WO2022062356A1 - Medicine for treating or preventing diseases related to activity of lrrk2 kinase or abnormal lrrk2 mutant kinase - Google Patents

Medicine for treating or preventing diseases related to activity of lrrk2 kinase or abnormal lrrk2 mutant kinase Download PDF

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WO2022062356A1
WO2022062356A1 PCT/CN2021/084876 CN2021084876W WO2022062356A1 WO 2022062356 A1 WO2022062356 A1 WO 2022062356A1 CN 2021084876 W CN2021084876 W CN 2021084876W WO 2022062356 A1 WO2022062356 A1 WO 2022062356A1
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谢伟东
程星
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广州智睿医药科技有限公司
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Definitions

  • the invention belongs to the field of medicine, in particular to a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
  • the protein encoded by the LRRK2 gene includes a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, an MLK-domain, and a WD40 domain.
  • LRR leucine-rich repeat
  • LRRK2 kinase activity with Parkinson's disease PD susceptibility, and pathogenic mutations in the LRRK2 gene (especially the most common Gly2019Ser mutation) increase LRRK2 kinase activity and decrease GTP hydrolysis rates in cells and tissues
  • Blocking these activities with small-molecule LRRK2 kinase inhibitors can also provide neuroprotection in certain models of PD, a finding that makes LRRK2 the most promising target for the treatment of Parkinson's disease (PD) disease (Tolosa et al., Nature Reviews in Neurology, Vol.16, 2020, PP.97-10; Paisan-Ruiz et al., J.
  • LRRK2 was identified as a gene potentially associated with elevated susceptibility to Crohn's disease and susceptibility to leprosy (Zhang et al., New England J. Med., Vol. 361, 2009, pp. 2609- 2618; Barrett et al, Nature Genetics, Vol. 40, 2008, pp.
  • LRRK2 is also associated with the following conditions: Alzheimer's transformation from mild cognitive impairment (WO2007149798); L-dopa-induced dyskinesia (Hurley et al., Eur.J, Neurosci., Vol.26, 2007, pp. 171-177); CNS disorders associated with neuroblastoid proliferation and migration, and modulation of LRRK2 may be used to improve neural outcomes and neuronal damage following ischemic injury (such as ischemic stroke, traumatic brain injury or Stimulation of CNS functional recovery after spinal cord injury) (Milosevic et al., Neurodegen., Vol. 4, 2009, 25; Zhang et al., J. Neurosci. Res, Vol. 88, 2010, pp. 3275-3281).
  • ischemic injury such as ischemic stroke, traumatic brain injury or Stimulation of CNS functional recovery after spinal cord injury
  • Cancers such as kidney cancer, breast cancer, prostate cancer (eg solid tumors), blood and lung cancer and acute myeloid leukemia (AML) (WO2011038572); lymphoma and leukemia (Ray et al., J. Immunolo., Vol. 230, 2011, 109); papillary renal and thyroid cancer (Brendan D Looyenga et al., Proc Natl Acad Sci U S A, Vol. 108(4), 2011, pp.
  • Immune system diseases including rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythropoiesis, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, Vasculitis, bullous skin disease, type I diabetes, Sjogren's syndrome, Delvic's disease, and inflammatory diseases (Nakamura et al., DNA Res., Vol. 13(4) , 2006, pp. 169-183; Engel et al., Pharmacol. Rev., Vol.
  • Lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (Araya et al., Intern. Med., Vol. 52, 2013, 2295-2303).
  • small molecules of LRRK2 kinase Inhibitors can also be used to increase the host's therapeutic response to a range of intracellular bacterial, parasitic, and viral infections, including diseases such as tuberculosis (Rubinsztein et al., Nat.
  • Alzheimer's disease and other neurodegenerative diseases (Nixon, Nat. Med., Vol. 19, 2013, pp. 983-97) and Gaucher disease (Westbroek et al., Trends. Mol. Med., Vol. 17, 2011, 485-493); tauopathy characterized by hyperphosphorylation of Tau, such as argillophilic granulosis, Pick's disease (Pi ck's disease), corticobasal degeneration, progressive supranuclear palsy, and hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (Jakes R et al., Biochemicaet Biophysica Acta, Vol. 1739, 2005, pp. 240-250); microglial pro-inflammatory responses (Moehle et al., J. Neuroscience, Vol. 32, 2012, pp. 1602-1611).
  • compounds that effectively modulate LRRK2 activity can provide treatment for diseases or conditions mediated by LRRK2, including neurodegenerative diseases, cancers, inflammatory diseases, bacterial, viral infections and other diseases.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and provide a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
  • the present invention provides a medicine for the treatment or prevention of diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising LRRK2 inhibitor, and the LRRK2 inhibitor includes the compound represented by Chemical formula 1, its optical isomer. , at least one of its prodrugs, its salts, its hydrates, its solvates, its N-oxides, its deuterated analogs;
  • L 1 , L 2 and L 3 are all independently C or N;
  • L 4 is C, N, O or S;
  • R 1 is independently unsubstituted or amido
  • L 3 is N, and L 1 , L 2 , R 1 and R 2 form together or -ArR b R d , wherein X is halogen;
  • R 3 is unsubstituted, -H, halogen, C 1-10 hydrocarbyl, or -NHR a ;
  • R 5 is independently
  • L 5 is -O-, -S-, or -NH-
  • Y 1 is a C 1-10 straight-chain or branched alkyl group that is unsubstituted or substituted by a third substituent
  • the Y ring is a benzene ring, or a 4- to 8-membered ring heterocycloalkyl or heterocyclic aryl group containing at least one heteroatom in N and O that is unsubstituted or substituted by a fourth substituent;
  • R 6 is unsubstituted or -H
  • R 7 is -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, -OR c , -O(CH 2 ) n R a , halogen, or unsubstituted or substituted by a third substituent containing N, A 4- to 8-membered ring heterocycloalkyl or heteroaryl of at least one heteroatom in O;
  • R 8 , R 9 , R 10 , R 11 are each independently -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, -O(CH 2 ) n R a , -C(O)OR a , halogen, -CF3 or -OCF3 ;
  • Each R is independently -H, C 1-10 hydrocarbyl, C 1-10 cyclohydrocarbyl, aryl, or unsubstituted or substituted with a fifth substituent containing at least one heteroatom of N, O. to 8-membered ring heterocycloalkyl or heteroaryl;
  • Each R b is independently at least one of -H, C 1-10 hydrocarbyl, -O(CH 2 ) n R a , -NR a R c , or N, O-containing unsubstituted or substituted with a sixth substituent A heteroatom 3- to 8-membered ring heterocyclyl;
  • Each R c is independently -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, aryl, or unsubstituted or substituted with a third substituent containing at least one heteroatom of N, O 4- to 8-membered ring heterocycloalkyl or heteroaryl;
  • each R d is independently -H or -O(CH 2 ) n R a ;
  • the first substituent, the second substituent, the fourth substituent, the fifth substituent and the sixth substituent are each independently -OH, halogen, -CN, nitro, -NH 2 , C 1-10 hydrocarbon group , at least one of substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 8-membered ring heterocycloalkyl containing at least one heteroatom in N and O;
  • n is independently selected from any integer from 0 to 4.
  • the structural formula of the compound represented by the chemical formula 1 is as follows:
  • R 3 is halogen or C 1-10 hydrocarbon group
  • R 4 is C 1-5 straight chain or branched chain alkylaminosulfonyl C 6-10 arylamino, di(C 1-5 straight chain or branched Chain alkyl) phosphate C 6-10 arylamino, A 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, either unsubstituted or substituted by a second substituent
  • the R 7 is R b is a C 1-10 hydrocarbon group, -NR a R c , or a 3- to 8-membered ring heterocyclic group containing at least one heteroatom of N and O substituted by a C 1-10 hydrocarbon group
  • R a is C 1- 10 hydrocarbon group
  • R c is -(CH 2 ) n OH
  • the R 10 and R 11 are independently -H, -O(CH2) n R a , C 1-10 hydrocarbon group or halogen.
  • the R 3 is -F, -Cl or -CH 3; the R 4 is The R7 is The R 10 and R 11 are independently -H, -OCH 3 , -CH 3 or -F.
  • the structural formula of the compound represented by the chemical formula 1 is as follows:
  • the L 4 is N, S or O; the R 5 is Or phenyl substituted by at least one of -O(CH 2 ) n R a and halogen; R b is -O(CH 2 ) n R a ; R a is -H, or unsubstituted or by the fifth substituent Substituted 5- to 8-membered cyclic heterocycloalkyl or heterocyclic aryl containing at least one heteroatom in N and O; R d is -H or -O(CH 2 ) n R a .
  • the L 4 is N, S or O; the R 5 is The R b is R d is -H or -OCH 3 .
  • the structural formula of the compound represented by the chemical formula 1 is as follows:
  • the R 4 is a 5- to 8-membered ring heterocyclylamino substituted with a C 1-10 hydrocarbon group; the L 4 is N, S or O; the R 7 is O(CH 2 ) n R a , R a is an aryl group, or a 5- to 8-membered ring heterocycloalkyl or heterocyclic aryl group containing at least one heteroatom of N and O which is unsubstituted or substituted by a fifth substituent.
  • the structural formula of the compound represented by the chemical formula 1 is as follows:
  • the R 2 is a 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent;
  • the L 4 is N;
  • the R 5 is
  • the structural formula of the compound represented by the chemical formula 1 is as follows:
  • the structural formula of the compound represented by the chemical formula 1 is as follows:
  • the compound represented by the chemical formula 1 is any one of the following compounds:
  • the disease includes at least one of neurodegenerative disease, precancerous conditions and cancer, autoimmune disease, inflammation.
  • the disease comprises Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, enhanced cognitive memory, central nervous system disorders, dementia, amyotrophic lateral sclerosis, kidney disease Cancer, Breast Cancer, Prostate Cancer, Blood Cancer, Papillary Cancer, Lung Cancer, Acute Myeloid Leukemia, Multiple Myeloma, Leprosy, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Muscular Atrophic Lateral At least one of sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
  • hydrocarbon groups include alkyl groups and unsaturated hydrocarbon groups, such as alkenyl; the above halogens include F, Cl, Br, etc.; Ar represents aryl groups, such as phenyl, naphthyl, etc.; Ph represents phenyl;
  • the 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent, means that the atoms constituting the 5- to 8-membered ring also contain N, O in addition to carbon atoms.
  • 5- to 8-membered ring heterocyclylamino substituted by C 1-10 hydrocarbyl means that the 5- to 8-membered ring heterocyclyl in the 5- to 8-membered ring heterocyclylamino is substituted by C 1-10 hydrocarbyl;
  • a 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N, O, either unsubstituted or substituted by the first substituent, means that R 2
  • the beneficial effect of the present invention lies in that: the medicine of the present invention contains a specific LRRK2 inhibitor, which can effectively treat or prevent diseases related to the activity of LRRK2 kinase or any of its mutants (such as LRRK2 mutant G2019S).
  • Parkinson's disease and other Lewy body diseases including diffuse Lewy body disease, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease Merger's disease, multiple system atrophy and dementia with Lewy bodies, etc.
  • cancers such as kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myeloid leukemia, multiple myeloid tumor, melanoma, etc.
  • autoimmune diseases and inflammations such as leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid joints inflammation or ankylosing spondylitis.
  • Fig. 1 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 1 by Experimental Example 11;
  • Figure 2 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 2 through Experimental Example 11;
  • Figure 3 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 4 by Experimental Example 11;
  • Figure 4 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 7 by Experimental Example 11;
  • FIG. 5 is a Kd curve of the kinase bioactivity of LRRK2WT and LRRK2G2019S determined by Experimental Example 11 for the compound of Example 9.
  • FIG. 5 is a Kd curve of the kinase bioactivity of LRRK2WT and LRRK2G2019S determined by Experimental Example 11 for the compound of Example 9.
  • the present invention relates to a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising an LRRK2 inhibitor, the LRRK2 inhibitor comprising a compound represented by Chemical Formula 1, its optical isomer, its prodrug, its At least one of pharmaceutically acceptable salts, hydrates, solvates, N-oxides, deuterated analogs thereof.
  • the compound represented by Chemical Formula 1 can be used for the prevention and treatment of LRRK2 or related disorders caused by abnormal LRRK2 mutations, such as Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, dementia, muscle Atrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colon inflammation, amyotrophic lateral sclerosis, rheumatoid arthritis, ankylosing spondylitis, etc.
  • LRRK2 or related disorders caused by abnormal LRRK2 mutations such as Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, dementia, muscle Atrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myeloid leukemia, multiple myel
  • the compound represented by Chemical Formula 1 can be used for the prevention and treatment of diseases or conditions mediated at least in part by LRRK2 or abnormal LRRK2 mutations as neurodegenerative diseases, for example, central nervous system (CNS) disorders such as Parkinson's disease (PD).
  • diseases or conditions mediated at least in part by LRRK2 or abnormal LRRK2 mutations as neurodegenerative diseases, for example, central nervous system (CNS) disorders such as Parkinson's disease (PD).
  • CNS central nervous system
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • dementia including Lewy body dementia and vascular dementia
  • amyotrophic lateral sclerosis ALS
  • age-related memory impairment mild cognitive impairment ( For example, including transition from mild cognitive impairment to Alzheimer's disease), argillophilic granulosa disease, lysosome disease (eg, Niemann-Pick type C, Gaucher disease), corticobasal degeneration , progressive supranuclear palsy, hereditary frontal dementia and Parkinson's disease (FTDP-17) associated with chromosome 17, withdrawal symptoms/relapse associated with drug addiction, L-dopa-induced Dyskinesia, Huntington's Disease (HD) and HIV-Associated Dementia (HAD).
  • the disorder is an ischemic disease of organs including, but not limited to, the brain, heart, kidneys, and liver.
  • the compound represented by Chemical Formula 1 for the treatment of a disease or condition mediated at least in part by LRRK2 or aberrant LRRK2 mutation is cancer, such as thyroid cancer, kidney cancer (including papillary kidney cancer), breast cancer, lung cancer, Blood and prostate cancers (eg solid tumors), leukemias (including acute myeloid leukemia (AML) or lymphomas.
  • cancer such as thyroid cancer, kidney cancer (including papillary kidney cancer), breast cancer, lung cancer, Blood and prostate cancers (eg solid tumors), leukemias (including acute myeloid leukemia (AML) or lymphomas.
  • the compound of Formula 1 for use in the treatment of a disease or condition mediated at least in part by LRRK2 or aberrant LRRK2 mutation is an inflammatory disorder.
  • Inflammatory disorders are inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis (the two are commonly referred to together as inflammatory bowel disease).
  • the inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.
  • the compound represented by Chemical Formula 1 is used to treat other diseases mediated at least in part by LRRK2 or aberrant LRRK2 mutations: multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythropoiesis, Idiopathic thrombocytopenic purpura (ITP), Ivan's syndrome, vasculitis, bullous skin disease, type 1 diabetes, Sugarcan's syndrome, Dewk's disease, and inflammatory myopathy.
  • diseases mediated at least in part by LRRK2 or aberrant LRRK2 mutations multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythropoiesis, Idiopathic thrombocytopenic purpura (ITP), Ivan's syndrome, vasculitis, bullous skin disease, type 1 diabetes, Sugarcan's syndrome, Dewk's disease, and inflammatory myopathy.
  • the compound represented by Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may be an acid addition salt formed from a pharmaceutically acceptable free acid.
  • Acid addition salts can be obtained from inorganic acids (such as hydrochloric, nitric, phosphoric, sulfuric, bromic, hydroiodic, nitrous, phosphorous, etc.), non-toxic organic acids (such as aliphatic mono- and dicarboxylates, benzene alkanoates, hydroxyalkanoates and alkanoates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.) or organic acids (e.g.
  • Acid addition salts can be obtained from pharmaceutically non-toxic salts including sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate , metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyric acid Salt, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate , Butyne-1,4-Dioleate, Hexane
  • the acid addition salt can be prepared by a conventional method, for example, by dissolving the compound represented by Chemical Formula 1 or a derivative thereof in an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile, and adding an organic solvent thereto acid or mineral acid to obtain a precipitate, which is then filtered and dried, or the solvent and excess acid are subjected to vacuum distillation, drying and then crystallization in the presence of an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile
  • the compound represented by Chemical Formula 1 can be prepared and used in the form of a pharmaceutically acceptable metal salt thereof.
  • the alkali metal or alkaline earth metal salt can be obtained by, for example, dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating the filtrate to dryness.
  • sodium, potassium or calcium salts are pharmaceutically suitable as metal salts.
  • the corresponding salts can be obtained by reacting alkali metal or alkaline earth metal salts with suitable silver salts such as silver nitrate.
  • the compound represented by Chemical Formula 1 can be at least one of its pharmaceutically acceptable deuterated analogs, prodrugs, stereoisomers, its salts, its hydrates, its solvates, and its N-oxides preparation and use in the form of species.
  • the compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be administered in a single dose or multiple doses at the time of clinical administration.
  • the medicaments of the present invention can be administered using a variety of methods including, for example, rectal, pulmonary, oral, buccal, intranasal, and transdermal routes.
  • the drug may be administered by intraarterial injection, intravenous, intraperitoneal, enteral, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation form.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., can be used in the preparation of the pharmaceutical preparation of the present invention.
  • Examples of the medicament of the present invention as preparations for oral administration include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, lozenges and the like.
  • these formulations may contain diluents (eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) or lubricants (eg silicon dioxide, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol).
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyethylene collidine, and the like, and may optionally contain disintegrating agents such as starch , agar, alginic acid or its sodium salt, or boiling mixture) absorbent, coloring agent, flavoring agent, sweetening agent, etc.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyethylene collidine, and the like
  • disintegrating agents such as starch , agar, alginic acid or its sodium salt, or boiling mixture) absorbent, coloring agent, flavoring agent, sweetening agent, etc.
  • One mode of administration of the medicament of the present invention is parenteral, such as by injection, which can be made into an aqueous or oily suspension or emulsion, containing one of sesame oil, corn oil, cottonseed oil, peanut oil and an elixir, mannose alcohol and dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.
  • the medicament of the present invention when used by inhalation or insufflation, it may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders.
  • Liquid or solid pharmaceuticals may contain suitable pharmaceutically acceptable excipients as described herein.
  • the drug is administered by oral or nasal respiratory route for local or systemic effect.
  • the drug in a pharmaceutically acceptable solvent can be nebulized by use of an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a mask holder or intermittent positive pressure breathing machine. It may be a solution, suspension or powder composition suitable for administration by a delivery device, preferably oral or nasal.
  • the present invention relates to a pharmaceutical kit for preventing or treating LRRK2 or related disorders caused by abnormal LRRK2 mutation
  • the kit comprises a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt, deuterated analog, interconversion Isomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, and labels and/or instructions for use of the compounds for therapeutic indications, including diseases or conditions described herein.
  • the containers can be vials, jars, ampoules, prefilled syringes, and intravenous bags.
  • the compound represented by Chemical Formula 1 may be administered in combination with other agents including (but not limited to): compounds that are apoptosis inhibitors, PARP poly(ADP-ribose) polymerization Enzyme inhibitors, Src inhibitors, agents for the treatment of vascular diseases, hypertension, hypercholesterolemia and type II diabetes, anti-inflammatory agents, anti-embolic agents, fibrinolytic agents, anti-platelet agents, lipid-lowering agents, Direct thrombin inhibitors, glycoprotein IIb/IIla receptor inhibitors, calcium channel blockers, beta-adrenergic receptor blockers, cyclooxygenases (eg, COX-1 and COX-2) Inhibitors, angiotensin system inhibitors (eg, angiotensin-converting enzyme (ACE) inhibitors), renin inhibitors, and/or agents that bind to cell adhesion molecules and inhibit the ability of white blood cells to attach to such molecules (eg, polypeptide antibodies, polyclonal agents, renin inhibitors, and/
  • the compounds of the present disclosure can be administered in combination with additional agents that are active in the treatment of neurodegenerative diseases.
  • the compounds may be administered in combination with one or more additional therapeutic agents useful in the treatment of Parkinson's disease.
  • the additional therapeutic agent is L-dopa (eg, sinemet CR), a dopamine agonist (eg, Ropinerol or Pramipexole), catechol -O-methyltransferase (COMT) inhibitors (eg, Entacapone), L-monoamine oxidase (MAO) inhibitors (eg, selegiline or rasagiline ( rasagiline) or an agent that increases dopamine release (eg, Zonisamide).
  • L-dopa eg, sinemet CR
  • a dopamine agonist eg, Ropinerol or Pramipexole
  • catechol -O-methyltransferase (COMT) inhibitors eg, Entacapone
  • LRRK2G2019S enzyme substrate (LRRK peptide), ATP, TR-FRET diluent buffer, pLRRK peptide antibody, 384-well assay plate, and DMSO.
  • Detection reaction conditions 1 ⁇ diluent buffer, 10 mM EDTA, 2 nM antibody, 23 °C reaction temperature, 10 ⁇ L total reaction volume.
  • 5 ⁇ L of the test solution was transferred to the assay plate, and the untreated blank control wells containing 5 ⁇ L of DMSO and the control group 5 ⁇ L of the DMSO solution of the known inhibitor comparative example were successively added to the source plate (384-well assay plate, Labcyte). The plates were centrifuged at 2500 rpm for 1 minute and sealed with foil.

Abstract

A medicine for treating or preventing diseases related to the activity of an LRRK2 kinase or an abnormal LRRK2 mutant kinase, which belongs to the field of medicine. The medicine comprises at least one of a compound represented by chemical formula 1, an optical isomer, a prodrug, a salt, a hydrate, a solvate, an N-oxide and a deuterated analog thereof, has a very good inhibition effect on the LRRK2 kinase or abnormal LRRK2 mutant kinase, and can be used for treating or preventing diseases related to the activity of the LRRK2 kinase or abnormal LRRK2 mutant kinase, such as Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, dementia, kidney cancer, breast cancer, prostate cancer, leukemia, papilloma, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.

Description

一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物A drug for the treatment or prevention of a disease associated with LRRK2 kinase or aberrant LRRK2 mutant kinase activity 技术领域technical field
本发明属于医药领域，具体涉及一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物。The invention belongs to the field of medicine, in particular to a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
背景技术Background technique
LRRK2基因编码的蛋白包括一个富含亮氨酸重复(LRR)结构域，激酶结构域，一个DFG样基序，一个RAS域，一个GTP酶域，MLK-域，和WD40结构域。很多遗传和生化证据证明LRRK2激酶活性与帕金森病PD易感性有关，LRRK2基因的致病性突变(特别是最常见的Gly2019Ser突变)会增加细胞和组织中的LRRK2激酶活性和GTP水解速率降低，在某些PD模型中，小分子LRRK2激酶抑制剂会阻断这些活动还可以提供神经保护作用，这一发现使LRRK2已成为治疗帕金森病(PD)疾病最有希望的靶标(Tolosa等，Nature Reviews in Neurology，Vol.16，2020，PP.97-10；Paisan-Ruiz等，J.Parkinson's Disease，Vol.3，2013，pp.85-103；Guo等，Experimental Cell Research，Vol.313(16)，2007，pp.3658-3670；Andrew B.West，Experimental Neurology，Vol.298，2017，pp.236-245)。LRRK2被鉴别为潜在地与升高的对克罗恩氏病的易感性和对麻风病的易感性相关的基因(Zhang等，New England J.Med.，Vol.361，2009，pp.2609-2618；Barrett等,Nature Genetics，Vol.40，2008，pp.955-962)；还与脊椎强直(ankyIosing spondylytis)(Danoy等，PLoS Genetics，Vol 6(12)，2010，pp.1-5)和肌萎缩侧索硬化(Shtilans等，Amyotrophic lateral Sclerosis，2011，pp.1-7)相关。The protein encoded by the LRRK2 gene includes a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, an MLK-domain, and a WD40 domain. Numerous genetic and biochemical evidences link LRRK2 kinase activity with Parkinson's disease PD susceptibility, and pathogenic mutations in the LRRK2 gene (especially the most common Gly2019Ser mutation) increase LRRK2 kinase activity and decrease GTP hydrolysis rates in cells and tissues, Blocking these activities with small-molecule LRRK2 kinase inhibitors can also provide neuroprotection in certain models of PD, a finding that makes LRRK2 the most promising target for the treatment of Parkinson's disease (PD) disease (Tolosa et al., Nature Reviews in Neurology, Vol.16, 2020, PP.97-10; Paisan-Ruiz et al., J. Parkinson's Disease, Vol.3, 2013, pp.85-103; Guo et al., Experimental Cell Research, Vol.313 (16 ), 2007, pp. 3658-3670; Andrew B. West, Experimental Neurology, Vol. 298, 2017, pp. 236-245). LRRK2 was identified as a gene potentially associated with elevated susceptibility to Crohn's disease and susceptibility to leprosy (Zhang et al., New England J. Med., Vol. 361, 2009, pp. 2609- 2618; Barrett et al, Nature Genetics, Vol. 40, 2008, pp. 955-962); also associated with ankylosing spondylytis (Danoy et al, PLoS Genetics, Vol 6(12), 2010, pp. 1-5) It is associated with amyotrophic lateral sclerosis (Shtilans et al., Amyotrophic lateral Sclerosis, 2011, pp. 1-7).
LRRK2还与以下病症相关:自轻度认知障得到阿兹海默氏症转化(WO2007149798)；L-多巴诱发性运动障碍(Hurley等，Eur.J,Neurosci.，Vol.26，2007，pp.171-177)；与神经母细胞增生和迁移相关联的CNS病症，并且LRRK2的调节可用于缺血性损伤后改良神经效果和神经元损伤(诸如缺血性中风、创伤性脑损伤或脊髓损伤)后刺激CNS官能复原(Milosevic等，Neurodegen.，Vol.4，2009，25；Zhang等，J.Neurosci.Res，Vol.88，2010，pp.3275-3281)。其他疾病：包括糖尿病、肥胖症、运动神经元疾病、癫痫症和一些癌症(Rubinsztein等，Nat.Rev.Drug Discovery，Vol.11，2012，709-730)。癌症如肾癌、乳腺癌、***癌(例如实体肿瘤)、血癌和肺癌以及急性髓性白血病(AML)(WO2011038572)；淋巴瘤和白血病(Ray等，J.Immunolo.，Vol.230，2011，109)；***状肾癌和甲状腺癌(Brendan D Looyenga等，Proc Natl Acad Sci U S A，Vol.108(4)，2011，pp.1439-44)；多发性骨髓瘤(Chapman等，Nature，Vol.471，2011，pp.467-472)。免疫***疾病：包括类风湿性关节炎、全身性红斑性狼疮症、自体免疫溶血性贫血、纯红细胞形成不全、特发性血小板减少性紫癜(ITP)、伊凡氏症候群((Evans syndrome)、血管炎、大疱性皮肤病、I型糖尿病、休格连氏症候群(Sjogren's syndrome)、德维克氏病(Delvic's disease)和炎症性疾病(Nakamura等，DNA Res.，Vol.13(4)，2006，pp.169-183；Engel等，Pharmacol.Rev.，Vol.63，2011，127-156；Homam等，J.Clin.Neuromuscular Disease，Vol.12，2010，pp.91-102)。肺部疾病如慢性阻塞性肺病和特发性肺纤维化(Araya等，Intern.Med.，Vol.52，2013，2295-2303)。作为自噬和吞噬过程的启动子，LRRK2激酶的小分子抑制剂也可用于增加宿主对一系列细胞内细菌感染、寄生虫感染和病毒感染(包括诸如结核病等疾病)的治疗反应(Rubinsztein等，Nat.Rev.，2012，709-730；Araya等，Intern.Med.，Vol.52，2013，95-2303；Gutierrez，Biochemical Society Conference，Leucine rich repeat kinase2:ten years along the road to therapeutic intervention,Henley Business School，UK 12July 2016)、HIV、西尼罗病毒和切昆贡亚病毒(Shoji-Kawata等，Nature，Vol.494，2013，pp.201-206)。也用于其他a-突触核蛋白病(Orenstein等，Nature Neurosci.，Vol.16，2013，394-406)、Tau蛋白病(Li等，Neurodegen.Dis.，Vol.7，2010，pp.265-271)、阿尔茨海默氏病和其他神经变性疾病(Nixon，Nat.Med.，Vol.19，2013，pp.983-97)和戈谢病(Westbroek等，Trends.Mol.Med.，Vol.17，2011，485-493)；特征在于Tau的过磷酸化的tau蛋白病，诸如嗜银颗粒病、皮克氏病(Pick's disease)、皮质基底核退化症、进行性核上麻痹以及与染色体17相关联的遗传性额颞叶型痴呆和帕金森氏症(Jakes R等，Biochemicaet Biophysica Acta，Vol.1739,2005，pp.240-250)；小神经胶质促炎性反应(Moehle等，J.Neuroscience，Vol.32，2012，pp.1602-1611)。LRRK2 is also associated with the following conditions: Alzheimer's transformation from mild cognitive impairment (WO2007149798); L-dopa-induced dyskinesia (Hurley et al., Eur.J, Neurosci., Vol.26, 2007, pp. 171-177); CNS disorders associated with neuroblastoid proliferation and migration, and modulation of LRRK2 may be used to improve neural outcomes and neuronal damage following ischemic injury (such as ischemic stroke, traumatic brain injury or Stimulation of CNS functional recovery after spinal cord injury) (Milosevic et al., Neurodegen., Vol. 4, 2009, 25; Zhang et al., J. Neurosci. Res, Vol. 88, 2010, pp. 3275-3281). Other diseases: including diabetes, obesity, motor neuron disease, epilepsy and some cancers (Rubinsztein et al., Nat. Rev. Drug Discovery, Vol. 11, 2012, 709-730). Cancers such as kidney cancer, breast cancer, prostate cancer (eg solid tumors), blood and lung cancer and acute myeloid leukemia (AML) (WO2011038572); lymphoma and leukemia (Ray et al., J. Immunolo., Vol. 230, 2011, 109); papillary renal and thyroid cancer (Brendan D Looyenga et al., Proc Natl Acad Sci U S A, Vol. 108(4), 2011, pp. 1439-44); multiple myeloma (Chapman et al., Nature, Vol.471, 2011, pp.467-472). Immune system diseases: including rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythropoiesis, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, Vasculitis, bullous skin disease, type I diabetes, Sjogren's syndrome, Delvic's disease, and inflammatory diseases (Nakamura et al., DNA Res., Vol. 13(4) , 2006, pp. 169-183; Engel et al., Pharmacol. Rev., Vol. 63, 2011, 127-156; Homam et al., J. Clin. Neuromuscular Disease, Vol. 12, 2010, pp. 91-102). Lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (Araya et al., Intern. Med., Vol. 52, 2013, 2295-2303). As a promoter of autophagy and phagocytic processes, small molecules of LRRK2 kinase Inhibitors can also be used to increase the host's therapeutic response to a range of intracellular bacterial, parasitic, and viral infections, including diseases such as tuberculosis (Rubinsztein et al., Nat. Rev., 2012, 709-730; Araya et al., Intern .Med., Vol.52, 2013, 95-2303; Gutierrez, Biochemical Society Conference, Leucine rich repeat kinase 2: ten years along the road to therapeutic intervention, Henley Business School, UK 12July 2016), HIV, West Nile virus and Chikungunya virus (Shoji-Kawata et al, Nature, Vol. 494, 2013, pp. 201-206). Also used for other alpha-synucleinopathies (Orenstein et al, Nature Neurosci., Vol. 16, 2013 , 394-406), tauopathies (Li et al., Neurodegen. Dis., Vol. 7, 2010, pp. 265-271), Alzheimer's disease and other neurodegenerative diseases (Nixon, Nat. Med., Vol. 19, 2013, pp. 983-97) and Gaucher disease (Westbroek et al., Trends. Mol. Med., Vol. 17, 2011, 485-493); tauopathy characterized by hyperphosphorylation of Tau, such as argillophilic granulosis, Pick's disease (Pi ck's disease), corticobasal degeneration, progressive supranuclear palsy, and hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (Jakes R et al., Biochemicaet Biophysica Acta, Vol. 1739, 2005, pp. 240-250); microglial pro-inflammatory responses (Moehle et al., J. Neuroscience, Vol. 32, 2012, pp. 1602-1611).
因此，有效调节LRRK2活性的化合物可以提供由LRRK2介导的疾病或病状为神经退化疾病，癌症，炎症性疾病，细菌、病毒感染和其它疾病的治疗。Thus, compounds that effectively modulate LRRK2 activity can provide treatment for diseases or conditions mediated by LRRK2, including neurodegenerative diseases, cancers, inflammatory diseases, bacterial, viral infections and other diseases.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于克服现有技术存在的不足之处而提供一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物。The purpose of the present invention is to overcome the shortcomings of the prior art and provide a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
为实现上述目的，本发明提供了一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物，含有LRRK2抑制剂，所述LRRK2抑制剂包括化学式1表示的化合物、其光学异构体、其前体药物、其盐、其水合物、其溶剂化物、其N-氧化物、其氘化类似物中的至少一种；In order to achieve the above object, the present invention provides a medicine for the treatment or prevention of diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising LRRK2 inhibitor, and the LRRK2 inhibitor includes the compound represented by Chemical formula 1, its optical isomer. , at least one of its prodrugs, its salts, its hydrates, its solvates, its N-oxides, its deuterated analogs;
[化学式1][Chemical formula 1]
Figure PCTCN2021084876-appb-000001
Figure PCTCN2021084876-appb-000001
在化学式1中，L 1、L 2、L 3均独立地为C或N；L 4为C、N、O或S； In Chemical Formula 1, L 1 , L 2 and L 3 are all independently C or N; L 4 is C, N, O or S;
R 1独立地为无取代基或酰胺基， R 1 is independently unsubstituted or amido,
R 2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
Figure PCTCN2021084876-appb-000002
或未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基， R 2 is independently unsubstituted, -H, -NHAr, -CH=CHPh,
Figure PCTCN2021084876-appb-000002
or a 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent,
或者L 3为N，L 1、L 2、R 1和R 2共同形成
Figure PCTCN2021084876-appb-000003
或-ArR bR d，其中，X为卤素； Or L 3 is N, and L 1 , L 2 , R 1 and R 2 form together
Figure PCTCN2021084876-appb-000003
or -ArR b R d , wherein X is halogen;
R 3为无取代基、-H、卤素、C 1-10烃基、或-NHR a； R 3 is unsubstituted, -H, halogen, C 1-10 hydrocarbyl, or -NHR a ;
R 4独立地为-H、-NHAr、-CH＝CHPh、-NHR a、取代或未取代的含有N、O、S中至少一种杂原子的5至8元环杂环基乙烯基、C 1-5直链或支链烷基氨基磺酰基C 6-10芳基氨基、二(C 1-5直链或支链烷基)磷酸基C 6-10芳基氨基、
Figure PCTCN2021084876-appb-000004
未取代或被第二取代基取代的含N、O中至少一种杂原子的5至8元环杂环基、或5至8元环杂环基氨基， R 4 is independently -H, -NHAr, -CH=CHPh, -NHR a , substituted or unsubstituted 5- to 8-membered cyclic heterocyclyl vinyl containing at least one heteroatom of N, O, S, C 1-5 straight-chain or branched-chain alkylaminosulfonyl C 6-10 arylamino, di(C 1-5 straight-chain or branched-chain alkyl) phosphoric acid group C 6-10 arylamino,
Figure PCTCN2021084876-appb-000004
A 5- to 8-membered ring heterocyclyl, or a 5- to 8-membered ring heterocyclylamino group containing at least one heteroatom in N and O, which is unsubstituted or substituted by a second substituent,
R 5独立地为
Figure PCTCN2021084876-appb-000005
R 5 is independently
Figure PCTCN2021084876-appb-000005
或者L 1为N，R 4和R 5共同形成
Figure PCTCN2021084876-appb-000006
Or L 1 is N, R 4 and R 5 together form
Figure PCTCN2021084876-appb-000006
其中，L 5为-O-、-S-、或-NH-， Wherein, L 5 is -O-, -S-, or -NH-,
Y 1为未取代或被第三取代基取代的C 1-10直链或支链烷基， Y 1 is a C 1-10 straight-chain or branched alkyl group that is unsubstituted or substituted by a third substituent,
Y环为苯环、或未取代或被第四取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基；The Y ring is a benzene ring, or a 4- to 8-membered ring heterocycloalkyl or heterocyclic aryl group containing at least one heteroatom in N and O that is unsubstituted or substituted by a fourth substituent;
R 6为无取代基或-H； R 6 is unsubstituted or -H;
R 7为-H、C 1-10烃基、-(CH 2) nOH、-OR c、-O(CH 2) nR a、卤素、或未取代或被第三取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基； R 7 is -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, -OR c , -O(CH 2 ) n R a , halogen, or unsubstituted or substituted by a third substituent containing N, A 4- to 8-membered ring heterocycloalkyl or heteroaryl of at least one heteroatom in O;
R 8、R 9、R 10、R 11均独立地为-H、C 1-10烃基、-(CH 2) nOH、-O(CH 2) nR a、-C(O)OR a、卤素、-CF 3或-OCF 3； R 8 , R 9 , R 10 , R 11 are each independently -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, -O(CH 2 ) n R a , -C(O)OR a , halogen, -CF3 or -OCF3 ;
每个R a均独立地为-H、C 1-10烃基、C 1-10环烃基、芳基、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基； Each R is independently -H, C 1-10 hydrocarbyl, C 1-10 cyclohydrocarbyl, aryl, or unsubstituted or substituted with a fifth substituent containing at least one heteroatom of N, O. to 8-membered ring heterocycloalkyl or heteroaryl;
每个R b均独立地为-H、C 1-10烃基、-O(CH 2) nR a、-NR aR c、或未取代或被第六取代基取代的含N、O中至少一种杂原子的3至8元环杂环基； Each R b is independently at least one of -H, C 1-10 hydrocarbyl, -O(CH 2 ) n R a , -NR a R c , or N, O-containing unsubstituted or substituted with a sixth substituent A heteroatom 3- to 8-membered ring heterocyclyl;
每个R c均独立地为-H、C 1-10烃基、-(CH 2) nOH、芳基、或未取代或被第三取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基； Each R c is independently -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, aryl, or unsubstituted or substituted with a third substituent containing at least one heteroatom of N, O 4- to 8-membered ring heterocycloalkyl or heteroaryl;
每个R d均独立地为-H或-O(CH 2) nR a； each R d is independently -H or -O(CH 2 ) n R a ;
所述第一取代基、第二取代基、第四取代基、第五取代基、第六取代基各自独立地为-OH、卤素、-CN、硝基、-NH 2、C 1-10烃基、取代或未取代的C 3-10环烷基、取代或未取代的含N、O中至少一种杂原子的3至8元环杂环烷基中的至少一种； The first substituent, the second substituent, the fourth substituent, the fifth substituent and the sixth substituent are each independently -OH, halogen, -CN, nitro, -NH 2 , C 1-10 hydrocarbon group , at least one of substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 8-membered ring heterocycloalkyl containing at least one heteroatom in N and O;
每个n均独立地选自0至4任意整数。Each n is independently selected from any integer from 0 to 4.
优选地，所述化学式1表示的化合物的结构式如下所示：Preferably, the structural formula of the compound represented by the chemical formula 1 is as follows:
Figure PCTCN2021084876-appb-000007
Figure PCTCN2021084876-appb-000007
所述R 3为卤素或C 1-10烃基；所述R 4为C 1-5直链或支链烷基氨基磺酰基C 6-10芳基氨基、二(C 1-5直链或支链烷基)磷酸基C 6-10芳基氨基、
Figure PCTCN2021084876-appb-000008
或未取代或被第二取代基取代的含N、O中至少一种杂原子的5至8元环杂环基；所述R 7为
Figure PCTCN2021084876-appb-000009
R b为C 1-10烃基、-NR aR c、或被C 1-10烃基取代的含N、O中至少一种杂原子的3至8元环杂环基，R a为C 1-10烃基，R c为-(CH 2) nOH；所述R 10、R 11均独立地为-H、-O(CH2) nR a、C 1-10烃基或卤素。 Described R 3 is halogen or C 1-10 hydrocarbon group; Described R 4 is C 1-5 straight chain or branched chain alkylaminosulfonyl C 6-10 arylamino, di(C 1-5 straight chain or branched Chain alkyl) phosphate C 6-10 arylamino,
Figure PCTCN2021084876-appb-000008
A 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, either unsubstituted or substituted by a second substituent; the R 7 is
Figure PCTCN2021084876-appb-000009
R b is a C 1-10 hydrocarbon group, -NR a R c , or a 3- to 8-membered ring heterocyclic group containing at least one heteroatom of N and O substituted by a C 1-10 hydrocarbon group, and R a is C 1- 10 hydrocarbon group, R c is -(CH 2 ) n OH; the R 10 and R 11 are independently -H, -O(CH2) n R a , C 1-10 hydrocarbon group or halogen.
进一步优选地，所述R 3为-F、-Cl或-CH 3；所述R 4为
Figure PCTCN2021084876-appb-000010
Figure PCTCN2021084876-appb-000011
所述R 7为
Figure PCTCN2021084876-appb-000012
所述R 10、R 11均独立地为-H、-OCH 3、-CH 3或-F。 Further preferably, the R 3 is -F, -Cl or -CH 3; the R 4 is
Figure PCTCN2021084876-appb-000010
Figure PCTCN2021084876-appb-000011
The R7 is
Figure PCTCN2021084876-appb-000012
The R 10 and R 11 are independently -H, -OCH 3 , -CH 3 or -F.
优选地，所述化学式1表示的化合物的结构式如下所示：Preferably, the structural formula of the compound represented by the chemical formula 1 is as follows:
Figure PCTCN2021084876-appb-000013
Figure PCTCN2021084876-appb-000013
所述L 4为N、S或O；所述R 5为
Figure PCTCN2021084876-appb-000014
或被-O(CH 2) nR a、卤素中至少一种取 代的苯基；R b为-O(CH 2) nR a；R a为-H、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基；R d为-H或-O(CH 2) nR a。 The L 4 is N, S or O; the R 5 is
Figure PCTCN2021084876-appb-000014
Or phenyl substituted by at least one of -O(CH 2 ) n R a and halogen; R b is -O(CH 2 ) n R a ; R a is -H, or unsubstituted or by the fifth substituent Substituted 5- to 8-membered cyclic heterocycloalkyl or heterocyclic aryl containing at least one heteroatom in N and O; R d is -H or -O(CH 2 ) n R a .
进一步优选地，所述L 4为N、S或O；所述R 5为
Figure PCTCN2021084876-appb-000015
所述R b为
Figure PCTCN2021084876-appb-000016
R d为-H或-OCH 3。 Further preferably, the L 4 is N, S or O; the R 5 is
Figure PCTCN2021084876-appb-000015
The R b is
Figure PCTCN2021084876-appb-000016
R d is -H or -OCH 3 .
优选地，所述化学式1表示的化合物的结构式如下所示：Preferably, the structural formula of the compound represented by the chemical formula 1 is as follows:
Figure PCTCN2021084876-appb-000017
Figure PCTCN2021084876-appb-000017
所述R 4为被C 1-10烃基取代的5至8元环杂环基氨基；所述L 4为N、S或O；所述R 7为O(CH 2) nR a，R a为芳基、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基。 The R 4 is a 5- to 8-membered ring heterocyclylamino substituted with a C 1-10 hydrocarbon group; the L 4 is N, S or O; the R 7 is O(CH 2 ) n R a , R a is an aryl group, or a 5- to 8-membered ring heterocycloalkyl or heterocyclic aryl group containing at least one heteroatom of N and O which is unsubstituted or substituted by a fifth substituent.
优选地，所述化学式1表示的化合物的结构式如下所示：Preferably, the structural formula of the compound represented by the chemical formula 1 is as follows:
Figure PCTCN2021084876-appb-000018
Figure PCTCN2021084876-appb-000018
所述R 2为未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基；所述L 4为N；所述R 4为-CH＝CHPh、或取代或未取代的含有N、O、S中至少一种杂原子的4至8元环杂环基乙烯基；所述R 5为
Figure PCTCN2021084876-appb-000019
The R 2 is a 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent; the L 4 is N; the R 4 is -CH= CHPh, or a substituted or unsubstituted 4- to 8-membered ring heterocyclyl vinyl containing at least one heteroatom in N, O, and S; the R 5 is
Figure PCTCN2021084876-appb-000019
优选地，所述化学式1表示的化合物的结构式如下所示：Preferably, the structural formula of the compound represented by the chemical formula 1 is as follows:
Figure PCTCN2021084876-appb-000020
Figure PCTCN2021084876-appb-000020
所述R 1为酰胺基；所述R 3为C 1-10烃基；所述R 4为5至8元环杂环基氨基；所述R 7为
Figure PCTCN2021084876-appb-000021
所述R b为未取代或被第六取代基取代的含N、O中至少一种杂原子的3至8元环杂环基；所述R 9为-O(CH 2) nR a。 The R 1 is an amide group; the R 3 is a C 1-10 hydrocarbon group; the R 4 is a 5- to 8-membered ring heterocyclylamino; the R 7 is
Figure PCTCN2021084876-appb-000021
The R b is a 3- to 8-membered ring heterocyclic group containing at least one heteroatom among N and O, which is unsubstituted or substituted by a sixth substituent; the R 9 is -O(CH 2 ) n R a .
优选地，所述化学式1表示的化合物的结构式如下所示：Preferably, the structural formula of the compound represented by the chemical formula 1 is as follows:
Figure PCTCN2021084876-appb-000022
Figure PCTCN2021084876-appb-000022
优选地，所述化学式1表示的化合物为以下化合物中的任意一种：Preferably, the compound represented by the chemical formula 1 is any one of the following compounds:
(1)(1S，2S，3R，4R)-3-[[5-氟-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]双环[2.2.1]庚-5-烯-2-甲酰胺；(1) (1S,2S,3R,4R)-3-[[5-Fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidine-4- base]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide;
(2)N-叔丁基-3-[[5-甲基-2-[4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]苯磺酰胺；(2) N-tert-butyl-3-[[5-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]benzenesulfonamide;
(3)2-[[1-[2-氟-4-[[5-甲基-4-(1-丙-2-基吡唑-4-基)嘧啶-2-基]氨基]苯基]哌啶-4-基]-甲基氨基]乙醇；(3) 2-[[1-[2-Fluoro-4-[[5-methyl-4-(1-prop-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]phenyl ]piperidin-4-yl]-methylamino]ethanol;
(4)5-氯-4-N-(2-二甲基磷酰苯基)-2-N-[2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基]嘧啶-2,4-二胺；(4) 5-Chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl] ) piperidin-1-yl]phenyl]pyrimidine-2,4-diamine;
(5)1-(4-甲基苯基)-3-[5-[7-(3-吗啉-4-基丙氧基)喹唑啉-4-基]磺酰基-1,3,4-噻二唑-2-基]脲；(5) 1-(4-Methylphenyl)-3-[5-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]sulfonyl-1,3, 4-thiadiazol-2-yl]urea;
(6)N-(2-氯-5-甲氧基苯基)-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹唑啉-4-胺；(6) N-(2-Chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline-4- amine;
(7)8-溴-2-[(1-甲基哌啶-4-基)氨基]-4-(4-苯氧基苯胺)-6H-吡啶[4,3-d]嘧啶-5-酮；(7) 8-Bromo-2-[(1-methylpiperidin-4-yl)amino]-4-(4-phenoxyaniline)-6H-pyridine[4,3-d]pyrimidine-5- ketone;
(8)6-(4-甲基哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)-2-[((E)-2-苯基乙烯基]嘧啶-4-胺；(8) 6-(4-Methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[((E)-2-phenylvinyl ] pyrimidin-4-amine;
(9)6-乙基-3-[3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯胺基]-5-(氧烷-4-基氨基)吡嗪-2-羧酰胺；(9) 6-Ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxane -4-ylamino)pyrazine-2-carboxamide;
(10)(16E)-11-(2-吡咯烷-1-乙氧基)-14,19-二恶英-5,7,27-三氮四环[19.3.1.12,6.18,12]庚-1(24)，2(27)，3,5,8(26)，9,11,16,21(25)，22-癸烯。(10)(16E)-11-(2-Pyrrolidine-1-ethoxy)-14,19-dioxin-5,7,27-triaztetracyclo[19.3.1.12,6.18,12]heptane -1(24), 2(27), 3,5,8(26), 9,11,16,21(25), 22-decene.
优选地，所述疾病包括神经退化性疾病、癌前病状和癌症、自身免疫性病、炎症中的至少一种。Preferably, the disease includes at least one of neurodegenerative disease, precancerous conditions and cancer, autoimmune disease, inflammation.
优选地，所述疾病包括阿兹海默氏症、L-多巴诱发性运动障得、帕金森氏病、增强认知记忆、中枢神经***病症、痴呆症、肌萎缩侧索硬化症、肾癌、乳腺癌、***癌、血癌、***状癌、肺癌、急性骨髓性白血病、多发性骨髓瘤、麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎中的至少一种。Preferably, the disease comprises Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, enhanced cognitive memory, central nervous system disorders, dementia, amyotrophic lateral sclerosis, kidney disease Cancer, Breast Cancer, Prostate Cancer, Blood Cancer, Papillary Cancer, Lung Cancer, Acute Myeloid Leukemia, Multiple Myeloma, Leprosy, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Muscular Atrophic Lateral At least one of sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
另外需要说明的是，以上烃基均包括烷基以及不饱和烃基，如烯基；以上卤素均包括F、Cl、Br等；Ar表示芳基，如苯基、萘基等；Ph表示苯基；未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基是指构成5至8元环的原子除碳原子外，还含有N、O中至少一种杂原子，且该5至8元环未被取代或被第一取代基取代，其他类似描述所表达的意思同理；二(C 1-5直链或支链烷基)磷酸基C 6-10芳基氨基中，磷酸基上的取代基烷基可以相同，也可以不同，如
Figure PCTCN2021084876-appb-000023
等；被C 1-10烃基取代的5至8元环杂环基氨基指的是5至8元环杂环基氨基中的5至8元环杂环基被C 1-10烃基取代；R 2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
Figure PCTCN2021084876-appb-000024
或未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基，指的是R 2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
Figure PCTCN2021084876-appb-000025
无取代基的含N、O中至少一种杂原子的5至8元环杂环基、或者被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基，其他类似描述同理。 In addition, it should be noted that the above hydrocarbon groups include alkyl groups and unsaturated hydrocarbon groups, such as alkenyl; the above halogens include F, Cl, Br, etc.; Ar represents aryl groups, such as phenyl, naphthyl, etc.; Ph represents phenyl; The 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent, means that the atoms constituting the 5- to 8-membered ring also contain N, O in addition to carbon atoms. At least one heteroatom, and the 5- to 8-membered ring is unsubstituted or substituted by the first substituent, and the meanings expressed in other similar descriptions are the same; two (C 1-5 linear or branched chain alkyl) phosphate group In the C 6-10 arylamino group, the substituent alkyl groups on the phosphoric acid group may be the same or different, such as
Figure PCTCN2021084876-appb-000023
etc.; 5- to 8-membered ring heterocyclylamino substituted by C 1-10 hydrocarbyl means that the 5- to 8-membered ring heterocyclyl in the 5- to 8-membered ring heterocyclylamino is substituted by C 1-10 hydrocarbyl; R 2 is independently unsubstituted, -H, -NHAr, -CH=CHPh,
Figure PCTCN2021084876-appb-000024
A 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N, O, either unsubstituted or substituted by the first substituent, means that R 2 is independently unsubstituted, -H, -NHAr, - CH=CHPh,
Figure PCTCN2021084876-appb-000025
Unsubstituted 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, or 5- to 8-membered ring heterocyclic ring containing at least one heteroatom in N and O substituted by the first substituent base, and other similar descriptions are the same.
相比现有技术，本发明的有益效果在于：本发明药物包含特定的LRRK2抑制剂，能有效治疗或 预防与LRRK2激酶或其任意突变体(如LRRK2突变体G2019S)活性相关疾病，如可用于预防和治疗神经变性疾病，诸如帕金森病和其它雷维小体型疾病，包括弥散性雷维小体疾病、阿尔茨海默氏病的雷维小体变型、复合的帕金森病和阿尔茨海默氏病、多***萎缩和痴呆伴雷维小体等；也可用于预防和治疗癌症，诸如肾癌、乳腺癌、***癌、血癌、***状瘤、肺癌、急性骨髓性白血病、多发性骨髓瘤、黑素瘤等；还可用于预防和治疗自身免疫疾病和炎症，诸如麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎。Compared with the prior art, the beneficial effect of the present invention lies in that: the medicine of the present invention contains a specific LRRK2 inhibitor, which can effectively treat or prevent diseases related to the activity of LRRK2 kinase or any of its mutants (such as LRRK2 mutant G2019S). Prevention and treatment of neurodegenerative diseases such as Parkinson's disease and other Lewy body diseases, including diffuse Lewy body disease, Lewy body variant of Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease Merger's disease, multiple system atrophy and dementia with Lewy bodies, etc.; can also be used to prevent and treat cancers such as kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myeloid leukemia, multiple myeloid tumor, melanoma, etc.; also used to prevent and treat autoimmune diseases and inflammations such as leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid joints inflammation or ankylosing spondylitis.
附图说明Description of drawings
图1是实施例1化合物通过实验实施例11测定的LRRK2WT和LRRK2G2019S的激酶生物活性Kd曲线；Fig. 1 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 1 by Experimental Example 11;
图2是实施例2化合物通过实验实施例11测定的LRRK2WT和LRRK2G2019S的激酶生物活性Kd曲线；Figure 2 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 2 through Experimental Example 11;
图3是实施例4化合物通过实验实施例11测定的LRRK2WT和LRRK2G2019S的激酶生物活性Kd曲线；Figure 3 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 4 by Experimental Example 11;
图4是实施例7化合物通过实验实施例11测定的LRRK2WT和LRRK2G2019S的激酶生物活性Kd曲线；Figure 4 is the kinase biological activity Kd curve of LRRK2WT and LRRK2G2019S determined by the compound of Example 7 by Experimental Example 11;
图5是实施例9化合物通过实验实施例11测定的LRRK2WT和LRRK2G2019S的激酶生物活性Kd曲线。5 is a Kd curve of the kinase bioactivity of LRRK2WT and LRRK2G2019S determined by Experimental Example 11 for the compound of Example 9. FIG.
具体实施方式detailed description
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below with reference to specific embodiments.
本发明涉及一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物，含有LRRK2抑制剂，该LRRK2抑制剂包括化学式1表示的化合物、其光学异构体、其前体药物、其药学上可接受的盐、其水合物、其溶剂化物、其N-氧化物、其氘化类似物中的至少一种。The present invention relates to a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising an LRRK2 inhibitor, the LRRK2 inhibitor comprising a compound represented by Chemical Formula 1, its optical isomer, its prodrug, its At least one of pharmaceutically acceptable salts, hydrates, solvates, N-oxides, deuterated analogs thereof.
根据本发明，化学式1表示的化合物可用于预防和治疗LRRK2或异常LRRK2突变引起的相关的病症，例如阿兹海默氏症、L多巴诱发性运动障碍、帕金森氏病、痴呆症、肌肉萎缩性侧索硬化、肾癌、乳腺癌、***癌、血癌、***状瘤、肺癌、急性骨髓性白血病、多发性骨髓瘤、麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎、强直性脊椎炎等。According to the present invention, the compound represented by Chemical Formula 1 can be used for the prevention and treatment of LRRK2 or related disorders caused by abnormal LRRK2 mutations, such as Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, dementia, muscle Atrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colon inflammation, amyotrophic lateral sclerosis, rheumatoid arthritis, ankylosing spondylitis, etc.
根据本发明，化学式1表示的化合物可用于预防和治疗至少部分由LRRK2或异常LRRK2突变介导的疾病或病状为神经退化疾病，例如，中枢神经***(CNS)病症(诸如帕金森氏病(PD)、阿兹海默氏病(AD))、痴呆症(包括路易体性痴呆和血管性痴呆)、肌肉萎缩性侧索硬化(ALS)、年龄相关记忆功能障得、轻度认知障碍(例如，包括自轻度认知障碍转变至阿兹海默氏症)、嗜银颗粒病、溶嗨体病(例如，C型尼曼一皮克病、高歇病)、皮质基底核退化症、进行性核上麻痹、与染色体17相关联的遗传性额题叶型痴呆和帕金森氏症(FTDP-17)、与药物成瘾相关联的停药症状/复发、L-多巴诱发性运动障得、亨廷顿氏病(HD)和HIV关联性痴呆症(HAD)。病症为包括(但不限于)大脑、心脏、肾脏和肝脏的器官的缺血性疾病。According to the present invention, the compound represented by Chemical Formula 1 can be used for the prevention and treatment of diseases or conditions mediated at least in part by LRRK2 or abnormal LRRK2 mutations as neurodegenerative diseases, for example, central nervous system (CNS) disorders such as Parkinson's disease (PD). ), Alzheimer's disease (AD)), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age-related memory impairment, mild cognitive impairment ( For example, including transition from mild cognitive impairment to Alzheimer's disease), argillophilic granulosa disease, lysosome disease (eg, Niemann-Pick type C, Gaucher disease), corticobasal degeneration , progressive supranuclear palsy, hereditary frontal dementia and Parkinson's disease (FTDP-17) associated with chromosome 17, withdrawal symptoms/relapse associated with drug addiction, L-dopa-induced Dyskinesia, Huntington's Disease (HD) and HIV-Associated Dementia (HAD). The disorder is an ischemic disease of organs including, but not limited to, the brain, heart, kidneys, and liver.
在一些实施方案中，化学式1表示的化合物用于治疗至少部分由LRRK2或异常LRRK2突变介导的疾病或病状为癌症，如甲状腺癌、肾癌(包括***状肾癌)、乳腺癌、肺癌、血癌和***癌(例如实体肿瘤)、白血病(包括急性骨髓性白血病(AML)或淋巴瘤。In some embodiments, the compound represented by Chemical Formula 1 for the treatment of a disease or condition mediated at least in part by LRRK2 or aberrant LRRK2 mutation is cancer, such as thyroid cancer, kidney cancer (including papillary kidney cancer), breast cancer, lung cancer, Blood and prostate cancers (eg solid tumors), leukemias (including acute myeloid leukemia (AML) or lymphomas.
在另一些实施方案中，化学式1表示的化合物用于治疗至少部分由LRRK2或异常LRRK2突变介导的疾病或病状为炎症性病症。炎症性病症为炎症性肠疾病，诸如克罗恩氏病或溃疡性结肠炎(两者一般一起称为炎症性肠病)。炎症性疾病为麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎。In other embodiments, the compound of Formula 1 for use in the treatment of a disease or condition mediated at least in part by LRRK2 or aberrant LRRK2 mutation is an inflammatory disorder. Inflammatory disorders are inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis (the two are commonly referred to together as inflammatory bowel disease). The inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.
在其它实施方案中，化学式1表示的化合物用于治疗至少部分由LRRK2或异常LRRK2突变介导 的其它疾病：多发性硬化症、全身性红斑狼疮症、自体免疫溶血性贫血、纯红细胞形成不全、特发性血小板减少性紫癜(ITP)、伊凡氏症候群、血管炎、大疱性皮肤病、1型糖尿病、休格连氏症候群、德维克氏病和炎症性肌病。In other embodiments, the compound represented by Chemical Formula 1 is used to treat other diseases mediated at least in part by LRRK2 or aberrant LRRK2 mutations: multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythropoiesis, Idiopathic thrombocytopenic purpura (ITP), Ivan's syndrome, vasculitis, bullous skin disease, type 1 diabetes, Sugarcan's syndrome, Dewk's disease, and inflammatory myopathy.
根据本发明，化学式1表示的化合物可以以其药学上可接受的盐的形式使用。这里，药学上可接受的盐可为药学上可接受的游离酸形成的酸加成盐。酸加成盐可获自无机酸(例如盐酸、硝酸、磷酸、硫酸、溴酸、氢碘酸、亚硝酸、亚磷酸等)、无毒有机酸(例如脂肪族单一和二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯和链烷酸酯、芳香酸、脂肪族和芳香族磺酸等)或有机酸(例如乙酸、苯甲酸、柠檬酸、乳酸、马来酸葡萄糖酸、甲磺酸、4-甲苯磺酸、酒石酸、富马酸等)。酸加成盐可获自药学上无毒的盐，包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐(decanoate)、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐(caprate)、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二油酸盐、己烷-1,6油酸盐、苯甲酸盐、氯苯甲酸盐、苯甲酸甲酯、二硝基苯甲酸盐、羟苤酸盐、甲苯基苯甲酸盐邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐，β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、禁-2-磺酸盐、扁桃酸盐等。According to the present invention, the compound represented by Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt thereof. Here, the pharmaceutically acceptable salt may be an acid addition salt formed from a pharmaceutically acceptable free acid. Acid addition salts can be obtained from inorganic acids (such as hydrochloric, nitric, phosphoric, sulfuric, bromic, hydroiodic, nitrous, phosphorous, etc.), non-toxic organic acids (such as aliphatic mono- and dicarboxylates, benzene alkanoates, hydroxyalkanoates and alkanoates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.) or organic acids (e.g. acetic acid, benzoic acid, citric acid, lactic acid, dextrose maleate acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.). Acid addition salts can be obtained from pharmaceutically non-toxic salts including sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate , metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyric acid Salt, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate , Butyne-1,4-Dioleate, Hexane-1,6oleate, Benzoate, Chlorobenzoate, Methyl Benzoate, Dinitrobenzoate, Carboxylic Acid salt, tolylbenzoate phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, Beta-Hydroxybutyrate, Glycolate, Maleate, Tartrate, Mesylate, Propanesulfonate, Naphthalene -1-sulfonate, ban-2-sulfonate, mandelate, etc.
根据本发明，酸加成盐可以通过常规方法制备，例如，通过将化学式1表示的化合物或其衍生物溶解在有机溶剂如甲醇、乙醇、丙酮、二氯甲烷或乙腈中，并向其中加入有机酸或无机酸以获得沉淀物，然后将沉淀物过滤并干燥，或者将溶剂和过量的酸进行真空蒸馏、干燥然后在有机溶剂存在下结晶。According to the present invention, the acid addition salt can be prepared by a conventional method, for example, by dissolving the compound represented by Chemical Formula 1 or a derivative thereof in an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile, and adding an organic solvent thereto acid or mineral acid to obtain a precipitate, which is then filtered and dried, or the solvent and excess acid are subjected to vacuum distillation, drying and then crystallization in the presence of an organic solvent.
另外，根据本发明，化学式1表示的化合物可以以其药学上可接受的金属盐的形式制备和使用。具体地，碱金属或碱土金属盐可通过以下方法获得：例如将化合物溶解在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中，过滤未溶解的化合物盐，并将滤液蒸发至干。这里，钠盐、钾盐或钙盐作为金属盐是药学上合适的。此外，相应的盐可通过使碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应来获得。In addition, according to the present invention, the compound represented by Chemical Formula 1 can be prepared and used in the form of a pharmaceutically acceptable metal salt thereof. Specifically, the alkali metal or alkaline earth metal salt can be obtained by, for example, dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating the filtrate to dryness. Here, sodium, potassium or calcium salts are pharmaceutically suitable as metal salts. Furthermore, the corresponding salts can be obtained by reacting alkali metal or alkaline earth metal salts with suitable silver salts such as silver nitrate.
根据本发明，化学式1表示的化合物可以以其药学上可接受的氘化类似物、前药、立体异构体、其盐、其水合物、其溶剂化物、其N-氧化物中的至少一种的形式制备和使用。According to the present invention, the compound represented by Chemical Formula 1 can be at least one of its pharmaceutically acceptable deuterated analogs, prodrugs, stereoisomers, its salts, its hydrates, its solvates, and its N-oxides preparation and use in the form of species.
在根据本发明的药物中，化学式1表示的化合物、其光学异构体或其药学上可接受的盐可在临床给药时以单一剂量或多剂量形式施用。本发明药物可利用各种方法施用，所述方法包括例如经直肠、肺部、口服、口腔、鼻内和经皮途径。在某些实施方案中，药物可通过动脉内注射、静脉内、腹膜内、经肠、非经肠、肌肉内、皮下、经口、局部或以吸入剂形式施用。In the medicament according to the present invention, the compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be administered in a single dose or multiple doses at the time of clinical administration. The medicaments of the present invention can be administered using a variety of methods including, for example, rectal, pulmonary, oral, buccal, intranasal, and transdermal routes. In certain embodiments, the drug may be administered by intraarterial injection, intravenous, intraperitoneal, enteral, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation form.
本发明药物制剂制备时可使用常用的稀释剂或赋形剂，如填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等。Common diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., can be used in the preparation of the pharmaceutical preparation of the present invention.
本发明药物用作口服给药制剂的实例包括片剂、丸剂、硬/软胶囊、液体、悬浮液、乳液、糖浆、颗粒、酏剂、锭剂等。除了活性成分外，这些制剂可含有稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素和/或甘氨酸)或润滑剂(如二氧化硅、滑石、硬脂酸及其镁盐或钙盐和/或聚乙二醇)。片剂可含有粘合剂，例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和聚乙烯叱咯烷等，并且可任选地含有崩解剂(例如淀粉、琼脂、海藻酸或其钠盐、或沸腾混合物)吸收剂、着色剂、调味剂、甜味剂等。Examples of the medicament of the present invention as preparations for oral administration include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, lozenges and the like. In addition to the active ingredient, these formulations may contain diluents (eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) or lubricants (eg silicon dioxide, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyethylene collidine, and the like, and may optionally contain disintegrating agents such as starch , agar, alginic acid or its sodium salt, or boiling mixture) absorbent, coloring agent, flavoring agent, sweetening agent, etc.
本发明药物的一种施用模式为非经肠，例如通过注射，可将其制成水性或油性悬浮液或乳液，含有芝麻油、玉米油、棉籽油、花生油中的一种以及酏剂、甘露糖醇和右旋糖，或无菌水溶液和类似医药媒剂。One mode of administration of the medicament of the present invention is parenteral, such as by injection, which can be made into an aqueous or oily suspension or emulsion, containing one of sesame oil, corn oil, cottonseed oil, peanut oil and an elixir, mannose alcohol and dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.
本发明药物以吸入或吹入方式使用时，可包括溶液和悬浮液的药学上可接受的水性溶剂或有机溶 剂或其混合物以及散剂。液体或固体药物可含有如本文中所描述的适合的药学可接受的赋形剂。在一些实施方案中，针对局部或全身性作用，通过经口或经鼻呼吸道途径施用药物。在其它实施方案中，药学上可接受的溶剂中的药物可通过使用惰性气体进行雾化。雾化溶液可直接自雾化装置吸入或雾化装置可连接到面罩托或间歇性正压呼吸机。可以是适合递送装置施用(优选经口或经鼻)的溶液、悬浮液或粉末组合物。When the medicament of the present invention is used by inhalation or insufflation, it may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid pharmaceuticals may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the drug is administered by oral or nasal respiratory route for local or systemic effect. In other embodiments, the drug in a pharmaceutically acceptable solvent can be nebulized by use of an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a mask holder or intermittent positive pressure breathing machine. It may be a solution, suspension or powder composition suitable for administration by a delivery device, preferably oral or nasal.
此外，本发明涉及一种用于预防或治疗LRRK2或异常LRRK2突变引起的相关病症的药物试剂盒，试剂盒包括化学式1表示的化合物或其药学上可接受的盐、氘化类似物、互变异构体、立体异构体、立体异构体的混合物、前药或氘化类似物，和使用所述化合物治疗适应症(包括本文所述的疾病或病状)的标签和/或说明。包括处于适合容器中的本文中所描述的化合物或其药学上可接受的盐、氘化类似物、互变异构体、立体异构体、立体异构体混合物、前药或氘化类似物。容器可为小瓶、广口瓶、安瓿、预装载注射器和静脉内袋。In addition, the present invention relates to a pharmaceutical kit for preventing or treating LRRK2 or related disorders caused by abnormal LRRK2 mutation, the kit comprises a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt, deuterated analog, interconversion Isomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, and labels and/or instructions for use of the compounds for therapeutic indications, including diseases or conditions described herein. Include a compound described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof in a suitable container . The containers can be vials, jars, ampoules, prefilled syringes, and intravenous bags.
此外，在本公开的另一方面中，化学式1表示的化合物可与其它药剂组合施用，所述药剂包括(但不限于)：为细胞凋亡抑制剂的化合物、PARP聚(ADP-核糖)聚合酶抑制剂、Src抑制剂、用于治疗血管疾病、高血压、高胆固醇血症和ⅡⅠ型糖尿病的药剂、抗炎症剂药剂、抗栓塞剂、纤维蛋溶解剂、抗血小板药剂、降脂剂、直接凝血酶抑制剂、糖蛋白IIb/IIla受体抑制剂、钙离子通道阻断剂、B肾上腺素激导性受体阻断剂、环加氧酶(例如，COX-1和COX-2)抑制剂、血管紧张素***抑制剂(例如，血管收缩素转化酶(ACE)抑制剂)、肾素抑制剂，和/或与细胞粘着分子结合并抑制白血细胞与此类分子连接的能力的药剂(例如，多肽抗体、多克隆抗体和单克隆抗体)。另外，本公开的化合物可与具有治疗神经退化疾病的活性的额外药剂组合施用。举例来说，在一些实施方案中，化合物可与适用于治疗帕金森氏病的一或多种额外治疗剂组合施用。在一些实施方案中，额外治疗剂为L-多巴(例如，sinemet CR)、多巴胺激导性促效剂(例如，罗宾奈索(Ropinerol)或普拉克索(Pramipexole))、儿茶酚-0-甲基转移酶(COMT)抑制剂(例如恩他卡朋(Entacapone))、L-单胺氧化酵素(MAO)抑制剂(例如，司来吉兰(selegiline)或雷沙吉兰(rasagiline))或增加多巴胺释放的药剂(例如，唑尼沙胺(Zonisamide))。In addition, in another aspect of the present disclosure, the compound represented by Chemical Formula 1 may be administered in combination with other agents including (but not limited to): compounds that are apoptosis inhibitors, PARP poly(ADP-ribose) polymerization Enzyme inhibitors, Src inhibitors, agents for the treatment of vascular diseases, hypertension, hypercholesterolemia and type II diabetes, anti-inflammatory agents, anti-embolic agents, fibrinolytic agents, anti-platelet agents, lipid-lowering agents, Direct thrombin inhibitors, glycoprotein IIb/IIla receptor inhibitors, calcium channel blockers, beta-adrenergic receptor blockers, cyclooxygenases (eg, COX-1 and COX-2) Inhibitors, angiotensin system inhibitors (eg, angiotensin-converting enzyme (ACE) inhibitors), renin inhibitors, and/or agents that bind to cell adhesion molecules and inhibit the ability of white blood cells to attach to such molecules (eg, polypeptide antibodies, polyclonal antibodies, and monoclonal antibodies). Additionally, the compounds of the present disclosure can be administered in combination with additional agents that are active in the treatment of neurodegenerative diseases. For example, in some embodiments, the compounds may be administered in combination with one or more additional therapeutic agents useful in the treatment of Parkinson's disease. In some embodiments, the additional therapeutic agent is L-dopa (eg, sinemet CR), a dopamine agonist (eg, Ropinerol or Pramipexole), catechol -O-methyltransferase (COMT) inhibitors (eg, Entacapone), L-monoamine oxidase (MAO) inhibitors (eg, selegiline or rasagiline ( rasagiline) or an agent that increases dopamine release (eg, Zonisamide).
实施例1Example 1
参考专利WO2006055561A3制备(1S，2S，3R，4R)-3-[[5-氟-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]双环[2.2.1]庚-5-烯-2-甲酰胺，其结构式如下：Preparation of (1S,2S,3R,4R)-3-[[5-fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidine-4 with reference to patent WO2006055561A3 -yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide, its structural formula is as follows:
Figure PCTCN2021084876-appb-000026
Figure PCTCN2021084876-appb-000026
实施例2Example 2
参考专利WO2016022460A1制备N-叔丁基-3-[[5-甲基-2-[4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]苯磺酰胺，其结构式如下：Preparation of N-tert-butyl-3-[[5-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]benzenesulfonamide with reference to patent WO2016022460A1 , and its structure is as follows:
Figure PCTCN2021084876-appb-000027
Figure PCTCN2021084876-appb-000027
实施例3Example 3
参考药物化学杂志(Journal of Medicinal Chemistry,(2019),62(22),10305-10320)制备2-[[1-[2-氟-4-[[5-甲基-4-(1-丙-2-基吡唑-4-基)嘧啶-2-基]氨基]苯基]哌啶-4-基]-甲基氨基]乙醇，其结构式如下：2-[[1-[2-Fluoro-4-[[5-methyl-4-(1-propane was prepared with reference to Journal of Medicinal Chemistry, (2019), 62(22), 10305-10320) -2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]phenyl]piperidin-4-yl]-methylamino]ethanol, its structural formula is as follows:
Figure PCTCN2021084876-appb-000028
Figure PCTCN2021084876-appb-000028
实施例4Example 4
参考专利WO2009143389制备5-氯-4-N-(2-二甲基磷酰苯基)-2-N-[2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基]嘧啶-2,4-二胺，其结构式如下：Reference patent WO2009143389 for the preparation of 5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazine-1- base) piperidin-1-yl]phenyl]pyrimidine-2,4-diamine, its structural formula is as follows:
Figure PCTCN2021084876-appb-000029
Figure PCTCN2021084876-appb-000029
实施例5Example 5
参考药物化学杂志(Journal of Medicinal Chemistry,(2012),55(8),3852-3866)制备1-(4-甲基苯基)-3-[5-[7-(3-吗啉-4-基丙氧基)喹唑啉-4-基]磺酰基-1,3,4-噻二唑-2-基]脲，其结构式如下：Refer to the Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, (2012), 55(8), 3852-3866) for the preparation of 1-(4-methylphenyl)-3-[5-[7-(3-morpholine-4] -ylpropoxy)quinazolin-4-yl]sulfonyl-1,3,4-thiadiazol-2-yl]urea, its structural formula is as follows:
Figure PCTCN2021084876-appb-000030
Figure PCTCN2021084876-appb-000030
实施例6Example 6
参考专利WO02092577A1制备N-(2-氯-5-甲氧基苯基)-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹唑啉-4-胺，其结构式如下：Preparation of N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline-4 with reference to patent WO02092577A1 -amines, the structural formula of which is as follows:
Figure PCTCN2021084876-appb-000031
Figure PCTCN2021084876-appb-000031
实施例7Example 7
参考专利WO 2013142382A1制备8-溴-2-[(1-甲基哌啶-4-基)氨基]-4-(4-苯氧基苯胺)-6H-吡啶[4,3-d]嘧啶-5-酮，其结构式如下：8-Bromo-2-[(1-methylpiperidin-4-yl)amino]-4-(4-phenoxyaniline)-6H-pyridine[4,3-d]pyrimidine- 5-ketone, its structural formula is as follows:
Figure PCTCN2021084876-appb-000032
Figure PCTCN2021084876-appb-000032
实施例8Example 8
参考专利WO2007041358A2制备6-(4-甲基哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)-2-[((E)-2-苯基乙烯基]嘧啶-4-胺，其结构式如下：Preparation of 6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[((E)-2-phenylethylene with reference to patent WO2007041358A2 base]pyrimidin-4-amine, its structural formula is as follows:
Figure PCTCN2021084876-appb-000033
Figure PCTCN2021084876-appb-000033
实施例9Example 9
参考专利WO2010128659A1制备6-乙基-3-[3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯胺基]-5-(氧烷-4-基氨基)吡嗪-2-羧酰胺，其结构式如下：Reference patent WO2010128659A1 to prepare 6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxygen Alkyl-4-ylamino)pyrazine-2-carboxamide, its structural formula is as follows:
Figure PCTCN2021084876-appb-000034
Figure PCTCN2021084876-appb-000034
实施例10Example 10
参考专利WO2007058627A1制备(16E)-11-(2-吡咯烷-1-乙氧基)-14,19-二恶英-5,7,27-三氮四环[19.3.1.12,6.18,12]庚-1(24)，2(27)，3,5,8(26)，9,11,16,21(25)，22-癸烯，其结构式如下：Preparation of (16E)-11-(2-pyrrolidine-1-ethoxy)-14,19-dioxin-5,7,27-triaztetracyclo[19.3.1.12,6.18,12] with reference to patent WO2007058627A1 Heptane-1(24), 2(27), 3,5,8(26), 9,11,16,21(25), 22-decene, its structural formula is as follows:
Figure PCTCN2021084876-appb-000035
Figure PCTCN2021084876-appb-000035
对比例Comparative ratio
参考专利WO2011151360制备[4-[[5-氯-4-(甲基氨基)嘧啶-2-基]氨基]-3-甲氧基苯基]吗啉-4-基甲酮，其结构式如下：With reference to patent WO2011151360, [4-[[5-chloro-4-(methylamino)pyrimidin-2-yl]amino]-3-methoxyphenyl]morpholin-4-ylmethanone is prepared, and its structural formula is as follows:
Figure PCTCN2021084876-appb-000036
Figure PCTCN2021084876-appb-000036
实施例1至10中制备的化合物的结构示于表1中。The structures of the compounds prepared in Examples 1 to 10 are shown in Table 1.
表1Table 1
Figure PCTCN2021084876-appb-000037
Figure PCTCN2021084876-appb-000037
Figure PCTCN2021084876-appb-000038
Figure PCTCN2021084876-appb-000038
实施例11：化合物的生物活性测定Example 11: Assays for Biological Activity of Compounds
(1)材料(1)Material
LRRK2G2019S酶、底物(LRRK肽)、ATP、TR-FRET稀释液缓冲液、pLRRK肽抗体、384孔测定培养盘以及DMSO。LRRK2G2019S enzyme, substrate (LRRK peptide), ATP, TR-FRET diluent buffer, pLRRK peptide antibody, 384-well assay plate, and DMSO.
(2)酶反应条件：50mM Tris pH7.5、10mM MgCl 2、1mM EGTA、0.01％Brij-35、2mM DTT，5nM LRRK2，134μM ATP，60分钟反应时间，23℃反应温度，10μL总反应体积。 (2) Enzyme reaction conditions: 50 mM Tris pH7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.01% Brij-35, 2 mM DTT, 5 nM LRRK2, 134 μM ATP, 60 minutes reaction time, 23° C. reaction temperature, 10 μL total reaction volume.
侦测反应条件：1×稀释液缓冲液，10mM EDTA，2nM抗体，23℃反应温度10μL总反应体积。Detection reaction conditions: 1× diluent buffer, 10 mM EDTA, 2 nM antibody, 23 °C reaction temperature, 10 μL total reaction volume.
(3)实验步骤(3) Experimental steps
用100％DMSO溶解稀释测试化合物得到10mM或100μM的储备原液)，以比例为原液体积：缓冲液体积＝1:3.16(20μL+43.2μL)稀释得到最高测试浓度100μM或1μM的待测液。将5μL待测液转移至测定板，未处理的空白对照孔含有5μL DMSO和对照组5μL已知抑制剂比较例的DMSO溶液相继添加到源培养盘(384孔测定培养盘，Labcyte)。将培养盘在2500rpm下离心1分钟并用箔片密封。使用反应缓冲液进行3倍连续稀释以得到11个测试点，并将稀释后100nL的测试化合物溶液、已知抑制剂比较例化合物溶液、DMSO溶液空白组转移至测定培养盘，每个浓度2个复孔。将测定培养盘在2500rpm下离心1分钟,并用箔片密封。Dissolve and dilute the test compound with 100% DMSO to obtain a stock solution of 10mM or 100μM), take the ratio as the volume of the stock solution: buffer volume=1:3.16 (20μL+43.2μL) and dilute to obtain the test solution with the highest test concentration of 100μM or 1μM. 5 μL of the test solution was transferred to the assay plate, and the untreated blank control wells containing 5 μL of DMSO and the control group 5 μL of the DMSO solution of the known inhibitor comparative example were successively added to the source plate (384-well assay plate, Labcyte). The plates were centrifuged at 2500 rpm for 1 minute and sealed with foil. Perform 3-fold serial dilutions with reaction buffer to obtain 11 test points, and transfer 100 nL of the diluted test compound solution, the known inhibitor comparative example compound solution, and the DMSO solution blank to the assay plate, 2 for each concentration Duplicate holes. The assay plates were centrifuged at 2500 rpm for 1 min and sealed with foil.
为进行酶反应，将5μL的含5nM LRRK2酶的50mM Tris pH7.5、10mM MgCl2、1mM EGTA、0.01％Brij-35、2mM DTT缓冲液添加到测定培养盘的所有孔。离心培养盘，以将混合物浓缩在孔的底部。在23℃下孵育测定培养盘20分钟。孵育之后，将5μL的1X的激酶反应缓冲液配制2x LRRKtide Substrate和ATP添加到各孔，并离心培养盘以将混合物浓缩在孔的底部。在23℃下孵育培养盘60分钟。To perform the enzymatic reaction, 5 μL of 5 nM LRRK2 enzyme in 50 mM Tris pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij-35, 2 mM DTT buffer was added to all wells of the assay plate. The plates were centrifuged to concentrate the mixture at the bottom of the wells. Incubate assay plates for 20 minutes at 23°C. After incubation, 5 μL of 2x LRRKtide Substrate and ATP in 1X Kinase Reaction Buffer was added to each well, and the plate was centrifuged to concentrate the mixture at the bottom of the well. Incubate the plates for 60 minutes at 23°C.
为进行反应的侦测，将10μL包含抗体试剂和10mM EDTA的TR-FRET稀释缓冲液侦测试剂添加到测定培养盘的各孔的所有孔，并离心培养盘以将混合物浓缩在孔的底部。随后，在23℃下孵育培养盘60分钟。使用340m激发滤波器、520nm荧光发射滤波器和490或495nm铽发射滤波器，在TR-FRET模式下的Perkin elmer envision 2104仪器上读取培养盘。变体G2019S LRRK2的抑制作用以完全相同的方法测量。底物ATP和酶的所有最终浓度均相同。For detection of the reaction, 10 μL of TR-FRET Dilution Buffer Detection Reagent containing antibody reagent and 10 mM EDTA was added to all wells of each well of the assay plate, and the plate was centrifuged to concentrate the mixture at the bottom of the wells. Subsequently, the plates were incubated at 23°C for 60 minutes. Plates were read on a Perkin elmer envision 2104 instrument in TR-FRET mode using a 340-m excitation filter, a 520-nm fluorescence emission filter, and a 490 or 495-nm terbium emission filter. The inhibitory effect of variant G2019S LRRK2 was measured in exactly the same way. All final concentrations of substrate ATP and enzyme were the same.
用Graphpad软件进行数据分析，计算得到Kd活性值。Data analysis was performed with Graphpad software, and Kd activity values were calculated.
本文中所公开的若干化合物根据上文方法来测试，每个测试浓度为复孔，求平均值，在表2中提供了LRRK2和LRRK2G2019S相应的Kd活性值。Several compounds disclosed herein were tested according to the above method, each tested concentration was in duplicate and averaged, and the corresponding Kd activity values for LRRK2 and LRRK2G2019S are provided in Table 2.
表2Table 2
Figure PCTCN2021084876-appb-000039
Figure PCTCN2021084876-appb-000039
在本说明书和实施例中认定的所有专利和其他出版物明确地为所有目的通过用并入本文。提供这 些出版物仅仅是因为它们的公开早于本申请的提交日期。就此而言，绝不应该被解释为承认本发明人无权凭借先有发明或出于任何其他原因在时间上早于这些公开。对于日期的所有陈述或对于这些文件内容的表述是基于本申请人可以获得的信息并且不对所述日期或这些文件的内容的正确性构成任何承认。All patents and other publications identified in this specification and examples are expressly incorporated herein by reference for all purposes. These publications are provided solely because their disclosure predates the filing date of this application. In this regard, nothing should be construed as an admission that the inventors have no right to predate these disclosures by virtue of prior invention or for any other reason. All statements of dates or representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates or the contents of these documents.
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit the protection scope of the present invention. Although the present invention is described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that, The technical solutions of the present invention may be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention.

Claims (10)

  1. 一种治疗或预防与LRRK2激酶或异常LRRK2突变激酶活性相关疾病的药物，其特征在于，所述药物含有LRRK2抑制剂，所述LRRK2抑制剂包括化学式1表示的化合物、其光学异构体、其前体药物、其盐、其水合物、其溶剂化物、其N-氧化物、其氘化类似物中的至少一种；A medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, characterized in that the medicine contains an LRRK2 inhibitor, and the LRRK2 inhibitor comprises a compound represented by Chemical Formula 1, an optical isomer thereof, an LRRK2 inhibitor. at least one of a prodrug, its salt, its hydrate, its solvate, its N-oxide, its deuterated analog;
    [化学式1][Chemical formula 1]
    Figure PCTCN2021084876-appb-100001
    Figure PCTCN2021084876-appb-100001
    在化学式1中，L 1、L 2、L 3均独立地为C或N；L 4为C、N、O或S； In Chemical Formula 1, L 1 , L 2 and L 3 are all independently C or N; L 4 is C, N, O or S;
    R 1独立地为无取代基或酰胺基， R 1 is independently unsubstituted or amido,
    R 2独立地为无取代基、-H、-NHAr、-CH＝CHPh、
    Figure PCTCN2021084876-appb-100002
    或未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基，     R 2 is independently unsubstituted, -H, -NHAr, -CH=CHPh,
    Figure PCTCN2021084876-appb-100002
    or a 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent,
    或者L 3为N，L 1、L 2、R 1和R 2共同形成
    Figure PCTCN2021084876-appb-100003
    或-ArR bR d，其中，X为卤素；     Or L 3 is N, and L 1 , L 2 , R 1 and R 2 form together
    Figure PCTCN2021084876-appb-100003
    or -ArR b R d , wherein X is halogen;
    R 3为无取代基、-H、卤素、C 1-10烃基、或-NHR a； R 3 is unsubstituted, -H, halogen, C 1-10 hydrocarbyl, or -NHR a ;
    R 4独立地为-H、-NHAr、-CH＝CHPh、-NHR a、取代或未取代的含有N、O、S中至少一种杂原子的5至8元环杂环基乙烯基、C 1-5直链或支链烷基氨基磺酰基C 6-10芳基氨基、二(C 1-5直链或支链烷基)磷酸基C 6-10芳基氨基、
    Figure PCTCN2021084876-appb-100004
    未取代或被第二取代基取代的含N、O中至少一种杂原子的5至8元环杂环基、或5至8元环杂环基氨基，R 5独立地为
    Figure PCTCN2021084876-appb-100005
    Figure PCTCN2021084876-appb-100006
    R 4 is independently -H, -NHAr, -CH=CHPh, -NHR a , substituted or unsubstituted 5- to 8-membered cyclic heterocyclyl vinyl containing at least one heteroatom of N, O, S, C 1-5 straight-chain or branched-chain alkylaminosulfonyl C 6-10 arylamino, di(C 1-5 straight-chain or branched-chain alkyl) phosphoric acid group C 6-10 arylamino,
    Figure PCTCN2021084876-appb-100004
    5- to 8-membered ring heterocyclyl, or 5- to 8-membered ring heterocyclylamino group containing at least one heteroatom in N, O, unsubstituted or substituted by a second substituent, R 5 is independently
    Figure PCTCN2021084876-appb-100005
    Figure PCTCN2021084876-appb-100006
    或者L 1为N，R 4和R 5共同形成
    Figure PCTCN2021084876-appb-100007
    Or L 1 is N, R 4 and R 5 together form
    Figure PCTCN2021084876-appb-100007
    其中，L 5为-O-、-S-、或-NH-， Wherein, L 5 is -O-, -S-, or -NH-,
    Y 1为未取代或被第三取代基取代的C 1-10直链或支链烷基； Y 1 is a C 1-10 straight-chain or branched alkyl group that is unsubstituted or substituted by a third substituent;
    Y环为苯环、或未取代或被第四取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基；The Y ring is a benzene ring, or a 4- to 8-membered ring heterocycloalkyl or heterocyclic aryl group containing at least one heteroatom in N and O that is unsubstituted or substituted by a fourth substituent;
    R 6为无取代基或-H； R 6 is unsubstituted or -H;
    R 7为-H、C 1-10烃基、-(CH 2) nOH、-OR c、-O(CH 2) nR a、卤素、或未取代或被第三取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基； R 7 is -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, -OR c , -O(CH 2 ) n R a , halogen, or unsubstituted or substituted by a third substituent containing N, A 4- to 8-membered ring heterocycloalkyl or heteroaryl of at least one heteroatom in O;
    R 8、R 9、R 10、R 11均独立地为-H、C 1-10烃基、-(CH 2) nOH、-O(CH 2) nR a、-C(O)OR a、卤素、-CF 3或-OCF 3； R 8 , R 9 , R 10 , R 11 are each independently -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, -O(CH 2 ) n R a , -C(O)OR a , halogen, -CF3 or -OCF3 ;
    每个R a均独立地为-H、C 1-10烃基、C 1-10环烃基、芳基、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基； Each R is independently -H, C 1-10 hydrocarbyl, C 1-10 cyclohydrocarbyl, aryl, or unsubstituted or substituted with a fifth substituent containing at least one heteroatom of N, O. to 8-membered ring heterocycloalkyl or heteroaryl;
    每个R b均独立地为-H、C 1-10烃基、-O(CH 2) nR a、-NR aR c、或未取代或被第六取代基取代的含N、O中至少一种杂原子的3至8元环杂环基； Each R b is independently at least one of -H, C 1-10 hydrocarbyl, -O(CH 2 ) n R a , -NR a R c , or N, O-containing unsubstituted or substituted with a sixth substituent A heteroatom 3- to 8-membered ring heterocyclyl;
    每个R c均独立地为-H、C 1-10烃基、-(CH 2) nOH、芳基、或未取代或被第三取代基取代的含N、O中至少一种杂原子的4至8元环杂环烷基或杂环芳基； Each R c is independently -H, C 1-10 hydrocarbyl, -(CH 2 ) n OH, aryl, or unsubstituted or substituted with a third substituent containing at least one heteroatom of N, O 4- to 8-membered ring heterocycloalkyl or heteroaryl;
    每个R d均独立地为-H或-O(CH 2) nR a； each R d is independently -H or -O(CH 2 ) n R a ;
    所述第一取代基、第二取代基、第四取代基、第五取代基、第六取代基各自独立地为-OH、卤素、-CN、硝基、-NH 2、C 1-10烃基、取代或未取代的C 3-10环烷基、取代或未取代的含N、O中至少一种杂原子的3至8元环杂环烷基中的至少一种； The first substituent, the second substituent, the fourth substituent, the fifth substituent and the sixth substituent are each independently -OH, halogen, -CN, nitro, -NH 2 , C 1-10 hydrocarbon group , at least one of substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted 3- to 8-membered ring heterocycloalkyl containing at least one heteroatom in N and O;
    每个第三取代基独立地为取代或未取代的含N、O中至少一种杂原子的3至8元环杂环烷基、或取代或未取代的氨基；Each third substituent is independently a substituted or unsubstituted 3- to 8-membered ring heterocycloalkyl containing at least one heteroatom of N and O, or a substituted or unsubstituted amino group;
    每个n均独立地选自0至4任意整数。Each n is independently selected from any integer from 0 to 4.
  2. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物的结构式如下所示：The medicine according to claim 1, wherein the structural formula of the compound represented by the chemical formula 1 is as follows:
    Figure PCTCN2021084876-appb-100008
    Figure PCTCN2021084876-appb-100008
    所述R 3为卤素或C 1-10烃基；所述R 4为C 1-5直链或支链烷基氨基磺酰基C 6-10芳基氨基、二(C 1-5直链或支链烷基)磷酸基C 6-10芳基氨基、
    Figure PCTCN2021084876-appb-100009
    或未取代或被第二取代基取代的含N、O中至少一种杂原子的5至8元环杂环基；所述R 7为
    Figure PCTCN2021084876-appb-100010
    R b为C 1-10烃基、-NR aR c、或被C 1-10烃基取代的含N、O中至少一种杂原子的3至8元环杂环基，R a为C 1-10烃基，R c为-(CH 2) nOH；所述R 10、R 11均独立地为-H、-O(CH2) nR a、C 1-10烃基或卤素；     Described R 3 is halogen or C 1-10 hydrocarbon group; Described R 4 is C 1-5 straight chain or branched chain alkylaminosulfonyl C 6-10 arylamino, di(C 1-5 straight chain or branched Chain alkyl) phosphate C 6-10 arylamino,
    Figure PCTCN2021084876-appb-100009
    A 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, either unsubstituted or substituted by a second substituent; the R 7 is
    Figure PCTCN2021084876-appb-100010
    R b is a C 1-10 hydrocarbon group, -NR a R c , or a 3- to 8-membered ring heterocyclic group containing at least one heteroatom of N and O substituted by a C 1-10 hydrocarbon group, and R a is C 1- 10 hydrocarbon group, R c is -(CH 2 ) n OH; said R 10 and R 11 are independently -H, -O(CH 2 ) n R a , C 1-10 hydrocarbon group or halogen;
    优选地，所述R 3为-F、-Cl或-CH 3；所述R 4为
    Figure PCTCN2021084876-appb-100011
    Figure PCTCN2021084876-appb-100012
    所述R 7为
    Figure PCTCN2021084876-appb-100013
    所述R 10、R 11均独立地为-H、-OCH 3、-CH 3或-F。     Preferably, the R 3 is -F, -Cl or -CH 3 ; the R 4 is
    Figure PCTCN2021084876-appb-100011
    Figure PCTCN2021084876-appb-100012
    The R7 is
    Figure PCTCN2021084876-appb-100013
    The R 10 and R 11 are independently -H, -OCH 3 , -CH 3 or -F.
  3. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物的结构式如下所示：The medicine according to claim 1, wherein the structural formula of the compound represented by the chemical formula 1 is as follows:
    Figure PCTCN2021084876-appb-100014
    Figure PCTCN2021084876-appb-100014
    所述L 4为N、S或O；所述R 5为
    Figure PCTCN2021084876-appb-100015
    或被-O(CH 2) nR a、卤素中至少一种取代的苯基；R b为-O(CH 2) nR a；R a为-H、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基；R d为-H或-O(CH 2) nR a；     The L 4 is N, S or O; the R 5 is
    Figure PCTCN2021084876-appb-100015
    Or phenyl substituted by at least one of -O(CH 2 ) n R a and halogen; R b is -O(CH 2 ) n R a ; R a is -H, or unsubstituted or by the fifth substituent Substituted 5- to 8-membered ring heterocycloalkyl or heterocyclic aryl containing at least one heteroatom in N and O; R d is -H or -O(CH 2 ) n R a ;
    优选地，所述L 4为N、S或O；所述R 5为
    Figure PCTCN2021084876-appb-100016
    所述R b为
    Figure PCTCN2021084876-appb-100017
    R d为-H或-OCH 3。     Preferably, the L 4 is N, S or O; the R 5 is
    Figure PCTCN2021084876-appb-100016
    The R b is
    Figure PCTCN2021084876-appb-100017
    R d is -H or -OCH 3 .
  4. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物的结构式如下所示：The medicine according to claim 1, wherein the structural formula of the compound represented by the chemical formula 1 is as follows:
    Figure PCTCN2021084876-appb-100018
    Figure PCTCN2021084876-appb-100018
    所述R 4为被C 1-10烃基取代的5至8元环杂环基氨基；所述L 4为N、S或O；所述R 7为O(CH 2) nR a，R a为芳基、或未取代或被第五取代基取代的含N、O中至少一种杂原子的5至8元环杂环烷基或杂环芳基。 The R 4 is a 5- to 8-membered ring heterocyclylamino substituted with a C 1-10 hydrocarbon group; the L 4 is N, S or O; the R 7 is O(CH 2 ) n R a , R a is an aryl group, or a 5- to 8-membered ring heterocycloalkyl or heterocyclic aryl group containing at least one heteroatom of N and O which is unsubstituted or substituted by a fifth substituent.
  5. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物的结构式如下所示：The medicine according to claim 1, wherein the structural formula of the compound represented by the chemical formula 1 is as follows:
    Figure PCTCN2021084876-appb-100019
    Figure PCTCN2021084876-appb-100019
    所述R 2为未取代或被第一取代基取代的含N、O中至少一种杂原子的5至8元环杂环基；所述L 4为N；所述R 4为-CH＝CHPh、或取代或未取代的含有N、O、S中至少一种杂原子的4至8元环杂 环基乙烯基；所述R 5为
    Figure PCTCN2021084876-appb-100020
    The R 2 is a 5- to 8-membered ring heterocyclic group containing at least one heteroatom in N and O, which is unsubstituted or substituted by the first substituent; the L 4 is N; the R 4 is -CH= CHPh, or a substituted or unsubstituted 4- to 8-membered ring heterocyclyl vinyl containing at least one heteroatom in N, O, and S; the R 5 is
    Figure PCTCN2021084876-appb-100020
  6. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物的结构式如下所示：The medicine according to claim 1, wherein the structural formula of the compound represented by the chemical formula 1 is as follows:
    Figure PCTCN2021084876-appb-100021
    Figure PCTCN2021084876-appb-100021
    所述R 1为酰胺基；所述R 3为C 1-10烃基；所述R 4为5至8元环杂环基氨基；所述R 7为
    Figure PCTCN2021084876-appb-100022
    所述R b为未取代或被第六取代基取代的含N、O中至少一种杂原子的3至8元环杂环基；所述R 9为-O(CH 2) nR a。     The R 1 is an amide group; the R 3 is a C 1-10 hydrocarbon group; the R 4 is a 5- to 8-membered ring heterocyclylamino; the R 7 is
    Figure PCTCN2021084876-appb-100022
    The R b is a 3- to 8-membered ring heterocyclic group containing at least one heteroatom among N and O, which is unsubstituted or substituted by a sixth substituent; the R 9 is -O(CH 2 ) n R a .
  7. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物的结构式如下所示：The medicine according to claim 1, wherein the structural formula of the compound represented by the chemical formula 1 is as follows:
    Figure PCTCN2021084876-appb-100023
    Figure PCTCN2021084876-appb-100023
  8. 根据权利要求1所述的药物，其特征在于，所述化学式1表示的化合物为以下化合物中的任意一种：The medicine according to claim 1, wherein the compound represented by the chemical formula 1 is any one of the following compounds:
    (1)(1S，2S，3R，4R)-3-[[5-氟-2-[3-甲基-4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]双环[2.2.1]庚-5-烯-2-甲酰胺；(1) (1S,2S,3R,4R)-3-[[5-Fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidine-4- base]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide;
    (2)N-叔丁基-3-[[5-甲基-2-[4-(4-甲基哌嗪-1-基)苯胺基]嘧啶-4-基]氨基]苯磺酰胺；(2) N-tert-butyl-3-[[5-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]benzenesulfonamide;
    (3)2-[[1-[2-氟-4-[[5-甲基-4-(1-丙-2-基吡唑-4-基)嘧啶-2-基]氨基]苯基]哌啶-4-基]-甲基氨基]乙醇；(3) 2-[[1-[2-Fluoro-4-[[5-methyl-4-(1-prop-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]phenyl ]piperidin-4-yl]-methylamino]ethanol;
    (4)5-氯-4-N-(2-二甲基磷酰苯基)-2-N-[2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基]嘧啶-2,4-二胺；(4) 5-Chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl] ) piperidin-1-yl]phenyl]pyrimidine-2,4-diamine;
    (5)1-(4-甲基苯基)-3-[5-[7-(3-吗啉-4-基丙氧基)喹唑啉-4-基]磺酰基-1,3,4-噻二唑-2-基]脲；(5) 1-(4-Methylphenyl)-3-[5-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]sulfonyl-1,3, 4-thiadiazol-2-yl]urea;
    (6)N-(2-氯-5-甲氧基苯基)-6-甲氧基-7-[(1-甲基哌啶-4-基)甲氧基]喹唑啉-4-胺；(6) N-(2-Chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline-4- amine;
    (7)8-溴-2-[(1-甲基哌啶-4-基)氨基]-4-(4-苯氧基苯胺)-6H-吡啶[4,3-d]嘧啶-5-酮；(7) 8-Bromo-2-[(1-methylpiperidin-4-yl)amino]-4-(4-phenoxyaniline)-6H-pyridine[4,3-d]pyrimidine-5- ketone;
    (8)6-(4-甲基哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)-2-[((E)-2-苯基乙烯基]嘧啶-4-胺；(8) 6-(4-Methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[((E)-2-phenylvinyl ] pyrimidin-4-amine;
    (9)6-乙基-3-[3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯胺基]-5-(氧烷-4-基氨基)吡嗪-2-羧酰胺；(9) 6-Ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxane -4-ylamino)pyrazine-2-carboxamide;
    (10)(16E)-11-(2-吡咯烷-1-乙氧基)-14,19-二恶英-5,7,27-三氮四环[19.3.1.12,6.18,12]庚-1(24)，2(27)，3,5,8(26)，9,11,16,21(25)，22-癸烯。(10)(16E)-11-(2-Pyrrolidine-1-ethoxy)-14,19-dioxin-5,7,27-triaztetracyclo[19.3.1.12,6.18,12]heptane -1(24), 2(27), 3,5,8(26), 9,11,16,21(25), 22-decene.
  9. 根据权利要求1所述的药物，其特征在于，所述疾病包括神经退化性疾病、癌前病状和癌症、自身免疫性病、炎症中的至少一种。The medicine of claim 1, wherein the disease comprises at least one of neurodegenerative disease, precancerous conditions and cancer, autoimmune disease, and inflammation.
  10. 根据权利要求1所述的药物，其特征在于，所述疾病包括阿兹海默氏症、L-多巴诱发性运动障得、帕金森氏病、增强认知记忆、中枢神经***病症、痴呆症、肌萎缩侧索硬化症、肾癌、乳腺癌、***癌、血癌、***状癌、肺癌、急性骨髓性白血病、多发性骨髓瘤、麻风病、克罗恩氏病、炎症性肠病、溃疡性结肠炎、肌肉萎缩性侧索硬化、类风湿性关节炎或强直性脊椎炎中的至少一种。The medicine according to claim 1, wherein the diseases include Alzheimer's disease, L-dopa-induced dyskinesia, Parkinson's disease, enhancement of cognitive memory, central nervous system disorders, dementia disease, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, At least one of ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
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