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WO2024179393A1 - Composés de sulfoximine et leur application en tant qu'inhibiteurs de la protéine kinase lrrk2 - Google Patents

Composés de sulfoximine et leur application en tant qu'inhibiteurs de la protéine kinase lrrk2 Download PDF

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WO2024179393A1
WO2024179393A1 PCT/CN2024/078490 CN2024078490W WO2024179393A1 WO 2024179393 A1 WO2024179393 A1 WO 2024179393A1 CN 2024078490 W CN2024078490 W CN 2024078490W WO 2024179393 A1 WO2024179393 A1 WO 2024179393A1
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amine
amino
compound
thiopyran
pyrazol
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Chinese (zh)
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朱振东
李旭珂
牛德强
蒋毅
张青
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Artivila Shenzhen Innovation Center Ltd
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Artivila Shenzhen Innovation Center Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to a class of sulfoximide compounds and stereoisomers, tautomers or pharmaceutically acceptable salts thereof, preparation methods thereof and pharmaceutical compositions containing the compounds.
  • the present invention also relates to the use of the compounds as LRRK2 protein kinase inhibitors.
  • LRRK2 Leucine-rich repeat kinase 2
  • PD Parkinson's disease
  • LRRK2 gene mutations were found to be associated with Parkinson's disease (PD) as early as 2004.
  • LRRK2 gene mutations are commonly found in the G2019S and I2020T in the kinase active region and the R1441G/C/H and Y1699C mutations in the GTPase region. These mutations can lead to increased LRRK2 protein kinase activity and induce a variety of pathological changes, including increased synuclein and TAU protein phosphorylation, nervous system inflammation, and neuronal mitochondrial dysfunction.
  • Parkinson’s disease is the second largest neurodegenerative disease after Alzheimer’s Disease, with more than 10 million patients worldwide, but no effective treatment has been found so far. 10% of PD patients have a clear family history, of which LRRK2 mutation is the most common cause. This mutation occurs in about 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 TAU protein, and pathological changes in TAU are a major feature of Alzheimer’s disease. LRRK2 is believed to be located in 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.
  • the inventors have found through research that the sulfoximide compounds of the present invention exhibit good inhibitory activity against protein kinases; moreover, the compounds also exhibit good water solubility.
  • the present invention provides a compound having a structure of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • A is selected from optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C6-14 aryl, 5-12 membered heteroaryl, 3-8 membered heterocyclyl, 5-18 membered bridged ring group or 5-18 membered spirocyclyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclyl, C1-4 alkylphosphoryl, C1-4 alkylsulfonyl, cyano, hydroxy, oxo, mercapto, amino and halogen;
  • L represents absence (covalent bond), -O-, -NH-, -N(C 1-4 alkyl)-, -S-, -S(O)-, or -S(O) 2 -;
  • R1 is hydrogen, or substituted or unsubstituted C1-4 alkyl, C3-6 cycloalkyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, oxo, cyano, hydroxyl, amino, dimethylamino, hydroxylamino, halogen;
  • R2 and R3 are each independently selected from hydrogen, deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclic group, cyano, hydroxyl and halogen;
  • Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1-3 alkyl, acetyl, C 1-3 alkylphosphoryl and C 1-3 alkylsulfonyl;
  • Rb is selected from hydrogen, amino and C 1-3 alkylamino
  • Ra, Rb and the C atom to which they are attached together form a 5- to 6-membered aromatic ring, a 5- to 8-membered heteroaromatic ring or a 5- to 8-membered heterocyclic ring;
  • n is selected from 0, 1 and 2.
  • the compound of formula (I) has the following structure of formula (II):
  • the compound of formula I has the following structure:
  • A, L, R 1 , R 2 , R 3 and n are as defined above, X and Y are each independently selected from C and N, Indicates a double bond or a single bond.
  • A may preferably be the following structure:
  • the wavy line indicates the position connected to the parent core compound.
  • a pharmaceutical composition which comprises a compound of formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof according to the present invention.
  • the compound of formula (I) has the above-mentioned structure (II) or (III).
  • the compound of formula (I) is the above-mentioned specific compound.
  • the compound itself includes its isotopic form, for example, a compound in which the hydrogen atom of the compound of formula (I) is replaced by deuterium, an isotope of hydrogen.
  • the compound itself also includes its solvate and hydrate forms.
  • LRRK2 protein kinase-related disease refers to a disease in which the development or symptoms of the disease are related to the signal transmission, mediation, regulation or adjustment of the LRRK2 protein kinase.
  • LRRK2 protein kinase-related diseases include the following disease types: neurodegenerative diseases, immune-related diseases and cancer.
  • the LRRK2 protein kinase-related disease is selected from Parkinson's disease, Alzheimer's disease, Hennessy's disease, and other diseases. Huntington's disease, Crohn's disease, inflammatory bowel disease, tuberculosis, leprosy, melanoma, non-melanoma skin cancer, and breast cancer.
  • a method for treating or preventing LRRK2 protein kinase-related diseases comprising administering the compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.
  • Diseases to which the compounds, compositions and methods described herein relate include, but are not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, Crohn's disease, inflammatory bowel disease, colitis, tuberculosis, leprosy, melanoma, non-melanoma skin cancer and breast cancer.
  • alkyl is used to represent a straight or branched saturated hydrocarbon group, for example, C1-3 alkyl refers to a saturated hydrocarbon group containing 1 to 3 carbon atoms, C1-4 alkyl refers to a saturated hydrocarbon group containing 1 to 4 carbon atoms, and C1-6 alkyl refers to a saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight, branched or cyclic alkyl groups.
  • the alkyl group herein is preferably C1-10 alkyl, C1-8 alkyl, C1-6 alkyl or C1-4 alkyl.
  • alkoxy refers to an alkyl-O-.
  • C 1-6 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy.
  • C 1-10 alkoxy refers to an -O-alkyl group, and the alkyl group includes linear, branched and cyclic alkyl groups, and the number of carbon atoms thereof is 1 to 10.
  • alkoxy examples 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.
  • cycloalkyl refers to a cyclized alkyl group based on a non-aromatic carbocyclic ring.
  • the cycloalkyl group may include a monocyclic, bicyclic or polycyclic system.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • C3-8 cycloalkyl groups refer to cycloalkyl groups containing 3 to 8 carbon atoms.
  • Preferred cycloalkyl groups herein are C3-8 cycloalkyl groups and C3-6 cycloalkyl groups.
  • heterocycloalkyl refers to a non-aromatic heterocycloalkyl group in which 1 or 2 or 3 ring-forming carbon atoms are substituted by heteroatoms selected from O, N and S atoms.
  • the heterocycloalkyl group preferably has 3, 4, 5 , 6, 7 or 8 ring-forming atoms.
  • Preferred heterocyclyl groups herein are C 3-8 heterocyclyl groups or C 3-6 heterocyclyl groups.
  • Aryl refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.
  • Aryl is preferably a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon having 6 to 14 or 6 to 12 ring members. or tricyclic ring system.
  • 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 is replaced by a non-hydrogen moiety, and the substituent of the aryl can be halogen, C 1-10 alkoxy, -CN, -OH, -SH, -NH 2 , C 1-6 alkyl.
  • Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl.
  • aralkyl or “arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc.
  • the fused aryl can be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring.
  • heteroaryl means a 5-12 membered aromatic monocyclic or aromatic bicyclic or aromatic polycyclic heterocyclic ring, which 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 herein is preferably a 5-12 membered heteroaryl.
  • the heteroaryl herein preferably has 1 or 2 or 3 heteroatoms independently selected from N, O and S.
  • the heteroaryl herein includes a 5-, 6- or 7-membered aromatic monocyclic ring or an 8-, 9-, 10-, 11- or 12-membered aromatic bicyclic or aromatic polycyclic heterocyclic ring; preferably, any heterocyclic ring defined above is fused to a benzene ring.
  • Nitrogen and sulfur heteroatoms may be optionally oxidized.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent).
  • the heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic group described herein can be substituted on carbon or nitrogen atom.
  • the nitrogen in the heterocycle can be optionally quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.
  • aromatic hetero groups includes but is not limited to acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiopyranyl, benzoxazolyl, benzoxazoline, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazoline, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, quinolyl , decahydroquinolinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolinyl, indoliziny
  • heteroaryl may also include a biaryl structure formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “-phenylbipyrimidyl-", “-pyridylbiphenyl-”, “-pyridylbipyrimidyl-", “-pyrimidylbiphenyl-”.
  • C 1-4 alkylphosphoryl group refers to a phosphoryl group substituted with a C 1-4 alkyl group, and the two alkyl groups on the phosphoryl group may be the same or different.
  • C 1-4 alkylsulfonyl group refers to a sulfonyl group substituted with a C 1-4 alkyl group.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Bridged ring group refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 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 14-membered, and even more preferably a 7 to 10-membered bridged ring 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 ring group herein allows 1, 2 or 3 of the ring atoms to be heteroatoms selected from N, O, S, SO and/or S(O) 2 .
  • Spirocyclyl refers to a polycyclic group of 5 to 18 members, preferably 6 to 12 members, containing two or more cyclic structures, sharing one carbon atom with each other. According to the number of constituent rings, it can be divided into bicyclic and tricyclic, preferably bicyclic. Spirocyclyl herein allows 1, 2 or 3 of the ring atoms to be heteroatoms selected from N, O, S, SO and/or S(O) 2 .
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” as used herein refers to salts that enable the compounds of the present invention to maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salts of the compounds represented by formula (I) may be salts formed by a carboxyl group or an amine group (mainly an amine group) and a suitable base or acid, such as a salt formed with a suitable base (including a metal salt, an ammonium salt), or a salt formed with a suitable acid.
  • the compounds of the present invention preferably form salts 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, Fruit 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.
  • the acid may be selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propi
  • 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, calcium 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.
  • a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium 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.
  • manufacturing aid e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid
  • solvent encapsulating substance e.g., solvent encapsulating substance, which is involved
  • 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, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form.
  • adjuents such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form.
  • TLC refers to thin layer chromatography
  • the instrument used for liquid chromatography-mass spectrometry was Shimadzu LCMS-2020, and the instrument used for preparative high performance liquid chromatography (Prep-HPLC) was Bonna-Agela FLEXA FL-H100G.
  • Thin layer chromatography The thin layer chromatography silica gel plate used for (TLC) was Yantai Huanghai HSGF254 thin layer chromatography silica gel plate, the specifications used for reaction monitoring were 2.5 ⁇ 8cm, the coating thickness was 0.2 ⁇ 0.03mm, the specifications used for separation and purification were 20 ⁇ 20cm, the coating thickness was 0.4–0.5mm.
  • the silica gel column chromatography method used Qingdao Marine Silica Gel 100–200 mesh or 200–300 mesh silica gel as the carrier.
  • Step 1 Synthesis of intermediate Amine-1-c:4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
  • Step 2 Synthesis of intermediate Amine-1-d: 5-chloro-4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
  • Step 3 Synthesis of intermediate Amine-1-e: 4-(5-chloro-4-nitro-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1-oxide
  • Step 4 Synthesis of intermediate Amine-1-fA: N-((1s,4s)-(4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-oxytetrahydro-2H-1 ⁇ 6 -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide and intermediate Amine-1-fB: N-((1r,4r)-(4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-oxytetrahydro-2H-1 ⁇ 6 -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide
  • the first eluted component is white solid Amine-1-f-A (340 mg, 34%)
  • the second eluting fraction was a colorless oily substance, Amine-1-f-B (320 mg, 32%).
  • Step 5 Synthesis of intermediate Amine-1-g: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-iminohexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 7 Synthesis of fragment Amine-1: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-iminohexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 1 Synthesis of intermediate Amine-2-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 2 Synthesis of intermediate Amine-2: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the implementation method is the same as Amine-2, and acetaldehyde is used to replace paraformaldehyde to obtain the target compound.
  • the stereo configuration of Amine-3-a is determined by X-ray single crystal diffraction.
  • Step 1 Synthesis of intermediate Amine-4-a: tetrahydrothiopyran-4-toluenesulfonate
  • Step 4 Synthesis of intermediate Amine-4-cA: (1s, 4s)-1-imino-4-(4-nitro-1H-pyrazol-1-yl)hexahydro-1 ⁇ 6 -thiopyran 1-oxide and intermediate Amine-4-cB: (1r, 4r)-1-imino-4-(4-nitro-1H-pyrazol-1-yl)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the first eluting fraction, Amine-4-c-B was a white solid (192 mg, 18%).
  • the second eluting component, Amine-4-c-A was a white solid (287 mg, 27%);
  • Step 5 Synthesis of fragment Amine-4: (1s, 4s)-4-(4-amino-1H-pyrazol-1-yl)-1-iminohexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the implementation method is the same as Amine-2, and the fragment Amine-1-g is replaced by the fragment Amine-4-c-A to obtain the target compound.
  • the implementation method is the same as Amine-2, replacing Amine-1-g with Amine-4-c-A and replacing paraformaldehyde with acetaldehyde to obtain the target compound.
  • Step 1 Synthesis of intermediate Amine-7-a: 4-nitro-5-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
  • 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (147 mg, 0.262 mmol) was added to a solution of 1,4-dioxane (4 mL) and water (0.4 mL) containing Amine-1-d (500 mg, 2.02 mmol), methylboric acid (363 mg, 6.06 mmol) and potassium carbonate (836 mg, 6.06 mmol). The mixture was reacted at 90 °C for 16 hours under a nitrogen atmosphere. The reaction was complete when monitored by TLC.
  • the mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (5 mL ⁇ 2), the filtrate was combined, 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 (petroleum ether elution solution containing 25% ethyl acetate) to obtain the intermediate Amine-7-a as a white solid (320 mg, 70%).
  • Step 3 Synthesis of intermediates Amine-7-cA: (1s, 4s)-1-imino-4-(4-nitro-5-methyl-1H-pyrazol-1-yl)-hexahydro-1 ⁇ 6 -thiopyran 1-oxide and Amine-7-cB: (1r, 4r)-1-imino-4-(4-nitro-5-methyl-1H-pyrazol-1-yl)-hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the first component, Amine-7-c-B was a white solid (196 mg, 37%).
  • the second component is Amine-7-c-A which is a white solid (235 mg, 44%).
  • Step 4 Synthesis of fragment Amine-7: (1s, 4s)-1-imino-4-(4-amino-5-methyl-1H-pyrazol-1-yl)-hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Implementation method The implementation method is the same as Amine-2, replacing Amine-1-g with the intermediate Amine-7-c-A to obtain the target product.
  • Implementation method The implementation method is the same as Amine-2, replacing Amine-1-g with the intermediate Amine-7-c-A, and replacing paraformaldehyde with acetaldehyde to obtain the target product.
  • Step 1 Synthesis of intermediate Amine-10-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 2 Synthesis of fragment Amine-10: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Implementation method The implementation method is the same as Amine-10, replacing Amine-10-a with Amine-11-a to obtain the target product.
  • Implementation method The implementation method is the same as Amine-10, replacing 2-iodoisopropane with 2-bromo-N,N-dimethylethane-1-amine hydrobromide to obtain the target product.
  • Methylmagnesium bromide (3M dissolved in tetrahydrofuran, 7.7ml, 23mmol) was added to a suspension of compound 1-a (1,4-cyclohexanedione monoethylene glycol acetal) (2g, 12.8mmol) in anhydrous tetrahydrofuran (20ml) at -60°C, and the reaction mixture was stirred at -60°C for 20 minutes, then heated to -30°C for 30 minutes, and then stirred at 0°C for 30 minutes. TLC monitored the reaction to be complete. The reaction mixture was quenched with saturated ammonium chloride solution (10ml) and extracted with ethyl acetate (20ml).
  • Step 3 Synthesis of intermediates 1-d: (1r, 4r)-1-methylcyclohexane-1,4-diol and 1-e: (1s, 4s)-1-methylcyclohexane-1,4-diol
  • Step 4 Synthesis of Intermediate 1-g: (1s, 4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexan-1-ol and Intermediate 1-h: (1s, 4s)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-methylcyclohexan-1-ol
  • reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (10 ml x 2).
  • the organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was separated and purified by silica gel column chromatography (eluted with n-hexane containing 6%-12.5% ethyl acetate) to obtain two groups of compounds: colorless oil 1-g (first effluent component) (28 mg, 12%);
  • Step 5 Synthesis of Compound 1: (1s, 4s)-4-(5-chloro-4-((4-(((1s, 4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • N,N-diisopropylethylamine (1.42 g, 10.95 mmol) was added to a solution of 1-f (2,4-dichloro-5-(trifluoromethyl)pyrimidine) (949 mg, 4.37 mmol) and 2-b (2-methoxymethylaniline) (500 mg, 3.65 mmol) in isopropanol (20 mL).
  • the mixture was reacted at 80 °C for 12 hours. TLC monitored the reaction to be complete. The mixture was concentrated under reduced pressure, and the residue was partitioned between water (15 mL) and dichloromethane (20 mL).
  • the first component is a yellow solid 2-d: 4-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-2-amine (320 mg, 28%).
  • the second component was a white solid 2-c: 2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-4-amine (670 mg, 58%).
  • Step 3 Synthesis of Compound 2A: (1s, 4s)-1-imino-4-(4-((4-(2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Trifluoroacetic acid (3.8 mg) was added to a solution of fragment Amine-4 (72 mg, 0.34 mmol) and intermediate 2-c (2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidine-4-amine) (107 mg, 0.34 mmol) in isopropanol (3 mL). The mixture was reacted at 80°C for 16 hours. TLC monitored the reaction to be complete. The mixture was partitioned between saturated sodium bicarbonate solution (5 mL) and ethyl acetate (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 8% methanol in dichloromethane) to give compound 2A as a white solid (14.2 mg, 8.5%).
  • Step 1 Synthesis of intermediate 3-c: 2-chloro-N-(2-(methylsulfonyl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • reaction mixture was dispersed in water (10 mL) and ethyl acetate (10 mL), the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 25% ethyl acetate) to obtain intermediate 3-c as a white solid (86 mg, 68%).
  • Step 2 Synthesis of intermediate 3-d: 4-(5-chloro-4-((4-(2-(methylsulfonyl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 3 Synthesis of Compound 3: (1s, 4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 1 Synthesis of intermediate 4-a: (1s, 4s)-4-(5-chloro-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 2 Synthesis of Compound 4: (1s, 4s)-4-(5-chloro-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the intermediate 1-e is replaced by the fragment 2-(methylsulfonyl)ethylamine hydrochloride, and the fragment Amine-2 is replaced by the fragment Amine-1 to obtain the title compound.
  • the intermediate 1-e is replaced by the fragment 2-(methylsulfonyl)ethylamine hydrochloride, and Amine-1-f-B is replaced by Amine-1-f-A in the synthesis of the fragment Amine-1 to obtain the title compound.
  • intermediate 1-e is replaced by 2-(methylsulfonyl)ethylamine hydrochloride
  • Amine-1-f-B is replaced by Amine-1-f-A in the synthesis of fragment Amine-1 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-1 to obtain the title compound.
  • intermediate 2-d is replaced by intermediate 1-a
  • intermediate 2-b is replaced by intermediate 14-e
  • fragment Amine-2 is replaced by fragment Amine-1 to obtain the title compound.
  • dimethylphosphine oxide ethylamine hydrochloride is used to replace intermediate 1-e to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-1 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-3 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-10 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-11 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-12 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-4 to obtain the title compound.
  • intermediate 1-e is used to replace intermediate 3-b to obtain the title compound.
  • the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, and the intermediate 3-b is replaced by the intermediate 2-b to obtain the title compound.
  • the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, and the intermediate 3-b is replaced by the intermediate 1-e to obtain the title compound.
  • the starting material 3-a is replaced by 2,4-dichloro-5-methylpyrimidine, and the intermediate 3-b is replaced by the intermediate 1-e to obtain the title compound.
  • fragment Amine-2 was used to replace fragment Amine-4 to obtain the title compound.
  • intermediate 1-e is replaced by methylamine hydrochloride to obtain the title compound.
  • methylamine hydrochloride is used to replace intermediate 1-e, and in the synthesis of fragment Amine-2, Amine-1-f-B is used to replace Amine-1-f-A to obtain the title compound.
  • intermediate 1-e is replaced by (2-aminophenyl)dimethylphosphine oxide
  • fragment Amine-2 is replaced by fragment Amine-4 to obtain the title compound.
  • intermediate 1-d was used to replace intermediate 1-e to obtain the title compound.
  • fragment Amine-1 was used to replace fragment Amine-4 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-7 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-7
  • fragment Amine-7-c-A was replaced by fragment Amine-7-c-B in the synthesis of fragment Amine-7 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-5 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-6 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-9 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-12 to obtain the title compound.
  • fragment Amine-3 was used to replace fragment Amine-4 to obtain the title compound.
  • 1,4-dioxaspiro[4.5]decan-8-ol was used to replace intermediate 1-e
  • fragment Amine-3 was used to replace fragment Amine-2 to obtain the title compound.
  • 1,4-dioxaspiro[4.5]decan-8-ol was used to replace intermediate 1-e
  • fragment Amine-3 was used to replace fragment Amine-2 to obtain the title compound.
  • intermediate 1-e was replaced by ethyl 4-hydroxypiperidine-1-carboxylate, and fragment Amine-2 was replaced by fragment Amine-3 to obtain the title compound.
  • intermediate 4-b is replaced by morpholine to obtain the title compound.
  • intermediate 2-b was replaced by 4-amino-1-methylcyclohexane-1-ol, and fragment Amine-4 was replaced by fragment Amine-3 to obtain the title compound.
  • intermediate 4-b was replaced with N,N-dimethylpiperidin-4-amine to obtain the title compound.
  • intermediate 4-b was replaced with piperidin-4-ylmethanol to obtain the title compound.
  • tetrakis(triphenylphosphine)palladium (7.5 mg, 0.0065 mmol) was added to acetonitrile (1 ml) and water (0.5 mL) containing 4-a((1s, 4s)-4-(5-chloro-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide) (30 mg, 0.065 mmol), 39-a(3-(methoxymethyl)phenylboronic acid) (12 mg, 0.072 mmol) and sodium carbonate (14 mg, 0.13 mmol).
  • the reaction system was replaced with nitrogen three times and heated to 90° C. for 18 hours.
  • the reaction was complete when monitored by TLC.
  • the mixture was concentrated under reduced pressure and the residue was distributed between dichloromethane (10 mL) and water (10 mL).
  • the organic phase was collected, dichloromethane was added to the aqueous phase for extraction (10 mL x 2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by preparative TLC (dichloromethane elution solution containing 3% methanol) to obtain compound 39 as a white solid (11.8 mg, 33%).
  • methylboronic acid was replaced with ethylboronic acid in the synthesis of fragment Amine-7 to obtain the title compound.
  • intermediate 4-b is replaced by N,N-dimethylethylenediamine to obtain the title compound.
  • ethylene glycol monomethyl ether is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
  • intermediate 1-e is replaced by 1-Boc-3-hydroxypyrrolidine, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
  • intermediate 1-e is replaced by tert-butyl cis-(4-hydroxymethyl)cyclohexylcarbamate, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
  • intermediate 1-e is replaced by trans-(4-hydroxymethyl)cyclohexylcarbamic acid tert-butyl ester, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
  • the starting material 3-a is replaced by 2,4,5-trichloropyrimidine
  • the intermediate 3-b is replaced by the intermediate 1-d
  • the fragment Amine-2 is replaced by the fragment Amine-3 to obtain the title compound.
  • intermediate 4-b is replaced by N-Boc-4-piperidinemethanol, and N,N-diisopropylethylamine is replaced by sodium hydride in step 2, and the title compound is obtained after deprotection.
  • 1-methyl-4-piperidinol is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
  • the starting material 3-a was replaced by 2,4,5-trichloropyrimidine, the intermediate 3-b was replaced by (2-aminophenyl) dimethylphosphine oxide, and the fragment Amine-2 was replaced by the fragment Amine-3 to obtain the title compound.
  • Example 52 Determination of the solubility of the compound in water and dilute hydrochloric acid
  • the compound was dissolved in acetonitrile (LCMS pure) and prepared into the following concentration gradient standard samples: 1000 ⁇ g/mL, 500 ⁇ g/mL, 250 ⁇ g/mL, 125 ⁇ g/mL, 62.5 ⁇ g/mL, 31.25 ⁇ g/mL.
  • the standard sample and the sample to be tested were analyzed by Shimadzu LCMS-2020, chromatographic column: Shim-pack GIST 5 ⁇ m C18 2.1*50nm; mobile phase: A: water, B: methanol; flow rate: 0.3mL/min. Gradient of B: 0min: 10%; 0-1.0min: 10%; 1.0-2.5min: 95%; 3.0-4.0min: 95%; 4.0-4.1min: 10%; 4.1-6.0min: 10%.
  • the relationship between the concentration and peak area of the standard sample is made into a standard curve, and the concentration of the sample to be tested is calibrated using this standard curve.
  • Compound solubility concentration of the sample to be tested ⁇ 10
  • the compound of the present invention has good solubility in water, and has even better solubility in dilute hydrochloric acid simulating gastric acid.
  • the ADP-Glo method was used to detect the inhibitory effect of the compound on the activity of LRRK2 kinase.
  • the compound was diluted with 1 ⁇ kinase buffer, 3 ⁇ L of 1mM compound DMSO storage solution was added to 57 ⁇ L 1 ⁇ kinase buffer D, and the compound was diluted 5 times with 1 ⁇ kinase buffer. 1 ⁇ L of the compound diluted with kinase buffer was added to the Greiner 384-well plate, and a DMSO blank control group and a buffer background group were set up.
  • IC 50 ranges of some compounds in the LRRK2 kinase activity assay are provided in Table 2 below: (IC 50 ranges: A ⁇ 0.1 ⁇ M; B: 0.1-0.5 ⁇ M; C: > 0.5 ⁇ M):
  • Biological test example-2 Inhibition rate detection of endogenous phosphorylated LRRK2 (S935) in cells
  • A549 cells with high expression of LRRK2 were resuspended in serum-free 1640 medium at a density of 1 ⁇ 10 ⁇ 6 cells/ml, and 1 ml was inoculated in each well of a 12-well plate and cultured at 37°C, 5% carbon dioxide for 6-8 hours. 1 ⁇ L of compound DMSO storage solution or DMSO (volume ratio of 0.1%) was added, mixed, and cultured at 37°C, 5% carbon dioxide for 15 hours. Cells were collected, and 50 ⁇ L RIPA III lysis buffer was added to each sample to lyse the cells on ice for 15 minutes, centrifuged at 4°C, 13000 rpm for 30 minutes, and the supernatant was taken.
  • the concentration of cell lysate was measured by BCA, and the concentration of all samples was normalized. 5 ⁇ loading buffer was added and 95°C for 10 minutes. WB was used to detect the content of endogenous LRRK2 phosphorylated S935.
  • the phosphorylated LRRK2 (S935) antibody was Abcam#133450. Image J was used to count the signal intensity of phosphorylated LRRK2 (S935), and beta-actin was used to normalize the phosphorylated LRRK2 (S935) signal in the sample for data analysis.
  • Table 3 below provides the inhibition rates of some compounds on LRRK2 (S935) activity in cells at a concentration of 10 ⁇ M:
  • Table 4 below provides the IC 50 ranges of the inhibitory activity of some compounds on LRRK2 (S935) in cells: (IC 50 range: A ⁇ 0.1 ⁇ M; B: 0.1-0.5 ⁇ M; C: > 0.5 ⁇ M)

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Abstract

La présente invention concerne une classe de composés sulfoximine représentés par la formule (I) et leur utilisation en tant qu'inhibiteurs de la protéine kinase LRRK2.
PCT/CN2024/078490 2023-02-27 2024-02-26 Composés de sulfoximine et leur application en tant qu'inhibiteurs de la protéine kinase lrrk2 Pending WO2024179393A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN102498110A (zh) * 2009-06-10 2012-06-13 雅培制药有限公司 作为激酶抑制剂的2-(lh-吡唑-4-基氨基)-嘧啶
CN103313978A (zh) * 2010-11-10 2013-09-18 霍夫曼-拉罗奇有限公司 作为lrrk2调节剂的吡唑氨基嘧啶衍生物
CN106232122A (zh) * 2013-09-27 2016-12-14 林伯士艾瑞斯公司 Irak抑制剂和其用途
WO2017004133A1 (fr) * 2015-06-29 2017-01-05 Nimbus Iris, Inc. Inhibiteurs d'irak et utilisations de ceux-ci
EA201892532A1 (ru) * 2017-05-24 2019-05-31 Денали Терапьютикс Инк. Пиримидин-2-иламино-1н-пиразолы в качестве ингибиторов lrrk2 для применения при лечении нейродегенеративных заболеваний
WO2022100688A1 (fr) * 2020-11-13 2022-05-19 南京红云生物科技有限公司 Modulateur de kinase hpk1, son procédé de préparation et son utilisation
WO2022216097A1 (fr) * 2021-04-08 2022-10-13 주식회사 스탠다임 Nouvel inhibiteur de lrrk2

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102498110A (zh) * 2009-06-10 2012-06-13 雅培制药有限公司 作为激酶抑制剂的2-(lh-吡唑-4-基氨基)-嘧啶
CN103313978A (zh) * 2010-11-10 2013-09-18 霍夫曼-拉罗奇有限公司 作为lrrk2调节剂的吡唑氨基嘧啶衍生物
CN106232122A (zh) * 2013-09-27 2016-12-14 林伯士艾瑞斯公司 Irak抑制剂和其用途
WO2017004133A1 (fr) * 2015-06-29 2017-01-05 Nimbus Iris, Inc. Inhibiteurs d'irak et utilisations de ceux-ci
EA201892532A1 (ru) * 2017-05-24 2019-05-31 Денали Терапьютикс Инк. Пиримидин-2-иламино-1н-пиразолы в качестве ингибиторов lrrk2 для применения при лечении нейродегенеративных заболеваний
WO2022100688A1 (fr) * 2020-11-13 2022-05-19 南京红云生物科技有限公司 Modulateur de kinase hpk1, son procédé de préparation et son utilisation
WO2022216097A1 (fr) * 2021-04-08 2022-10-13 주식회사 스탠다임 Nouvel inhibiteur de lrrk2

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