Proteolysis targeting chimeras for treating neurodegeneration

Abstract

The present disclosure provides proteolysis targeting chimeras containing (i) a piperidine-1-carboxylate-based targeting ligand capable of binding toxic peptide and / or protein aggregates in brain tissues (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) for degradation; (ii) a ubiquitin ligase recruiting ligand; and (iii) a linker between (i) and (ii). These proteolysis targeting chimeras are useful, e.g., for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia.

Description

[0001] Attorney Docket No.29539-0727WO1 PROTEOLYSIS TARGETING CHIMERAS FOR TREATING NEURODEGENERATION CLAIM OF PRIORITY This application claims the benefit of U.S. Provisional Application Serial No. 63 / 527,513, filed on July 18, 2023. The entire contents of the foregoing are incorporated herein by reference. TECHNICAL FIELD This invention relates to bi-functional conjugates (PROTACs, or proteolysis targeting chimeras) containing at least three elements: (i) a targeting ligand capable of binding toxic protein aggregates in brain tissues (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles) for degradation; (ii) a ubiquitin ligase recruiting ligand; and (iii) a linker between the ubiquitin ligase (ii) and the targeting ligand (i). These conjugates are useful, e.g., for treating neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA), and Lewy body dementia. BACKGROUND There are numerous deadly diseases affecting current human population. For example, neurodegenerative diseases affect a significant segment of population, especially the elderly. As one example, Parkinson’s disease (“PD”), a synucleinopathy that affects movement, affects more than 10 million people worldwide with an estimated total annual economic burden of more than $52 billion. As another example, Alzheimer’s disease (“AD”), a β-amyloidopathy that affects approximately 44 million people world- wide, is the sixth leading cause of death with an estimated socioeconomic burden of more than $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 cost of treatment per patient of about $100,000. In sum, neurodegenerative diseases impose a substantial burden on patients, their family members, the healthcare system, and the society overall. Because of aging population worldwide, neurodegenerative disorders pose an increasing threat to public health. Attorney Docket No.29539-0727WO1 SUMMARY The present disclosure is based, at least in part, on a realization that piperidine-1- carboxylate compounds bind with high affinity to insoluble peptide and / or protein aggregates in brain tissues (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles). These compounds are advantageously selective binders specific to the pathological protein aggregates as opposed to soluble cytoplasmic peptides and / or proteins (such as α- synuclein amyloid, and / or tau peptides or proteins). What is more, the compounds are also relatively selective for α-synuclein fibrils as opposed to amyloid plaques or tau tangles located in the brain tissues (e.g., neurons, glial cells, as well as the extracellular space) of individuals affected with neurodegeneration. What is more, the compounds are also relatively selective for α-synuclein fibrils as opposed to amyloid plaques or tau tangles located in the brain tissues of individuals affected with neurodegeneration. In one example, the piperidine-1-carboxylate compounds are about 30× to about 50× more selective to α-synuclein fibrils as 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 present claims to protein aggregates involved in pathology of neurodegenerative disorders allows using these compounds as targeting ligands in proteolysis targeting chimera (“PROTAC”) conjugates. Accordingly, in a general aspect, the present disclosure provides a PROTAC comprising (i) a piperidine-1- carboxylate-based targeting ligand capable of selectively binding a protein aggregate implicated in pathology of a neurodegenerative disorder for degradation; (ii) a ubiquitin ligase recruiting ligand; and (iii) a linker between the ubiquitin ligase (ii) and the targeting ligand (i). Without being bound by any theory, it is believed that the PROTAC of this disclosure allows to degrade a peptide and / or protein aggregate (e.g., α-synuclein fibril, amyloid plaque, and / or tau tangle) implicated in the pathology of a neurodegenerative disorder utilizing cellular proteasome “machinery,” advantageously leading to favorable therapeutic outcomes. In one general aspect, the present disclosure provides a compound of Formula (I): P—L—E (I), Attorney Docket No.29539-0727WO1 or a pharmaceutically acceptable salt thereof, wherein P, L, and E are as described herein. In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In yet another general aspect, the present disclosure provides a method of treating a neurodegenerative disease or disorder as described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a therapeutically acceptable salt thereof. 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 the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DETAILED DESCRIPTION Over the past decade, the small molecule-induced selective degradation of specific protein targets has emerged as a novel modality in biomedical research that holds promise to revolutionize drug development, providing access to new classes of therapeutics that can act on disease-relevant proteins previously considered to be undruggable. The concept of targeted protein degradation (TPD) is based on the ligand- induced recruitment of a protein of interest (POI) to an E3 ubiquitin ligase complex. In this arrangement, the POI is ubiquitinated and subsequently eliminated by proteasomal degradation. There are two fundamental classes of small molecules that are employed for TPD, commonly referred to as “molecular glues” and PROTACs. Molecular glues are monofunctional ligands, which stabilize the interaction between two proteins that would Attorney Docket No.29539-0727WO1 otherwise not bind. In TPD, molecular glues can enable the recruitment of POIs as neosubstrates to E3 ligase complexes. PROTACs, in contrast, are heterobifunctional molecules that are formally composed of two individual ligands, one for binding the E3 ligase complex and one for targeting the POI, that are tethered by a linker. PROTACs are particularly advantageous due to, e.g., the large number of E3 ligases (e.g., over 600 E3 ligases in the human proteome) that could potentially be employed in the PROTAC development. On the one hand, targeting of multiple ligase complexes with a “promiscuous” ligase ligand in the PROTAC molecule provides a means for efficient TPD that is indiscriminate to cell and tissue types. On the other hand, selective targeting of a specific E3 ligase may provide cell type- and / or tissue-specific degradation. Furthermore, by selecting a targeting ligand moiety for recruiting to an E3 ubiquitin ligase of a specific protein of interest (POI) implicated in pathology of a disease, a PROTAC may be developed specifically focusing to treat the disease by eliminating the pathological protein from the patient’s cells and tissues. In neuropathology, neurodegeneration is often featured by accumulation in brain cells and intracellular spaces of insoluble protein aggregates, such as α-synuclein fibrils, amyloid-β plaques, and tau tangles, as well as by marked neuroinflammation. Together, these pathologies lead to a reduction of brain volume and brain cell number, degeneration of neurons, dysfunction of microglia, 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 lobar degeneration (FTD), Huntington’s disease (HD), Pick’s disease, and dementia, including dementia specifically associated with any of the aforementioned disorders. Without being bound by any theory, in one general aspect, the present disclosure provides PROTAC compounds containing targeting ligands that selectively bind to protein aggregates that are implicated in neuropathology and neurodegeneration. As such, the PROTAC compounds promote ubiquitination and subsequent proteasomal degradation of these protein aggregates, thereby contributing to amelioration of neuronal loss and concomitant treatment of the underlying neurological and / or neurodegenerative disorder (e.g., PD, MSA, PAF, AD, HD, or Pick’s disease). Certain embodiments of the therapeutic PROTAC compounds (e.g., compounds Attorney Docket No.29539-0727WO1 of Formula I) and exemplary embodiments of diseases treatable by these compounds (e.g., synucleinopathies) are described herein. Pharmaceutical compositions and combination treatments are also described. Therapeutic compounds Generally, the present disclosure provides a compound useful as a bi-functional PROTAC conjugate containing three elements: (i) a targeting ligand; (ii) a ubiquitin ligase recruiting ligand; and (iii) a linker between the ubiquitin ligase ligand (ii) and the targeting ligand (i). In some embodiments, and without being bound by any speculation, the targeting ligand (i) in the PROTAC conjugate of this disclosure is a piperidine-1- carboxylate-based targeting ligand that is a selective and specific binder to toxic peptide and / or protein aggregates in brain tissues (e.g., α-synuclein fibrils, amyloid plaques, and / or tau tangles). In some embodiments, the present application provides a compound of Formula (I): P—L—E(I),or a pharmaceutically acceptable salt thereof, wherein P, L, and E are as described herein. In some embodiments: P is a protein-binding moiety; E is a ligase binding moiety; and L is a linker moiety connecting the ligase binding moiety E and the protein binding moiety P. Protein binding moieties In some embodiments, the protein-binding moiety P has formula: , wherein rings A In some X1is selected from O, NH, and S; Attorney Docket No.29539-0727WO1 L1is selected from bond and C1-3alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; Ring A is selected from C6-10aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1A; each R1Ais independently selected from Cy1, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each Cy1is independently selected from C6-10aryl, C3-10cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3alkylamino, and di(C1-3 alkyl)amino; X2is selected from CR2and N; R2is selected from H, C1-3alkyl, C1-3haloalkyl, and L2-C(=O)N(R1a)(R4), wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from OH, CN, NO2, C1-3 alkoxy, and C1-3 haloalkoxy; L2is selected from bond and C1-3alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3haloalkyl, C1-3alkoxy, and C1-3 haloalkoxy; Ring B is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1B; each R1Bis independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3alkylamino, and di(C1-3alkyl)amino; each R1ais independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; each R4is independently selected from H, C1-3alkyl, and C1-3haloalkyl, wherein said C1-3alkyl is optionally substituted with 1 or 2 substituents independently selected Attorney Docket No.29539-0727WO1 from Cy2, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each Cy2is independently selected from C6-10aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; and each RCyis independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, X1is O. In some embodiments, X1is S. In some embodiments, X1is O or S. In some embodiments, X1is NH. In some embodiments, L1is a bond. In some embodiments, L1is C1-3 alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, L1is C1-3 alkylene, optionally substituted with halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, or C1-3haloalkoxy. In some embodiments, L1is C1-3alkylene, optionally substituted with halo, CN, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, L1is C1-3alkylene (e.g., unsubstituted alkylene). In some embodiments, L1is selected from methylene, ethylene, and propylene. In some embodiments, ring A is selected from C6-10aryl and 5-14 membered heteroaryl, each of which is optionally substituted with one substituent independently selected from R1A. In some embodiments, ring A is C6-10aryl, optionally substituted with R1A. In some embodiments, ring A is 5-14 membered heteroaryl, optionally substituted with R1A. In some embodiments, ring A is C6-10 aryl (e.g., phenyl or naphthyl) substituted with R1A. In some embodiments, ring A is 5-14 membered heteroaryl (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine) substituted with R1A. In some embodiments, Attorney Docket No.29539-0727WO1 ring A is phenyl substituted with R1A(e.g., in ortho, meta, or para position). In some embodiments, ring A is naphthyl substituted with R1A(e.g., in 1-, 2-, 3-, 5-, 6- 7-, or 8- position). In some embodiments, the moiety P has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the moiety P has formula: , or a In some embodiments, the moiety P has formula: , or a In some embodiments, R1Ais selected from halo, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, R1Ais selected from Cy1, halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)NH2, C(=O)O(C1-3 alkyl), and C(=O)NH(C1-3 alkyl). In some embodiments, R1Ais selected from halo, OH, CN, NH2, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)NH2, C(=O)O(C1-3 alkyl), and C(=O)NH(C1-3 alkyl). In some embodiments, R1Ais selected from halo, CN, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2. In some embodiments, R1Ais selected from halo, CN, C1-3alkoxy, and C1-3haloalkoxy. In some embodiments, R1Ais halo. In some embodiments, R1Ais CN. In some embodiments, R1Ais C1-3 alkoxy. In some embodiments, R1Ais C1-3 haloalkoxy. In some embodiments, R1Ais Cy1. In some embodiments, Cy1is selected from C6- Attorney Docket No.29539-0727WO110aryl and C3-10cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, Cy1is C6-10aryl. In some embodiments, Cy1is C3-10cycloalkyl. In some embodiments, Cy1is C6-10 aryl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, Cy1is C3-10cycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, Cy1is C6-10aryl, optionally substituted with halo, CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, or C(=O)NH2. In some embodiments, Cy1is (or R1Ais) C6-10 aryl substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or C(=O)NH2. In some embodiments, Cy1is (or R1Ais) C6-10aryl substituted with halo, CN, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, Cy1is (or R1Ais) C6-10 aryl substituted with halo. In some embodiments, Cy1is (or R1Ais) C6-10 aryl substituted with halo or CN. In some embodiments: X1is O; L1is selected from bond and C1-3 alkylene; each R1Ais independently selected from Cy1, halo, OH, CN, NH2, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, and C(=O)NH2; and each Cy1is independently selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NH2, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, and C(=O)NH2. In some embodiments, X2is CR2. In some embodiments, X2is N. In some embodiments, the moiety P has formula: , or a Attorney Docket No.29539-0727WO1 In some embodiments, moiety P has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, R2is selected from H, C1-3alkyl, C1-3haloalkyl, and L2- C(=O)N(R1a)(R4), wherein said C1-3alkyl is optionally substituted with OH, CN, NO2, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, R2is selected from H, C1-3 alkyl, C1-3haloalkyl, and L2-C(=O)N(R1a)(R4). In some embodiments, R2is H. In some embodiments, R2is C1-3alkyl. In some embodiments, R2is C1-3 haloalkyl. In some embodiments, R2is L2-C(=O)N(R1a)(R4). In some embodiments, R2is selected from H and L2-C(=O)N(R1a)(R4). In some embodiments, R1ais selected from H and C1-3alkyl. In some embodiments, R1ais H. In some embodiments, R1ais C1-3 alkyl. In some embodiments, the moiety P has formula: , or a In some embodiments, the moiety P has formula: , or a In some a some L2is C1-3alkylene, optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, L2is C1-3 alkylene, optionally substituted with halo, OH, CN, NO2, C1-3haloalkyl, C1-3alkoxy, or C1-3 haloalkoxy. In some embodiments, L2is C1-3 alkylene (e.g., methylene, ethylene, or Attorney Docket No.29539-0727WO1 propylene). In some embodiments, R4is selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, R4is selected from H, C1-3alkyl, and C1-3haloalkyl. In some embodiments, R4is H. In some embodiments, R4is C1-3 alkyl (e.g., methyl, ethyl, or propyl). In some embodiments, R4is C1-3 haloalkyl. In some embodiments, R4is C1-3 alkyl optionally substituted with 1 or 2 substituents independently selected from Cy2, halo, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. In some embodiments, R4is C1-3 alkyl substituted with Cy2and optionally substituted with a substituent selected from CN, NO2, C1-3alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)NH2, C(=O)NH(C1-3 alkyl), and C(=O)N(C1-3 alkyl)2. In some embodiments, R4is C1-3 alkyl substituted with Cy2and optionally substituted with halo or CN. In some embodiments, R4is C1-3alkyl substituted with Cy2and C(=O)NH(C1-3 alkyl) and optionally substituted with halo or CN. In some embodiments, R4is C1-3 alkyl substituted with Cy2. In some embodiments, R4is C1-3 alkyl substituted with Cy2and C(=O)NH(C1-3alkyl). In some embodiments, Cy2is selected from C6-10aryl and 5-14 membered heteroaryl, each of which is optionally substituted with a substituent selected from RCy, halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), and C(=O)N(C1-3alkyl)2. In some embodiments, Cy2is C6-10 aryl, optionally substituted with a substituent selected from RCy, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, Cy2is C6-10aryl, substituted with RCyand optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, Cy2is C6-10 aryl substituted with RCy. In some embodiments, Cy2is 5-14 membered heteroaryl, optionally substituted with a substituent selected from RCy, halo, CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy. In some embodiments, Attorney Docket No.29539-0727WO1 Cy2is 5-14 membered heteroaryl, substituted with RCyand optionally substituted with halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments, Cy2is 5-14 membered heteroaryl substituted with RCy. In some embodiments, RCyis selected from C6-10aryl and 5-14 membered heteroaryl, each of which is optionally substituted with halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3alkylamino, or di(C1-3alkyl)amino. In some embodiments, RCyis C6-10 aryl, optionally substituted with halo, CN, C1-3 alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, or C(=O)NH2. In some embodiments, RCyis C6-10aryl, optionally substituted with halo, CN, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, RCyis C6-10 aryl, optionally substituted with halo or CN. In some embodiments, R4is C1-3 alkyl substituted with C6-10 aryl-C6-10 aryl, wherein each of said C6-10aryl groups is optionally substituted with halo, CN, C1-3alkyl, C1-3haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy. In some embodiments: L2is C1-3alkylene; R4is C1-3 alkyl substituted with Cy2and C(=O)NH(C1-3 alkyl); Cy2is selected from C6-10 aryl-RCyand 5-14 membered heteroaryl-RCy; and each RCyis independently selected from C6-10aryl and 5-14 membered heteroaryl. In some embodiments: L2is a bond; R4is C1-3 alkyl substituted with Cy2; Cy2is selected from C6-10aryl-RCyand 5-14 membered heteroaryl-RCy; and each RCyis independently selected from C6-10 aryl and 5-14 membered heteroaryl. In some embodiments, each of said C6-10 aryl and 5-14 membered heteroaryl groups of Cy2and RCyis optionally substituted with 1, 2, or 3 substituents (e.g., 1 or 2 substituents) independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, and C(=O)NH(C1-3alkyl). Attorney Docket No.29539-0727WO1 In some embodiments, R3is C6-10aryl (phenyl or naphthyl) substituted with R1B. In some embodiments, R3is phenyl substituted with R1B(e.g., in ortho, meta, or para position). In some embodiments, R3is naphthyl substituted with R1B. In some embodiments, R3is 5-14 membered heteroaryl (e.g., benzothiazole, quinoline, pyridine, pyrimidine, or pyrazine) substituted with R1B. In some embodiments, the moiety P has formula: , or a In some embodiments, X3is selected from N and CH. In some embodiments, X3is N. In some embodiments, X3is CH. In some embodiments, the moiety P has formula: , or a In some embodiments, the moiety P has formula: , or a In some embodiments, the moiety P has formula: , or a In some , or a Attorney Docket No.29539-0727WO1 In some embodiments, the moiety P has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, R1Bis selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)NH2, C(=O)OH, C(=O)O(C1-3alkyl), and C(=O)NH(C1-3alkyl). In some embodiments, R1Bis halo, CN, C1-3alkyl, C1-3haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, or C(=O)NH2. In some embodiments, R1Bis halo, CN, C(=O)NH2, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, R1Bis halo or CN. In some embodiments, R1Bis halo. In some embodiments, R1Bis CN. In some embodiments, R1Bis C(=O)NH2. In some embodiments, R1Bis C1-3 alkoxy or C1-3 haloalkoxy. In some embodiments, R1Bis C1-3haloalkoxy. In some embodiments, R1Bis C1-3alkoxy. In some embodiments, the moiety P is selected from any one of the following formulae: or a In some L2-C(=O)N(R1a)(R4). In some embodiments, the moiety P is selected from any one of the following formulae: Attorney Docket No.29539-0727WO1 or a In some embodiments, the moiety P has formula: or a In some

[0002] Attorney Docket No.29539-0727WO1 or a pharmaceutically acceptable salt thereof. In some embodiments, the moiety P is selected from any one of the following compounds: Attorney Docket No.29539-0727WO1

[0003] Attorney Docket No.29539-0727WO1 Linker moieties In some embodiments, the linker moiety L has formula (L3)m. 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. In some embodiments, each L3is independently selected from N(RN), O, C(=O), C1-6 alkylene, C3-7 cycloalkylene, 4-10- membered heterocycloalkylene, 5-10-membered heteroarylene, C6-10arylene, –(OCH2CH2)x–, and –(CH2CH2O)x–. In some embodiments, each L3is independently selected from NH, O, C(=O), C1-6alkylene, C3-7 cycloalkylene, 4-10-membered heterocycloalkylene, 5-10-membered heteroarylene, C6-10arylene, –(OCH2CH2)x–, and –(CH2CH2O)x–. In some embodiments, at least one L3is C1-6alkylene. In some embodiments, at least one L3is C(=O). In some embodiments, at least one L3is O. In some embodiments, group (L3)m comprises at least one 4-10-membered heterocycloalkylene. In some embodiments, group (L3)m comprises at least one C6-10arylene. In some embodiments, group (L3)mcomprises at least one moiety 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, one L3is –(OCH2CH2)x– or – Attorney Docket No.29539-0727WO1 (CH2CH2O)x–. In some embodiments: m is an integer from 2 to 20; each L3is independently selected from N(RN), O, C(=O), S, S(=O), S(=O)2, C1-6alkylene, C3-7 cycloalkylene, 4-10- membered heterocycloalkylene, 5-10-membered heteroarylene, C6-10 arylene, –(OCH2CH2)x–, –(CH2CH2O)x–, –(OCH(CH3)CH2)x–, – (CH2CH(CH3)O)x–, each of which is optionally substituted with 1 or 2 substituents independently selected from OH, NH2, C(O)OH, SO3H, C1-3 alkylamino, di(C1-3- alkyl)amino, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; each x is independently an integer from 1 to 2,000; and each RNis independently selected from H, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some embodiments: m is 2, 4, 5, 6, or 8; each L3is independently selected from NH, O, C(=O), C1-6 alkylene, C3-7 cycloalkylene, 4-10- membered heterocycloalkylene, 5-10-membered heteroarylene, C6-10 arylene, –(OCH2CH2)x–, and –(CH2CH2O)x–; and x is an integer from 1 to 10. In some embodiments: at least one L3is C1-6alkylene; at least one L3is C(=O)O or C(=O)NH; and at least one L3is –(OCH2CH2)x– or –(CH2CH2O)x–. In some embodiments, (L3)m comprises at least one 4-10-membered heterocycloalkylene or C6-10arylene. In some embodiments, (L3)m comprises at least one moiety 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, 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. Attorney Docket No.29539-0727WO1 In some embodiments, RNis selected from H and C1-6alkyl. In some embodiments, RNis H. In some embodiments, RNis C1-6 alkyl. In some embodiments, at least one L3is NH. In some embodiments, N(RN) is NH. In some embodiments, the linker moiety can be flexible or rigid, hydrophobic, hydrophilic, or amphiphilic. In some embodiments, length of the linker moiety is between about 10 Å to about 1,000 Å, from about 15 Å to about 800 Å, from about 20 Å to about 500 Å, from about 20 Å to about 400 Å, from about 20 Å to about 250 Å, from about 20 Å to about 20 Å to about 200 Å, or from about 20 Å to about 150 Å. Without being bound by any theory, it is believed that the length and physical properties of the linker moiety are selected for each moiety P and subsequently for each target protein such that upon binding of the E moiety to the ligase, the target protein can be efficiently ubiquitinated within the ligase complex and then degraded by the proteasome machinery of the cell. In some embodiments, the (L3)mmoiety comprises any one of the foregoing flexible structural fragments, or any combination thereof: , rigid or any , Attorney Docket No.29539-0727WO1 . In some embodiments, the conjugate has formula: , or a pharmaceutically acceptable salt thereof. In some embodiments, the conjugate has formula: , or a In some embodiments, the conjugate has formula: , or a Ligase ligands The compounds provided herein contain a targeting moiety, such as a small molecule targeting moiety, that is capable of binding to a ligase (e.g., an E3 ubiquitin ligase). Any appropriate ligase (e.g., E3 ligase) 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 protein (IAP) (e.g., cellular inhibitor of the apoptosis 1 and 2, c- IAP-1 and c-IAP-2) and mouse double minute 2 homolog (MDM2). Other suitable examples of ubiquitin ligases targeted by PROTAC compounds of this disclosure 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), among others. Attorney Docket No.29539-0727WO1 The ligase-targeting moiety can be any small-molecule moiety known to bind the ligase with sufficient affinity. The small molecule moiety can have a molecular weight, e.g., 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 contain any combination of these features. The small-molecule moiety may contain carbocyclic and heterocyclic rings. The heterocyclic rings within the moiety may be saturated or unsaturated, and may contain any suitable number of heteroatoms, such as O, N, P, or S. 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. Accordingly, in some embodiments, the PROTAC compounds provided herein can include a thalidomide, pomalidomide, or lenalidomide- based moiety (e.g., the entire small-molecule ligand but for the functional group used for conjugation to a linker moiety) that is capable of binding to the cereblon E3 ubiquitin ligase. In some embodiments, the ligase recruiting ligand has formula: , wherein X is selected In some embodiments, the ligase recruiting ligand has formula: . In some embodiments, has formula: . Attorney Docket No.29539-0727WO1 In some embodiments, the ligase recruiting ligand has formula: . In some embodiments, the ligase recruiting ligand has formula: . In some embodiments, the formula: . In some embodiments, the has formula: . Another example of a a ligase recruiting ligand within the PROTAC compound of this disclosure is a cullin-RING E3 ubiquitin ligase (CRL) such as von Hippel Lindau (VHL). Accordingly, in some embodiments, the PROTAC compounds provided herein can include, e.g., a small-molecule ligand capable of binding to the VHL E3 ubiquitin ligase. In some embodiments, the ligase recruiting ligand has formula: , wherein: Attorney Docket No.29539-0727WO1 Rois selected from H and halo; and each Rpis selected from H and C1-3 alkyl. In some embodiments, the ligase recruiting ligand has formula: N . Additional examples of useful as ligase targeting ligands in PROTAC compounds of this disclosure include binders targeted to IAPs (e.g., bestatin and its esters), ligands targeted to MDM2 (e.g., nutlin, idasanutlin, or their derivatives), ligands targeted to DCAF (e.g., indisulam), ligands targeted to RNF (e.g., nimbolide), and ligands targeted to KEAP1 (e.g., CDDO or its methyl ester). See, e.g., Steinebach et al., Chem. Sci. 2020, 11, 3474-3486; Heider et al., Blood 2019, 134 (1), 314; and Lee at al., Molecules, 2022, 27, 6515, among others. These publications are incorporated herein by reference in their entirety. In some embodiments, the conjugate of Formula (I) is selected from any one of the following compounds: Attorney Docket No.29539-0727WO1 each n is independently an integer from 1 to 100; and each R is independently selected from any one of the following moieties: . Attorney Docket No.29539-0727WO1 Pharmaceutically acceptable salts In some embodiments, a salt of any one of the compounds of the present disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or 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. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-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, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate 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 especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the 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 Attorney Docket No.29539-0727WO1 amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), 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, lysine, and the like. Compositions, formulations, and routes of administration The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure disclosed herein, or a pharmaceutically acceptable salt thereof; 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 the additional therapeutic agents described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic Attorney Docket No.29539-0727WO1 agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients. Routes of administration and dosage forms The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods 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 preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product. In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the Attorney Docket No.29539-0727WO1 active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia. Compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and Attorney Docket No.29539-0727WO1 suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant. The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols. The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000. The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, Attorney Docket No.29539-0727WO1 towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners. Dosages and regimens In the pharmaceutical compositions of the present application, a compound of the present disclosure is present in an effective amount. For example, the compound of Formula (I) may be present in a therapeutically effective amount. Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other compounds, e.g., therapeutic treatments, other imaging agents, metabolism inhibitors, etc., and the judgment of the treating physician. In some embodiments, an effective amount of the compound (e.g., Formula (I)) can range, 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 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 Attorney Docket No.29539-0727WO1 about 0.5 mg / kg). In some embodiments, an effective amount of a 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. The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month) as determined by a treating physician. Kits The present invention also includes kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein. Methods of treatment Without being bound by any particular theory, it is believed that the binding of moiety (iii) of a PROTAC molecule of this disclosure to a ligase leads to ubiquitination and subsequent degradation of the ligase complex by a proteasome. When a protein target is bound 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 is further degraded by the proteasome machinery of the cell. When the protein target is implicated in a pathology of a disease or condition, contacting a cell containing the target protein by a PROTAC of this disclosure results in degradation of the target protein and, concomitantly, a favorable therapeutic outcome. Accordingly, in some embodiments, the present disclosure provides a method of reducing level of a protein (e.g., a target protein) in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method Attorney Docket No.29539-0727WO1 of reducing level of an insoluble peptide and / or protein aggregate (e.g., a target protein) in a cell and / or tissue, the method comprising contacting the cell and / or the tissue with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In the above embodiments, contacting the cell and / or the tissue may occur in vitro, in vivo, or ex vivo. In some embodiments, the present disclosure provides a method of modulating α- synuclein, β-amyloid, and / or tau protein in a cell and / or tissue, the method comprising contacting the cell and / or tissue with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the modulating comprises binding, inhibiting, activating, or reducing the level of, or any combination of the foregoing. In some embodiments, the modulating comprises reducing the level of α-synuclein, β-amyloid, and / or tau protein in the cell and / or tissue. In some embodiments, the present disclosure provides a method of modulating an α-synuclein fibril, a β-amyloid plaque, and / or tau tangle in a cell and / or tissue, the method comprising contacting the cell and / or tissue with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the modulating comprises binding, inhibiting, activating, or reducing the level of, or any combination of the foregoing. In some embodiments, the modulating comprises reducing the level of α-synuclein fibril, a β-amyloid plaque, and / or tau tangle in the cell and / or tissue. In some embodiments, the contacting occurs in vitro, in vivo, or ex vivo. In some embodiments, the cell and / or tissue is a brain cell and / or tissue (e.g., a neuron or a glial cell). In some embodiments, the modulation is selective with respect to α-synuclein, as opposed to β-amyloid, and / or tau protein (e.g., the modulation is 10×, 20×, 50×, 100×, or 1000× more selective with respect to α-synuclein). In some embodiments, the modulation is selective with respect to insoluble aggregates of α-synuclein, β-amyloid, and / or tau protein as opposed to soluble cytoplasmic forms of any of those proteins (the modulation is 10×, 20×, 50×, 100×, or 1000× more selective with respect to insoluble aggregate as opposed to soluble protein). In some embodiments, the present disclosure provides a method of modulating α-synuclein, β-amyloid, and / or tau protein in a subject (e.g., a brain of a subject), the method comprising administering to a subject a therapeutically Attorney Docket No.29539-0727WO1 effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the present disclosure provides a method of modulating an α-synuclein fibril, a β-amyloid plaque, and / or tau tangle in a subject (e.g., a brain of a subject), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the compounds of Formula (I) and related salts and compositions of the present disclosure are useful in treating neurodegenerative disease or disorder that affects the motor system. Numerous scientific publications provide credible evidence of association between multisystem neurodegeneration and progressive aggregation of insoluble fibrillary synuclein (e.g., α-synuclein or αSyn) in neurons and glia. 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, among others. As such, without being bound by any particular theory or speculation, as used herein, the term “synucleinopathy” refers to a group of neurodegenerative disorders where aggregation of insoluble synuclein (e.g., αSyn) protein fibrils in various CNS and / or peripheral nervous system (PNS) cells is implicated in pathology. In some embodiments, the present disclosure provides a method of treating a synucleinopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the synucleinopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of synucleinopathies include dementia with Lewy bodies, 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), among other neurodegenerative disorders where synuclein is involved, at least in part, in the disease pathology. Attorney Docket No.29539-0727WO1 Numerous scientific publications provide credible evidence of association between neurodegeneration and amyloid peptide (e.g., β-amyloid such as Aβ40 peptide and / or Aβ42 peptide) misfolding and concomitant accumulation of amyloid peptide 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, among many others. In one example, β-amyloid is used as a diagnostic biomarker of 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 main target for therapeutics (See, e.g., Swanson C et al., Alzheimer’s Res. Ther., 2021, 13, 1, 80. As such, without being bound by any particular theory or speculation, as used herein, the term “amyloidopathy” or “β-amyloidopathy” refers to a group of neurodegenerative disorders where aggregation of insoluble amyloid plaques (e.g., β-amyloid plaques) in the brain is implicated in pathology. In some embodiments, the present disclosure provides a method of treating an amyloidopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the amyloidopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of amyloidopathies include premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), and dementia associated with AD or FAD, among other neurodegenerative disorders where formation of amyloid plaques is involved, at least in part, in the disease pathology. Numerous scientific publications provide credible evidence of association between neurodegeneration and misfolding of the tau protein and subsequent formation of neurofibrillary or gliofibrillary tangles in the brain (e.g., neurons, glial cells, and extracellular space). 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, among many others. As such, without being bound by any particular theory or speculation, as used herein, the term “tauopathy” refers to a group of neurodegenerative disorders where tau-positive inclusions in the brain are implicated in pathology. In some embodiments, the present disclosure provides a method of treating a Attorney Docket No.29539-0727WO1 tauopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the tauopathy), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of tauopathies 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 glial tauopathy, and argyrophilic grain disease, among other neurodegenerative disorders where misfolding of tau protein is involved, at least in part, in the disease pathology. In some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder where any combination of synuclein, amyloid, and / or tau peptide or protein is implicated in the disease pathology. See, e.g., 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, among others. Without being bound by any particular theory or speculation, it is believed that misfolding and / or aggregation of synuclein, amyloid, and / or tau peptides or proteins causes, induces, increases, and / or enhances neuroinflammation, which process further contributes to the progression of neurodegeneration and related symptomology. See, e.g., Gate D et al, Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al, Elife, 2020, 9, e54083, among others. Accordingly, in some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder (e.g., where inflammation is implicated in the disease pathology) in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the neurodegenerative disorder), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the neurodegenerative disorder is selected from motor neuron disease (MND), Prion disease, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), and dementia associated with HD, Creutzfeldt- Jakob disease, Machado-Joseph disease, Binswanger’s disease, dementia, multiple Attorney Docket No.29539-0727WO1 sclerosis (“MS”), hippocampal sclerosis, Gaucher’s disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinal cerebellar ataxias, disturbances of consciousness disorders, hearing and balance impairments, CNS hypoxia, cerebral senility, brain injuries (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 disorder treatable by a compound of this disclosure is 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. Combination treatments The compounds of the present disclosure can be used on combination with at least one medication or therapy useful, e.g., in treating or alleviating symptoms of a neurodegenerative disorder such as PD. Suitable examples of such medications 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 a pharmaceutically acceptable salt thereof. The compound can also be used in combination with deep brain stimulation (DBS) neurosurgery. The compound of the present disclosure may be administered to the patient simultaneously with the additional therapeutic agent (in the same dosage form or in different dosage forms) or consecutively (the additional therapeutic agent may be administered before or after administration of the compound of the present disclosure). Definitions As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value). At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such Attorney Docket No.29539-0727WO1 groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3- yl, or pyridin-4-yl ring. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized π (pi) electrons where n is an integer). The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. 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-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution 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. It is to be understood that substitution at a given atom is limited by valency. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which Attorney Docket No.29539-0727WO1 are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like. As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n- hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, the term “Cn-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-1,2-diyl, propan- 1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms. As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl. Attorney Docket No.29539-0727WO1 As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 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 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 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 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five 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 ring heteroaryls are 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, Attorney Docket No.29539-0727WO1 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having 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 ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin- 2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For Attorney Docket No.29539-0727WO1 example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3-position. As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m haloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term “amino” refers to a group of formula –NH2. As used herein, the term “Cn-m alkylamino” refers to a group of 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), N-butylamino (e.g., N-(n- butyl)amino and N-(tert-butyl)amino), and the like. As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, 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. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Any atom identified in the compounds herein that is not specifically designated as radioisotope is present at is natural isotopic abundance. Attorney Docket No.29539-0727WO1 The compounds described herein can 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 that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)- configuration. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Attorney Docket No.29539-0727WO1 As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology). As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility 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 Materials and methods All commercially available reagents were used without further purification unless otherwise stated. Analytical thin layer chromatography (TLC) was performed using Silica Gel GF254 plates (Merck Millipore co, .ltd, 0.2 mm thick). Compounds were purified using CombiFlash Rf150 (Teledyne ISCO co, .ltd).1H and13C spectra were recorded on Bruker 500 MHz. Chemical shifts in1H NMR spectra were reported in parts per million (ppm) on the δ scale from an 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. Chemical shifts of13C NMR spectra were reported in ppm from the central peak of CDCl3(77.0 ppm) on the δ scale. MS data was recorded on Agilent Technologies 6310 quadrupole mass spectrometer. Attorney Docket No.29539-0727WO1 Example 1 – proteolysis targeting chimeras For each of the above compounds, R-group can be selected from any one of the Attorney Docket No.29539-0727WO1 following moieties: OTHER EMBODIMENTS It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.29539-0727WO1 WHAT IS CLAIMED IS:

1. A conjugate of Formula (I): P—L—E (I), or a pharmaceutically acceptable salt thereof, wherein: P is a protein-binding moiety of formula: , wherein:X1is selected from O, NH, and S; L1is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; Ring A is selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1A; each R1Ais independently selected from Cy1, halo, OH, CN, NO2, C1-3 alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3alkylamino, and di(C1-3 alkyl)amino; each Cy1is independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3alkylamino, and di(C1-3alkyl)amino; X2is selected from CR2and N;Attorney Docket No.29539-0727WO1 R2is selected from H, C1-3 alkyl, C1-3 haloalkyl, and L2-C(=O)N(R1a)(R4), wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from OH, CN, NO2, C1-3alkoxy, and C1-3haloalkoxy; L2is selected from bond and C1-3 alkylene, which is optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, NO2, C1-3 haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; Ring B is selected from C6-10aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R1B; each R1Bis independently selected from halo, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3alkyl)amino; each R1ais independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; each R4is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3alkyl), C(=O)N(C1-3alkyl)2, amino, C1-3alkylamino, and di(C1-3alkyl)amino; each Cy2is independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy, halo, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(C1-3 alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; and each RCyis independently selected from C6-10 aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)NH2, C(=O)NH(C1-3 alkyl), C(=O)N(C1-3 alkyl)2, amino, C1-3 alkylamino, and di(C1-3Attorney Docket No.29539-0727WO1 alkyl)amino; E is a ligase binding moiety; L is a linker moiety connecting the ligase binding moiety E and the protein binding moiety P.

2. The conjugate of claim 1, wherein the linker moiety L has formula (L3)m, wherein: m is an integer from 2 to 20; each L3is independently selected from N(RN), O, C(=O), S, S(=O), S(=O)2, C1-6alkylene, C3-7 cycloalkylene, 4-10- membered heterocycloalkylene, 5-10-membered heteroarylene, C6-10arylene, –(OCH2CH2)x–, –(CH2CH2O)x–, –(OCH(CH3)CH2)x–, – (CH2CH(CH3)O)x–, each of which is optionally substituted with 1 or 2 substituents independently selected from OH, NH2, C(O)OH, SO3H, C1-3 alkylamino, di(C1-3- alkyl)amino, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; each x is independently an integer from 1 to 2,000; and each RNis independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

3. The conjugate of claim 2, having formula: , or a4. The conjugate of claim 2, having formula: , or aAttorney Docket No.29539-0727WO1 The conjugate of claim 2, having formula: ,or a pharmaceutically acceptable salt thereof, 6. The conjugate of any one of claims 1-5, wherein: m is 2, 4, 5, 6, or 8; each L3is independently selected from NH, O, C(=O), C1-6alkylene, C3-7cycloalkylene, 4-10- membered heterocycloalkylene, 5-10-membered heteroarylene, C6-10 arylene, –(OCH2CH2)x–, and –(CH2CH2O)x–; and x is an integer from 1 to 10.

7. The conjugate of claim 6, wherein: at least one L3is C1-6 alkylene; at least one L3is C(=O)O or C(=O)NH; and at least one L3is –(OCH2CH2)x– or –(CH2CH2O)x–.

8. The conjugate of claim 6, wherein (L3)mmoiety comprises any one of the foregoing flexible structural fragments, or any combination thereof: ,Attorney Docket No.29539-0727WO1 9. The conjugate of claim 6, wherein (L3)m moiety comprises any one of the foregoing rigid structural fragments, or any combination thereof: ,10. The conjugate of any one of claims 1-9, wherein ring B is C6-10aryl substituted with R1B.

11. The conjugate of any one of claims 1-9, wherein ring B is 5-14 membered heteroaryl substituted with R1B.

12. The conjugate of any one of claims 1-9, wherein RBis selected from:

13. The conjugate of any one of claims 1-9, wherein ring A is selected from: R1A 14. The conjugate ofbinding moiety E is capable of binding to cereblon, von Hippel Lindau (VHL), inhibitor of apoptosis protein (IAP), and / or and mouse double minute 2 homolog (MDM2).Attorney Docket No.29539-0727WO1 15. The conjugate of claim 14, wherein the ligase-binding moiety E is selected from any one of the following formulae:

16. The conjugate of claim 14, wherein the ligase-binding moiety E has formula: , wherein:Rois selected from H and halo; and each Rpis selected from H and C1-3alkyl.

17. The conjugate of claim 16, wherein the moiety E has formula: .Attorney Docket No.29539-0727WO1 18. The conjugate of claim 1, selected from any one of the following compounds:Attorney Docket No.29539-0727WO1 X is O or NH; n is an integer from 1 to 100; and each R is selected from any one of the following moieties: .

19. A pharmaceutical composition comprising a conjugate of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A method of treating a neurodegenerative disease or disorder selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (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 grain disease, dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a conjugate of claim 1, or a therapeutically acceptable salt thereof.

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