～3 Alkylphosphoryl, C 1～3 Alkylsulfonyl, oxo, cyano or halogen; L is selected from -H, -O-, -NH-, -S- or -N(C 1～4 alkyl)-, when L is -H, A does not exist; R1 is selected from hydrogen, cyano, hydroxyl, C 3～6 Cycloalkyl, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 1～6 Alkoxy, wherein the substituted substituent is selected from hydroxy, methylamino, dimethylamino, methoxy, carboxyl, oxo, cyano or halogen; R2 is selected from C 1～4 Alkyl, C 1～6 Alkoxy, C 3～6 Cycloalkyl, cyano or halogen; m is selected from 0, 1 or 2, when m is 0, the substituent is absent; when m is 2, the two R2 are the same or different; X is selected from CH or N; Y and Z are independently selected from C or N; R a is selected from hydrogen, cyano, halogen, C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 Alkylphosphoryl or C 1～3 Alkylsulfonyl; R b Selected from hydrogen, amino or C 1～3 Alkylamino; and R a and R b It can exist independently or be linked together with the carbon atoms to form a 5- to 12-membered heteroaromatic ring or a 5- to 8-membered heterocyclic ring.

2. The sulfoximine compound according to claim 1 or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt, wherein: The structure of the sulfoximine compound is shown in Formula II: Among them, A, L, R1, R2, m, X, Y, Z and R a It has the same definition as claim 1.

3. The sulfoximine compound according to claim 1 or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt, wherein: The structure of the sulfoximine compound is shown in Formula III: Wherein, A, L, R1, R2, m, X, Y and Z have the same defined ranges as in claim 1; M is selected from C or N. When M is selected from C, R3 is selected from hydrogen, fluorine or chlorine; when M is selected from N, R3 is absent.

4. The sulfoximine compound or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt according to claim 1, wherein: The structure of the sulfoximine compound is shown in Formula IV: Wherein, A, L, R1, R2, m, X, Y and Z have the same defined ranges as in claim 1; R4, R5 are independently selected from hydrogen or fluorine, R6 is selected from hydrogen or C 1～3 alkyl.

5. The sulfoximine compound or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein: The A is selected from the following structures: Preferably, said L is selected from -O- or -NH-.

6. The sulfoximine compound or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein: The sulfoximine compound is selected from any one of the following structures:

7. Use of the sulfoximine compound or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt according to any one of claims 1 to 6 in the preparation of an LRRK2 protein kinase inhibitor.

8. A pharmaceutical composition comprising at least one sulfoximine compound according to any one of claims 1 to 6 or a stereoisomer, a tautomer, an isotope-labeled substance or a pharmaceutically acceptable salt thereof.

9. Use of the sulfoximine compound or its stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating and / or preventing LRRK2 protein kinase-related diseases.

10. The use according to claim 9, wherein: The disease includes a neurodegenerative disease, an immune-related disease or a cancer, specifically including Parkinson's disease, Alzheimer's disease, Huntington's disease, Crohn's disease, inflammatory bowel disease, colitis, tuberculosis, leprosy, melanoma, non-melanoma skin cancer or breast cancer.

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