Protein degradation targeting chimera for treating neurodegeneration

Abstract

This disclosure provides protein degradation targeting chimeras comprising (i) a piperidine-1-carboxylic acid ester-based targeting ligand capable of binding to toxic peptides and / or protein aggregates (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) in brain tissue for degradation; (ii) a ubiquitin ligase recruiting the ligand; and (iii) a linker group between (i) and (ii). These protein degradation targeting chimeras can be used, for example, to treat neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia.

Description

[0001] Claiming priority

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 527,513, filed July 18, 2023. The entire contents of the aforementioned application are incorporated herein by reference. Technical Field

[0003] This invention relates to bifunctional conjugates (PROTACs, or protein degradation-targeting chimeras) comprising at least three elements: (i) a targeting ligand capable of binding to toxic protein aggregates in brain tissue (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) for degradation; (ii) a ubiquitin ligase recruiting the ligand; and (iii) a linker group between the ubiquitin ligase (ii) and the targeting ligand (i). These conjugates can be used, for example, to treat neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. Background Technology

[0004] Many deadly diseases affect current human populations. For example, neurodegenerative diseases affect a large segment of the population, particularly the elderly. As one example, Parkinson's disease (“PD”) (a synucleinic disease affecting movement) affects more than 10 million people globally, with an estimated total economic burden exceeding $52 billion annually. As another example, Alzheimer's disease (“AD”) (a beta-amyloid disease affecting approximately 44 million people globally) is the sixth leading cause of death, with an estimated socioeconomic burden exceeding $200 billion. Yet another example, Pick's disease (a rare tau protein disease characterized by a series of progressive neurological symptoms) affects one in 250,000 people, with an estimated annual treatment cost of approximately $100,000 per patient. In summary, neurodegenerative diseases place a significant burden on patients, their families, healthcare systems, and society as a whole. Due to the aging global population, neurodegenerative diseases pose an increasing threat to public health. Summary of the Invention

[0005] This disclosure is based, at least in part, on the understanding that piperidine-1-carboxylic acid ester compounds bind with high affinity to insoluble peptide and / or protein aggregates (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) in brain tissue. These compounds are advantageously selective binders with specificity to pathological protein aggregates compared to soluble cytoplasmic peptides and / or proteins (e.g., α-synuclein amyloid and / or tau peptides or proteins). Furthermore, the compounds also exhibit relative selectivity for α-synuclein fibrils compared to amyloid plaques or tau tangles located in the brain tissue (e.g., neurons, glial cells, and extracellular space) of individuals affected by neurodegeneration. Additionally, the compounds also exhibit relative selectivity for α-synuclein fibrils compared to amyloid plaques or tau tangles located in the brain tissue of individuals affected by neurodegeneration. In one instance, piperidine-1-carboxylate compounds exhibit about 30 to about 50 times higher selectivity for α-synuclein fibrils compared to β-amyloid plaques. Advantageously, and without being bound by any theory or speculation, the specific affinity of piperidine-1-carboxylate compounds within the scope of these claims for protein aggregates involved in the pathology of neurodegenerative diseases allows the use of these compounds as targeting ligands in protein degradation-targeting chimeric (“PROTAC”) conjugates. Thus, in one general aspect, this disclosure provides a PROTAC comprising (i) a piperidine-1-carboxylate-based targeting ligand capable of selectively binding to protein aggregates involved in the pathology of neurodegenerative diseases for degradation; (ii) a ubiquitin ligase recruiting the ligand; and (iii) a linker group between the ubiquitin ligase (ii) and the targeting ligand (i). Without being bound by any theory, it is believed that the PROTAC disclosed herein allows the use of the cellular proteasome "machinery" to degrade peptide and / or protein aggregates (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) involved in the pathology of neurodegenerative diseases, advantageously leading to favorable therapeutic outcomes.

[0006] In one general aspect, this disclosure provides compounds of formula (I):

[0007] P—L—E

[0008] (I),

[0009] Or a pharmaceutically acceptable salt thereof, wherein P, L and E are as described herein.

[0010] In another general aspect, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] In another general aspect, this disclosure provides a method for treating neurodegenerative diseases or conditions as described herein, the method comprising administering to a subject in need a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof.

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Methods and materials used in this application are described herein; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification, including the definitions, shall prevail.

[0013] Other features and advantages of this application will be apparent from the following detailed description, drawings, and claims. Detailed Implementation

[0014] Over the past decade, small molecule-induced selective degradation of specific protein targets has emerged as a novel paradigm in biomedical research, promising to revolutionize drug development and provide pathways to new classes of therapeutics that target previously untreatable disease-related proteins. The concept of targeted protein degradation (TPD) is based on ligand-induced recruitment of a target protein (POI) to the E3 ubiquitin ligase complex. In this mechanism, the POI is ubiquitinated and subsequently eliminated via proteasome degradation. Two main classes of small molecules exist for TPD, commonly referred to as “molecular glues” and PROTACs. Molecular glues are monofunctional ligands that stabilize interactions between two proteins that would not bind without them. In TPD, molecular glues can recruit POIs as novel substrates to the E3 ligase complex. In contrast, PROTACs are heterobifunctional molecules that formally contain two separate ligands, one for binding to the E3 ligase complex and one for targeting the POI, tethered by a linker group. PROTACs are particularly advantageous because a large number of E3 ligases (e.g., over 600 E3 ligases in the human proteome) can potentially be used for PROTAC development. On the one hand, targeting multiple ligase complexes with “promiscuous” ligase ligands in the PROTAC molecule provides a highly efficient TPD approach that does not require differentiation of cell and tissue types. On the other hand, selectively targeting specific E3 ligases can provide cell-type and / or tissue-specific degradation. Furthermore, by selectively targeting the ligand moiety to recruit specific target proteins (POIs) involved in the pathology of the disease to E3 ubiquitin ligases, PROTACs specifically focused on treating the disease by clearing pathological proteins from the patient's cells and tissues can be developed.

[0015] In neuropathology, neurodegeneration is typically characterized by the accumulation of insoluble protein aggregates such as α-synuclein fibrils, amyloid-β plaques, and tau tangles in brain cells and intracellular spaces, as well as significant neuroinflammation. These pathologies collectively lead to a reduction in brain volume and number of brain cells, neuronal degeneration, microglial dysfunction, and the development of various neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer's disease (AD), frontotemporal degeneration (FTD), Huntington's disease (HD), Pick's disease, and dementia (including dementia specifically associated with any of the aforementioned disorders).

[0016] Without being bound by any theory, in one general aspect, this disclosure provides PROTAC compounds comprising targeting ligands that selectively bind to protein aggregates involved in neuropathology and neurodegeneration. Thus, the PROTAC compounds promote ubiquitination of these protein aggregates and subsequent proteasomal degradation, thereby contributing to the improvement of neuronal loss and simultaneously treating underlying neurological and / or neurodegenerative conditions (e.g., PD, MSA, PAF, AD, HD, or Pick's disease).

[0017] This document describes certain embodiments of therapeutic PROTAC compounds (e.g., compounds of Formula I) and exemplary embodiments of diseases treatable by these compounds (e.g., synucleinopathy). Pharmaceutical compositions and combination therapies are also described.

[0018] Therapeutic compounds

[0019] Typically, this disclosure provides compounds that can be used as bifunctional PROTAC conjugates, said conjugates comprising three elements: (i) a targeting ligand; (ii) a ubiquitin ligase recruiting ligand; and (iii) a linker group between the ubiquitin ligase ligand (ii) and the targeting ligand (i). In some embodiments, without being bound by any speculation, the targeting ligand (i) in the PROTAC conjugates of this disclosure is a piperidine-1-carboxylic acid ester-based targeting ligand, which is a selective and specific binder to toxic peptide and / or protein aggregates (e.g., α-synuclein fibrils, amyloid plaques, and / or tau protein tangles) in brain tissue. In some embodiments, this application provides compounds of formula (I):

[0020] P—L—E (I),

[0021] Or a pharmaceutically acceptable salt thereof, wherein P, L and E are as described herein.

[0022] In some implementation schemes:

[0023] P stands for the protein-binding portion;

[0024] E is the ligase-binding region; and

[0025] L is the linker group that connects the ligase-binding part E and the protein-binding part P.

[0026] Protein binding portion

[0027] In some implementations, the protein-binding portion P has the following formula:

[0028] ,

[0029] Among them, rings A and B, L 1X 1 and X 2 As described in this article.

[0030] In some implementation schemes:

[0031] X 1 Selected from O, NH and S;

[0032] L 1 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0033] Ring A is selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1A Substituents of the substituents;

[0034] Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino;

[0035] Each Cy 1 Selected independently from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14-membered heteroaryl, and 4-10-membered heterocycloalkyl, each optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3Alkylamino and di(C) 1-3 alkyl)amino;

[0036] X 2 Selected from CR 2 and N;

[0037] R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: OH, CN, NO2, C. 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0038] L 2 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0039] Ring B is selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1B Substituents of the substituents;

[0040] Each R 1B Independently selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino;

[0041] Each R 1a Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0042] Each R 4 Independently selected from H and C 1-3 Alkyl and C1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino;

[0043] Each Cy 2 Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by 1, 2 or 3 independent substituents selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; and

[0044] Each R Cy Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

[0045] In some implementation schemes, X1 For O. In some implementations, X 1 For S. In some implementations, X 1 For O or S. In some implementations, X 1 It is NH.

[0046] In some implementations, L 1 As a key. In some implementations, L 1 C 1-3 Alkylene, optionally substituted by one or two independent substituents selected from: halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, L... 1 C 1-3 Alkylene, optionally coated with halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, L... 1 C 1-3 Alkylene, optionally coated with halogen, CN, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, L... 1 C 1-3 Alkylene (e.g., unsubstituted alkylene). In some embodiments, L 1 Selected from methylene, ethylene, and propylene.

[0047] In some implementations, ring A is selected from C. 6-10 Aryl and 5-14 heteroaryl groups, each optionally selected independently from R 1A Substituents are substituted.

[0048] In some implementations, ring A is optionally R 1A Replacement C 6-10 Aryl. In some embodiments, ring A is optionally R 1A The substituted 5-14 heteroaryl group. In some embodiments, ring A is replaced by R. 1A Replacement C 6-10 Aryl (e.g., phenyl or naphthyl). In some embodiments, ring A is R 1A Substituted 5-14 membered heteroaryl groups (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine). In some embodiments, ring A is (e.g., at the ortho, meta, or para position) occupied by R. 1ASubstituted phenyl group. In some embodiments, ring A is (e.g., at position 1, 2, 3, 5, 6, 7, or 8) replaced by R. 1A Substituted naphthyl group.

[0049] In some implementations, part of P has the following formula:

[0050] ,

[0051] Or its pharmaceutically acceptable salt.

[0052] In some implementations, part of P has the following formula:

[0053] ,

[0054] Or its pharmaceutically acceptable salt.

[0055] In some implementations, part of P has the following formula:

[0056] ,

[0057] Or its pharmaceutically acceptable salt.

[0058] In some implementation schemes, R 1A Selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino. In some embodiments, R 1A Selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)NH2, C(=O)O(C 1-3 Alkyl) and C(=O)NH(C 1-3 Alkyl group). In some embodiments, R 1A Selected from halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Haloalkoxy group, C(=O)OH, C(=O)NH2, C(=O)O(C 1-3 Alkyl) and C(=O)NH(C 1-3 Alkyl group). In some embodiments, R 1A Selected from halogens, CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C(=O)NH2. In some embodiments, R 1A Selected from halogens, CN, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1A It is a halogen. In some implementations, R 1A For CN. In some implementations, R 1A C 1-3 Alkyl group. In some embodiments, R 1A C 1-3 Halogenated alkoxy groups.

[0059] In some implementation schemes, R 1A For Cy 1 In some implementations, Cy 1 Selected from C 6-10 Aryl and C 3-10 Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH, and C(=O)NH2. In some embodiments, Cy 1 C 6-10 Aryl. In some implementations, Cy 1 C 3-10 Cycloalkyl. In some embodiments, Cy 1 C 6-10 The aryl group, optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH, and C(=O)NH2. In some embodiments, Cy 1 C 3-10 Cycloalkyl groups, optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH, and C(=O)NH2. In some embodiments, Cy 1 C 6-10 Aryl groups, optionally bonded by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C(=O)NH2 substitution. In some embodiments, Cy 1 For (or R) 1A (for) halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C(=O)NH2-substituted C 6-10 Aryl. In some implementations, Cy 1 For (or R) 1A (for) halogens, CN, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy-substituted C 6-10 Aryl. In some implementations, Cy 1 For (or R) 1A (for) C replaced by halogen 6-10 Aryl. In some implementations, Cy 1 For (or R) 1A (for) C replaced by halogens or CN 6-10 Aryl.

[0060] In some implementation schemes:

[0061] X 1 It is O;

[0062] L 1 Selected from key and C 1-3 Alkylene;

[0063] Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NH2, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, C(=O)OH and C(=O)NH2; and

[0064] Each Cy 1 Selected independently from C 6-10 Aryl and C 3-10Cycloalkyl groups, each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NH2, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C(=O)OH and C(=O)NH2.

[0065] In some implementation schemes, X 2 For CR 2 In some implementations, X 2 Let N be the number of elements in the array.

[0066] In some implementations, part of P has the following formula:

[0067] ,

[0068] Or its pharmaceutically acceptable salt.

[0069] In some implementations, part of P has the following formula:

[0070] ,

[0071] Or its pharmaceutically acceptable salt.

[0072] In some implementation schemes, R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 Alkyl groups are optionally surrounded by OH, CN, NO2, or C. 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups are substituted. In some embodiments, R... 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ).

[0073] In some implementation schemes, R 2 For H. In some implementations, R 2 C 1-3 Alkyl group. In some embodiments, R 2 C 1-3 Halogenated alkyl groups. In some embodiments, R 2 For L 2 -C(=O)N(R 1a(R) 4 In some implementations, R 2 Selected from H and L 2 -C(=O)N(R 1a (R) 4 In some implementations, R 1a Selected from H and C 1-3 Alkyl group. In some embodiments, R 1a For H. In some implementations, R 1a C 1-3 alkyl.

[0074] In some implementations, part of P has the following formula:

[0075] ,

[0076] Or its pharmaceutically acceptable salt.

[0077] In some implementations, part of P has the following formula:

[0078] ,

[0079] Or its pharmaceutically acceptable salt.

[0080] In some implementations, L 2 As a key. In some implementations, L 2 C 1-3 Alkylene, optionally substituted by one or two independent substituents selected from: halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups. In some embodiments, L... 2 C 1-3 Alkylene, optionally coated with halogen, OH, CN, NO2, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, L... 2 C 1-3 Alkylene (e.g., methylene, ethylene, or propylene).

[0081] In some implementation schemes, R 4 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino.

[0082] In some implementation schemes, R 4 Selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups. In some embodiments, R 4 For H. In some implementations, R 4 C 1-3 Alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, R 4 C 1-3 Halogenated alkyl groups. In some embodiments, R 4 C 1-3 Alkyl group, optionally substituted by one or two independent substituents selected from the following: Cy 2 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 Alkyl)amino. In some embodiments, R 4 For Cy 2 Replaces and optionally is selected from CN, NO2, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)NH2, C(=O)NH(C 1-3 Alkyl) and C(=O)N(C 1-3 C substituents of alkyl)2 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 C that is substituted and optionally replaced by halogen or CN 1-3 Alkyl group. In some embodiments, R 4 For Cy 2and C(=O)NH(C 1-3 C(alkyl) substituted and optionally substituted with halogen or CN 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 Replacement C 1-3 Alkyl group. In some embodiments, R 4 For Cy 2 and C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl.

[0083] In some implementations, Cy 2 Selected from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted with a substituent selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl) and C(=O)N(C 1-3 Alkyl)2.

[0084] In some implementations, Cy 2 C 6-10 Aryl groups, which are optionally selected from R Cy Halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups. In some embodiments, Cy 2 C 6-10 Aryl, which is R Cy Replaced and optionally replaced by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, Cy 2 For R Cy Replacement C 6-10 Aryl. In some implementations, Cy 2 It is a 5-14 quinone heteroaryl group, optionally selected from R Cy Halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C1-3 Substituents of haloalkoxy groups. In some embodiments, Cy 2 It is a 5-14 quinone heteroaryl group, which is R Cy Replaced and optionally replaced by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, Cy 2 For R Cy Substituted 5-14 heteroaryl groups.

[0085] In some implementation schemes, R Cy Selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally bonded by a halogen, OH, CN, NO2, or C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino or di(C) 1-3 Alkyl)amino substitution.

[0086] In some implementation schemes, R Cy C 6-10 Aryl groups, optionally bonded by halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C(=O)OH, or C(=O)NH2 substitution. In some embodiments, R Cy C 6-10 Aryl groups, optionally bonded by halogens, CN, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups are substituted. In some embodiments, R... Cy C can be optionally replaced by halogen or CN. 6-10 Aryl. In some implementations, R 4 For being C 6-10 Aryl-C 6-10 aryl-substituted C 1-3 Alkyl, wherein each of the C 6-10 The aryl group is optionally replaced by halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

[0087] In some implementation schemes:

[0088] L 2 C 1-3 Alkylene;

[0089] R 4 For Cy 2 and C(=O)NH(C 1-3 alkyl) substituted C 1-3 alkyl;

[0090] Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and

[0091] Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl compounds.

[0092] In some implementation schemes:

[0093] L 2 For key;

[0094] R 4 For Cy 2 Replacement C 1-3 alkyl;

[0095] Cy 2 Selected from C 6-10 Aryl-R Cy and 5-14 quinone heteroaryl-R Cy ;and

[0096] Each R Cy Selected independently from C 6-10 Aryl and 5-14 heteroaryl compounds.

[0097] In some implementations, Cy 2 and R Cy Each of the C 6-10 The aryl and 5-14 heteroaryl groups are optionally substituted independently by one, two, or three substituents selected from the following (e.g., one or two substituents): halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3Alkyl), C(=O)NH2 and C(=O)NH(C 1-3 alkyl).

[0098] In some implementation schemes, R 3 For R 1B Replacement C 6-10 Aryl (phenyl or naphthyl). In some embodiments, R 3 For example, in adjacent, intermediate, or opposite positions, R is used. 1B Substituted phenyl groups. In some embodiments, R 3 For R 1B Substituted naphthyl group. In some embodiments, R 3 For R 1B Substituted 5-14 heteroaryl groups (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine).

[0099] In some implementations, part of P has the following formula:

[0100] ,

[0101] Or its pharmaceutically acceptable salt.

[0102] In some implementation schemes, X 3 Selected from N and CH. In some implementations, X 3 For N. In some implementations, X 3 For CH.

[0103] In some implementations, part of P has the following formula:

[0104] ,

[0105] Or its pharmaceutically acceptable salt.

[0106] In some implementations, part of P has the following formula:

[0107] ,

[0108] Or its pharmaceutically acceptable salt.

[0109] In some implementations, part of P has the following formula:

[0110] ,

[0111] Or its pharmaceutically acceptable salt.

[0112] In some implementations, part of P has the following formula:

[0113] ,

[0114] Or its pharmaceutically acceptable salt.

[0115] In some implementations, part of P has the following formula:

[0116] ,

[0117] Or its pharmaceutically acceptable salt.

[0118] In some implementation schemes, R 1B Selected from halogens, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)NH2, C(=O)OH, C(=O)O(C 1-3 Alkyl) and C(=O)NH(C 1-3 Alkyl group). In some embodiments, R 1B Halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups or C(=O)NH2. In some embodiments, R 1B Halogen, CN, C(=O)NH2, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1B It is halogen or CN. In some implementations, R 1B It is a halogen. In some implementations, R 1B For CN. In some implementations, R 1B For C(=O)NH2. In some implementations, R 1B C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1B C 1-3 Halogenated alkoxy groups. In some embodiments, R... 1B C 1-3 Alkyl group.

[0119] In some implementations, part P is selected from any of the following formulas:

[0120]

[0121]

[0122] Or its pharmaceutically acceptable salt.

[0123] In some implementation schemes, X2 Selected from N, CH and CL 2 -C(=O)N(R 1a (R) 4 ).

[0124] In some implementations, part P is selected from any of the following formulas:

[0125]

[0126] Or its pharmaceutically acceptable salt.

[0127] In some implementations, part of P has the following formula:

[0128]

[0129] Or its pharmaceutically acceptable salt.

[0130] In some implementations, part of P has the following formula:

[0131]

[0132] Or its pharmaceutically acceptable salt.

[0133] In some embodiments, part P is selected from any of the following compounds:

[0134]

[0135]

[0136]

[0137] Or its pharmaceutically acceptable salt.

[0138] Linking group portion

[0139] In some embodiments, the linker group portion L has the formula (L 3 ) m .

[0140] In some implementations, m is an integer from 2 to 20. In some implementations, m is an integer from 2 to 10. In some implementations, m is 2, 4, 5, 6, or 8.

[0141] In some implementation schemes, each L 3 Independently selected from N(R) N O, C (=O), C 1-6 Alkylene, C 3-7 Cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 Aromatic, -(OCH2CH2)x - and -(CH2CH2O) x -

[0142] In some implementation schemes, each L 3 Independently selected from NH, O, C (=O), C 1-6 Alkylene, C 3-7 Cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 Aromatic, -(OCH2CH2) x - and -(CH2CH2O) x -. In some implementations, at least one L 3 C 1-6 Alkylene. In some embodiments, at least one L 3 For C (=O). In some implementations, at least one L 3 For O. In some embodiments, the group (L) 3 ) m It contains at least one 4-10 membered heterocyclic alkyl group. In some embodiments, the group (L 3 ) m Contains at least one C 6-10 Arylene group. In some embodiments, the group (L...) 3 ) m It contains at least one C(=O)O, OC(=O), C(=O)NH, C(=O)NH, NHC(=O)NH, NHC(=S)NH, OC(=O)NH, or NHC(=O)O portion. In some embodiments, at least one L 3 -(OCH2CH2) x -or-(CH2CH2O) x -

[0143] In some implementation schemes:

[0144] m is an integer from 2 to 20;

[0145] Each L 3 Independently selected from N(R) N ), O, C(=O), S, S(=O), S(=O)2, C 1-6 Alkylene, C 3-7 Cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 Aromatic, -(OCH2CH2) x -、-(CH2CH2O) x -、-(OCH(CH3)CH2) x -、-(CH2CH(CH3)O) x-, each of which is optionally substituted by one or two independent substituents selected from the following: OH, NH2, C(O)OH, SO3H, C 1-3 Alkylamino, di(C) 1-3 -alkyl)amino, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0146] Each x is an independent integer from 1 to 2000; and

[0147] Each R N Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0148] In some implementation schemes:

[0149] m is 2, 4, 5, 6 or 8;

[0150] Each L 3 Independently selected from NH, O, C (=O), C 1-6 Alkylene, C 3-7 Cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 Aromatic, -(OCH2CH2) x - and -(CH2CH2O) x -;and

[0151] x is an integer from 1 to 10.

[0152] In some implementation schemes:

[0153] At least one L 3 C 1-6 Alkylene;

[0154] At least one L 3 It is C(=O)O or C(=O)NH; and

[0155] At least one L 3 -(OCH2CH2) x -or-(CH2CH2O) x -

[0156] In some implementations, (L 3 ) m Contains at least one 4-10 member heterocyclic alkyl group or C 6-10 Alpha-aryl.

[0157] In some implementations, (L 3 ) mIt contains at least one of the following components: C(=O)O, OC(=O), C(=O)NH, C(=O)NH, NHC(=O)NH, NHC(=S)NH, OC(=O)NH or NHC(=O)O.

[0158] In some implementations, x is an integer from 1 to 100. In some implementations, x is an integer from 1 to 20. In some implementations, x is an integer from 1 to 10. In some implementations, x is 1. In some implementations, x is 2. In some implementations, x is 3. In some implementations, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0159] In some implementation schemes, R N Selected from H and C 1-6 Alkyl group. In some embodiments, R N For H. In some implementations, R N C 1-6 Alkyl group. In some embodiments, at least one L 3 For NH. In some implementations, N(R) N ) is NH.

[0160] In some embodiments, the linker moiety can be flexible or rigid, hydrophobic, hydrophilic, or amphiphilic. In some embodiments, the length of the linker moiety is between about 10 Å and about 1,000 Å, about 15 Å and about 800 Å, about 20 Å and about 500 Å, about 20 Å and about 400 Å, about 20 Å and about 250 Å, about 20 Å and about 20 Å and about 200 Å, or about 20 Å and about 150 Å. Without being bound by any theory, it is considered that the length and physical properties of the linker moiety are selected for each moiety P and subsequently for each target protein, such that after the E moiety binds to the ligase, the target protein can be efficiently ubiquitinated within the ligase complex and then degraded by the cell's proteasome machinery.

[0161] In some implementations, (L 3 ) m Some of these flexible structural segments may contain any one or any combination thereof:

[0162] , , , , , , , , ,and .

[0163] In some implementations, (L3 ) m Some of these rigid structural segments may contain any one or any combination thereof:

[0164] , , , , , ,and .

[0165] In some implementations, the conjugate has the following formula:

[0166] ,

[0167] Or its pharmaceutically acceptable salt.

[0168] In some implementations, the conjugate has the following formula:

[0169] ,

[0170] Or its pharmaceutically acceptable salt.

[0171] In some implementations, the conjugate has the following formula:

[0172] ,

[0173] Or its pharmaceutically acceptable salt.

[0174] ligase ligand

[0175] The compounds described herein contain targeting moieties, such as small molecule targeting moieties, capable of binding to ligases (e.g., E3 ubiquitin ligases). Any suitable ligase (e.g., E3 ligases) can be targeted, including cullin-RING (CRL) ligases such as cereblon and von Hippel-Lindau (VHL) and non-CRL ligases such as inhibitor of apoptosis (IAP) proteins (e.g., inhibitor of apoptosis 1 and 2, c-IAP-1 and c-IAP-2) and mouse dual microsome 2 homologs (MDM2). Other suitable examples of ubiquitin ligases targeted by the PROTAC compounds disclosed herein include HECT, TRAF (e.g., TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6), DCAF (e.g., DCAF11, DCAF15, DCAF16), RNF (e.g., RNF4, RNF114), AhR, FEM1B, KEAP1, XIAP, and MIB (e.g., MIB1, MIB2).

[0176] The targeting ligase moiety can be any small molecule known to bind to the ligase with sufficient affinity. The molecular weight of the small molecule moiety can be, for example, less than 2000 Da (e.g., less than 1000 Da, less than 500 Da, less than 200 Da, about 1000 to about 2000 Da, about 500 to about 1000 Da, or about 200 to about 500 Da). The small molecule moiety can be aliphatic or aromatic, linear, branched, or cyclic, or any combination of these characteristics. The small molecule moiety can contain carbocyclic rings and heterocyclic rings. The heterocyclic rings within the moiety can be saturated or unsaturated and can contain any suitable number of heteroatoms, such as O, N, P, or S.

[0177] In some embodiments, the ligase is a cerebellar protein. Compounds such as thalidomide, pomalidomide, and lenalidomide can bind to cerebellar proteins and modulate their role in ubiquitination and degradation. Therefore, in some embodiments, the PROTAC compounds provided herein may comprise a thalidomide, pomalidomide, or lenalidomide-based moiety (e.g., the entire small molecule ligand except for the functional group used for conjugation with the linker group) capable of binding to the cerebellar protein E3 ubiquitin ligase.

[0178] In some implementations, the ligase recruits ligands with the following formula:

[0179] ,

[0180] X is selected from O and H2.

[0181] In some implementations, the ligase recruits ligands with the following formula:

[0182] .

[0183] In some implementations, the ligase recruits ligands with the following formula:

[0184] .

[0185] In some implementations, the ligase recruits ligands with the following formula:

[0186] .

[0187] In some implementations, the ligase recruits ligands with the following formula:

[0188] .

[0189] In some implementations, the ligase recruits ligands with the following formula:

[0190] .

[0191] In some implementations, the ligase recruits ligands with the following formula:

[0192] .

[0193] Another example of a ligase that can be targeted by a ligand recruited by the ligase in the PROTAC compounds of this disclosure is a cullin-RING E3 ubiquitin ligase (CRL), such as Hipper-Rindau (VHL). Therefore, in some embodiments, the PROTAC compounds provided herein may include, for example, small molecule ligands capable of binding to VHL E3 ubiquitin ligases.

[0194] In some implementations, the ligase recruits ligands with the following formula:

[0195] ,

[0196] in:

[0197] R o Selected from H and halogens; and

[0198] Each R p Selected from H and C 1-3 alkyl.

[0199] In some implementations, the ligase recruits ligands with the following formula:

[0200] .

[0201] Other examples of ubiquitin ligase-binding molecules that can be used as ligase-targeting ligands in the PROTAC compounds of this disclosure include binders targeting IAP (e.g., bestatin and its esters), ligands targeting MDM2 (e.g., nutlin, idasanutlin, or derivatives thereof), ligands targeting DCAF (e.g., indisulam), ligands targeting RNF (e.g., nimbolide), and ligands targeting KEAP1 (e.g., CDDO or its methyl ester). See, for example, Steinebach et al., Chem. Sci. 2020, 11, 3474-3486; Heider et al., Blood 2019, 134(1), 314; and Lee et al., Molecules, 2022, 27, 6515, etc. These publications are incorporated herein by reference in their entirety.

[0202] In some embodiments, the conjugate of formula (I) is selected from any of the following compounds:

[0203]

[0204]

[0205] Or its pharmaceutically acceptable salt, wherein:

[0206] Each X is independently O or NH;

[0207] Each n is an independent integer from 1 to 100; and

[0208] Each R is independently selected from any of the following:

[0209]

[0210] .

[0211] Pharmaceutically acceptable salts

[0212] In some embodiments, the salt of any of the compounds disclosed herein is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0213] In some embodiments, acids commonly used to form pharmaceutically acceptable salts of said compounds include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprates, acrylates, formates, isobutyrates, caprates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebates, fumarates, and malonic acid salts. Salts, butyn-1,4-diacidates, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, especially those formed with organic acids such as maleic acid.

[0214] In some embodiments, the bases typically used to form pharmaceutically acceptable salts of said compounds include hydroxides of alkali metals (including sodium, potassium, and lithium); hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia; organic amines such as unsubstituted or hydroxylated monoalkylamines, dialkylamines, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tri-(2-OH-(C1-C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucosamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine and lysine.

[0215] Compositions, formulations and routes of administration

[0216] This application also provides pharmaceutical compositions comprising an effective amount of the compounds disclosed herein or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions may also comprise any additional therapeutic agent described herein. In some embodiments, this application also provides pharmaceutical compositions and dosage forms comprising any additional therapeutic agent described herein. The carrier is "acceptable" in the sense of compatibility with other components of the formulation, and in the case of a pharmaceutically acceptable carrier, the amount used in the medicament is harmless to the recipient.

[0217] Pharmaceutically acceptable carriers, adjuvants, and solvents that can be used in the pharmaceutical compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers (e.g., phosphates, glycine, sorbic acid, potassium sorbate, a mixture of glycerides of saturated vegetable fatty acids), water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0218] The composition or dosage form may contain 0.005% to 100% of any of the compounds and therapeutic agents described herein, with the balance consisting of suitable pharmaceutically acceptable excipients. The intended composition may contain 0.001% to 100% of any of the compounds and therapeutic agents provided herein, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, wherein the balance may consist of any pharmaceutically acceptable excipients described herein or any combination of such excipients.

[0219] route of administration and dosage form

[0220] The pharmaceutical compositions of this application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, cervix, sinus, trachea, intestine, epidural, interstitial, intraperitoneal, intraarterial, bronchial, intrabursal, brain, cisterns, coronary artery, skin, catheter, duodenum, epidural, epidermal, esophagus, stomach, gingiva, ileum, lymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, peritoneum, prostate, lung, sinus, intraspinal, synovium, testis, intrasheath, tubule, intratumoral, uterus, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectum, respiratory tract (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, trachea, ureter, urethra, and vagina.

[0221] The compositions and formulations described herein can be conveniently present in unit dosage forms (e.g., tablets, sustained-release capsules) and in liposomes, and can be prepared by any method known in the pharmaceutical field. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th edition, 2000). Such preparation methods involve the step of binding the molecule to be administered with a component constituting one or more auxiliary ingredients, such as a carrier. Typically, compositions are prepared by uniformly and tightly binding the active ingredient with a liquid carrier, liposomes, or finely fragmented solid carrier, or both, and then shaping the product as needed.

[0222] In some embodiments, any of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of this application suitable for oral administration may be present as discrete units, each comprising a predetermined amount (e.g., an effective amount) of the active ingredient, such as capsules, sachets, granules, or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water liquid emulsions; water-in-oil liquid emulsions; packaged in liposomes; or as bolus formulations, etc. Soft gelatin capsules may be used to contain such suspensions, which can advantageously increase the rate of compound absorption. In the case of oral tablets, commonly used carriers include lactose, sucrose, glucose, mannitol, as well as silicic acid and starch. Other acceptable excipients may include: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifiers and suspending agents. Sweeteners and / or flavorings and / or colorings may be added as needed. Suitable compositions for oral administration include tablets containing ingredients in a flavoring matrix (typically sucrose and gum arabic or tragacanth gum); and soft tablets (pastilles) containing the active ingredient in an inert matrix (e.g., gelatin and glycerin, or sucrose and gum arabic).

[0223] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable or infusion solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. The formulations may be present in single-dose or multi-dose containers (e.g., sealed ampoules and vials) and may be stored under lyophilized (freeze-dried) conditions, requiring only the immediate addition of a sterile liquid carrier, such as water for injection, saline (e.g., 0.9% saline solution), or 5% glucose solution, prior to use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injectable solutions may be in the form of, for example, sterile injectable aqueous or oily suspensions. The suspension may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable solvents and media that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glycerol derivatives, as well as naturally occurring pharmaceutically acceptable oils such as olive oil or castor oil (especially their polyoxyethylated forms), can be used in the preparation of injections. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0224] The pharmaceutical compositions of this application can be administered in the form of suppositories for rectal use. These compositions can be prepared by mixing the compounds of this application with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and thus melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0225] The pharmaceutical compositions of this application can be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art. See, for example, U.S. Patent No. 6,803,031. Other formulations and methods for intranasal administration are described in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0226] The topical compositions disclosed herein can be prepared and used in the following forms: aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towel, soap, or other forms commonly used in the fields of topical application and / or cosmetic and skin care preparations. The topical compositions may be in emulsion form. Topical application of the pharmaceutical compositions of this application is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. In some embodiments, the topical composition comprises any of the compounds and therapeutic agents disclosed herein combined with one or more additional ingredients, carriers, excipients, or diluents (including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients, emulsifiers, film-forming / holding agents, fragrances, no-rinse exfoliants, prescription drugs, preservatives, scrubs, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / cleaners, penetration enhancers, and thickeners).

[0227] Dosage and regimen

[0228] In the pharmaceutical compositions of this application, the disclosed compounds are present in an effective amount. For example, the compounds of formula (I) may be present in a therapeutically effective amount. The effective dose may vary depending on the disease being treated, the severity of the disease, the route of administration, the subject's sex, age and general health status, the use of excipients, the possibility of co-use with other compounds (e.g., therapeutic treatments, other imaging agents, metabolic inhibitors, etc.), and the judgment of the attending physician.

[0229] In some embodiments, the effective amount of the compound (e.g., formula (I)) can be from, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about The effective amount of the compound of formula (I) is within the range of about 0.01 mg / kg to about 0.5 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 200 mg / kg; about 0.1 mg / kg to about 150 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 50 mg / kg; about 0.1 mg / kg to about 10 mg / kg; about 0.1 mg / kg to about 5 mg / kg; about 0.1 mg / kg to about 2 mg / kg; about 0.1 mg / kg to about 1 mg / kg; or about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, the effective amount of the compound of formula (I) is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0230] The aforementioned dosage may be determined by the attending physician and administered daily (e.g., as a single dose or as two or more divided doses, such as once daily, twice daily, or three times daily) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0231] Reagent test kit

[0232] The present invention also includes kits for the treatment of conditions, diseases, and illnesses, such as those mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the present disclosure. Where appropriate, such kits may further include one or more of various conventional pharmaceutical kit components, such as, for example, containers having one or more pharmaceutically acceptable carriers, other containers, etc. The kit may also include instructions (as inserts or labels) specifying the amount of the component to be administered, administration guidelines, and / or mixing guidelines for the components. The kit may optionally include additional therapeutic agents as described herein.

[0233] Treatment

[0234] Without being bound by any particular theory, it is believed that the binding of part (iii) of the PROTAC molecule of this disclosure to the ligase leads to ubiquitination and subsequent degradation of the ligase complex by the proteasome. When the protein target binds to the targeting ligand (i) of the PROTAC molecule, a complex is formed between the ligase and the protein target. As a result, the protein target is ubiquitinated within the ligase complex and further degraded by the cell's proteasome machinery. When the protein target is involved in the pathology of a disease or condition, contacting cells containing the target protein with the PROTAC of this disclosure results in the degradation of the target protein and is accompanied by favorable therapeutic outcomes. Therefore, in some embodiments, this disclosure provides a method for reducing the level of a protein (e.g., the target protein) in cells, the method comprising contacting the cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides a method for reducing the level of insoluble peptides and / or protein aggregates (e.g., the target protein) in cells and / or tissues, the method comprising contacting the cells and / or tissues with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In the above implementation scheme, contact with cells and / or tissues can occur in vitro, in vivo, or ex vivo.

[0235] In some embodiments, this disclosure provides a method for regulating α-synuclein, β-amyloid, and / or tau protein in cells and / or tissues, the method comprising contacting the cells and / or tissues with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. In some embodiments, the regulation comprises binding, inhibiting, activating, or reducing levels, or any combination thereof. In some embodiments, the regulation comprises reducing the levels of α-synuclein, β-amyloid, and / or tau protein in cells and / or tissues. In some embodiments, this disclosure provides a method for regulating α-synuclein fibrils, β-amyloid plaques, and / or tau tangles in cells and / or tissues, the method comprising contacting the cells and / or tissues with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. In some embodiments, the regulation comprises binding, inhibiting, activating, or reducing levels, or any combination thereof. In some embodiments, the modulation includes reducing levels of α-synuclein fibrils, β-amyloid plaques, and / or tau protein tangles in cells and / or tissues. In some embodiments, the contact occurs in vitro, in vivo, or ex vivo. In some embodiments, the cells and / or tissues are brain cells and / or tissues (e.g., neurons or glial cells). In some embodiments, the modulation is selective for α-synuclein compared to β-amyloid and / or tau protein (e.g., the modulation is 10-fold, 20-fold, 50-fold, 100-fold, or 1000-fold more selective for α-synuclein). In some embodiments, the regulation is selective for insoluble aggregates of α-synuclein, β-amyloid, and / or tau protein compared to the soluble cytoplasmic form of any of them (the regulation is 10-fold, 20-fold, 50-fold, 100-fold, or 1000-fold more selective for insoluble aggregates than for soluble proteins). In some embodiments, this disclosure provides a method for regulating α-synuclein, β-amyloid, and / or tau protein in a subject (e.g., the subject's brain), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. In some embodiments, this disclosure provides a method for regulating α-synuclein fibrils, β-amyloid plaques, and / or tau tangles in a subject (e.g., the subject's brain), the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0236] In some embodiments, the compounds of formula (I) of this disclosure, as well as related salts and compositions, can be used to treat neurodegenerative diseases or conditions affecting the motor system.

[0237] Numerous scientific publications provide robust evidence of a link between multisystem neurodegeneration and the progressive accumulation of insoluble fibrillary synuclein proteins (e.g., α-synuclein or αSyn) in neurons and glial cells. See, for example, Galvin et al., Arch Neurol., 2001, 58, 2, 186–190; and Sekiya et al., Mol Neurodegeneration 16, 83, 2021; Wong Y et al., Nat. Med., 2017, 23(2), 1–13; Lashuel H et al., Nat. Rev. Neurosci., 2013, 14, 1, 38–48, etc. Therefore, without being bound by any particular theory or speculation, as used herein, the term "synucleinopathy" refers to a group of neurodegenerative conditions involving the accumulation of insoluble synuclein (e.g., αSyn) protein fibrils in various CNS and / or peripheral nervous system (PNS) cells. In some embodiments, this disclosure provides a method of treating a subject (e.g., a subject in need of treatment, such as a subject identified as having a diagnosis of synucleinopathy) with synucleinopathy, said method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof. Suitable examples of synucleinic diseases include Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Alzheimer's disease, Hallervorden-Spatz syndrome, and lysosomal storage diseases (e.g., Gaucher's disease), as well as neurodegenerative diseases in which synuclein is involved at least partially in the disease pathology.

[0238] Numerous scientific publications provide information on neurodegeneration and amyloid peptides (e.g., β-amyloid protein such as Aβ). 40 Peptides and / or Aβ 42Reliable evidence linking misfolding of peptides and the resulting accumulation of amyloid plaques in the brain. See, for example, Spires-Jones et al., Acta Neuropathologica, 134, 187-205, 2017; Selkoe D et al., J EMBO Mol. Med., 2016, 8, 6, 595-608; and Selkoe D et al., Science, 2002, 19;297, 5580, 353-6, etc. In one instance, β-amyloid is used as a diagnostic biomarker for Alzheimer's disease (see, for example, Nakamura et al., Nature, 2018, 554, 7691, 249-254 and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804) and a primary target for its therapeutics (see, for example, Swanson C et al., Alzheimer's Res. Ther., 2021, 13, 1, 80). Therefore, without being bound by any particular theory or speculation, as used herein, the terms "amyloidosis" or "β-amyloidosis" refer to a group of neurodegenerative conditions involving the accumulation of insoluble amyloid plaques (e.g., β-amyloid plaques) in the brain. In some embodiments, this disclosure provides a method of treating amyloidosis in a subject (e.g., a subject requiring treatment, such as a subject identified as having a diagnosis of amyloidosis), said method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof. Suitable examples of amyloidosis include premature aging, cerebral amyloid angiopathy, Alzheimer's disease (AD), familial AD (FAD), and dementia associated with AD or FAD, as well as neurodegenerative conditions in which the pathology of the disease is at least partially involved in the formation of amyloid plaques.

[0239] Numerous scientific publications provide robust evidence of a link between neurodegeneration and the misfolding of tau protein, and the subsequent formation of neurofibrils or glial fibrillary tangles in the brain (e.g., neurons, glial cells, and the extracellular space). See, for example, Zhang et al., Molecular Neurodegeneration, 17, 28, 2022 and Handb ClinNeurol, 2017, 145, 355-368; Guo J et al., Cell, 2013, 154, 1, 103-17; Giasson et al., Science, 2003, 300, 5619, 636-40; and Bassil F et al., Neuron, 2020, 105, 2, 260-275, etc. Therefore, without being bound by any particular theory or speculation, as used herein, the term "tau proteinopathy" refers to a group of neurodegenerative conditions with pathological involvement of tau-positive inclusions in the brain. In some embodiments, this disclosure provides a method of treating a subject (e.g., a subject in need of treatment, such as a subject identified as having a diagnosis of tau proteinopathy) with tau proteinopathy, the method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof. Suitable examples of tau protein diseases include Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glialtauopathy, and argyrophilic grain disease, as well as neurodegenerative diseases in which the pathology of the disease involves at least part of the misfolding of tau protein.

[0240] In some embodiments, this disclosure provides methods for treating neurodegenerative diseases in which any combination of synuclein, amyloid, and / or tau peptides or proteins is involved in the disease pathology. See, for example, Irwin D et al., Nat. Rev. Neurosci., 2013, 14, 9, 626-36; Lloyd G et al., Mol Neurodegener., 2021, 16, 1, 63; and Ruffian C et al., Neuropathol. Appl. Neurobiol., 2016, 42, 5, 436-50, etc.

[0241] Without being bound by any particular theory or speculation, it is believed that the misfolding and / or aggregation of synuclein, amyloid, and / or tau peptides or proteins causes, induces, increases, and / or enhances neuroinflammation, a process that further contributes to the progression of neurodegeneration and related symptomatology. See, for example, Gate D et al., Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al., Elife, 2020, 9, e54083, etc. Therefore, in some embodiments, this disclosure provides a method of treating a subject (e.g., a subject in need of treatment, such as a subject identified as having a neurodegenerative disease) with a neurodegenerative condition (e.g., one involving inflammation in the disease pathology), said method comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereto. In some implementations, neurodegenerative disorders are selected from motor neuron disease (MND), prion disease, frontotemporal degeneration (FTD), FTD-related dementia, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), Huntington's disease (HD), HD-related dementia, Creutzfeldt-Jakob disease, Machado-Joseph disease, Binswanger's disease, dementia, multiple sclerosis (“MS”), hippocampal sclerosis, Gaucher's disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinocerebellar ataxia, and disorders of consciousness. Disorders, hearing and balance impairments, CNS hypoxia, cerebral senility, brain injury (e.g., stroke, traumatic brain injury, ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA).In some embodiments, the conditions that can be treated by the compounds of this disclosure are selected from accessory nerve disorder, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret's syndrome, Charcot-Marie-Tooth disease, diabetic neuropathy, nerve paralysis, and Horner's syndrome.

[0242] Combination therapy

[0243] The compounds disclosed herein can be used in combination with at least one drug or therapy that can be used, for example, to treat or alleviate symptoms of neurodegenerative diseases such as PD. Suitable examples of such drugs include levodopa, carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, istradefylline, donepezil, rivastigmine, galantamine, memantine, midodrine, fludrocortisone, physostigmine, droxidopa, botulinum toxin, or pharmaceutically acceptable salts thereof. The compounds can also be used in combination with deep brain stimulation (DBS) neurosurgery. The disclosed compounds can be administered to patients simultaneously or sequentially with additional therapeutic agents (in the same or different dosage forms) (the additional therapeutic agents can be administered before or after the administration of the disclosed compounds).

[0244] definition

[0245] As used herein, the term "about" means "approximately" (e.g., specifying a value ± about 10%).

[0246] Throughout this specification, substituents of the compounds of the present invention are disclosed by group or by scope. The invention is particularly intended to include each individual subcombination of members of such groups and scopes. For example, the term "C" 1-6 The term "alkyl" is specifically intended to separately disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0247] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described throughout this specification. Unless otherwise stated, these rings may be attached to the remainder of the molecule at any ring member, provided that the valence allows. For example, the terms "pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0248] It is further recognized that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

[0249] The term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings with aromatic properties (i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer).

[0250] The term "n-membered" (where n is an integer) typically describes the number of cyclic atoms in a portion having n cyclic atoms. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cyclic alkyl group.

[0251] As used herein, the phrase “optionally substituted” means either unsubstituted or substituted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as an oxo group, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valence.

[0252] It is further recognized that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

[0253] Throughout all definitions, the term "C" n-m "" indicates a range including the endpoints, where n and m are integers and represent the number of carbons. Examples include C. 1-4 and C 1-6 wait.

[0254] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkyl" refers to a saturated hydrocarbon group having n to m carbon atoms, which can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, the alkyl group comprises 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0255] As used herein, the term "C" is used alone or in combination with other terms. n-m "alkylene" refers to a divalent alkyl linking group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, and 2-methyl-propane-1,3-diyl. In some embodiments, the alkylene moiety comprises 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0256] As used herein, the term "C" is used alone or in combination with other terms. n-m "Halogenated alkyl" refers to an alkyl group having 1 to 2s+1 halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the halogenated alkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0257] As used herein, the term "aryl" alone or in combination with other terms refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m"Aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthraceneyl, phenanthryl, indenyl, and indenyl. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

[0258] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon, including cyclic alkyl and / or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. The cyclic carbon atom of the cycloalkyl group may optionally be substituted with one or two independently selected oxo or thio groups (e.g., C(O) or C(S)). The definition of cycloalkyl also includes portions having one or more aromatic rings fused with the cycloalkyl ring (i.e., sharing a common bond with the cycloalkyl ring), such as benzo or thiophene derivatives of cyclopentane and cyclohexane. Cycloalkyl groups containing fused aromatic rings can be linked by any cyclic atom (including the cyclic atom of the fused aromatic ring). Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbons (C 3-10 In some embodiments, the cycloalkyl group is C10. 3-10 Monocyclic or bicyclic cycloalkyl group. In some embodiments, the cycloalkyl group is C10. 3-7 Monocyclic cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptanetrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0259] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from nitrogen, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any cyclic N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five- or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl having a ring containing 5 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl groups are thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. Six-membered heteroaryl rings are heteroaryl groups having a ring containing six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0260] As used herein, “heterocyclic alkyl” refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more cyclic heteroatoms selected from O, N, or S. Heterocyclic alkyl groups include monocyclic 4, 5, 6, 7, 8, 9, or 10-membered heterocyclic alkyl groups. Heterocyclic alkyl groups may also include spirocyclic groups. Examples of heterocyclic alkyl groups include pyrrolidine-2-one, 1,3-isooxazolidinyl-2-one, pyranyl, tetrahydropyran, oxoheterocyclic butyl, azaheterocyclic butyl, morpholino, thiomorpholino, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolidine, isoxazolidinyl, isothiazolidinyl, pyrazolidine, oxazolidinyl, thiazolyl, imidazolyl, azaheptanyl, and benzo[a]azolidinyl, etc. The cyclic carbon atom and heteroatom of the heterocyclic alkyl group may optionally be substituted with one or two independently selected oxo or thio groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocyclic alkyl group may be linked by a cyclic carbon atom or a cyclic heteroatom. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes a portion having one or more aromatic rings fused to a cycloalkyl ring (i.e., sharing a common bond with the cycloalkyl ring), such as benzo[a] or thiophene derivatives of piperidine, morpholine, aziridine, etc. The heterocyclic alkyl group containing the fused aromatic ring may be linked by any cyclic atom (including the cyclic atom of the fused aromatic ring). In some embodiments, the heterocyclic alkyl is a monocyclic 4-6 membered heterocyclic alkyl having one or two independently selected heteroatoms selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocyclic alkyl group is a monocyclic or bicyclic 4-10 membered heterocyclic alkyl group having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen or sulfur and having one or more oxidized ring members.

[0261] In some places, the definition or embodiment refers to a specific ring (e.g., azahexacyclic butane ring, pyridine ring, etc.). Unless otherwise stated, these rings can be attached to any ring member, provided it does not exceed the valence of the atom. For example, azahexacyclic butane ring can be attached at any position on the ring, while a pyridine-3-yl ring is attached at the 3-position.

[0262] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkoxy" refers to a group of the formula -O-alkyl, wherein the alkyl group has n to m carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy and tert-butoxy). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0263] As used in this article, "C" n-m"Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An example of a haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0264] As used herein, "halogen" refers to F, Cl, Br, or I. In some embodiments, the halogen is F, Cl, or Br.

[0265] As used herein, the term "amino" refers to a group of the formula -NH2.

[0266] As used in this article, the term "C" n-m "Alkylamino" refers to a group of the formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino) and N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino).

[0267] As used in this article, the term "two (C)" n-m "-alkyl)amino" refers to a group of the formula -N(alkyl)2, wherein each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0268] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein by name or structure as a particular tautomer are intended to include other tautomers. Any atom in compounds identified herein that is not specifically designated as a radioactive isotope is present at its natural isotopic abundance.

[0269] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are intended to be covered. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, and N=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are contemplated in this invention. Cis and trans geometric isomers of the compounds of the present invention are described, and they can be isolated as mixtures of isomers or as separate isomeric forms. In some embodiments, the compounds have an (R)-configuration. In some embodiments, the compounds have an (S)-configuration.

[0270] The compounds described herein also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds, accompanied by the migration of protons. Tautomeric forms include proton-transfer tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-transfer tautomers include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or stereolocked into one form through appropriate substitution.

[0271] As used herein, the interchangeable terms “individual,” “patient,” or “subject” refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0272] As used herein, the phrase “effective amount” or “therapeutic effective amount” refers to the amount of an active compound or agent that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician in an tissue, system, animal, individual or human.

[0273] As used herein, the terms “treating” or “treatment” mean 1) suppressing a disease; for example, suppressing a disease, condition, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or symptom (i.e., preventing further development of the pathology and / or symptoms), or 2) improving a disease; for example, improving a disease, condition, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or symptom (i.e., reversing the pathology and / or symptoms).

[0274] As used herein, the term "preventing" or "prevention" of a disease, condition, or symptom refers to reducing the risk of a disease, condition, or symptom occurring in a subject or subject group (e.g., a subject or subject group susceptible to or affected by a disease, condition, or symptom). In some embodiments, preventing a disease, condition, or symptom means reducing the likelihood of acquiring a disease, condition, or symptom and / or its associated symptoms. In some embodiments, preventing a disease, condition, or symptom means completely or almost completely preventing the occurrence of a disease, condition, or symptom.

[0275] Example

[0276] Materials and methods

[0277] Unless otherwise stated, all commercially available reagents were used without further purification. Analytical thin-layer chromatography (TLC) was performed using silica gel GF254 plates (Merck Millipore co., Ltd., 0.2 mm thick). Compounds were analyzed using CombiFlash R... f Purification was performed using 150 (Teledyne ISCO co, .ltd). Recording was performed on a Bruker 500 MHz recorder. 1 H and 13 C spectrum. 1 Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) on the delta scale, with CDCl3 (7.26 ppm) as an internal standard. Data are reported as follows: chemical shifts (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad peak), coupling constant in Hertz (Hz), and integral. 13 Chemical shifts in the C10 NMR spectra are reported on the δ scale in ppm from the central peak of CDCl3 (77.0 ppm). MS data were recorded on an Agilent Technologies 6310 quadrupole mass spectrometer.

[0278] Example 1 - Protein Degradation Targeting Chimera

[0279]

[0280]

[0281]

[0282]

[0283] For each of the above compounds, X is O or NH.

[0284] For each of the above compounds, n is an integer from 1 to 100;

[0285] For each of the above compounds, the R group can be selected from any of the following:

[0286]

[0287] .

[0288] Other implementation plans

[0289] It should be understood that although this application has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of this application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

Claims

1. A conjugate of formula (I): P—L—E (I)， Or its pharmaceutically acceptable salt, wherein: P represents the protein-binding portion of the following formula: ， in: X 1 Selected from O, NH and S; L 1 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; Ring A is selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1A Substituents of the substituents; Each R 1A Independently selected from Cy 1 Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; Each Cy 1 Selected independently from C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14-membered heteroaryl, and 4-10-membered heterocycloalkyl, each optionally substituted by one, two, or three independent substituents selected from: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; X 2 Selected from CR 2 and N; R 2 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl and L 2 -C(=O)N(R 1a (R) 4 ), wherein C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: OH, CN, NO2, C. 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; L 2 Selected from key and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted by one or two independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; Ring B is selected from C 6-10 Aryl and 5-14 heteroaryl groups, each optionally composed of 1, 2 or 3 independently selected from R 1B Substituents of the substituents; Each R 1B Independently selected from halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; Each R 1a Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Each R 4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups, wherein the C 1-3 The alkyl group is optionally substituted by one or two independent substituents selected from the following: Cy 2 OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; Each Cy 2 Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by 1, 2 or 3 independent substituents selected from the following: R Cy Halogens, OH, CN, NO2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; and Each R Cy Selected independently from C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally substituted by one, two, or three independent substituents selected from the following: halogen, OH, CN, NO2, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, C(=O)OH, C(=O)O(C 1-3 Alkyl), C(=O)NH2, C(=O)NH(C 1-3 Alkyl), C(=O)N(C 1-3 Alkyl)2, amino, C 1-3 Alkylamino and di(C) 1-3 alkyl)amino; E represents the ligase-binding region; L is the linker group that connects the ligase-binding portion E and the protein-binding portion P.

2. The conjugate according to claim 1, wherein the linking group portion L has the formula (L 3 ) m ,in: m is an integer from 2 to 20; Each L 3 Independently selected from N(R) N ), O, C(=O), S, S(=O), S(=O)2, C 1-6 Alkylene, C 3-7 Cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 Aromatic, -(OCH2CH2) x -、-(CH2CH2O) x -、-(OCH(CH3)CH2) x -、-(CH2CH(CH3)O) x -, each of which is optionally substituted by one or two independent substituents selected from the following: OH, NH2, C(O)OH, SO3H, C 1-3 Alkylamino, di(C) 1-3 Alkyl)amino, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; Each x is an independent integer from 1 to 2000; and Each R N Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

3. The conjugate according to claim 2, having the following formula: ， Or its pharmaceutically acceptable salt.

4. The conjugate according to claim 2, having the following formula: ， Or its pharmaceutically acceptable salt.

5. The conjugate according to claim 2, having the following formula: ， Or its pharmaceutically acceptable salt.

6. The conjugate according to any one of claims 1-5, wherein: m is 2, 4, 5, 6 or 8; Each L 3 Independently selected from NH, O, C (=O), C 1-6 Alkylene, C 3-7 Cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C 6-10 Aromatic, -(OCH2CH2) x - and -(CH2CH2O) x -;and x is an integer from 1 to 10.

7. The conjugate according to claim 6, wherein: At least one L 3 C 1-6 Alkylene; At least one L 3 For C(=O)O or C(=O)NH; and At least one L 3 -(OCH2CH2) x -or-(CH2CH2O) x - 8. The conjugate according to claim 6, wherein (L 3 ) m Some of these flexible structural segments may contain any one or any combination thereof: , , , , , , , , ,and .

9. The conjugate according to claim 6, wherein (L 3 ) m Some of these rigid structural segments may contain any one or any combination thereof: , , , , , ,and .

10. The conjugate according to any one of claims 1-9, wherein ring B is R 1B Replacement C 6-10 Aryl.

11. The conjugate according to any one of claims 1-9, wherein ring B is R 1B Substituted 5-14 heteroaryl groups.

12. The conjugate according to any one of claims 1-9, wherein R B Selected from: 。 13. The conjugate according to any one of claims 1-9, wherein ring A is selected from: 。 14. The conjugate according to any one of claims 1-13, wherein the ligase-binding moiety E is capable of binding to cerebellar protein, Hipper-Lindau (VHL), inhibitor of apoptosis protein (IAP), and / or mouse two-microsome 2 homolog (MDM2).

15. The conjugate according to claim 14, wherein the ligase-binding moiety E is selected from any of the following formulas: 。 16. The conjugate according to claim 14, wherein the ligase-binding moiety E has the following formula: ， in: R o Selected from H and halogens; and Each R p Selected from H and C 1-3 alkyl.

17. The conjugate according to claim 16, wherein the portion E has the following formula: 。 18. The conjugate according to claim 1, wherein the conjugate is selected from any of the following compounds: Or its pharmaceutically acceptable salt, wherein: X is either O or NH; n is an integer from 1 to 100; and Each R is selected from any of the following: 。 19. A pharmaceutical composition comprising the conjugate of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. A method for treating a neurodegenerative disease or condition selected from Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer's disease (AD), familial AD (FAD), frontotemporal degeneration (FTD), Huntington's disease (HD), dementia associated with PD, AD, FAD, or HD, Pick's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, auricularial granuloma, dementia, chronic traumatic encephalopathy (CTE), age-related tau astropathy, Richardson's syndrome, cerebellar ataxia, glioblastoma tau disease, auricularial granuloma, motor neuron disease (MND), and prions, the method comprising administering to a subject in need a therapeutically effective amount of the conjugate of claim 1 or a therapeutically acceptable salt thereof.

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