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WO2023078411A1 - Composé azaspiro - Google Patents

Composé azaspiro Download PDF

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Publication number
WO2023078411A1
WO2023078411A1 PCT/CN2022/129958 CN2022129958W WO2023078411A1 WO 2023078411 A1 WO2023078411 A1 WO 2023078411A1 CN 2022129958 W CN2022129958 W CN 2022129958W WO 2023078411 A1 WO2023078411 A1 WO 2023078411A1
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compound
mmol
reaction
mobile phase
dissolved
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PCT/CN2022/129958
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English (en)
Chinese (zh)
Inventor
吴凌云
王才林
徐雄彬
赵乐乐
黎健
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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    • 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
    • A61P25/00—Drugs for disorders of the nervous 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
    • A61P25/28—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
    • 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

Definitions

  • the present invention relates to a class of azaspiro compounds, in particular to the application of compounds represented by formula (II-1) or pharmaceutically acceptable salts thereof in the preparation of drugs for treating related diseases.
  • LRRK2 kinase are increasingly proven to be the fundamental factors in inducing neurodegenerative diseases, characterized by selective degeneration and cell death of dopaminergic neurons in the substantia nigra. Affects 1% of the population over the age of 65, of which genetic patients account for 5-10% of the affected population. Early in the disease, the most obvious symptoms are shaking, slowness of movement and difficulty walking. Cognitive and behavioral problems also develop later, and dementia usually occurs later.
  • LRRK2 leucine-rich repeat kinase 2
  • NM_198578.2 The NCBI participating sequence for human LRRK2 mRNA.
  • Evidence shows that LRRK2 phosphorylates ⁇ -synuclein at serine-129 and that this phosphorylated form constitutes an important part of Lewy bodies.
  • SNPs in the functional domains of LRRK2 have been shown to cause common and sporadic neurodegenerative diseases.
  • LRRK2 mutations have identified more than 20 LRRK2 mutations in families with late-onset neurodegenerative disease.
  • the G2019S mutation co-segregates with autosomal dominant and it is responsible for approximately 6% of familial cases and 3% of sporadic cases in Europe.
  • the G2019S mutation occurs in a highly conserved kinase domain, so the G2019S mutation may have an effect on kinase activity.
  • an amino acid substitution at another residue, R1441 has also been associated with neurodegenerative diseases and was shown to increase LRRK2 kinase activity.
  • the present invention aims to invent a compound that can highly inhibit LRRK2 kinase, so as to further invent a drug that can well treat neurodegenerative diseases.
  • J.Med.Chem.2012,55,9416-9433 discloses compound GNE-7915, which belongs to LRRK2 kinase inhibitor, and its structural formula is as follows:
  • the present invention provides compounds represented by formulas (III-1), (II-2), (II-3), (II-4) and (III-2) or pharmaceutically acceptable salts thereof:
  • X 1 is CH, X 2 is CA; or, X 1 is CA, X 2 is CH;
  • Y is -C(R 9 R 10 )- or -O-;
  • Z 1 is CH, Z 2 is N; or, Z 1 is N, Z 2 is CH;
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
  • R 3 and R 4 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
  • R 5 and R 6 are independently selected from H, F, CH 3 and CF 3 ;
  • R 7 is selected from CH 3 and CHF 2 ;
  • R 9 and R 10 are independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Each group is independently optionally substituted by 1, 2 or 3 halogens;
  • n, q, t are independently selected from 0, 1 and 2, respectively.
  • the above-mentioned compounds are selected from compounds shown in formulas (II-1), (II-2), (II-3) and (II-4):
  • X 1 is CH, X 2 is CA; or, X 1 is CA, X 2 is CH;
  • Y is -C(R 9 R 10 )- or -O-;
  • Z 1 is CH, Z 2 is N; or, Z 1 is N, Z 2 is CH;
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
  • R 3 and R 4 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
  • R 5 and R 6 are independently selected from H and F;
  • R 7 is selected from CH 3 and CHF 2 ;
  • R 9 and R 10 are independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Each group is independently optionally substituted by 1, 2 or 3 halogens;
  • n, q, t are independently selected from 0, 1 and 2, respectively.
  • the above compounds are selected from:
  • R 1 , R 2 , R 3 , R 6 and R 7 are as defined in the present invention.
  • Y, R 1 , R 2 , R 3 , R 4 , m, n, q and t are as defined in the present invention.
  • Y is -C(R 9 R 10 )- or -O-;
  • R 1 and R 2 are independently selected from H, F, Cl, Br, I, CH 3 and CF 3 ;
  • R 3 and R 4 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens;
  • R 9 and R 10 are independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Each group is independently optionally substituted by 1, 2 or 3 halogens;
  • n, q, t are independently selected from 0, 1 and 2, respectively.
  • R 1 is selected from H and F, and other variables are as defined in the present invention.
  • R 2 is selected from Cl and F, and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from CH 3 , and other variables are as defined in the present invention.
  • R 9 and R 10 are independently selected from H, F, CH 3 , -OCHF 2 and -OCH 3 , and other variables are as defined in the present invention.
  • R 9 and R 10 are independently selected from H, F and -OCH 3 , and other variables are as defined in the present invention.
  • the above-mentioned Y is -CHF-, -CF 2 -, -CH 2 -, -CH(OCH 3 )-, -CH(OCHF 2 )- and -O-, other variables are as in the present invention defined.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
  • the present invention also provides the application of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Parkinson's disease.
  • the compound of the present invention has remarkable kinase inhibition, cell activity, membrane permeability and solubility for LRRK2, and has excellent pharmacokinetic and pharmacodynamic properties, such as better brain entry properties.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the terms "effective amount” or “therapeutically effective amount” refer to a non-toxic amount that achieves the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0alkyl -A means that the structure is actually -A.
  • this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring.
  • the carbon atom is attached to the group being substituted.
  • a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • the solvent used in the present invention is commercially available.
  • CDCl 3 stands for deuterated chloroform
  • CD 3 OD stands for deuterated methanol
  • DMSO-d 6 stands for deuterated dimethyl sulfoxide.
  • Fig. 1 is the result of immunoblotting experiment on brain tissue of the compound of the present invention.
  • reaction liquid was filtered, and the filtrate was extracted with ethyl acetate (20 ml ⁇ 3), the organic phase was washed with saturated brine (50 ml ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was passed through a silica gel column layer.
  • reaction solution was concentrated under reduced pressure, then, water (50 ml) was added, and the pH of the solution was adjusted to 8 with saturated sodium bicarbonate solution, then dichloromethane (50 ml) was added to dilute the reaction solution, and dichloromethane was added to Extracted with methane (50 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, then, water (50 ml) was added, and the pH of the solution was adjusted to 8 with saturated sodium bicarbonate solution, then dichloromethane (30 ml) was added to dilute the reaction solution, and dichloromethane was added to Extracted with methane (30 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was filtered, and water (50 milliliters) was added to the filtrate for dilution, and extracted with ethyl acetate (50 milliliters) mL ⁇ 2), the organic phase was washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate.
  • reaction solution was filtered with diatomaceous earth, and the crude product concentrated under reduced pressure of the filtrate was subjected to high performance liquid chromatography (chromatographic column: Waters Xbridge C18 15 ⁇ 50 millimeters ⁇ 10 microns; mobile phase: mobile phase A: ammonium bicarbonate aqueous solution; Mobile phase B: acetonitrile; B%: 40%-70%, 10 minutes) isolated to obtain compound 36.
  • chromatographic column Waters Xbridge C18 15 ⁇ 50 millimeters ⁇ 10 microns
  • mobile phase mobile phase A: ammonium bicarbonate aqueous solution
  • Mobile phase B acetonitrile
  • B% 40%-70%, 10 minutes
  • reaction solution was quenched with saturated ammonium chloride solution (50 mL) at 25°C, diluted with ethyl acetate (50 mL), and extracted with ethyl acetate (40 mL ⁇ 3).
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product.
  • the crude product was separated by high-performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150 ⁇ 40 mm ⁇ 15 microns; mobile phase: mobile phase A: formic acid solution; mobile phase B: acetonitrile; B%: 20%-50%, 10 minutes) separation Compound 49-5 was obtained.
  • the reaction solution was filtered and concentrated to obtain a crude product.
  • reaction solution was quenched by adding water (20 ml), diluted with ethyl acetate (50 ml), extracted with ethyl acetate (50 ml ⁇ 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. , concentrated to obtain the crude product.
  • the reaction solution was filtered and concentrated to obtain a crude product.
  • reaction solution was filtered and concentrated to obtain a crude product.
  • the crude product was subjected to high performance liquid chromatography (chromatographic column: Unisil 3-100C18Ultra 150 ⁇ 50 mm ⁇ 10 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%: 44%-74%, 10 minutes ) to isolate compound 51.
  • high-performance liquid chromatography chromatographic column: Phenomenex C18 75 ⁇ 30 mm ⁇ 3 Micron; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%: 38%-68%, 7 minutes
  • reaction solution was filtered, diluted with water (20 ml), extracted with ethyl acetate (20 ml ⁇ 2), the combined organic phase was washed with saturated saline solution (20 ml), and the organic phase was dried over anhydrous sodium sulfate. , filtered, and the concentrated residue was subjected to high performance liquid chromatography (chromatographic column: YMC Triart C18 150 mm ⁇ 25 mm ⁇ 5 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%: 59%-89 %, 8.5 min) to isolate compound 56.
  • chromatographic column YMC Triart C18 150 mm ⁇ 25 mm ⁇ 5 microns
  • mobile phase mobile phase A: formic acid aqueous solution
  • mobile phase B acetonitrile
  • B% 59%-89 %, 8.5 min
  • the crude product was separated by high performance liquid chromatography (column: Phenomenex luna C18 150 mm ⁇ 25 mm ⁇ 10 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%: 10%-40%) to obtain the compound 60.
  • the purpose of the experiment to detect the phosphorylated Fluorescein-ERM (LRRKtide) peptide phosphate group and Energy signal transfer (520nM/485nM fluorescence signal ratio) generated after Tb-pERM (pLRRKtide) Antibody binding. Calculate the LRRK2 kinase inhibitory IC 50 value of the test compound.
  • Reaction solution 10mM hydroxyethylpiperazineethanesulfonic acid (PH7.5); 2mM magnesium chloride; 0.5mM ethylene glycol diethyl ether diamine tetraacetic acid; 0.002% polyoxyethylene fatty alcohol ether; 1mM dithiothreitol and 1%DMSO;
  • LRRK2 human recombinant protein using GST tag to express recombinant full-length human LRRK2 protein in insect Sf9 cells with baculovirus;
  • Substrate 0.4 ⁇ M Fluorescein-ERM (LRRKtide) peptide; 57 ⁇ M ATP.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the relative enzyme activity inhibition relative to DMSO blank was calculated by the signal ratio, and the IC 50 value was calculated by using the software XLfit5 to fit the curve.
  • Compound 3 6 Compound 23 6 Compound 4 7 Compound 24 5 Compound 5 5 Compound 25 5 Compound 6 5 Compound 26 5 Compound 7 3 Compound 27 4 Compound 8 4 Compound 28 15 Compound 9 4 Compound 29 14 Compound 10 3 Compound 30 5 Compound 11 14 Compound 31 10 Compound 12 12 Compound 32 7 Compound 15 16 Compound 33 13 Compound 17 5 Compound 36 10 Compound 18 4 Compound 37 7 Compound 19 6 Compound 39 16 Compound 20 4 / /

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Abstract

L'invention concerne un composé azaspiro, et spécifiquement une application d'un composé représenté par la formule (II-1), etc. et un sel pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament pour le traitement de maladies associées.
PCT/CN2022/129958 2021-11-05 2022-11-04 Composé azaspiro Ceased WO2023078411A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202111308839 2021-11-05
CN202111308839.8 2021-11-05
CN202210837792.2 2022-07-15
CN202210837792 2022-07-15
CN202211351816 2022-10-31
CN202211351816.X 2022-10-31

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009127642A2 (fr) * 2008-04-15 2009-10-22 Cellzome Limited Utilisation d’inhibiteurs de lrrk2 pour maladies neurodégénératives
WO2016000581A1 (fr) * 2014-07-04 2016-01-07 南京明德新药研发股份有限公司 Oxyde d'aryl-phosphore et sulfure d'aryl-phosphore spirocycliques
WO2017086832A1 (fr) * 2015-11-19 2017-05-26 Акционерное Общество "Р-Фарм" (Ао "Р-Фарм") N2-(4-amino-2-méthoxyphényl)-n4-[2-(diméthyl-phosphinoyl)phényl]-5-chlor-pirimidin-2,4-diamines substituées en tant que modulateurs d'alk et d'egfr destinés au traitement du cancer
WO2019201334A1 (fr) * 2018-04-20 2019-10-24 南京明德新药研发有限公司 Composé d'oxyde de diméthylphosphine
WO2021073600A1 (fr) * 2019-10-18 2021-04-22 贵州伊诺其尼科技有限公司 Forme cristalline d'inhibiteur de lrrk2 et son procédé de préparation
WO2021125803A1 (fr) * 2019-12-16 2021-06-24 한국화학연구원 Nouveau dérivé de pyrimidine et utilisation correspondante

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009127642A2 (fr) * 2008-04-15 2009-10-22 Cellzome Limited Utilisation d’inhibiteurs de lrrk2 pour maladies neurodégénératives
WO2016000581A1 (fr) * 2014-07-04 2016-01-07 南京明德新药研发股份有限公司 Oxyde d'aryl-phosphore et sulfure d'aryl-phosphore spirocycliques
WO2017086832A1 (fr) * 2015-11-19 2017-05-26 Акционерное Общество "Р-Фарм" (Ао "Р-Фарм") N2-(4-amino-2-méthoxyphényl)-n4-[2-(diméthyl-phosphinoyl)phényl]-5-chlor-pirimidin-2,4-diamines substituées en tant que modulateurs d'alk et d'egfr destinés au traitement du cancer
WO2019201334A1 (fr) * 2018-04-20 2019-10-24 南京明德新药研发有限公司 Composé d'oxyde de diméthylphosphine
WO2021073600A1 (fr) * 2019-10-18 2021-04-22 贵州伊诺其尼科技有限公司 Forme cristalline d'inhibiteur de lrrk2 et son procédé de préparation
WO2021125803A1 (fr) * 2019-12-16 2021-06-24 한국화학연구원 Nouveau dérivé de pyrimidine et utilisation correspondante

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