Proteolytically targeted chimeras for treating neurodegeneration

Abstract

This disclosure provides (i) a benzo[c][1,2,5]thiadiazolyl-based target ligand that can bind to toxic peptides and / or protein aggregates in brain tissue (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) for degradation; (ii) a ubiquitin ligase mobilizing ligand; and (iii) a proteolytically targeted chimera containing a linker between (i) and (ii). These proteolytically targeted chimeras are useful for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia.

Description

[Technical Field]

[0001] Claim of priority This application claims the benefits of U.S. Provisional Application No. 63 / 527,519, filed on 18 July 2023. The entire foregoing is incorporated herein by reference.

[0002] The present invention relates to a bifunctional conjugate (PROTAC, or proteolytically targeted chimera) comprising at least three elements: (i) a target 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 mobilizing ligand; and (iii) a linker between the ubiquitin ligase (ii) and the target ligand (i). These conjugates are useful for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. [Background technology]

[0003] There are numerous deadly diseases that affect the current human population. Neurodegenerative diseases, for example, affect significant segments of the population, particularly the elderly. As one example, Parkinson's disease ("PD"), a synucleinopathy affecting movement, affects more than 10 million people worldwide, with an estimated overall annual economic burden exceeding $52 billion. As another example, Alzheimer's disease ("AD"), a beta-amyloidopathy affecting approximately 44 million people worldwide, is the sixth leading cause of death, with an estimated socioeconomic burden exceeding $200 billion. In yet another example, Pick's disease, a rare tauopathy characterized by a range of progressive neurological symptoms, affects 1 in 250,000 individuals, with an estimated annual treatment cost per patient of approximately $100,000. In short, neurodegenerative diseases place a substantial burden on patients, their families, healthcare systems, and society as a whole. Due to the global aging population, neurodegenerative disorders pose an increasing threat to public health. [Overview of the Initiative]

[0004] This disclosure is based at least in part on the recognition that benzo[c][1,2,5]thiadiazolyl 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 specific to pathological protein aggregates rather than to soluble cytoplasmic peptides and / or proteins (e.g., α-synuclein amyloid, and / or tau peptides or proteins). Furthermore, these compounds are relatively selective to α-synuclein fibrils rather than to amyloid plaques or tau tangles located in the brain tissue (e.g., neurons, glial cells, and extracellular space) of individuals suffering from neurodegeneration. In one example, benzo[c][1,2,5]thiadiazolyl compounds are about 30× to about 50× more selective to α-synuclein fibrils compared to β-amyloid plaques. Advantageously, and without being constrained by any theory or speculation, the specific affinity of the benzo[c][1,2,5]thiadiazolyl compounds in this claim to protein aggregates involved in the pathogenesis of neurodegenerative disorders allows these compounds to be used as target ligands in proteolytically targeted chimeric ("PROTAC") conjugates. Thus, in a general embodiment, the disclosure provides a PROTAC comprising (i) a benzo[c][1,2,5]thiadiazolyl-based target ligand capable of selectively binding to protein aggregates involved in the pathogenesis of neurodegenerative disorders for degradation; (ii) a ubiquitin ligase mobilizing ligand; and (iii) a linker between the ubiquitin ligase (ii) and the target ligand (i).Without being constrained by any theory, the PROTACs of this disclosure utilize the cellular proteasome “mechanism” to enable the degradation of peptides and / or protein aggregates (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) involved in the pathogenesis of neurodegenerative disorders, which is likely to lead to favorable therapeutic outcomes.

[0005] In one general embodiment, this disclosure relates to formula (I): PLE(I) The present invention provides compounds of or pharmaceutically acceptable salts thereof (wherein P, L, and E are as described herein).

[0006] In another general embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] In another general embodiment, the present disclosure provides a method for treating a neurodegenerative disease or disorder as described herein, comprising administering a therapeutically effective amount of the compound of formula (I) or a therapeutically acceptable salt thereof to a subject in need thereof.

[0008] Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by those skilled in the art to which this application belongs. Methods and materials are described herein for use in this application; other suitable methods and materials known in the art may also be used. Materials, methods and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references described herein are incorporated by reference in their entirety. In case of any inconsistency, this specification shall prevail, including definitions.

[0009] Other features and advantages of this application are evident from the following detailed description and figures, as well as from the claims. [Modes for carrying out the invention]

[0010] Over the past decade, small molecule-induced selective degradation of specific protein targets has emerged as a novel modality in biomedical research that has the potential to revolutionize drug development, providing access to a new class of therapeutics that can act on disease-related proteins previously thought to be undruggable. The concept of targeted proteolysis (TPD) is based on ligand-induced recruitment of a protein of interest (POI) to an E3 ubiquitin ligase complex. In this mechanism, the POI is ubiquitinated and subsequently eliminated by proteasomal degradation. There are two fundamental classes of small molecules used for TPD, commonly referred to as "molecular adhesives" and PROTACs. Molecular adhesives are monofunctional ligands that stabilize the interaction between two proteins that would not otherwise bind. In TPD, molecular adhesives can enable the recruitment of POIs as neosubstrates to the E3 ligase complex. PROTACs, in contrast, are heterobifunctional molecules formally composed of two individual ligands, one for binding to an E3 ligase complex and the other for targeting a POI, linked by a linker. PROTACs are particularly advantageous due to the large number of E3 ligases (e.g., over 600 E3 ligases in the human proteome) that can potentially be used in PROTAC development. On the one hand, targeting multiple ligase complexes with "messy" ligase ligands in a PROTAC molecule provides a means for effective TPD that is indifferent to cell type and tissue type. On the other hand, selective targeting of a specific E3 ligase can provide cell type and / or tissue-specific degradation. Furthermore, by selecting target ligand moieties for mobilization to E3 ubiquitin ligases of specific POIs involved in the pathogenesis of a disease, PROTACs can be developed with a particular focus on treating the disease by eliminating the pathogenic protein from the patient's cells and tissues.

[0011] In neuropathology, neurodegeneration is often 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 by marked neuroinflammation. Together, these conditions lead to a reduction in brain volume and brain cell number, neuronal degeneration, microglial dysfunction, and the development of a variety of neurodegenerative disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysplasia (PAF), Alzheimer's disease (AD), frontotemporal lobar degeneration (FTD), Huntington's disease (HD), Pick's disease, and dementia, which are specifically associated with any of the previously described disorders.

[0012] Without being bound by any theory, in one general embodiment, this disclosure provides PROTAC compounds containing target ligands that selectively bind to protein aggregates involved in neuropathology and neurodegeneration. Thus, the PROTAC compounds promote the ubiquitination and subsequent proteasomal degradation of these protein aggregates, thereby contributing to the improvement of neuronal loss and the concomitant treatment of underlying neurological and / or neurodegenerative disorders (e.g., PD, MSA, PAF, AD, HD, or Pick's disease).

[0013] Specific embodiments of therapeutic PROTAC compounds (e.g., compounds of formula I) and illustrative embodiments of diseases treatable by these compounds (e.g., synucleinopathy) are described herein. Pharmaceutical compositions and combination treatments are also described.

[0014] therapeutic compounds Generally, this disclosure provides compounds useful as bifunctional PROTAC conjugates containing three elements: (i) a target ligand; (ii) a ubiquitin ligase mobilizing ligand; and (iii) a linker between the ubiquitin ligase ligand (ii) and the target ligand (i). In some embodiments, and without being bound by any speculation, the target ligand (i) in the PROTAC conjugates of this disclosure is a piperidine-1-carboxylate-based target ligand that is a selective and specific binder for toxic peptides and / or protein aggregates in brain tissue (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles). In some embodiments, this application provides a compound of formula (I): PLE(I) The present invention provides compounds of or pharmaceutically acceptable salts thereof (wherein P, L, and E are as described herein).

[0015] In some embodiments: P is the protein-binding site; E is the ligase binding site; L is the linker portion that connects the ligase binding portion E and the protein binding portion P.

[0016] Protein binding portion In some embodiments, the protein-binding moiety P is given by formula:

[0017] [ka] It has, in the formula, X 1 , R 1 , R 2 , R 3 , R 4 , L 1 , Ring A, X 2 And ring B is as described herein.

[0018] In some embodiments: X 1 It is selected from S and O; R 1 、R 2 and R 3 are each independently selected from halo, OH, CN, NO2, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkoxy, C 1~3 haloalkoxy, 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;<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​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 It is optionally substituted with one, two, or three substituents independently selected from alkyl)amino; R 5 and R 6 H, C 1~3 Alkyl, and C 1~3 (Each haloalkyl is independently selected.) This is part of it; X 2 It is selected from C(=O) and S(=O)²; Ring B is C 6~10 Selected from aryls and 5- to 14-membered heteroaryls, each of which is a halo, OH, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 alkyl), S(=O)2OH, 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 It is optionally substituted with one, two, or three substituents independently selected from the alkyl)amino molecule.

[0020] In some embodiments, L 1 It does not exist. In some embodiments, ring A does not exist.

[0021] In some embodiments, the compound of formula (I) is of formula

[0022] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, L 1 C 1~6 Alkylene and C 3~6 Selected from cycloalkylenes, the C 1~6 The alkylene is optionally suspended by one or two groups independently selected from C(=O), S(=O)2, O, and NH. In some embodiments, ring A is part of formula (i).

[0024] In some embodiments, the ring C is a halo, OH, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, or C 1~3 It is substituted with a haloalkoxy. In some embodiments, the ring C is halo, OH, CN, NO2, C 1~3 Alkyl, and C 1~3 It is substituted with a haloalkyl group.

[0025] In some embodiments, part (i) is the following:

[0026] [ka] It has one of the following:

[0027] In some embodiments, the compound of formula (I) is:

[0028] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound of formula (I) is:

[0030] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of formula (I) is:

[0032] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound of formula (I) is:

[0034] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, R 5 H is R 6 C 1~3 Alkyl and C 1~3 Selected from haloalkyls. In some embodiments, R 6 is C 1~3 It is alkyl.

[0036] In some embodiments, L 1 C is interrupted by choice in O or NH. 1~6 It is alkylene. 1 C 1~6 Alkylene (e.g., ethylene or propylene). In some embodiments, L 1 C is interrupted at O 1~6 It is alkylene. 1- C 1~3 Alkylene-OC 1~3 It is alkylene.

[0037] In some embodiments, L 1 C 3~6It is a cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene).

[0038] In some embodiments, the compound of formula (I) is of the formula:

[0039]

Chemical formula

[0040] In some embodiments, R 4 is H. In some embodiments, R 4 is C 1~3 alkyl.

[0041] In some embodiments, R 1 , R 2 and R 3 are each independently selected from halo, CN, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkoxy, C 1~3 haloalkoxy, and C(=O)NH2.

[0042] In some embodiments, X 1 is O. In some embodiments, X 1 is S.

[0043] In some embodiments, X 2 is C(=O). In some embodiments, X 2 is S(=O)2.

[0044] In some embodiments, ring B is halo, CN, NO2, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkoxy, C 1~3 haloalkoxy, S(=O)2(C 1~3 alkyl), S(=O)2OH, C(=O)OH, C(=O)O(C 1~3C(=O)NH2 is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2. 6~10 It is Ariel.

[0045] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 C(=O)NH2 is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2. 6~10 It is Ariel.

[0046] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 C(=O)NH2 is optionally substituted with alkyl or C(=O)NH2. 6~10 It is Ariel.

[0047] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 C(=O)NH2 is optionally substituted with two substituents independently selected from alkyl and C(=O)NH2. 6~10 It is Ariel.

[0048] In some embodiments, ring B is halo, CN, NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 alkyl), S(=O)2OH, C(=O)OH, C(=O)O(C 1~3It is a 5- to 14-membered heteroaryl molecule that is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2.

[0049] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 It is a 5- to 14-membered heteroaryl molecule that is optionally substituted with one or two substituents independently selected from alkyl and C(=O)NH2.

[0050] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 It is a 5- to 14-membered heteroaryl substituted with alkyl or C(=O)NH2 as an optional substitution.

[0051] In some embodiments, ring B is halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, S(=O)2(C) 1~3 It is a 5- to 14-membered heteroaryl molecule that is optionally substituted with two substituents independently selected from alkyl and C(=O)NH2.

[0052] In some embodiments, partial P is the following compound:

[0053] [ka]

[0054] [ka]

[0055] [ka] Selected from one of the following or a pharmaceutically acceptable salt thereof.

[0056] Linker section In some embodiments, the linker portion L is given by formula (L 3 ) m It holds.

[0057] In some embodiments, m is an integer from 2 to 20. In some embodiments, m is an integer from 2 to 10. In some embodiments, m is 2, 4, 5, 6, or 8.

[0058] In some embodiments, each L 3 N(R) N ), O, C (=O), C 1~6 Alkilen, C 3~7 Cycloalkylene, 4-10 member heterocycloalkylene, 5-10 member heteroarylene, C 6~10 Arirene, -(OCH2CH2) x -, and -(CH2CH2O) x - is selected independently of the others.

[0059] In some embodiments, each L 3 is NH, O, C (=O), C 1~6 Alkilen, C 3~7 Cycloalkylene, 4-10 member heterocycloalkylene, 5-10 member heteroarylene, C 6~10 Arirene, -(OCH2CH2) x -, and -(CH2CH2O) x - Selected independently from. In some embodiments, at least one L 3 C 1~6 It is an alkylene. In some embodiments, at least one L 3 is C(=O). In some embodiments, at least one L 3is O. In some embodiments, (L 3 ) m The group comprises at least one 4- to 10-membered heterocycloalkylene. In some embodiments, (L 3 ) m The base is at least one C 6~10 Contains arylene. In some embodiments, (L 3 ) m The group comprises at least one partial C(=O)O, OC(=O), C(=O)NH, C(=O)NH, NHC(=O)NH, NHC(=S)NH, OC(=O)NH, or NHC(=O)O. In some embodiments, at least one L 3 is -(OCH2CH2) x -or-(CH2CH2O) x - is

[0060] In some embodiments: m is an integer between 2 and 20; Each L 3 N(R) N ), O, C(=O), S, S(=O), S(=O)2, C 1~6 Alkilen, C 3~7 Cycloalkylene, 4-10 member heterocycloalkylene, 5-10 member heteroarylene, C 6~10 Arirene, -(OCH2CH2) x -,-(CH2CH2O) x -,-(OCH(CH3)CH2) x -,-(CH2CH(CH3)O) x -Independently selected from, each of these is 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 They are optionally substituted with one or two substituents independently selected from the haloalkoxy; Each x is an independent integer between 1 and 2,000; Each R N H, C 1~6Alkyl, C 2~6 Alkenyl and C 2~6 It is selected independently of alkinil.

[0061] In some embodiments: m is 2, 4, 5, 6, or 8; Each L 3 is NH, O, C (=O), C 1~6 Alkilen, C 3~7 Cycloalkylene, 4-10 member heterocycloalkylene, 5-10 member heteroarylene, C 6~10 Arirene, -(OCH2CH2) x -, and -(CH2CH2O) x -Selected independently of; x is an integer between 1 and 10.

[0062] In some embodiments: at least one L 3 C 1~6 It is alkylene; at least one L 3 is C(=O)O or C(=O)NH; at least one L 3 is -(OCH2CH2) x -or-(CH2CH2O) x - is

[0063] In some embodiments, (L 3 ) m This includes at least one 4-10 member heterocycloalkylene or C 6~10 Contains allerenes.

[0064] In some embodiments, (L 3 ) m It contains at least one subdivision: C(=O)O, OC(=O), C(=O)NH, C(=O)NH, NHC(=O)NH, NHC(=S)NH, OC(=O)NH, or NHC(=O)O.

[0065] In some embodiments, x is an integer from 1 to 100. In some embodiments, x is an integer from 1 to 20. In some embodiments, x is an integer from 1 to 10. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0066] In some embodiments, R N H and C 1~6 Selected from alkyl. In some embodiments, R N is H. In some embodiments, R N is C 1~6 It is alkyl. In some embodiments, at least one L 3 NH is NH. In some embodiments, N(R N ) is NH.

[0067] In some embodiments, the linker portion may be flexible or rigid, hydrophobic, hydrophilic, or amphiphilic. In some embodiments, the length of the linker portion 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 200 Å, or about 20 Å and about 150 Å. Without being constrained by any theory, it is thought that by selecting the length and physical properties of the linker portion for each portion P and subsequently for each target protein, the binding of the E portion to the ligase may enable the target protein to be effectively ubiquitinated within the ligase complex and subsequently degraded by the cellular proteasome mechanism.

[0068] In some embodiments, (L 3 ) m The part is one of the aforementioned flexible structural fragments, or any combination thereof:

[0069] [ka] Includes.

[0070] In some embodiments, (L 3 ) m The part is one of the aforementioned rigid structural fragments, or any combination thereof:

[0071] [ka] Includes.

[0072] In some embodiments, the conjugate is given by the formula:

[0073] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the conjugate is given by the formula:

[0075] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the conjugate is given by the formula:

[0077] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the conjugate is given by the formula:

[0079] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the conjugate is given by the formula:

[0081] [ka] It has or is a pharmaceutically acceptable salt thereof.

[0082] Ligase ligand The compounds provided herein contain a target moiety, such as a small molecule targeting moiety, that can bind to a ligase (e.g., E3 ubiquitin ligase). Any suitable ligase (e.g., E3 ligase) can be targeted, including karin ring (CRL) ligases, such as cereblon and von Hipperlindau (VHL), as well as non-CRL ligases, such as apoptosis protein inhibitors (IAPs) (e.g., cell inhibitors of apoptosis 1 and 2, c-IAP-1 and c-IAP-2) and mouse double micro2 homologs (MDM2). Other suitable examples of ubiquitin ligases targeted by the PROTAC compounds of this disclosure include, among others, 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).

[0083] The ligase-targeting portion may be any small molecule portion known to bind to a ligase with sufficient affinity. The small molecule portion may have a molecular weight of less than 2000 Da (e.g., less than 1000 Da, less than 500 Da, less than 200 Da, about 1000 Da to about 2000 Da, about 500 Da to about 1000 Da, or about 200 Da to about 500 Da). The small molecule portion may be aliphatic or aromatic, linear, branched, or cyclic, or may contain any combination of these features. The small molecule portion may contain carbocyclic and heterocyclic rings. The heterocyclic ring within the portion may be saturated or unsaturated and may contain any appropriate number of heteroatoms such as O, N, P, or S.

[0084] In some embodiments, the ligase is cereblon. Compounds such as thalidomide, pomalidomide, and lenalidomide can bind to cereblon and modulate its role in ubiquitination and degradation. Therefore, in some embodiments, the PROTAC compounds provided herein may include a thalidomide, pomalidomide, or lenalidomide-based moiety (e.g., the entire small molecule ligand excluding the functional group used for conjugation to the linker moiety) that can bind to the cereblon E3 ubiquitin ligase.

[0085] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0086] [ka] The formula has such that X is selected from O and H2.

[0087] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0088] [ka] It holds.

[0089] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0090] [ka] It holds.

[0091] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0092] [ka] It holds.

[0093] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0094] [ka] It holds.

[0095] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0096] [ka] It holds.

[0097] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0098] [ka] It holds.

[0099] Another example of a ligase that can be targeted by the ligase-mobilizing ligand in the PROTAC compounds of this disclosure is a karin ring E3 ubiquitin ligase (CRL), such as von Hipper-Lindau (VHL). Therefore, in some embodiments, the PROTAC compounds provided herein may include, for example, small molecule ligands that can bind to VHL E3 ubiquitin ligase.

[0100] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0101] [ka] It has, in the formula: R o It is selected from H and halo; Each R p H and C 1~3 Selected from alkyl groups.

[0102] In some embodiments, the ligase-mobilizing ligand is of the formula:

[0103] [ka] It holds.

[0104] Additional examples of ubiquitin ligase-binding molecules useful 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., nutrin, idasanutrin, or their derivatives), ligands targeting DCAF (e.g., indislam), ligands targeting RNF (e.g., nimbolid), and ligands targeting KEAP1 (e.g., CDDO or its methyl esters). 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. These publications are incorporated herein by reference in their entirety.

[0105] In some embodiments, the conjugate of formula (I) is the following compound:

[0106] [ka] Selected from any one of the following or a pharmaceutically acceptable salt thereof, in the formula, Each X is independently either O or NH; Each n is an independent integer between 1 and 100 (for example, 1, 2, 3, 4, or 5).

[0107] Pharmaceutically acceptable salts In some embodiments, a salt of any one of the compounds of this disclosure is formed between an amino functional group of the compound, 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.

[0108] In some embodiments, acids commonly used to form pharmaceutically acceptable salts of 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-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. These pharmaceutically acceptable salts therefore include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprinates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, and hexin-1,6-dioate. Examples of salts include ethates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylenesulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfons, propanesulfons, 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, and in particular, those formed with organic acids such as maleic acid.

[0109] In some embodiments, bases commonly used to form pharmaceutically acceptable salts of compounds include alkali metal hydroxides, including sodium, potassium, and lithium; alkaline earth metal hydroxides, such as calcium and magnesium; other metals, such as aluminum and zinc hydroxides; ammonia; organic amines, such as unsubstituted or hydroxyl-substituted mono, di, or trialkylamines, dicyclohexylamines; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono, bis, or tris(2-OH-(C1~C6)-alkylamines), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids, such as arginine and lysine.

[0110] Compositions, formulations, and routes of administration This application also provides pharmaceutical compositions comprising an effective amount of the compounds disclosed herein or pharmaceutically acceptable salts thereof, as disclosed herein; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one of the additional therapeutic agents described herein. A carrier(s) is “acceptable” in the sense that it is compatible with the other components of the formulation and, in the case of a pharmaceutically acceptable carrier, is not harmful to the recipient in the amount used in the pharmaceutical.

[0111] Examples of pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, monopotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0112] The composition or dosage form may contain any one of the compounds and therapeutic agents described herein in an amount ranging from 0.005% to 100%, with the remainder consisting of a suitable pharmaceutically acceptable excipient. The composition to be conceived may contain any one of the compounds and therapeutic agents provided herein in an amount ranging from 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, with the remainder consisting of any pharmaceutically acceptable excipient described herein or any combination thereof.

[0113] Route of administration and dosage form 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, intracervical, sinus, tracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, bronchial, sacral, intracerebral, cisterna magna, coronary, intradermal, intraductal, duodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, lymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, paranasal sinus, intramedullary, synovial, testicular, subarachnoid, intraductal, intratumoral, intrauterine, intravascular, intravenous, transnasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, transtracheal, ureter, urethra, and vaginal.

[0114] The compositions and formulations described herein may, conveniently, be present in unit dosage forms, e.g., tablets, sustained-release capsules, and liposomes, and may be prepared by any method well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparation methods involve the step of associating components, such as carriers constituting one or more minor components, with the molecules to be administered. Generally, compositions are prepared by homogeneously and closely associating the active ingredient with a liquid carrier, liposomes, or a micronized solid carrier, or both, and then, if necessary, shaping the product.

[0115] In some embodiments, any one of the compounds and therapeutic agents disclosed herein is administered orally. Compositions of this application suitable for oral administration may be expressed as individual units such as capsules, sachets, granules or tablets, each containing a predetermined amount (e.g., an effective amount) of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; as oil-in-water liquid emulsions; as water-in-oil liquid emulsions; filled in liposomes; or as boluses, etc. Soft gelatin capsules may be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, commonly used carriers include lactose, sucrose, glucose, mannitol, as well as silicic acid and starch. Other acceptable excipients include: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) water-retaining agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption accelerators, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, lactose and dried corn starch are useful diluents. When an aqueous suspension is administered orally, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners and / or flavorings and / or colorings may be added if desired.Suitable compositions for oral administration include lozenges containing flavoring agents, usually sucrose and acacia or tragacanth; and aromatic tablets containing active ingredients in inert agents, such as gelatin and glycerin, or sucrose and acacia.

[0116] Suitable compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions or infusions that may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the intended recipient's blood; as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, e.g., water for injection, physiological saline (e.g., 0.9% physiological saline solution), or 5% dextrose solution, immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injection solutions may be, for example, in the form of sterile, injectable aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may be, for example, a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils have traditionally been used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic mono or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable preparations, particularly natural pharmaceutically acceptable oils such as olive oil or castor oil in polyoxyethylated versions. Solutions or suspensions of these oils may also contain long-chain alcohol diluents or dispersants.

[0117] The pharmaceutical compositions of this application can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of this application with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the active components. Examples of such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0118] The pharmaceutical compositions of this application can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, carbon fluoride, and / or other solubilizers or dispersants known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration can be found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0119] The topical compositions of this disclosure may be prepared and used in the form of aerosol sprays, creams, emulsions, solids, liquids, dispersions, foams, oils, gels, hydrogels, lotions, mousses, ointments, powders, patches, pomades, solutions, pump sprays, sticks, towels, soaps, or other forms commonly used in the art for topical administration, as well as / or cosmetic and topical formulations. The topical compositions may be in emulsion form. Topical administration of the pharmaceutical compositions of this application is particularly useful when the desired treatment involves a region or organ that is easily accessible by topical application. In some embodiments, the topical composition comprises one of the compounds and therapeutic agents disclosed herein, as well as one or more additional components, carriers, excipients, or diluents in combination, including but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (humidifiers), emulsifiers, film-forming / retaining agents, fragrances, leave-on exfoliants, formulating agents, preservatives, scrubs, silicones, skin-identifying / repairing agents, lubricants, sunscreens, surfactants / detergents, cleansing agents, penetration enhancers, and thickeners.

[0120] Dosage and regimen In the pharmaceutical compositions of this application, the compounds of the disclosure are present in an effective amount. For example, the compound 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 sex, age and overall health status of the subject, the use of excipients, the possibility of co-use with other compounds, such as therapeutic treatments, other imaging agents, metabolic inhibitors, etc., and the judgment of the treating physician.

[0121] In some embodiments, the effective amount of the compound (e.g., formula (I)) is, for example, about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 200 mg / kg; about 0.01 mg / kg to about 150 mg / kg; about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 50 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 5 mg / kg; about 0.01 mg / kg to about 1 mg / kg; about The effective amount of the compound of formula (I) may range from 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; or from 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.

[0122] The aforementioned dosage may be administered daily (for example, as a single dose or as two or more divided doses, e.g., once a day, twice a day, three times a day) or not daily (for example, every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month), as determined by the treating physician.

[0123] kit The present invention further includes a kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the present disclosure, which is useful, for example, in the treatment of disorders, diseases and conditions referred to herein. Such kits may further, if desired, include one or more of various conventional pharmaceutical kit components, e.g., containers having one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions indicating the amount of component to be administered, guidelines for administration, and / or guidelines for mixing the components may be included in the kit, either as inserts or as labels. The kit may optionally include additional therapeutic agents as described herein.

[0124] Treatment method Without being constrained by any particular theory, the binding of portion (iii) of the PROTAC molecule of this disclosure to a ligase appears to lead to ubiquitination and subsequent degradation of the ligase complex by the proteasome. When a protein target is bound to the target 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 cellular proteasome mechanism. If the protein target is involved in the pathogenesis 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, at the same time, a favorable therapeutic outcome. Therefore, in some embodiments, this disclosure provides a method for reducing the level of a protein (e.g., a target protein) in cells, comprising contacting the cells with an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the Disclosure provides a method for reducing the level of insoluble peptides and / or protein aggregates (e.g., target proteins) in cells and / or tissues, 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 embodiments described above, contacting the cells and / or tissues may occur in vitro, in vivo, or ex vivo.

[0125] In some embodiments, the Disclosure provides a method for modulating α-synuclein, β-amyloid, and / or tau protein in cells and / or tissues, comprising contacting cells and / or tissues with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. In some embodiments, modulation includes binding, inhibiting, activating, or reducing levels, or any combination thereof. In some embodiments, modulation includes reducing levels of α-synuclein, β-amyloid, and / or tau protein in cells and / or tissues. In some embodiments, the Disclosure provides a method for modulating α-synuclein fibrils, β-amyloid plaques, and / or tau tangles in cells and / or tissues, comprising contacting cells and / or tissues with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. In some embodiments, modulation includes binding, inhibiting, activating, or reducing levels, or any combination thereof. In some embodiments, modulation involves reducing the levels of α-synuclein fibrils, β-amyloid plaques, and / or tau tangles in cells and / or tissues. In some embodiments, contact occurs in vitro, in vivo, or ex vivo. In some embodiments, cells and / or tissues are brain cells and / or brain tissue (e.g., neurons or glial cells). In some embodiments, modulation is selective with respect to α-synuclein as opposed to β-amyloid and / or tau proteins (e.g., modulation is more selective with respect to α-synuclein than 10×, 20×, 50×, 100×, or 1000×).In some embodiments, the modulation is selective with respect to insoluble aggregates of α-synuclein, β-amyloid, and / or tau proteins, and not with respect to the soluble cytoplasmic form of any of those proteins (modulation is more selective with respect to insoluble aggregates than to soluble proteins, such as 10×, 20×, 50×, 100×, or 1000×). In some embodiments, the disclosure provides a method for modulating α-synuclein, β-amyloid, and / or tau proteins in a subject (e.g., the brain of the subject), comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject. In some embodiments, the disclosure provides a method for modulating α-synuclein fibrils, β-amyloid plaques, and / or tau tangles in a subject (e.g., the brain of the subject), comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject.

[0126] In some embodiments, compounds of formula (I) and related salts, as well as compositions of the present disclosure, are useful in treating neurodegenerative diseases or disorders affecting the motor system.

[0127] Numerous scientific publications provide reliable evidence of a link between multisystem neurodegeneration and the progressive aggregation of insoluble fibrillary synuclein (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. Neurosct., 2013, 14, 1, 38-48. Therefore, without being bound by any particular theory or speculation, as used herein, the term “synucleinopathy” refers to a group of neurodegenerative disorders in which the aggregation of insoluble synuclein (e.g., α-Syn) protein fibrils in various CNS and / or peripheral nervous system (PNS) cells is involved in the pathogenesis. In some embodiments, the Disclosure provides a method for treating synucleinopathy in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with synucleinopathy), comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, to the subject. Appropriate examples of synucleinopathy include other neurodegenerative disorders in which synuclein is at least partially involved in the pathogenesis, such as Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysregulation (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), axonal dystrophy, Shy-Drager syndrome, Alzheimer's disease, Haller-Holden-Spats syndrome, and lysosomal storage disorders (e.g., Gaucher disease).

[0128] Numerous scientific publications describe neurodegeneration in the brain and amyloid peptides (e.g., Aβ) in amyloid peptide plaques. 40 Peptides and / or Aβ 42This provides reliable evidence of a relationship between β-amyloid misfolding of peptides and other substances, and the associated accumulation. 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. In one example, β-amyloid is used as a diagnostic biomarker for Alzheimer's disease (see, e.g., Nakamura et al., Nature, 2018, 554, 7691, 249-254, and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804), as well as its primary target for therapeutic purposes (see, e.g., Swanson C et al., Alzheimer's Res. Ther., 2021, 13, 1, 80). Thus, without being bound by any particular theory or speculation, the terms “amyloidopathy” or “β-amyloidopathy” as used herein refer to a group of neurodegenerative disorders in which the aggregation of insoluble amyloid plaques (e.g., β-amyloid plaques) in the brain is involved in the pathogenesis. In some embodiments, the Disclosure provides a method for treating amyloidopathy in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with amyloidopathy), comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to the subject. Suitable examples of amyloidopathy include progeria, cerebral amyloid angiopathy, Alzheimer's disease (AD), familial AD (FAD), and dementia associated with AD or FAD, among other neurodegenerative disorders in which the formation of amyloid plaques is at least partially involved in the pathogenesis of the disease.

[0129] Numerous scientific publications provide reliable evidence of a relationship between neurodegeneration in the brain (e.g., neurons, glial cells, and extracellular space) and tau protein misfolding and subsequent formation of neurofibrillary or glial fibrillary condensates. See, for example, Zhang et al., Molecular Neurodegeneration, 17, 28, 2022 and Handb Clin Neurol, 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. Accordingly, without being bound by any particular theory or speculation, as used herein, the term “tauopathy” refers to a group of neurodegenerative disorders in which tau-positive inclusions in the brain are involved in the pathogenesis. In some embodiments, the Disclosure provides a method for treating tauopathy in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with tauopathy), comprising administering to the subject a compound of the Disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same. Suitable examples of tauopathy include Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic granule disease, primary age-related tauopathy, neurofibrillary sparse dementia, chronic traumatic brain injury (CTE), age-related tauastropathy, Richardson syndrome, cerebellar ataxia, globulogliary tauopathy, and argyrophilic granule disease, among other neurodegenerative disorders in which tau protein misfolding is at least partially involved in the pathogenesis.

[0130] In some embodiments, the disclosure provides methods for treating neurodegenerative disorders in which any combination of synuclein, amyloid, and / or tau peptides or proteins is involved in the disease pathogenesis. See, for example, Irwin D et al., Nat. Rev, Neurosci., 2013, 14, 9, 626-36; Lloyd G et al., Mol Neurodener., 2021, 16, 1, 63; and Ruffian C et al., Neuropathol., Appl. Neurobiol., 2016, 42, 5, 436-50.

[0131] Without being bound by any particular theory or speculation, misfolding and / or aggregation of synuclein, amyloid, and / or tau peptides or proteins appears to cause, induce, increase, and / or enhance neuroinflammation, and this process is thought to further contribute to the progression of neurodegeneration and associated total symptoms. See, for example, Gate D et al., Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al, Elife, 2020, 9, e54083. Accordingly, in some embodiments, the present disclosure provides a method for treating a neurodegenerative disorder (e.g., one in which inflammation is involved in the pathogenesis of the disease) in a subject (e.g., a subject requiring treatment, e.g., a subject identified as having been diagnosed with a neurodegenerative disorder), the method comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same. In some embodiments, neurodegenerative disorders are selected from motor neuron disease (MND), prion disease, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), Huntington's disease (HD), and dementia associated with HD, Creutzfeldt-Jakob disease, Machado-Joseph disease, Binswanger disease, dementia, multiple sclerosis ("MS"), hippocampal sclerosis, Gaucher disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinocerebellar ataxia, impaired consciousness, hearing and balance disorders, CNS hypoxia, cerebral aging, brain injury (e.g., stroke, traumatic brain injury, ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar degeneration (SCA), and spinal muscular atrophy (SMA). In some embodiments, disorders treatable by the compounds of this disclosure are selected from accessory neuropathy, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Vilaret syndrome, Charcot-Marie-Tooth disease, diabetic neuropathy, neuropathy, and Horner syndrome.

[0132] Combination treatment The compounds of this disclosure can be used in combination with at least one pharmacotherapy or treatment useful for treating or alleviating symptoms of neurodegenerative disorders, such as Parkinson's disease (PD). Suitable examples of such pharmacotherapy include levodopa (L-dopa), 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 compounds of this disclosure may be administered to a patient simultaneously with (in the same or different dosage forms) or consecutively with an additional therapeutic agent (the additional therapeutic agent may be administered before or after the administration of the compounds of this disclosure).

[0133] definition As used herein, the term “about” means “approximately” (for example, approximately plus or minus 10% of the indicated value).

[0134] In various places in this specification, substituents of the compounds of the present invention are disclosed in groups or as a range. The present invention is specifically intended to include each of the members of such groups and ranges and any individual subcombinations. For example, "C 1~6 The term "alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually.

[0135] Various aryl rings, heteroaryl rings, cycloalkyl rings, and heterocycloalkyl rings are described in various places in this specification. Unless otherwise specified, these rings may be attached to the rest of the molecule with any ring member, where permitted by valence. For example, the terms “pyridine ring” or “pyridinyl” may refer to a pyridine-2-yl ring, a pyridine-3-yl ring, or a pyridine-4-yl ring.

[0136] Furthermore, for clarity, it is understood that certain features of the invention described in the context of separate embodiments 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 simplicity may also be provided separately or in any suitable sub-combination.

[0137] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings that are aromatic (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

[0138] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a given part, where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0139] As used herein, the phrase "substituted by choice" means either unsubstituted or substituted. Substituents are selected independently, and substitutions may be 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, e.g., oxo, can replace two hydrogen atoms. Substitutions at a given atom should be understood to be limited by their valence.

[0140] Furthermore, for clarity, it is understood that certain features of the invention described in the context of separate embodiments 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 simplicity may also be provided separately or in any suitable sub-combination.

[0141] Throughout the definition, "C n~m The term "C" indicates a range that includes the endpoints, where n and m are integers and represent the number of carbon atoms. For example, C 1~4 , C 1~6 These are some examples.

[0142] As used herein, "C" when used alone or in combination with other terms n~m The term "alkyl" refers to a saturated hydrocarbon group that may be linear or branched, having n to m carbon atoms. Examples of alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl; and higher-order homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, alkyl groups contain one to six carbon atoms, one to four carbon atoms, one to three carbon atoms, or one to two carbon atoms.

[0143] As used herein, "C" when used alone or in combination with other terms n~mThe term "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-methylpropane-1,3-diyl. In some embodiments, the alkylene portion contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0144] As used herein, "C" when used alone or in combination with other terms n~m The term "haloalkyl" refers to an alkyl group having 2s+1 halogen atoms, which may be the same or different from one halogen atom, where "s" is the number of carbon atoms in the alkyl group, and where the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is simply fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0145] As used herein, the term “aryl,” used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (for example, having two, three, or four fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenantrenyl, indanyl, and indenyl. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.

[0146] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon including a cyclized alkyl group and / or alkenyl group. Cycloalkyl groups may include monocyclic or polycyclic groups (e.g., having two, three, or four fused rings) and spiro rings. The ring-forming carbon atoms of a cycloalkyl group may be optionally substituted with one or two independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Further included in the definition of cycloalkyl is a moiety having one or more aromatic rings condensed (i.e., generally bonded) to a cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing condensed aromatic rings may be attached via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. Cycloalkyl groups may have three, four, five, six, seven, eight, nine, or ten ring-forming carbon atoms (C 3~10 ) can have. In some embodiments, the cycloalkyl is C 3~10 It is a monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3~7 It is a monocyclic cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and adamantyl. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0147] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl portion may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having one, two, three, or four heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl having one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl ring having five ring atoms, where one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Illustrative five-membered heteroaryl rings include thienyl, furyl, 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. A six-membered heteroaryl ring is a heteroaryl ring having six ring atoms, where one or more (e.g., one, two, or three) ring atoms are independently selected from N, O, and S. Illustrative six-membered heteroaryl rings include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0148] As used herein, “heterocycloalkyl” refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Heterocycloalkyls include monocyclic 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings. Examples of heterocycloalkyl groups include pyrrolidine-2-one, 1,3-isoxazolidine-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, and benzazepine. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally substituted with one or two independently selected oxo or sulfide groups (e.g., C(O), S(O), C(S), or S(O)2). Heterocycloalkyl groups can be attached via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl groups contain zero to three double bonds. In some embodiments, heterocycloalkyl groups contain zero to two double bonds. Further included in the definition of a heterocycloalkyl group is a moiety having one or more aromatic rings condensed (i.e., generally having bonds) to a cycloalkyl ring, such as benzo or thienyl derivatives like piperidine, morpholine, and azepine. Heterocycloalkyl groups containing condensed aromatic rings can be attached via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, and one or more oxidation ring members.In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4- to 10-membered heterocycloalkyl having one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, or sulfur, and having one or more oxidation ring members.

[0149] In certain contexts, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings can be attached to any ring member, provided that the valence does not exceed that of the atom. For example, an azetidine ring may be attached at any position on the ring, while a pyridine-3-yl ring is attached at position 3.

[0150] As used herein, "C" when used alone or in combination with other terms n~m The term "alkoxy" refers to a group of the formula -O-alkyl, where 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.

[0151] When used herein, "C n~m A "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 simply fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0152] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br.

[0153] As used herein, the term "amino" refers to the group of formula -NH2.

[0154] When used herein, "C n~m The term "alkylamino" refers to a group of the formula -NH(alkyl), where 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).

[0155] When used herein, "Ji (C) n~m The term "-alkyl)amino" refers to a group of the formula -N(alkyl)2, where 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.

[0156] The term “compound,” as used herein, means all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structure. Compounds identified herein by name or structure as a particular tautomer form are intended to include other tautomer forms unless otherwise specified. Any atom not identified in a compound herein that is not specifically designated as a radioactive isotope exists in its natural isotopic abundance.

[0157] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. 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 inert starting materials are known in the art, such as by the division of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins, C=N double bonds, and N=N double bonds, may also be present in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomers. In some embodiments, the compounds have a (R)-configuration. In some embodiments, the compounds have a (S)-configuration.

[0158] The compounds provided herein also include tautomer forms. Tautomer forms result from the exchange of adjacent double and single bonds along with the simultaneous transfer of protons. Tautomer forms include prototropic tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomer forms may be in equilibrium or sterically fixed into one form by appropriate substitution.

[0159] As used herein, the terms "individual," "patient," or "subject," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans.

[0160] As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual, or human being being investigated by a researcher, veterinarian, physician, or other clinician.

[0161] As used herein, the terms "treating" or "treatment" refer to: 1) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or presenting the pathology or general symptoms of the disease, condition, or disorder (i.e., preventing further development of the pathology and / or general symptoms), or 2) alleviating a disease; e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or presenting the pathology or general symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or general symptoms).

[0162] As used herein, the terms "preventing" or "prevention" of a disease, condition, or disorder refer to reducing the risk of the occurrence of the disease, condition, or disorder in a subject or group of subjects (e.g., a subject or group of subjects who are susceptible or sensitive to the disease, condition, or disorder). In some embodiments, preventing a disease, condition, or disorder refers to reducing the likelihood of acquiring the disease, condition, or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition, or disorder refers to completely or almost completely stopping the disease, condition, or disorder from occurring.

Examples

[0163] Materials and Methods All commercially available reagents were used without further purification unless otherwise specified. Analytical thin-layer chromatography (TLC) was performed using Silica Gel GF254 plates (Merck Millipore co., ltd, 0.2 mm thick). Compounds were purified using a CombiFlash R f 150 (Teledyne ISCO co., ltd). 1 H and 13 C spectra were recorded on a Bruker 500 MHz. 1 Chemical shifts in the H NMR spectra were reported in parts per million (ppm) on the δ scale relative to the internal standard of CDCl3 (7.26 ppm). Data were reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant in Hertz (Hz), and integration value. 13 Chemical shifts in the C NMR spectra were reported in ppm relative to the central peak of CDCl3 (77.0 ppm) on the δ scale. MS data were recorded on an Agilent Technologies 6310 quadrupole mass spectrometer.

[0164] [Example 1] Proteolytic targeting chimera

[0165] [Chemical formula] For each of the above compounds, X is O or NH. For each of the above compounds, n is an integer from 1 to 100 (e.g., 1, 2, 3, 4, or 5).

[0166] Other embodiments Although this application has been described in conjunction with its detailed description, the foregoing description is to be understood as illustrative of the scope of this application as defined by the scope of the appended claims and not as intended to be limiting. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Equation (I): P-L-E (I) The conjugate or a pharmaceutically acceptable salt thereof [in the formula, P is given by the formula: 【Chemistry 1】 (In the formula: X １ It is selected from S and O; R １ 、 R ２ and R ３ are each independently selected from halo, OH, CN, NO ２ , C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, C(=O)OH, C(=O)O(C １～３ alkyl), C(=O)NH ２ , 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; R ４ H, C １～３ Alkyl and C １～３ Selected from haloalkyls; L １ does not exist; or L １ C １～６ Alkylene and C ３～６ Selected from cycloalkylenes, the C １～６ Alkylenes are C(=O), S(=O) ２ It is optionally suspended by one or two bases independently selected from , O, and NH; Ring A does not exist, or ring A is given by equation (i): 【Chemistry 2】 (In the formula, a is X ２ It indicates the attachment point; b is L １ It indicates the attachment point; Ring C is C ３～６ Selected from cycloalkyl and 4- to 7-membered heterocycloalkyl groups, each of which is a halo, OH, CN, NO ２ , C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, C(=O)OH, C(=O)O(C １～３ Alkyl), C(=O)NH ２ , 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 It is optionally substituted with one, two, or three substituents independently selected from alkyl)amino; R ５ and R ６ H, C １～３ Alkyl and C １～３ (Each haloalkyl group is independently selected.) This is the part; X ２ C (=O) and S (=O) ２ Selected from; Ring B is C ６～１０ Selected from aryls and 5- to 14-membered heteroaryls, each of which is a halo, OH, CN, NO ２ , C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, S (=O) ２ (C １～３ Alkyl), S (=O) ２ OH, C(=O)OH, C(=O)O(C １～３ Alkyl), C(=O)NH ２ , 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 (Optionally substituted with one, two, or three substituents independently selected from the alkyl(amino) group.) It is the protein-binding site; E is the ligase binding site; L is the linker portion that connects the ligase binding portion E and the protein binding portion P.

2. The linker portion L is given by formula (L ３ ) ｍ It has, in the formula, m is an integer between 2 and 20; Each L ３ However, N(R Ｎ ), O, C (=O), S, S (=O), S (=O) ２ , C １～６ Alkylene, C ３～７ Cycloalkylene, 4-10 member heterocycloalkylene, 5-10 member heteroarylene, C ６～１０ Arirene, - (OCH ２ CH ２ ) ｘ -, - (CH ２ CH ２ O) ｘ -,-(OCH(CH ３ )CH ２ ) ｘ -, - (CH ２ CH (CH ３ )O) ｘ - Selected independently from, and each of these is OH, NH ２ , C(O)OH, SO ３ H, C １～３ Alkylamino, di(C) １～３ -Alkyl)amino, C １～３ Haloalkyl, C １～３ Alkoxy, and C １～３ They are optionally substituted with one or two substituents independently selected from the haloalkoxy; Each x is an independent integer between 1 and 2,000; Each R Ｎ is independently selected from H, C １～６ alkyl, C ２～６ alkenyl, and C ２～６ alkynyl The conjugate according to claim 1.

3. formula: 【Transformation 3】 The conjugate according to claim 2, having or a pharmaceutically acceptable salt thereof.

4. formula: 【Chemistry 4】 The conjugate according to claim 2, having or a pharmaceutically acceptable salt thereof.

5. formula: 【Transformation 5】 The conjugate according to claim 2, having or a pharmaceutically acceptable salt thereof.

6. formula: 【Transformation 6】 The conjugate according to claim 2, having or a pharmaceutically acceptable salt thereof.

7. formula: 【Transformation 7】 The conjugate according to claim 2, having or a pharmaceutically acceptable salt thereof.

8. m is 2, 4, 5, 6, or 8; Each L ３ is independently selected from NH, O, C(=O), C １～６ alkylene, C ３～７ cycloalkylene, 4- to 10-membered heterocycloalkylene, 5- to 10-membered heteroarylene, C ６～１０ arylene, -(OCH ２ CH ２ ), ｘ and -(CH ２ CH ２ O) ｘ -; x is an integer from 1 to 10. The conjugate according to any one of claims 1 to 7.

9. at least one L ３ However, C １～６ It is alkylene; at least one L ３ However, it is C(=O)O or C(=O)NH; at least one L ３ However, -(OCH ２ CH ２ ) ｘ - or - (CH ２ CH ２ O) ｘ - is, The conjugate according to claim 8.

10. (L ３ ) ｍ The part is one of the aforementioned flexible structural fragments, or any combination thereof: 【Transformation 8】 The conjugate according to claim 8, including the following:

11. (L ３ ) ｍ The part is one of the aforementioned rigid structural fragments, or any combination thereof: 【Chemistry 9】 The conjugate according to claim 8, including the following:

12. L １ However, C is interrupted by choice in O or NH. １～６ The conjugate according to any one of claims 5 to 11, wherein the conjugate is alkylene.

13. L １ C １～６ The conjugate according to any one of claims 5 to 11, wherein the conjugate is alkylene.

14. L １ However, C is interrupted at O. １～６ The conjugate according to any one of claims 5 to 11, wherein the conjugate is alkylene.

15. L １ C ３～６ The conjugate according to any one of claims 5 to 11, wherein the conjugate is a cycloalkylene.

16. The conjugate according to any one of claims 1 to 13, wherein the ligase-binding portion E can bind to cereblon, von Hipperlindau (VHL), an inhibitor of apoptotic protein (IAP), and / or a mouse double micro2 homolog (MDM2).

17. The ligase binding portion E is given by the following formula: 【Chemistry 10】 The conjugate according to claim 14, selected from any one of the following.

18. The ligase binding portion E is given by formula: 【Chemistry 11】 (In the formula, R ｏ is selected from H and halo; Each R ｐ H and C １～３ (Selected from alkyl groups) The conjugate according to claim 14, having the following characteristics.

19. The aforementioned part E is given by the formula: 【Chemistry 12】 The conjugate according to claim 16, having the following characteristics.

20. The following compounds: 【Chemistry 13】 (In the formula, X is either O or NH; n is an integer between 1 and 100 (for example, 1, 2, 3, 4, or 5). The conjugate according to claim 1, selected from any one of the or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the conjugate described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A method for treating a neurodegenerative disease or disorder selected from Lewy body dementia, Parkinson's disease (PD), multiple system atrophy (MSA), pure autonomic dysplasia (PAF), Alzheimer's disease (AD), familial AD (FAD), frontotemporal lobar 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, argyrophilic granule disease, dementia, chronic traumatic brain injury (CTE), age-related tauastropathy, Richardson syndrome, cerebellar ataxia, spheroclamoglial tauopathy, argyrophilic granule disease, motor neuron disease (MND), and prion diseases, comprising administering a therapeutically effective dose of the conjugate described in claim 1 or a therapeutically acceptable salt thereof to a subject in need.

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