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WO2022184111A1 - Composé à petites molécules lié à la protéine tau - Google Patents

Composé à petites molécules lié à la protéine tau Download PDF

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Publication number
WO2022184111A1
WO2022184111A1 PCT/CN2022/078882 CN2022078882W WO2022184111A1 WO 2022184111 A1 WO2022184111 A1 WO 2022184111A1 CN 2022078882 W CN2022078882 W CN 2022078882W WO 2022184111 A1 WO2022184111 A1 WO 2022184111A1
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alkyl
compound
methyl
cycloalkyl
alkoxy
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Chinese (zh)
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汪义朋
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Shanghai Qiangrui Biotech Co Ltd
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Shanghai Qiangrui Biotech Co Ltd
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Priority to CN202280015846.5A priority Critical patent/CN116964038A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms

Definitions

  • the present disclosure relates to the field of medicinal chemistry, in particular to a small molecule compound bound to tau protein, a preparation method and use thereof.
  • Tau protein is a microtubule associated protein that plays an important role in stabilizing cytoskeletal microtubules.
  • Tau protein is a natively unfolded protein, which itself has no tendency to form polymers, but its aggregation occurs in a series of neurodegenerative diseases collectively known as "tauopathies", including Alzheimer's disease (AD), frontotemporal dementia linked to chromosome 17 with Parkinson's disease (frontotemporal dementia linked to chromosome-17parkinsonism, FTDP-17), Pick's disease (PiD) , progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), primary age-related tauopathy (PART), argyrophilic grain disease, AGD), aging-related tau astrogliopathy (ARTAG), chronic traumatic encephalopathy (chronic traumatic encephalopathy, CTE), spherical glial tauopathy (Globular glial tauopathy, GGT), Parkinson's disease (Parkinson's disease, PD),
  • Tau protein is an important cause of neurodegeneration in these diseases, so it is also an important target for the diagnosis and treatment of these diseases.
  • tau is involved in the regulation of neuronal excitability and is therefore a potential target for the treatment of epilepsy, autism and stroke.
  • tau polymers have been successfully developed as tracers for Positron Emission Computed Tomography (PET) for Alzheimer's disease and other tau Early diagnosis of disease. It has been reported that some small-molecule compounds (such as Methylene blue and its derivatives) can inhibit tau aggregation, potentially for the treatment of Alzheimer's disease or other tau diseases, but the mechanism by which they inhibit tau aggregation is not clear. It is not entirely clear which tau protein (tau monomers) or aggregates (aggregates) it binds to. Tau is a natural unstructured protein, and its monomers (monomers) have no binding for ligand binding.
  • PTT Positron Emission Computed Tomography
  • PROTAC protein degradation targeting chimeras
  • AUTAC autophagy targeting chimeras
  • PROTAC protein degradation targeting chimeras
  • AUTAC autophagy targeting chimeras
  • PROTAC consists of three parts, including (1) target protein ligands; (2) specific E3 ubiquitin transferase (E3 ligase) ligands; and (3) ) linker that connects the ligand of the target protein and the ligand of the E3 ubiquitin transferase.
  • the target protein ligand has a weak affinity for the target protein, it can still be very effective due to the catalytic effect of PROTAC. Down-regulates the target protein. Therefore, even if the small molecule compound that can bind to tau has a low affinity for tau, it can also be used to construct a bifunctional molecule PROTAC that mediates tau degradation for the treatment of tau disease and other tau-related diseases. treat.
  • the present invention develops a plurality of small molecule compounds with strong affinity to tau protein.
  • the present disclosure synthesized a series of small molecule compounds that can bind to tau protein monomers. These small molecule compounds can potentially be used to develop inhibitors of tau aggregation for the treatment of tau disease and other tau-related diseases. In addition, these small molecule compounds can also be used to construct bifunctional molecules, such as PROteolysis TArgeting Chimeras (PROTAC) and Autophagy targeting Chimeras (AUTAC), etc. Degrader for the treatment of tau disease and other tau-related diseases.
  • PROTAC PROteolysis TArgeting Chimeras
  • AUTAC Autophagy targeting Chimeras
  • the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:
  • a 1 , A 2 and A 3 are independently selected from C and N atoms; preferably, A 1 , A 2 and A 3 are N atoms at the same time;
  • L 1 is -(CH 2 ) n - or -(CH 2 O) n -; preferably, L 1 is -(CH 2 ) n -;
  • R 1 is selected from phenyl, pyridyl, pyranyl, thiopyranyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl;
  • R 1 is selected from phenyl, 2-pyridyl, 2-thienyl, 2-thiazolyl;
  • R 1 is selected from 2-thienyl
  • R 2 is selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered aryl or 5-6 membered containing 1-2 heteroatoms independently selected from N, S, O Heteroaryl;
  • R 2 is selected from H
  • R 2 is connected to an atom on the ring of R 1 , so that R 1 , R 2 and the atoms to which they are connected together form an 8-10 membered partially unsaturated or aromatic carbocyclic bicyclic ring, containing 1-2 atoms independently selected from 8-10 membered partially unsaturated or aromatic bicyclic ring of heteroatoms of N, S, O; preferably, R 1 , R 2 and the atoms to which they are attached together form
  • n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;
  • R 3 is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 5 R 6 , -OR 16 ; preferably, R 3 is selected from methyl, ethyl, propyl, isopropyl, methoxy , ethoxy, -NR 5 R 6 ;
  • R 5 and R 6 are each independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH 2 )-, (C3-C6 cycloalkyl) -(CH 2 CH 2 )-, aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, S, O, the C1-C6 alkyl, C3-C6 ring Alkyl, (C3-C6cycloalkyl)-( CH2 )-, (C3 - C6cycloalkyl)-(CH2CH2) - , aryl, heteroaryl optionally surrounded by one or more R 7 to replace;
  • R 5 and R 6 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, optionally substituted with one or more R7 ;
  • R 5 is H and R 6 is selected from methyl, cyclopropyl, phenyl, naphthyl, The methyl, cyclopropyl, phenyl, naphthyl, optionally substituted with one or more R7 ;
  • R 5 is H and R 6 is methyl
  • R5 is H and R6 is phenyl optionally substituted with one or more R7 ; preferably, R3 is
  • R3 is and wherein R 5 is H;
  • R 4 is a 3-8-membered saturated ring containing 1-2 atoms independently selected from N and O, which is connected to the The rings are connected, and the 3-8 membered saturated ring containing 1-2 N, O atoms is optionally substituted by one or more R 8 ;
  • R 4 is selected from the following groups optionally substituted with one or more R 8 :
  • R4 is
  • R 10 and R 11 are each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 12 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon group;
  • R 9 is selected from C1-C3 alkyl
  • R 9 is selected from -CH 3 .
  • the present disclosure provides a compound of formula (II) or formula (III) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxidation thereof Object:
  • a 1 , A 2 and A 3 are independently selected from C and N atoms; preferably, A 1 , A 2 and A 3 are N atoms at the same time;
  • R 2 is selected from H, D, C1-C6 alkyl
  • R 2 is selected from H, D, methyl, ethyl, propyl, isopropyl;
  • R 2 is selected from H
  • n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;
  • R 5 and R 6 are each independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH 2 )-, (C3-C6 cycloalkyl) -(CH 2 CH 2 )-, aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, S, O, the C1-C6 alkyl, C3-C6 ring Alkyl, (C3-C6cycloalkyl)-( CH2 )-, (C3 - C6cycloalkyl)-(CH2CH2) - , aryl, heteroaryl optionally surrounded by one or more R 7 to replace;
  • R 5 and R 6 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, optionally substituted with one or more R7 ;
  • R 5 is H and R 6 is selected from methyl, cyclopropyl, phenyl, naphthyl, The methyl, cyclopropyl, phenyl, naphthyl, optionally substituted with one or more R7 ;
  • R 5 is H and R 6 is methyl
  • R5 is H and R6 is phenyl optionally substituted with one or more R7 ;
  • R 6 is
  • R 6 is and wherein R 5 is H;
  • R 10 and R 11 are each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 10 and R 11 are each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, and acetyl;
  • R 12 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon group;
  • R 9 is selected from C1-C3 alkyl
  • R 9 is selected from -CH 3 .
  • the present disclosure also provides a compound represented by formula (IIA) or formula (IIIA) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N- Oxides:
  • R 2 is selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered aryl or 5-6 membered containing 1-2 heteroatoms independently selected from N, S, O Heteroaryl;
  • R 2 is selected from H, D, methyl, ethyl, propyl, isopropyl;
  • R 2 is selected from H
  • n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;
  • R 5 is selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH 2 )-, (C3-C6 cycloalkyl)-(CH 2 CH 2 )-, the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)- are optionally replaced by a or multiple R 13 substitutions;
  • R 5 is selected from H, D, C1-C4 alkyl
  • R 5 is selected from H, D, methyl, ethyl, propyl, isopropyl;
  • R 5 is selected from H
  • R 10 and R 11 are each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 10 and R 11 are each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, and acetyl;
  • R 12 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon group;
  • R 9 is selected from C1-C3 alkyl
  • R 9 is selected from -CH 3 ;
  • the present disclosure also provides a small molecule compound that specifically degrades tau protein, characterized in that the chemical structure of the compound is TBM-L-ULM or TBM-L-AUM and pharmaceutically acceptable salts thereof , enantiomer, stereoisomer, solvate, polymorph or N-oxide, wherein TBM is the tau protein binding moiety, L is the linker group, ULM is the ubiquitin ligase binding moiety, and AUM is the Binding moiety of the ZZ segment of the autophagy receptor p62/SQSTM1/Sequestosome-1, the TBM is L-linked to the ULM or AUM moiety.
  • TBM is a compound group represented by the aforementioned formulas (I), (II), (III), (IIA), (IIIA), and when R 3 is -
  • the ULM can bind to E3 ubiquitin ligase; preferably, the E3 ubiquitin ligase is VHL E3 ubiquitin ligase or CRBN E3 ubiquitin ligase; preferably, The ULM is the compound shown below, which is connected to L through the amino N atom shown in positions 1 and 2,
  • the AUM can bind to the ZZ segment of the autophagy receptor p62/SQSTM1/Sequestosome-1, exemplarily, the AUM has the structure shown below, which is connected with the position of 3.
  • the C atom of the aminoalkyl group in L or the O atom in the ether group is attached to L,
  • R One or more Hs on the methylene group replaced by R;
  • Y is -E 1 -(CH 2 CH 2 O) p -E 2 -, -E 1 -(CH 2 ) q -E 2 -,
  • TBM is attached to the attached alkylene C atom of the X group
  • ULM is attached to the carbonyl C atom of the Z group
  • m is selected from 0, 1, 2, 3 or 4
  • p is selected from 0, 1, 2, 3, 4, 5 or 6
  • q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R 14 is selected from H, C1-C3 alkyl; preferably, R 14 is selected from H, methyl, ethyl; preferably, R 14 is selected from H, methyl;
  • E 1 and E 2 are independently selected from single bond, And at least one of E 1 and E 2 is a single bond;
  • E is selected from a single bond, -(CH 2 ) m O-, optionally, one or more Hs on the methylene group in the -(CH 2 ) m O- are substituted with R;
  • R is D, -OH, C1-C3 alkyl, C1-C3 alkoxy, preferably, R is selected from single bond, D, methyl, ethyl, -OH;
  • the L is selected from the following groups:
  • the aforementioned small molecule compound that specifically degrades tau protein, the -L-ULM group is shown in the following structure:
  • the present disclosure also provides compounds of formula (I), (II), (III), (IIA), (IIIB), and small molecule compounds TBM-L-ULM or TBM-L-AUM that degrade tau protein Preparation.
  • the present disclosure also provides a tau protein binding agent, the structure of which is shown in formulas (I), (II), (III), (IIA), (IIIB) and the recited exemplary structures.
  • the present disclosure also provides the use of compounds of formula (I), (II), (III), (IIA), (IIIB), and the recited exemplary structures, in the preparation of tau protein binding agents.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof , or the above-mentioned small molecule compounds and pharmaceutically acceptable excipients.
  • the present disclosure also provides a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound as described above, or The application of the aforementioned pharmaceutical composition in the preparation of a medicine for treating a patient's condition caused by accumulation of tau protein;
  • the condition caused by accumulation of tau protein is selected from Alzheimer's disease (AD), frontotemporal dementia linked to chromosome-17 parkinsonism linked to chromosome 17 with Parkinson's disease, FTDP-17), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), primary age-related tau disease (primary age-related tau disease) age-related tauopathy (PART), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), chronic traumatic encephalopathy (CTE) , Globular glial tauopathy (GGT), Parkinson's disease (PD), Huntington's Disease (HD), or one or more of stroke, epilepsy and autism.
  • AD Alzheimer's disease
  • PiD progressive supranuclear palsy
  • CBD corticobasal degeneration
  • primary age-related tau disease primary age-related tau disease
  • PART age-related tauopathy
  • ARTAG aging-related tau a
  • the present disclosure also provides a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound as described above, or Application of the aforementioned pharmaceutical composition in the preparation of a tau degrading agent.
  • the present disclosure also provides a method of degrading tau protein in a patient in need thereof, comprising administering to the patient a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate thereof , polymorphs or N-oxides, or the small molecule compounds described above, or the aforementioned pharmaceutical compositions.
  • the present disclosure also provides a method for degrading tau protein in a biological sample, comprising combining the biological sample with the above-described compound, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, The polymorph or N-oxide, or the small molecule compound described above, or the aforementioned pharmaceutical composition is contacted.
  • the present disclosure also provides a method for treating a disorder caused by accumulation of tau protein in a patient in need thereof, comprising administering to said patient a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer thereof Conforms, solvates, polymorphs or N-oxides, or the aforementioned small molecule compounds, or the aforementioned pharmaceutical compositions.
  • FIG. 2 shows the nuclear magnetic spectrum of PROTAC molecules prepared in Example 16 of the present disclosure
  • FIG. 3 Coomassie brilliant blue staining and immunoblot hybridization of tau protein.
  • the gel staining shows that tau protein is mainly a band of about 56kD, with a small amount of degraded fragments ( ⁇ 10%) (a), and the tau band can be Recognized by tau-specific polyclonal antibody (b) and monoclonal antibody (c).
  • the compounds of the present invention may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers.
  • the compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are included within the scope of the present invention.
  • the compounds of the present invention also include tautomeric forms.
  • Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.
  • C1-C6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; “C3-C6” is It is meant that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • substituted refers to the substitution of any one or more hydrogen atoms on a specified atom or group with a substituent, so long as the valence of the specified atom or group is normal and the substituted compound is stable.
  • the kind and number of substituents can be arbitrary on the basis of chemical realization.
  • any variable eg, Rn
  • its definition in each case is independent.
  • the group may optionally be substituted with up to 5 Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms.
  • C1-C6 alkyl includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc. It may be divalent, eg methylene, ethylene.
  • halo and halogen-substituted refer to substitution with one or more halogen atoms, examples of which include fluorine, chlorine, bromine, and iodine atoms.
  • cycloalkyl refers to a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds.
  • C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system by removing a hydrogen from a single carbon atom of the parent aromatic ring system obtained from atoms.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-10 carbon atoms. Included are bicyclic groups containing aromatic rings fused to saturated, partially unsaturated rings, or aromatic carbocyclic rings. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, indene, indan, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene.
  • heteroaryl refers to a monovalent aryl group containing at least one 5-, 6-, 7-membered ring independently selected from nitrogen, oxygen, and sulfur heteroatoms, and including a fused ring system of 5-10 atoms ( At least one of them is aromatic).
  • heteroaryl examples include, but are not limited to, pyridyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, furanyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, benzene Imidazolyl, imidazopyridyl, benzofuranyl, pyridazinyl, isoindolyl.
  • membered refers to the number of backbone atoms that make up a ring.
  • “5-10 membered” means that the number of backbone atoms making up the ring is 5, 6, 7, 8, 9 or 10.
  • pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene, pyrrole are five-membered rings.
  • heterocycle refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valence permits.
  • a heterocycle can be a monocyclic or polycyclic ring system, such as a bicyclic ring, in which two or more rings are present as fused, bridged, or spiro rings, wherein at least one ring contains one or more heteroatoms.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.
  • the substituent R n can be bonded to any atom on the ring, as long as the valence allows it. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. It will be understood by those skilled in the art that for any group containing one or more Rn substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • protecting group means that when a multifunctional organic compound undergoes a reaction, in order to make the reaction only occur at the desired group and avoid other groups from being affected, other groups are added before the reaction. Protection, when the reaction is completed and then recover.
  • the reagent that can protect a certain group is called the protecting group of the group, common hydroxyl protecting agent, amino protecting agent, etc.
  • the protecting group of hydroxyl includes but is not limited to: acetyl (Ac ), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether (MTM), pivaloyl (Piv ), tetrahydropyran (THP), silyl ether protecting group, methyl ether, etc.; amino protecting groups include but are not limited to: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenemethoxycarbonyl (FMOC), benzyl (Bn), p-methoxyphenyl (PMP), trityl derivative protecting groups and the like.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without, commensurate with a reasonable benefit/risk ratio, excessive toxicity, irritation, allergic reaction or other problems or complications of those compounds, materials, compositions and/or dosage forms.
  • pharmaceutically acceptable salts refers to salts that retain the biological efficacy of the free acids and bases of a specified compound without biologically adverse effects. Examples are acid (including organic and inorganic acid) addition salts or base addition salts (including organic and inorganic bases).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the medicaments or pharmaceutical compositions of the present disclosure may be formulated orally, topically, parenterally, or mucosally (eg, bucally, by inhalation, or rectally) in dosage units containing conventional non-toxic pharmaceutically acceptable carriers apply. It is usually desirable to use the oral route.
  • the active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).
  • the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (eg, pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethyl methacrylate) cellulose); fillers (eg, lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (eg , magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (eg, potato starch or hydroxyl sodium starch acetate); or wetting agents (for example, sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweetening agents, natural and synthetic gums (such as acacia, traga, traga, tragag,
  • the pharmaceutical components can be combined with non-toxic, pharmaceutically acceptable inert carriers (eg, ethanol, glycerol, water), anti-settling agents (eg, sorbitol syrup, cellulose-derived or hydrogenated edible fats), emulsifiers (eg, lecithin or acacia), non-aqueous carriers (eg, almond oil, oily esters, ethanol, or fractionated vegetable oils), preservatives (eg, p- methyl hydroxybenzoate or p-hydroxybenzoic acid propyl ester or sorbic acid) and other combinations.
  • Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.
  • compositions of the present disclosure comprising the compound of formula I as the active compound may also be incorporated into beads, microspheres or microcapsules, eg constructed from polyglycolic acid/lactic acid (PGLA).
  • PGLA polyglycolic acid/lactic acid
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions or they may be presented as a dry product for reconstitution with water or other suitable excipient before use.
  • Formulations for oral administration may be suitably formulated to provide controlled or delayed release of the active compound.
  • a drug or pharmaceutical composition of the present disclosure can be delivered parenterally, ie, by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.) or intradermal (i.d.) administration, by direct injection, via eg bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, eg, in ampoules or in multi-dose containers with an added preservative.
  • compositions may take the form of excipients, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as anti-settling, stabilizing and/or dispersing agents.
  • the active ingredient may be reconstituted in powder form with a suitable vehicle, eg, sterile pyrogen-free water, before use.
  • the medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, eg, as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter or other glycerides).
  • rectal administration eg, as suppositories or retention enemas (eg, containing conventional suppository bases such as cocoa butter or other glycerides).
  • treating includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide a desired pharmacological and/or physiological effect dose.
  • the precise dosage will vary depending on a variety of factors, such as subject-dependent variables (eg, age, immune system health, etc.), the disease or disease, and the treatment administered.
  • the effect of an effective amount can be relative to a control.
  • controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of a drug or drug combination, or in the case of a drug combination, the effect of the combination can be combined Compared to the effect of administering only one drug.
  • excipient is used herein to include any other compound that is not a therapeutic or biologically active compound that may be contained in or on the microparticles. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, eg, the excipient is generally not toxic to the subject. "Excipient” includes a single such compound, and is also intended to include multiple compounds.
  • composition means a composition comprising a compound described in this disclosure, or a pharmaceutically acceptable salt thereof, and, depending on the mode of administration and the nature of the dosage form, at least one pharmaceutically acceptable ingredient selected from the group consisting of: Including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, flavoring agents, antibacterial agents , antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.
  • patient refers to any animal or cells thereof, whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • a compound or composition may be administered using any amount and any route of administration effective to treat or lessen the severity of a disease associated with accumulation of tau protein.
  • the present invention relates to a method of reducing tau protein in a biological sample comprising the step of contacting said biological sample with a compound of the invention or a composition comprising said compound.
  • biological sample includes, but is not limited to, cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof thing. Inhibition of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological analysis, gene expression studies, and biological target identification.
  • a method of the present invention for inhibiting tau protein in a patient comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.
  • the provided compounds are tau protein inhibitors and are therefore useful in the treatment of one or more disorders associated with tau protein activity. Accordingly, in certain embodiments, the present invention provides a method for treating a tau protein-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof .
  • tau protein-mediated disorder, disease and/or condition means any disease or other deleterious condition in which tau protein or mutants thereof are known to play a role.
  • another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which tau protein or mutants thereof are known to play a role.
  • tau proteins disorders mediated by tau proteins are well established in the art.
  • the relationship between tau protein and tau protein-mediated disorders, diseases and/or conditions as described herein is well established in the related art. Examples include Alzheimer's disease (AD), frontotemporal dementia linked to chromosome-17 parkinsonism (FTDP-17) linked to chromosome 17 with Parkinson's disease, Pick's disease (Pick's disease, PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), primary age-related tauopathy (PART), Argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), chronic traumatic encephalopathy (CTE), Globular tau glial tauopathy, GGT), Parkinson's disease (Parkinson's disease, PD), Huntington's disease (Huntington's Disease, HD).
  • AD Alzheimer's disease
  • FTDP-17 frontotemporal dementia linked to chromosome-17 parkinsonism linked to chromosome 17 with
  • Tau protein is an important cause of neurodegeneration in these diseases, so it is also an important target for the diagnosis and treatment of these diseases.
  • tau is involved in the regulation of neuronal excitability and is therefore a potential target for the treatment of epilepsy, autism and stroke.
  • proteolysis targeting chimeras is a chemical molecule containing different ligands at both ends and a ligand that binds E3 ligase at one end (such as the ULM moiety described in this disclosure). ), the other end is a ligand that binds to intracellular proteins (eg, the TBM part of the tau protein described in the present disclosure), and the two ligands are connected by a linker (eg, the L described in the present disclosure).
  • Such chemical molecules can bind to both E3 ubiquitin ligase and intracellular proteins, and achieve polyubiquitination of the targeted protein by recruiting the targeted protein to the vicinity of the E3 ubiquitin ligase, which is finally degraded by the proteasome.
  • PROTAC can be recycled without being degraded by the proteasome.
  • autophagy-targeted chimera adopts a similar design to PROTAC and is well suited for degrading target proteins in the cytoplasm that are resistant to PROTAC molecules.
  • Cargo proteins are first phagocytosed to form autophagosomes, and then autophagy receptors such as SQSTM1/p62 recognize Lys63 (K63) polyubiquitinated cargo proteins and transfer them to autophagosomes for degradation.
  • K63 Lys63
  • ubiquitin ligase refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, which are targeted for degradation.
  • cereblon is an E3 ubiquitin ligase protein that, alone or in combination with E2 ubiquitin conjugating enzymes, causes the attachment of ubiquitin to lysines on target proteins, and subsequently targets specific protein substrates for access by the proteasome degradation.
  • E3 ubiquitin ligases alone or in complex with E2 ubiquitin conjugating enzymes, are responsible for the transfer of ubiquitin to target proteins.
  • ubiquitin ligases are involved in polyubiquitination such that a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on.
  • Polyubiquitination marks proteins for degradation by the proteasome.
  • ubiquitination events which are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase.
  • Monoubiquitinated proteins are not targeted to the proteasome for degradation, but can be altered in their cellular location or function, eg, via binding to other proteins with domains capable of binding ubiquitin.
  • Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.
  • the term "combination therapy” includes administration of the agents in a sequential manner, ie, where each therapeutic agent is administered at a different time, and administration of the therapeutic agents, or at least two agents, substantially simultaneously.
  • the sequential, or substantially simultaneous, administration of each agent can be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue.
  • the agents can be administered by the same route or by different routes. For example, a first agent may be administered orally, while a second agent may be administered intravenously.
  • selected combination agents can be administered by intravenous injection, while the other agents of the combination can be administered orally.
  • two or more agents can be administered by intravenous or subcutaneous injection.
  • the present disclosure provides compounds of formula (I), pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof:
  • a 1 , A 2 and A 3 are independently selected from C and N atoms; preferably, A 1 , A 2 and A 3 are N atoms at the same time;
  • L 1 is -(CH 2 ) n - or -(CH 2 O) n -;
  • L 1 is -(CH 2 ) n -;
  • R 1 is selected from phenyl, pyridyl, pyranyl, thiopyranyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl;
  • R 1 is selected from phenyl, 2-pyridyl, 2-thienyl, 2-thiazolyl;
  • R 1 is selected from 2-thienyl
  • R 2 is selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered aryl or 5-6 membered containing 1-2 heteroatoms independently selected from N, S, O Heteroaryl;
  • R 2 is selected from H
  • R 2 is attached to an atom on the R 1 ring, so that R 1 , R 2 and the atoms to which they are attached together form an 8-10 membered partially unsaturated or aromatic carbocyclic bicyclic ring containing 1 -2 8-10 membered partially unsaturated or aromatic bicyclic rings of heteroatoms independently selected from N, S, O; preferably, R 1 , R 2 and the atoms to which they are attached together form
  • n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;
  • R 3 is selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 5 R 6 , -OR 16 ; preferably, R 3 is selected from methyl, ethyl, propyl, isopropyl, methoxy , ethoxy, -NR 5 R 6 ;
  • R 5 and R 6 are each independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH 2 )-, (C3-C6 cycloalkyl) -(CH 2 CH 2 )-, aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, S, O, the C1-C6 alkyl, C3-C6 ring Alkyl, (C3-C6cycloalkyl)-( CH2 )-, (C3 - C6cycloalkyl)-(CH2CH2) - , aryl, heteroaryl optionally surrounded by one or more R 7 to replace;
  • R 5 and R 6 are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, optionally substituted with one or more R7 ;
  • R 5 is H and R 6 is selected from methyl, cyclopropyl, phenyl, naphthyl, The methyl, cyclopropyl, phenyl, naphthyl, optionally substituted with one or more R7 ;
  • R 5 is H and R 6 is methyl
  • R 5 is H and R 6 is phenyl optionally substituted with one or more R 7 ; preferably, R 3 is
  • R 3 is and wherein R 5 is H;
  • R 4 is a 3-8-membered saturated ring containing 1-2 atoms independently selected from N and O, which is connected to the The rings are connected, and the 3-8 membered saturated ring containing 1-2 N, O atoms is optionally substituted by one or more R 8 ;
  • R is selected from the following groups optionally substituted with one or more R:
  • R 4 is
  • R 10 and R 11 are each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 12 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon group;
  • R 9 is selected from C1-C3 alkyl
  • R9 is selected from -CH3 .
  • the present disclosure provides a compound of formula (II) or formula (III) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxidation thereof Object:
  • a 1 , A 2 , A 3 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and n are as defined above.
  • the present disclosure also provides a compound represented by formula (IIA) or formula (IIIA) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N- Oxides:
  • R 2 is selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 membered aryl or 5-6 membered containing 1-2 heteroatoms independently selected from N, S, O Heteroaryl;
  • R 2 is selected from H, D, methyl, ethyl, propyl, isopropyl;
  • R 2 is selected from H
  • n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;
  • R 5 is selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH 2 )-, (C3-C6 cycloalkyl)-(CH 2 CH 2 )-, the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)- are optionally replaced by a or multiple R 13 substitutions;
  • R 5 is selected from H, D, C1-C4 alkyl
  • R 5 is selected from H, D, methyl, ethyl, propyl, isopropyl;
  • R 5 is selected from H
  • R 10 and R 11 are each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;
  • R 10 , R 11 are each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, acetyl;
  • R 12 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon group;
  • R 9 is selected from C1-C3 alkyl
  • R 9 is selected from -CH 3 ;
  • tau protein-binding compound tau binder
  • the present disclosure also provides a preparation method of any of the aforementioned compounds, comprising the following steps:
  • the compound of formula (IV) was dissolved in a solvent, R 3 -H was added to a suitable reaction system, and the reaction mixture was stirred at room temperature; LCMS monitored the completion of the reaction; the reaction mixture was poured into water, extracted with ethyl acetate, and the combined organic phases were Then washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained crude product was purified by chromatography to obtain the solid compound represented by formula (I); or,
  • the present disclosure also provides a small molecule compound that specifically degrades tau protein, characterized in that the chemical structure of the compound is TBM-L-ULM or TBM-L-AUM and pharmaceutically acceptable salts thereof , enantiomer, stereoisomer, solvate, polymorph or N-oxide, wherein TBM is the tau protein binding moiety, L is the linker group, ULM is the ubiquitin ligase binding moiety, and AUM is the Binding moiety of the ZZ segment of the autophagy receptor p62/SQSTM1/Sequestosome-1, the TBM is L-linked to the ULM or AUM moiety.
  • TBM is a compound group represented by the aforementioned formulas (I), (II), (III), (IIA), (IIIA), and when R 3 is -
  • an exemplary structure of the TBM group is shown below, wherein Show the connection position to the X part in L:
  • the ULM can bind to E3 ubiquitin ligase; preferably, the E3 ubiquitin ligase is VHL E3 ubiquitin ligase or CRBN E3 ubiquitin ligase;
  • exemplary compounds of the ULM are shown below, which are attached to the Z moiety of L through the amino N atom shown in positions 1 and 2, respectively,
  • the AUM can bind to the ZZ segment of the autophagy receptor p62/SQSTM1/Sequestosome-1, and its exemplary structure is shown below, and is linked to the aminoalkane in L through the 3 position
  • the C atom of the radical or the O atom in the ether group is attached to the Z moiety of L,
  • L is a group -X-Y-Z-
  • Y is -E 1 -(CH 2 CH 2 O) p -E 2 -, -E 1 -(CH 2 ) q -E 2 -,
  • TBM is attached to the attached alkylene C atom of the X group
  • ULM is attached to the carbonyl C atom of the Z group
  • m is selected from 0, 1, 2, 3 or 4
  • p is selected from 0, 1, 2, 3, 4, 5 or 6
  • q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R 14 is selected from H, C1-C3 alkyl; preferably, R 14 is selected from H, methyl, ethyl; preferably, R 14 is selected from H, methyl;
  • E 1 and E 2 are independently selected from single bond, And at least one of E 1 and E 2 is a single bond;
  • E is selected from a single bond, -(CH 2 ) m O-, optionally, one or more Hs on the methylene group in the -(CH 2 ) m O- are substituted with R;
  • R is D, -OH, C1-C3 alkyl, C1-C3 alkoxy, preferably, R is selected from single bond, D, methyl, ethyl, -OH;
  • the small molecule compound that specifically degrades tau protein described in the present disclosure is as follows:
  • the -L-AUM group is shown in the following structure:
  • the exemplary structures of the small molecule compounds that specifically degrade tau protein described in the present disclosure include:
  • the preparation method of the aforementioned small molecule compound that specifically degrades tau protein adopts conventional technical methods in the art.
  • the preparation method comprises combining the TBM group with the -L-ULM or -L-AUM group connected. It can be known that, in order to obtain greater reaction efficiency or yield, those skilled in the art can use other methods to prepare the small molecule compounds described in the present disclosure as required, and the connection between each group and its substituents is not covered by the present disclosure. Restrictions on the way of recording.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxidation thereof compound, or any of the aforementioned small molecule compounds and pharmaceutically acceptable excipients.
  • the present disclosure also provides a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any of the foregoing , or the application of the aforementioned pharmaceutical composition in the preparation of a medicine for treating a patient's condition caused by accumulation of tau protein;
  • the condition caused by accumulation of tau protein is selected from Alzheimer's disease (AD), frontotemporal dementia linked to chromosome-17 parkinsonism linked to chromosome 17 with Parkinson's disease, FTDP-17), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), primary age-related tau disease (primary age-related tau disease) age-related tauopathy (PART), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), chronic traumatic encephalopathy (CTE) , Globular glial tauopathy (GGT), Parkinson's disease (PD), Huntington's Disease (HD), or one or more of stroke, epilepsy and autism.
  • AD Alzheimer's disease
  • PiD progressive supranuclear palsy
  • CBD corticobasal degeneration
  • primary age-related tau disease primary age-related tau disease
  • PART age-related tauopathy
  • ARTAG aging-related tau a
  • the present disclosure also provides a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any of the foregoing , or the application of the aforementioned pharmaceutical composition in the preparation of a tau degrading agent.
  • the present disclosure also provides a method of degrading tau protein in a patient in need thereof, comprising administering to said patient a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvent thereof compound, polymorph, or N-oxide, or a small molecule compound of any of the foregoing, or a pharmaceutical composition of the foregoing.
  • the present disclosure also provides a method of degrading tau protein in a biological sample, comprising combining the biological sample with a compound of any of the foregoing, pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates thereof , a polymorph or N-oxide, or a small molecule compound of any of the foregoing, or a pharmaceutical composition of the foregoing.
  • the present disclosure also provides a method for treating a disorder caused by accumulation of tau protein in a patient in need thereof, comprising administering to said patient a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer thereof Isomers, solvates, polymorphs, or N-oxides, or a small molecule compound of any of the foregoing, or a pharmaceutical composition of the foregoing.
  • Embodiment 1 the preparation of compound QR10000
  • Embodiment 2 the preparation of compound QR10010
  • Embodiment 3 the preparation of compound QR10014
  • Embodiment 4 the preparation of compound QR10033
  • Embodiment 5 the preparation of compound QR10034
  • Embodiment 6 the preparation of compound QR10035
  • Embodiment 7 the preparation of compound QR10036
  • Embodiment 8 the preparation of compound QR10037
  • Embodiment 9 the preparation of compound QR10038
  • Coomassie Brilliant Blue R250 Beyotime
  • the gel was transferred to a semi-dry membrane transfer apparatus (Bio-Rad) under constant current flow of 80 mA for 60 minutes, and the transferred PVDF membrane (Sigma) was transferred to 5% nonfat dry milk (dissolved in Tris-Tween). Buffer (TBST: 20 mM Tris-HCl, pH 7.4, 150 mM NaCl, 0.1% Tween-20) was blocked at room temperature for 30 minutes. The membranes were then mixed with tau polyclonal antibody (Proteintech, 1:5000) or monoclonal antibody (Abcam, 1:500) (dissolved in TBST) for 1 hour at 37°C or overnight at 4°C. The membrane was washed three times with TBST for 5 minutes each.
  • the membrane was then mixed with horseradish peroxidase-labeled goat anti-rabbit or Horseradish peroxidase-conjugated goat anti-mouse secondary antibody (Proteintech, 1:10000 dilution) was incubated at 37° C. for 1 hour. After washing the membrane (5 minutes/time, three times in total), the membrane was visualized by ECL chemiluminescence. The color solution was developed for one minute, and then a gel imaging system (Shanghai Qinxiang Scientific Instrument Co., Ltd.) was used for signal acquisition.
  • Sample test conditions use PBS buffer pH 7.4 containing 0.05% Tween-20 and 1% DMSO as the running buffer, use the running buffer as a control test sample, set a series of concentrations (15.625 ⁇ M, 31.25 ⁇ M, 62.5 ⁇ M, 125 ⁇ M, 250 ⁇ M, 500 ⁇ M, 1mM), the flow rate was set to 30 ⁇ L/min, the binding time was 40s, and the dissociation time was 40s during sample analysis.
  • KD values where "A” means KD ⁇ 200 ⁇ M; “B” means KD is between 200 ⁇ M and 500 ⁇ M; and “C” means KD > 500 ⁇ M.
  • the above data show that the compound of formula (I) of the present disclosure has the ability to bind to tau protein, can be used for binding to protein, and can further prepare the small molecule compound described in the present disclosure for degrading tau protein.

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Abstract

La présente invention concerne le domaine technique des composés. L'invention concerne une pluralité de composés à petites molécules qui sont spécifiquement liés à une protéine tau et une application de ceux-ci, les structures chimiques de ces composés à petites molécules étant telles que représentées par la formule (I), ou des énantiomères, des stéréoisomères, des solvates, des polymorphes, des N-oxydes ou des sels pharmaceutiquement acceptables de ceux-ci.
PCT/CN2022/078882 2021-03-03 2022-03-02 Composé à petites molécules lié à la protéine tau Ceased WO2022184111A1 (fr)

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CN112047935A (zh) * 2019-06-05 2020-12-08 上海强睿生物科技有限公司 一种自噬靶向性蛋白降解技术及其应用
WO2021160012A1 (fr) * 2020-02-13 2021-08-19 上海强睿生物科技有限公司 Composé à petites molécules capable de dégrader de manière spécifique la protéine tau et son utilisation

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