Small molecule compounds binding to tau

Abstract

The present disclosure relates to the technical field of compounds, and discloses a plurality of small-molecule compounds specifically binding to tau protein and applications thereof. The chemical structure of the small-molecule compounds is as shown in formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof.

Description

Technical Field

[0001] This disclosure relates to the field of medicinal chemistry, and in particular to a small molecule compound that binds to tau protein, its preparation method, and its uses. Background Technology

[0002] Tau protein is a microtubule-associated protein that plays an important role in stabilizing the cytoskeleton microtubules. Tau protein is a naturally unfolded protein that does not tend to form polymers. However, its aggregation occurs in a series of neurodegenerative diseases collectively known as "tau diseases," including Alzheimer's disease (AD), frontotemporal dementia linked to chromosome 17-17 parkinsonism (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), and chronic traumatic encephalopathy (CTA). Tau is a protein responsible for the neurodegenerative changes in diseases such as traumatic encephalopathy (CTE), globulular glial tauopathy (GGT), Parkinson's disease (PD), and Huntington's disease (HD). It is also a key target for diagnosis and treatment. Furthermore, recent research indicates that tau is involved in regulating neuronal excitability, making it a potential target for treating epilepsy, autism, and stroke.

[0003] Currently, some small molecule compounds that specifically bind to tau polymers have been successfully developed as tracers for positron emission tomography (PET) imaging, for the early diagnosis of Alzheimer's disease and other tau diseases. Reports indicate that some small molecule compounds (such as methylene blue and its derivatives) can inhibit tau aggregation, potentially offering treatment for Alzheimer's disease or other tau disorders. However, the mechanism by which they inhibit tau aggregation is not fully understood, and it remains unclear which tau protein (tau monomers or aggregates) they bind to. Tau is a naturally occurring, structureless protein, and its monomers lack binding pockets for ligands, making the development of small molecule compounds with high affinity for tau monomers challenging. To date, research on compounds binding to tau monomers is extremely limited. Recently, several series of small molecule compounds binding to tau monomers have been reported. Interestingly, although their affinity for tau monomers is not strong (KD is approximately 100 μM or higher), some of these compounds can still inhibit tau aggregation. Furthermore, small molecule compounds binding to tau have other applications. Recent breakthroughs in small molecule compound research include the development of bifunctional small molecules, such as protein degradation targeting chimeras (PROteolysis TArrigs). PROTACs (Protacid Chimeras) and autophagy-targeting chimeras (AUTACs) are used to mediate the degradation of target proteins. PROTACs consist of three parts: (1) a target protein ligand; (2) a specific E3 ubiquitin-transferase ligand; and (3) a linker connecting the target protein ligand and the E3 ubiquitin-transferase ligand. Interestingly, even if the target protein ligand has a low affinity for the target protein, PROTACs can still effectively downregulate the target protein due to their catalytic effect. Therefore, small molecule compounds that bind to tau, even with low affinity for tau, can be used to construct bifunctional PROTAC molecules that mediate tau degradation for the treatment of tau diseases and other tau-related diseases.

[0004] Because small molecule compounds that bind to tau have many applications in drug development, this invention has developed several small molecule compounds with strong affinity for tau protein. Summary of the Invention

[0005] This disclosure discloses the synthesis of a series of small molecule compounds capable of binding to tau protein monomers. These small molecule compounds have the potential to be used to develop inhibitors of tau aggregation for the treatment of tau disease and other tau-related diseases. Furthermore, these small molecule compounds can also be used to construct bifunctional molecules, such as protein degradation-targeting chimeras (PROTAC) and autophagy-targeting chimeras (AUTAC), to develop tau protein degraders for the treatment of tau disease and other tau-related diseases.

[0006] On the one hand, this disclosure provides compounds of formula (I), pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs, or N-oxides:

[0007]

[0008] in:

[0009] A1, A2, and A3 are each independently selected from C and N atoms; preferably, A1, A2, and A3 are all N atoms.

[0010] L1 is -(CH2) n -or-(CH2O) n - Preferably, L1 is -(CH2). n -;

[0011] R 1 Selected from 5-6-membered aryl groups or 5-6-membered heteroaryl groups containing 1-2 heteroatoms independently selected from N, S, and O, wherein the 5-6-membered aryl group or 5-6-membered heteroaryl group is optionally separated by one or more R groups. 15 Instead, the R 15 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogens;

[0012] Preferably, R 1 Selected from phenyl, pyridyl, pyranyl, thiaranyl, pyrroleyl, furanyl, thiophenyl, imidazolyl, oxazolyl, and thiazolyl;

[0013] Preferably, R 1 Selected from phenyl, 2-pyridyl, 2-thienyl, and 2-thiazolyl;

[0014] Preferably, R 1 Selected from 2-thienyl;

[0015] R 2 Selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 aryl, or 5-6 heteroaryl containing 1-2 heteroatoms independently selected from N, S, and O;

[0016] Preferably, R 2 Selected from H;

[0017] Or R 2 Through R 1 The atoms on the ring are connected, making R 1 R 2 Together with the atoms bonded to them, they form an 8-10 member partially unsaturated or aromatic carbocyclic bicycle, containing 1-2 heteroatoms independently selected from N, S, and O; preferably, R 1 R 2 Together with the atoms they are bonded to, they form

[0018] n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;

[0019] R 3 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 5 R 6 -OR 16 Preferably, R 3 Selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -NR 5 R 6 ;

[0020] R 5 R 6 Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, aryl, or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, S, or O, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, aryl, or heteroaryl is optionally separated by one or more R 7 replace;

[0021] Preferably, R 5 R 6 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, Optionally by one or more R 7 replace;

[0022] Preferably, R 5 For H and R 6 Selected from methyl, cyclopropyl, phenyl, naphthyl, The methyl, cyclopropyl, phenyl, naphthyl, Optionally by one or more R 7 replace;

[0023] Preferably, R 5 For H and R 6 It is methyl;

[0024] Preferably, R 5 For H and R 6 To be optionally used by one or more R 7 Substituted phenyl; preferably, R 3 for

[0025] Preferably, R 3 for And R 5 For H;

[0026] R 4 It is a 3-8 membered saturated ring containing 1-2 independently selected N or O atoms, which is connected to the N atom by formula (I). The rings are connected, and the 3-8 saturated rings containing 1-2 N and O atoms are optionally connected by one or more R atoms. 8 replace;

[0027] Preferably, R 4 To select arbitrarily by one or more R 8 The following groups are substituted:

[0028]

[0029] Preferably, R 4 for

[0030] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogen, 5-8 membered saturated ring containing 1-2 N, S, O atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, or 5-8 membered saturated ring containing 1-2 N, S, O atoms is optionally surrounded by one or more R 9 replace;

[0031] R 8 Selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C(=O)R 12 -S(=O)2R 12 ;

[0032] R 9 Selected from C1-C6 alkyl groups, -NO2, -CN, -NH2, -OH, halogens, and -C(=O)R. 12 ;

[0033] R 10 R 11 Each is independently selected from H, D, C1-C6 alkyl, and C1-C6 alkanoyl groups;

[0034] R 12 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C2-C6 unsaturated hydrocarbon groups;

[0035] Preferably, R 7 Selected from -CH3, -CF3, -CH2F, -CHF2, -CCl3, -OCH3, -NO2, -NH2, -C(=O)NH2, -OH, F, Cl, Br, I,

[0036] Preferably, R 7 Selected from -CF3, -OCH3, -NO2, -NH2, -C(=O)NH2, -Br,

[0037] Preferably, R 8 Selected from -CH3, -OH, -OCH3, -C(=O)CH3, -C(=O)CH2, -C(=O)-cyclopropyl, -S(=O)2-cyclopropyl;

[0038] Preferably, R 8 Selected from -C(=O)CH3;

[0039] Preferably, R 9 Selected from C1-C3 alkyl groups;

[0040] Preferably, R 9 Selected from -CH3.

[0041] On the other hand, this disclosure provides compounds of formula (II) or formula (III) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof:

[0042]

[0043] in,

[0044] A1, A2, and A3 are each independently selected from C and N atoms; preferably, A1, A2, and A3 are all N atoms.

[0045] R 2 Selected from H, D, and C1-C6 alkyl groups;

[0046] Preferably, R 2 Selected from H, D, methyl, ethyl, propyl, and isopropyl;

[0047] Preferably, R 2 Selected from H;

[0048] n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;

[0049] R 5 R 6 Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, aryl, or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, S, or O, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, aryl, or heteroaryl is optionally separated by one or more R 7 replace;

[0050] Preferably, R 5 R 6 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, Optionally by one or more R 7 replace;

[0051] Preferably, R 5 For H and R 6 Selected from methyl, cyclopropyl, phenyl, naphthyl, The methyl, cyclopropyl, phenyl, naphthyl, Optionally by one or more R 7 replace;

[0052] Preferably, R 5 For H and R 6 It is methyl;

[0053] Preferably, R 5 For H and R 6 To be optionally used by one or more R7 Substituted phenyl;

[0054] Preferably, R 6 for

[0055] Preferably, R 6 for And R 5 For H;

[0056] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogen, 5-8 membered saturated ring containing 1-2 N, S, O atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, or 5-8 membered saturated ring containing 1-2 N, S, O atoms is optionally surrounded by one or more R 9 replace;

[0057] R 8 Selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C(=O)R 12 -S(=O)2R 12 ;

[0058] R 9 Selected from C1-C6 alkyl groups, -NO2, -CN, -NH2, -OH, halogens, and -C(=O)R. 12 ;

[0059] R 10 R 11 Each is independently selected from H, D, C1-C6 alkyl, and C1-C6 alkanoyl groups;

[0060] Preferably, R 10 R 11 Each is independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, and acetyl groups;

[0061] R 12 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C2-C6 unsaturated hydrocarbon groups;

[0062] Preferably, R 7 Selected from -CH3, -OCH3, -NO2, -NH2, -C(=O)NH2, -OH, F, Cl, Br, I,

[0063] Preferably, R 7Selected from -OCH3, -NO2, -NH2, -C(=O)NH2, -Br,

[0064] Preferably, R 8 Selected from -CH3, -OH, -OCH3, -C(=O)CH3, -C(=O)CH2, -C(=O)C3H5-cyclopropyl, -S(=O)2-cyclopropyl;

[0065] Preferably, R 8 Selected from -C(=O)CH3;

[0066] Preferably, R 9 Selected from C1-C3 alkyl groups;

[0067] Preferably, R 9 Selected from -CH3.

[0068] On the other hand, this disclosure also provides compounds of formula (IIA) or formula (IIIA) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof:

[0069]

[0070]

[0071] in:

[0072] R 2 Selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 aryl, or 5-6 heteroaryl containing 1-2 heteroatoms independently selected from N, S, and O;

[0073] Preferably, R 2 Selected from H, D, methyl, ethyl, propyl, and isopropyl;

[0074] Preferably, R 2 Selected from H;

[0075] n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;

[0076] R 5 Selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)- is optionally separated by one or more R 13 replace;

[0077] Preferably, R 5 Selected from H, D, and C1-C4 alkyl groups;

[0078] Preferably, R 5 Selected from H, D, methyl, ethyl, propyl, and isopropyl;

[0079] Preferably, R 5 Selected from H;

[0080] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogen, 5-8 membered saturated ring containing 1-2 N, S, O atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, or 5-8 membered saturated ring containing 1-2 N, S, O atoms is optionally surrounded by one or more R 9 Replacement;

[0081] R 8 Selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C(=O)R 12 -S(=O)2R 12 ;

[0082] R 9 Selected from C1-C6 alkyl groups, -NO2, -CN, -NH2, -OH, halogens, and -C(=O)R. 12 ;

[0083] R 10 R 11 Each is independently selected from H, D, C1-C6 alkyl, and C1-C6 alkanoyl groups;

[0084] Preferably, R 10 R 11 Each is independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, and acetyl groups;

[0085] R 12 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C2-C6 unsaturated hydrocarbon groups;

[0086] Preferably, R 7 Selected from -CH3, -OCH3, -NO2, -NH2, -C(=O)NH2, -OH, F, Cl, Br, I,

[0087] Preferably, R 7Selected from -OCH3, -NO2, -NH2, -C(=O)NH2, -Br,

[0088] Preferably, R 8 Selected from -CH3, -OH, -OCH3, -C(=O)CH3, -C(=O)CH2, -C(=O)-cyclopropyl, -S(=O)2-cyclopropyl;

[0089] Preferably, R 8 Selected from -C(=O)CH3;

[0090] Preferably, R 9 Selected from C1-C3 alkyl groups;

[0091] Preferably, R 9 Selected from -CH3;

[0092] R 13 Selected from C1-C3 alkyl, C1-C3 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogens;

[0093] Preferably, R 13 Selected from methyl, ethyl, propyl, isopropylmethoxy, ethoxy, -NO2, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -OH, and halogens.

[0094] On the other hand, this 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 its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides, 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, wherein the TBM and the ULM or AUM moiety are linked by L.

[0095] The aforementioned small molecule compounds that specifically degrade tau protein are characterized in that TBM is a compound group represented by formulas (I), (II), (III), (IIA), and (IIIA), and when R 3 For -NR 5 R 6 At that time, the TBM via R3 The N atom is bonded to L, or when R 8 When selected from -C(=O)CH3, the TBM passes through R 8 The carbonyl group C atom is bonded to L, or when R 8 When selected from C1-C6 alkoxy groups, the TBM is obtained through R 8 The oxygen atom is bonded to L.

[0096] The aforementioned small molecule compound that specifically degrades tau protein, wherein 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 a compound shown below, wherein the amino N atom is linked to the L atom through positions ① and ②.

[0097]

[0098] The aforementioned small molecule compound that specifically degrades tau protein, wherein the AUM can bind to the ZZ region of the autophagy receptor p62 / SQSTM1 / Sequestosome-1, exemplarily, the AUM has the following structure, wherein it is connected to L via position ③ to the C atom of the aminoalkyl group or the O atom of the ether group.

[0099]

[0100] The aforementioned small molecule compound that specifically degrades tau protein, wherein L is a group -XYZ-, and X is a single bond, -(CH2). m C(=O)NR 14 -、-(CH2) m NR 14 -、-(CH2) m NR 14 C(=O)-、-(CH2) m C(=O)-, optionally, the -(CH2) m C(=O)NR 14 -、-(CH2) m NR 14 -、-(CH2) m NR 14 C(=O)-、-(CH2) m One or more H atoms on the methylene group in C(=O)- are replaced by R;

[0101] Y is -E1-(CH2CH2O) p -E2-, -E1-(CH2) q -E2-,

[0102] Z stands for -(CH2).m C(=O)-,-(CH2) m NR 14 -E-, optionally, the -(CH2) m C(=O)-,-(CH2) m NR 14 One or more H atoms on the methylene group in -E- are replaced by R atoms;

[0103] TBM is attached to the alkylene C atom of the X group, and ULM is attached to the carbonyl C atom of the Z group.

[0104] Where m is selected from 0, 1, 2, 3 or 4, p is selected from 0, 1, 2, 3, 4, 5 or 6, and q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0105] R 14 Selected from H, C1-C3 alkyl; preferably, R 14 Selected from H, methyl, ethyl; preferably, R 14 Selected from H, methyl;

[0106] E1 and E2 are independently selected from single bonds, And at least one of E1 and E2 is a single bond;

[0107] E is selected from single bond, -(CH2) m O-, optionally, the -(CH2) m One or more H atoms on the methylene group in O- are replaced by R atoms;

[0108] The R is D, -OH, C1-C3 alkyl, C1-C3 alkoxy, and preferably, R is selected from single bond, D, methyl, ethyl, and -OH;

[0109] Preferably, the L is selected from the following groups:

[0110]

[0111] The aforementioned small molecule compounds that specifically degrade tau protein, wherein the -L-ULM group has the following structure:

[0112]

[0113] The aforementioned small molecule compounds that specifically degrade tau protein, wherein the -L-AUM group has the following structure:

[0114]

[0115] Compounds of formulas (I), (II), (III), (IIA), and (IIIB) are wherein the compounds are capable of binding to the tau protein.

[0116] This disclosure also provides compounds of formulas (I), (II), (III), (IIA), and (IIIB), as well as methods for preparing small molecule compounds TBM-L-ULM or TBM-L-AUM that degrade tau protein.

[0117] This disclosure also provides a tau protein binding agent with the structure shown in formulas (I), (II), (III), (IIA), (IIIB) and listed exemplary structures.

[0118] This disclosure also provides the use of compounds of formulas (I), (II), (III), (IIA), (IIIB) and the exemplary structures listed herein in the preparation of tau protein binding agents.

[0119] This disclosure also provides a pharmaceutical composition comprising the compounds described above, pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof, or small molecule compounds described above, and pharmaceutically acceptable excipients.

[0120] This disclosure also provides the use of the compounds described above, their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides, or the small molecule compounds described above, or the aforementioned pharmaceutical compositions in the preparation of a medicament for treating patients with symptoms caused by tau protein accumulation.

[0121] Preferably, the symptoms caused by tau protein accumulation are selected from Alzheimer's disease (AD), frontotemporal dementiallinked to chromosome-17 parkinsonism (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 (CTE), globular glial tauopathy (GGT), and Parkinson's disease. One or more of the following: disease, PD, Huntington's disease (HD), or stroke, epilepsy, and autism.

[0122] This disclosure also provides the use of the compounds described above, their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides, or the small molecule compounds described above, or the aforementioned pharmaceutical compositions in the preparation of tau degrading agents.

[0123] This disclosure also provides a method for degrading tau protein in a patient in need, comprising administering to the patient the above-described compound, its pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide, or the above-described small molecule compound, or the aforementioned pharmaceutical composition.

[0124] This disclosure also provides a method for degrading tau protein in a biological sample, comprising contacting the biological sample with the compounds described above, their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides, or the small molecule compounds described above, or the aforementioned pharmaceutical compositions.

[0125] This disclosure also provides a method for treating a patient in need of a condition caused by the accumulation of tau protein, comprising administering to the patient the above-described compound, its pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide, or the aforementioned small molecule compound, or the aforementioned pharmaceutical composition. Attached Figure Description

[0126] Figure 1A -O shows the NMR spectra of the compounds in Examples 1-15 of this disclosure.

[0127] Figure 2 The PROTAC molecular NMR spectrum prepared in Example 16 of this disclosure is shown.

[0128] Figure 3 The image shows Coomassie brilliant blue staining and immunoblotting of tau protein. Gel staining shows that tau protein is mainly a band of about 56 kDa with a small amount of degradation fragments (<10%) (a). The tau band can be recognized by tau-specific polyclonal antibody (b) and monoclonal antibody (c). Detailed Implementation

[0129] Based on the above content of this disclosure, and in accordance with common technical knowledge and practices in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas of this disclosure.

[0130] I. Definition

[0131] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0132] The compounds of this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of this invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemic, diastereomers, and enantiomers are all included within the scope of this invention.

[0133] The compounds of this invention also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0134] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0135] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0136] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the atom or group is normal and the resulting compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0137] When any variable (e.g., R) n When a substituent appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-5 Rs, the group can optionally be substituted by up to 5 Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0138] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups having the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, examples of which 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 can be divalent, such as methylene or ethylene.

[0139] The terms "halogenation" or "halogen substitution" refer to the substitution of one or more halogen atoms, including fluorine, chlorine, bromine, and iodine atoms.

[0140] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system without heteroatoms or double bonds. Examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0141] The terms "aryl" and "aromatic" refer to aromatic ring groups with a conjugated π-electron system, consisting of an all-carbon monocyclic or fused polycyclic aromatic ring, obtained by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. For example, aryl groups can have 6-20, 6-14, or 6-10 carbon atoms. This includes bicyclic groups comprising an aromatic ring fused with a saturated, partially unsaturated, or aromatic carbon ring. Examples include, but are not limited to, phenyl, naphthyl, anthracene, indene, indane, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthalene.

[0142] The term "heteroaryl" refers to a monovalent aryl group comprising at least one 5-, 6-, or 7-membered ring independently selected from nitrogen, oxygen, and sulfur heteroatoms, and comprising 5-10 atoms in a fused ring system (at least one of which is aromatic). Examples of aromatic heterogroups include, but are not limited to, pyridyl, thiophene, imidazolyl, pyrimidinyl, furanyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, imidazopyridyl, benzofuranyl, pyridazinyl, and isoyindolyl.

[0143] The term "membered ring" refers to the number of skeleton atoms that make up the ring. For example, "5-10 members" means that the number of skeleton atoms in the ring is 5, 6, 7, 8, 9, or 10. Thus, for example, pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene and pyrrole are five-membered rings.

[0144] The term "heterocycle" refers to a 5-12 member saturated non-aromatic system having a ring carbon atom and one or two ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur, or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the connecting point can be a carbon or nitrogen atom, provided the valence allows. Heterocycles can be monocyclic or polycyclic systems, such as bicyclic systems, wherein two or more rings exist in the form of fused rings, bridged rings, or spirocyclic rings, wherein at least one ring contains one or more heteroatoms.

[0145] As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0146] Substituent R n It can bond to any atom on the ring, as long as the valence allows. Combinations of substituents and / or their variants are permitted only if such combinations produce a stable compound. Those skilled in the art will understand that for compounds containing one or more R... n No substituent group introduces any substitution or substitution pattern that is spatially impossible and / or cannot be synthesized.

[0147] It refers to the junction of chemical bonds.

[0148] As used herein, the term "protecting group" refers to the protection of other groups before a reaction occurs in a multifunctional organic compound, ensuring that the reaction occurs only at the desired group and preventing other groups from being affected. The protecting group is then removed after the reaction is complete. A reagent that can protect a particular group is called a protecting group for that group. Common protecting groups include hydroxyl protecting agents and amino protecting agents. Protecting groups for hydroxyl groups include, but are not limited to: acetyl (Ac), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methyl thiomethyl ether (MTM), pivaloyl (Piv), tetrahydropyran (THP), silyl ether protecting groups, methyl ethers, etc.; protecting groups for amino groups include, but are not limited to: benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenemethoxycarbonyl (FMOC), benzyl (Bn), p-methoxyphenyl (PMP), triphenylmethyl derivative protecting groups, etc.

[0149] Drugs or drug compositions

[0150] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0151] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0152] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0153] The pharmaceutical products or pharmaceutical compositions disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier. Oral administration is generally preferred. The active agent can be administered orally in capsule, tablet, or other similar forms (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0154] For oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium hydroxyacetic acid starch); or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorings, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or alginate), buffer salts, carboxymethyl cellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical component may be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, esters, ethanol, or fractionated vegetable oils), and a preservative (e.g., methylparaben, propylparaben, or sorbic acid). Stabilizers such as antioxidants (BHA, BHT, propyl iodide, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0155] Tablets containing the active compound can be coated using methods well known in the art. The compositions of this disclosure containing a compound of formula I as the active compound can also incorporate beads, microspheres, or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, emulsions, or suspensions, or they can be presented as dry products reconstituted with water or other suitable excipients prior to use. Formulations for oral administration can be suitably formulated to allow for controlled or delayed release of the active compound.

[0156] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0157] The pharmaceutical or pharmaceutical composition disclosed herein can also be formulated for rectal administration, for example as a suppository or retention enema (e.g., containing a conventional suppository base such as cocoa butter or other glycerides).

[0158] The term "treatment" includes suppressing, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0159] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used relative to a control. Those skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with the compound is compared to a response in a subject or cell not treated with the compound.

[0160] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or alleviate one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0161] The term "excipient" is used herein to include any other compound that is not therapeutic or biologically active and may be contained in or on microparticles. Therefore, excipients should be pharmaceutically or biologically acceptable or relevant, for example, excipients that are generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include multiple compounds.

[0162] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0163] Uses and treatments

[0164] The terms “patient,” “subject,” “individual,” etc., are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, that conform to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a person.

[0165] According to the method of the present invention, the compound or composition may be administered in any amount and via any route of administration for the effective treatment of diseases associated with tau protein accumulation or to reduce their severity.

[0166] This invention relates to a method for reducing tau protein in a biological sample, comprising the step of contacting the biological sample with a compound of the invention or a composition containing the compound.

[0167] The term "biological sample" includes (but is not limited to) cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. Inhibition of enzymes in biological samples can be used to achieve a variety of purposes known to those skilled in the art. Examples of such purposes include (but are not limited to) bioanalysis, gene expression studies, and identification of biological targets.

[0168] The method of the present invention for inhibiting tau protein in a patient comprises the step of administering the compound of the present invention or a composition comprising the compound to the patient.

[0169] The provided compounds are tau protein inhibitors and therefore can be used to treat one or more conditions related to tau protein activity. Accordingly, in some embodiments, the present invention provides a method for treating tau protein-mediated conditions, comprising the step of administering the compounds of the present invention or pharmaceutically acceptable compositions thereof to a patient in need.

[0170] As used herein, the term "tau protein-mediated" refers to any disease, ailment, and / or symptom where the tau protein or its mutants are known to act. Therefore, another embodiment of the invention relates to treating one or more diseases where the tau protein or its mutants are known to act, or to reducing their severity.

[0171] The conditions mediated by tau protein are well established in the art. The relationship between tau protein and the conditions, diseases, and / or symptoms mediated by tau protein as described herein is well established in the relevant art. Examples include Alzheimer's disease (AD), frontotemporal dementia linked to chromosome-17 parkinsonism (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 (CTE), globular glialtauopathy (GGT), and Parkinson's disease. Diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are mentioned. Tau protein is a key factor contributing to the neurodegenerative changes in these diseases, making it an important target for their diagnosis and treatment. Furthermore, recent research indicates that tau is involved in regulating neuronal excitability, thus making it a potential target for treating epilepsy, autism, and stroke.

[0172] As used herein, the term "protein degradation targeting chimera" (PROTAC) is a chemical molecule containing different ligands at both ends. One end is a ligand that binds to E3 ligases (e.g., the ULM portion described in this disclosure), and the other end is a ligand that binds to intracellular proteins (e.g., the TBM portion that binds to tau protein described in this disclosure). These two ligands are then linked together by a linker (e.g., the L portion described in this disclosure). Such a chemical molecule can bind to both E3 ubiquitin ligases and intracellular proteins, achieving polyubiquitination of the targeted protein by recruiting it to the vicinity of the E3 ubiquitin ligase. Finally, the protein is degraded by the proteasome. PROTACs can be recycled and are not degraded by the proteasome.

[0173] As used in this article, the term "autophagy-targeted chimera," or AUTAC, employs a design similar to PROTAC, making it well-suited for degrading target proteins in the cytoplasm that are resistant to PROTAC molecules. Cargo proteins are first phagocytosed to form autophagosomes, then autophagy receptors such as SQSTM1 / p62 recognize Lys63 (K63) polyubiquitinated cargo proteins and transfer them to autophagosomes for degradation. Both AUTAC and PROTAC molecules function through ubiquitination, but AUTAC molecules induce target degradation by triggering K63 polyubiquitination.

[0174] As used herein, the term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugate, causes ubiquitin to attach to a lysine residue on a target protein and subsequently targets a specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with an E2 ubiquitin conjugate, are responsible for the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases involve polyubiquitination, where a second ubiquitin attaches to a first ubiquitin; a third ubiquitin attaches to a second ubiquitin, and so on. Polyubiquitination tags proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule via a ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome but can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysine residues in ubiquitin can be targeted by E3 to prepare the chain. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, which is recognized by the proteasome.

[0175] combination therapy

[0176] This disclosure provides combination therapies using compounds as described herein in combination with other therapeutic agents. As used herein, the term "combination therapy" includes the sequential administration of these agents, i.e., each therapeutic agent is administered at different times, and the administration of these agents, or at least two agents, substantially simultaneously. The order, or substantially simultaneous administration, of each agent may be influenced by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous routes, and direct absorption through mucosal tissues. Agents may be administered via the same or different routes. For example, a first agent may be administered orally, while a second agent may be administered intravenously. Furthermore, selected combinations may be administered intravenously, while other agents in the combination may be administered orally. Alternatively, for example, two or more agents may be administered intravenously or subcutaneously.

[0177] II. Detailed Implementation

[0178] This disclosure provides compounds of formula (I), pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs, or N-oxides:

[0179]

[0180] in:

[0181] A1, A2, and A3 are each independently selected from C and N atoms; preferably, A1, A2, and A3 are all N atoms.

[0182] L1 is -(CH2) n -or-(CH2O) n -;

[0183] In one specific embodiment, L1 is -(CH2). n -;

[0184] R 1 Selected from 5-6-membered aryl groups or 5-6-membered heteroaryl groups containing 1-2 heteroatoms independently selected from N, S, and O, wherein the 5-6-membered aryl group or 5-6-membered heteroaryl group is optionally separated by one or more R groups. 15 Instead, the R 15 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogens;

[0185] In one specific embodiment, R 1 Selected from phenyl, pyridyl, pyranyl, thiaranyl, pyrroleyl, furanyl, thiophenyl, imidazolyl, oxazolyl, and thiazolyl;

[0186] In one specific embodiment, R 1 Selected from phenyl, 2-pyridyl, 2-thienyl, and 2-thiazolyl;

[0187] In one specific embodiment, R 1 Selected from 2-thienyl;

[0188] R 2 Selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 aryl, or 5-6 heteroaryl containing 1-2 heteroatoms independently selected from N, S, and O;

[0189] In one specific embodiment, R 2 Selected from H;

[0190] In one specific embodiment, R 2 Through R 1 The atoms on the ring are connected, making R 1 R 2 Together with the atoms bonded to them, they form an 8-10 member partially unsaturated or aromatic carbocyclic bicycle, containing 1-2 heteroatoms independently selected from N, S, and O; preferably, R 1 R 2 Together with the atoms they are bonded to, they form

[0191] n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;

[0192] R 3 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NR 5 R 6 -OR 16 Preferably, R 3 Selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -NR 5 R 6 ;

[0193] R 5 R 6 Each of the following is independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, aryl, or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, S, or O, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, aryl, or heteroaryl is optionally separated by one or more R 7 replace;

[0194] In one specific embodiment, R 5 R 6 Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, Optionally by one or more R 7 replace;

[0195] In one specific embodiment, R 5 For H and R 6 Selected from methyl, cyclopropyl, phenyl, naphthyl, The methyl, cyclopropyl, phenyl, naphthyl, Optionally by one or more R 7 replace;

[0196] In one specific embodiment, R 5 For H and R 6 It is methyl;

[0197] In one specific embodiment, R 5 For H and R 6 To be optionally used by one or more R 7 Substituted phenyl; preferably, R 3 for

[0198] In one specific embodiment, R 3 for And R 5 For H;

[0199] R 4 It is a 3-8 membered saturated ring containing 1-2 independently selected N or O atoms, which is connected to the N atom by formula (I). The rings are connected, and the 3-8 saturated rings containing 1-2 N and O atoms are optionally connected by one or more R atoms. 8 replace;

[0200] In one specific embodiment, R 4 To select arbitrarily by one or more R 8 The following groups are substituted:

[0201]

[0202] In one specific embodiment, R 4 for

[0203] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogen, 5-8 membered saturated ring containing 1-2 N, S, O atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, or 5-8 membered saturated ring containing 1-2 N, S, O atoms is optionally surrounded by one or more R 9 replace;

[0204] R 8 Selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C(=O)R 12 -S(=O)2R12 ;

[0205] R 9 Selected from C1-C6 alkyl groups, -NO2, -CN, -NH2, -OH, halogens, and -C(=O)R. 12 ;

[0206] R 10 R 11 Each is independently selected from H, D, C1-C6 alkyl, and C1-C6 alkanoyl groups;

[0207] R 12 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C2-C6 unsaturated hydrocarbon groups;

[0208] In one specific embodiment, R 7 Selected from -CH3, -CF3, -CH2F, -CHF2, -CCl3, -OCH3, -NO2, -NH2, -C(=O)NH2, -OH, F, Cl, Br, I,

[0209] In one specific embodiment, R 7 Selected from -CF3, -OCH3, -NO2, -NH2, -C(=O)NH2, -Br,

[0210] In one specific embodiment, R 8 Selected from -CH3, -OH, -OCH3, -C(=O)CH3, -C(=O)CH2, -C(=O)-cyclopropyl, -S(=O)2-cyclopropyl;

[0211] In one specific embodiment, R 8 Selected from -C(=O)CH3;

[0212] In one specific embodiment, R 9 Selected from C1-C3 alkyl groups;

[0213] In one specific embodiment, R 9 Selected from -CH3.

[0214] On the other hand, this disclosure provides compounds of formula (II) or formula (III) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof:

[0215]

[0216] in,

[0217] A1, A2, A3, R2 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 The definitions of n are as described above.

[0218] On the other hand, this disclosure also provides compounds of formula (IIA) or formula (IIIA) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof:

[0219]

[0220]

[0221] in:

[0222] R 2 Selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 aryl, or 5-6 heteroaryl containing 1-2 heteroatoms independently selected from N, S, and O;

[0223] In one specific embodiment, R 2 Selected from H, D, methyl, ethyl, propyl, and isopropyl;

[0224] In one specific embodiment, R 2 Selected from H;

[0225] n is selected from 1, 2, 3, 4 or 5; preferably, n is 1, 2 or 3; more preferably, n is 1 or 2;

[0226] R 5 Selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)-, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-(CH2)-, (C3-C6 cycloalkyl)-(CH2CH2)- is optionally separated by one or more R 13 replace;

[0227] In one specific embodiment, R 5 Selected from H, D, and C1-C4 alkyl groups;

[0228] In one specific embodiment, R 5 Selected from H, D, methyl, ethyl, propyl, and isopropyl;

[0229] In one specific embodiment, R 5 Selected from H;

[0230] R 7 Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogen, 5-8 membered saturated ring containing 1-2 N, S, O atoms, wherein the C1-C6 alkyl, C1-C6 alkoxy, or 5-8 membered saturated ring containing 1-2 N, S, O atoms is optionally surrounded by one or more R 9 Replacement;

[0231] R 8 Selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C(=O)R 12 -S(=O)2R 12 ;

[0232] R 9 Selected from C1-C6 alkyl groups, -NO2, -CN, -NH2, -OH, halogens, and -C(=O)R. 12 ;

[0233] R 10 R 11 Each is independently selected from H, D, C1-C6 alkyl, and C1-C6 alkanoyl groups;

[0234] In one specific embodiment, R 10 R 11 Each is independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, and acetyl groups;

[0235] R 12 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C2-C6 unsaturated hydrocarbon groups;

[0236] In one specific embodiment, R 7 Selected from -CH3, -OCH3, -NO2, -NH2, -C(=O)NH2, -OH, F, Cl, Br, I,

[0237] In one specific embodiment, R 7 Selected from -OCH3, -NO2, -NH2, -C(=O)NH2, -Br,

[0238] In one specific embodiment, R 8Selected from -CH3, -OH, -OCH3, -C(=O)CH3, -C(=O)CH2, -C(=O)-cyclopropyl, -S(=O)2-cyclopropyl;

[0239] In one specific embodiment, R 8 Selected from -C(=O)CH3;

[0240] In one specific embodiment, R 9 Selected from C1-C3 alkyl groups;

[0241] In one specific embodiment, R 9 Selected from -CH3;

[0242] R 13 Selected from C1-C3 alkyl, C1-C3 alkoxy, -NO2, -CN, -NR 10 R 11 -C(=O)NR 10 R 11 -OH, halogens;

[0243] In one specific embodiment, R 13 Selected from methyl, ethyl, propyl, isopropylmethoxy, ethoxy, -NO2, -CN, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -OH, halogen.

[0244] An exemplary structure of the tau protein-binding compound (tau binder) described in this disclosure is shown below:

[0245]

[0246]

[0247]

[0248]

[0249] On the other hand, this disclosure also provides a method for preparing any of the aforementioned compounds, comprising the following steps:

[0250] Option A:

[0251]

[0252] The compound of formula (IV) is dissolved in a solvent, and R is added to a suitable reaction system. 3-H, the reaction mixture was stirred at room temperature; the reaction was monitored by LCMS until completion; the reaction mixture was poured into water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to obtain the solid compound shown in formula (I); or,

[0253] Option B:

[0254]

[0255] Compound (V) was dissolved in a solvent under stirring at 0°C, and R was added to a suitable reaction system. 4 -H, the reaction mixture was stirred at room temperature; after the reaction was completed by LCMS monitoring, the reaction mixture was poured into water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to obtain the solid compound shown in formula (I). It is understood that the preparation of any of the aforementioned compounds can be carried out using conventional methods in the art. For example, R in scheme A or scheme B above... 3 -H and / or R 4 -H or reactants in specific preparation steps can take appropriate reaction forms, such as using a protective agent to protect the sites where no reaction is desired.

[0256] On the other hand, this 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 its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides, 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, wherein the TBM and the ULM or AUM moiety are linked by L.

[0257] The aforementioned small molecule compounds that specifically degrade tau protein are characterized in that TBM is a compound group represented by formulas (I), (II), (III), (IIA), and (IIIA), and when R 3 For -NR 5 R 6 At that time, the TBM via R 3 The N atom is bonded to L, or when R 8 When selected from -C(=O)CH3, the TBM passes through R 8 The carbonyl group C atom is bonded to L, or when R 8 When selected from C1-C6 alkoxy groups, the TBM is obtained through R 8 The oxygen atom is bonded to L.

[0258] In a specific embodiment, an exemplary structure of the TBM group is shown below, wherein... The connection point with the X portion in L is shown:

[0259]

[0260]

[0261]

[0262]

[0263]

[0264] The aforementioned small molecule compound that specifically degrades tau protein, wherein the ULM is capable of binding to an E3 ubiquitin ligase; preferably, the E3 ubiquitin ligase is a VHL E3 ubiquitin ligase or a CRBN E3 ubiquitin ligase.

[0265] In a specific embodiment, an exemplary compound of the ULM is shown below, which is connected to the Z portion of L through the amino N atom shown at positions ① and ②, respectively.

[0266]

[0267] The aforementioned small molecule compound that specifically degrades tau protein, wherein the AUM can bind to the ZZ region of the autophagy receptor p62 / SQSTM1 / Sequestosome-1, has the following exemplary structure, and is connected to the Z portion of L by the C atom of the aminoalkyl group or the O atom of the ether group in L at position ③.

[0268]

[0269] The disclosed small molecule compound specifically degrades tau protein, wherein in TBM-L-ULM or TBM-L-AUM, L is a group -XYZ-.

[0270] in,

[0271] X is a single bond, -(CH2) m C(=O)NR 14 -、-(CH2) m NR 14 -、-(CH2) m NR 14 C(=O)-、-(CH2) m C(=O)-, optionally, the -(CH2) m C(=O)NR 14-、-(CH2) m NR 14 -、-(CH2) m NR 14 C(=O)-、-(CH2) m One or more H atoms on the methylene group in C(=O)- are replaced by R;

[0272] Y is -E1-(CH2CH2O) p -E2-, -E1-(CH2) q -E2-,

[0273] Z stands for -(CH2). m C(=O)-,-(CH2) m NR 14 -E-, optionally, the -(CH2) m C(=O)-,-(CH2) m NR 14 One or more H atoms on the methylene group in -E- are replaced by R atoms;

[0274] TBM is attached to the alkylene C atom of the X group, and ULM is attached to the carbonyl C atom of the Z group.

[0275] Where m is selected from 0, 1, 2, 3 or 4, p is selected from 0, 1, 2, 3, 4, 5 or 6, and q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0276] R 14 Selected from H, C1-C3 alkyl; preferably, R 14 Selected from H, methyl, ethyl; preferably, R 14 Selected from H, methyl;

[0277] E1 and E2 are independently selected from single bonds, And at least one of E1 and E2 is a single bond;

[0278] E is selected from single bond, -(CH2) m O-, optionally, the -(CH2) m One or more H atoms on the methylene group in O- are replaced by R atoms;

[0279] R is D, -OH, C1-C3 alkyl, C1-C3 alkoxy, preferably, R is selected from single bond, D, methyl, ethyl, -OH;

[0280] In a specific embodiment, an exemplary structure of the L group of this disclosure is shown below:

[0281]

[0282] or:

[0283]

[0284] In a specific embodiment, the exemplary structure of the -L-ULM group in the small molecule compound that specifically degrades tau protein according to this disclosure is shown below:

[0285]

[0286] In a specific embodiment, the small molecule compound that specifically degrades tau protein according to this disclosure has the -L-AUM group as shown in the following structure:

[0287]

[0288] In specific embodiments, exemplary structures of the small molecule compounds that specifically degrade tau protein according to this disclosure include:

[0289] TBM-L-ULM molecule (PROTAC)

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308] TBM-L-AUM molecule (AUTAC):

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] The aforementioned method for preparing the small molecule compound that specifically degrades tau protein employs conventional techniques in the art. Exemplarily, the method includes linking the TBM group to the -L-ULM or -L-AUM group. However, it is understood that, to obtain greater reaction efficiency or yield, those skilled in the art may prepare the small molecule compound described herein using other methods as needed, and the connection between the groups and their substituents is not limited to the methods described herein.

[0336] This disclosure also provides a pharmaceutical composition comprising any of the foregoing compounds, pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof, or small molecule compounds of any of the foregoings, and pharmaceutically acceptable excipients.

[0337] This disclosure also provides the use of any of the foregoing compounds, pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof, or small molecule compounds of any of the foregoing compounds, or the use of the foregoing pharmaceutical compositions in the preparation of a medicament for treating a patient’s condition caused by tau protein accumulation.

[0338] Preferably, the symptoms caused by tau protein accumulation are selected from Alzheimer's disease (AD), frontotemporal dementiallinked to chromosome-17 parkinsonism (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 (CTE), globular glial tauopathy (GGT), and Parkinson's disease. One or more of the following: disease, PD, Huntington's disease (HD), or stroke, epilepsy, and autism.

[0339] This disclosure also provides the use of any of the foregoing compounds, pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof, or small molecule compounds thereof, or the use of the foregoing pharmaceutical compositions in the preparation of tau degrading agents.

[0340] This disclosure also provides a method for degrading tau protein in a patient in need, comprising administering to the patient any of the preceding compounds, a pharmaceutically acceptable salt thereof, an enantiomer, a stereoisomer, a solvate, a polymorph or an N-oxide thereof, or a small molecule compound of any of the preceding compounds, or a pharmaceutical composition thereof.

[0341] This disclosure also provides a method for degrading tau protein in a biological sample, comprising contacting the biological sample with any of the preceding compounds, their pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides, or any of the preceding small molecule compounds, or the preceding pharmaceutical compositions.

[0342] This disclosure also provides a method for treating a patient in need of a condition caused by the accumulation of tau protein, comprising administering to the patient any of the preceding compounds, a pharmaceutically acceptable salt thereof, an enantiomer, a stereoisomer, a solvate, a polymorph or an N-oxide thereof, or a small molecule compound of any of the preceding compounds, or a pharmaceutical composition thereof.

[0343] III. Examples

[0344] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0345] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0346] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0347] Example 1: Preparation of compound QR10000

[0348]

[0349] (1) Compound 0-a (2 g, 10.85 mmol) was dissolved in acetone (20 mL). Compound 0-b (1.3 g, 10.85 mmol) and N,N-diisopropylethylamine (DIEA, 1.4 g, 10.85 mmol) were added to the reaction mixture while stirring at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. LCMS: m / z 275.4 [M+H] + .

[0350] (2) Compound O-d (1.5 g, 10.85 mmol) and DIEA (1.4 g, 10.85 mmol) were added to the above reaction solution at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to give a white solid compound O-e (3.28 g, yield 81%). The reaction was monitored by LCMS until completion. LCMS: m / z = 381.1 [M+H]+ .

[0351] (3) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in acetone (3 mL), and methylammonium aqueous solution (2 mL) and DIEA (100 mg, 0.78 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound O (120 mg, yield 41%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.32 (dd, J=5.0, 1.2Hz, 1H), 6.95 (dd, J=5.1, 3.4Hz, 1H), 6.90-6. 40(m,3H),3.89–3.38(m,10H),3.01(s,2H),2.70(s,3H),2.05-1.90(m,3H),1.78(s,2H). LCMS:m / z=376.1[M+H] + . ( Figure 1A )

[0352] Example 2: Preparation of compound QR10010

[0353]

[0354] (1) The synthesis of compound 0-e is the same as described above.

[0355] (2) Compound O-e (300 mg, 0.78 mmol) was dissolved in acetone (3 mL), and ammonia solution (2 mL) and DIEA (100 mg, 0.78 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 10 (41 mg, yield 15%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ7.32(dd,J=5.1,1.2Hz,1H),6.95(dd,J=5.1,3.4Hz,1H),6.88(s,1H),6.70(s,1H),6.25(s,1H),6. 11(s,1H),3.87–3.39(m,10H),3.01(d,J=7.1Hz,2H),1.96(d,J=30.9Hz,3H),1.71(d,J=53.1Hz,2H).LCMS:m / z=362.1[M+H] + . ( Figure 1B )

[0356] Example 3: Preparation of compound QR10014

[0357]

[0358] (1) The synthesis of compound 0-e is the same as described above.

[0359] (2) Compound O-e (300 mg, 0.78 mmol) was dissolved in acetone (3 mL), and aniline (73 mg, 0.78 mmol) and DIEA (100 mg, 0.78 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 14 (100 mg, yield 29%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.00(d,J=46.2Hz,1H),7.74(d,J=8.1Hz,2H),7.34(d,J=6.1Hz,1H),7.22(t,J=7.9Hz,2H),7.08(d,J=25.7Hz,1H) ,6.94(d,J=23.5Hz,3H),3.91–3.39(m,10H),3.06(t,J=7.5Hz,2H),1.97(d,J=28.0Hz,3H),1.80(d,J=52.2Hz,2H).LCMS:m / z=438.1[M+H] + . ( Figure 1C )

[0360] Example 4: Preparation of compound QR10033

[0361]

[0362] (1) The synthesis of compound 0-e is the same as described above.

[0363] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of 4-nitroaniline (108 mg, 0.78 mmol), tris(dibenzylacetone)dipalladium (73 mg, 0.08 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (93 mg, 0.16 mmol), and cesium carbonate (104 mg, 0.32 mmol). The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 33 (25 mg, yield 7%). 1 H NMR(400MHz,DMSO-d6)δ9.94–9.73(m,1H),8.19–8.11(m,2H),8.06–7.99(m,2H),7.40–7.27(m,2H),7.00 –6.87(m,2H),3.96–3.42(m,10H),3.07(t,J=7.3Hz,2H),1.97(d,J=26.5Hz,3H),1.81(d,J=50.1Hz,2H). LCMS m / z 483.1[M+H] + . ( Figure 1D )

[0364] Example 5: Preparation of compound QR10034

[0365]

[0366] (1) The synthesis of compound 0-e is the same as described above.

[0367] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 4-methoxyaniline (96 mg, 0.78 mmol) and DIEA (100 mg, 0.78 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 34 (25 mg, yield 7%). 1H NMR (400MHz, DMSO-d6) δ8.82(d,J=51.7Hz,1H),7.61(s,2H),7.34(s,1H),6.93(d,J=25.7Hz,3H),6.81 (d, J=8.5Hz, 2H), 3.70 (s, 13H), 3.04 (t, J=7.5Hz, 2H), 1.97 (d, J=29.0Hz, 3H), 1.78 (d, J=53.6Hz, 2H). LCMS m / z 468.1[M+H] + . ( Figure 1E )

[0368] Example 6: Preparation of compound QR10035

[0369]

[0370] (1) The synthesis of compound 0-e is the same as described above.

[0371] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of phenyl-1,4-diamine (2 mL) and DIEA (100 mg, 0.78 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 35 (130 mg, yield 37%). 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=59.2Hz,1H),7.44–7.23(m,3H),6.93(d,J=27.3Hz,3H),6.47(d,J=8.2Hz, 2H), 4.72 (s, 2H), 3.94–3.40 (m, 10H), 3.04 (t, J = 7.5Hz, 2H), 1.97 (d, J = 28.1Hz, 3H), 1.76 (d, J = 52.7Hz, 2H). LCMS m / z 453.2[M+H] + . ( Figure 1F )

[0372] Example 7: Preparation of compound QR10036

[0373]

[0374] (1) The synthesis of compound 0-e is the same as described above.

[0375] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 4-aminobenzamide (106 mg, 0.78 mmol) and DIEA (100 mg, 0.78 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 36 (25 mg, yield 7%). 1 H NMR(400MHz,DMSO-d6)δ9.41–9.18(m,1H),7.92–7.69(m,5H),7.39–7.29(m,1H),7.16(s,2H),7.01–6 .85(m,2H),3.98–3.58(m,10H),3.07(t,J=7.4Hz,2H),1.97(d,J=27.8Hz,3H),1.80(d,J=48.9Hz,2H). LCMS m / z418.2[M+H] + . ( Figure 1G )

[0376] Example 8: Preparation of compound QR10037

[0377]

[0378] (1) The synthesis of compound 0-e is the same as described above.

[0379] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 4-bromoaniline (134 mg, 0.78 mmol) and DIEA (100 mg, 0.78 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 37 (25 mg, yield 6%). 1H NMR(400MHz, DMSO-d6)δ9.18(d,J=42.9Hz,1H),7.74(d,J=8.7Hz,2H),7.44–7.31(m,3H),7.14(d,J=21.9Hz,1H) ,6.93(d,J=21.7Hz,2H),3.96–3.43(m,10H),3.12–3.00(m,2H),1.97(d,J=28.2Hz,3H),1.79(d,J=51.0Hz,2H). LCMS m / z 518.0[M+2H] + . ( Figure 1H )

[0380] Example 9: Preparation of compound QR10038

[0381]

[0382] (1) The synthesis of compound 0-e is the same as described above.

[0383] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of naphthyl-1-amine (112 mg, 0.78 mmol) and DIEA (100 mg, 0.78 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 38 (19 mg, yield 5%). 1 H NMR(400MHz,CD3OD)δ8.03(s,1H),7.90–7.63(m,3H),7.53–7.40(m,3H),7.18(d,J= 5.1Hz,1H),6.95–6.78(m,2H),3.85–3.42(m,10H),3.07(s,2H),2.16–1.72(m,5H). LCMS m / z 488.3[M+H] + . ( Figure 1I )

[0384] Example 10: Preparation of compound QR10039

[0385]

[0386] (1) The synthesis of compound 0-e is the same as described above.

[0387] (2) Compound O-e (300 mg (crude product), 0.78 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 4-(4-methylpiperazin-1-yl)aniline (149 mg, 0.78 mmol) and DIEA (100 mg, 0.78 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 39 (10 mg, yield 2%). 1 H NMR(500MHz,DMSO-d6)δ8.35(s,1H),7.33(d,J=5.1Hz,1H),7.00–6.86(m,3H),6.80(d,J=8.2Hz,2H),6.47(d,J=8.9Hz,2H),3. 69(dd,J=71.2,12.8Hz,14H),3.02(t,J=7.4Hz,2H),2.90(s,4H),2.62(s,3H),1.97(d,J=25.9Hz,3H),1.77(d,J=50.9Hz,2H). LCMS m / z 536.2[M+H] + . ( Figure 1J )

[0388] Example 11: Preparation of compound QR10044

[0389]

[0390] (1) Compound 44-a (5 g, 20 mmol) was dissolved in acetonitrile (50 mL), and then 44-b (3.1 g, 20 mmol), palladium dichloride bis(triphenylphosphine) (1.4 g, 2 mmol), cuprous iodide (760 mg, 4 mmol), and triethylamine (6 g, 60 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction mixture was filtered and poured into water, then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to give a white solid compound 44-c (1.5 g, yield 26.6%). LCMS m / z 238.1 [M+H] + .

[0391] (2) 44-c (500 mg, 2.11 mmol) was dissolved in methanol (5 mL), and palladium on carbon (10%) was added. The reaction was carried out overnight under hydrogen atmosphere, and the reaction was monitored by LCMS until completion. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain compound 44-d (212 mg, crude product). LCMS m / z 242.1 [M+H] + .

[0392] (3) 44-d (212 mg, 0.88 mmol) was dissolved in dichloromethane (2 mL) at 0 °C, and trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure. The crude compound 44-e (37 mg, crude product) was obtained. LCMS m / z 142.1 [M+H] + .

[0393] (4) Compound 44-e (37 mg, 0.26 mmol) was dissolved in acetone (2 mL), and 44-f (76 mg, 0.26 mmol) and DIEA (34 mg, 0.26 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give a white solid compound 44-g (50 mg, yield 48.2%).

[0394] (5) Compound 44-g (50 mg, 0.13 mmol) was dissolved in acetone (2 mL), and aniline (0.5 mL) and DIEA (17 mg, 0.13 mmol) were added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give compound 44 (24 mg, yield 41%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.96–9.30(m,1H),7.84–7.48(m,3H),7.41–7.19(m,3H),7.11–6.92(m,2H),6 .90–6.85(m,1H),3.91–3.74(m,4H),3.46–3.32(m,6),2.86(t,J=7.6Hz,2H),2.08–1.65(m,7H).LCMS m / z 452.1[M+H] + . ( Figure 1K )

[0395] Example 12: Preparation of compound QR10047

[0396]

[0397] (1) Compound 47-a (1 g, 4.4 mmol) was dissolved in acetone (10 mL). Compound 0-b (560 mg, 4.4 mmol) and DIEA (568 mg, 4.4 mmol) were added to the reaction mixture while stirring at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. LCMS m / z 274.2 [M+H] + .

[0398] (2) Compound O-d (259 mg, 1.82 mmol) and DIEA (235 mg, 1.82 mmol) were added to the above reaction solution at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion, and the LCMS m / z was 380.1 [M+H]. + .

[0399] (3) Aniline (1 mL) and DIEA (137 mg, 1.06 mmol) were added to the above reaction solution at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 47 (206 mg, yield 45%). 1 H NMR(400MHz,CD3OD)δ8.38(s,1H),7.36(s,4H),7.26–7.04(m,2H),6.99–6.79(m,2H),3.9 4–3.45(m,11H),3.22–3.07(m,2H),2.06(dd,J=21.6,1.2Hz,3H),1.95–1.71(m,2H).LCMS m / z 437.1[M+H] + . ( Figure 1L )

[0400] Example 13: Preparation of compound QR10048

[0401]

[0402] (1) Compound 48-a (500 mg, 2.20 mmol) and compound 0-b (280 mg, 2.20 mmol) were dissolved in NMP (10 mL) and stirred at room temperature until homogeneous. DIEA (568 mg, 4.40 mmol) was added dropwise. The reaction mixture was stirred at 160 °C for 30 minutes. After the reaction was complete as detected by LCMS, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give a yellow solid compound 48-b (320 mg, yield 53.2%). LCMS m / z 273.1 [M+H] + .

[0403] (2) Compound 0-d (0.5 mL) was added to compound 48-b (310 mg, 1.13 mmol) at room temperature, and the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was completed by LCMS monitoring, dichloromethane (10 mL) was added to dissolve the compound, and the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a pale yellow solid compound 48-c (200 mg, 46.5%).

[0404] (3) Sodium tert-butoxide (36 mg, 0.42 mmol), Brettphos Pd G3 (17 mg, 0.02 mmol), and aniline (137 mg, 1.06 mmol) were added to a 2 mL solution of 1,4-dioxane (70 mg, 0.21 mmol) of compound 48-c. The reaction mixture was stirred at 100 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC to give compound 48 (26 mg, yield 28.3%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.72(s,1H),7.58(s,1H),7.42(t,J=7.7Hz,2H),7.35(dd,J=5.0,1.3Hz,1H),7.28–7.13(m,3H),6.99–6 .88(m,2H),5.75(s,1H),5.41(s,1H),3.84–3.62(m,8H),3.47–3.38(m, 2H),3.10–2.95(m,2H),2.00(d,J=18.3Hz,3H),1.91–1.77(m,2H).LCMS m / z 436.2[M+H] +. ( Figure 1M )

[0405] Example 14: Preparation of compound QR10049

[0406]

[0407] (1) Compound 49-a (200 mg, 1 mmol) was dissolved in dichloromethane (2 mL) at 0 °C, and trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure. The crude compound 49-b (200 mg, crude product) was obtained.

[0408] (2) Compound 0-a (372 mg, 2.1 mmol) was dissolved in acetone (4 mL). Compound 49-b (200 mg, 2.1 mmol) and DIEA (271 mg, 2.1 mmol) were added to the reaction mixture while stirring at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. LCMS m / z 247.1 [M+H] + .

[0409] (3) Compound 0-d (115 mg, 0.81 mmol) and DIEA (105 mg, 0.81 mmol) were added to the above reaction solution at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until it was complete.

[0410] (4) Aniline (1 mL) and DIEA (73 mg, 0.57 mmol) were added to the above reaction solution at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to give a white solid compound 49 (77 mg, yield 33%). 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.17(s,1H),7.78(d,J=7.9Hz,2H),7.28(td,J=7.9,2.9Hz,2H),6.97(t,J=7.2H LCMS m / z 410.1[M+H] + . ( Figure 1N )

[0411] Example 15: Preparation of compound QR10050

[0412]

[0413] (1) Compound O-c (100 mg, 0.36 mmol) was dissolved in 1,4-dioxane (2 mL), and then 14-a (33.5 mg, 0.36 mmol) and DIEA (46.5 mg, 0.36 mmol) were added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction was monitored by LCMS until it was complete.

[0414] (2) 50-b (59.5 mg, 0.3 mmol) and DIEA (38.7 mg, 0.3 mmol) were added to the above reaction solution under stirring at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed by LCMS monitoring, the reaction mixture was poured into water and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to give a white solid compound 50-c (90 mg, two-step yield 50.1%).

[0415] (3) Compound 50-c (90 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL) at 0 °C, and trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure. The crude compound 50-d (60 mg, crude product) was obtained.

[0416] (4) Compound 50-d (60 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). Acetic acid (1.5 mL), DIEA (19 mg, 0.15 mmol), EDCI (35 mg, 0.18 mmol), and HOBT (203 mg, 0.15 mmol) were added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by HPLC (0.5% formic acid / water / methanol) to give a white solid compound 50 (5 mg, yield 8%). 1H NMR(600MHz,CD3OD)δ7.66(s,2H),7.33–7.15(m,3H),6.99–6.85(m,3H),4.38(s ,2H),4.18(d,J=42.6Hz,6H),3.63(s,2H),3.11(t,J=7.4Hz,2H),1.86(s,3H). LCMS m / z 436.1[M+H] + . ( Figure 10 )

[0417] Example 16: Preparation of compound 42 (QR10042)

[0418]

[0419] (1) 42-a (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL). O-c (5.5 mg, 0.02 mmol) and triethylamine (2 mg, 0.02 mmol) were added to the reaction mixture while stirring at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS until completion. After the reaction mixture was evaporated to dryness, it was purified by PLC (dichloromethane:methanol = 20:1) to obtain compound 42-b (10 mg, yield 72.2%). LCMS m / z 858.3 [M+H] + .

[0420] (2) Compound 42-b (10 mg, 0.01 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of 1-(1,4-diaza-1-yl)ethyl-1-one (2 mg, 0.01 mmol) and DIEA (2 mg, 0.01 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction was monitored by LCMS until completion. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC (0.5% formic acid / water / methanol) to obtain a white solid compound 42 (3 mg, yield 31%). 1H NMR (400MHz, CD3OD) δ8.87(s,1H),7.65(d,J=8.0Hz,1H),7.43(d,J=4.0Hz,1H),7.29(d,J=7.6Hz ,1H),7.03(s,1H),6.84(s,2H),6.65(s,1H),4.54(d,J=38.4Hz,5H),4.24–3.52(m,13H),3.52–3. 41(m,1H),3.31(s,2H),3.23–3.17(m,4H),3.16–3.06(m,1H),2.80(s,6H),2.47(s,1H),2.25(s, 2H),2.17–1.77(m,7H),1.69–1.49(m,1H),1.32(d,J=23.7Hz,3H),1.04(s,3H),0.90(s,3H).LCMS m / z 483.1[M+H] + . ( Figure 2 )

[0421] Example of effect: Assay for tau protein inhibitory activity

[0422] I. Preparation of tau protein

[0423] The tau protein was expressed and purified according to the detailed protocol described by Barghorn S, Biernat J, Mandelkow E. Purification of recombinant tau protein and preparation of Alzheimer-paired helical filaments in vitro. Methods Mol Biol. 2005; 299:35-51, or purchased from Abcam (catalog number: Ab84700).

[0424] II. Testing for the purity of tau protein

[0425] Coomassie brilliant blue staining and immunoblotting hybridization

[0426] 1. Add tau protein to 4xSDS gel loading buffer (200mM Tris-HCl, pH 6.8, 8% SDS, 0.4% bromophenol blue, 40% glycerol, 400mM dithiothreitol (DTT, all purchased from Sigma), and boil in a metal bath for 5-10 minutes. After cooling, vortex and centrifuge briefly, then load onto a 10% SDS-polyacrylamide gel for electrophoresis. After electrophoresis, cut the SDS-polyacrylamide gel at the positions indicated by the two-color pre-stained protein molecular weight marker (Ruichu Biotechnology Co., Ltd.). A 2.25μg tau protein sample is used for Coomassie Brilliant Blue staining; a 75ng tau protein sample is used for Western blot hybridization.

[0427] 2. Coomassie brilliant blue staining

[0428] After staining the gel in 0.25% Coomassie Brilliant Blue R250 (Beyotime) solution (methanol:water:acetic acid = 4.5:4.5:1, methanol and acetic acid purchased from Titan Biotechnology Co., Ltd.) for 1 hour, the gel was then placed in destaining solution (methanol:water:acetic acid = 4.5:4.5:1) for 3 hours, changing the destaining solution three or four times during this period. Once the gel background was clear, it was photographed.

[0429] 3. Immunoblotting hybridization

[0430] The gel was transferred using a semi-dry transfer apparatus (Bio-Rad) at a constant current of 80 mA for 60 minutes. The transferred PVDF membrane (Sigma) was then dissolved in 5% skim milk in Tris-Tween buffer (TBST: 20 mM Tris-HCl, pH 7.4, 150 mM). Block the membrane with NaCl (0.1% Tween-20) at room temperature for 30 minutes. Then incubate the membrane with tau polyclonal antibody (Proteintech, 1:5000) or monoclonal antibody (Abcam, 1:500) (dissolved in TBST) at 37°C for 1 hour or at 4°C overnight. Wash the membrane three times with TBST for 5 minutes each time. Then incubate the membrane with horseradish peroxidase-labeled goat anti-rabbit or horseradish peroxidase-labeled goat anti-mouse secondary antibody (Proteintech, 1:10000 dilution) at 37°C for 1 hour. After washing the membrane (5 minutes each time, three times in total), develop the membrane with ECL chemiluminescence solution for 1 minute, and then acquire the signal using a gel imaging system (Shanghai Qinxiang Scientific Instruments Co., Ltd.).

[0431] III. Surface Plasmon Resonance Measurement of the Affinity of Compounds with Tau

[0432] 1. Protein Coupling: Tau protein was diluted to 157 μg / mL with NaAc buffer at pH 4.0. The flow rate was set to 10 μL / min. The chip activation time for the mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) was set to the default value of 420 s. Tau protein was fixed to approximately 4000 RU using a fixed-time coupling mode. The activating groups that were not bound to the test sample were blocked with ethanolamine.

[0433] 2. Sample testing conditions: PBS buffer containing 0.05% Tween-20 and 1% DMSO at pH 7.4 was used as the run buffer. The run buffer was used as the control test sample. A series of concentrations were set (15.625 μM, 31.25 μM, 62.5 μM, 125 μM, 250 μM, 500 μM, 1 mM). The flow rate for sample analysis was set to 30 μL / min, the binding time to 40 s, and the dissociation time to 40 s.

[0434] 3. Parameter Fitting: The experiment employed multiple cycles, with the analysis time plotted on the x-axis and the response value on the y-axis. After dual-parameter subtraction, the obtained data were fitted using BIAcore T200 analysis software. The fitting model used was the 1:1 Langmuir binding model, and affinity indices such as the binding dissociation constant were determined.

[0435] Table 1: Affinity of compounds in each example to tau protein

[0436]

[0437] For KD values, “A” indicates KD < 200 μM; “B” indicates KD is between 200 μM and 500 μM; and “C” indicates KD > 500 μM.

[0438] The above data indicate that the compound of this disclosure (I) has the ability to bind to tau proteins, can be used to bind to proteins, and can be further used to prepare the small molecule compound for degrading tau proteins as described in this disclosure.

Claims

1. The compound represented by formula (II) or a pharmaceutically acceptable salt thereof: in, A1, A2, and A3 are each independently selected from C and N atoms; R 2 For H; n is selected from 1, 2, 3, 4, or 5; R 5 For H and R 6 Selected from phenyl or naphthyl; The phenyl or naphthyl group is optionally surrounded by one or more R groups. 7 replace; R 7 Selected from -OCH3, -NO2, -NH2, -C(=O)NH2, Br, R 8 It is -C(=O)CH3; R 9 Selected from C1-C3 alkyl groups.

2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, A1, A2, and A3 are all N atoms.

3. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, n is 1, 2, or 3.

4. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, n is 1 or 2.

5. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 6 for .

6. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 9 Selected from -CH3.

7. The compound represented by formula (IIA) or a pharmaceutically acceptable salt thereof: in: R 2 For H; n is selected from 1, 2, 3, 4, or 5; R 5 Selected from H and D; R 7 Selected from -OCH3, -NO2, -NH2, -C(=O)NH2, Br, R 8 It is -C(=O)CH3; R 9 Selected from C1-C3 alkyl groups.

8. The compound of formula (IIA) according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, n is 1, 2, or 3.

9. The compound of formula (IIA) according to claim 7, characterized in that, n is 1 or 2.

10. The compound of formula (IIA) according to claim 7, characterized in that, R 5 For H.

11. The compound of formula (IIA) according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, R 9 Selected from -CH3.

12. The following compounds or their pharmaceutically acceptable salts: 。 13. 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 its pharmaceutically acceptable salt, 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, wherein the TBM is linked to the ULM or AUM moiety via L; TBM is a compound group according to any one of claims 1-12, and the TBM is transmitted via -NR 5 R 6 The N atom in the atom is bonded to the L atom.

14. The small molecule compound according to claim 13, characterized in that, The ULM can bind to E3 ubiquitin ligase.

15. The small molecule compound according to claim 14, characterized in that, The E3 ubiquitin ligase is either VHL E3 ubiquitin ligase or CRBN E3 ubiquitin ligase.

16. The small molecule compound according to claim 13, characterized in that, The ULM is a compound as shown below, in which the amino N atom is bonded to the L atom at positions ① and ②. The AUM can bind to the ZZ region of the autophagy receptor p62 / SQSTM1 / Sequestosome-1.

17. The small molecule compound according to claim 16, characterized in that, The AUM has the structure shown below, in which it is connected to L via position ③, where the C atom of the aminoalkyl group or the O atom of the ether group is connected to L. 。 18. The small molecule compound according to any one of claims 13-17, characterized in that, L is a group -XYZ-, where X is a single bond and -(CH2). m C(=O)NR 14 -、-(CH2) m NR 14 -、-(CH2) m NR 14 C(=O)-、-(CH2) m C(=O)-; The -(CH2) m C(=O)NR 14 -、-(CH2) m NR 14 -、-(CH2) m NR 14 C(=O)-、-(CH2) m One or more H atoms on the methylene group in C(=O)- are replaced by R; Y-E1-(CH2CH2O) p -E2-, -E1-(CH2) q -E2-, Z stands for -(CH2). m C(=O)-,-(CH2) m NR 14 -E-, referring to -(CH2) m C(=O)-,-(CH2) m NR 14 One or more H atoms on the methylene group in -E- are replaced by R atoms; TBM is attached to the alkylene C atom of the X group, and ULM is attached to the carbonyl C atom of the Z group. Where m is selected from 0, 1, 2, 3 or 4, p is selected from 0, 1, 2, 3, 4, 5 or 6, and q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R 14 Selected from H, methyl; E1 and E2 are independently selected from single bonds, And at least one of E1 and E2 is a single bond; E is selected from single bond, -(CH2) m O-, the -(CH2) m One or more H atoms on the methylene group in O- are replaced by R atoms; R is selected from single bond, D, methyl, ethyl, -OH.

19. The small molecule compound according to any one of claims 13-17, characterized in that, The L is selected from the following groups: 。 20. The small molecule compound according to any one of claims 13-17, characterized in that, The -L-ULM group has the following structure: The -L-AUM group has the following structure: 。 21. The compound according to any one of claims 1-12, wherein, The compound can bind to the tau protein.

22. A pharmaceutical composition, characterized in that, The composition comprises a compound according to any one of claims 1-12, 21 or a pharmaceutically acceptable salt thereof, or a small molecule compound according to any one of claims 13-20 and a pharmaceutically acceptable excipient.

23. The use of any compound of claims 1-12, 21 or a pharmaceutically acceptable salt thereof, or any small molecule compound of claims 13-20, or the pharmaceutical composition of claim 22 in the preparation of a medicament for treating a patient’s condition caused by tau protein accumulation.

24. The application according to claim 23, characterized in that, The conditions caused by tau protein accumulation are selected from one or more of the following: Alzheimer's disease, frontotemporal dementia linked to chromosome 17 with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, primary age-related tau disease, aurophilic granuloma, age-related tau astropathy, chronic traumatic encephalopathy, glioblastoma tau disease, Parkinson's disease, Huntington's disease, or stroke, epilepsy, and autism.

25. The use of the compound of any one of claims 1-12, 21 or a pharmaceutically acceptable salt thereof, or the small molecule compound of any one of claims 13-20, or the pharmaceutical composition of claim 22 in the preparation of a tau degrading agent.

26. A method for degrading tau protein in a biological sample, comprising contacting the biological sample with a compound of any one of claims 1-12, 21 or a pharmaceutically acceptable salt thereof, or a small molecule compound of any one of claims 13-20, or a pharmaceutical composition of claim 22.

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