CN116964038A

CN116964038A - Small molecule compounds that bind to tau proteins

Info

Publication number: CN116964038A
Application number: CN202280015846.5A
Authority: CN
Inventors: 汪义朋
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-03-03
Filing date: 2022-03-02
Publication date: 2023-10-27
Also published as: WO2022184111A1

Abstract

The present disclosure relates to the technical field of compounds, and discloses a plurality of small molecule compounds specifically binding tau protein and application thereof. The chemical structure of the small molecule compounds is shown as a formula (I) or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof.

Description

Small molecule compounds that bind to tau proteins

Technical Field

The present disclosure relates to the field of pharmaceutical chemistry, and in particular to a small molecule compound which binds tau protein, a method for preparing the same and uses thereof.

Background

tau protein is a microtubule-associated protein (microtubule associated protein) which plays an important role in stabilizing cytoskeletal microtubules. tau protein is a natural unstructured protein (natively unfolded protein), which does not have a tendency to form polymers by itself, but whose aggregation (aggregation) occurs in a range of neurodegenerative diseases collectively known as "tau diseases" (argyrophilic grain Disease, AGD), including Alzheimer's Disease (AD), frontotemporal dementia linked to chromosome 17 with Parkinson's Disease (frontotemporal dementia linked to chromosome-17parkinsonism, ftdp-17), pick's Disease (Pick's Disease, piD), progressive supranuclear palsy (progressive supranuclear palsy, PSP), corticobasal degeneration (corticobasal degeneration, CBD), primary age-related tauopathy (primary age-related tauopathy, PART), silver-philic granulosis (argyrophilic grain Disease, AGD), aging-related astrocytopathy (ag-related tau astrogliopathy, ARTAG), chronic traumatic encephalopathy (chronic traumatic encephalopathy, CTE), spherical gliosis (Globular glial tauopathy, GGT), parkinson's Disease (PD), huntington's Disease, HD's Disease, and the like. Tau protein is an important cause of neurodegenerative changes in this class of diseases and is an important target for diagnosis and treatment of this class of diseases. In addition, recent studies have shown that tau is involved in the regulation of neuronal excitability and is thus also a potential target for the treatment of epilepsy, autism and stroke.

Some small molecule compounds that specifically bind tau polymers are known to be successfully developed as tracers (tracers) for positron emission tomography (Positron Emission Computed Tomography, PET) for early diagnosis of alzheimer's disease and other tau diseases. It has been reported that some small molecule compounds such as methyl blue (methyl blue) and its derivatives inhibit tau aggregation, potentially useful in the treatment of Alzheimer's disease or other tau diseases, but their mechanism of inhibition of tau aggregation is not completely understood, and it is unclear which tau protein (tau monomers) or polymer (aggregates) is bound to, tau is a natural unstructured protein, and its monomers (monomers) do not have binding pockets for ligand binding, and there is difficulty in developing small molecule compounds with high affinity for tau monomers, so far few studies have been done on compounds that bind tau monomers, in addition, small molecule compounds that bind tau have other applications in recent years, innovative advances in the research of small molecule compounds have been the development of bifunctional molecules for small molecules, such as protein degradation targeting chimeras (PROteolysis TArgeting Chimeras, PROTAC) and autophagy targeting chimeras (AUtophagy TArgeting Chimeras, AUTAC), for mediating degradation of target proteins. (2) a specific E3 ubiquitin transferase (E3 ligand), and (3) a linker linking the target protein ligand and the ligand of E3 ubiquitin transferase, interestingly, even if the target protein ligand does not have strong affinity for the target protein, it is still very effective in down-regulating target proteins due to the catalytic effect of PROTAC. Thus, small molecule compounds capable of binding tau, even though they have low affinity for tau, can be used to construct the bifunctional molecule PROTAC that mediates tau degradation for the treatment of tau diseases and other tau-associated diseases.

Because of the versatile use of small molecule compounds that bind tau in drug development, the present invention has developed a number of small molecule compounds that have a strong affinity for tau protein.

Disclosure of Invention

The present disclosure synthesizes a series of small molecule compounds capable of binding tau protein monomers. These small molecule compounds may be potentially useful in the development of inhibitors of tau aggregation for the treatment of tau diseases and other tau-associated diseases. In addition, these small molecule compounds can also be used to construct bifunctional molecules, such as protein degradation targeting chimeras (PROteolysis TArgeting Chimeras, procac) and autophagy targeting chimeras (Autophagy targeting Chimeras, aucac), to develop degradation products of tau protein (degrader) for the treatment of tau diseases and other tau-related diseases.

In one aspect, the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:

wherein:

A ₁ 、A ₂ 、A ₃ each independently selected from C, N atoms; preferably, A ₁ 、A ₂ 、A ₃ And simultaneously is an N atom;

L ₁ is- (CH) ₂ ) _n -or- (CH) ₂ O) _n -; preferably L ₁ Is- (CH) ₂ ) _n -；

R ¹ Selected from 5-6 membered aryl or 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, S, O, said 5-6 membered aryl or 5-6 membered heteroaryl optionally being substituted with one or more R ¹⁵ Substitution, said R ¹⁵ Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen;

preferably, R ¹ Selected from phenyl, pyridyl, pyranyl, thiopyranyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl;

preferably, R ¹ Selected from phenyl, 2-pyridyl, 2-thienyl, 2-thiazolyl;

preferably, R ¹ Selected from 2-thienyl;

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

preferably, R ² Selected from H;

or R is ² By combining with R ¹ On ringsTo which atoms are connected, R ¹ 、R ² And together with the atoms to which they are attached form an 8-10 membered partially unsaturated or aromatic carbocyclic bicyclic ring, an 8-10 membered partially unsaturated or aromatic bicyclic ring containing 1-2 heteroatoms independently selected from N, S, O; preferably, R ¹ 、R ² And together with the atoms to which they are attached form

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

R ³ selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ⁵ R ⁶ 、-OR ¹⁶ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R ³ Selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -NR ⁵ R ⁶ ；

R ⁵ 、R ⁶ Each independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, aryl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, S, O, said C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, aryl, heteroaryl optionally substituted with one or more R ⁷ Substitution;

preferably, R ⁵ 、R ⁶ Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,Optionally by one or more R ⁷ Substitution;

preferably, R ⁵ Is H and R ⁶ Selected from methyl, cyclopropyl, phenyl, naphthyl,The methyl, cyclopropyl, phenyl, naphthyl,Optionally by one or more R ⁷ Substitution;

preferably, R ⁵ Is H and R ⁶ Is methyl;

preferably, R ⁵ Is H and R ⁶ To optionally be covered by one or more R ⁷ A substituted phenyl group; preferably, R ³ Is that

Preferably, R ³ Is thatAnd wherein R is ⁵ Is H;

R ⁴ is a 3-8 membered saturated ring containing 1-2 atoms independently selected from N, O, which is substituted with a compound of formula (I) through an N atomThe rings being linked, the 3-8 membered saturated ring containing 1-2N, O atoms being optionally interrupted by one or more R ⁸ Substitution;

preferably, R ⁴ To selectOptionally by one or more R ⁸ The substituted following groups:

preferably, R ⁴ Is that

R ⁷ Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen, a 5-8 membered saturated ring containing 1-2N, S, O atoms, said C1-C6 alkyl, C1-C6 alkoxy, a 5-8 membered saturated ring containing 1-2N, S, O atoms optionally being substituted with one or more R ⁹ Substitution;

R ⁸ selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C (=O) R ¹² 、-S(＝O) ₂ R ¹² ；

R ⁹ Selected from C1-C6 alkyl, -NO ₂ 、-CN、-NH ₂ -OH, halogen, -C (=o) R ¹² ；

R ¹⁰ 、R ¹¹ Each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;

R ¹² selected from H, C C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon groups;

preferably, R ⁷ Selected from-CH ₃ 、-CF ₃ 、-CH ₂ F、-CHF ₂ 、-CCl ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

Preferably, R ⁷ Selected from-CF ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

Preferably, R ⁸ Selected from-CH ₃ 、-OH、-OCH ₃ 、-C(＝O)CH ₃ 、-C(＝O)CH ₂ -C (=o) -cyclopropyl, -S (=o) ₂ -cyclopropyl;

preferably, R ⁸ Selected from-C (=O) CH ₃ ；

Preferably, R ⁹ Selected from C1-C3 alkyl;

preferably, R ⁹ Selected from-CH ₃ 。

In another aspect, the present disclosure provides a compound of formula (II) or formula (III), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:

wherein,

R ² selected from H, D, C1-C6 alkyl;

Preferably, R ² Selected from H, D, methyl, ethyl, propyl, isopropyl;

preferably, R ² Selected from H;

preferably, R ⁵ Is H and R ⁶ Is methyl;

preferably, R ⁵ Is H and R ⁶ To optionally be covered by one or more R ⁷ A substituted phenyl group;

Preferably, R ⁶ Is that

Preferably, R ⁶ Is thatAnd wherein R is ⁵ Is H;

preferably, R ¹⁰ 、R ¹¹ Each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, acetyl;

preferably, R ⁷ Selected from-CH ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

Preferably, R ⁷ Selected from-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

Preferably, R ⁸ Selected from-CH ₃ 、-OH、-OCH ₃ 、-C(＝O)CH ₃ 、-C(＝O)CH ₂ 、-C(＝O)C ₃ H ₅ -cyclopropyl, -S (=o) ₂ -cyclopropyl;

preferably, R ⁸ Selected from-C (=O) CH ₃ ；

Preferably, R ⁹ Selected from C1-C3 alkyl;

preferably, R ⁹ Selected from-CH ₃ 。

In another aspect, the present disclosure also provides a compound of formula (IIA) or formula (IIIA) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:

wherein:

preferably, R ² Selected from H, D, methyl, ethyl, propyl, isopropyl;

preferably, R ² Selected from H;

R ⁵ selected from H, D, C-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, said C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH 2) -, (C3-C6 cycloalkyl) - (CH 2CH 2) -, optionally substituted with one or more R ¹³ Substitution;

preferably, R ⁵ Selected from H, D, C1-C4 alkyl;

preferably, R ⁵ Selected from H, D, methyl, ethyl, propyl, isopropyl;

preferably, R ⁵ Selected from H;

R ⁷ selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen, a 5-8 membered saturated ring containing 1-2N, S, O atoms, said C1-C6 alkyl, C1-C6 alkoxy, a 5-8 membered saturated ring containing 1-2N, S, O atoms optionally being substituted with one or more R ⁹ Substituted;

R ¹⁰ 、R ¹¹ Each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl A base;

preferably, R ⁸ Selected from-C (=O) CH ₃ ；

Preferably, R ⁹ Selected from C1-C3 alkyl;

preferably, R ⁹ Selected from-CH ₃ ；

R ¹³ Selected from C1-C3 alkyl, C1-C3 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen;

preferably, R ¹³ Selected from methyl, ethyl, propyl, isopropyl methoxy, ethoxy, -NO ₂ 、-CN、-NH ₂ -NH (C1-C3 alkyl), -N (C1-C3 alkyl) ₂ 、-C(＝O)NH ₂ -C (=o) NH (C1-C3 alkyl), -C (=o) N (C1-C3 alkyl) ₂ -OH, halogen.

In another aspect, the present disclosure also provides a small molecule compound for specifically degrading tau protein, characterized in that the chemical structure of the compound is TBM-L-ULM or TBM-L-AUM and pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof, wherein TBM is a tau protein binding moiety, L is a linker group, ULM is a ubiquitin ligase binding moiety, AUM is a binding moiety of the ZZ segment of autophagy receptor p62/SQSTM 1/sequensite-1, and TBM is linked to said ULM or AUM moiety by L.

The small molecular compound for specifically degrading tau protein is characterized in that TBM is a compound group shown in the formula (I), (II), (III), (IIA) and (IIIA), and when R ³ is-NR ⁵ R ⁶ When the TBM passes through R ³ Is linked to L, or when R ⁸ Selected from-C (=O) CH ₃ When the TBM passes through R ⁸ Is attached to L, or when R ⁸ Selected from C1-C6 alkoxy, said TBM is prepared by R ⁸ Is linked to L.

The aforementioned small molecule compounds that specifically degrade tau protein, said ULM being capable of binding E3 ubiquitin ligase; preferably, the E3 ubiquitin ligase is VHL E3 ubiquitin ligase or CRBN E3 ubiquitin ligase; preferably, the ULM is a compound wherein L is linked to the ULM through an amino N atom shown in the (1) and (2) positions,

the aforementioned small molecule compounds specifically degrading tau protein, said AUM being capable of binding to the ZZ segment of the autophagy receptor p62/SQSTM 1/sequencer-1, said AUM illustratively having the structure shown below, which is linked to L by (3) a position to a C atom of an aminoalkyl group in L or to an O atom in an ether group,

the small molecule compound for specifically degrading tau protein, wherein L is a group-X-Y-Z-, wherein X is a single bond, - (CH) ₂ ) _m C(＝O)NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ C(＝O)-、-(CH ₂ ) _m C (=o) -, optionally, the- (CH) ₂ ) _m C(＝O)NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ C(＝O)-、-(CH ₂ ) _m One or more H on the methylene group in C (=o) -is substituted with R;

y is-E ₁ -(CH ₂ CH ₂ O) _p -E ₂ -，-E ₁ -(CH ₂ ) _q -E ₂ -，

Z is- (CH) ₂ ) _m C(＝O)-，-(CH ₂ ) _m NR ¹⁴ -E-, optionally, the- (CH) ₂ ) _m C(＝O)-，-(CH ₂ ) _m NR ¹⁴ -one or more H on methylene groups in E-are substituted by R;

TBM is attached to the alkylene C atom of the X group, ULM is attached to the carbonyl C atom of the Z group,

wherein m is selected from 0, 1, 2, 3 or 4, p is selected from 0, 1, 2, 3, 4, 5 or 6, q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R ¹⁴ selected from H, C1-C3 alkyl; preferably, R ¹⁴ Selected from HMethyl, ethyl; preferably, R ¹⁴ Selected from H and methyl;

E ₁ 、E ₂ are each independently selected from a single bond,And E is ₁ 、E ₂ At least one of them is a single bond;

e is selected from single bond, - (CH) ₂ ) _m O-, optionally, the- (CH) ₂ ) _m One or more H on the methylene group in O-is replaced by R;

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

preferably, said L is selected from the following groups:

the aforementioned small molecule compounds that specifically degrade tau protein, the-L-ULM group is shown in the following structure:

the aforementioned small molecule compounds that specifically degrade tau protein, the-L-AUM group is shown in the following structure:

a compound comprised by formula (I), (II), (III), (IIA), (IIIB), wherein said compound is capable of binding tau protein.

The present disclosure also provides methods for preparing compounds of formula (I), (II), (III), (IIA), (IIIB), and small molecule compounds TBM-L-ULM or TBM-L-AUM that degrade tau protein.

The present disclosure also provides a tau protein binding agent having a structure as shown in formulas (I), (II), (III), (IIA), (IIIB) and the exemplified structures listed.

The present disclosure also provides the use of compounds of formula (I), (II), (III), (IIA), (IIIB) and the exemplified structures listed in the preparation of tau binding agents.

The present disclosure also provides a pharmaceutical composition comprising a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound as described above and a pharmaceutically acceptable adjuvant.

The present disclosure also provides the use of a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for treating a condition caused by tau protein accumulation in a patient;

preferably, the condition caused by tau protein accumulation is selected from one or more of Alzheimer's Disease (AD), frontotemporal dementia linked to chromosome 17 with Parkinson's Disease (frontotemporal dementia linked to chromosome-17 parkinsonism,FTDP-17), pick's Disease (PiD), progressive supranuclear palsy (progressive supranuclear palsy, PSP), corticobasal degeneration (corticobasal degeneration, CBD), primary age-related tauopathy (primary age-related tauopathy, PART), silvered granulosis (argyrophilic grain Disease, AGD), age-related astrocytopathy (imaging-related tau astrogliopathy, ARTAG), chronic traumatic encephalopathy (chronic traumatic encephalopathy, CTE), globoid tauopathy (Globular glial tauopathy, GGT), parkinson's Disease (PD), huntington's Disease (Huntington's Disease, HD), or stroke, epilepsy and autism.

The present disclosure also provides the use of a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound as described above, or a pharmaceutical composition as described above, in the preparation of a tau degrading agent.

The present disclosure also provides a method of degrading tau protein in a patient in need thereof, comprising administering to the patient a compound as described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound as described above, or a pharmaceutical composition of the foregoing.

The present disclosure also provides a method of degrading tau protein in a biological sample comprising contacting the biological sample with a compound described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound described above, or a pharmaceutical composition described above.

The present disclosure also provides a method for treating a disorder caused by tau protein accumulation in a patient in need thereof, comprising administering to the patient a compound described above, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound described above, or a pharmaceutical composition described above.

Drawings

FIGS. 1A-O show nuclear magnetic spectra of compounds of examples 1-15 of the present disclosure

FIG. 2 shows a PROTAC molecular nuclear magnetic spectrum prepared in example 16 of the present disclosure

FIG. 3 shows Coomassie blue staining and immunoblot hybridization patterns of tau protein, gel staining showing bands of tau protein predominantly about 56kD with a small amount of degradation fragments (< 10%) (a), tau bands recognized by tau-specific polyclonal antibodies (b) and monoclonal antibodies (c).

Detailed Description

In light of the foregoing disclosure, many other modifications, substitutions, or alterations are also possible in the form of modifications, substitutions, or alterations without departing from the spirit and scope of this disclosure.

I. Definition of the definition

Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.

The compounds of the invention may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present invention.

The compounds of the invention also include tautomeric forms. Tautomers originate from the exchange of one single bond with an adjacent double bond and accompany the migration of one proton.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Numerical ranges herein refer to individual integers within a given range. For example, "C1-C6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; "C3-C6" means that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The term "substituted" means that any one or more hydrogen atoms on a particular atom or group is substituted with a substituent, provided that the valence of the particular atom or group is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o), it means that two hydrogen atoms are substituted. The kind and number of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

When any variable (e.g. R ⁿ ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. Thus, for example, if a group is substituted with 1 to 5R, the group may optionally be substituted with up to 5R, and R in each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the indicated number of carbon atoms. The term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like. It may be divalent, e.g. methylene, ethylene.

The terms "halo", "halogen substituted" refer to substitution with one or more halogen atoms, examples of which include fluorine, chlorine, bromine, iodine atoms.

The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system, free of heteroatoms, and free of double bonds. Examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The terms "aryl", "aromatic" and "aromatic" refer to an all-carbon monocyclic or fused polycyclic aromatic ring radical having a conjugated pi-electron system, which is obtained by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-10 carbon atoms. Including bicyclic groups comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, indene, indane, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthalene.

The term "heteroaryl" refers to a monovalent aromatic radical comprising at least one 5-, 6-, 7-membered ring independently selected from nitrogen, oxygen, and sulfur heteroatoms, and includes fused ring systems of 5-10 atoms, at least one of which is aromatic. Examples of aryl radicals include, but are not limited to, pyridinyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, furanyl, pyrazinyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, imidazopyridinyl, benzofuranyl, pyridazinyl, isoindolyl.

The term "meta" refers to the number of backbone atoms that make up the ring. For example, "5-10 membered" means that the number of backbone atoms constituting 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.

The term "heterocycle" refers to a 5-12 membered saturated non-aromatic system having ring carbon atoms and 1 to 2 ring heteroatoms, wherein the heteroatoms are independently selected from nitrogen, sulfur or oxygen atoms. In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as the valency permits. The heterocyclic ring may be a single ring or a multiple ring system, such as a bicyclic ring, in which two or more rings are present in the form of a parallel ring, a bridged ring, or a spiro ring, in which at least one ring contains one or more heteroatoms.

As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

Substituent R ⁿ May be bonded to any atom on the ring as long as the valency permits. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. Those skilled in the art will appreciate that for a composition comprising one or more R' s _n Any group of substituents does not introduce any substitution or substitution pattern that is sterically impossible and/or impossible to synthesize.

Refers to a chemical bond junction.

As used herein, the term "protecting group" refers to a protecting group that protects the other group prior to the reaction and then resumes after the reaction is completed, when the multifunctional organic compound is reacted, such that the reaction occurs only at the desired group while the other group is protected. Agents capable of protecting a group are referred to as protecting groups for that group, commonly hydroxy protecting agents, amino protecting agents, and the like. Protecting groups for hydroxyl groups include, but are not limited to: acetyl (Ac), 2-Methoxyethoxymethyl Ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether (MTM), pivaloyl (Piv), tetrahydropyran (THP), a silyl ether protecting group, methyl ether, and the like; amino protecting groups include, but are not limited to: benzyloxycarbonyl (Cbz), t-butyloxycarbonyl (Boc), 9-Fluorenylmethoxycarbonyl (FMOC), benzyl (Bn), p-methoxyphenyl (PMP), trityl derivative protecting groups, and the like.

Medicament or pharmaceutical composition

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acids and bases of the particular compounds without biological adverse effects. Such as acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The medicaments or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent may be administered orally in the form of capsules, tablets, etc. (see Remington: the Science and Practice of Pharmacy,20th Edition).

For oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be in the form of a non-toxic, pharmaceutically acceptable adjuvant such as a binder (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 behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweetening agents, natural and synthetic gums (e.g., acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like. For oral administration in liquid form, the pharmaceutical component may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous carriers (e.g., almond oil, oil esters, ethanol, or fractionated vegetable oils), preserving agents (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid), and the like. Stabilizers such as antioxidants (BHA, BHT, propyl citrate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

Tablets containing the active compound may be coated by methods well known in the art. The compositions of the present disclosure comprising as active compound a compound of formula I may also be incorporated into beads, microspheres or microcapsules, for example constructed from polyglycolic acid/lactic acid (PGLA). Liquid formulations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may be suitably formulated so as to provide controlled or delayed release of the active compound.

The medicaments or pharmaceutical compositions of the present disclosure may be administered parenterally, i.e. by intravenous (i.v.), intraventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subcutaneous (s.d.), or intradermal (i.d.), by direct injection, via bolus injection or continuous infusion, for example. Formulations for injection may be presented in unit dosage form, for example, in ampules or multi-dose containers with added preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, in the form of excipients (vehicles), and may contain formulatory agents such as anti-settling agents, stabilisers 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.

The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

The terms "reduce", "inhibit", "reduce" or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate controls for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

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

The term "excipient" is used herein to include any other compound that is not a therapeutically or biologically active compound that may be contained in or on a microparticle. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, e.g., the excipient is generally non-toxic to the subject. "excipient" includes a single such compound, and is also intended to include multiple compounds.

The term "pharmaceutical composition" means a composition comprising a compound described in the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature sensitive materials, temperature adjusting agents, adhesives, stabilizers, suspending agents, and the like.

Use and method of treatment

The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, amenable to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a human.

According to the methods of the invention, the compounds or compositions may be administered in any amount and by any route of administration effective to treat or reduce the severity of a disease associated with tau protein accumulation.

The present invention relates to a method of reducing tau protein in a biological sample comprising the step of contacting the biological sample with a compound of the invention or a composition comprising the compound.

The term "biological sample" includes, but is not limited to, a cell culture or extract thereof; a biopsy material or extract thereof obtained from a mammal; and blood, saliva, urine, stool, semen, tears, or other bodily fluids or extracts thereof. Inhibition of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, bioassays, gene expression studies, and biological target identification.

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

The compounds provided are tau inhibitors and thus are useful in the treatment of one or more conditions associated with tau activity. Thus, in certain embodiments, the present invention provides a method for treating a tau protein mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

As used herein, the term "tau-mediated" disorder, disease, and/or condition, as used herein, refers to any disease or other deleterious condition in which tau protein or mutant thereof is known to function. Thus, another embodiment of the invention relates to the treatment or lessening the severity of one or more diseases in which tau protein or a mutant thereof is known to play a role.

Tau-mediated conditions are well established in the art. The relationship between tau protein and tau protein mediated disorders, diseases and/or conditions as described herein is well established in the relevant art. For example, include Alzheimer's Disease (AD), frontotemporal dementia linked to chromosome 17 with Parkinson's Disease (frontotemporal dementia linked to chromosome-17 parkinsonism,FTDP-17), pick's Disease (PiD), progressive supranuclear palsy (progressive supranuclear palsy, PSP), corticobasal degeneration (corticobasal degeneration, CBD), primary age-related tauopathy (primary age-related tauopathy, PART), silver-philic granulomatosis (argyrophilic grain Disease, AGD), aging-related tau astrocytopathy (ranging-related tau astrogliopathy, ARTAG), chronic traumatic encephalopathy (chronic traumatic encephalopathy, CTE), spherical glial tauopathy (Globular glial tauopathy, GGT), parkinson's Disease (PD), huntington's Disease (HD), and the like. tau protein is an important cause of neurodegenerative changes in this class of diseases and is therefore also an important target for diagnosis and treatment of this class of diseases. In addition, recent studies have shown that tau is involved in the regulation of neuronal excitability and is thus also a potential target for the treatment of epilepsy, autism and stroke.

As used herein, the term "protein degradation targeting chimera", PROTAC (proteolysis targeting chimeras), is a chemical molecule containing different ligands at both ends, one ligand that binds E3 ligase (e.g., ULM moiety as described in the present disclosure) and the other ligand that binds intracellular proteins (e.g., TBM moiety that binds tau protein as described in the present disclosure), which are then joined by a linker (e.g., L as described in the present disclosure). Such chemical molecules can bind both E3 ubiquitin ligase and intracellular proteins, and by recruiting the targeted protein to the vicinity of the E3 ubiquitin ligase, the target protein is polyubiquitinated and finally degraded by the proteasome, and PROTAC can be recycled without degradation by the proteasome.

As used herein, the term "autophagy targeting chimera", i.e. AUTAC, employs a similar design as that of PROTAC, well suited for degrading target proteins in the cytoplasm that are resistant to the PROTAC molecule. Cargo proteins (cargo proteins) are first phagocytosed to form autophagosomes, and then autophagy receptors such as SQSTM1/p62 recognize Lys63 (K63) polyubiquitinated cargo proteins and transfer them to autophagosomes for degradation. Both the AUTAC and PROTAC molecules act through ubiquitination, but the AUTAC molecules induce target degradation by triggering K63 polyubiquitination.

As used herein, the term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein, alone or in combination with an E2 ubiquitin conjugating enzyme, causes attachment of ubiquitin to lysine on the target protein, and subsequently targets specific protein substrates for degradation by the proteasome. Thus, the E3 ubiquitin ligase alone or in complex with the E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to the target protein. Generally, ubiquitin ligases are involved in polyubiquitination such that a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to the second ubiquitin and so on. Polyubiquitination labels proteins for degradation by proteasome. However, there are some ubiquitination events, which are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligases. Monoubiquitinated proteins are not targeted to proteasome for degradation, but rather may be altered in their cellular location or function, for example, via binding to other proteins having domains capable of binding ubiquitin. More complex, different lysines of ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is lysine used to prepare polyubiquitin recognized by the proteasome.

Combination therapy method

The present disclosure provides combination therapies using compounds as described in the present disclosure with other therapeutic agents. The term "combination therapy" as used in this disclosure includes the administration of these agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, and the administration of these therapeutic agents, or at least two agents, occurs substantially simultaneously. The sequential, or substantially simultaneous, administration of each agent may be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and direct absorption through mucosal tissue. The agents may be administered by the same route or by different routes. For example, a first agent may be administered orally, while a second agent is administered intravenously. In addition, the selected combination agents may be administered by intravenous injection, while the other agents of the combination may be administered orally. Alternatively, for example, two or more agents may be administered by intravenous or subcutaneous injection.

Detailed description of the preferred embodiments

The present disclosure provides compounds of formula (I), pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, or N-oxides thereof:

Wherein:

L ₁ is- (CH) ₂ ) _n -or- (CH) ₂ O) _n -；

In a specific embodiment, L ₁ Is- (CH) ₂ ) _n -；

in a specific embodiment, R ¹ Selected from phenyl, pyridyl, pyranyl, thiopyranyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl;

in a specific embodiment, R ¹ Selected from phenyl, 2-pyridyl, 2-thienyl, 2-thiazolyl;

in a specific embodiment, R ¹ Selected from 2-thienyl;

R ² selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, 5-6 aryl or 5-6 membered heteroatomic ring containing 1-2 heteroatoms independently selected from N, S, OAn aryl group;

in a specific embodiment, R ² Selected from H;

in a specific embodiment, R ² By combining with R ¹ The atoms of the ring being bound to each other to give R ¹ 、R ² And together with the atoms to which they are attached form an 8-10 membered partially unsaturated or aromatic carbocyclic bicyclic ring, an 8-10 membered partially unsaturated or aromatic bicyclic ring containing 1-2 heteroatoms independently selected from N, S, O; preferably, R ¹ 、R ² And together with the atoms to which they are attached form

in a specific embodiment, R ⁵ 、R ⁶ Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,Optionally by one or more R ⁷ Substitution;

in a specific embodiment, R ⁵ Is H and R ⁶ Selected from methyl, cyclopropyl, phenyl, naphthyl,The methyl, cyclopropyl, phenyl, naphthyl,Optionally by one or more R ⁷ Substitution;

in a specific embodiment, R ⁵ Is H and R ⁶ Is methyl;

in a specific embodiment, R ⁵ Is H and R ⁶ To optionally be covered by one or more R ⁷ A substituted phenyl group; preferably, R ³ Is that

In a specific embodiment, R ³ Is thatAnd wherein R is ⁵ Is H;

in a specific embodiment, R ⁴ To select optionally one or more R ⁸ The substituted following groups:

in a specific embodiment, R ⁴ Is that

In one ofIn particular embodiments, R ⁷ Selected from-CH ₃ 、-CF ₃ 、-CH ₂ F、-CHF ₂ 、-CCl ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

In a specific embodiment, R ⁷ Selected from-CF ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

In a specific embodiment, R ⁸ Selected from-CH ₃ 、-OH、-OCH ₃ 、-C(＝O)CH ₃ 、-C(＝O)CH ₂ -C (=o) -cyclopropyl, -S (=o) ₂ -cyclopropyl;

in a specific embodiment, R ⁸ Selected from-C (=O) CH ₃ ；

In a specific embodiment, R ⁹ Selected from C1-C3 alkyl;

in a specific embodiment, R ⁹ Selected from-CH ₃ 。

wherein,

A ₁ 、A ₂ 、A ₃ 、R ² 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² the definition of n is as described above.

wherein:

in a specific embodiment, R ² Selected from H, D, methyl, ethyl, propyl, isopropyl;

in a specific embodiment, R ² Selected from H;

in a specific embodiment, R ⁵ Selected from H, D, C1-C4 alkyl;

in a specific embodiment, R ⁵ Selected from H, D, methyl, ethyl, propyl, isopropyl;

in a specific embodiment, R ⁵ Selected from H;

in a specific embodiment, R ¹⁰ 、R ¹¹ Each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, acetyl;

in a specific embodiment, R ⁷ Selected from-CH ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

In a specific embodiment, R ⁷ Selected from-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

in a specific embodiment, R ⁸ Selected from-C (=O) CH ₃ ；

In a specific embodiment, R ⁹ Selected from C1-C3 alkyl;

in a specific embodiment, R ⁹ Selected from-CH ₃ ；

in a specific embodiment, R ¹³ Selected from methyl, ethyl, propyl, isopropyl methoxy, ethoxy, -NO ₂ 、-CN、-NH ₂ -NH (C1-C3 alkyl), -N (C1-C3 alkyl) ₂ 、-C(＝O)NH ₂ -C (=o) NH (C1-C3 alkyl), -C (=o) N (C1-C3 alkyl) ₂ -OH, halogen.

Exemplary structures of tau protein binding compounds (tau binders) described in the present disclosure are shown below:

in another aspect, the present disclosure also provides a method of preparing any one of the foregoing compounds, comprising the steps of:

scheme a:

dissolving a compound of formula (IV) in a solvent, adding R in a proper reaction system ³ -H, the reaction mixture is stirred at room temperature; LCMS monitors the reaction; pouring the reaction mixture into water, extracting with ethyl acetate, washing the combined organic phases with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained crude product by chromatography to obtain a solid compound shown in a formula (I); or alternatively, the first and second heat exchangers may be,

Scheme B:

dissolving a compound of formula (V) in a solvent with stirring at 0deg.C, adding R in a proper reaction system ⁴ -H, stirring the reaction mixture at room temperature; after completion of 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, and the crude product obtained was purified by chromatography to give a solid compound of formula (I). It will be appreciated that any of the foregoingThe compounds may be prepared by methods conventional in the art. For example, R in the above scheme A or scheme B ³ -H and/or R ⁴ H or the reactants in a specific preparation step, may take the form of a suitable reaction, for example by taking a protecting agent to protect the site where the reaction is not intended to take place, etc.

In particular embodiments, an exemplary structure of the TBM group is shown below, whereinShowing the connection location with the X portion in L:

the aforementioned small molecule compounds that specifically degrade tau protein, said ULM being capable of binding E3 ubiquitin ligase; preferably, the E3 ubiquitin ligase is VHL E3 ubiquitin ligase or CRBN E3 ubiquitin ligase;

in specific embodiments, exemplary compounds of the ULM are shown below, which are linked to the Z portion of L through the amino N atom shown in positions (1) and (2), respectively,

the aforementioned small molecule compounds that specifically degrade tau protein, the AUM being capable of binding to the ZZ segment of the autophagy receptor p62/SQSTM 1/sequencer-1, are shown in the following exemplary structures and are linked to the Z portion of L by (3) a C atom of an aminoalkyl group in L or an O atom of an ether group,

The small molecule compound for specifically degrading tau protein disclosed by the disclosure, wherein in TBM-L-ULM or TBM-L-AUM, L is a group-X-Y-Z-,

wherein,

x is a single bond, - (CH) ₂ ) _m C(＝O)NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ C(＝O)-、-(CH ₂ ) _m C (=o) -, optionally, the- (CH) ₂ ) _m C(＝O)NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ C(＝O)-、-(CH ₂ ) _m One or more H on the methylene group in C (=o) -is substituted with R;

y is-E ₁ -(CH ₂ CH ₂ O) _p -E ₂ -，-E ₁ -(CH ₂ ) _q -E ₂ -，

R ¹⁴ selected from H, C1-C3 alkyl; preferably, R ¹⁴ Selected from H, methyl, ethyl; preferably, R ¹⁴ Selected from H and methyl;

in specific embodiments, an exemplary structure of the L group of the present disclosure is shown below:

or:

in specific embodiments, small molecule compounds of the present disclosure that specifically degrade tau protein, an exemplary structure of the-L-ULM group is shown below:

In a specific embodiment, the small molecule compounds of the present disclosure that specifically degrade tau protein, the-L-AUM group is shown in the following structure:

in particular embodiments, exemplary structures of small molecule compounds of the present disclosure that specifically degrade tau protein include:

TBM-L-ULM molecule (PROTAC)

TBM-L-AUM molecule (AUTAC):

the aforementioned preparation methods of small molecule compounds that specifically degrade tau protein employ methods conventional in the art, which illustratively include linking the TBM group to the-L-ULM or-L-AUM group. It is understood, however, that the connection between each group and its substituent is not limited by the means described in the present disclosure, and those skilled in the art may prepare the small molecule compounds of the present disclosure in other ways as needed in order to obtain greater reaction efficiency or yield.

The present disclosure also provides a pharmaceutical composition comprising a compound of any one of the preceding claims, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of the preceding claims, and a pharmaceutically acceptable adjuvant.

The present disclosure also provides the use of a compound of any one of the preceding claims, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of the preceding claims, or a pharmaceutical composition of the preceding claims, in the manufacture of a medicament for treating a condition caused by tau protein accumulation in a patient;

The present disclosure also provides the use of a compound of any one of the preceding claims, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of the preceding claims, or a pharmaceutical composition of the preceding in the preparation of a tau degrading agent.

The present disclosure also provides a method of degrading tau protein in a patient in need thereof, comprising administering to the patient a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any of the foregoing, or a pharmaceutical composition of the foregoing.

The present disclosure also provides a method of degrading tau protein in a biological sample comprising contacting the biological sample with a compound of any of the foregoing, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any of the foregoing, or a pharmaceutical composition of the foregoing.

The present disclosure also provides a method for treating a disorder caused by tau protein accumulation in a patient in need thereof, comprising administering to the patient a compound of any one of the preceding, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of the preceding, or a pharmaceutical composition of the preceding.

III. Examples

The present disclosure is further illustrated below with reference to examples. The description of specific exemplary embodiments of the present disclosure is presented for purposes of illustration and description. The description is not intended to limit the disclosure to the precise form disclosed, and obviously many modifications and variations are possible in light of the teaching of the present specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and its practical application to thereby enable one skilled in the art to make and utilize the present disclosure in various exemplary embodiments and with various modifications as are suited to the particular use contemplated.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.

EXAMPLE 1 preparation of Compound QR10000

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

(2) To the above reaction solution were added compound 0-d (1.5 g,10.85 mmol) and DIEA (1.4 g,10.85 mmol) at 0℃and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 compound 0-e (3.28 g, yield 81%) as a white solid. LCMS monitored the reaction was complete. LCMS m/z=381.1 [ m+h ]] ⁺ 。

(3) Compound 0-e (300 mg (crude), 0.78 mmol) was dissolved in acetone (3 mL), aqueous methylal (2 mL) and DIEA (100 mg,0.78 mmol) were added at 0deg.C, and the reaction mixture was stirred at room temperature for 30 min. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 0 (120 mg, yield 41%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1A)

Example 2 preparation of Compound QR10010

(1) The synthesis of compounds 0-e is as described above.

(2) Compounds 0-e (300 mg,0.78 mmol) were dissolved in acetone (3 mL), aqueous ammonia (2 mL) and DIEA (100 mg,0.78 mmol) were added at 0deg.C and the reaction mixture was stirred at room temperature for 30 min. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1B)

EXAMPLE 3 preparation of Compound QR10014

(1) The synthesis of compounds 0-e is as described above.

(2) Compound 0-e (300 mg,0.78 mmol) was dissolved in acetone (3 mL), aniline (73 mg,0.78 mmol) and DIEA (100 mg,0.78 mmol) were added at 0deg.C, and the reaction mixture was stirred at room temperature for 30 min. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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-d ₆ )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] ⁺ . (FIG. 1C)

EXAMPLE 4 preparation of Compound QR10033

(1) The synthesis of compounds 0-e is as described above.

(2) Compounds 0-e (300 mg (crude), 0.78 mmol) were dissolved in 1, 4-dioxane (3 mL) and 4-nitroaniline (108 mg,0.78 mmol) and tris (dibenzylideneacetone) dipalladium (73 mg,0.08 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (93 mg,0.16 mmol) and cesium carbonate (104 mg,0.32 mmol) were added and the reaction mixture stirred under nitrogen at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 in water/methanol) to give compound 33 (25 mg, yield 7%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1D)

EXAMPLE 5 preparation of Compound QR10034

(1) The synthesis of compounds 0-e is as described above.

(2) Compound 0-e (300 mg (crude), 0.78 mmol) was dissolved in N, N-dimethylformamide(3 mL) 4-methoxyaniline (96 mg,0.78 mmol) and DIEA (100 mg,0.78 mmol) were added and the reaction mixture was stirred at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 34 (25 mg, yield 7%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1E)

EXAMPLE 6 preparation of Compound QR10035

(1) The synthesis of compounds 0-e is as described above.

(2) Compounds 0-e (300 mg (crude), 0.78 mmol) were dissolved in N, N-dimethylformamide (3 mL) and benzene-1, 4-diamine (2 mL) and DIEA (100 mg,0.78 mmol) were added and the reaction mixture stirred at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 35 (130 mg, yield 37%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1F)

EXAMPLE 7 preparation of Compound QR10036

(1) The synthesis of compounds 0-e is as described above.

(2) Compounds 0-e (300 mg (crude), 0.78 mmol) were dissolved in N, N-dimethylformamide (3 mL) and 4-aminobenzamide (106 mg,0.78 mmol) and DIEA (100 mg,0.78 mmol) were added and the reaction mixture stirred at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 36 (25 mg, yield 7%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1G)

EXAMPLE 8 preparation of Compound QR10037

(1) The synthesis of compounds 0-e is as described above.

(2) Compounds 0-e (300 mg (crude), 0.78 mmol) were dissolved in N, N-dimethylformamide (3 mL) and 4-bromoaniline (134 mg,0.78 mmol) and DIEA (100 mg,0.78 mmol) were added and the reaction mixture stirred at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 in water/methanol) to give compound 37 (25 mg, yield 6%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1H)

EXAMPLE 9 preparation of Compound QR10038

(1) The synthesis of compounds 0-e is as described above.

(2) Compounds 0-e (300 mg (crude), 0.78 mmol) were dissolved in N, N-dimethylformamide (3 mL) and naphthalene-1-amine (112 mg,0.78 mmol) and DIEA (100 mg,0.78 mmol) were added and the reaction mixture stirred at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 38 (19 mg, yield 5%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)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] ⁺ . (FIG. 1I)

Example 10 preparation of Compound QR10039

(1) The synthesis of compounds 0-e is as described above.

(2) Compound 0-e (300 mg (crude), 0.78 mmol) was dissolved in N, N-dimethylformamide (3 mL) and 4- (4-methylpiperazin-1-yl) aniline (149 mg,0.78 mmol) and DIEA (100 mg,0.78 mmol) were added and the reaction mixture was stirred at 100deg.C for 12 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained was purified by HPLC (0.5% formazan)Acid water/methanol) to give compound 39 (10 mg, yield 2%) as a white solid. ¹ H NMR(500MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1J)

EXAMPLE 11 preparation of Compound QR10044

(1) Compound 44-a (5 g,20 mmol) was dissolved in acetonitrile (50 mL) and 44-b (3.1 g,20 mmol) and ditolylphosphine palladium dichloride (1.4 g,2 mmol), cuprous iodide (760 mg,4 mmol), triethylamine (6 g,60 mmol) were added and the reaction mixture stirred under nitrogen at 100deg.C for 2 hours. LCMS monitored the reaction was complete. The reaction mixture was filtered and poured into water and extracted with ethyl acetate (3×10 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 compound 44-c (1.5 g, yield 26.6%) as a white solid. LCMS m/z 238.1[ M+H ] ] ⁺ 。

(2) 44-c (500 mg,2.11 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%) was added and the reaction was allowed to react overnight under hydrogen, and LCMS monitored for completion. The reaction mixture was filtered through celite and concentrated under reduced pressure. Compound 44-d (212 mg, crude) was obtained. LCMS m/z 242.1[ M+H ]] ⁺ 。

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

(4) Compound 44-e (37 mg,0.26 mmol) was dissolved in acetone (2 mL), 44-f (76 mg,0.26 mmol) and DIEA (34 mg,0.26 mmol) were added at 0deg.C, and the reaction mixture was stirred at room temperature for 30 min. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 44-g (50 mg, yield 48.2%) of a white solid compound.

(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 and the reaction mixture was stirred at 60℃for 12 h. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 44 (24 mg, yield 41%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1K)

EXAMPLE 12 preparation of Compound QR10047

(1) Compound 47-a (1 g,4.4 mmol) was dissolved in acetone (10 mL), and compound 0-b (560 mg,4.4 mmol) and DIEA (560 mg,4.4 mmol) were added to the reaction solution under stirring at 0℃and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete. LCMS m/z 274.2[ M+H ]] ⁺ 。

(2) To the above reaction solution were added compound 0-d (299 mg,1.82 mmol) and DIEA (235 mg,1.82 mmol) at 0 ℃, and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitoring the completion of the reaction, LCMS m/z 380.1[ M+H ]] ⁺ 。

(3) At 0 ℃ toTo the reaction mixture was added aniline (1 mL) and DIEA (137 mg,1.06 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 47 as a white solid (206 mg, yield 45%). ¹ H NMR(400MHz,CD ₃ OD)δ8.38(s,1H),7.36(s,4H),7.26–7.04(m,2H),6.99–6.79(m,2H),3.94–3.45(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] ⁺ . (FIG. 1L)

EXAMPLE 13 preparation of Compound QR10048

(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 to give DIEA (618 mg,4.40 mmol) as a solution. The reaction mixture was stirred at 160℃for 30 minutes, and after completion of the reaction by LCMS, water (10 mL) was added thereto and extracted with ethyl acetate (3X 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 48-b (320 mg, yield 53.2%) as a yellow solid. LCMS m/z 273.1[ M+H ] ] ⁺ 。

(2) To compound 48-b (310 mg,1.13 mmol) was added compound 0-d (0.5 mL) at room temperature, and the reaction mixture was stirred at 100deg.C for 2 hours. After completion of LCMS monitoring the reaction, dichloromethane (10 mL) was added for dissolution, and then purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 48-c (200 mg, 46.5%) as a pale yellow solid.

(3) To a solution of compound 48-c (70 mg,0.21 mmol) in 1, 4-dioxane (2 mL) was added sodium tert-butoxide (36 mg,0.42 mmol), brettphos Pd G3 (17 mg,0.02 mmol) and (137 mg,1.06 mmol) and aniline(21 mg,0.25 mmol) and the reaction mixture was stirred at 100deg.C for 2 hours. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC to give compound 48 (26 mg, yield 28.3%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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] ⁺ . (FIG. 1M)

EXAMPLE 14 preparation of Compound QR10049

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

(2) Compound 0-a (372 mg,2.1 mmol) was dissolved in acetone (4 mL), and compound 49-b (200 mg,2.1 mmol) and DIEA (271mg, 2.1 mmol) were added to the reaction solution under stirring at 0℃and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete. LCMS m/z 247.1[ M+H ]] ⁺ 。

(3) To the above reaction solution at 0℃were added compound 0-d (115 mg,0.81 mmol) and DIEA (105 mg,0.81 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete.

(4) To the reaction mixture was added aniline (1 mL) and DIEA (73 mg,0.57 mmol) at 0deg.C, and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine and driedDried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:2) to give compound 49 (77 mg, yield 33%) as a white solid. ¹ H NMR(400MHz,DMSO-d ₆ )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＝7.2Hz,1H),6.90(s,1H),6.84(d,J＝4.5Hz,1H),6.70(s,1H),4.06–3.60(m,8H),2.06–1.92(m,3H),1.90–1.73(m,2H).LCMS m/z 410.1[M+H] ⁺ . (FIG. 1N)

EXAMPLE 15 preparation of Compound QR10050

(1) Compound 0-c (100 mg,0.36 mmol) was dissolved in 1, 4-dioxane (2 mL) and 14-a (33.5 mg,0.36 mmol) and DIEA (46.5 mg,0.36 mmol) were added and the reaction mixture was stirred at 60℃for 12 h. LCMS monitored the reaction was complete.

(2) 50-b (59.5 mg,0.3 mmol) and DIEA (38.7 mg,0.3 mmol) were added to the above reaction mixture with stirring at 0deg.C, and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (3×5 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 compound 50-c (90 mg, two-step yield 50.1%) as a white solid.

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

(4) Compound 50-d (60 mg,0.15 mmol) was dissolved in dichloromethane (2 mL), acetic acid (1.5 mL) and DIEA (19 mg,0.15 mmol), EDCI (35 mg,0.18 mmol), HOBT (203 mg,0.15 mmol) were added to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. LCMS monitored the reaction was complete. ReactionThe mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by HPLC (0.5% formic acid in water/methanol) afforded compound 50 (5 mg, yield 8%) as a white solid. ¹ H NMR(600MHz,CD ₃ OD)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] ⁺ . (FIG. 1O)

EXAMPLE 16 preparation of Compound 42 (QR 10042)

(1) 42-a (10 mg,0.02 mmol) was dissolved in tetrahydrofuran (1 mL), 0-c (5.5 mg,0.02 mmol) and triethylamine (2 mg,0.02 mmol) were added to the reaction solution under stirring at 0℃and the reaction mixture was stirred at room temperature for 30 minutes. LCMS monitored the reaction was complete. After spin-drying the reaction solution, it was purified by PLC (dichloromethane: methanol=20:1) to give compound 42-b (10 mg, yield 72.2%) LCMS m/z 858.3[ m+h] ⁺ 。

(2) Compound 42-b (10 mg,0.01 mmol) was dissolved in 1, 4-dioxane (2 mL) and 1- (1, 4-diaza-1-yl) ethan-1-one (2 mg,0.01 mmol) and DIEA (2 mg,0.01 mmol) were added and the reaction mixture stirred at 80℃for 12 h. LCMS monitored the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 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 isolated and purified by HPLC (0.5% formic acid in water/methanol) to give compound 42 (3 mg, yield 31%) as a white solid. ¹ H NMR(400MHz,CD ₃ OD)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] ⁺ . (FIG. 2)

Effect example: tau inhibition activity assay

1. Preparation of tau protein

tau protein is referenced Barghorn S, biennat J, mandelkow e.purification of recombinant tau protein and preparation of Alzheimer-paired helical filaments in vitro methods Mol biol 2005;299:35-51. The detailed protocol expressed purification or purchased from Abcam corporation (cat# Ab 84700).

2. Assay for tau protein purity

Coomassie brilliant blue staining and immunoblotting hybridization

1. Tau protein was added to 4xSDS gel loading buffer (200 mM Tris-HCl, pH 6.8,8% SDS,0.4% bromophenol blue, 40% glycerol, 400mM Dithiothreitol (DTT), all purchased from Sigma) and boiled on a metal bath for 5-10 min. After cooling, the mixture was centrifuged, vortexed, centrifuged briefly, loaded onto 10% SDS polyacrylamide gel and electrophoresed. After electrophoresis, SDS polyacrylamide gel was cut at the position of a molecular mass standard (marker, ruiche biotechnology Co., ltd.) of double-colored pre-dyed protein, and a gel with tau protein loading of 2.25. Mu.g was used for coomassie brilliant blue dyeing; a gel with a tau loading of 75ng was used for immunoblot hybridization experiments.

2. Coomassie brilliant blue staining

After the gel was stained in 0.25% coomassie brilliant blue R250 (Beyotime) solution (methanol: water: acetic acid=4.5:4.5:1, methanol and acetic acid were purchased from taitan biotechnology limited) for 1 hour, the gel was decolorized in a decolorizing solution (methanol: water: acetic acid=4.5:4.5:1) for 3 hours, during which time the decolorizing solution should be replaced three times. And after the gel background is clear, photographing.

3. Immunoblot hybridization

The gel was incubated with semi-dry transfer film (Bio-Rad) at constant flow 80mA for 60 min, after transfer, the transferred PVDF film (Sigma) was blocked with 5% skimmed milk powder (dissolved in Tris-Tween buffer (TBST: 20mM Tris-HCl, pH 7.4, 150mM NaCl,0.1%Tween-20) for 30 min at room temperature, then with polyclonal antibody of tau (Protech, 1:5000) or monoclonal antibody (Abcam, 1:500) (dissolved in TBST) for 1 h or overnight at 4℃at 37℃after incubation of the film with TBST for three times for 5 min, and then with horseradish peroxidase-labeled goat anti-rabbit or horseradish peroxidase-labeled goat anti-mouse secondary antibody (Protectech, 1:10000 dilution) for 1 h at 37℃after washing of the film (5 min/time, three times total), the film was developed with ECL chemiluminescent chromogenic solution for one min, and then signal acquisition was performed with gel imaging system (maritime-limited scientific instrument).

3. Surface plasmon resonance (Surface Plasmon Resonance) measures affinity of compounds to tau

1. Coupling of proteins: tau protein was diluted to 157 μg/mL with NaAc buffer pH 4.0, the flow rate was set to 10 μl/min, the chip was activated with a mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) for a default period of 420s, tau protein was immobilized to about 4000RU levels using a fixed time coupling mode, and the activated groups of unbound test sample were blocked with ethanolamine.

2. Sample test conditions: the control test samples were set to a series of concentrations (15.625. Mu.M, 31.25. Mu.M, 62.5. Mu.M, 125. Mu.M, 250. Mu.M, 500. Mu.M, 1 mM) using PBS buffer pH 7.4 containing 0.05% Tween-20 and 1% DMSO as running buffer, the sample was analyzed at a flow rate of 30. Mu.L/min, the binding time was 40s, and the dissociation time was 40s.

3. Parameter fitting: the experiment adopts multi-cycle operation, the response signal of the experiment takes analysis time as an abscissa and the response value as an ordinate. After the obtained data are subjected to double-reference deduction, fitting is carried out through BIAcore T200 analysis software, a fitting model is a 1:1Langmuir binding model, and affinity indexes such as binding dissociation constant and the like are determined.

Table 1: affinity of the Compounds of the examples with tau protein

For KD values, where "A" represents KD < 200. Mu.M; "B" means KD between 200 and 500. Mu.M; and "C" means KD > 500. Mu.M.

The above data demonstrate that the compounds of formula (I) of the present disclosure possess tau protein binding capacity, can be used to bind proteins, and can be further prepared into small molecule compounds for degradation of tau proteins as described in the present disclosure.

Claims

A compound of formula (I), a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:

wherein:

A ₁ 、A ₂ 、A ₃ each independently selected from C, N atoms;

preferably, A ₁ 、A ₂ 、A ₃ And simultaneously is an N atom;

L ₁ is- (CH) ₂ ) _n -or- (CH) ₂ O) _n -；

Preferably L ₁ Is- (CH) ₂ ) _n -；

R ¹ Selected from 5-6 membered aryl or 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, S, O, said 5-6 membered aryl or 5-6 membered heteroaryl optionally being substituted with one or more R ¹⁵ Substitution, said R ¹⁵ Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen;

preferably, R ¹ Selected from phenyl, pyridyl and pyranA group, thiopyranyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl;

preferably, R ¹ Selected from phenyl, 2-pyridyl, 2-thienyl, 2-thiazolyl;

Preferably, R ¹ Selected from 2-thienyl;

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

preferably, R ² Selected from H;

or R is ² By combining with R ¹ The atoms of the ring being bound to each other to give R ¹ 、R ² And together with the atoms to which they are attached form an 8-10 membered partially unsaturated or aromatic carbocyclic bicyclic ring, an 8-10 membered partially unsaturated or aromatic bicyclic ring containing 1-2 heteroatoms independently selected from N, S, O;

preferably, R ¹ 、R ² And together with the atoms to which they are attached form

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

R ³ selected from C1-C6 alkyl, C1-C6 alkoxy, -NR ⁵ R ⁶ 、-OR ¹⁶ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R ³ Selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -NR ⁵ R ⁶ ；

R ⁵ 、R ⁶ Each independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, aryl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, S, O, said C1-C6 alkyl, C3-C6Cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, aryl, heteroaryl optionally substituted with one or more R ⁷ Substitution;

Preferably, R ⁵ 、R ⁶ Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,Optionally by one or more R ⁷ Substitution;

preferably, R ⁵ Is H and R ⁶ Selected from methyl, cyclopropyl, phenyl, naphthyl,The methyl, cyclopropyl, phenyl, naphthyl,Optionally by one or more R ⁷ Substitution;

preferably, R ⁵ Is H and R ⁶ Is methyl;

preferably, R ⁵ Is H and R ⁶ To optionally be covered by one or more R ⁷ A substituted phenyl group; preferably, R ³ Is thatPreferably, R ³ Is thatAnd wherein R is ⁵ Is H;

R ⁴ is a 3-8 membered saturated ring containing 1-2 atoms independently selected from N, O, which is substituted with a compound of formula (I) through an N atomThe rings being linked, the 3-8 membered saturated ring containing 1-2N, O atoms being optionally interrupted by one or more R ⁸ Substitution;

preferably, R ⁴ To select optionally one or more R ⁸ The substituted following groups:

preferably, R ⁴ Is that

R ⁷ Selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen, a 5-8 membered saturated ring containing 1-2N, S, O atoms, said C1-C6 alkyl, C1-C6 alkoxy, a 5-8 membered saturated ring containing 1-2N, S, O atoms optionally being substituted with one or more R ⁹ Substitution;

R ⁸ selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C (=O) R ¹² 、-S(＝O) ₂ R ¹² ；

R ⁹ Selected from C1-C6 alkyl, -NO ₂ 、-CN、-NH ₂ -OH, halogen, -C (=o) R ¹² ；

R ¹⁰ 、R ¹¹ Each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;

R ¹² selected from H, C C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon groups;

preferably, R ⁷ Selected from-CH ₃ 、-CF ₃ 、-CH ₂ F、-CHF ₂ 、-CCl ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

Preferably, R ⁷ Selected from-CF ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

Preferably, R ⁸ Selected from-CH ₃ 、-OH、-OCH ₃ 、-C(＝O)CH ₃ 、-C(＝O)CH ₂ -C (=o) -cyclopropyl, -S (=o) ₂ -cyclopropyl;

preferably, R ⁸ Selected from-C (=O) CH ₃ ；

Preferably, R ⁹ Selected from C1-C3 alkyl;

preferably, R ⁹ Selected from-CH ₃ 。
A compound of formula (II) or formula (III) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:

wherein,

A ₁ 、A ₂ 、A ₃ each independently selected from C, N atoms; preferably, A ₁ 、A ₂ 、A ₃ And simultaneously is an N atom;

R ² selected from H, D, C1-C6 alkyl;

preferably, R ² Selected from H, D, methyl, ethyl, propyl, isopropyl;

preferably, R ² Selected from H;

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

R ⁵ 、R ⁶ each independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, aryl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, S, O, said C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, aryl, heteroaryl optionally substituted with one or more R ⁷ Substitution;

preferably, R ⁵ 、R ⁶ Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine,The methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl, naphthyl, pyrimidine, pyridine, Optionally by one or more R ⁷ Substitution;

preferably, R ⁵ Is H and R ⁶ Selected from methyl, cyclopropyl, phenyl, naphthyl,The methyl, cyclopropyl, phenyl, naphthyl,Optionally by one or more R ⁷ Substitution;

preferably, R ⁵ Is H and R ⁶ Is methyl;

preferably, R ⁵ Is H and R ⁶ To optionally be covered by one or more R ⁷ A substituted phenyl group;

preferably, R ⁶ Is that

Preferably, R ⁶ Is thatAnd wherein R is ⁵ Is H;

R ⁷ selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen, a 5-8 membered saturated ring containing 1-2N, S, O atoms, said C1-C6 alkyl, C1-C6 alkoxy, containing 1-2N, S, O atomsThe 5-8 membered saturated ring optionally being substituted by one or more R ⁹ Substitution;

R ⁸ selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C (=O) R ¹² 、-S(＝O) ₂ R ¹² ；

R ⁹ Selected from C1-C6 alkyl, -NO ₂ 、-CN、-NH ₂ -OH, halogen, -C (=o) R ¹² ；

R ¹⁰ 、R ¹¹ Each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;

Preferably, R ¹⁰ 、R ¹¹ Each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, acetyl;

R ¹² selected from H, C C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon groups;

preferably, R ⁷ Selected from-CH ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

Preferably, R ⁷ Selected from-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

Preferably, R ⁸ Selected from-CH ₃ 、-OH、-OCH ₃ 、-C(＝O)CH ₃ 、-C(＝O)CH ₂ 、-C(＝O)C ₃ H ₅ -cyclopropyl, -S (=o) ₂ -cyclopropyl;

preferably, R ⁸ Selected from-C (=O) CH ₃ ；

Preferably, R ⁹ Selected from C1-C3 alkyl;

preferably, R ⁹ Selected from-CH ₃ 。
A compound of formula (IIA) or formula (IIIA) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof:

wherein:

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

preferably, R ² Selected from H, D, methyl, ethyl, propyl, isopropyl;

preferably, R ² Selected from H;

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

R ⁵ selected from H, D, C-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH) ₂ ) -, (C3-C6 cycloalkyl) - (CH) ₂ CH ₂ ) -, said C1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl) - (CH 2) -, (C3-C6 cycloalkyl) - (CH 2CH 2) -, optionally substituted with one or more R ¹³ Substitution;

preferably, R ⁵ Selected from H, D, C1-C4 alkyl;

preferably, R ⁵ Selected from H, D, methyl, ethyl, propyl, isopropyl;

preferably, R ⁵ Selected from H;

R ⁷ selected from C1-C6 alkyl, C1-C6 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen, a 5-8 membered saturated ring containing 1-2N, S, O atoms, said C1-C6 alkyl, C1-C6 alkoxy, a 5-8 membered saturated ring containing 1-2N, S, O atoms optionally being substituted with one or more R ⁹ Substituted;

R ⁸ selected from C1-C6 alkyl, C1-C6 alkoxy, -OH, -C (=O) R ¹² 、-S(＝O) ₂ R ¹² ；

R ⁹ Selected from C1-C6 alkyl, -NO ₂ 、-CN、-NH ₂ -OH, halogen, -C (=o) R ¹² ；

R ¹⁰ 、R ¹¹ Each independently selected from H, D, C1-C6 alkyl, C1-C6 alkanoyl;

preferably, R ¹⁰ 、R ¹¹ Each independently selected from H, D, methyl, ethyl, propyl, isopropyl, formyl, acetyl;

R ¹² selected from H, C C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 unsaturated hydrocarbon groups;

preferably, R ⁷ Selected from-CH ₃ 、-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-OH、F、Cl、Br、I、

Preferably, R ⁷ Selected from-OCH ₃ 、-NO ₂ 、-NH ₂ 、-C(＝O)NH ₂ 、-Br、

Preferably, R ⁸ Selected from-CH ₃ 、-OH、-OCH ₃ 、-C(＝O)CH ₃ 、-C(＝O)CH ₂ -C (=o) -cyclopropyl, -S (=o) ₂ -cyclopropyl;

preferably, R ⁸ Selected from-C (=O) CH ₃ ；

Preferably, R ⁹ Selected from C1-C3 alkyl;

preferably, R ⁹ Selected from-CH ₃ ；

R ¹³ Selected from C1-C3 alkyl, C1-C3 alkoxy, -NO ₂ 、-CN、-NR ¹⁰ R ¹¹ 、-C(＝O)NR ¹⁰ R ¹¹ -OH, halogen;

preferably, R ¹³ Selected from methyl, ethyl, propyl, isopropyl methoxy, ethoxy, -NO ₂ 、-CN、-NH ₂ -NH (C1-C3 alkyl), -N (C1-C3 alkyl) ₂ 、-C(＝O)NH ₂ -C (=o) NH (C1-C3 alkyl), -C (=o) N (C1-C3 alkyl) ₂ -OH, halogen.
The following compounds or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, or N-oxides thereof:

preferably, the following compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, or N-oxides thereof:
a process for the preparation of a compound according to any one of claims 1 to 4, characterized in that it comprises the steps of:

scheme a:

dissolving a compound of formula (IV) in a solvent, adding R in a proper reaction system ³ -H, the reaction mixture is stirred at room temperature; LCMS monitors the reaction; pouring the reaction mixture into water, extracting with ethyl acetate, washing the combined organic phases with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained crude product by chromatography to obtain a solid compound shown in a formula (I); or alternatively, the first and second heat exchangers may be,

scheme B:

dissolving a compound of formula (V) in a solvent with stirring at 0deg.C, adding R in a proper reaction system ⁴ -H, stirring the reaction mixture at room temperature; after completion of 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, and the crude product obtained was purified by chromatography to give a solid compound of formula (I).
A small molecule compound for specifically degrading tau protein, characterized in that the chemical structure of the compound is TBM-L-ULM or TBM-L-AUM and pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs or N-oxides thereof, wherein TBM is a tau protein binding moiety, L is a linker group, ULM is a ubiquitin ligase binding moiety, AUM is a binding moiety of the ZZ segment of autophagy receptor p62/SQSTM 1/sequenssome-1, said TBM is linked to said ULM or AUM moiety by L.
A small molecule compound according to claim 6, wherein TBM is a compound group according to any one of claims 1 to 4, and when R ³ is-NR ⁵ R ⁶ When the TBM passes through R ³ Is linked to L, or when R ⁸ Selected from-C (=O) CH ₃ When the TBM passes through R ⁸ Is attached to L, or when R ⁸ Selected from C1-C6 alkoxy, said TBM is prepared by R ⁸ Is linked to L.
The small molecule compound according to claim 6 or 7, characterized in that said ULM is capable of binding E3 ubiquitin ligase; preferably, the E3 ubiquitin ligase is VHL E3 ubiquitin ligase or CRBN E3 ubiquitin ligase; preferably, the ULM is a compound wherein L is linked to the ULM through an amino N atom shown in the (1) and (2) positions,

The AUM is capable of binding to the ZZ segment of the autophagy receptor p62/SQSTM 1/sequencer-1, preferably the AUM has a structure as shown below, which is linked to L via the (3) position to the C atom of the aminoalkyl group in L or to the O atom of the ether group,
the small molecule compound according to any one of claims 6 to 8, wherein L is a group-X-Y-Z-, wherein X is a single bond, - (CH) ₂ ) _m C(＝O)NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ C(＝O)-、-(CH ₂ ) _m C(＝O)-；

Optionally, the- (CH) ₂ ) _m C(＝O)NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ -、-(CH ₂ ) _m NR ¹⁴ C(＝O)-、-(CH ₂ ) _m One or more H on the methylene group in C (=o) -is substituted with R;

y is-E ₁ -(CH ₂ CH ₂ O) _p -E ₂ -，-E ₁ -(CH ₂ ) _q -E ₂ -，

Z is- (CH) ₂ ) _m C(＝O)-，-(CH ₂ ) _m NR ¹⁴ -E-, optionally, the- (CH) ₂ ) _m C(＝O)-，-(CH ₂ ) _m NR ¹⁴ -one or more H on methylene groups in E-are substituted by R;

TBM is attached to the alkylene C atom of the X group, ULM is attached to the carbonyl C atom of the Z group,

wherein m is selected from 0, 1, 2, 3 or 4, p is selected from 0, 1, 2, 3, 4, 5 or 6, q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R ¹⁴ selected from H, C1-C3 alkyl; preferably, R ¹⁴ Selected from H, methyl, ethyl; preferably, R ¹⁴ Selected from H and methyl;

E ₁ 、E ₂ are each independently selected from a single bond,And E is ₁ 、E ₂ At least one of them is a single bond;

e is selected from single bond, - (CH) ₂ ) _m O-, optionally, the- (CH) ₂ ) _m One or more H on the methylene group in O-is replaced by R;

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

Preferably, said L is selected from the following groups:
a small molecule compound according to any one of claims 6-9, characterized in that the-L-ULM group has the structure:

the-L-AUM group has the following structure:
the compound according to any one of claims 1-4, wherein the compound is capable of binding tau protein.
Pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 4, 11, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound according to any one of claims 6 to 10, together with pharmaceutically acceptable excipients.
Use of a compound according to any one of claims 1-4, 11, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound according to any one of claims 6-10, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment of a condition caused by tau protein accumulation in a patient;

preferably, the condition caused by tau protein accumulation is selected from one or more of Alzheimer's Disease (AD), frontotemporal dementia linked to chromosome 17 with Parkinson's Disease (frontotemporal dementia linked to chromosome-17 parkinsonism,FTDP-17), pick's Disease (PiD), progressive supranuclear palsy (progressive supranuclear palsy, PSP), corticobasal degeneration (corticobasal degeneration, CBD), primary age-related tauopathy (primary age-related tauopathy, PART), silvered granulosis (argyrophilic grain Disease, AGD), age-related astrocytopathy (imaging-related tau astrogliopathy, ARTAG), chronic traumatic encephalopathy (chronic traumatic encephalopathy, CTE), spherical glial tauopathy (Globular glial tauopathy, GGT), parkinson's Disease (PD), huntington's Disease (Huntington's Disease, HD), or Stroke (Stroke), epilepsy (epipresy), and Autism (Autism).
Use of a compound according to any one of claims 1-4, 11, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound according to any one of claims 6-10, or a pharmaceutical composition according to claim 12, for the preparation of a tau degrading agent.
A method of degrading tau protein in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-4, 11, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of claims 6-10, or a pharmaceutical composition of claim 12.
A method of degrading tau protein in a biological sample comprising contacting the biological sample with a compound of any one of claims 1-4, 11, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of claims 6-10, or a pharmaceutical composition of claim 12.
A method for treating a condition caused by tau protein accumulation in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-4, 11, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or N-oxide thereof, or a small molecule compound of any one of claims 6-10, or a pharmaceutical composition of claim 12.