DEUBIQUITINASE-TARGETING CHIMERAS AND RELATED METHODS CLAIM OF PRIORITY The present application claims priority to U.S. Application No.63/421,958, filed on November 2, 2022. The entire contents of the foregoing application is incorporated herein by reference in its entirety. BACKGROUND The Ubiquitin-Proteasome Pathway (UPP) is a critical process that plays a role in a variety of cellular functions, including protein degradation, quality control, trafficking, and signaling. Ubiquitin and other ubiquitin-like proteins (collectively, “Ubls”) are covalently attached to specific protein substrates, which depending on the specific modification, either ultimately targets these proteins for degradation by the proteasome or affects protein function in other ways. These Ubls, however, may be removed through the action of deubiquitinases (DUBs), which hydrolyze the Ubl from a target protein. Removal of a Ubl from a ubiquitinated target protein can modulate the function of the target protein in a number of ways, including improving stability and preventing proteasomal degradation. As degradation of certain cellular proteins has been linked to disease progression, there is a need for new tools to stabilize certain proteins and slow or inhibit their degradation. DETAILED DESCRIPTION The present disclosure features bifunctional compounds, as well as pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, that are useful for recruiting one or more deubiquitinases to a target protein for modulation (e.g., stabilization) of the target protein, as well as methods of use thereof. A hallmark of many diseases entails the active ubiquitination and degradation of certain proteins, including misfolded, mutated, or otherwise unstable proteins. As such, targeted stabilization of these key proteins through deliberate deubiquitination may thwart disease progression and impart a therapeutic benefit in a cell or subject. Described herein are a set of bifunctional compounds comprising both a Target Ligand, capable of binding to a target protein (e.g., CFTR), and a DUB Recruiter, capable of binding to a deubiquitinase (e.g., OTUB1). These bifunctional compounds may, inter alia, bring the deubiquitinase in proximity to a ubiquitinated protein, thus allowing for directed removal of Ubls and potential target protein stabilization. Further embodiments relating to these bifunctional compounds and their use are provided herein. Definitions Selected Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C1-C6 alkyl” or ““C1-6 alkyl” is intended to encompass, C1, C2, C ₃ , C ₄ , C ₅ , C ₆ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ - C4, C4-C6, C4-C5, and C5-C6 alkyl. The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 6 carbon atoms (“C1–6 alkyl”). In some embodiments, an alkyl group has ^{1 to 5 carbon atoms (“C} 1–5 ^{alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms} (“C _1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C _1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6 alkyl”). Examples of C1–6 alkyl groups include methyl (C1), ethyl (C ₂ ), propyl (C ₃ ) (e.g., n-propyl, isopropyl), butyl (C ₄ ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). “Alkylene” refers to a divalent radical of an alkyl group, e.g., –CH ₂ –, –CH ₂ CH ₂ –, and –CH2CH2CH2–. “Heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC _1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC _1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC _1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 ^{heteroatoms within the parent chain (“heteroC} _2–6 ^{alkyl”). Unless otherwise specified, each} instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC _1–10 alkyl. “Heteroalkylene” refers to a divalent radical of a heteroalkyl group. “Alkoxy” or “alkoxyl” refers to an -O-alkyl radical. In some embodiments, the alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. In some embodiments, alkoxy groups are lower alkoxy, i.e., with between 1 and 6 carbon atoms. In some embodiments, alkoxy groups have between 1 and 4 carbon atoms. As used herein, the term “aryl” refers to a stable, aromatic, mono- or bicyclic ring radical having the specified number of ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. The related term “aryl ring” likewise refers to a stable, aromatic, mono- or bicyclic ring having the specified number of ring carbon atoms. As used herein, the term “heteroaryl” refers to a stable, aromatic, mono- or bicyclic ring radical having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur. The heteroaryl radical may be bonded via a carbon atom or heteroatom. Examples of heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, oxadiazolyl, benzothiazolyl, quinoxalinyl, and the like. The related term “heteroaryl ring” likewise refers to a stable, aromatic, mono- or bicyclic ring having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur. As used herein, the term “cycloalkyl” refers to a stable, saturated or unsaturated, non- aromatic, mono- or bicyclic (fused, bridged, or spiro) ring radical having the specified number of ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, the cycloalkyl groups identified above, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. In an ^{embodiment, the specified number is C} 3 ^–C 12 ^{carbons. The related term “carbocyclic ring”} likewise refers to a stable, saturated or unsaturated, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) ring having the specified number of ring carbon atoms. In an embodiment, the cycloalkyl can be substituted or unsubstituted. In an embodiment, the cycloalkyl can be substituted with 0-4 occurrences of R ^a , wherein each R ^a is independently selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxyl, and halogen. As used herein, the term “heterocyclyl” refers to a stable, saturated or unsaturated, non- aromatic, mono- or bicyclic (fused, bridged, or spiro) ring radical having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur. The heterocyclyl radical may be bonded via a carbon atom or heteroatom. In an embodiment, the specified number is C3–C12 carbons. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, perhydroazepinyl, tetrahydropyridinyl, tetrahydroazepinyl, octahydropyrrolopyrrolyl, and the like. The related term “heterocyclic ring” likewise refers to a stable, saturated or unsaturated, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) ring having the specified number of ring atoms and comprising one or more heteroatoms individually selected from nitrogen, oxygen and sulfur. In an embodiment, the heterocyclyl can be substituted or unsubstituted. In an embodiment, the heterocyclyl can be substituted with 0-4 occurrences of R ^a , wherein each R ^a is independently selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxyl, and halogen. As used herein, “spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. For example, a (C3– C ₁₂ )spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. As used herein, “spiroheterocycloalkyl” or “spiroheterocyclyl” means a spirocycle wherein at least one of the rings is a heterocycle wherein one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings). One or both of the rings in a spiroheterocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. As used herein, “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). As used herein, “haloalkyl” means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl. As used herein, “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. Various embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features, including as indicated in the embodiments below, to provide further embodiments of the present disclosure. It is understood that in the following embodiments, combinations of substituents or variables of the depicted formulae are permissible only if such combinations result in stable compounds. Certain compounds described herein may exist in particular geometric or stereoisomeric forms. If, for instance, a particular enantiomer of a compound described herein is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Unless otherwise stated, structures depicted herein are also meant to include geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the disclosed compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds described herein are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the disclosed structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³ C or ¹⁴ C enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the disclosure. The “enantiomeric excess” or “% enantiomeric excess” of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee = (90−10)/100 × 100 = 80%. Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. The compounds or compositions described herein may contain an enantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one form of the compound, e.g., the S-enantiomer. In other words such compounds or compositions contain an enantiomeric excess of the S enantiomer over the R enantiomer. Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization. Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds described herein into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Other Definitions The following definitions are more general terms used throughout the present disclosure. As used herein, the term “a,” “an,” “the” and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. As used herein, the term “about” means within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When about is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range. “Acquire” or “acquiring” as used herein, refer to obtaining possession of a value, e.g., a numerical value, or image, or a physical entity (e.g., a sample), by “directly acquiring” or “indirectly acquiring” the value or physical entity. “Directly acquiring” means performing a process (e.g., performing an analytical method or protocol) to obtain the value or physical entity. “Indirectly acquiring” refers to receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Directly acquiring a value or physical entity includes performing a process that includes a physical change in a physical substance or the use of a machine or device. Examples of directly acquiring a value include obtaining a sample from a human subject. Directly acquiring a value includes performing a process that uses a machine or device, e.g., mass spectrometer to acquire mass spectrometry data. The terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof. As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably. As used herein, the terms “degrades”, “degrading”, or “degradation” refers to the partial or full breakdown of a target protein by the cellular proteasome system to an extent that reduces or eliminates the biological activity (especially aberrant activity) of target protein. As used herein, the terms “inhibit”, “inhibition”, or “inhibiting” refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term “modulating a target protein” or “modulating target protein activity” means the alteration of at least one feature of a target protein. For example, modulation may comprise one or more of: (i) modulating the folding of the target protein; (ii) modulating the half-life of the target protein; (iii) modulating trafficking of the target protein to the proteasome; (iv) modulating the level of ubiquitination of the target protein; (v) modulating degradation (e.g., proteasomal degradation) of the target protein; (vi) modulating target protein signaling; (vii) modulating target protein localization; (viii) modulating trafficking of the target protein to the lysosome; (ix) modulating trafficking of the target protein to the ER, Golgi, vesicle, plasma membrane; (x) modulating target protein interactions with another protein (e.g., other proteins in the UPS); (xi) modulating posttranslational modifications of the target protein (e.g., SUMOlyation, phosphorylation, glycosylation). In an embodiment, modulating a target protein refers to one or more of: improving the folding of a protein, increasing the half-life of a protein, preventing the trafficking of the target protein to the proteasome, decreasing the level of ubiquitination of the target protein, preventing degradation of the target protein, improving target protein signaling, improving target protein signaling, preventing trafficking of the target protein to the lysosome, and improving target protein interactions with another protein. Modulating a target protein may be achieved by stabilizing the level the target protein in vivo or in vitro. The amount of target protein stabilized can be measured by comparing the amount of target protein remaining after treatment with a bifunctional compound described herein as compared to the initial amount or level of target protein present as measured prior to treatment with a bifunctional compound described herein. In an embodiment, at least about 30% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 40% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 50% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 60% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 70% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 80% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 90% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 95% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, over 95% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, at least about 99% of the target protein is modulated (e.g., stabilized) compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 30% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 40% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 50% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 60% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 70% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 80% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 90% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 95% to about 99% compared to initial levels. In an embodiment, the target protein is modulated (e.g., stabilized) in an amount of from about 90% to about 95% compared to initial levels. The terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprised therein. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. As used herein, the term “selectivity for the target protein” means, for example, a bifunctional compound described herein binds to the target protein in preference to, or to a greater extent than, another protein or proteins. As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In an embodiment, the subject is a primate. In a preferred embodiment, the subject is a human. As used herein, the term “a therapeutically effective amount” of a compound described herein refers to an amount of the compound described herein that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one embodiment, the term “a therapeutically effective amount” refers to the amount of the compound described herein that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by a target protein, (ii) associated with activity of a target protein, or (iii) characterized by activity (normal or abnormal) of a target protein; or (2) reduce or inhibit the activity of a target protein; or (3) reduce or inhibit the expression of a target protein. These effects may be achieved for example by increasing the amount of a target protein by stabilizing the target protein or preventing degradation of the target protein. In one embodiment, the term “a therapeutically effective amount” refers to the amount of the compound described herein that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least prevent or partially prevent reduction of the level of a target protein; or at least maintain or partially increase the activity of a target protein, for example by removing a Ubl covalent bound to the target protein. As used herein, the terms “treat”, “treating”, or “treatment” of any disease or disorder refer in an embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In an embodiment, “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. As used herein, the term “preventing” refers to a reduction in the frequency of, or delay in the onset of, symptoms of the condition or disease. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment. Bifunctional Compounds The present disclosure describes bifunctional compounds capable of binding to a target protein and a deubiquitinase, e.g., to affect the deubiquitination of the target protein and prevent its degradation by the proteasome. Without being bound by theory, these bifunctional compounds work to bring a deubiquitinase in proximity with a ubiquitinated target protein, such that the deubiquitinase is capable of removing one or more Ubl proteins from the ubiquitinated target protein to modulate (e.g., stabilize and/or prevent degradation of) the target protein. In an embodiment, the bifunctional compounds simultaneously bind to a target protein (e.g., CFTR) and a deubiquitinase (e.g., OTUB1). The bifunctional compounds may bind to their respective ligands in any order. In an embodiment, the bifunctional compounds first bind to a target protein (e.g., CFTR), then bind to a deubiquitinase (e.g., OTUB1). In another embodiment, the bifunctional compounds first bind to a deubiquitinase (e.g., OTUB1), then a target protein (e.g., CFTR). In still another embodiment, the bifunctional compounds engage with both a target protein (e.g., CFTR) and a deubiquitinase (e.g., OTUB1) at the same time. In some embodiments, modulating a target protein (e.g., CFTR) comprises one or more of: (i) modulating the folding of the target protein; (ii) modulating the half-life of the target protein; (iii) modulating trafficking of the target protein to the proteasome; (iv) modulating the level of ubiquitination of the target protein; (v) modulating degradation (e.g., proteasomal degradation) of the target protein; (vi) modulating target protein signaling; (vii) modulating target protein localization; (viii) modulating trafficking of the target protein to the lysosome; (ix) modulating trafficking of the target protein to the ER, Golgi, vesicle, plasma membrane; (x) modulating target protein interactions with another protein (e.g., other proteins in the UPS); (xi) modulating posttranslational modifications of the target protein (e.g., SUMOlyation, phosphorylation, glycosylation). In an embodiment, the modulating comprises (i). In an embodiment, the modulating comprises (ii). In an embodiment, the modulating comprises (i). In an embodiment, the modulating comprises (iii). In an embodiment, the modulating comprises (iv). In an embodiment, the modulating comprises (v). In an embodiment, the modulating comprises (vi). In an embodiment, the modulating comprises (vii). In an embodiment, the modulating comprises (viii). In an embodiment, the modulating comprises (ix). In an embodiment, the modulating comprises (x). In an embodiment, the modulating comprises (xi). In an embodiment, the modulating comprises two of (i)-(xi). In an embodiment, the modulating comprises three of (i)-(xi). In an embodiment, the modulating comprises four of (i)-(xi). In an embodiment, the modulating comprises five of (i)-(xi). In an embodiment, the modulating comprises six of (i)-(xi). In an embodiment, the modulating comprises seven of (i)-(xi). In an embodiment, the modulating comprises eight of (i)-(xi). In an embodiment, the modulating comprises nine of (i)-(xi). In an embodiment, the modulating comprises ten of (i)-(xi). In an embodiment, the modulating comprises each of (i)-(xi). In some embodiments, the bifunctional compound has the structure of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein (i) the Target Ligand comprises a moiety capable of binding to a target protein; (ii) L1 comprises a linker; and (iii) the DUB Recruiter comprises a moiety capable of binding to a deubiquitinase. In some embodiments, the bifunctional compound has the structure of Formula (I-a): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the DUB Recruiter comprises a moiety capable of binding to a deubiquitinase. In some embodiments, the bifunctional compound has the structure of Formula (I-b): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein (i) the Target Ligand comprises a moiety capable of binding to a target protein; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to OTUB1. In some embodiments, the bifunctional compound has the structure of Formula (I-c): (I-c), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to OTUB1. Each of the components of the bifunctional compounds of Formula (I) are described herein in turn. Target Ligands The Target Ligand within the bifunctional compound is a small molecule moiety capable of binding to a target protein or other protein of interest. In some embodiment, the Target Ligand binds to a target protein described herein, e.g., an enzyme, receptor, membrane channel, hormone, transcription factor, tumor suppressor, ion channel, apoptotic factor, oncogenic protein, epigenetic regulator, or fragment thereof. In some embodiments, the Target Ligand binds to a kinase. In some embodiments, the Target Ligand binds to a membrane channel (e.g., CFTR). In some embodiments, the Target Ligand binds to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof. In some embodiments, the Target Ligand is a CFTR Ligand and comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof. In an embodiment, the CFTR Ligand binds to CFTR comprising a sequence mutation (e.g., a Class I, Class II, Class III, Class IV, Class V, or Class VI mutation). In some embodiments, the CFTR Ligand binds to a CFTR comprising a Class I mutation, e.g., a nonsense mutation, splice mutation, or deletion (e.g., G542X, W1282X, R553X). In some embodiments, the CFTR Ligand binds to a CFTR comprising a Class II mutation, e.g., a processing mutation (e.g., ΔF508, N130K, ΔI507). In some embodiments, the CFTR Ligand binds to a CFTR comprising a Class III mutation, e.g., a gating mutation (e.g., G551D, S549N). In some embodiments, the CFTR Ligand binds to a CFTR comprising a Class IV mutation, e.g., a conduction mutation (e.g., D1152H, R347P, R117H). In some embodiments, the CFTR Ligand binds to a CFTR comprising a Class V mutation, e.g., a splice mutation. In some embodiments, the CFTR Ligand binds to CFTR comprising a sequence mutation selected from the group consisting of G551D, R177H, and A445E. In some embodiments, the CFTR Ligand binds to a CFTR comprising a Class VI mutation. In some embodiments, the CFTR binds to CFTR comprising a ΔF508 mutation. In some embodiments, the CFTR Ligand is a CFTR potentiator. In some embodiments, the CFTR Ligand comprises ivacaftor, lumacaftor, tezacaftor, elexacaftor, or icenticaftor, or a derivative thereof. In some embodiments, the CFTR Ligand is a compound disclosed in one or more of. US. Patent No.7,999,113; U.S. Patent No.8,247,436; U.S.8,410,274; WO 2011/133953; and WO 2018/037350, each of which is incorporated by reference in its entirety. In some embodiments, the CFTR Ligand has the structure of Formula (II-a): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, or halo; R ^7c is H or C1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C _1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and denotes the point of attachment to L1 in Formula (I). In some embodiments, X is O. In some embodiments, Z is O. In some embodiments, each of X and Z is independently O. In some embodiments, Y is C(R ^7a )(R ^7b ). In some embodiments, each of R ^7a and R ^7b is independently halo (e.g., fluoro). In some embodiments, X is O, Z is O, and Y is C(R ^7a )(R ^7b ). In some embodiments, X is O, Z is O, and Y is CF ₂ . In some embodiments, R ^3a and R ^3b are each independently H. In some embodiments, R ^4a and R ^4b are each independently H. In some embodiments, each of R ^3a , R ^3b , R ^4a , R ^4b is independently H. In some embodiments, R ^5’ is C1–6 alkyl (e.g., methyl). In some embodiments, R ¹ is H. In some embodiments, p is 0. In some embodiments, p’ is 1. In some embodiments, q is 0. In some embodiments, each of p and q is independently 0. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is C1–6 alkyl. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is methyl. In some embodiments, the CFTR Ligand has the structure of Formula (II-b): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; ^{R1 is H or C} 1–6 ^{alkyl; R2 is H or C} 1–6 ^{alkyl; R3a, R3b, R4a, R4b are each independently H, C} 1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, or halo; R ^7c is H or C1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and denotes the point of attachment to L1 in Formula (I). In some embodiments, X is O. In some embodiments, Z is O. In some embodiments, each of X and Z is independently O. In some embodiments, Y is C(R ^7a )(R ^7b ). In some embodiments, each of R ^7a and R ^7b is independently halo (e.g., fluoro). In some embodiments, X is O, Z is O, and Y is C(R ^7a )(R ^7b ). In some embodiments, X is O, Z is O, and Y is CF2. In some embodiments, R ^3a and R ^3b are each independently H. In some embodiments, R ^4a and R ^4b are each independently H. In some embodiments, each of R ^3a , R ^3b , R ^4a , R ^4b is independently H. In some embodiments, R ^5’ is C _1–6 alkyl (e.g., methyl). In some embodiments, R ¹ is H. In some embodiments, R ² is H. In some embodiments, each of R ¹ and R ² is independently H. In some embodiments, p is 0. In some embodiments, p’ is 1. In some embodiments, q is 0. In some embodiments, each of p and q is independently 0. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is C1–6 alkyl. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is methyl. In some embodiments, the CFTR Ligand has the structure of Formula (II-c): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, or halo; R ^7c is H or C1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and each denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-d): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-e): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-f): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-g): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein each of independently denotes a point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-h): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-i): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-j): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the CFTR Ligand is lumacaftor or a derivative thereof. In some embodiments, the CFTR Ligand has the structure of Formula (II-k): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). In some embodiments, the bifunctional compound of Formula (I) has the structure (II-l): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C _1–6 alkyl, C _1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, or halo; R ^7c is H or C1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, X is O. In some embodiments, Z is O. In some embodiments, each of X and Z is independently O. In some embodiments, Y is C(R ^7a )(R ^7b ). In some embodiments, R ^7a and R ^7b are each independently halo (e.g., fluoro). In some embodiments, X is O, Z is O, and Y is C(R ^7a )(R ^7b ). In some embodiments, X is O, Z is O, and Y is CF2. In some embodiments, R ^3a and R ^3b are each independently H. In some embodiments, R ^4a and R ^4b are each independently H. In some embodiments, each of R ^3a , R ^3b , R ^4a , R ^4b is independently H. In some embodiments, R ^5’ is C1–6 alkyl (e.g., methyl). In some embodiments, R ¹ is H. In some embodiments, p is 0. In some embodiments, p’ is 1. In some embodiments, q is 0. In some embodiments, each of p and q is independently 0. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is C1–6 alkyl. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is methyl. In some embodiments, the bifunctional compound of Formula (I) has the structure (II-m): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C _1–6 alkyl; R ² is H or C _1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, or halo; R ^7c is H or C _1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C _1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, X is O. In some embodiments, Z is O. In some embodiments, each of X and Z is independently O. In some embodiments, Y is C(R ^7a )(R ^7b ). In some embodiments, R ^7a and R ^7b are each independently halo (e.g., fluoro). In some embodiments, X is O, Z is O, and Y is C(R ^7a )(R ^7b ). In some embodiments, X is O, Z is O, and Y is CF2. In some embodiments, R ^3a and R ^3b are each independently H. In some embodiments, R ^4a and R ^4b are each independently H. In some embodiments, each of R ^3a , R ^3b , R ^4a , R ^4b is independently H. In some embodiments, R ^5’ is C1–6 alkyl (e.g., methyl). In some embodiments, R ¹ is H. In some embodiments, R ² is H. In some embodiments, each of R ¹ and R ² is independently H. In some embodiments, p is 0. In some embodiments, p’ is 1. In some embodiments, q is 0. In some embodiments, each of p and q is independently 0. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is C1–6 alkyl. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is methyl. In some embodiments, the bifunctional compound of Formula (I) has the structure (II-n): (II-n) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C _1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, or halo; R ^7c is H or C _1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, X is O. In some embodiments, Z is O. In some embodiments, each of X and Z is independently O. In some embodiments, Y is C(R ^7a )(R ^7b ). In some embodiments, R ^7a and R ^7b are each independently halo (e.g., fluoro). In some embodiments, X is O, Z is O, and Y is C(R ^7a )(R ^7b ). In some embodiments, X is O, Z is O, and Y is CF2. In some embodiments, R ^3a and R ^3b are each independently H. In some embodiments, R ^4a and R ^4b are each independently H. In some embodiments, each of R ^3a , R ^3b , R ^4a , R ^4b is independently H. In some embodiments, R ^5’ is C1–6 alkyl (e.g., methyl). In some embodiments, R ¹ is H. In some embodiments, R ² is H. In some embodiments, each of R ¹ and R ² is independently H. In some embodiments, p is 0. In some embodiments, p’ is 1. In some embodiments, q is 0. In some embodiments, each of p and q is independently 0. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is C1–6 alkyl. In some embodiments, p is 0, q is 0, p’ is 1, and R ^5’ is methyl. In some embodiments, the bifunctional compound of Formula (I) has the structure (II-o): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, the bifunctional compound of Formula (I) has the structure (II-p): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, the bifunctional compound of Formula (I) has the structure (II-q): (II-q) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, the bifunctional compound of Formula (I) has the structure (II-r): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L1 and OTUB1 Recruiter are as defined for Formula (I). In some embodiments, the bifunctional compound of Formula (I) has the structure (II-s): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L1 and OTUB1 Recruiter are as defined for Formula (I). Linkers The present disclosure features bifunctional compounds comprising a Target Ligand (e.g., CFTR Ligand) and a DUB Recruiter (e.g., OTUB1 Recruiter), separated by a linker (i.e., L1). In some embodiments, the linker is covalently bound to the CFTR Ligand. In some embodiments, the linker is covalently bound to the OTUB1 Recruiter. In some embodiments, the linker is covalently bound to both the CFTR Ligand and the OTUB1 Recruiter. The linker may be a cleavable linker or a non-cleavable linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is not degraded or hydrolyzed at physiological conditions. In some embodiments, the linker comprises a bond that is not cleavable in a cell (e.g, a cell organelle) or the serum, e.g., of a sample or subject. In some embodiments, the linker comprises an alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, ether, amine, alkoxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, the linker comprises an alkylene or heteroalkylene. In some embodiments, the linker (e.g., L1) has the structure of Formula (III-a): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R ^12a , R ^12b , R ^13a , R ^13b , R ^14a , and R ^14b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, or -OR ^A ; or each of R ^12a and R ^12b , R ^13a and R ^13b , and R ^14a and R ^14b independently may be taken together with the carbon atom to which they are attached to form an oxo group; W is C(R ^15a )(R ^15b ), O, N(R ¹⁶ ), or S; R ^15a and R ^15b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; or R ^15a and R ^15b may be taken together with the carbon atom to which they are attached to form an oxo group; R ¹⁶ is H or C _1–6 alkyl; R ^A is H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; o and x are each independently an integer between 0 and 10; * denotes the point of attachment to the Target Ligand in Formula (I); and denotes the point of attachment to the DUB Recruiter in Formula (I). In some embodiments, each of R ^12a , R ^12b , R ^13a , and R ^13b is independently H. In some embodiments, each of R ^14a and R ^14b are taken together with the carbon atom to which they are attached form an oxo group. In some embodiments, W is N(R ¹⁶ ) (e.g., NH). In some embodiments, o is selected from 2, 3, 4, 5, and 6. In some embodiments, p is selected from 1, 2, and 3. In some embodiments, L1 has the structure of Formula (III-b): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R* is H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl; o is an integer between 0 and 10; * denotes the point of attachment to the CFTR Ligand in Formula (I); and denotes the point of attachment to the OTUB1 Recruiter in Formula (I). In some embodiments, L1 has the structure of Formula (III-c): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R” is H or C1–6 alkyl , and o is an integer between 0 and 10; * denotes the point of attachment to the CFTR Ligand in Formula (I); and denotes the point of attachment to the OTUB1 Recruiter in Formula (I). In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, the linker (e.g., L1) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , stereoisomer, or tautomer thereof, wherein “*” denotes the point of attachment to the CFTR Ligand or OTUB1 Recruiter. In some embodiments, the linker (e.g., L1) is a variant of a linker described herein, e.g., wherein the linker (e.g., L1) comprises an additional C1-C6 alkyl or C1-C6 heteroalkyl moiety at a point of attachment, e.g., to the CFTR Ligand or the OTUB1 Recruiter. In some embodiments, the linker is a cleavable linker, e.g., a linker that is degraded or hydrolyzed at physiological conditions. In some embodiments, the linker comprises a bond cleavable in a cell (e.g, a cell organelle) or the serum, e.g., of a sample or subject. For example, the linker may be pH sensitive (e.g., acid labile or base labile) or cleaved through the action of an enzyme. In an embodiment, the rate of hydrolysis of the linker is increased by at least 0.5 times (e.g., at least 1, 1.5, 2, 2.5, 3, 4, 5, 7.5, 10, 12.5, 15, 20, 25, 50, 75, 100, 250, 500, 750, 1000 or more) compared with the rate of hydrolysis of the linker in the absence of an enzyme. In some embodiments, the enzyme is an esterase. In an embodiment, the linker comprises an ester, disulfide, thiol, hydrazone, ether, or amide. In an embodiment, the linker (e.g., L1) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein “*”denotes the point of attachment to the CFTR Ligand or OTUB1 Recruiter. In some embodiments, the linker (e.g., L1) is a variant of a linker described herein, e.g., wherein the linker (e.g., L1) comprises an additional C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl moiety at a point of attachment, e.g., to the CFTR Ligand or the OTUB1 Recruiter. In an embodiment, the linker (e.g., L1) is selected from the group consisting of: , , , , , , , , , , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein “*” denotes the point of attachment to the CFTR Ligand or the OTUB1 Recruiter. In some embodiments, the linker (e.g., L1) is a variant of a linker described herein, e.g., wherein the linker (e.g., L1) comprises an additional C ₁ -C ₆ alkyl or C1-C6 heteroalkyl moiety at a point of attachment, e.g., to the CFTR Ligand or the OTUB1 Recruiter. In an embodiment, L1 has the structure of Formula (L1-I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein each of R ^7a and R ^7b is independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, and halo; G is absent, C1–6 alkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-(C _1–6 )alkylene, heteroaryl-(C _1–6 )alkylene, aryl-(C _{1– 6} )heteroalkylene, heteroaryl-(C _1–6 )heteroalkylene, or -NR’-, wherein R’ is H, C _1–6 alkyl, or – (CH2)1-2-C(O)2H, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-6 occurrences of R ^c , wherein R ^c is selected from the group consisting of halo, –C(O)OCH ₂ -aryl, and –C(O)OCH ₂ -heteroaryl; y is 0, 1, 2, 3, 4, or 5; and each “*” and “**” independently denote the point of attachment to the Target Ligand or DUB Recruiter in Formula (I). In an embodiment, L1 is selected from the group consisting of: , (L1-8), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein “*” and “**” each independently denote the point of attachment to the Target Ligand or the OTUB1 Recruiter. In some embodiments, the linker (e.g., L1) is a variant of a linker described herein, e.g., wherein the linker (e.g., L1) comprises an additional C ₁ -C ₆ alkyl or C ₁ -C ₆ heteroalkyl moiety at a point of attachment, e.g., to the CFTR Ligand or the OTUB1 Recruiter. In some embodiments, the linker (e.g., L1) has the structure of Formula (III-d): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R ²⁰ and R ²² are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl; R ^21a and R ^21b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; or each of R ^12a and R ^12b , R ^13a and R ^13b , and R ^14a and R ^14b independently may be taken together with the carbon atom to which they are attached to form an oxo group; R ^A is H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C1– ₆ heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer between 0 and 20; * denotes the point of attachment to the Target Ligand in Formula (I); and ** denotes the point of attachment to the OTUB1 Recruiter in Formula (I). In some embodiments, each of R ^21a and R ^21b is independently H. In some embodiments, each of R ^21a and R ^21b are taken together with the carbon atom to which they are attached form an oxo group. In some embodiments, m is selected from 2, 3, 4, 5, and 6. DUB Recruiter The DUB Recruiter within the bifunctional compound is a small molecule moiety capable of binding to a deubiquitinase. In some embodiments, the DUB Recruiter is a OTUB1 Recruiter, i.e., binds to the OTUB1 deubiquitinase, or a mutant, fragment, or isoform thereof. In some embodiments, the OTUB1 Recruiter binds to a cysteine amino acid residue within OTUB1. The OTUB1 Recruiter may bind to OTUB1 covalently or non-covalently. In some embodiments, the OTUB1 Recruiter binds to OTUB1 covalently, e.g., through a thiol or thioester bond. In some embodiments, the OTUB1 Recruiter binds to OTUB1 non-covalently, e.g., ionically. The OTUB1 Recruiter may bind to full-length OTUB1 or a fragment thereof. In some embodiments, the OTUB1 Recruiter binds to a surface of OTUB1. In some embodiments, the OTUB1 Recruiter binds to an internal cavity of OTUB1. In some embodiments, the OTUB1 Recruiter binds to a OTUB1 fragment or variant thereof. In some embodiments, the deubiquitinase is OTUB1 (Uniprot ID Q96FW1). OTUB1 is a deubiquitinase that cleaves ubiquitin from branched polyubiquitin chains, with limited activity for removing ubiquitin bound directly to ubiquitin substrates. OTUB1 has been shown to remove ubiquitin bound to other ubiquitin molecules through lysine-48 (Lys-48)-linkages, with minimal effect on ubiquitin molecules bound through other linkages. In an embodiment, the OTUB Recruiter binds to OTUB1 isoform 1. In an embodiment, the OTUB Recruiter binds to OTUB1 isoform 2. The OTUB1 Recruiter described herein may bind to (e.g., covalently bind to) any cysteine residue within the OTUB1 sequence, e.g., C23, C91, C204, or C212. In some embodiments, the OTUB1 Recruiter does not bind to a catalytic cysteine amino acid within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter binds to an allosteric cysteine amino acid residue within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter binds to a cysteine residue on a surface of OTUB1. In some embodiments, the OTUB1 Recruiter binds to a cysteine residue on or in the interior of OTUB1. In some embodiments, the OTUB1 Recruiter binds to C23 within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter binds to C91 within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter binds to C204 within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter binds to C212 within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter binds preferentially to C23 over another cysteine amino acid residue within the OTUB1 sequence (e.g., C91, C204, or C212). In some embodiments, the OTUB1 Recruiter binds preferentially to C23 over C91 within the OTUB1 sequence. In some embodiments, the OTUB1 Recruiter does not substantially bind to C91 within the OTUB1 sequence. In some embodiments, binding of the DUB Recruiter (e.g., the OTUB1 Recruiter) to OTUB1 does not modulate the activity of OTUB1 more than 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99%, relative to the activity of OTUB1 in the absence of the OTUB1 Recruiter. In some embodiments, binding of the DUB Recruiter (e.g., OTUB1 Recruiter) to C23 within the OTUB1 sequence does not modulate the activity of OTUB1 more than 0.1-50%, 1-50%, 1-25%, 1-10%, 0.1-10%, 1-5%, or 0.1-2%, relative to the activity of the deubiquitinase in the absence of the bifunctional compound. In some embodiments, the binding of the DUB Recruiter (e.g., OTUB1 Recruiter) to OTUB1 does not substantially modulate (e.g., inhibit) the activity (e.g., deubiquitinase activity) of OTUB1. In some embodiments, the binding of the DUB Recruiter (e.g., OTUB1 Recruiter) to C23 within the OTUB1 sequence does not substantially modulate (e.g., inhibit) the activity (e.g., deubiquitinase activity) of OTUB1. In some embodiments, the OTUB1 Recruiter binds to a site other than a catalytic site within OTUB1. In some embodiments, the OTUB1 Recruiter binds to an allosteric site within OTUB1. In some embodiments, binding of the OTUB1 Recruiter to OTUB1 does not modulate the activity of OTUB1 more than 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99%, relative to the activity of OTUB1 in the absence of the OTUB1 Recruiter. In some embodiments, binding of the OTUB1 Recruiter to OTUB1 does not modulate the activity of OTUB1 more than 0.1-50%, 1-50%, 1-25%, 1-10%, 0.1-10%, 1-5%, or 0.1-2%, relative to the activity of OTUB1 in the absence of the OTUB1 Recruiter. In some embodiments, the binding of the OTUB1 Recruiter to OTUB1 does not substantially modulate (e.g., inhibit) the activity (e.g., deubiquitinase activity) of OTUB1. In some embodiments, the OTUB1 Recruiter binds to a site other than a catalytic site within OTUB1. In some embodiments, the OTUB1 Recruiter binds to an allosteric site within OTUB1. In some embodiments, the OTUB1 Recruiter binds to a cysteine amino acid residue within OTUB1. In some embodiments, the OTUB1 Recruiter preferentially binds to an allosteric amino acid residue (e.g., an allosteric cysteine amino acid residue) over a catalytic amino acid residue (e.g., a catalytic cysteine amino acid residue). In some embodiments, the OTUB1 Recruiter does not substantially bind to a cysteine amino acid residue in the catalytic site of OTUB1 (e.g., a catalytic cysteine). In some embodiments, the OTUB1 Recruiter does not substantially bind to cysteine 91 (C91) in OTUB1. In some embodiments, the OTUB1 Recruiter binds preferentially to C23 in OTUB1. In some embodiments, the OTUB1 Recruiter binds preferentially to C212 in OTUB1. In some embodiments, the OTUB1 Recruiter comprises a functional group selected from the group consisting of an amide, heterocyclyl, cycloalkyl, heterocyclyl, cycloalkyl, carbonyl, ester, alkyl, alkenyl, alkynyl, acyl, or acrylamide. In some embodiments, the OTUB1 Recruiter comprises a heterocyclyl (e.g., a piperazinonyl). In some embodiments, the OTUB1 Recruiter comprises an acrylamide moiety. In some embodiments, the OTUB1 Recruiter comprises a heteroaryl (e.g., a furan moiety). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-a): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0-12 R ⁴ ; L ¹ is absent, -O-, C _1–12 alkylene, C _2–12 alkenylene, C _2–12 alkynylene, C _{1– 12} heteroalkyl, wherein each alkylene, alkenylene, and heteroalkyl is optionally substituted with one or more R ⁵ ; each R ¹ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, -OR ^A , -C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 0-12 R ⁵ ; R ² is H, C1–6 alkyl, or an electrophilic moiety (e.g., C2–6 alkenyl); each R ³ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, or -OR ^A , wherein each alkyl, haloalkyl and heteroalkyl is optionally substituted with 1-6 R ⁶ ; or two R ³ are taken together with the atoms to which they are attached to form an oxo, cycloalkyl, or heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted with 1-6 R ⁶ ; each R ⁴ , R ⁵ and R ⁶ is independently C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, oxo, -OR ^A , -C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C , or wherein two of R ⁴ , R ⁵ , or R ⁶ are taken together with the atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^A is H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl; each R ^B and R ^C is independently H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, 4, or 6. In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-b): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0-12 R ⁴ ; L ¹ is -O-, C _1–12 alkylene, C _2–12 alkenylene, C _2–12 alkynylene, C _1–12 heteroalkyl, wherein each alkylene, alkenylene, and heteroalkyl is optionally substituted with one or more R ⁵ ; each R ¹ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, -OR ^A , - C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 0-12 R ⁵ ; R ² is H, C1–6 alkyl, or an electrophilic moiety (e.g., C _2–6 alkenyl); each R ³ is independently C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, or -OR ^A , wherein each alkyl, haloalkyl and heteroalkyl is optionally substituted with 1-6 R ⁶ ; or two R ³ are taken together with the atoms to which they are attached to form an oxo, cycloalkyl, or heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted with 1-6 R ⁶ ; each R ⁴ , R ⁵ and R ⁶ is independently C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, oxo, -OR ^A , -C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C , or wherein two of R ⁴ , R ⁵ , or R ⁶ are taken together with the atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^A is H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C1–6 heteroalkyl, halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl; each R ^B and R ^C is independently H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, 4, or 6. In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-c): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-c): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-b). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-d): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-e): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-f): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-g): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-):h or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-i): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-j): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-k): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-l): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-m): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-n): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a); each of X and Y is independently C(R ⁷ ), N, N(R ^4a ), or O; R ^4a is H, C1–6 alkyl, C1–6 haloalkyl, C1– ₆ heteroalkyl, halo, cyano, -C(O)R ^A ; R ⁷ is H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C ; R ^A , R ^B , and R ^C are as described for Formula (V-a); and wherein the bonds in the ring comprising X and Y are single or double bonds depending on valency. In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-o): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-p): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-q): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z, R ² , R ³ , R ⁵ , n, and subvariables thereof are as described for Formula (V- a), Ring W is cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 0-12 R ⁵ ; and p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-r): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z, L ¹ , R ² , R ³ , n, and subvariables thereof are as described for Formula (V- a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-s): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L ¹ , R ² , R ³ , R ⁴ , n, and subvariables thereof are as described for Formula (V-b). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-t): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z, L ¹ , R ² , R ³ , n, and subvariables thereof are as described for Formula (V- a). In some embodiments, the OTUB1 Recruiter has the structure of Formula (V-u): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z, L ¹ , R ² , R ³ , n, and subvariables thereof are as described for Formula (V- a), and m is 0, 1, 2, or 3. In some embodiments, Ring Z is heteroaryl (e.g., a monocyclic heteroaryl). In some embodiments, Ring Z is a 5-membered heteroaryl (e.g., furanyl). In some embodiments, R ² is an electrophilic moiety. In some embodiments, R ² is H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, azido, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0-12 R ¹⁰ . In some embodiments, R ² is C _2–6 alkenyl (e.g., CH=CH2). In some embodiments, n is 0. In some embodiments, R ² is an electrophilic moiety. In some embodiments, R ² is a structure selected from one of: or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: R ¹⁶ is H, halogen, -CX ¹⁶ ₃ , -CHX16 ₂ , -CH ₂ X ¹⁶ , -CN, -SO _n16 R ^16A , -SO _v16 NR ^16A R ^16B , - NHNR ^16A R ^16B , ONR ^16A R ^16B , - NHC(O)NHNR ^16A R ^16B , -N(O)m16, -NR ^16A R ^16B , -C(O)R ^16A , -C(O)-OR ^16A , -C(O)NR ^16A R ^16B , -OR ^16A , NHC(O)NR ^16A R ^16B , -NR ^16A SO R ^16B , -NR ^16A C( ^{16B 16A 16B 16A 16B 16} 16 2 O)R , -NR C(O)OR , -NR OR , -OCX 3, -OCHX 2, -OCH2X ¹⁶ , C1-6 alkyl, C1-6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0-12 R ²⁵ ; R ¹⁷ is H, halogen, -CX ¹⁷ ₃ , -CHX17 ₂ , -CH ₂ X ¹⁷ , -CN, -SO _n17 R ^17A , -SO _v17 NR ^17A R ^17B , - NHNR ^17A R ^17B , -ONR ^17A R ^17B , -NHC(O)NHNR ^17A R ^17B , - NHC(O)NR ^17A R ^17B , -N(O) _m17 , -NR ^17A R ^17B , -C(O)R ^17A , -C(O)-OR ^17A , -C(O)NR ^17A R ^17B , -OR ^17A , -NR ^17A SO ₂ R ^17B , -NR ^17A C(O)R ^17B , -NR ^17A C(O)OR ^17B , -NR ^17A OR ^17B , -OCX ¹⁷ ₃ , -OCHX17 ₂ , -OCH 2X ¹⁷ , C1-6 alkyl, C1-6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0-12 R ²⁵ ; R ¹⁸ is H, halogen, -CX ¹⁸ ₃ , -CHX18 ₂ , -CH ₂ X ¹⁸ , -CN, -SO _n18 R ^18A , -SOv18NR ^18A R ^18B , -NHNR ^18A R ^18B , -ONR ^18A R ^18B , -NHC(O)NHNR ^18A R ^18B , - NHC(O)NR ^18A R ^18B , -N(O)m18, -NR ^18A R ^18B , -C(O)R ^18A , -C(O)-OR ^18A , -C(O)NR ^18A R ^18B , -OR ^18A , - NR ^18A SO ₂ R ^18B , -NR ^18A C(O)R ^18B , -NR ^18A C(O)OR ^18B , -NR ^18A OR ^18B , -OCX ¹⁸ ₃ , -OCHX18 ₂ , -OCH ₂ X ¹⁸ , C _1-6 alkyl, C _1-6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0-12 R ²⁵ ; R ¹⁹ is H, halogen, -CX ¹⁹ 3, -CHX19 2, -CH2X ¹⁹ , -CN, -SOn19R ^19A , -SO _v19 NR ^19A R ^19B , -NHNR ^19A R ^19B , -ONR ^19A R ^19B , -NHC(O)NHNR ^19A R ^19B , - NHC(O)NR ^19A R ^19B , -N(O)m19, -NR ^19A R ^19B , -C(O)R ^19A , -C(O)-OR ^19A , -C(O)NR ^19A R ^19B , -OR ^19A , -NR ^19A SO2R ^19B , -NR ^19A C(O)R ^19B , -NR ^19A C(O)OR ^19B , -NR ^19A OR ^19B , -OCX ¹⁹ 19 3, -OCHX 2, -OCH ₂ X ¹⁹ , C _1-6 alkyl, C _1-6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is substituted with 0-12 R ²⁵ ; H, -CX ₃ , -CHX ₂ , -CH ₂ X, -CN, -OH, -COOH, -CONH ₂ , C _1-6 alkyl, C _1-6 heteroalkyl, cycloalkyl, heterocyclyl, aryl; or R ^16A and R ^16B substituents bonded to the same nitrogen atom may optionally be joined to form a heterocyclyl or heteroaryl; R ^17A and R ^17B substituents bonded to the same nitrogen atom may optionally be joined to form a heterocyclyl or heteroaryl; R ^18A and R ^18B substituents bonded to the same nitrogen atom may optionally be joined to form a heterocyclyl or heteroaryl; R ^19A and R ^19B substituents bonded to the same nitrogen atom may optionally be joined to form a heterocyclyl or heteroaryl; each X, X ¹⁶ , X ¹⁷ , X ¹⁸ , and X ¹⁹ is independently –F, -Cl, -Br, or –I; n16, n17, n18, and n19 are independently an integer from 0 to 4; and m16, m17, m18, m19, v16, v17, v18, and v19 are independently 1 or 2. In some embodiments, R ² is selected from the group consisting of: , , , , , , , , , , , , , , , , , , wherein the electrophilic moiety is bound to the structure of Formula (V-a) at any position. In some embodiments, the DUB Recruiter is compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Table 1: Exemplary DUB Recruiters 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 In some embodiments, the DUB Recruiter is Compound 100 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 101 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 102 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 103 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 104 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 105 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 106 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 107 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 108 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 109 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 110 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 111 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 112 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 113 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 114 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 115 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 116 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 117 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 118 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 119 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 120 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 121 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 122 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 123 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 124 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 125 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 126 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 127 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 128 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 129 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 130 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 131 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 133 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 134 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 135 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 136 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 137 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 138 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 139 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 140 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 141 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 142 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 143 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 144 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 145 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 146 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 147 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 148 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 149 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 150 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 151 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 152 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 153 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 154 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 155 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 156 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 157 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 158 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 159 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 160 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 161 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 162 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 163 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 164 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 165 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 166 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 168 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 169 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 170 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 171 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 172 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 173 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 174 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 175 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 176 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 177 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 178 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 179 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 180 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 181 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 182 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 183 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 184 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 185 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 186 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 187 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 188 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 189 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 190 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 191 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 192 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 193 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the DUB Recruiter is Compound 194 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Target Proteins In one aspect, the disclosure provides a bifunctional compound or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is capable of binding to a target protein (e.g., a target protein described herein). The target protein may be any class of protein, for example, any protein found in a cell (e.g., a mammalian cell, a plant cell, a fungal cell, an insect cell, a bacterial cell) or a viral particle. In some embodiments, the protein is a soluble protein or a membrane protein. In some embodiments, the protein is a soluble protein. In some embodiments, the protein is a membrane protein. The target protein may comprise a post-translational modification, e.g., a sugar moiety, acyl moiety, lipid moiety. In some embodiments, the target protein is glycosylated, e.g., at an asparagine, serine, threonine, tyrosine, or tryptophan residue. Exemplary target proteins include enzymes (e.g., kinases, hydrolases, phosphatases, ligases, isomerases, oxidoreductases), receptors, membrane channels, hormones, transcription factors, tumor suppressors, ion channels, apoptotic factors, oncogenic proteins, epigenetic regulators, or a fragment thereof. In some embodiments, the target protein is an enzyme (e.g., a kinase or phosphatase). In some embodiments, the target protein is a kinase (e.g., PKN1, BCR, MAP4K4, TYK2, MAP4K2, EPHB4, MAP4K5, MAP3K2, DDR1, TGFBR1, RIPK2, TNK1, LYN, STK10, PKMYT1, LYN, EGFR, EPHA1, GAK, SIK2, MAP2K2, SLK, PRKACB, EPHA2, WEE1, or glucokinase). In some embodiments, the target protein is a tumor suppressor kinase (e.g., WEE1). In some embodiments, the target protein is WEE1 or a fragment thereof. In some embodiments, the target protein is a ligase (e.g., an E3 ligase, e.g., MDM2). In some embodiments, the target protein is a receptor. In some embodiments, the target protein is a transcription factor (e.g., MYC). In some embodiments, the target protein is a hormone. In some embodiments, the target protein is a tumor suppressor (e.g., TP53, AXIN1, BAX, CDKN1A, CKDN1C, PTEN, or SMAD4). In some embodiments, the target protein is related to a genetic disorder (e.g., SMN1/2, GLUT1, CFTR, phenylalanine hydroxylase (PAH), fumarylacetoacetate hydrolase (FAH), or acid alpha-glucosidase (GAA)). In some embodiments, the target protein is a membrane channel (e.g., CFTR). In some embodiments, the target protein is CFTR or a fragment thereof. In some embodiments, the CFTR comprises a sequence mutation (e.g., a Class I, Class II, Class III, Class IV, or Class V mutation). In some embodiments, the CFTR, SMN1/2, GLUT1, PAH, FAH, or GAA comprises a sequence mutation, e.g., an addition mutation, deletion mutation, or substitution mutation (e.g., ΔF508-CFTR). In some embodiments, the CFTR comprises a sequence mutation selected from the group consisting of G551D, R177H, and A445E. In some embodiments, the target protein is BAX or a fragment thereof. In some embodiments, the target protein is STING or a fragment thereof In some embodiments, the target protein is modified with a ubiquitin or a ubiquitin-like protein (collectively referred to herein as “Ubls”). In some embodiments, the Ubl is ubiquitin. In some embodiments, the Ubl is SUMO, NEDD8, or Agp12. In some embodiments, the target protein is monoubiquitinated or polyubiquitinated. The target protein may contain at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Ubl chains, e.g., on a lysine amino acid residue. The target protein may comprise polyubiquitin chains linked in any manner, for example, K48-linked polyubiquitin chains, K63-linked polyubiquitin linked chains, K29-linked polyubiquitin chains, or K33-linked polyubiquitin chains. In some embodiments, the target protein comprises a plurality of polyubiquitin chains. In some embodiments, the target protein comprising a Ubl is capable of binding to a protein comprising a Ubl-binding domain (e.g., a ubiquitin binding domain). The target protein may comprise a feature that increases its instability or impairs its activity, e.g., relative to the wild-type target protein. For example, the target protein may be mutated or misfolded. In some embodiments, the target protein has a reduced capacity for binding to a binding partner, e.g., by about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% relative to the wild type target protein. In some embodiments, the target protein is less active than the wild type target protein, e.g., by about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99%. In some embodiments, the target protein is more active than the wild type target protein, e.g., by about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99%. Deubiquitinases Described herein are bifunctional compounds comprising a moiety capable of binding to a deubiquitinase (DUB). Deubiquitinases comprise a large family of proteases responsible for hydrolyzing Ubl-Ubl bonds or Ubl-target protein bonds and play a role in numerous cellular processes. Deubiquitinases serve several functions, including generating free ubiquitin monomers from polyubiquitin chains, modulating the size of polyubiquitin chains, and reversing ubiquitin signaling by removal of a from a ubiquitinated target protein. Misregulation of deubiquitinase function is associated with many diseases, including cancer, metabolic diseases, genetic disorders, haploinsufficiency targets, and neurological diseases. Roughly 80 different functional deubiquitinases have been identified in human cells to date. The present disclosure features bifunctional compounds comprising a DUB Recruiter capable of binding to a deubiquitinase. The deubiquitinase may be any deubiquitinase, e.g., in a cell, including cysteine protease deubiquitinases and metalloprotease deubiquitinases. In some embodiments, the deubiquitinase is a cysteine protease, e.g., comprising a catalytic site cysteine amino acid residue. The deubiquitinase may be a full-length protein or a fragment thereof. In some embodiments, the deubiquitinase comprises a single active site. In other embodiments, the deubiquitinase is one function of a multifunctional protein. Exemplary deubiquitinases include BAP1, CYLD, OTUB1, OTUB2, OTUD3, OTUD5, OTUD7A, OTUD7B, TNFAIP3, UCHL1, UCHL3, UCHL5, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17L1, USP17L2, USP17L24, USP17L3, USP17L5, USP18, USP19, USP2, USP20, USP21, USP22, USP24, USP25, USP26, USP27X, USP28, USP3, USP30, USP31, USP33, USP34, USP35, USP36, USP37, USP38, USP4, USP40, USP41, USP42, USP43, USP44, USP45, USP46, USP47, USP48, USP49, USP5, USP50, USP51, USP54, USP7, USP8, USP9X, VCPIP1, WDR48, YOD1, ZRANB1, and ZUP1, or a fragment or variant thereof. In some embodiments, the deubiquitinase is selected from the group consisting of WDR48, YOD1, OYUD3, OTUB1, USP8, USP5, USP16, UCHL3, UCHL1, and USP14, or a fragment thereof. In some embodiments, the deubiquitinase is OTUB1 or a fragment or variant thereof. The bifunctional compounds of the present disclosure may bind to OTUB1 in a covalent or non- covalent manner. In some embodiments, the bifunctional compound (e.g., the OTUB1 Recruiter) binds to a site other than a catalytic site within OTUB1. In some embodiments, the bifunctional compound (e.g., the OTUB1 Recruiter) binds to an allosteric site within OTUB1. In some embodiments, binding of the bifunctional compound (e.g., the OTUB1 Recruiter) to OTUB1 does not modulate the activity of OTUB1 more than 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99%, relative to the activity of OTUB1 in the absence of the bifunctional compound. In some embodiments, binding of the bifunctional compound (e.g., the OTUB1 Recruiter) to OTUB1 does not modulate the activity of OTUB1 more than 0.1-50%, 1-50%, 1-25%, 1-10%, 0.1-10%, 1-5%, or 0.1-2%, relative to the activity of OTUB1 in the absence of the bifunctional compound. In some embodiments, the binding of the bifunctional compound (e.g., the OTUB1 Recruiter) to OTUB1 does not substantially modulate (e.g., inhibit) the activity (e.g., OTUB1 activity) of OTUB1. The bifunctional compound (e.g., a bifunctional compound described herein) is capable of binding to a cysteine amino acid residue (e.g., a thiol moiety), e.g., within OTUB1. In some embodiments, the cysteine amino acid residue is an allosteric cysteine amino acid residue. In some embodiments, the cysteine amino acid residue is present on a surface of OTUB1. In some embodiments, the cysteine amino acid residue is present on or in the interior of OTUB1. In some embodiments, the cysteine amino acid residue is not a catalytic cysteine amino acid residue. In some embodiments, the bifunctional compound preferentially binds to an allosteric cysteine amino acid residue over a catalytic cysteine amino acid residue. In some embodiments, the bifunctional compound does not substantially bind to a cysteine amino acid residue in the catalytic site of OTUB1 (e.g., a catalytic cysteine). Pharmaceutically Acceptable Salts Pharmaceutically acceptable salts of the compounds described herein are also contemplated for the uses described herein. As used herein, the terms “salt” or “salts” refer to an acid addition or base addition salt of a compound described herein. “Salts” include in particular “pharmaceutical acceptable salts.” The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds disclosed herein and, which typically are not biologically or otherwise undesirable. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. In some embodiments, the bifunctional compound of Formula (I) is provided as an acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate, or xinafoate salt form. Pharmaceutical Compositions Another embodiment is a pharmaceutical composition comprising one or more compounds described herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more pharmaceutically acceptable carrier(s). The term “pharmaceutically acceptable carrier” refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions of the disclosure are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions 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 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 di- glycerides. 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, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutically acceptable compositions of this disclosure may also 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 conventional solubilizing or dispersing agents. The amount of the compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01–100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. Isotopically Labelled Compounds A compound described herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ² H, 3H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example, those into which radioactive isotopes, such as ³ H and ¹⁴ C, or those into which non-radioactive isotopes, such as ² H and ¹³ C are present. Such isotopically labelled compounds are useful in metabolic studies (with ¹⁴ C), reaction kinetic studies (with, for example ² H or ³ H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue ^{distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled} compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds described herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. Further, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound described herein or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound described herein is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Dosages Toxicity and therapeutic efficacy of compounds described herein, including pharmaceutically acceptable salts and deuterated variants, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The LD50 is the dose lethal to 50% of the population. The ED50 is the dose therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects (LD ₅₀ /ED ₅₀ ) is the therapeutic index. Compounds that exhibit large therapeutic indexes are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and thereby reduce side effects. Data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds may lie within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC ₅₀ (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. Methods of Use In one aspect, the present disclosure features a method of modulating a target protein, e.g., a target protein described herein, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the modulating comprises one or more of: (i) modulating the folding of the target protein; (ii) modulating the half-life of the target protein; (iii) modulating trafficking of the target protein to the proteasome; (iv) modulating the level of ubiquitination of the target protein; (v) modulating degradation (e.g., proteasomal degradation) of the target protein; (vi) modulating target protein signaling; (vii) modulating target protein localization; (viii) modulating trafficking of the target protein to the lysosome; (ix) modulating trafficking of the target protein to the ER, Golgi, vesicle, plasma membrane; (x) modulating target protein interactions with another protein (e.g., other proteins in the UPS); (xi) modulating posttranslational modifications of the target protein (e.g., SUMOlyation, phosphorylation, glycosylation). In another aspect, the present disclosure features a method of stabilizing a target protein, e.g., a target protein described herein, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the stabilizing comprises increasing the half-life of a target protein or removal of a Ubl from a target protein, e.g., compared to a reference standard. In some embodiments, the stabilizing improves the function of a target protein. In another aspect, the present disclosure features a method of forming a protein complex comprising a deubiquitinase, e.g., a deubiquitinase described herein, and a target protein, upon administration of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the protein complex is formed in vitro (e.g., in a sample) or in vivo (e.g., in a cell or tissue, e.g., in a subject). Formulation of the protein complex may be observed and characterized by any method known in the art, e.g., mass spectrometry (native mass spectrometry) or SDS PAGE. In some embodiments, forming the protein complex modulates the level of a target protein, e.g., increases the half-life of the target protein, e.g., compared to a reference standard. In some embodiments, forming the protein enhances removal of a Ubl from the target protein, e.g., compared to a reference standard. In some embodiments, the deubiquitinase is OTUB1. In some embodiments, the target protein comprises CFTR. Another embodiment is a method for removing a Ubl (e.g., a ubiquitin or ubiquitin-like protein) from a target protein, e.g., a target protein described herein, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another aspect, the present disclosure provides a method of maintaining, improving, or increasing the activity of a target protein, e.g., a target protein described herein, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In an embodiment, maintaining, improving, or increasing the activity of a target protein comprises recruiting a deubiquitinase (e.g., a deubiquitinase of Table 1) with the bifunctional compound described herein (e.g., the DUB Recruiter within the bifunctional compound), e.g., a compound of Formula (I), forming a ternary complex of the target protein, the bifunctional compound, and the deubiquitinase, to thereby maintain, improve, or increase the activity of the target protein. In another aspect, the present disclosure features a method of treating or preventing a disease, disorder or condition mediated by a target protein, e.g., a target protein described herein, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the disease, disorder, or condition is selected from the group consisting of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a metabolic disorder, a neurological disorder, and an infectious disease. In some embodiments, the disease, disorder, or condition is selected from the group consisting of a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease. In some embodiments, the disease, disorder, or condition comprises a respiratory disorder. In some embodiments, the disease, disorder, or condition comprises a proliferative disorder. In some embodiments, the disease, disorder, or condition comprises an autoinflammatory disorder. In some embodiments, the disease, disorder, or condition comprises an inflammatory disorder. In some embodiments, the disease, disorder, or condition comprises a metabolic disorder. In some embodiments, the disease, disorder, or condition comprises a neurological disorder. In some embodiments, the disease, disorder, or condition comprises an infectious disease. In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the disease, disorder, or condition is cystic fibrosis. In some embodiments, the disease, disorder, or condition is diabetes (e.g., maturity-onset diabetes of the young type 2, MODY2). In another aspect, the disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting or modulating a target protein in a subject in need thereof. Another embodiment is a use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating or preventing a respiratory disorder, a proliferative disorder, an autoimmune disorder, an autoinflammatory disorder, an inflammatory disorder, a neurological disorder, and an infectious disease or disorder in a subject in need thereof. ENUMERATED EMBODIMENTS 1. A bifunctional compound of Formula (I-c): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 2. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 1, wherein the CFTR is mutated or misfolded. 3. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the CFTR is ubiquitinated (e.g., polyubiquitinated). 4. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the CFTR is ΔF508-CFTR. 5. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter covalently binds to OTUB1. 6. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to a site other than a catalytic site within OTUB1. 7. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to an allosteric site within OTUB1. 8. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to a cysteine amino acid residue within OTUB1. 9. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 8, wherein the cysteine amino acid residue is an allosteric cysteine amino acid residue. 10. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter preferentially binds to an allosteric amino acid residue (e.g., an allosteric amino acid residue) over a catalytic amino acid residue (e.g., a catalytic cysteine amino acid residue). 11. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter does not substantially bind to a cysteine amino acid residue in the catalytic site of OTUB1 (e.g., a catalytic cysteine). 12. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 10, wherein OTUB1 Recruiter binds to cysteine 23 (C23) within the OTUB1 sequence. 13. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 11-12, wherein OTUB1 Recruiter binds preferentially to cysteine 23 (C23) over cysteine 91 (C91) within the OTUB1 sequence. 14. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 10-12, wherein the OTUB1 Recruiter does not substantially bind to cysteine 91 (C91) within the OTUB1 sequence. 15. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the CFTR Ligand binds to (e.g., covalently binds to) CFTR, or a mutant, fragment, or isoform thereof. 16. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the CFTR Ligand is capable of modulating CFTR, or a mutant, fragment, or isoform thereof. 17. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 16, wherein the modulating comprises one or more of: (i) modulating the folding of the target protein; (ii) modulating the half-life of the target protein; (iii) modulating trafficking of the target protein to the proteasome; (iv) modulating the level of ubiquitination of the target protein; (v) modulating degradation (e.g., proteasomal degradation) of the target protein; (vi) modulating target protein signaling; (vii) modulating target protein localization; (viii) modulating trafficking of the target protein to the lysosome; (ix) modulating trafficking of the target protein to the ER, Golgi, vesicle, plasma membrane; (x) modulating target protein interactions with another protein (e.g., other proteins in the UPS); and (xi) modulating posttranslational modifications of the target protein (e.g., SUMOlyation, phosphorylation, glycosylation). 18. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (i). 19. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (ii). 20. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (iii). 21. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (iv). 22. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (v). 23. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (vi). 24. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (vii). 25. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (viii). 26. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (ix). 27. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (x). 28. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising (xi). 29. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 17, comprising each of (i)-(xi). 30. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the CFTR Ligand has the structure of Formula (II-a): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, ^{cyano, -ORA, -C(O)N(RB)(RC), or -N(RB)CO(RD);} R ^7a and R ^7b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, or halo; R ^7c is H or C1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and denotes the point of attachment to L1 in Formula (I). 31. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to embodiment 30, wherein each of X and Z is independently O. 32. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 30-31, wherein Y is C(R ^7a )(R ^7b ). 33. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 30-32, wherein each of R ^7a and R ^7b is independently halo (e.g., fluoro). 34. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 30-33, wherein each of R ^3a , R ^3b , R ^4a , R ^4b is independently H. 35. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 30-34, wherein R ¹ is H. 36. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 30-35, wherein each of p and q is 0. 37. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the CFTR Ligand has the structure of Formula (II-f): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein denotes the point of attachment to L1 in Formula (I). 38. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the bifunctional compound of Formula (I-c) has the structure (II-l): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: X and Z are each independently O, S, or C(R ^7a )(R ^7b ); Y is C(R ^7a )(R ^7b ) or NR ^7c ; R ¹ is H or C1–6 alkyl; R ^3a , R ^3b , R ^4a , R ^4b are each independently H, C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, cyano, or -OR ^A ; each R ⁵ , R ^5’ , and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, -OR ^A , -C(O)N(R ^B )(R ^C ), or -N(R ^B )CO(R ^D ); R ^7a and R ^7b are each independently H, C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, or halo; R ^7c is H or C1–6 alkyl; R ^A , R ^B , R ^C , and R ^D are each independently H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C _1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; p’ is 0, 1, 2, 3, or 4; q is 0, 1, 2, or 3; and L1 and OTUB Recruiter are as defined in claim 1. 39. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to (e.g., covalently binds to) OTUB1. 40. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the binding of the OTUB1 Recruiter to OTUB1 does not substantially inhibit the activity of OTUB1. 41. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to a site other than a catalytic site within OTUB1. 42. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to an allosteric site within OTUB1. 43. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to a cysteine amino acid residue within OTUB1. 44. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter preferentially binds to an allosteric amino acid residue (e.g., an allosteric amino acid residue) over a catalytic amino acid residue (e.g., a catalytic cysteine amino acid residue). 45. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter does not substantially bind to a cysteine amino acid residue in the catalytic site of OTUB1 (e.g., a catalytic cysteine). 46. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter comprises an acrylamide moiety. 47. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter comprises a furan moiety. 48. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter has the structure of Formula (V-a): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted with 0- 12 R ⁴ ; L ¹ is absent, -O-, C1–12 alkylene, C2–12 alkenylene, C2–12 alkynylene, C1–12 heteroalkyl, wherein each alkylene, alkenylene, and heteroalkyl is optionally substituted with one or more R ⁵ ; each R ¹ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, -OR ^A , - C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 0-12 R ⁵ ; R ² is H, C1–6 alkyl, or an electrophilic moiety (e.g., C2–6 alkenyl); each R ³ is independently C _1–6 alkyl, C _1–6 haloalkyl, C _1–6 heteroalkyl, halo, or -OR ^A , wherein each alkyl, haloalkyl and heteroalkyl is optionally substituted with 1-6 R ⁶ ; or two R ³ are taken together with the atoms to which they are attached to form an oxo, cycloalkyl, or heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted with 1-6 R ⁶ ; each R ⁴ , R ⁵ and R ⁶ is independently C1–6 alkyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cyano, oxo, -OR ^A , -C(O)R ^A , -C(O)OR ^A , -NR ^B R ^C , -NR ^B C(O)R ^A , -C(O)NR ^B R ^C , or wherein two of R ⁴ , R ⁵ , or R ⁶ are taken together with the atoms to which they are attached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^A is H, C1–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C1–6 haloalkyl, C1–6 heteroalkyl, halo, cycloalkyl, heterocyclyl, aryl, or heteroaryl; each R ^B and R ^C is independently H, C _1–6 alkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _1–6 haloalkyl, C1–6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and n is 0, 1, 2, 3, 4, or 6. 49. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to claim 48, wherein Ring Z is heteroaryl (e.g., a monocyclic heteroaryl). 50. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 48-49, wherein Ring Z is a 5-membered heteroaryl (e.g., furanyl). 51. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of embodiments 48-50, wherein Ring Z is selected from the following group: , , , , 52. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according any one of embodiments 48-51, wherein Ring Z is selected from 53. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according any one of embodiments 48-52, wherein L ¹ is absent, C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, 54. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according any one of embodiments 48-53, wherein L ¹ is absent or C1-6 alkylene. 55. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according any one of embodiments 48-54, wherein R ¹ is absent, aryl, heteroaryl, -C(O)OR ^A , -C(O)NH-R ^C , -OR ^A , or -NR ^B R ^C . 51. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according any one of embodiments 48-50, wherein R ² is an electrophilic moiety. 52. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according any one of embodiments 48-51, wherein R ² is C _2–6 alkenyl (e.g., CH=CH2). 53. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter has the structure of Formula (V-p): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Ring Z, R ² , R ³ , R ⁵ , n, and subvariables thereof are as described for Formula (V- a), Ring W is cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 0-12 R ⁵ ; and p is 0, 1, 2, 3, 4, 5, or 6. 54. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds to cysteine 23 (C23) within the OTUB1 sequence. 55. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter binds preferentially to cysteine 23 (C23) over cysteine 91 (C91) within the OTUB1 sequence. 56. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the OTUB1 Recruiter does not substantially bind to cysteine 91 (C91) within the OTUB1 sequence. 57. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein L1 is a non-cleavable linker. 58. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein L1 comprises an alkylene or heteroalkylene. 59. The bifunctional compound or pharmaceutically acceptable salt hydrate, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, wherein the bifunctional compound of Formula (I-c) is selected from a bifunctional compound provided in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. 60. A pharmaceutical composition comprising a bifunctional compound, or pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof according to any one of the preceding embodiments, and one or more pharmaceutically acceptable carriers. 61. A composition for use in providing a compound to a subject, wherein the composition comprises a bifunctional compound of Formula (I): (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 62. A composition for use in treating a disease, disorder, or condition in a subject, comprising a bifunctional compound of Formula (I): (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 63. The composition for use of claim 62, wherein administering the composition ameliorates a symptom or element of the disease, disorder, or condition. 64. The composition for use of any one of embodiments 62-63, wherein the disease, disorder, or condition is cystic fibrosis. 65. A composition for use in treating cystic fibrosis in a subject, comprising a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 66. A composition for use in modulating a protein in a cell or subject comprising a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 67. A composition for use in recruiting a deubiquitinase to a target protein in a cell or subject, wherein the composition comprises a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 68. The composition for use of embodiment 67, wherein the deubiquitinase is OTUB1. 69. A composition for use in deubiquitinating a protein comprising a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1. 70. A method of treating a disease, disorder, or condition in a subject, wherein the method comprises administering to the subject a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1, thereby treating disease, disorder, or condition in the subject 71. The method of embodiment 70, wherein the method comprises ameliorating a symptom or element of the disease, disorder, or condition. 72. The method of any one of embodiments 70-71, wherein the disease, disorder, or condition is cystic fibrosis. 73. A method of treating cystic fibrosis in a subject, the method comprising administering to the subject a bifunctional compound of Formula (I): (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1, thereby treating cystic fibrosis. 74. A method of modulating a protein in a cell or subject comprising contacting the cell or administering to the subject a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1, thereby modulating a protein in a cell or subject. 75. A method of recruiting a deubiquitinase to a target protein comprising contacting a mixture (e.g., in a cell or sample) with a bifunctional compound of Formula (I): (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1, thereby recruiting a deubiquitinase to a target protein in a mixture, e.g., a cell or subject. 76. A method of deubiquitinating a protein comprising contacting a cell or sample with a bifunctional compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein: (i) the CFTR Ligand comprises a moiety capable of binding to the cystic fibrosis transmembrane conductance regulator (CFTR), or a mutant, fragment, or isoform thereof; (ii) L1 comprises a linker; and (iii) the OTUB1 Recruiter comprises a moiety capable of binding to the deubiquitinase OTUB1, thereby deubiquitinating a protein in a cell or subject. EXAMPLES The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims. Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. General Methods Cell Culture CFBE41o-4.7 ΔF508-CFTR Human CF Bronchial Epithelial cells were purchased from Millipore Sigma (SCC159). CFBE41o-4.7 ΔF508-CFTR Human CF Bronchial Epithelial cells were cultured in MEM (Gibco) containing 10% (v/v) fetal bovine serum (FBS) and maintained at 37 °C with 5% CO2. Synthesis of exemplary DUB Recruiters and bifunctional compounds Chemical Synthesis and Characterization Starting materials, reagents and solvents were purchased from commercial suppliers and were used without further purification unless otherwise noted. All reactions were monitored by thin layer chromatography. Reaction products were purified by flash column chromatography.1H NMR spectra were recorded on a 400 MHz Bruker Avance spectrometer . Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane (TMS). Coupling constants (J) are reported in Hz. Spin multiplicities are described as br (broad), s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). Lumacaftor was purchased from Medchemexpress. Preparative HPLC purification: prep-HPLC purification was performed using one of the following HPLC conditions: Condition 1: Column, Phenomenex C1880*40mm*3um; Mobile Phase A: water(NH ₄ HCO ₃ ); Mobile Phase B: MeCN; Gradient a: 1% B to 30% B in 8 min; Gradient b: 20% B to 55% B in 8 min; Gradient c: 1% B to 20% B in 8 min; Gradient d: 15% B to 45% B in 8 min; Gradient e: 5% B to 35% B in 8 min; Gradient f: 15% B to 50% B in 8 min; Gradient g: 30% B to 60% B in 8 min; Gradient h: 10% B to 35% B in 8 min; Condition 2: Column, Waters Xbridge BEH C18100*30 mm*10 um; Mobile Phase A: water(10 mM NH4HCO3); Mobile Phase B: MeCN; Gradient a: 15% B to 45% B in 8 min; Gradient b: 1% B to 27% B in 8 min; Gradient c: 20% B to 50% B in 8 min; Gradient d: 1% B to 15% B in 8 min; Gradient e: 2% B to 40% B in 8 min; Gradient f: 25% B to 55% B in 8 min; Gradient g: 5% B to 35% B in 8 min; Gradient h: 1% B to 35% B in 8 min; Gradient i: 10% B to 40% B in 8 min; Condition 3: Column, Welch Xtimate C18250*70mm*10um; Mobile Phase A: water(NH4HCO3); Mobile Phase B: MeCN; Gradient a: 25% B to 55% B in 20 min; Gradient b: 20% B to 55% B in 20 min; Gradient c: 45% B to 75% B in 20 min; Condition 4: Column, Waters Xbridge Prep OBD C18150*40 mm*10 um; Mobile Phase A: water (10 mM NH ₄ HCO ₃ ); Mobile Phase B: MeCN; Gradient a: 15% B to 65% B in 8 min; Gradient b: 5% B to 40% B in 8 min; Gradient c: 20% B to 50% B in 8 min; Gradient d: 1% B to 30% B in 8 min; Gradient e: 10% B to 45% B in 8 min; Gradient f: 25% B to 55% B in 8 min; Gradient g: 25% B to 65% B in 8 min; Gradient h: 30% B to 60% B in 8 min; Gradient i: 20% B to 60% B in 8 min; Gradient j: 40% B to 70% B in 8 min; Condition 5: Column, Phenomenex C1875*30mm*3um; Mobile Phase A: water (NH ₄ HCO ₃ ); Mobile Phase B: MeCN; Gradient a: 5% B to 35% B in 8 min; Gradient b: 1% B to 20% B in 8 min, Mobile Phase A: water (NH ₃ H ₂ O+NH ₄ HCO ₃ ); Gradient c: 1% B to 15% B in 8 min; Gradient d: 1% B to 30% B in 8 min; Condition 6: Column, Waters Xbridge BEH C18250*50 mm*10 um; Mobile Phase A: water(10 mM NH ₄ HCO ₃ ); Mobile Phase B: MeCN; Gradient a: 25% B to 45% B in 10 min; Gradient b: 1% B to 20% B in 8 min; Gradient c: 1% B to 40% B in 10 min; Gradient d: 1% B to 30% B in 10 min; Condition 7: Column: Phenomenex Luna C1875*30 mm*3um; Mobile Phase A: water(FA); Mobile Phase B: ACN; Gradient a: 1% B to 25% B in 8 min; Gradient b: 1% B to 35% B in 8 min; Gradient c: 5% B to 45% B in 8 min; Gradient d: 5% B to 35% B in 8 min; Gradient e: 1% B to 20% B in 8 min; Condition 8: Column: Phenomenex Luna C18200*40 mm*10um; Mobile Phase A: water(FA); Mobile Phase B: ACN; Gradient a: 1% B to 28% B in 8 min; Condition 9: Column: Phenomenex Luna C18100*30 mm*3um; Mobile Phase A: water(FA); Mobile Phase B: ACN; Gradient a: 5% B to 35% B in 8 min; Gradient b: 25% B to 55% B in 8 min; Gradient c: 1% B to 30% B in 8 min; Gradient d: 1% B to 20% B in 8 min; Gradient e: 20% B to 50% B in 8 min. Example 1: Synthesis of Compound 100 Step 1: tert-butyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazine-1-carboxylate To a solution of 2-bromoimidazo[1,2-a]pyridine (A1, 300 mg, 1.5 mmol, 1 eq) and tert- butyl 3-oxopiperazine-1-carboxylate (A2, 305 mg, 1.5 mmol, 1 eq) in dioxane (4 mL) was added CuI (116 mg, 609 µmol, 0.4 eq), N,N'-dimethylethane-1,2-diamine (107 mg, 1.2 mmol, 131 uL, 0.8 eq) and K ₂ CO ₃ (421 mg, 3.05 mmol, 2 eq), and the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was quenched by addition of 12 mL H ₂ O, then extracted with ethylene acetate (6 mL x3). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (50% EtOAc in PE) to give tert-butyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo- piperazine-1-carboxylate (A3, 250 mg, 790 µmol, 52% yield) as an oil. MS (ESI) m/z 316.1 [M+H] ⁺ . Step 2: 1-(imidazo[1,2-a]pyridin-2-yl)piperazin-2-one To a solution of tert-butyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazine-1-carboxylate (A3, 230 mg, 727 µmol, 1 eq) in DCM (5 mL) was added trifluoroacetic acid (TFA, 1.77 g, 15.5 mmol, 1.15 mL, 21.4 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 1-imidazo[1,2-a]pyridin-2-ylpiperazin- 2-one (A4, 170 mg, crude) as an oil. MS (ESI) m/z 217.1 [M+H] ⁺ . Step 3: 1-imidazo[1,2-a]pyridin-2-yl-4-prop-2-enoyl-piperazin-2-one To a solution of 1-imidazo[1,2-a]pyridin-2-ylpiperazin-2-one (A4, 160 mg, 740 µmol, 1 eq) in DCM (2 mL) was added triethylamine (TEA, 224.6 mg, 2.2 mmol, 309 uL, 3 eq) and prop- 2-enoyl chloride (73.7 mg, 814 µmol, 66.4 uL, 1.1 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition 0.5 mL of H2O at 0 °C, and then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 1, Gradient a) to give 1-imidazo[1,2-a]pyridin-2-yl-4-prop-2-enoyl-piperazin-2-one (Compound 100, 71 mg, 263 umol) as a solid. MS (ESI) m/z 271.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.55 (td, J = 1.1, 6.8 Hz, 1H), 8.31 (s, 1H), 7.49 (dd, J = 0.6, 9.0 Hz, 1H), 7.24 (ddd, J = 1.3, 6.9, 9.0 Hz, 1H), 6.90 (dt, J = 1.1, 6.8 Hz, 1H), 6.79 (dd, J = 10.5, 16.8 Hz, 1H), 6.18 (dd, J = 2.3, 16.8 Hz, 1H), 5.74 (dd, J = 2.3, 10.5 Hz, 1H), 4.39 (br s, 2H), 4.27 - 4.14 (m, 2H), 3.94 (br t, J = 5.4 Hz, 2H). An analogous method was followed to obtain the following compounds. Example 2: Synthesis of Compound 102 Step 1: tert-butyl 3-oxo-4-(2-phenyloxazol-5-yl)piperazine-1-carboxylate To a solution of 5-bromo-2-phenyl-oxazole (A8, 200 mg, 893 µmol, 1 eq), tert-butyl 3- oxopiperazine-1-carboxylate (A2, 178.7 mg, 893 µmol, 1 eq) in dioxane (2 mL) was added CuI (25.5 mg, 134 µmol, 0.15 eq), K ₂ CO ₃ (370 mg, 2.7 mmol, 3 eq) and N,N'-dimethylethane-1,2- diamine (19.7 mg, 223 µmol, 24 uL, 0.25 eq), and the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H2O 5 mL, and then extracted with EtOAc (3 mL x3). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (33% EtOAc in Petroleum ether) to give tert-butyl 3-oxo-4-(2-phenyloxazol- 5-yl)piperazine-1-carboxylate (A9, 130 mg, 379 umol) as a solid. MS (ESI) m/z 344.1 [M+H] ⁺ . Step 2: 1-(2-phenyloxazol-5-yl)piperazin-2-one To a solution of tert-butyl 3-oxo-4-(2-phenyloxazol-5-yl)piperazine-1-carboxylate (A9, 100 mg, 291 µmol, 1 eq) in DCM (1 mL) was added TFA (513.3 mg, 4.5 mmol, 333.3 uL, 15.5 eq) at 0 °C, The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The mixture was used for the next steps without purification. A10 (1-(2-phenyloxazol-5-yl)piperazin-2-one (90 mg, crude)) was obtained as an oil. MS (ESI) m/z 244.1 [M+H] ⁺ . Step 3: 4-acryloyl-1-(2-phenyloxazol-5-yl)piperazin-2-one To a solution of 1-(2-phenyloxazol-5-yl)piperazin-2-one (A10, 85 mg, 349.4 µmol, 1 eq) in DCM (1.5 mL) was added TEA (106 mg, 1.05 mmol, 146 uL, 3 eq) and prop-2-enoyl chloride (34.8 mg, 384 µmol, 31.3 uL, 1.1 eq) at 0 °C. The mixture was stirred at 0 °C for 20 min. Upon completion, the reaction mixture was quenched by addition H2O 0.5 mL at 0 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient c) to afford Compound 102 (1-(2-phenyloxazol-5-yl)-4-prop-2-enoyl- piperazin-2-one, 60 mg, 201 umol) as a solid. MS (ESI) m/z 298.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.00 - 7.91 (m, 2H), 7.57 - 7.48 (m, 3H), 7.23 (s, 1H), 6.80 (dd, J = 10.5, 16.8 Hz, 1H), 6.19 (dd, J = 2.1, 16.8 Hz, 1H), 5.76 (dd, J = 2.2, 10.6 Hz, 1H), 4.42 (s, 2H), 4.00 (s, 4H). Example 3: Synthesis of Compound 103 Step 1: benzyl 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3 -oxopiperazine-1- carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyridine-1-carboxylate (A11, 2 g, 6.47 mmol, 1 eq) in DMSO (20 mL), was added benzyl 3- oxopiperazine-1-carboxylate (2.27 g, 9.70 mmol, 1.5 eq) and CuI (1.23 g, 6.47 mmol, 1 eq). The mixture was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was poured into H2O (100 mL), filtered and filtrate extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (18-100% EtOAc in PE) to give A12 (benzyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-oxo- piperazine-1-carboxylate, 0.5 g, 1.20 mmol,) as an oil. MS (ESI) m/z 416.1 [M+H] ⁺ . Step 2: tert-butyl 4-(2-oxopiperazin-1-yl)piperidine-1-carboxylate To a mixture of benzyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-oxo- piperazine-1-carboxylate (A12, 0.4 g, 963 µmol, 1 eq) in MeOH (4 mL) and DCM (4 mL), was added Pd/C (0.2 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H ₂ (x3), then stirred under H ₂ (15 Psi) at 25 °C for 16 h. Upon completion, the residue was filtered and concentrated under vacuum. The crude material was used in the next step without further purification (A13, tert-butyl 4-(2-oxopiperazin-1-yl)piperidine-1-carboxylate (0.2 g, crude)). MS (ESI) m/z 284.1 [M+H] ⁺ . Step 3: tert-butyl 4-(4-acryloyl-2-oxopiperazin-1-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-oxopiperazin-1-yl)piperidine-1-carboxylate (A13, 0.1 g, 353 µmol, 1 eq) in DCM (1 mL), was added TEA (71.4 mg, 706 µmol, 98.2 uL, 2 eq), then prop- 2-enoyl chloride (32 mg, 353 µmol, 28.8 uL, 1 eq) in DCM (0.5 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL) at 0 °C, and then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 4, Gradient c) to yield Compound 103 (30 mg, 89 umol) as an oil. MS (ESI) m/z 338.1 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4) δ ppm 6.58 - 6.86 (m, 1 H), 6.27 (dd, J=16.75, 1.83 Hz, 1 H), 5.80 (br d, J=10.64 Hz, 1 H), 4.50 (br d, J=8.19 Hz, 1 H), 4.22 - 4.36 (m, 2 H), 4.19 (br d, J=13.08 Hz, 2 H), 3.85 (br d, J=4.77 Hz, 2 H), 3.34 - 3.47 (m, 2 H), 2.84 (br s, 2 H), 1.54 - 1.74 (m, 4 H), 1.46 (s, 9 H). Example 4: Synthesis of Compound 104 Step 1: 2-[(3-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethy l-silane To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (A14, 3.0 g, 15.2 mmol, 1 eq) in THF (45 mL) was added portionwise NaH (670 mg, 16.75 mmol, 60% purity, 1.1 eq) at 0°C. After addition, the mixture was stirred at this temperature for 15 min, and then SEM-Cl (2.79 g, 16.75 mmol, 2.96 mL, 1.1 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20°C for 1 h. Upon completion, the reaction mixture was quenched by addition ice water 70 mL at 0 °C, and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (3-50% EtOAc in PE) to give A15 (2-[(3- bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-sila ne, 1.5 g, 4.58 mmol) as a solid. MS (ESI) m/z 327.1 [M+H] ⁺ . Step 2: tert-butyl 3-oxo-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3 -b]pyridin-3- yl)piperazine-1-carboxylate To a mixture of 2-[(3-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethy l-silane (A15, 900 mg, 2.75 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (A2, 551 mg, 2.75 mmol, 1 eq), CuI (78.6 mg, 412.5 µmol, 0.15 eq), K ₂ CO ₃ (1.14 g, 8.2 mmol, 3 eq) and N1,N2- dimethylcyclohexane-1,2-diamine (98 mg, 687.5 µmol, 0.25 eq) in toluene (13.5 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 120 degC for 16 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by addition H ₂ O (20 mL), and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (50-67% EtOAc in PE) to give A16 (tert-butyl 3-oxo-4- [1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-3-yl] piperazine-1-carboxylate, 650 mg, 1.45 mmol) as a solid. MS (ESI) m/z 447.1 [M+H] ⁺ . Step 3: tert-butyl 3-oxo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxyl ate To a solution of tert-butyl 3-oxo-4-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-3-yl]piperazine-1-carboxylate (A16, 0.5 g, 1.12 mmol, 1 eq) in THF (8 mL), was added TBAF (1 M, 8 mL, 7.15 eq). The mixture was stirred at 60 °C for 16 h. Upon completion, the residue was diluted with water (30 mL). The aqueous phase was extracted with EtOAc (10 mL * 3), and the combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude residue. The residue was purified by prep-TLC (9% MeOH in EtOAc) to give A17 (tert-butyl 3-oxo-4-(1H-pyrrolo[2,3- b]pyridin-3-yl)piperazine-1-carboxylate, 0.24 g, 759 umol) as an oil. MS (ESI) m/z 317.1 [M+H] ⁺ . Step 4: 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazin-2-one To a mixture of tert-butyl 3-oxo-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1- carboxylate (A17, 0.22 g, 695 µmol, 1 eq) in DCM (5 mL), was added TFA (1.54 g, 13.5 mmol, 1 mL, 19.4 eq), and the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give A18 (1-(1H-pyrrolo[2,3-b]pyridin-3- yl)piperazin-2-one, 0.15 g, crude)) as an oil, which was used in the next step without further purification. MS (ESI) m/z 217.1 [M+H] ⁺ . Step 5: 4-prop-2-enoyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazin-2- one To a solution of 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazin-2-one (A18, 0.15 g, 694 µmol, 1 eq) in DCM (1 mL), was added TEA (140.4 mg, 1.4 mmol, 193 uL, 2 eq), followed by addition of prop-2-enoyl chloride (62.8 mg, 693.7 µmol, 56.6 uL, 1 eq) in DCM (0.5 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL) at 0°C, and then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 4, Gradient d) to give Compound 104 (4-prop-2- enoyl-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazin-2-one, 30 mg, 104.3 umol) as an oil. MS (ESI) m/z 431.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.81 - 12.67 (m, 1 H), 8.24 (dd, J=4.59, 1.49 Hz, 1 H), 7.84 (br d, J=7.75 Hz, 1 H), 7.56 (s, 1 H), 7.07 (dd, J=7.87, 4.65 Hz, 1 H), 6.78 - 6.96 (m, 1H), 6.21 (dd, J=16.63, 1.61 Hz, 1H), 5.77 (dd, J=10.49, 2.03 Hz, 1H), 4.24 - 4.50 (m, 2H), 3.89 - 4.08 (m, 2 H), 3.79 (br dd, J=10.55, 4.35 Hz, 2H). Example 5: Synthesis of Compound 105 Step 1: tert-butyl 4-(5-methylfuran-2-yl)-3-oxopiperazine-1-carboxylate A mixture of 2-bromo-5-methyl-furan (A19, 200 mg, 1.24 mmol, 1 eq), tert-butyl 3- oxopiperazine-1-carboxylate (A2, 248.7 mg, 1.24 mmol, 1 eq), CuI (94.6 mg, 497 µmol, 0.4 eq), DMEDA (87.6 mg, 994 µmol, 107 uL, 0.8 eq) and K ₂ CO ₃ (343.4 mg, 2.48 mmol, 2 eq) in dioxane (5 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (20 mL) at 20 °C, and then diluted with H ₂ O (10 mL) and extracted with EtOAc (30 mL x3). The combined organic layers was washed with brine (30 mL x2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (50% EtOAc in PE) to afford Tert-butyl 4-(5-methyl-2-furyl)-3-oxo-piperazine-1-carboxylate (A20, 270 mg, 963 µmol, 78% yield) as a solid. MS (ESI) m/z 281.14 [M+H] ⁺ . Step 2: 1-(5-methylfuran-2-yl)piperazin-2-one To a solution of tert-butyl 4-(5-methyl-2-furyl)-3-oxo-piperazine-1-carboxylate (A20, 270 mg, 963.2 µmol, 1eq) in DCM (5 mL) was added TFA (109.8 mg, 963.2 µmol, 71.3 uL, 1 eq). The mixture was stirred at 20 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was used to next step without further purification. 1-(5-methyl-2-furyl) piperazin-2-one (A21, 170 mg, crude) was obtained as an oil. MS (ESI) m/z 181.09 [M+H] ⁺ . Step 3: 4-acryloyl-1-(5-methylfuran-2-yl)piperazin-2-one To a mixture of 1-(5-methyl-2-furyl)piperazin-2-one (A21, 85 mg, 471.7 µmol, 1 eq), TEA (143.2 mg, 1.42 mmol, 197 uL, 3 eq) in DCM (3 mL) and the mixture cooled to 0 °C, then prop- 2-enoyl chloride (47 mg, 519 µmol, 42.3 uL, 1.1 eq) was added and stirred for 0.5 h. Upon completion, the reaction mixture was quenched by addition H2O (0.5 mL) at 20°C. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was then purified by prep-HPLC (Condition 4, Gradient e) to give Compound 105 (1-(5-methyl-2-furyl)-4-prop-2- enoyl-piperazin-2-one (42.4 mg, 181 umol) as a solid. MS (ESI) m/z 235.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.76 (dd, J = 10.6, 16.7 Hz, 1H), 6.22 - 6.11 (m, 2H), 6.07 (qd, J = 1.0, 3.2 Hz, 1H), 5.73 (dd, J = 2.2, 10.5 Hz, 1H), 4.31 (s, 2H), 3.93 - 3.87 (m, 2H), 3.80 - 3.75 (m, 2H), 2.23 (d, J = 1.0 Hz, 3H). An analogous method was performed to obtain the following compounds. An analogous method was performed to obtain the following compounds. Example 6: Synthesis of Compound 106 Step 1: 4-(2-fluoroprop-2-enoyl)-1-imidazo [1, 2-a] pyridin-2-yl-piperazin-2-one A mixture of 1-imidazo[1,2-a]pyridin-2-ylpiperazin-2-one (A4, 143 mg, 463 µmol, 1 eq), 2-fluoroprop-2-enoic acid (50 mg, 555.5 µmol, 1.2 eq), HOBt (68.8 mg, 509 µmol, 1.1 eq), EDCI (97.6 mg, 509 µmol, 1.1 eq) and TEA (140.5 mg, 1.39 mmol, 193.3 uL, 3 eq) in DMF (4 mL) was degassed and purged with N2 (x3), and the mixture was stirred at 25°C for 12h under N2 atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 4, Gradient d) to give 4-(2- fluoroprop-2-enoyl)-1-imidazo[1,2-a]pyridin-2-yl-piperazin-2 -one (Compound 106, 40 mg, 139 umol) as a solid. MS (ESI) m/z 289.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ -d): δ = 8.28 (s, 1H), 8.12 (d, J = 6.7 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.25 - 7.14 (m, 1H), 6.83 (t, J = 6.7 Hz, 1H), 5.59 - 5.34 (m, 1H), 5.32 - 5.18 (m, 1H), 4.49 (br s, 2H), 4.43 - 4.27 (m, 2H), 4.19 - 3.82 ppm (m, 2H). Example 7: Synthesis of Compound 107 To a solution of (E)-4-(dimethylamino)but-2-enoic acid (A4, 51.1 mg, 396 µmol, 1 eq) in DMF (1.2 mL) was added HATU (150.5 mg, 396 µmol, 1 eq), it was stirred at 25 °C for 0.5 h. Then DIEA (153.4 mg, 1.19 mmol, 206.8 uL, 3 eq) and 1-imidazo[1,2-a]pyridin-2-ylpiperazin-2- one (142.9 mg, 396 µmol, 70% purity, 1 eq, HCl) were added at 0 °C. The mixture was stirred at 25 °C for 1 h, then the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 2, Gradient i) to give 4-[(E)-4-(dimethylamino)but- 2-enoyl]-1-imidazo[1,2-a]pyridin-2-yl-piperazin-2-one (Compound 107, 62 mg, 189.4 umol) as a solid. MS (ESI) m/z 327.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ -d): δ = 8.28 (s, 1H), 8.12 (d, J = 6.7 Hz, 1H), 7.51 (br d, J = 8.9 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.05 - 6.91 (m, 1H), 6.83 (t, J = 6.7 Hz, 1H), 6.58 - 6.35 (m, 1H), 4.49 (br s, 2H), 4.34 (br s, 2H), 4.11 - 3.90 (m, 2H), 3.13 (br d, J = 5.6 Hz, 2H), 2.29 ppm (s, 6H). Example 8: Synthesis of Compound 108 Step 1: benzyl 4-(1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxo-piperazine-1- carboxylate To a solution of tert-butyl 3-bromopyrrolidine-1-carboxylate (A22, 1 g, 4.0 mmol, 1 eq) and benzyl 3-oxopiperazine-1-carboxylate (936.5 mg, 4.0 mmol, 1 eq) in DMF (40 mL) was added Cs ₂ CO ₃ (3.9 g, 12 mmol, 3 eq) at 20 °C, and the mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (Condition 3, Gradient b) to give (A23, benzyl 4-(1-tert-butoxycarbonylpyrrolidin-3-yl)-3- oxo-piperazine-1-carboxylate (170 mg, 421.3 umol)) as an oil. MS (ESI) m/z 404.4 [M+H] ⁺ . Step 2: tert-butyl 3-(2-oxopiperazin-1-yl) pyrrolidine-1-carboxylate A mixture of benzyl 4-(1-tert-butoxycarbonylpyrrolidin-3-yl)-3-oxo-piperazine-1- carboxylate (A23, 170 mg, 421.3 µmol, 1 eq), Pd/C (170 mg, 10% purity) in tBuOH (10 mL) was degassed and purged with H2 (x3), and the mixture was stirred at 20 °C for 1 hr under H2 atmosphere. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue containing tert-butyl 3-(2-oxopiperazin-1-yl) pyrrolidine-1-carboxylate (A24, 113 mg, crude) as an oil. MS (ESI) m/z 270.2 [M+H] ⁺ . Step 3: tert-butyl 3-(2-oxo-4-prop-2-enoyl-piperazin-1-yl) pyrrolidine-1-carboxylate To a solution of tert-butyl 3-(2-oxopiperazin-1-yl)pyrrolidine-1-carboxylate (A24, 100 mg, 371.3 µmol, 1 eq) and TEA (112.7 mg, 1.1 mmol, 155 uL, 3 eq) in DCM (3 mL) was added prop- 2-enoyl chloride (40.3 mg, 445.5 µmol, 36.3 uL, 1.2 eq) at 0 °C, and the mixture was stirred at 0 °C for 1 hr. Upon completion, the mixture was quenched by H ₂ O (2 mL) and the reaction mixture was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Condition 5, Gradient a) to give tert-butyl 3-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)pyrrolidine-1- carboxylate (Compound 108, 24 mg, 74.21 umol) as a solid. MS (ESI) m/z 324.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3-d): δ = 6.60 - 6.44 (m, 1H), 6.43 - 6.36 (m, 1H), 5.81 (br d, J = 10.1 Hz, 1H), 5.19 (br s, 1H), 4.51 - 4.06 (m, 2H), 4.05 - 3.69 (m, 2H), 3.68 - 3.45 (m, 2H), 3.45 - 3.08 (m, 4H), 2.19 - 1.85 (m, 2H), 1.47 ppm (s, 9H). Example 9: Synthesis of Compound 109 Step 1: methyl (2-((tert-butoxycarbonyl)amino)ethyl)phenylalaninate To a solution of tert-butyl N-(2-oxoethyl)carbamate (A24, 2 g, 12.6 mmol, 1 eq) and methyl 2-amino-3-phenyl-propanoate (3.25 g, 15.1 mmol, 1.2 eq, HCl) in MeOH (20 mL), was added HOAc (1.06 g, 17.6 mmol, 1.01 mL, 1.4 eq) and NaBH3CN (1.18 g, 18.9 mmol, 1.5 eq) at 0 °C under N ₂ , and the mixture was stirred at 25°C for 1 h. Upon completion, the reaction mixture was quenched by addition sat. aq. NaHCO ₃ (80 mL) at 0 °C, and then diluted with H ₂ O (20 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (18-50% EtOAc in PE) to give methyl 2-[2- (tert-butoxycarbonylamino)ethylamino]-3-phenyl-propanoate (A26, 2.8 g, 8.7 mmol) as an oil. MS (ESI) m/z 323.1 [M+H] ⁺ . Step 2: methyl N-((benzyloxy)carbonyl)-N-(2-((tert-butoxycarbonyl)amino)eth yl)phenylalaninate To a mixture of methyl 2-[2-(tert-butoxycarbonylamino)ethylamino]-3-phenyl- propanoate (A26, 0.5 g, 1.55 mmol, 1 eq) in DCM (10 mL), was added CbzCl (397 mg, 2.33 mmol, 330.7 uL, 1.5 eq) and DIEA (802 mg, 6.2 mmol, 1.08 mL, 4 eq) at 0 °C under N2. The mixture was stirred at 25°C for 16 h. Upon completion, the reaction mixture was diluted with H2O (60 mL) and extracted with DCM (20 mL x3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (18-50% EtOAc in PE) to give methyl 2- [benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino] -3-phenyl-propanoate (A27, 0.5 g, 1.10 mmol) as an oil. MS (ESI) m/z 457.1 [M+H] ⁺ . Step 3: methyl N-(2-aminoethyl)-N-((benzyloxy)carbonyl)phenylalaninate A solution of methyl 2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amin o]- 3-phenyl-propanoate (A27, 0.5 g, 1.1 mmol, 1 eq) in HCl/dioxane (4 M, 8 mL, 29.2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under vacuum to give methyl 2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-phenyl-propanoate (A28, 0.4 g, crude) as an oil which was used in the next step without further purification. MS (ESI) m/z 357.1 [M+H] ⁺ . Step 4: benzyl 2-benzyl-3-oxopiperazine-1-carboxylate To a mixture of methyl 2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-phenyl-propanoate (A28, 0.38 g, 1.07 mmol, 1 eq) in DMF (4 mL), was added Cs ₂ CO ₃ (695 mg, 2.13 mmol, 2 eq). The mixture was stirred at 80 °C for 2 h. Upon completion, water (30 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL x3). The combined organic phase was washed with brine (10 mL x3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (18-100% EtOAc in PE) to give benzyl 2-benzyl-3-oxo-piperazine-1-carboxylate (A29, 0.3 g, 925 umol) as a solid. MS (ESI) m/z 325.1 [M+H] ⁺ . Step 5: benzy To a solution of 2-bromoimidazo[1,2-a]pyridine (A30, 0.14 g, 710.5 µmol, 1 eq) and benzyl 2-benzyl-3-oxo-piperazine-1-carboxylate (253.5 mg, 781.6 µmol, 1.1 eq) in dioxane (3 mL), was added MEDA (15.7 mg, 177.6 µmol, 19.1 uL, 0.25 eq), CuI (20.3 mg, 106.6 µmol, 0.15 eq) and K2CO3 (295 mg, 2.13 mmol, 3 eq) under N2. The mixture was stirred at 100 °C for 16 h. Upon completion, water (20 mL) was added, and the aqueous phase was extracted with EtOAc (7 mL x3). The combined organic phase was washed with brine (9 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was then purified by prep- TLC (50% EtOAc in PE) to give benzyl 2-benzyl-4-imidazo[1,2-a]pyridin-2-yl-3-oxo- piperazine-1-carboxylate (A30, 0.2 g, 454 umol) as an oil. MS (ESI) m/z 441.1 [M+H] ⁺ . To a solution of benzyl 2-benzyl-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazine-1- carboxylate (A30, 100 mg, 227 µmol, 1 eq) in TFA (2 mL), and the mixture was stirred at 70 °C for 3 h. Upon completion, the mixture solution was concentrated with N ₂ to give 3-benzyl-1- imidazo[1,2-a]pyridin-2-yl-piperazin-2-one (A31, 60 mg, crude) as an oil which was used in the next step without further purification. MS (ESI) m/z 307.1 [M+H] ⁺ . Step 7: 4-acryloyl-3-benzyl-1-(imidazo[1,2-a]pyridin-2-yl)piperazin- 2-one

To a solution of 3-benzyl-1-imidazo[1,2-a]pyridin-2-yl-piperazin-2-one (A31, 60 mg, 196 µmol, 1 eq) in DCM (1 mL) was added TEA (39.6 mg, 391.7 µmol, 54.5 uL, 2 eq), followed by addition of prop-2-enoyl chloride (17.7 mg, 196 µmol, 16 uL, 1 eq) in DCM (0.5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H2O (0.5 mL) at 0 °C, and then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 1, Gradient d) to give 3-benzyl-1-imidazo[1,2- a]pyridin-2-yl-4-prop-2-enoyl-piperazin-2-one (Compound 109, 14.7 mg, 38.1 umol) as a solid. MS (ESI) m/z 361.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.63 - 8.59 (m, 1 H), 8.43 - 8.40 (m, 1 H), 7.50 - 7.47 (m, 1 H), 7.27 - 7.18 (m, 6 H), 7.14 - 6.80 (m, 1 H), 6.77 - 6.31 (m, 1 H), 6.25 - 5.89 (m, 1 H), 5.75 - 5.38 (m, 1 H), 5.35 - 5.00 (m, 1 H), 4.58 - 4.30 (m, 1 H), 4.11 - 3.91 (m, 1 H), 3.91 - 3.76 (m, 1 H), 3.27 - 3.13 (m, 3 H). Example 10: Synthesis of Compound 110 Step 1: tert-butyl 3-oxo-4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperazine-1-car boxylate A mixture of 3-bromo-[1,2,4]triazolo[4,3-a]pyridine (A31, 500 mg, 2.5 mmol, 1 eq), tert- butyl 3-oxopiperazine-1-carboxylate (A2, 607 mg, 3.0 mmol, 1.2 eq), Cs2CO3 (1.65 g, 5.0 mmol, 2 eq), iodocopper;tetrabutylammonium;diiodide (56.5 mg, 50.5 µmol, 0.02 eq) and 3,4,7,8- tetramethyl-1,10-phenanthroline (11.9 mg, 50.5 µmol, 0.02 eq) in dioxane (5 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 90 °C for 16 h under N ₂ atmosphere. The reaction mixture was quenched by addition H2O (0.5 mL) at 0 °C, and then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 6, Gradient a) to give a tert-butyl 3-oxo-4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperazine-1-car boxylate (A32, 380 mg, 1.20 mmol) as a solid. MS (ESI) m/z 318.2 [M+H] ⁺ . To a solution of tert-butyl 3-oxo-4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperazine-1- carboxylate (A32, 100 mg, 315 µmol, 1 eq) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 21.4 eq), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which contained 1-([1,2,4]triazolo[4,3- a]pyridin-3-yl)piperazin-2-one (A33, 70 mg, crude) as an oil. MS (ESI) m/z 218.2 [M+H] ⁺ . S To a solution of 1-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperazin-2-one (A33, 70 mg, 322.2 µmol, 1 eq) in DCM (2 mL) was added TEA (130.4 mg, 1.3 mmol, 179.4 uL, 4 eq) and prop-2- enoyl prop-2-enoate (40.6 mg, 322.2 µmol, 1 eq), and the mixture was stirred at -40 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 5, Gradient b) to give 4-prop-2-enoyl-1-([1,2,4]triazolo[4,3- a]pyridin-3-yl)piperazin-2-one (Compound 110, 10 mg, 37 umol) as a solid. MS (ESI) m/z 272.2 NMR (400 MHz, CDCl ₃ -d): δ = 7.87 - 7.61 (m, 2H), 7.33 (br t, J = 7.6 Hz, 1H), 6.96 - 6.86 (m, 1H), 6.70 - 6.54 (m, 1H), 6.52 - 6.38 (m, 1H), 5.88 (br d, J = 9.8 Hz, 1H), 4.60 (br s, 2H), 4.33 - 3.97 ppm (m, 4H). Example 11: Synthesis of Compound 113 Step 1: tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-3-oxo-piperazine-1-carboxylate A mixture of 7-bromoimidazo[1,2-a]pyridine (A40, 300 mg, 1.52 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (305 mg, 1.52 mmol, 1 eq), CuI (43.5 mg, 228 µmol, 0.15 eq), DMEDA (33.6 mg, 381 µmol, 41 uL, 0.25 eq) and K ₂ CO ₃ (421 mg, 3.05 mmol, 2 eq) in dioxane (3 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by addition H2O (30 mL) at 20 °C, and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL x2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by prep-TLC (50% EtOAc in PE) to afford tert-butyl 4- imidazo[1,2-a]pyridin-7-yl-3-oxo-piperazine-1-carboxylate (A41, 280 mg, 885 umol) was obtained as a solid. MS (ESI) m/z 316.3 [M+H] ⁺ . Step 2: 1-imidazo[1,2-a]pyridin-7-ylpiperazin-2-one A solution of tert-butyl 4-imidazo[1,2-a]pyridin-7-yl-3-oxo-piperazine-1-carboxylate (A41, 150 mg, 474 µmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 28.5 eq) at 20 °C and stirred at 20 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give A42 (1-imidazo[1,2-a]pyridin-7-ylpiperazin-2-one, 156 mg, crude, TFA) as an oil. MS (ESI) m/z 217.2 [M+H] ⁺ . Step 3: 1-imidazo[1,2-a]pyridin-7-yl-4-prop-2-enoyl-piperazin-2-one To a solution of 1-imidazo[1,2-a]pyridin-7-ylpiperazin-2-one (A42, 156 mg, 472.4 µmol, 1 eq, TFA) in DCM (3 mL) was added TEA (143.4 mg, 1.42 mmol, 197.2 uL, 3 eq) and prop-2- enoyl chloride (47 mg, 519.6 µmol, 42.4 uL, 1.1 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition MeOH (0.5 mL) at 20 °C. The reaction mixture was concentrated under reduced pressure to remove solvent, and the residue was purified by prep-HPLC (Condition 2, Gradient b) to afford 1-imidazo[1,2-a]pyridin-7-yl-4-prop- 2-enoyl-piperazin-2-one (Compound 113, 15.2 mg, 55.9 umol) as a solid. MS (ESI) m/z 271.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.52 (d, J = 7.3 Hz, 1H), 7.93 (s, 1H), 7.57 (s, 2H), 7.00 (br d, J = 7.1 Hz, 1H), 6.93 - 6.76 (m, 1H), 6.21 (br d, J = 16.6 Hz, 1H), 5.77 (br d, J = 10.3 Hz, 1H), 4.44 (s, 1H), 4.29 (s, 1H), 3.99 (br d, J = 4.8 Hz, 1H), 3.94 - 3.78 (m, 3H). Example 12: Synthesis of Compound 114 Step 1: tert-butyl 3-oxo-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)piperazine-1-car boxylate A mixture of 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (A43, 500 mg, 2.52 mmol, 1 eq), tert- butyl 3-oxopiperazine-1-carboxylate (A2, 505.6 mg, 2.52 mmol, 1 eq), CuI (72 mg, 379 µmol, 0.15 eq), DMEDA (55.7 mg, 631.3 µmol, 67.9 uL, 0.25 eq) and K2CO3 (697.9 mg, 5.05 mmol, 2 eq) in dioxane (7 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was quenched by water (12 mL), and then extracted with EtOAc (15 mL x3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a that residue was purified by column chromatography (17-100% EtOAc in PE) to give tert-butyl 3-oxo-4- ([1,2,4]triazolo[1,5-a]pyridin-6-yl)piperazine-1-carboxylate (A44, 350 mg, 1.10 mmol) as a solid. MS (ESI) m/z 318.3 [M+H] ⁺ . Step 2: 1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)piperazin-2-one To a solution of tert-butyl 3-oxo-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)piperazine-1- carboxylate (A44, 350 mg, 1.10 mmol, 1 eq) in DCM (4 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 12.25 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that yielded 1-([1,2,4]triazolo[1,5-a]pyridin-6- yl)piperazin-2-one (A45, 240 mg, crude) as an oil. MS (ESI) m/z 218.2 [M+H] ⁺ . Step 3: 4-prop-2-enoyl-1-([1,2,4]triazolo[1,5-a]pyridin-7-yl)piperaz in-2-one To a solution of 1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)piperazin-2-one (A45, 120 mg, 552.4 µmol, 1 eq) in DCM (2.5 mL) was added TEA (223.6 mg, 2.21 mmol, 307.6 uL, 4 eq) and prop- 2-enoyl chloride (60 mg, 662.9 µmol, 54 uL, 1.2 eq). The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 2, Gradient b) to give 4-prop-2-enoyl-1-([1,2,4]triazolo[1,5-a]pyridin- 7-yl)piperazin-2-one (Compound 114, 30 mg, 110.6 umol) as a solid. MS (ESI) m/z 272.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 9.15 (d, J = 1.4 Hz, 1H), 8.54 (s, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.76 - 7.70 (m, 1H), 6.95 - 6.78 (m, 1H), 6.21 (br d, J = 16.6 Hz, 1H), 5.78 (br d, J = 10.4 Hz, 1H), 4.51 - 4.22 (m, 2H), 4.07 - 3.76 ppm (m, 4H). Example 13: Synthesis of Compound 115 Step 1: tert-butyl 4-(1,3-benzothiazol-2-yl)-3-oxo-piperazine-1-carboxylate A mixture of 2-bromo-1,3-benzothiazole (A45, 500 mg, 2.3 mmol, 1 eq), tert-butyl 3- oxopiperazine-1-carboxylate (468 mg, 2.3 mmol, 1 eq), CuI (66.7 mg, 350.3 µmol, 0.15 eq), DMEDA (51.5 mg, 584 µmol, 63 uL, 0.25 eq) and K ₂ CO ₃ (645.6 mg, 4.7 mmol, 2 eq) in dioxane (8 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 12 hr under N2 atmosphere. Upon completion, the reaction mixture was quenched by water (12 mL), and then extracted with EtOAc (20 mL x3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (25-33% EtOAc in PE) to give tert-butyl 4- (1,3-benzothiazol-2-yl)-3-oxo-piperazine-1-carboxylate (A47, 350 mg, 892 umol) as a solid. Step 2: 1-(1,3-benzothiazol-2-yl)piperazin-2-one To a solution of tert-butyl 4-(1,3-benzothiazol-2-yl)-3-oxo-piperazine-1-carboxylate (A47, 350 mg, 1.05 mmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 12.9 eq), and the mixture was stirred at 25 °C for 2 hr . Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue that yielded 1-(1,3-benzothiazol-2- yl)piperazin-2-one (A48, 240 mg, crude) as a solid. Step 3: 1-(1,3-benzothiazol-2-yl)-4-prop-2-enoyl-piperazin-2-one To a solution of 1-(1,3-benzothiazol-2-yl)piperazin-2-one (A48, 240 mg, 1.03 mmol, 1 eq) in DCM (5 mL) was added prop-2-enoyl chloride (112 mg, 1.23 mmol, 101 uL, 1.2 eq) and TEA (416.4 mg, 4.12 mmol, 573 uL, 4 eq), and the mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient a) to give 1-(1,3-benzothiazol-2-yl)-4-prop-2- enoyl-piperazin-2-one (Compound 115, 100 mg, 340.6 umol) as a solid. MS (ESI) m/z= 288.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.02 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.47 (dt, J = 1.2, 7.7 Hz, 1H), 7.40 - 7.31 (m, 1H), 6.86 (br d, J = 10.7 Hz, 1H), 6.21 (br d, J = 16.7 Hz, 1H), 5.87 - 5.69 (m, 1H), 4.76 - 4.41 (m, 2H), 4.39 - 4.21 (m, 2H), 4.14 - 3.93 (m, 2H). Example 14: Synthesis of Compound 117 Step 1: tert-butyl 4-imidazo[1, 2-a]pyrimidin-6-yl-3-oxo-piperazine-1-carboxylate A mixture of 6-bromoimidazo[1, 2-a]pyrimidine (A52, 1 g, 5.05 mmol, 1 eq), tert-butyl 3- oxopiperazine-1-carboxylate (1.01 g, 5.05 mmol, 1 eq), CuI (384.71 mg, 2.02 mmol, 0.4 eq), N1, N2-dimethylcyclohexane-1, 2-diamine (574.7 mg, 4.04 mmol, 0.8 eq) and K ₂ CO ₃ (1.4 g, 10.1 mmol, 2 eq) in toluene (10 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 120 °C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (9% MeOH in EtOAc) to give tert-butyl 4-imidazo[1,2-a]pyrimidin-6-yl-3-oxo-piperazine-1- carboxylate (A53, 100 mg, 315 umol) as a solid. MS (ESI) m/z 318.3 [M+H] ⁺ . Step 2: 1-imidazo[1,2-a]pyrimidin-6-ylpiperazin-2-one A solution of tert-butyl 4-imidazo[1,2-a]pyrimidin-6-yl-3-oxo-piperazine-1-carboxylat e (A53, 100 mg, 315 µmol, 1 eq) in HCl/dioxane (4 M, 3 mL, 38.1 eq) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 1- imidazo[1,2-a]pyrimidin-6-ylpiperazin-2-one (A54, 65 mg, crude) as a solid. MS (ESI) m/z 218.2 [M+H] ⁺ . Step 3: 1-imidazo[1, 2-a]pyrimidin-6-yl-4-prop-2-enoyl-piperazin-2-one To a solution of 1-imidazo[1, 2-a]pyrimidin-6-ylpiperazin-2-one (A54, 65 mg, 299.2 µmol, 1 eq) in THF (1 mL) and H ₂ O (1 mL) was added KOH (35.3 mg, 628.4 µmol, 2.1 eq) at 0 °C, then prop-2-enoyl chloride (24.4 mg, 269.3 µmol, 22 uL, 0.9 eq) in THF (1 mL) was added drop-wise at 0 °C, the mixture was stirred at 0 °C for 10 min. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 6, Gradient b) to give 1-imidazo [1, 2-a] pyrimidin-6-yl-4-prop-2-enoyl-piperazin-2- one (Compound 117, 25 mg, 91.5 umol) as a solid. MS (ESI) m/z 272.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.12 (d, J = 2.5 Hz, 1H), 8.57 (d, J = 2.6 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 6.95 - 6.80 (m, 1H), 6.22 (br d, J = 16.7 Hz, 1H), 5.78 (br d, J = 10.6 Hz, 1H), 4.49 - 4.30 (m, 2H), 4.07 - 3.77 (m, 4H). Example 15: Synthesis of Compound 118 Step 1: benzyl 4-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-oxo- piperazine-1- carboxylate A mixture of tert-butyl 4-(4-bromopyrazol-1-yl)piperidine-1-carboxylate (A56, 500 mg, 1.51 mmol, 1 eq), benzyl 3-oxopiperazine-1-carboxylate (354.7 mg, 1.5 mmol, 1 eq), CuI (43.3 mg, 227.1 µmol, 0.15 eq), DMEDA (33.4 mg, 378.5 µmol, 40.7 uL, 0.25 eq) and K2CO3 (418.5 mg, 3.03 mmol, 2 eq) in dioxane (7 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was quenched by water (12 mL), and then extracted with EtOAc (15 mL x3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (100% EtOAc) to give benzyl 4-[1-(1- tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-oxo-piperazi ne-1-carboxylate (A56, 400 mg, 827 umol) as a solid. MS (ESI) m/z 484.2 [M+H] ⁺ . Step 2: tert-butyl 4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]piperidine-1-carboxyl ate To a solution of benzyl 4-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-oxo- piperazine-1-carboxylate (A56, 200 mg, 413.6 µmol, 1 eq) in 75-65-0 (10 mL) was added Pd/C (250 mg), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue to give tert-butyl 4-[4-(2-oxopiperazin-1-yl)pyrazol-1- yl]piperidine-1-carboxylate (A57, 130 mg, crude) as a solid. MS (ESI) m/z 350.2 [M+H] ⁺ . Step 3: tert-butyl 4-[4-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)pyrazol-1-yl]piper idine-1- carboxylate To a solution of tert-butyl 4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]piperidine-1- carboxylate (A58, 130 mg, 372 µmol, 1 eq) was added TEA (131.8 mg, 1.3 mmol, 181 uL, 3.5 eq) and prop-2-enoyl chloride (40.4 mg, 446.5 µmol, 36.4 uL, 1.2 eq) in DCM (2.5 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Condition 2, Gradient c) to give (tert-butyl 4-[4-(2- oxo-4-prop-2-enoyl-piperazin-1-yl)pyrazol-1-yl]piperidine-1- carboxylate (Compound 118, 10 mg, 24.8 umol)) as a solid. MS (ESI) m/z 404.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.10 (s, 1H), 7.69 (s, 1H), 6.93 - 6.75 (m, 1H), 6.18 (br d, J = 16.5 Hz, 1H), 5.76 (br d, J = 8.8 Hz, 1H), 4.43 - 4.27 (m, 2H), 4.23 (s, 1H), 4.08 - 3.82 (m, 4H), 3.78 - 3.66 (m, 2H), 2.89 (br s, 2H), 2.01 - 1.90 (m, 2H), 1.82 - 1.66 (m, 2H), 1.41 ppm (s, 9H). Example 16: Synthesis of Compound 119 Step 1: 2-[(5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimet hyl-silane To a solution of 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (A58, 5 g, 25.3 mmol, 1 eq) in THF (25 mL) was added dropwise NaH (1.11 g, 27.8 mmol, 60% purity, 1.1 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 15 min, and then SEM-Cl (4.6 g, 27.8 mmol, 4.9 mL, 1.1 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by water (50 mL), and then extracted with EtOAc (50 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (25% EtOAc in PE) to give 2-[(5-bromopyrrolo[2,3-d]pyrimidin-7- yl)methoxy]ethyl-trimethyl-silane (A59, 2.6 g, 7.9 mmol) as an oil. MS (ESI) m/z 328.1 [M+H] ⁺ . Step 2: tert-butyl 3-oxo-4-[7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrim idin-5- yl]piperazine-1-carboxylate A mixture of 2-[(5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimet hyl-silane (A59, 3.3 g, 10 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (2.01 g, 10 mmol, 1 eq), CuI (766 mg, 4 mmol, 0.4 eq), DMEDA (709 mg, 8 mmol, 866 uL, 0.8 eq) and K ₂ CO ₃ (2.78 g, 20 mmol, 2 eq) in dioxane (35 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. The reaction mixture was diluted with H ₂ O 40 mL and extracted with EtOAc (35 mL x3). The combined organic layers were dried over sat. Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (5-100% EtOAc in Petroleum ether) to give A60 (tert-butyl 3-oxo-4-[7- (2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-5-yl]p iperazine-1-carboxylate (3.6 g, 6.76 mmol) as a solid. MS (ESI) m/z 448.3 [M+H] ⁺ . Step 3: tert-butyl 3-oxo-4-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperazine-1-carbox ylate To a solution of tert-butyl 3-oxo-4-[7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- d]pyrimidin-5-yl]piperazine-1-carboxylate (A60, 400 mg, 894 µmol, 1 eq) in THF (5 mL) was added TBAF (1 M, 5 mL, 5.60 eq), and the mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with H2O 15 mL and extracted with EtOAc (15mL x3). The combined organic layers were dried over sat. Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (5% MeOH in EtOAc) to give tert-butyl 3-oxo-4- (7H-pyrrolo [2,3-d]pyrimidin-5-yl)piperazine-1-carboxylate (A61, 60 mg, 189 umol) as a solid. MS (ESI) m/z 318.3 [M+H] ⁺ . Step 4: 1-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperazin-2-one To a solution of tert-butyl 3-oxo-4-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperazine-1- carboxylate (A61, 160 mg, 504 µmol, 1 eq) was added HCl/dioxane (4 M, 4.7 mL, 37.3 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue containing A62 (1-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperazin-2-one (116 mg, crude)) as an oil. MS (ESI) m/z 218.3 [M+H] ⁺ . To a solution of 1-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperazin-2-one (A62, 116 mg, 534 µmol, 1 eq) in DCM (2.5 mL) was added TEA (270 mg, 2.67 mmol, 371.6 uL, 5 eq) and prop-2- enoyl prop-2-enoate (60.6 mg, 480.6 µmol, 0.9 eq) in DCM (0.25 mL), and the mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 5, Gradient c) to give Compound 119 (4- prop-2-enoyl-1-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperazin-2- one (17 mg, 59.53 umol)) as a solid. MS (ESI) m/z 272.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ = 12.19 (br s, 1H), 8.94 (s, 1H), 8.82 - 8.68 (m, 1H), 7.67 (s, 1H), 6.99 - 6.72 (m, 1H), 6.37 - 6.07 (m, 1H), 5.77 (br d, J = 10.5 Hz, 1H), 4.57 - 4.22 (m, 2H), 4.14 - 3.68 ppm (m, 4H). Example 17: Synthesis of Compound 120 Step 1: tert-butyl 4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-3-oxo-piperazine-1 -carboxylate A mixture of 3-bromo-5-methyl-pyrazolo[1,5-a]pyrimidine (A63, 400 mg, 1.89 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (377.7 mg, 1.89 mmol, 1 eq), iodocopper (53.9 mg, 283 µmol, 0.15 eq), N,N'-dimethylethane-1,2-diamine (41.6 mg, 471.6 µmol, 50.8 uL, 0.25 eq) and dipotassium;carbonate (521.4 mg, 3.8 mmol, 2 eq) in dioxane (6 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. Upon completion, the reaction mixture was diluted with H ₂ O 10 mL and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (5-100% EtOAc in PE) to give A64 (tert-butyl 4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-3-oxo-piperazine-1 - carboxylate (400 mg, 1.21 mmol, 64% yield) as a solid. Step 2: 1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)piperazin-2-one To a solution of tert-butyl 4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-3-oxo-piperazine-1 - carboxylate (A64, 200 mg, 603.56 µmol, 1 eq) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 11.19 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in vacuum (30 °C), then was added DCM (2 mL), and concentrated to give A65 (1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)piperazin-2-one (140 mg, crude)) as an oil. Step 3: 1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-4-prop-2-enoyl-pip erazin-2-one To a solution of 1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)piperazin-2-one (139 mg, 601.07 µmol, 1 eq) in DCM (2 mL) was cooled to 0 °C then was added TEA (304.11 mg, 3.01 mmol, 418.31 uL, 5 eq) and prop-2-enoyl chloride (48.96 mg, 540.96 µmol, 44.11 uL, 0.9 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 3, Gradient a) to give 1-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-4-prop-2-enoyl-pip erazin-2-one (14 mg, 47.60 µmol, 8% yield, 97% purity) as a solid. MS (ESI) m/z 286.2 [M+H] ⁺ . NMR (400 MHz, CDCl3-d) δ = 8.47 (d, J = 7.3 Hz, 1H), 8.28 (br s, 1H), 6.70 (d, J = 7.1 Hz, 1H), 6.65 - 6.53 (m, 1H), 6.48 - 6.40 (m, 1H), 5.84 (br d, J = 9.6 Hz, 1H), 4.62 - 4.37 (m, 2H), 4.21 - 3.90 (m, 4H), 2.60 (s, 3H). ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 8.74 (d, J = 7.3 Hz, 1H), 8.21 (s, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.90 - 6.75 (m, 1H), 6.33 (dd, J = 1.9, 16.8 Hz, 1H), 5.94 - 5.72 (m, 1H), 4.57 - 4.41 (m, 2H), 4.11 (br d, J = 2.3 Hz, 2H), 4.01 - 3.88 (m, 2H), 2.61 (s, 3H). The synthesis was taken further to provide the final OTUB1 Recruiter, Compound 120. Example 18: Synthesis of Compound 121 Step 1: tert-butyl 4-(5-methylthiazol-2-yl)-3-oxo-piperazine-1-carboxylate A mixture of 2-bromo-5-methyl-thiazole (A66, 500 mg, 2.8 mmol, 1 eq), tert-butyl 3- oxopiperazine-1-carboxylate (562.3 mg, 2.8 mmol, 1 eq), CuI (80.2 mg, 421.2 µmol, 0.15 eq), DMEDA (61.9 mg, 702 µmol, 75.6 uL, 0.25 eq) and K2CO3 (776.2 mg, 5.6 mmol, 2 eq) in dioxane ^{(7 mL) was degassed and purged with N} 2 ^{(x3), and then the mixture was stirred at 100 °C for 16 h} under N ₂ atmosphere. The reaction mixture was quenched by addition H ₂ O 15 mL at 25 °C, and then extracted with EtOAc (15 mL * 3). The combined organic layers were dried over sat. Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (3-18% EtOAc in PE) to give A67 (tert-butyl 4-(5-methylthiazol-2-yl)- 3-oxo-piperazine-1-carboxylate (290 mg, 975 umol)) as a solid. MS (ESI) m/z 298.2 [M+H] ⁺ . Step 2: 1-(5-methylthiazol-2-yl)piperazin-2-one To a solution of tert-butyl 4-(5-methylthiazol-2-yl)-3-oxo-piperazine-1-carboxylate (A67, 100 mg, 336.3 µmol, 1 eq) in DCM (2 mL) was added TFA (550 mg, 4.82 mmol, 357.14 uL, 14.34 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that contained A68 (1-(5-methylthiazol-2-yl) piperazin-2-one (66 mg, crude)) as an oil. MS (ESI) m/z 198.2 [M+H] ⁺ . Step 3: 1-(5-methylthiazol-2-yl)-4-prop-2-enoyl-piperazin-2-one To a solution of 1-(5-methylthiazol-2-yl) piperazin-2-one (A68, 60 mg, 304 µmol, 1 eq) in DCM (2 mL) was added TEA (153.9 mg, 1.52 mmol, 211.7 uL, 5 eq) and prop-2-enoyl chloride (27.5 mg, 304.2 µmol, 24.8 uL, 1 eq). The mixture was stirred at -40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 1, Gradient e) to give Compound 121 (1-(5-methylthiazol-2-yl)-4-prop- 2-enoyl-piperazin-2-one (18.6 mg, 71.1 umol)) as a solid. MS (ESI) m/z 252.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.25 (d, J = 0.9 Hz, 1H), 6.95 - 6.73 (m, 1H), 6.19 (br d, J = 16.8 Hz, 1H), 5.77 (br d, J = 9.0 Hz, 1H), 4.65 - 4.32 (m, 2H), 4.21 - 3.86 (m, 4H), 2.36 ppm (s, 3H) Example 19: Synthesis of Compound 123 Step 1: tert-butyl 4-(8-methylimidazo[1,2-a]pyridin-2-yl)-3-oxo-piperazine-1-ca rboxylate A mixture of 2-bromo-8-methyl-imidazo[1,2-a]pyridine (A72, 100 mg, 473.8 µmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (95 mg, 473.8 µmol, 1 eq), iodocopper (36.1 mg, 189.5 µmol, 0.4 eq), N,N'-dimethylethane-1,2-diamine (33.4 mg, 379 µmol, 40.8 uL, 0.8 eq) and dipotassium;carbonate (131 mg, 947.6 µmol, 2 eq) in dioxane (2 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with aq. EDTA 10 mL and extracted with EtOAc (10 mL x2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (10% EtOAc in PE) to give A73 (tert-butyl 4-(8-methylimidazo[1,2-a]pyridin-2-yl)-3-oxo-piperazine-1- carboxylate (70 mg, 212 umol)) as a solid. Step 2: 1-(8-methylimidazo[1,2-a]pyridin-2-yl)piperazin-2-one To a solution of tert-butyl 4-(8-methylimidazo[1,2-a]pyridin-2-yl)-3-oxo-piperazine-1- carboxylate (A73, 70 mg, 212 µmol, 1 eq) in DCM (2 mL) was added TFA (616 mg, 5.4 mmol, 0.4 mL, 25.5 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in vacuum (30 °C), then was added DCM(2 mL), and concentrated, and repeat to give A74 (1-(8-methylimidazo[1,2-a]pyridin-2-yl)piperazin-2-one (48 mg, crude)) as an oil. Step 3: 1-(8-methylimidazo[1,2-a]pyridin-2-yl)-4-prop-2-enoyl-pipera zin-2-one To a solution of 1-(8-methylimidazo[1,2-a]pyridin-2-yl)piperazin-2-one (A74, 48 mg, 208.5 µmol, 1 eq) in DCM (2 mL) was cooled to 0 °C then was added TEA (105.5 mg, 1.04 mmol, 145 uL, 5 eq) and prop-2-enoyl chloride (17 mg, 187.6 µmol, 15.3 uL, 0.9 eq). The mixture was stirred at 0 °C for1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 3, Gradient a) to give Compound 123 (1-(8-methylimidazo[1,2-a]pyridin-2-yl)-4-prop-2-enoyl-piper azin-2-one (25.8 mg, 88.8 umol)) as a solid. MS (ESI) m/z 285.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.48 - 8.41 (m, 1H), 8.33 (s, 1H), 7.10 - 7.03 (m, 1H), 6.92 - 6.77 (m, 2H), 6.25 - 6.12 (m, 1H), 5.84 - 5.68 (m, 1H), 4.56 - 4.30 (m, 2H), 4.27 - 4.16 (m, 2H), 4.03 - 3.84 (m, 2H), 2.47 (s, 3H). Example 20: Synthesis of Compound 125 Step 1: tert-butyl 4-imidazo[1,2-b]pyridazin-3-yl-3-oxo-piperazine-1-carboxylat e To a solution of 3-bromoimidazo[1,2-b]pyridazine (A78, 1 g, 5 mmol, 1 eq) and tert-butyl 3-oxopiperazine-1-carboxylate (1.01 g, 5 mmol, 1 eq) in dioxane (10 mL) was added iodocopper (385 mg, 2 mmol, 0.4 eq), N,N'-dimethylethane-1,2-diamine (356.1 mg, 4 mmol, 435 uL, 0.8 eq) and dipotassium;carbonate (1.4 g, 10 mmol, 2 eq). The mixture was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with H ₂ O 10 mL and extracted with EtOAc ( 5 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (5-100% EtOAc in PE) to give A79 (tert-butyl 4-imidazo[1,2-b]pyridazin-3-yl-3-oxo-piperazine-1- carboxylate (600 mg, 1.89 mmol)) as a solid. MS (ESI) m/z 318.1 [M+H] ⁺ . Step 2: 1-imidazo[1,2-b]pyridazin-3-ylpiperazin-2-one To a solution of tert-butyl 4-imidazo[1,2-b]pyridazin-3-yl-3-oxo-piperazine-1-carboxylat e (300 mg, 945.4 µmol, 1 eq) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 14.3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was used in the next step directly, and contained A80 (1-imidazo[1,2-b]pyridazin-3-ylpiperazin-2-one (200 mg, 921 umol). MS (ESI) m/z 218.1 [M+H] ⁺ . Step 3: 1-imidazo[1,2-b]pyridazin-3-yl-4-prop-2-enoyl-piperazin-2-on e To a solution of 1-imidazo[1,2-b]pyridazin-3-ylpiperazin-2-one (A80, 180 mg, 829 µmol, 1 eq) and prop-2-enoyl chloride (113 mg, 1.24 mmol, 101.4 uL, 1.5 eq) in DCM (5 mL) was added TEA (419 mg, 4.14 mmol, 576.7 uL, 5 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to to give a residue. The residue was purified by prep-HPLC (Condition 2, Gradient d) to give Compound 125 (1- imidazo[1,2-b]pyridazin-3-yl-4-prop-2-enoyl-piperazin-2-one (118 mg, 436 umol)) as a solid. MS (ESI) m/z 272.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.57 (d, J = 4.4 Hz, 1H), 8.23 - 8.13 (m, 1H), 7.81 (s, 1H), 7.30 (dd, J = 4.5, 9.2 Hz, 1H), 6.97 - 6.82 (m, 1H), 6.23 (br d, J = 16.7 Hz, 1H), 5.79 (br d, J = 10.4 Hz, 1H), 4.65 - 4.30 (m, 2H), 4.15 - 3.92 (m, 2H), 3.87 - 3.69 (m, 2H). Example 21: Synthesis of Compound 126 Step 1: tert-butyl 4-imidazo[1,2-a]pyrimidin-3-yl-3-oxo-piperazine-1-carboxylat e To a solution of 3-bromoimidazo[1,2-a]pyrimidine (A81, 500 mg, 2.52 mmol, 1 eq), tert- butyl 3-oxopiperazine-1-carboxylate (505.59 mg, 2.52 mmol, 1 eq), DMEDA (178.07 mg, 2.02 mmol, 217.42 uL, 0.8 eq) and K ₂ CO ₃ (697.94 mg, 5.05 mmol, 2 eq) in dioxane (5 mL) was added CuI (192.35 mg, 1.01 mmol, 0.4 eq) under N2. The mixture was stirred at 100 °C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was poured into H2O 30 mL, and celite filtered then extracted with EtOAc (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (25-50% EtOAc in PE) to give A82 (tert-butyl 4-imidazo[1,2- a]pyrimidin-3-yl-3-oxo-piperazine-1-carboxylate (370 mg, 933 umol)) as a solid. MS (ESI) m/z 318.2 [M+H] ⁺ . Step 2: 1-imidazo[1,2-a]pyrimidin-3-ylpiperazin-2-one A mixture of tert-butyl 4-imidazo[1,2-a]pyrimidin-3-yl-3-oxo-piperazine-1-carboxylat e (A82, 200 mg, 630.2 µmol, 1 eq) in HCl/dioxane (4 M, 30 mL, 190.4 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The crude was used to next step without further purification. A83 (1-imidazo[1,2- a]pyrimidin-3-ylpiperazin-2-one (136 mg, crude)) was obtained as a solid. MS (ESI) m/z 218.2 [M+H] ⁺ . Step 3: 4-acryloyl-1-(5-methylfuran-2-yl)piperazin-2-one To a solution of 1-imidazo[1,2-a]pyrimidin-3-ylpiperazin-2-one (A83, 136 mg, 626 µmol, 1 eq) in DCM (3 mL) was added TEA (190 mg, 1.88 mmol, 261.4 uL, 3 eq) and prop-2-enoyl chloride (51 mg, 563.5 µmol, 45.9 uL, 0.9 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient b) to give Compound 126 (1- imidazo[1,2-a]pyrimidin-3-yl-4-prop-2-enoyl-piperazin-2-one (10.48 mg, 37.4 umol)) as a solid. MS (ESI) m/z 272.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.01 (dd, J = 1.9, 6.7 Hz, 1H), 8.50 (dd, J = 1.9, 4.2 Hz, 1H), 8.33 (s, 1H), 7.09 (dd, J = 4.2, 6.7 Hz, 1H), 6.87 (br dd, J = 10.4, 16.7 Hz, 1H), 6.20 (br d, J = 16.7 Hz, 1H), 5.85 - 5.69 (m, 1H), 4.59 - 4.29 (m, 2H), 4.28 - 4.10 (m, 2H), 4.05 - 3.87 (m, 2H) An analogous method was performed to obtain the following compounds. Example 22: Synthesis of Compound 127 Step 1: tert-butyl 2-(4-benzyloxycarbonyl-2-oxo-piperazin-1-yl)-6,7-dihydro-4H- thiazolo[4,5- c]pyridine-5-carboxylate A mixture of tert-butyl 2-bromo-6,7-dihydro-4H-thiazolo[4,5-c]pyridine-5-carboxylate (400 mg, 1.25 mmol, 1 eq), benzyl 3-oxopiperazine-1-carboxylate (293.53 mg, 1.25 mmol, 1 eq), CuI (35.8 mg, 188 µmol, 0.15 eq), DMEDA (27.6 mg, 313.3 µmol, 33.7 uL, 0.25 eq) and K2CO3 (346.4 mg, 2.5 mmol, 2 eq) in dioxane (6 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction mixture was quenched by water (15 mL), and then extracted with EtOAc (20 mL *3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (25% EtOAc in PE) to give A85 (tert- butyl 2-(4-benzyloxycarbonyl-2-oxo-piperazin-1-yl)-6,7-dihydro-4H- thiazolo[4,5-c]pyridine-5- carboxylate (220 mg, 465.6 umol)) as a solid. MS (ESI) m/z 473.2 [M+H] ⁺ . Step 2: tert-butyl 2-(2-oxopiperazin-1-yl)-6,7-dihydro-4H-thiazolo[4,5-c]pyridi ne-5-carboxylate To a solution of tert-butyl 2-(4-benzyloxycarbonyl-2-oxo-piperazin-1-yl)-6,7-dihydro-4H- thiazolo[4,5-c]pyridine-5-carboxylate (150 mg, 317.42 µmol, 1 eq) in i-PrOH (5 mL) was added Pd/C (200 mg, 10% purity).The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that contains A86 (tert-butyl 2-(2- oxopiperazin-1-yl)-6,7-dihydro-4H-thiazolo[4,5-c]pyridine-5- carboxylate (84 mg, crude). MS (ESI) m/z 339.2 [M+H] ⁺ . Step 3: tert-butyl 2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-6,7-dihydro-4H-thiaz olo[4,5- c]pyridine-5-carboxylate To a solution of tert-butyl 2-(2-oxopiperazin-1-yl)-6,7-dihydro-4H-thiazolo[4,5- c]pyridine-5-carboxylate (84 mg, 248.21 µmol, 1 eq) in DCM (2 mL) was added TEA (125.58 mg, 1.24 mmol, 172.74 uL, 5 eq) and prop-2-enoyl chloride (22.46 mg, 248.21 µmol, 20.24 uL, 1 eq) in DCM (0.25 mL).The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient g) to give Compound 127 (tert-butyl 2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-6,7- dihydro-4H-thiazolo[4,5-c]pyridine-5-carboxylate (17.13 mg, 43.65 umol)) as a solid. MS (ESI) m/z 393.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 6.96 - 6.69 (m, 1H), 6.26 - 6.09 (m, 1H), 5.78 (br d, J = 9.6 Hz, 1H), 4.67 - 4.28 (m, 4H), 4.23 - 3.88 (m, 4H), 3.63 (t, J = 5.6 Hz, 2H), 2.74 (br t, J = 5.4 Hz, 2H), 1.42 ppm (s, 9H). Example 23: Synthesis of Compound 129 Step 1: 2-[(2-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethy l-silane A solution of 2-bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol, 1 eq) in THF (30 mL) was added NaH (609.04 mg, 15.23 mmol, 60% purity, 1.5 eq) stirred at 0 °C for 0.5 h, then added SEM-Cl (2.54 g, 15.23 mmol, 2.69 mL, 1.5 eq) was drop-wise, the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 60 mL, and then extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine 90 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-20% EtOAc in PE) to give A88 (2-[(2- bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-sila ne (2.1 g, 5.8 mmol)) as a solid. MS (ESI) m/z 327.0 [M+H] ⁺ . Step 2: tert-butyl 3-oxo-4-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrid in-2- yl]piperazine-1-carboxylate A solution of 2-[(2-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethy l-silane (2.1 g, 6.42 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (1.54 g, 7.70 mmol, 1.2 eq) in dioxane (30 mL) was added K ₂ CO ₃ (1.77 g, 12.83 mmol, 2 eq), CuI (488.79 mg, 2.57 mmol, 0.4 eq) and N,N'-dimethylethane-1,2-diamine (452.48 mg, 5.13 mmol, 552.48 uL, 0.8 eq) under N ₂ , the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL, and then extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine 70 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-20% EtOAc in Petroleum ether), TLC (50% EtOAc in PE, Rf = 0.46) to give A89 (tert-butyl 3-oxo-4-[1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2-yl]pipera zine-1-carboxylate (890 mg, 1.79 mmol)) as a solid.. MS (ESI) m/z 447.2 [M+H] ⁺ . Step 3: 1-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperazin-2-one A solution of tert-butyl 3-oxo-4-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrid in- 2-yl]piperazine-1-carboxylate (200 mg, 223.9 µmol, 1 eq) in DCM (0.5 mL) and TFA (3.08 g, 27 mmol, 2 mL, 120.6 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove DCM. A90 (1-(1H-pyrrolo[2,3-b]pyridin-2- yl)piperazin-2-one (100 mg, crude) was obtained as a solid. MS (ESI) m/z 217.1 [M+H] ⁺ . Step 4: 4-prop-2-enoyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperazin-2- one A solution of prop-2-enoyl chloride (37.7 mg, 416.2 µmol, 33.9 uL, 0.9 eq) in DCM (2 mL) was added TEA (93.6 mg, 924.9 µmol, 128.7 uL, 2 eq), then 1-(1H-pyrrolo[2,3-b]pyridin-2- yl)piperazin-2-one (100 mg, 462.5 µmol, 1 eq) in DCM (0.2 mL) was added drop-wise, the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 0.2 mL and remove DCM. The residue was purified by prep-HPLC (Condition 7, Gradient a), then the residue was purified by prep-HPLC (Condition 2, Gradient e) to give Compound 129 (1-prop- 2-enoyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperazin-2-one (12 mg, 43.5 umol)) as a solid. MS (ESI) m/z 271.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 11.65 (br d, J = 1.9 Hz, 1H), 8.16 (dd, J = 1.5, 4.8 Hz, 1H), 7.88 (dd, J = 1.5, 7.8 Hz, 1H), 7.06 (dd, J = 4.8, 7.8 Hz, 1H), 6.95 - 6.78 (m, 1H), 6.35 (s, 1H), 6.21 (br d, J = 16.5 Hz, 1H), 5.78 (br d, J = 9.6 Hz, 1H), 4.50 (br s, 1H), 4.35 (s, 1H), 4.03 (br d, J = 4.3 Hz, 1H), 3.96 - 3.84 (m, 3H). An analogous method was performed to obtain the following compounds. Example 24: Synthesis of Compound 128 Step 1: tert-butyl 3-oxo-4-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazine-1-car boxylate To a solution of 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (90 mg, 454.50 µmol, 1 eq) and tert-butyl 3-oxopiperazine-1-carboxylate (91.01 mg, 454.50 µmol, 1 eq) in dioxane (3 mL) was added Cs ₂ CO ₃ (444.25 mg, 1.36 mmol, 3 eq), then Pd ₂ (dba) ₃ (41.62 mg, 45.45 µmol, 0.1 eq) and Xantphos (52.60 mg, 90.90 µmol, 0.2 eq) was added under N2. The mixture was stirred at 130 °C for 2 h under N ₂ . Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (100% EtOAc) to give tert-butyl 3-oxo-4-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazine-1- carboxylate (130 mg, 287 µmol, 63% yield, 70% purity) as a solid. MS (ESI) m/z 318.2 [M+H] ⁺ . Step 2: 1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazin-2-one A mixture of tert-butyl 3-oxo-4-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazine-1- carboxylate (100 mg, 315 µmol, 1 eq) in DCM (1.5 mL) was added drop-wise TFA (462 mg, 4.05 mmol, 0.3 mL, 12.86 eq), the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 1-([1,2,4]triazolo[1,5-a]pyridin-2- yl)piperazin-2-one (65 mg, crude) as an oil. MS (ESI) m/z 218.2 [M+H] ⁺ . Step 3: 4-prop-2-enoyl-1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperaz in-2-one To a solution of 1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazin-2-one (65 mg, 299.2 µmol, 1 eq) in THF (1 mL) and H ₂ O (1 mL) was added K ₂ CO ₃ (91 mg, 658 µmol, 2.2 eq) at 0 °C, then prop-2-enoyl chloride (27.1 mg, 299.2 µmol, 24.4 uL, 1 eq) in THF (0.5 mL) was added drop- wise, the mixture was stirred at 0 °C for 0.5 h. Upon completion, the reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC (Condition 8, Gradient a) to give the 4- prop-2-enoyl-1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)piperazin -2-one (Compound 128, 11 mg, 39.9 µmol, 13% yield, 98% purity) as a solid. MS (ESI) m/z 272.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.93 (d, J = 6.8 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.74 - 7.66 (m, 1H), 7.26 - 7.17 (m, 1H), 6.91 - 6.77 (m, 1H), 6.20 (br d, J = 16.6 Hz, 1H), 5.77 (br d, J = 10.1 Hz, 1H), 4.55 - 4.32 (m, 2H), 4.09 - 3.87 (m, 4H). Example 25: Synthesis of Compound 133 A solution of (2R)-2-amino-4-phenyl-butanoic acid (5 g, 27.9 mmol, 1 eq) in HCl/MeOH (4 M, 50 mL, 7.17 eq) was stirred at 25 °C for 4 h. Upon completion, the mixture was diluted with 200 mL EtOAc, washed with NaHCO ₃ , water, brine, then dried over Na ₂ SO ₄ . To give methyl (2R)- 2-amino-4-phenyl-butanoate (5.28 g, crude) as an oil. Step 2: methyl (2S)-2-[2-(tert-butoxycarbonylamino)ethylamino]-4-phenyl-but anoate

To a solution of tert-butyl N-(2-oxoethyl)carbamate (1 g, 6.28 mmol, 1 eq) and methyl (2R)-2-amino-4-phenyl-butanoate (3.46 g, 7.54 mmol, 50% purity, 1.2 eq, HCl) in MeOH (10 mL), was added AcOH (528.14 mg, 8.79 mmol, 502.99 uL, 1.4 eq) and NaBH3CN (592.15 mg, 9.42 mmol, 1.5 eq) at 0 °C under N ₂ , the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition Sat. aq. NaHCO ₃ (15 mL) at 0 °C, and then diluted with H2O (10 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 3, Gradient c) to afford methyl (2S)-2-[2-(tert-butoxycarbonylamino)ethylamino]-4-phenyl-but anoate (1.45 g, 3.88 mmol, 62% yield, 90% purity) as an oil. Step 3: methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl ]amino]-4-phenyl- butanoate To a soution of methyl (2S)-2-[2-(tert-butoxycarbonylamino)ethylamino]-4-phenyl- butanoate (1.45 g, 4.31 mmol, 1 eq) in DCM (15 mL) was added CbzCl (1.10 g, 6.47 mmol, 919 uL, 1.5 eq) and DIEA (2.23 g, 17.2 mmol, 3 mL, 4 eq) at 0 °C, the mxture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 * 3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (33-50% EtOAc in PE) to give methyl (2R)-2- [benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino] -4-phenyl-butanoate (2 g, 3.95 mmol, 92% yield, 93% purity) as an oil. To a solution of methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino) ethyl]amino]-4-phenyl-butanoate (2 g, 4.3 mmol, 1 eq) in DCM (15 mL) was added TFA (7.7 g, 67.5 mmol, 5 mL, 15.9 eq), the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction concentrated in vacuo. To give methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-4- phenyl-butanoate (1.5 g, crude) as an oil. To solution of methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-4-phenyl- butanoate (1.5 g, 4.05 mmol, 1 eq) in DMF (20 mL) was added Cs2CO3 (3.30 g, 10.12 mmol, 2.5 eq), the mixture was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (50-100% EtOAc in PE) to give benzyl (2R)-3-oxo-2-(2-phenylethyl)piperazine-1-carboxylate (1.25 g, 2.96 mmol, 73% yield, 80% purity) as a solid. Step 6: benzyl (2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(2-phenylethyl)pip erazine-1- carboxylate A mixture of 2-bromoimidazo[1,2-a]pyridine (698.7 mg, 3.55 mmol, 1 eq), benzyl (2R)-3- oxo-2-(2-phenylethyl)piperazine-1-carboxylate (1.2 g, 3.55 mmol, 1 eq), CuI (101.3 mg, 532 µmol, 0.15 eq), DMEDA (78.2 mg, 886.5 µmol, 95.4 uL, 0.25 eq) and K2CO3 (980.2 mg, 7.1 mmol, 2 eq) in dioxane (12 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (33-50% EtOAc in Petroleum ether) to afford benzyl (2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(2- phenylethyl)piperazine-1-carboxylate (600 mg, 1.23 mmol, 35% yield, 93% purity) as a solid. A solution of benzyl (2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(2- phenylethyl)piperazine-1-carboxylate (150 mg, 330 µmol, 1 eq) in TFA (2 mL) was stirred at 70 °C for 4 h. Upon completion, the solution was concentrated to dryness to give crude. The crude was used directly for the next step. To give (3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(2- phenylethyl)piperazin-2-one (100 mg, crude) as an oil. Step 8: (3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(2-phenylethyl)-4-prop-2 -enoyl-piperazin-2-one To a solution of (3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(2-phenylethyl)piperazin -2-one (100 mg, 312.12 µmol, 1 eq) in DCM (13 mL) was added TEA (94.75 mg, 936.37 µmol, 130.33 uL, 3 eq) and then prop-2-enoyl chloride (33.90 mg, 374.55 µmol, 30.54 uL, 1.2 eq) was added at 0 °C. The solution was stirred for 1 h at 0 °C. Upon completion, the reaction concentrated in vacuo. The residue was purified by prep-HPLC (Condition 2, Gradient f) to afford (3R)-1-imidazo[1,2- a]pyridin-2-yl-3-(2-phenylethyl)-4-prop-2-enoyl-piperazin-2- one (Compound 133 (R), 30 mg, 79.4 µmol, 25% yield, 99% purity) as a solid. MS (ESI) m/z= 375.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.71 - 8.33 (m, 2H), 7.51 (br d, J = 8.9 Hz, 1H), 7.36 - 7.14 (m, 6H), 6.92 (dt, J = 0.9, 6.7 Hz, 2H), 6.22 (dd, J = 2.3, 16.6 Hz, 1H), 5.79 (br d, J = 10.1 Hz, 1H), 5.17 - 4.78 (m, 1H), 4.60 - 4.22 (m, 2H), 4.07 - 3.41 (m, 2H), 2.81 - 2.56 (m, 2H), 2.38 - 2.11 (m, 2H). An analogous method was performed to obtain the following compounds. Step 9: 1-imidazo[1,2-a]pyridin-2-yl-3-(2-phenylethyl)-4-prop-2-enoy l-piperazin-2-one

(3S)-1-imidazo[1,2-a]pyridin-2-yl-3-(2-phenylethyl)-4-prop-2 -enoyl-piperazin-2-one (Compound 133-(S), 10 mg, 26.7 µmol, 1 eq) and (3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(2- phenylethyl)-4-prop-2-enoyl-piperazin-2-one (Compound 133-(R), 10 mg, 26.7 µmol, 1 eq) was dissolved in MeCN 0.5 mL and H ₂ O 2 mL, then lyophilized to give 1-imidazo[1,2-a]pyridin-2-yl- 3-(2-phenylethyl)-4-prop-2-enoyl-piperazin-2-one (Compound 133, 15 mg, 40 umol). MS (ESI) m/z 375.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.58 (br d, J = 6.6 Hz, 1H), 8.37 (br s, 1H), 7.50 (br d, J = 8.9 Hz, 1H), 7.31 - 7.15 (m, 6H), 6.91 (br t, J = 6.8 Hz, 2H), 6.21 (dd, J = 2.1, 16.6 Hz, 1H), 5.78 (br d, J = 9.8 Hz, 1H), 5.15 - 4.78 (m, 1H), 4.28 (br d, J = 10.3 Hz, 2H), 4.08 - 3.75 (m, 2H), 2.71 - 2.57 (m, 2H), 2.33 - 2.14 (m, 2H) Example 26: Synthesis of Compound 134 To a solution of 2-amino-5-phenyl-pentanoic acid (5 g, 25.9 mmol, 1 eq) in MeOH (50 mL) was added SOCl2 (9.23 g, 77.6 mmol, 5.6 mL, 3 eq) at 0 °C, the mixture was stirred at 80 °C for 3 h. Upon completion, the mixture was concentrated in vacuum and was diluted with DCM and then was concentrated in vacuum to give methyl 2-amino-5-phenyl-pentanoate (6 g, crude, HCl) as a solid. MS (ESI) m/z 208.2 [M+H] ⁺ . Step 2: methyl 2-[2-(tert-butoxycarbonylamino)ethylamino]-5-phenyl-pentanoa te

To a solution of methyl 2-amino-5-phenyl-pentanoate (2 g, 8.21 mmol, 1 eq, HCl) and tert- butyl N-(2-oxoethyl)carbamate (1.31 g, 8.21 mmol, 1 eq) in MeOH (20 mL) was added NaBH ₃ CN (773.51 mg, 12.31 mmol, 1.5 eq) and AcOH (689.89 mg, 11.49 mmol, 657.04 uL, 1.4 eq) at 0 °C under N2, the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition sat. NaHCO3 (100 mL) at 0 °C, and then diluted with H2O (100 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-50% PE in EtOAc) to give methyl 2-[2-(tert- butoxycarbonylamino)ethylamino]-5-phenyl-pentanoate (1.3 g, 2.97 mmol, 36% yield, 80% purity) as an oil. MS (ESI) m/z 351.3 [M+H] ⁺ . Step 3: methyl 2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amin o]-5-phenyl- pentanoate To a solution of methyl 2-[2-(tert-butoxycarbonylamino)ethylamino]-5-phenyl- pentanoate (1.3 g, 3.71 mmol, 1 eq) in DCM (30 mL) was added DIEA (1.92 g, 14.84 mmol, 2.58 mL, 4 eq) and CbzCl (949.22 mg, 5.56 mmol, 791.02 uL, 1.5 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O (200 mL) and extracted with DCM (100 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column (0-25% EtOAc in PE) to give methyl 2-[benzyloxycarbonyl-[2-(tert- butoxycarbonylamino)ethyl]amino]-5-phenyl-pentanoate (1.5 g, 2.2 mmol, 58% yield, 70% purity) as a gum. MS (ESI) m/z 485.2 [M+H] ⁺ . A solution of methyl 2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amin o]- 5-phenyl-pentanoate (1.5 g, 3.1 mmol, 1 eq) in HCl/dioxane (20 mL, 4M) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated in vacuum to give methyl 2-[2- aminoethyl(benzyloxycarbonyl)amino]-5-phenyl-pentanoate (1.3 g, crude, HCl) as an oil. MS (ESI) m/z 385.2 [M+H] ⁺ . Step 5: benzyl 3-oxo-2-(3-phenylpropyl)piperazine-1-carboxylate To a solution of methyl 2-[2-aminoethyl(benzyloxycarbonyl)amino]-5-phenyl-pentanoate (1.3 g, 3.38 mmol, 1 eq) in DMF (15 mL) was added Cs ₂ CO ₃ (2.75 g, 8.45 mmol, 2.5 eq), the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 200 mL and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column (0-33% EtOAc in PE) to give benzyl 3-oxo-2-(3- phenylpropyl)piperazine-1-carboxylate (1.2 g, 2.4 mmol, 71% yield, 70% purity) as an oil. MS (ESI) m/z 353.2 [M+H] ⁺ . Step 6: benzyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(3-phenylpropyl)piperaz ine-1-carboxylate

To a solution of 2-bromoimidazo[1,2-a]pyridine (375.70 mg, 1.91 mmol, 1.2 eq), benzyl 3-oxo-2-(3-phenylpropyl)piperazine-1-carboxylate (800 mg, 1.59 mmol, 70% purity, 1 eq) in dioxane (16 mL) was added K2CO3 (439.21 mg, 3.18 mmol, 2 eq), CuI (121.05 mg, 635.59 µmol, 0.4 eq) and N,N'-dimethylethane-1,2-diamine (112.06 mg, 1.27 mmol, 136.82 uL, 0.8 eq) under N ₂ , the mixture was stirred at 100 °C for 20 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 100 mL and extracted with EtOAc (40 mL * 3). The combined organic layers were washed with NaCl 20 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column (0-25-50% EtOAc in PE) to give benzyl 4-imidazo[1,2- a]pyridin-2-yl-3-oxo-2-(3-phenylpropyl)piperazine-1-carboxyl ate (280 mg, 568 µmol, 36% yield, 95% purity) as a gum. MS (ESI) m/z 469.2 [M+H] ⁺ . A solution of benzyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(3-phenylpropyl)piperaz ine-1- carboxylate (250 mg, 534 µmol, 1 eq) in TFA (4 mL) was stirred at 70 °C for 2 h. Upon completion, the mixure was dried by blowing N ₂ to obtained 1-imidazo[1,2-a]pyridin-2-yl-3-(3- phenylpropyl)piperazin-2-one (180 mg, crude) as a gum. MS (ESI) m/z 335.2 [M+H] ⁺ . Step 8: 1-imidazo[1,2-a]pyridin-2-yl-3-(3-phenylpropyl)-4-prop-2-eno yl-piperazin-2-one

To a solution of 1-imidazo[1,2-a]pyridin-2-yl-3-(3-phenylpropyl)piperazin-2-o ne (240 mg, 473.66 µmol, 66% purity, 1 eq) in DCM (25 mL) was added TEA (239.65 mg, 2.37 mmol, 329.64 uL, 5 eq) and then was added prop-2-enoyl chloride (42.87 mg, 473.66 µmol, 38.62 uL, 1 eq) dropwised at 0 °C, the mixture was stirred at 0 °C for 0.5 h. Upon completion, the mixture was quenched with water (0.5 mL) and was dried by blowing N ₂ . The crude product was purified by prep-HPLC (Condition 4, Gradient f) to give 1-imidazo[1,2-a]pyridin-2-yl-3-(3-phenylpropyl)-4- prop-2-enoyl-piperazin-2-one (Compound 134, 40 mg, 103 µmol, 22% yield, 100% purity) as a solid. MS (ESI) m/z 389.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.57 (d, J = 6.6 Hz, 1H), 8.35 (s, 1H), 7.50 (br d, J = 8.8Hz, 1H), 7.31 - 7.21 (m, 3H), 7.21 - 7.12 (m, 3H), 6.96 - 6.81 (m, 2H), 6.20 (br d, J = 16.6 Hz, 1H), 5.84 - 5.68 (m, 1H), 5.10 - 4.77 (m, 1H), 4.59 - 4.17 (m, 2H), 4.08 - 3.64 (m, 2H), 2.72 - 2.53 (m, 2H), 2.05 - 1.84 (m, 2H), 1.77 - 1.50 (m, 2H). Example 27: Synthesis of Compound 135 Step1 : tert-butyl 3-oxo-2-(4-phenylbutyl)piperazine-1-carboxylate To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1 g, 4.99 mmol, 1 eq) in THF (10 mL) was added LDA (2.5 M, 4 mL, 2 eq). The mixture was stirred at -70 °C for 30 min, then a solution of (4-bromobutyl) benzene (745 mg, 3.5 mmol, 0.7 eq) in THF (2 mL) was added to the mixture. The mixture was stirred for 1 h. Upon completion, the mixture was quenched by NaHCO3 aq. (10 mL), then extract with EtOAc (20 mL * 3). The combined organic layers were washed with sat. NaCl (20 mL * 3), dried over Na ₂ SO ₄ to give a residue. The residue was purified by silica gel column (9-50% EtOAc in PE) to give tert-butyl 3-oxo-2-(4-phenylbutyl)piperazine-1-carboxylate as a solid. MS (ESI) m/z 333.2 [M+H] ⁺ . Step2 : tert-butyl 4-imidazo[1 To a solution of tert-butyl 3-oxo-2-(4-phenylbutyl)piperazine-1-carboxylate (350 mg, 1.05 mmol, 1 eq) and 2-bromoimidazo[1,2-a]pyridine (207.4 mg, 1.05 mmol, 1 eq) in dioxane (5 mL) was added K2CO3 (291 mg, 2.11 mmol, 2 eq), DMEDA (23.2 mg, 263.2 µmol, 28.3 uL, 0.25 eq), then exchanged N ₂ (x3), then added CuI (30.1 mg, 157.9 µmol, 0.15 eq) and exchange N ₂ (x3), The mixture was stirred at 100 °C for 12 h. Upon completion, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with sat. NaCl (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-50% EtOAc in PE) to give tert-butyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(4-phenylbutyl)piperazi ne-1- carboxylate (210 mg, 468 µmol, 45% yield) as a solid. MS (ESI) m/z 449.3[M+H] ⁺ To a solution of tert-butyl 4-imidazo[1,2-a]pyridin-2-yl-3-oxo-2-(4- phenylbutyl)piperazine-1-carboxylate (200 mg, 446 µmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.51 mmol, 30.29 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the resulting solution was concentrated in vacuum to give 1-imidazo [1, 2-a] pyridin-2-yl-3-(4- phenylbutyl) piperazin-2-one (150 mg, crude) as a solid. MS (ESI) m/z 349.3[M+H] ⁺ Step4 : 1-imidazo[1,2-a]pyridin-2-yl-3-(4-phenylbutyl)-4-prop-2-enoy l-piperazin-2-one

To a solution of 1-imidazo[1,2-a]pyridin-2-yl-3-(4-phenylbutyl)piperazin-2-on e (150 mg, 430.5 µmol, 1 eq) in DCM (2 mL) was added TEA (217.8 mg, 2.15 mmol, 299.6 uL, 5 eq) and prop-2-enoyl chloride (39 mg, 430 µmol, 35 uL, 1 eq) at 0 °C under N2 protection. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (Condition 1, Gradient g) to give 1- imidazo[1,2-a]pyridin-2-yl-3-(4-phenylbutyl)-4-prop-2-enoyl- piperazin-2-one (Compound 135, 62.3 mg, 154.7 µmol, 36% yield, 100% purity) as a solid. MS (ESI) m/z 403.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.62 - 8.55 (m, 1H), 8.41 - 8.33 (m, 1H), 7.55 - 7.45 (m, 1H), 7.29 - 7.11 (m, 6H), 6.95 - 6.80 (m, 2H), 6.27 - 6.09 (m, 1H), 5.82 - 5.66 (m, 1H), 4.80 (br s, 1H), 4.25 (br d, J = 9.7 Hz, 2H), 4.12 - 3.68 (m, 2H), 2.60 - 2.53 (m, 2H), 2.03 - 1.86 (m, 2H), 1.68 - 1.52 (m, 2H), 1.46 - 1.23 (m, 2H). An analogous method was followed to obtain the following compounds. Example 28: Synthesis of Compound 139 Step 1: methyl (R)-2-amino-3-(4-fluorophenyl)propanoate To a solution of (2R)-2-amino-3-(4-fluorophenyl)propanoic acid (5 g, 27.3 mmol, 1 eq) in MeOH (60 mL) was added SOCl ₂ (13 g, 109 mmol, 7.9 mL, 4 eq) at 0 °C. And then, the reaction mixture was stirred at 60 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2R)-2-amino-3-(4-fluorophenyl)propanoate (6.2 g, crude, HCl) as a solid. Step 2: methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(4-fluorop henyl)propanoate

To a solution of tert-butyl N-(2-oxoethyl)carbamate (3.5 g, 22 mmol, 1 eq) and methyl (2R)-2-amino-3-(4-fluorophenyl)propanoate (6.17 g, 26 mmol, 1.2 eq, HCl) in MeOH (50 mL) was added NaBH ₃ CN (2.07 g, 33 mmol, 1.5 eq) and AcOH (1.85 g, 30.8 mmol, 1.76 mL, 1.4 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was adjusted pH to 7 by NaHCO3 aq., then extracted with EtOAc (50 mL * 3), then washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (5-100% EtOAc in PE) to give methyl (2R)-2-[2-(tert- butoxycarbonylamino)ethylamino]-3-(4-fluorophenyl)propanoate (5 g, 13.2 mmol, 60% yield, 90% purity) as an oil. MS (ESI) m/z 341.3 [M+H] ⁺ . Step 3: methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl ]amino]-3-(4- fluorophenyl)propanoate To a solution of methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(4- fluorophenyl)propanoate (5 g, 14.7 mmol, 1 eq) and in DCM (50 mL) was added DIEA (7.59 g, 58.8 mmol, 10.2 mL, 4 eq) and CbzCl (3.8 g, 22 mmol, 3.13 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was poured into H ₂ O (150 mL) at 20 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (5-100% EtOAc in PE) to give methyl (2R)-2- [benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl]amino] -3-(4-fluorophenyl)propanoate (5 g, 9.5 mmol, 65% yield, 90% purity) as an oil. MS (ESI) m/z 375.2 [M+H-100] ⁺ . Step 4: methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(4-fluorophe nyl)propanoate A solution of methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)- ethyl]amino]-3-(4-fluorophenyl)propanoate (5 g, 10.5 mmol, 1 eq) in HCl/dioxane (4 M, 50 mL, 19 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(4- fluorophenyl)propanoate (4.8 g, crude, HCl) as an oil. MS (ESI) m/z 375.2 [M+H] ⁺ . Step 5: benzyl (2R)-2-[(4-fluorophenyl)methyl]-3-oxo-piperazine-1-carboxyla te A solution of methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(4- fluorophenyl)propanoate (4.8 g, 11.7 mmol, 1 eq, HCl) in MeOH (70 mL) was added DBU (1.78 g, 11.7 mmol, 1.76 mL, 1 eq), the reaction mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was poured into H ₂ O (50 mL) at 20 °C, and then extracted with EtOAc (70mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (5- 75% EtOAc in PE) to give benzyl (2R)-2-[(4-fluorophenyl)methyl]-3-oxo-piperazine-1- carboxylate (3.2 g, 9.4 mmol, 80% yield) as a solid. MS (ESI) m/z 343.3 [M+H] ⁺ . Step 6: benzyl (2R)-2-[(4-fluorophenyl)methyl]-4-imidazo[1,2-a]pyridin-2-yl -3-oxo-piperazine- 1-carboxylate A solution of benzyl (2R)-2-[(4-fluorophenyl)methyl]-3-oxo-piperazine-1-carboxyla te (1.2 g, 3.5 mmol, 1 eq) and 2-bromoimidazo[1,2-a]pyridine (828.7 mg, 4.2 mmol, 1.2 eq) in dioxane (15 mL) and dipotassium;carbonate (968.84 mg, 7.01 mmol, 2 eq) was gassed and purged with N ₂ (x3). Then CuI (267 mg, 1.4 mmol, 0.4 eq) and N,N'-dimethylethane-1,2-diamine (247.2 mg, 2.8 mmol, 302 uL, 0.8 eq) was added under N2, the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was poured into H2O (10 mL) at 20 °C, and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (5-35% EtOAc in PE) to give benzyl (2R)-2-[(4-fluorophenyl)methyl]-4- imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazine-1-carboxylate (750 mg, 1.6 mmol, 47% yield) as a solid. MS (ESI) m/z 459.2 [M+H] ⁺ . Step 7: (3R)-3-[(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl -piperazin-2-one

A solution of benzyl (2R)-2-[(4-fluorophenyl)methyl]-4-imidazo[1,2-a]pyridin-2-yl -3- oxo-piperazine-1-carboxylate (400 mg, 872.4 µmol, 1 eq) in TFA (5 mL) was stirred at 70 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (3R)- 3-[(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl-pipe razin-2-one (280 mg, crude) was obtained as an oil. MS (ESI) m/z 325.3 [M+H] ⁺ . Step 8: (3R)-3-[(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl -4-prop-2-enoyl-piperazin- 2-one To a solution of (3R)-3-[(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl -piperazin- 2-one (280 mg, 863.3 µmol, 1 eq) in DCM (4 mL) was added TEA (262 mg, 2.6 mmol, 360.5 uL, 3 eq) and then prop-2-enoyl chloride (78.1 mg, 863.3 µmol, 70.4 uL, 1 eq) in DCM (1 mL) was added at 0 °C. The solution was stirred for 0.5 h at 0 °C. Upon completion, the reaction mixture was quenched by addition H2O (0.5 mL) at 0 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient i) to give (3R)-3- [(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl-4-prop -2-enoyl-piperazin-2-one (Compound 139-(R), 128 mg, 338 µmol, 39% yield) as a solid. MS (ESI) m/z 379.1 [M+H] ⁺ . An analogous method was followed to obtain the following compound. Step 9: 3-[(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl-4-pr op-2-enoyl-piperazin-2- one (3R)-3-[(4-fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl -4-prop-2-enoyl-piperazin- 2-one (Compound 139-(R), 10 mg, 26.4 μmol, 1 eq) and (3S)-3-[(4-fluorophenyl)methyl]-1- imidazo[1,2-a]pyridin-2-yl-4-prop-2-enoyl-piperazin-2-one (Compound 139-(S), 10 mg, 26.4 μmol, 1 eq) was dissolved in MeCN (0.5 mL) and H2O (2 mL), The mixture was stirred at 25 °C for 5 min. Upon completion, the mixture was obtained by freeze-drying to give 3-[(4- fluorophenyl)methyl]-1-imidazo[1,2-a]pyridin-2-yl-4-prop-2-e noyl-piperazin-2-one (Compound 139, 18 mg, 47.6 μmol, 90% yield, 100% purity) as a solid. MS (ESI) m/z 379.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.62 (t, J = 7.3 Hz, 1H), 8.42 (d, J = 12.6 Hz, 1H), 7.52 (t, J = 10.0 Hz, 1H), 7.31 - 7.14 (m, 3H), 7.13 - 7.04 (m, 2H), 6.94 (t, J = 6.7 Hz, 1H), 6.88 - 6.19 (m, 1H), 6.17 - 5.82 (m, 1H), 5.81 - 5.32 (m, 1H), 5.22 (s, 1H), 4.68 - 4.27 (m, 1H), 4.24 - 4.03 (m, 1H), 4.01 - 3.70 (m, 1H), 3.47 - 3.37 (m, 1H), 3.29 - 3.17 (m, 2H). An analogous method was followed to obtain the following compounds. Example 29: Synthesis of Compound 144 Step 1: methyl (2R)-2-amino-3-(4-nitrophenyl)propanoate A solution of (2R)-2-amino-3-(4-nitrophenyl)propanoic acid (10 g, 47.6 mmol, 1 eq) in MeOH (100 mL) was added SOCl2 (22.6 g, 190.3 mmol, 13.8 mL, 4 eq). The mixture was stirred at 80 °C for 2 hr. Upon completion, the reaction mixture was poured into H2O 300 mL at 20 °C, and then extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine 300 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl (2R)-2-amino-3-(4-nitrophenyl)propanoate (12 g, crude) as a solid. MS (ESI) m/z 225.2 [M+H] ⁺ . Step 2: methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(4-nitroph enyl)propanoate

A solution of methyl (2R)-2-amino-3-(4-nitrophenyl)propanoate (6 g, 26.8 mmol, 1.2 eq) and tert-butyl N-(2-oxoethyl)carbamate (3.55 g, 22.3 mmol, 1 eq) in MeOH (60 mL) was added NaBH ₃ CN (2.1 g, 33.5 mmol, 1.5 eq) and AcOH (1.87 g, 31.2 mmol, 1.79 mL, 1.4 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was poured into H2O 200 mL at 20 °C, and then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc in PE) (TLC, 100% EtOAc, Rf = 0.5) to give methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(4- nitrophenyl)propanoate (6 g, 15.2 mmol, 70% yield, 93% purity) as a solid. MS (ESI) m/z 368.2 [M+H] ⁺ . Step 3: methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl ]amino]-3-(4- nitrophenyl)propanoate A solution of methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(4- nitrophenyl)propanoate (5.5 g, 15 mmol, 1 eq) in DCM (50 mL) was added DIEA (7.74 g, 59.88 mmol, 10.43 mL, 4 eq) and CbzCl (3.8 g, 22.5 mmol, 3.2 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. Upon completion, the reaction mixture was poured into H2O 100 mL at 20 °C, and then extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-100% EtOAc in PE) to give methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)-ethy l]amino]-3-(4- nitrophenyl)propanoate (6.3 g, 12 mmol, 81% yield, 96% purity) as an oil. MS (ESI) m/z 524.2 [M+Na] ⁺ . Step 4: methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(4-nitrophen yl)propanoate A solution of methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl ]- amino]-3-(4-nitrophenyl)propanoate (6.3 g, 12.6 mmol, 1 eq) in HCl/dioxane (4 M, 60 mL) was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated under reduced pressure to give methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(4-nitrophen yl)propanoate (4.6 g, crude) as an oil. MS (ESI) m/z 402.2 [M+H] ⁺ . Step 5: benzyl (2R)-2-[(4-nitrophenyl)methyl]-3-oxo-piperazine-1-carboxylat e A solution of methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(4- nitrophenyl)propanoate (4.6 g, 11.5 mmol, 1 eq) in DMF (60 mL) was added Cs ₂ CO ₃ (7.47 g, 22.9 mmol, 2 eq). The mixture was stirred at 80 °C for 2 hr. Upon completion, the reaction mixture was quenched by addition H2O 100 mL at 25 °C, and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (100 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0- 50% EtOAc in PE) to give benzyl (2R)-2-[(4-nitrophenyl)methyl]-3-oxo-piperazine-1-carboxylat e (1.96 g, 3.9 mmol, 25% yield, 74% purity) as an oil. MS (ESI) m/z 370.2 [M+H] ⁺ . Step 6: benzyl (2R)-4-imidazo[1,2-a]pyridin-2-yl-2-[(4-nitrophenyl)methyl]- 3-oxo-piperazine-1- carboxylate A mixture of benzyl (2R)-2-[(4-nitrophenyl)methyl]-3-oxo-piperazine-1-carboxylat e (1.96 g, 5.3 mmol, 1 eq), 2-bromoimidazo[1,2-a]pyridine (1.25 g, 6.4 mmol, 1.2 eq), K ₂ CO ₃ (1.47 g, 10.6 mmol, 2 eq), CuI (404.2 mg, 2.12 mmol, 0.4 eq) and DMEDA (374.2 mg, 4.25 mmol, 456.9 uL, 0.8 eq) in dioxane (20 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 °C for 16 hr under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition H ₂ O 60 mL, and then extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine 70 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-50% EtOAc in PE) to give benzyl (2R)-4-imidazo[1,2-a]pyridin-2-yl-2-[(4-nitrophenyl)methyl]- 3-oxo- piperazine-1-carboxylate (1 g, 1.85 mmol, 35% yield, 90% purity) as a solid. MS (ESI) m/z 486.2 [M+H] ⁺ . Step 7: benzyl (2R)-2-[(4-aminophenyl)methyl]-4-imidazo[1,2-a]pyridin-2-yl- 3-oxo-piperazine- 1-carboxylate

A solution of benzyl (2R)-4-imidazo[1,2-a]pyridin-2-yl-2-[(4-nitrophenyl)methyl]- 3-oxo- piperazine-1-carboxylate (500 mg, 1.03 mmol, 1 eq) and NH ₄ Cl (551 mg, 10.3 mmol, 10 eq) in EtOH (15 mL) and H2O (3 mL) then Fe (287.6 mg, 5.15 mmol, 5 eq) was added at 60 °C and was stirred at 80 °C for 2 h. Upon completion, the solids were filtered out and the resulting solution was concentrated under vacuum. The residue was purified by column chromatography (0-100% EtOAc in PE) to give benzyl (2R)-2-[(4-aminophenyl)methyl]-4-imidazo[1,2-a]pyridin-2-yl- 3- oxo-piperazine-1-carboxylate (500 mg, crude) as an oil. MS (ESI) m/z 456.2 [M+H] ⁺ . Step 8: benzyl (2R)-2-[(4-acetamidophenyl)methyl]-4-imidazo[1,2-a]pyridin-2 -yl-3-oxo- piperazine-1-carboxylate A solution of benzyl (2R)-2-[(4-aminophenyl)methyl]-4-imidazo[1,2-a]pyridin-2-yl- 3- oxo-piperazine-1-carboxylate (500 mg, 1.10 mmol, 1 eq) in DCM (5 mL) was added Py (260.48 mg, 3.29 mmol, 265.79 uL, 3 eq) then Ac2O (123.27 mg, 1.21 mmol, 113.09 uL, 1.1 eq) was added, and was stirred at 20°C for 1 h. Upon completion, the reaction mixture was poured into H ₂ O 20 mL at 20 °C, and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give benzyl (2R)-2-[(4-acetamidophenyl)methyl]-4-imidazo[1,2-a]pyridin-2 -yl-3-oxo-piperazine- 1-carboxylate (660 mg, crude) as an oil. MS (ESI) m/z 498.2 [M+H] ⁺ . Step 9: N-[4-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2- yl]methyl]phenyl]acetamide A mixture of benzyl (2R)-2-[(4-acetamidophenyl)methyl]-4-imidazo[1,2-a]pyridin-2 -yl-3- oxo-piperazine-1-carboxylate (660 mg, 1.33 mmol, 1 eq), Pd/C (660 mg, 1.33 mmol, 10% purity, 1 eq) in EtOH (5 mL) was degassed and purged with H ₂ (x3), and then the mixture was stirred at 20 °C for 10 min under H2 (15 Psi) atmosphere. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give N-[4-[[(2R)-4-imidazo[1,2-a]pyridin-2- yl-3-oxo-piperazin-2-yl]methyl]phenyl]acetamide (290 mg, crude) as an oil. MS (ESI) m/z 364.2 [M+H] ⁺ . Step 10: N-[4-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1-prop-2-enoy l-piperazin-2- yl]methyl]phenyl]acetamide A solution of N-[4-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2- yl]methyl]phenyl]acetamide (540 mg, 1.60 mmol, 1 eq) in DCM (6 mL) was added TEA (807.48 mg, 7.98 mmol, 1.11 mL, 5 eq) and prop-2-enoyl chloride (216.67 mg, 2.39 mmol, 194.50 μL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 1, Gradient h) to give N-[4-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1- prop-2-enoyl-piperazin-2-yl]methyl]phenyl]acetamide (Compound 152, 38.6 mg, 92.5 μmol, 6% yield, 100% purity) as a solid. MS (ESI) m/z 418.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 9.86 (d, J = 7.4 Hz, 1H), 8.61 (t, J = 6.7 Hz, 1H), 8.41 (d, J = 10.4 Hz, 1H), 7.55 - 7.37 (m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 7.05 (br dd, J = 8.3, 18.8 Hz, 2H), 6.93 (t, J = 6.6 Hz, 1H), 6.86 - 6.20 (m, 1H), 6.17 - 5.85 (m, 1H), 5.77 - 5.35 (m, 1H), 5.20 - 4.89 (m, 1H), 4.61 - 4.22 (m, 1H), 4.13 - 3.70 (m, 2H), 3.30 - 3.06 (m, 3H), 2.00 (d, J = 3.3 Hz, 3H). An analogous method was followed to obtain the following compound. Step 11: N-[4-[(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1-prop-2-enoyl-pip erazin-2- yl)methyl]phenyl]acetamide N-[4-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1-prop-2-enoy l-piperazin-2-yl]methyl]- phenyl]acetamide (Compound 152, 6 mg, 14.4 µmol, 1 eq) and N-[4-[[(2S)-4-imidazo[1,2- a]pyridin-2-yl-3-oxo-1-prop-2-enoyl-piperazin-2-yl]methyl]ph enyl]acetamide (Compound 151, 6 mg, 14.37 µmol, 1 eq) was dissolved in MeCN 0.5 mL and H2O 2 mL, then lyophilized to give N-[4-[(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1-prop-2-enoyl-pip erazin-2-yl)methyl]phenyl] acetamide (Compound 144, 10.4 mg, 25 µmol, 100% yield). MS (ESI) m/z 418.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 9.85 (br d, J = 7.2 Hz, 1H), 8.61 (br t, J = 6.4 Hz, 1H), 8.41 (d, J = 10.2 Hz, 1H), 7.55 - 7.41 (m, 3H), 7.25 (br t, J = 7.8 Hz, 1H), 7.05 (br dd, J = 8.2, 18.8 Hz, 2H), 6.93 (t, J = 6.6 Hz, 1H), 6.86 - 6.21 (m, 1H), 6.16 - 5.85 (m, 1H), 5.77 - 5.36 (m, 1H), 5.18 - 4.91 (m, 1H), 4.58 - 4.24 (m, 1H), 4.12 - 3.71 (m, 2H), 3.29 - 3.06 (m, 3H), 2.00 (br d, J = 3.0 Hz, 3H). Example 30: Synthesis of Compound 150 Step 1: methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(1H-indol- 3-yl)propanoate To a solution of tert-butyl N-(2-oxoethyl)carbamate (1 g, 6.3 mmol, 1 eq) and methyl (2R)- 2-amino-3-(1H-indol-3-yl)propanoate (1.9 g, 7.5 mmol, 1.2 eq, HCl) in MeOH (40 mL), was added NaBH ₃ CN (592 mg, 9.42 mmol, 1.5 eq), AcOH (528.2 mg, 8.79 mmol, 503 uL, 1.4 eq) at 0 °C under N ₂ atmosphere, and then the mixture was stirred at 25 °C for 1 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition of sat. aq. NaHCO3 (10 mL) at 0 °C, and then diluted with H2O (20 mL) and extracted with DCM (20 mL x3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-50% EtOAc in PE) to give methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(1H-indol- 3- yl)propanoate (1.78 g, 4.9 mmol, 78% yield, 97% purity) as an oil. MS (ESI) m/z 362.2 [M+H] ⁺ . Step 2: methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)ethyl ]amino]-3-(1H- indol-3-yl)propanoate To a solution of methyl (2R)-2-[2-(tert-butoxycarbonylamino)ethylamino]-3-(1H-indol- 3- yl)propanoate (1.7 g, 4.70 mmol, 1 eq) in DCM (20 mL), was added CbzCl (1.20 g, 7 mmol, 1 mL, 1.5 eq) and DIEA (2.43 g, 18.8 mmol, 3.28 mL, 4 eq) at 0 °C. The mixture was stirred at 25 °C for 2.5h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-20% EtOAc in PE) to give methyl (2R)-2-[benzyloxycarbonyl-[2-(tert- butoxycarbonylamino)ethyl]amino]-3-(1H-indol-3-yl)propanoate (1.54 g, 3.1 mmol, 66% yield, 100% purity) as an oil. MS (ESI) m/z 396.3 [M+H-Boc] ⁺ . Step 3: methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(1H-indol-3- yl)propanoate A solution of methyl (2R)-2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino)- ethyl]amino]-3-(1H-indol-3-yl)propanoate (1.54 g, 3.11 mmol, 1 eq) and TFA (11.86 g, 104 mmol, 7.70 mL, 33.5 eq) in DCM (24 mL), the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2R)-2-[2- aminoethyl(benzyloxycarbonyl)amino]-3-(1H-indol-3-yl)propano ate (1.2 g, crude) as an oil. MS (ESI) m/z 396.2 [M+H] ⁺ . To solution of methyl (2R)-2-[2-aminoethyl(benzyloxycarbonyl)amino]-3-(1H-indol-3- yl)propanoate (1.2 g, 3.03 mmol, 1 eq) in DMF (25 mL), was added Cs ₂ CO ₃ (2.47 g, 7.6 mmol, 2.5 eq), the mixture was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (50-100% EtOAc in PE) to give benzyl (2R)-2-(1H-indol-3-ylmethyl)-3-oxo-piperazine-1-carboxylate (1.1 g, 3 mmol, 99.8% yield, 97.7% purity) as a solid. MS (ESI) m/z 364.2 [M+H] ⁺ . Step 5: tert-butyl 3-[[(2R)-1-benzyloxycarbonyl-3-oxo-piperazin-2-yl]methyl]ind ole-1- carboxylate To a solution of benzyl (2R)-2-(1H-indol-3-ylmethyl)-3-oxo-piperazine-1-carboxylate (1 g, 2.75 mmol, 1 eq) and DMAP (33.6 mg, 275.2 µmol, 0.1 eq) in DCM (10 mL), was added tert- butoxycarbonyl tert-butyl carbonate (540.5 mg, 2.48 mmol, 568.9 uL, 0.9 eq) at 0 °C, the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was added aq.citric acid (5 mL), and extracted with DCM (10 mL * 2). The combined organic layers were washed with NaHCO3 (10 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (50-100% EtOAc in PE) to give tert-butyl 3-[[(2R)-1-benzyloxycarbonyl-3-oxo-piperazin-2-yl]methyl]ind ole-1- carboxylate (400 mg, 863 µmol, 31% yield) as an oil. MS (ESI) m/z 464.2 [M+H] ⁺ . Step 6: tert-butyl 3-[[(2R)-1-benzyloxycarbonyl-4-imidazo[1,2-a]pyridin-2-yl-3- oxo-piperazin-2- yl]methyl]indole-1-carboxylate To a solution of tert-butyl 3-[[(2R)-1-benzyloxycarbonyl-3-oxo-piperazin-2- yl]methyl]indole-1-carboxylate (410 mg, 884.5 µmol, 1 eq), 2-bromoimidazo[1,2-a]pyridine (174.3 mg, 884.5 µmol, 1 eq), CuI (25.3 mg, 132.7 µmol, 0.15 eq), DMEDA (19.5 mg, 221 µmol, 23.8 uL, 0.25 eq) and K2CO3 (244.5 mg, 1.77 mmol, 2 eq) in dioxane (10 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and extracted with DCM (10 mL * 3). The combined organic layers were, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0- 50% EtOAc in PE) to give tert-butyl 3-[[(2R)-1-benzyloxycarbonyl-4-imidazo[1,2-a]pyridin-2-yl- 3-oxo-piperazin-2-yl]methyl]indole-1-carboxylate (250 mg, 431 µmol, 49% yield) as an oil. MS (ESI) m/z 580.2 [M+H] ⁺ . Step 7: tert-butyl 3-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2-yl]m ethyl]indole-1- carboxylate

To a solution of tert-butyl 3-[[(2R)-1-benzyloxycarbonyl-4-imidazo[1,2-a]pyridin-2-yl-3- oxo-piperazin-2-yl]methyl]indole-1-carboxylate (250 mg, 431.3 µmol, 1 eq) in i-PrOH (5 mL) was added and Pd/C (100 mg, 10% purity), the mixture was degassed and purged with H ₂ (x3), and stirred at 25 °C for 30 min at 15 Psi under H2. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl- 3-oxo-piperazin-2-yl]methyl]indole-1-carboxylate (185 mg, crude) as an oil. MS (ESI) m/z 446.3 [M+H] ⁺ . To a solution of tert-butyl 3-[[(2R)-4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2- yl]methyl]indole-1-carboxylate (180 mg, 404 µmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL, 33.4 eq), the mixture was stirred at 25 °C for 30 min. Upon completion, the reaction mixture was concentrated under reduced pressure to give (3R)-1-imidazo[1,2-a]pyridin- 2-yl-3-(1H-indol-3-ylmethyl)piperazin-2-one (135 mg, crude) as an oil. MS (ESI) m/z 346.3 [M+H] ⁺ . Step 9: (3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(1H-indol-3-ylmethyl)-4- prop-2-enoyl-piperazin-2- one

To a solution of (3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(1H-indol-3-ylmethyl)pip erazin-2- one (135 mg, 391 µmol, 1 eq) and TEA (237 mg, 2.35 mmol, 326.4 uL, 6 eq) in DCM (10 mL) and then prop-2-enoyl chloride (31.8 mg, 352 µmol, 29 uL, 0.9 eq) was added at 0 °C, the solution was stirred for 30 min at 0 °C. Upon completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient j) to give (3R)-1- imidazo[1,2-a]pyridin-2-yl-3-(1H-indol-3-ylmethyl)-4-prop-2- enoyl-piperazin-2-one (Compound 150, 45 mg, 113 μmol, 29% yield, 100% purity) as a solid. MS (ESI) m/z 400.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 - 10.70 (m, 1H), 8.62 (t, J = 7.4 Hz, 1H), 8.45 (d, J = 17.8 Hz, 1H), 7.61 - 7.38 (m, 2H), 7.37 - 7.15 (m, 2H), 7.14 - 6.68 (m, 4H), 6.33 - 4.86 (m, 3H), 5.20 - 4.86 (m, 1H), 4.57 - 4.18 (m, 1H), 4.06 - 3.63 (m, 2H), 3.60 - 3.35 (m, 2H), 3.30 - 2.91 (m, 1H). An analogous method was followed to obtain the following compound. Step 10: 1-imidazo[1,2-a]pyridin-2-yl-3-(1H-indol-3-ylmethyl)-4-prop- 2-enoyl-piperazin-2-one

(3R)-1-imidazo[1,2-a]pyridin-2-yl-3-(1H-indol-3-ylmethyl)-4- prop-2-enoyl-piperazin-2-one (Compound 150, 7 mg, 17.5 μmol, 1 eq) and (3S)-1-imidazo[1,2-a]pyridin-2-yl-3-(1H-indol-3- ylmethyl)-4-prop-2-enoyl-piperazin-2-one (Compound 149, 7 mg, 17.5 μmol, 1 eq) was dissolved in ACN (2 mL) and H ₂ O (10 mL) and lyophilized to give 1-imidazo[1,2-a]pyridin-2-yl-3-(1H- indol-3-ylmethyl)-4-prop-2-enoyl-piperazin-2-one (Compound 143, 12 mg, crude) as a solid. MS (ESI) m/z 400.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 10.99 - 10.72 (m, 1H), 8.62 (t, J = 7.4 Hz, 1H), 8.45 (d, J = 17.8 Hz, 1H), 7.60 - 7.39 (m, 2H), 7.35 - 7.16 (m, 2H), 7.08 - 6.88 (m, 4H), 6.83 - 5.22 (m, 3H), 5.21 - 4.88 (m, 1H), 4.55 - 4.16 (m, 1H), 4.06 - 3.63 (m, 2H), 3.55 - 3.34 (m, 2H), 3.18 - 2.96 (m, 1H). An analogous method to the last step was followed to obtain the following compound. Example 31: Synthesis of Compound 154 Step 1: methyl 2-(3-oxopiperazin-2-yl)acetate To a solution of dimethyl maleate (10 g, 69.38 mmol, 8.70 mL, 1 eq) in i-PrOH (100 mL) was added ethane-1, 2-diamine (4.57 g, 76.04 mmol, 5.09 mL, 1.10 eq) at 25 °C. The mixture was stirred at 50 °C for 16 h. Upon completion, the reaction mixture filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE: EA = 1:1 at 25 °C for 30 min to give methyl 2-(3-oxopiperazin-2-yl)acetate (9.3 g, 54 mmol, 78% yield, 100% purity) as a solid. MS (ESI) m/z 173.2 [M+H] ⁺ . Step.2: tert-butyl 2-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate To a solution of methyl 2-(3-oxopiperazin-2-yl)acetate (8.8 g, 51.1 mmol, 1 eq) in DCM (150 mL) was added TEA (7.24 g, 71.5 mmol, 9.96 mL, 1.4 eq) and Boc2O (11.15 g, 51.1 mmol, 11.7 mL, 1 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (33-100% EtOAc in Petroleum ether) to give tert-butyl 2-(2-methoxy-2- oxoethyl)-3-oxopiperazine-1-carboxylate (13.2 g, 48.5 mmol, 95% yield, 100% purity) as a solid. MS (ESI) m/z 273.1 [M+H] ⁺ . Step.3: tert-butyl 4-(imidazo[1,2-a]pyridin-2-yl)-2-(2-methoxy-2-oxoethyl)-3-ox opiperazine-1- carboxylate A solution of tert-butyl 2-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate (5 g, 18.4 mmol, 1 eq) in dioxane (20 mL) was added K ₂ CO ₃ (5.1 g, 36.7 mmol, 2 eq) and N,N'- dimethylethane-1,2-diamine (1.29 g, 14.7 mmol, 1.58 mL, 0.8 eq). Then CuI (1.40 g, 7.34 mmol, 0.4 eq) and 2-bromoimidazo[1,2-a]pyridine (4.34 g, 22.03 mmol, 1.2 eq) was added. The mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H2O (20 mL) at 25 °C, and then diluted with EtOAc (15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (18-50% EtOAc in PE) to give tert-butyl 4-(imidazo[1,2-a]pyridin-2-yl)-2-(2- methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate (2.5 g, 6.2 mmol, 34% yield, 97% purity) as a solid. MS (ESI) m/z 389.1 [M+H] ⁺ . Step.4: methyl 2-(4-(imidazo[1,2-a]pyridin-2-yl)-3-oxopiperazin-2-yl)acetat e A mixture of tert-butyl 4-(imidazo[1,2-a]pyridin-2-yl)-2-(2-methoxy-2-oxoethyl)-3- oxopiperazine-1-carboxylate (500 mg, 1.29 mmol, 1 eq) in HCl/dioxane (4 M, 25 mL, 77.7 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under N2 to give methyl 2-(4-(imidazo[1,2-a]pyridin-2-yl)-3-oxopiperazin-2-yl)acetat e (400 mg, crude) as an oil. MS (ESI) m/z 289.1 [M+H] ⁺ . Step 5: methyl 2-(1-acryloyl-4-(imidazo[1,2-a]pyridin-2-yl)-3-oxopiperazin- 2-yl)acetate To a solution of methyl 2-(4-(imidazo[1,2-a]pyridin-2-yl)-3-oxopiperazin-2-yl)acetat e (371 mg, 1.29 mmol, 1 eq) in DCM (2 mL) was added TEA (390.64 mg, 3.86 mmol, 537.34 uL, 3 eq) at 0 °C, then added a solution of prop-2-enoyl chloride (139.76 mg, 1.54 mmol, 125.91 uL, 1.2 eq) in DCM (0.5 mL) to the mixture and was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H2O (1 mL) at 25 °C and concentrated under N2 to give a residue. The residue was purified by prep-HPLC (Condition 6, Gradient c) to give methyl 2-(1-acryloyl-4-(imidazo[1,2-a]pyridin-2-yl)-3-oxopiperazin- 2-yl)acetate (Compound 154, 500 mg, crude) as an oil. MS (ESI) m/z 343.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6): δ = 8.54 (d, J = 6.8 Hz, 1H), 8.32 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.18-7.27 (m, 1H), 6.74-6.95 (m, 2H), 6.17 (dd, J = 16.8, 2.1 Hz, 1H), 5.76 (dd, J = 10.6, 2.2 Hz, 1H), 5.20 (t, J = 6.0 Hz, 1H), 4.28-4.49 (m, 2H), 3.81-3.98 (m, 1H), 3.63-3.76 (m, 1H), 3.62 (s, 3H), 2.98 ppm (t, J = 5.8 Hz, 2H). Example 32: Synthesis of Compound 155 Step 1: 2-(1-tert-butoxycarbonyl-4-imidazo[1,2-a]pyridin-2-yl-3-oxo- piperazin-2-yl)acetic acid To a solution of tert-butyl 4-imidazo[1,2-a]pyridin-2-yl-2-(2-methoxy-2-oxo-ethyl)-3- oxo- piperazine-1-carboxylate (1.5 g, 3.86 mmol, 1 eq) in THF (15 mL) and H2O (5 mL) was added LiOH.H2O (486.17 mg, 11.59 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched by addition HCl (1M, 15 mL) at 0 °C, and then extracted with DCM (6 mL * 8). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue 2-(1-tert- butoxycarbonyl-4-imidazo[1,2-a] pyridin-2-yl-3-oxo-piperazin-2-yl)acetic acid (1.14 g, crude) as a solid. MS (ESI) m/z 375.2 [M+H] ⁺ . Step 2: 2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2-yl)acetic acid A mixture of 2-(1-tert-butoxycarbonyl-4-imidazo[1,2-a]pyridin-2-yl-3-oxo- piperazin-2- yl)acetic acid (140 mg, 373.94 μmol, 1 eq) in TFA (0.5 mL) and DCM (2.5 mL). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under the reduced pressure to give 2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2-yl)acetic acid (100 mg, crude) as an oil. MS (ESI) m/z 275.1 [M+H] ⁺ . Step 3: 2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1-prop-2-enoyl-piperaz in-2-yl)acetic acid To a solution of 2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2-yl)acetic acid (100 mg, 257.53 μmol, 1 eq, TFA) in DCM (5 mL) was added TEA (78.18 mg, 772.60 μmol, 107.54 μL, 3 eq) at 0 °C, then added to a solution of prop-2-enoyl chloride (13.99 mg, 154.52 μmol, 12.60 μL, 0.6 eq) in DCM (1 mL).The mixture was stirred at 0 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated under the reduced pressure to give the residue. The residue was purified by prep-HPLC (Condition 4, Gradient b) to give 2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo- 1-prop-2-enoyl-piperazin-2-yl)acetic acid (Compound 155, 24 mg, 73 μmol, 28% yield, 100% purity) as a solid. MS (ESI) m/z 329.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO+D2O-d6): δ = 8.51 (d, J = 6.8 Hz, 1H), 8.29 (s, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.16 - 7.30 (m, 1H), 6.80 - 7.04 (m, 2H), 6.14 (dd, J = 16.7, 2.2 Hz, 1H), 5.71 (dd, J = 10.5, 2.1 Hz, 1H), 5.09 (t, J = 5.5 Hz, 1H), 4.17 - 4.50 (m, 2H), 3.53 - 3.94 (m, 2H), 2.64 - 2.91 (m, 2H). Example 33: Synthesis of Compound 156 Step 1: tert-butyl 2-[2-(cyclopropylamino)-2-oxo-ethyl]-4-imidazo[1,2-a]pyridin -2-yl-3-oxo- piperazine-1-carboxylate To a solution of 2-(1-tert-butoxycarbonyl-4-imidazo[1,2-a]pyridin-2-yl-3-oxo- piperazin- 2-yl)acetic acid (200 mg, 534.2 μmol, 1 eq) in DMF (10 mL) was added HATU (203.1 mg, 534.2 μmol, 1 eq) and DIEA (69 mg, 534 μmol, 93 μL, 1 eq). The mixture was stirred at 25 °C for 0.5 hr, then cyclopropanamine (61 mg, 1.07 mmol, 74 μL, 2 eq) was added, the mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was poured into H2O (100 mL) at 20 °C, and then extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (9-100% EtOAc in PE) to give tert-butyl 2- [2-(cyclopropylamino)-2-oxo-ethyl]-4-imidazo[1,2-a]pyridin-2 -yl-3-oxo-piperazine-1- carboxylate (160 mg, 348.3 μmol, 65% yield, 90% purity) as a solid. MS (ESI) m/z 414.2 [M+H] ⁺ . Step 2: N-cyclopropyl-2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazi n-2-yl)acetamide To a solution of tert-butyl 2-[2-(cyclopropylamino)-2-oxo-ethyl]-4-imidazo[1,2-a]pyridin - 2-yl-3-oxo-piperazine-1-carboxylate (160 mg, 387 μmol, 1 eq) in DCM (3 mL) and TFA (4.6 g, 40.4 mmol, 3 mL, 104.4 eq). The mixture was stirred at 20 °C for 1 hr. Upon completion, the reaction mixture was concentrated under the reduced pressure to give N-cyclopropyl-2-(4- imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazin-2-yl)acetamide (100 mg, crude) as a solid. MS (ESI) m/z 314.2 [M+H] ⁺ . Step 3: N-cyclopropyl-2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1-prop-2 -enoyl-piperazin-2- yl)acetamide To a solution of N-cyclopropyl-2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-piperazi n-2- yl)acetamide (100 mg, 319 μmol, 1 eq) in DCM (5 mL) was added TEA (161.5 mg, 1.6 mmol, 222 μL, 5 eq) at 0 °C, then prop-2-enoyl chloride (43.3 mg, 478.7 μmol, 39 μL, 1.5 eq) in DCM (1 mL) was added. The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was concentrated under the reduced pressure to give the residue. The residue was purified by prep- HPLC (Condition 7, Gradient b) to give N-cyclopropyl-2-(4-imidazo[1,2-a]pyridin-2-yl-3-oxo-1- prop-2-enoyl-piperazin-2-yl)acetamide (Compound 156, 15 mg, 39 μmol, 12% yield, 95% purity) as a solid. MS (ESI) m/z 368.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.59 (d, J = 6.7 Hz, 1H), 8.36 (s, 1H), 8.24 - 7.91 (m, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.34 - 7.17 (m, 1H), 6.97 - 6.78 (m, 2H), 6.29 - 6.06 (m, 1H), 5.75 (d, J = 10.1 Hz, 1H), 5.07 (s, 1H), 4.69 - 4.13 (m, 2H), 3.99 - 3.57 (m, 2H), 3.04 - 2.58 (m, 3H), 0.57 (d, J = 6.4 Hz, 2H), 0.33 (d, J = 2.1 Hz, 2H). Example 34: Synthesis of Compound 160 Step 1: methyl 2-[[3-(nitromethyl)oxetan-3-yl]amino]acetate oxetan-3-one (15 g, 208.2 mmol, 1 eq) nitromethane (19.5 g, 320 mmol, 17.3 mL, 1.54 eq) and TEA (4.21 g, 41.6 mmol, 5.8 mL, 0.2 eq) were stirred at 25 °C for 60 min. DCM (200 mL) was added and the reaction mixture cooled to -70 °C. TEA (42 g, 416.3 mmol, 57.9 mL, 2 eq) was added followed by the dropwise addition of a solution of MsCl (23.16 g, 202.2 mmol, 15.7 mL, 0.97 eq) in DCM (200 mL). The reaction mixture was left to stir at -70 °C for 90 min. Meanwhile, to a solution of methyl 2-aminoacetate; hydrochloride (52.3 g, 416.3 mmol, 2 eq) in DCM (200 mL) was added TEA (42.13 g, 416.3 mmol, 57.9 mL, 2 eq) and stirred at room temperature for 10 min. This solution was added to the oxetane mixture via syringe at -78 °C. The reaction mixture was allowed to warm to 25 °C and stirred for 16 h. Upon completion, a saturated solution of NH ₄ Cl (200 mL) was added to the reaction mixture and stirred for 10 min. The layers were separated and the aqueous extracted with DCM (2 * 50 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column (30% EtOAc in PE) to give methyl 2-[[3- (nitromethyl)oxetan-3-yl]amino]acetate (11 g, 54 mmol, 26% yield) as an oil. Step 2: 2-oxa-5,8-diazaspiro[3.5]nonan-7-one To a solution of methyl 2-[[3-(nitromethyl)oxetan-3-yl]amino]acetate (8 g, 39.2 mmol, 1 eq) in MeOH (400 mL) was added Raney-Ni (8 g, 93.4 mmol, 2.4 eq) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ (x3). The mixture was stirred under H ₂ (15Psi) at 25 °C for 6 h. Upon completion, the reaction was filtered and washed with MeOH (50 mL * 3), then was concentrated under reduced pressure to give 2-oxa-5,8-diazaspiro[3.5]nonan-7-one (5.5 g, crude) as an oil. Step 3: tert-butyl 7-oxo-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate Boc ₂ O (12.7 g, 58 mmol, 13.3 mL, 1.5 eq) was added to a suspension of 2-oxa-5,8- diazaspiro[3.5]nonan-7-one (5.5 g, 39 mmol, 1 eq) in DCM (50 mL). The mixture was stirred at 25 °C for 12 h. Upon completion, the solvent was concentrated in vacuum. The crude product was triturated with PE (100 mL) at 25 ^o C for 2 h to give tert-butyl 7-oxo-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxylate (7.5 g, 31 mmol, 80% yield) as a solid. Step 4: tert-butyl 4-(5-methyl-2-furyl)-3-oxo-piperazine-1-carboxylate To a solution of tert-butyl 7-oxo-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate (800 mg, 3.30 mmol, 1 eq) and 2-bromo-5-methyl-furan (797.44 mg, 4.95 mmol, 1.5 eq) in dioxane (10 mL) was added K2CO3 (1.37 g, 9.91 mmol, 3 eq) and CuI (251.55 mg, 1.32 mmol, 0.4 eq) was degassed and purged with N ₂ (x3), then N,N'-dimethylethane-1,2-diamine (232.9 mg, 2.6 mmol, 284.3 uL, 0.8 eq) was added under N2, the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was purified by prep-TLC (50% EtOAC in PE) to give tert-butyl 8-(5-methyl-2-furyl)-7-oxo-2-oxa- 5,8-diazaspiro[3.5]nonane-5-carboxylate (0.8 g, 2.23 mmol, 68% yield, 90% purity) as a solid. MS (ESI) m/z 323.2 [M+H] ⁺ . Step 5: 8-(5-methyl-2-furyl)-2-oxa-5,8-diazaspiro[3.5]nonan-7-one To a solution of tert-butyl 8-(5-methyl-2-furyl)-7-oxo-2-oxa-5,8-diazaspiro[3.5]nonane-5 - carboxylate (0.5 g, 1.55 mmol, 1 eq) in DCM (3 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 26.12 eq), the solution was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a 8-(5-methyl-2-furyl)-2-oxa-5,8-diazaspiro[3.5]nonan-7-one (0.4 g, crude, HCl) as an oil. MS (ESI) m/z 223.2 [M+H] ⁺ . Step 6: 8-(5-methyl-2-furyl)-5-prop-2-enoyl-2-oxa-5,8-diazaspiro[3.5 ]nonan-7-one To a solution of 8-(5-methyl-2-furyl)-2-oxa-5,8-diazaspiro[3.5]nonan-7-one (0.3 g, 1.35 mmol, 1 eq) in DCM (5 mL) was added TEA (682.98 mg, 6.75 mmol, 939.45 μL, 5 eq) at 0 °C, and prop-2-enoyl chloride (183.26 mg, 2.02 mmol, 165.10 μL, 1.5 eq) in DCM (1 mL) was added, the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 1, Gradient h) to give 8-(5-methyl-2-furyl)-5-prop-2-enoyl-2-oxa-5,8-diazaspiro[3.5 ]- nonan-7-one (Compound 160, 20 mg, 69 μmol, 5% yield, 95% purity) as a solid. MS (ESI) m/z 277.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.78 - 6.58 (m, 1H), 6.26 - 6.13 (m, 2H), 6.10 (dd, J = 1.0, 3.0 Hz, 1H), 5.85 - 5.71 (m, 1H), 4.88 (d, J = 7.0 Hz, 2H), 4.45 (d, J = 6.9 Hz, 2H), 4.32 (s, 2H), 4.14 (s, 2H), 2.24 (s, 3H). An analogous method was followed to obtain the following compounds. Example 35: Synthesis of Compound 163 Step 1: 5-methylpiperazin-2-one and 6-methylpiperazin-2-one A solution of ethyl 2-chloroacetate (16.5 g, 134.9 mmol, 14.4 mL, 0.2 eq) in EtOH (600 mL) was added the solution of propane-1,2-diamine (50 g, 674.5 mmol, 57.6 mL, 1 eq) in EtOH (100 mL) drop-wise at 20 °C over 1.5 h, after 2 h K2CO3 (18.7 g, 134.9 mmol, 0.2 eq) was added. And the mixture was stirred at 20 °C for another 2 h. Upon completion, insoluble material was removed by filteration, and the filtrare was concentrated under reduced pressure to give the mixture of 5-methylpiperazin-2-one (B56A, 12.5 g, crude) and 6-methylpiperazin-2-one (B56B, 37.5 g, crude) as an oil. Step 2: tert-butyl 2-methyl-5-oxo-piperazine-1-carboxylate and tert-butyl 3-methyl-5-oxo- piperazine-1-carboxylate A mixture of 6-methylpiperazin-2-one (37.5 g, 328.53 mmol, 1 eq) and 5-methylpiperazin- 2-one (12.5 g, 109.51 mmol, 3.33e-1 eq) in DCM (1000 mL) was added (Boc)2O (93.21 g, 427.09 mmol, 98.12 mL, 1.3 eq) and the mixture was sitrred at 20 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (9-50% EtOAc in PE) to give the mixture tert-butyl 2-methyl- 5-oxo-piperazine-1-carboxylate (4 g, 18.7 mmol, 6% yield) and tert-butyl 3-methyl-5-oxo- piperazine-1-carboxylate (6 g, 28 mmol, 9% yield) as a solid. To a mixture of tert-butyl 3-methyl-5-oxo-piperazine-1-carboxylate (500 mg, 2.33 mmol, 1 eq) and tert-butyl 2-methyl-5-oxo-piperazine-1-carboxylate (500 mg, 2.33 mmol, 1 eq) and 2- bromo-5-methyl-furan (902 mg, 5.60 mmol, 2.4 eq) in dioxane (20 mL) was added CuI (178 mg, 933 μmol, 0.4 eq) and K ₂ CO ₃ (645 mg, 4.67 mmol, 2 eq) under N ₂ . Then DMEDA (164.6 mg, 1.87 mmol, 201 μL, 0.8 eq) was added to the mixture and was stirred at 100 °C for 16 h. Upon completion, the solids were filtered out and the resulting solution was concentrated under vacuum to give a residue. The residue was purified by column chromatography (0-20% EtOAc in PE) to give tert-butyl 3-methyl-4-(5-methyl-2-furyl)-5-oxo-piperazine-1-carboxylate (240 mg, 815 μmol, 48% yield) and tert-butyl 2-methyl-4-(5-methyl-2-furyl)-5-oxo-piperazine-1-carboxylate (250 mg, 849.3 μmol, 50% yield) as an oil. MS (ESI) m/z 295.2 [M+H] ⁺ . Step 4: 5-methyl-1-(5-methyl-2-furyl)piperazin-2-one A solution of tert-butyl 2-methyl-4-(5-methyl-2-furyl)-5-oxo-piperazine-1-carboxylate (100 mg, 339.7 μmol, 1 eq) in DCM (2 mL) was added TFA (200 mg, 1.75 mmol, 130 μL, 5.15 eq) and stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 5-methyl-1-(5-methyl-2-furyl)piperazin-2-one (60 mg, crude) as an oil. MS (ESI) m/z 195.3 [M+H] ⁺ . Step 5: 5-methyl-1-(5-methyl-2-furyl)-4-prop-2-enoyl-piperazin-2-one A solution of 5-methyl-1-(5-methyl-2-furyl)piperazin-2-one (60 mg, 308.9 μmol, 1 eq) in DCM (3 mL) was added TEA (31.3 mg, 308.9 μmol, 43 μL, 1 eq) at 0 °C, then prop-2-enoyl chloride (28 mg, 308.9 μmol, 25.1 μL, 1 eq) was added. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient e) to give 5-methyl- 1-(5-methyl-2-furyl)-4-prop-2-enoyl-piperazin-2-one (Compound 163, 11 mg, 44 μmol, 14% yield, 100% purity) as an oil. MS (ESI) m/z 249.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.77 - 6.70 (m, 1H), 6.19 - 6.14 (m, 2H), 6.10 (s 1H), 5.75 (d, J = 10.6 Hz, 1H), 4.63 (s, 1H), 4.50 - 4.46 (m, 1H), 4.08 - 4.03 (m, 1H), 3.98 - 3.94 (m, 1H), 3.67 - 3.63 (m, 1H), 2.24 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H). An analogous method was followed to obtain the following compounds. Example 36: Synthesis of Compound 167 Step 1: tert-butyl 4-(2,1,3-benzoxadiazol-5-yl)-3-oxo-piperazine-1-carboxylate To a solution of 5-bromo-2,1,3-benzoxadiazole (350 mg, 1.76 mmol, 1 eq) and tert-butyl 3-oxopiperazine-1-carboxylate (528.2 mg, 2.6 mmol, 1.5 eq) in dioxane (14 mL) was added Pd ₂ (dba) ₃ (161 mg, 176 µmol, 0.1 eq) and Xantphos (203.5 mg, 352 µmol, 0.2 eq) and then K ₂ CO ₃ (729 mg, 5.3 mmol, 3 eq), and the mixture was stirred for 2 h at 130 °C. Upon completion, the reaction was filtered to give crude. The crude was purified by pre-TLC (50% EtOAc in PE) to give tert-butyl 4-(2,1,3-benzoxadiazol-5-yl)-3-oxo-piperazine-1-carboxylate (400 mg, 1.26 mmol, 72% yield) as a solid. MS (ESI) m/z 319.1 [M+H] ⁺ . Step 2: 1-(2,1,3-benzoxadiazol-5-yl)piperazin-2-one A solution of tert-butyl 4-(2,1,3-benzoxadiazol-5-yl)-3-oxo-piperazine-1-carboxylate (159 mg, 499 µmol, 1 eq) in HCl/dioxane (3 mL) was stirred for 1 h at 20 °C. Upon completion, the reaction was concentrated to give 1-(2,1,3-benzoxadiazol-5-yl)piperazin-2-one (108 mg, 495 µmol, 99% yield) as a solid. MS (ESI) m/z 219.2 [M+H] ⁺ . Step 3: 1-(2,1,3-benzoxadiazol-5-yl)-4-prop-2-enoyl-piperazin-2-one To a solution of 1-(2,1,3-benzoxadiazol-5-yl)piperazin-2-one (108 mg, 495 µmol, 1 eq) in DCM (10 mL) was added TEA (150 mg, 1.5 mmol, 207 uL, 3 eq). Prop-2-enoyl chloride (58 mg, 643 µmol, 52.5 uL, 1.3 eq) was added. The mixture was stirred for 1 h at 0 °C. Upon completion, the reaction was concentrated to give crude. The crude was purified by pre-HPLC (Condition 4, Gradient b) to give 1-(2,1,3-benzoxadiazol-5-yl)-4-prop-2-enoyl-piperazin-2-one (Compound 167, 44 mg, 161.6 µmol, 33% yield) as a solid. MS (ESI) m/z 273.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ = 8.12 - 7.91 (m, 2H), 7.69 (d, J=9.4 Hz, 1H), 6.96 - 6.75 (m, 1H), 6.21 (d, J=16.6 Hz, 1H), 5.78 (d, J=10.0 Hz, 1H), 4.56 - 4.28 (m, 2H), 4.02 (br s, 1H), 3.99 - 3.86 (m, 3H). Example 37: Synthesis of Compound 169 Step 1: 6-bromo-2-[(4-methoxyphenyl)methyl]-[1,2,4]triazolo[4,3-a]py ridin-3-one To a solution of 6-bromo-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (800 mg, 3.74 mmol, 1 eq) and 1-(chloromethyl)-4-methoxy-benzene (643.9 mg, 4.11 mmol, 560 μL, 1.1 eq) in DMF (12 mL) was added K2CO3 (1.55 g, 11.2 mmol, 3 eq). The mixture was stirred for 5 h at 50 °C. Upon completion, the reaction was diluted with H ₂ O (60mL) and extracted with EtOAc (60mL*2) and washed with brine (60mL) and concentrated to give crude. The crude was triturated with petroleum ether (20mL) to give product 6-bromo-2-[(4-methoxyphenyl)methyl]-[1,2,4]triazolo-[4,3- a]pyridin-3-one (850 mg, 2.5 mmol, 68% yield) as a solid. MS (ESI) m/z 334.1 [M+H] ⁺ . Step 2: tert-butyl 4-[2-[(4-methoxyphenyl)methyl]-3-oxo-[1,2,4]triazolo[4,3-a]p yridin-6-yl]-3- oxo-piperazine-1-carboxylate To a solution of 6-bromo-2-[(4-methoxyphenyl)methyl]-[1,2,4]triazolo[4,3-a]py ridin-3- one (230 mg, 688.28 μmol, 1 eq) and tert-butyl 3-oxopiperazine-1-carboxylate (551.27 mg, 2.75 mmol, 4 eq) in dioxane (30 mL) was added Xantphos (79.65 mg, 137.66 μmol, 0.2 eq) and Pd ₂ (dba) ₃ (63.03 mg, 68.83 μmol, 0.1 eq) and then K ₂ CO ₃ (475.62 mg, 3.44 mmol, 5 eq). The mixture was stirred for 12 h at 130 °C. Upon completion, the reaction was filtered and concentrated to give crude. The crude was purified by prep-TLC (100% EtOAc) to give tert-butyl 4-[2-[(4- methoxyphenyl)methyl]-3-oxo-[1,2,4]triazolo[4,3-a]pyridin-6- yl]-3-oxo-piperazine-1- carboxylate (170 mg, 375 μmol, 55% yield) as a solid. MS (ESI) m/z 454.2 [M+H] ⁺ . Step 3: 2-[(4-methoxyphenyl)methyl]-6-(2-oxopiperazin-1-yl)-[1,2,4]t riazolo[4,3-a]pyridin-3- one A solution of tert-butyl 4-[2-[(4-methoxyphenyl)methyl]-3-oxo-[1,2,4]triazolo[4,3- a]pyridin-6-yl]-3-oxo-piperazine-1-carboxylate (400 mg, 882 μmol, 1 eq) in DCM (15 mL) and TFA (5 mL) was stirred for 1 h at 20 °C. Upon completion, the reaction was concentrated to give 2-[(4-methoxyphenyl)methyl]-6-(2-oxopiperazin-1-yl)-[1,2,4]t riazolo[4,3-a]pyridin-3-one (311 mg, 880 μmol, 99.8% yield) as a solid and used directly in the next step. MS (ESI) m/z 354.1 [M+H] ⁺ . Step 4: 2-[(4-methoxyphenyl)methyl]-6-(2-oxo-4-prop-2-enoyl-piperazi n-1-yl)- [1,2,4]triazolo[4,3-a]pyridin-3-one To a solution of 2-[(4-methoxyphenyl)methyl]-6-(2-oxopiperazin-1-yl)- [1,2,4]triazolo[4,3-a]pyridin-3-one (311 mg, 880 μmol, 1 eq) and prop-2-enoyl chloride (95.6 mg, 1.06 mmol, 86.1 μL, 1.2 eq) in DCM (30 mL) was added TEA (267.2 mg, 2.6 mmol, 367.5 μL, 3 eq). Then prop-2-enoyl chloride (95.6 mg, 1.06 mmol, 86.1 μL, 1.2 eq) was added. The mixture was stirred for 1 h at 0 °C. Upon completion, the reaction was concentrated to give crude. The crude was purified by prep-TLC (100% EtOAc) to give 2-[(4-methoxyphenyl)methyl]-6-(2-oxo- 4-prop-2-enoyl-piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin -3-one (240 mg, 589 μmol, 67% yield) as a solid. MS (ESI) m/z 408.2 [M+H] ⁺ . Step 5: 6-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-2H-[1,2,4]triazolo[4 ,3-a]pyridin-3-one A solution of 2-[(4-methoxyphenyl)methyl]-6-(2-oxo-4-prop-2-enoyl-piperazi n-1-yl)- [1,2,4]triazolo[4,3-a]pyridin-3-one (110 mg, 269.99 μmol, 1 eq) in methanesulfonic acid (3 mL) was stirred for 1 h at 70°C. Upon completion, the solution was filtered to give crude. The crude was purified by prep-HPLC (Condition 9, Gradient a) to give 6-(2-oxo-4-prop-2-enoyl-piperazin- 1-yl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (Compound 169, 25 mg, 84.4 μmol, 31% yield, 97% purity) as a solid. MS (ESI) m/z 288.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.55 (br s, 1H), 7.98 (s, 1H), 7.14-7.35 (m, 2H), 6.95-6.72 (m, 1H), 6.19 (br d, J = 16.6 Hz, 1H), 5.76 (br d, J = 10.4 Hz, 1H), 4.45-4.22 (m, 2H), 4.04-3.85 (m, 2H), 3.79 - 3.67 (m, 2H). Example 38: Synthesis of Compound 170 Step 1: tert-butyl 4-[5-ethoxycarbonyl-4-methyl-1-(2-trimethylsilylethoxymethyl )imidazol-2-yl]- 3-oxo-piperazine-1-carboxylate

A solution of ethyl 2-bromo-5-methyl-3-(2-trimethylsilylethoxymethyl)imidazole- 4-carboxylate (1 g, 2.75 mmol, 1 eq) and tert-butyl 3-oxopiperazine-1-carboxylate (1.65 g, 8.3 mmol, 3 eq) in DMF (8 mL) was added K ₃ PO ₄ (1.17 g, 5.5 mmol, 2 eq), then CuI (52.4 mg, 275.2 μmol, 0.1 eq) and 1,10-phenanthroline (148.8 mg, 826 μmol, 0.3 eq) was added under N ₂ , the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was poured into H ₂ O 10 mL at 20 °C, and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine 60 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give tert-butyl 4-[5-ethoxycarbonyl-4-methyl-1-(2-trimethylsilylethoxymethyl ) imidazol-2-yl]-3-oxo-piperazine-1-carboxylate (1.1 g, crude) as a solid. MS (ESI) m/z 483.2 [M+H] ⁺ . Step 2: ethyl 4-methyl-2-(2-oxopiperazin-1-yl)-1H-imidazole-5-carboxylate A solution of tert-butyl 4-[5-ethoxycarbonyl-4-methyl-1-(2-trimethylsilylethoxymethyl )- imidazol-2-yl]-3-oxo-piperazine-1-carboxylate (100 mg, 207 μmol, 1 eq) in DCM (5 mL) was added diethyloxonio(trifluoro)boranuide (117.6 mg, 829 μmol, 102 μL, 4 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give ethyl 4-methyl-2-(2-oxopiperazin-1-yl)-1H-imidazole-5-carboxylate (50 mg, crude) as an oil. MS (ESI) m/z 253.2 [M+H] ⁺ . Step 3: ethyl 4-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-1H-imidazol e-5-carboxylate

A solution of ethyl 4-methyl-2-(2-oxopiperazin-1-yl)-1H-imidazole-5-carboxylate (50 mg, 198.2 μmol, 1 eq) and TEA (60 mg, 595 μmol, 82.8 μL, 3 eq) in DCM (3 mL) was added prop-2- enoyl chloride (21.5 mg, 237.8 μmol, 19.3 μL, 1.2 eq) at 0 °C and the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 2, Gradient b) to give ethyl 4-methyl- 2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-1H-imidazole-5-carbo xylate (Compound 170, 10.8 mg, 35 μmol, 18% yield, 100% purity) as a solid. MS (ESI) m/z 307.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD) δ = 6.90 - 6.68 (m, 1H), 6.30 (br d, J = 16.6 Hz, 1H), 5.84 (dd, J = 1.8, 10.6 Hz, 1H), 4.59 - 4.42 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.17 - 3.95 (m, 4H), 2.49 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). Example 39: Synthesis of Compound 171 Step 1: methyl 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)imidazo[1,2-a] pyridine-6- carboxylate A solution of methyl 2-bromoimidazo[1,2-a]pyridine-6-carboxylate (5 g, 19.6 mmol, 1 eq) , tert-butyl 3-oxopiperazine-1-carboxylate (4.7 g, 23.5 mmol, 1.2 eq) in dioxane (100 mL) was added K2CO3 (5.4 g, 39.2 mmol, 2 eq) , CuI (1.49 g, 7.8 mmol, 0.4 eq) and N,N'-dimethylethane- 1,2-diamine (1.38 g, 15.7 mmol, 1.7 mL, 0.8 eq) under N2, the mixture was stirred at 110 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (130 mL), and then extracted with EtOAc (80 mL*3). The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (15-20% EtOAc in PE) to give methyl 2-(4-tert- butoxycarbonyl-2-oxo-piperazin-1-yl)imidazo[1,2-a]pyridine-6 -carboxylate (4.8 g, 10.1 mmol, 52% yield, 79% purity) as a solid. MS (ESI) m/z 375.2 [M+H] ⁺ . Step 2: 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)imidazo[1,2-a] pyridine-6-carboxylic acid A solution of methyl 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)imidazo[1,2- a]pyridine-6-carboxylate (2.15 g, 4.6 mmol, 80% purity, 1 eq) in MeOH (40 mL) and H2O (13 mL) was added K ₂ CO ₃ (1.9 g, 13.8 mmol, 3 eq), the mixture was stirred at 50 °C for 2 h. Upon completion, the two batches of reaction mixtures were quenched by addition H2O 100 mL. The Two reaction mixtures were combined and added 1M HCl adjust to pH~3 and extracted with EtOAc (50mL x5). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(4-tert-butoxycarbonyl-2-oxo- piperazin-1-yl)imidazo[1,2-a]pyridine-6-carboxylic acid (2.6 g, crude) as a solid. MS (ESI) m/z 361.4 [M+H] ⁺ . Step 3: tert-butyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-pipe razine-1- carboxylate A solution of 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)imidazo[1,2-a] pyridine-6- carboxylic acid (200 mg, 554.99 µmol, 1 eq), HATU (316.5 mg, 832.5 µmol, 1.5 eq) and DIEA (143.5 mg, 1.1 mmol, 193.3 uL, 2 eq) in DCM (3 mL) was stirred at 25 °C for 0.5 h, then added methanamine;hydrochloride (45 mg, 666 µmol, 1.2 eq), the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H2O 30 mL, and then extracted with DCM (25 mL x3). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (100% EtOAc, Rf = 0.64) to give tert-butyl 4-[6-(methylcarbamoyl) imidazo[1,2-a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (109 mg, 277 µmol, 50% yield, 95% purity) as a solid. MS (ESI) m/z 374.2 [M+H] ⁺ . Step 4: N-methyl-2-(2-oxopiperazin-1-yl)imidazo[1,2-a]pyridine-6-car boxamide A solution of tert-butyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo- piperazine-1-carboxylate (109 mg, 292 µmol, 1 eq) in DCM (0.1 mL) and TFA (3.36 g, 29.4 mmol, 2.18 mL, 101 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove DCM. N-methyl-2-(2-oxopiperazin-1- yl)imidazo[1,2-a]pyridine-6-carboxamide (80 mg, crude) was obtained as a solid. MS (ESI) m/z 274.1 [M+H] ⁺ . Step 5: N-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)imidazo[1,2- a]pyridine-6- carboxamide A solution of N-methyl-2-(2-oxopiperazin-1-yl)imidazo[1,2-a]pyridine-6-car boxamide (80 mg, 293 µmol, 1 eq) in DCM (7 mL) was added TEA (89 mg, 878 µmol, 122.2 uL, 3 eq), then prop-2-enoyl chloride (26.5 mg, 293 µmol, 24 uL, 1 eq) in DCM (1 mL) was added drop-wise at 0 °C, the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove DCM. The residue was purified by prep-HPLC (Condition 7, Gradient c) to give a N-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)imidazo- [1,2-a]pyridine-6-carboxamide (Compound 171, 30 mg, 89.3 μmol, 31% yield, 97% purity) as a ^{solid. MS (ESI) m/z 328.1 [M+H]+. 1H NMR (400 MHz, DMSO-d} 6 ^{) δ = 9.11 (s, 1H), 8.54 - 8.42} (m, 2H), 7.67 - 7.62 (m, 1H), 7.58 - 7.53 (m, 1H), 6.91 - 6.77 (m, 1H), 6.20 (br d, J = 16.8 Hz, 1H), 5.80 - 5.72 (m, 1H), 4.51 (s, 1H), 4.34 (s, 1H), 4.24 - 4.12 (m, 2H), 4.03 - 3.85 (m, 2H), 2.80 (d, J = 4.5 Hz, 3H). Example 40: Synthesis of Compound 172 Step 1: tert-butyl 3-oxo-2-(2-phenoxyethyl)piperazine-1-carboxylate

To solution of tert-butyl 3-oxopiperazine-1-carboxylate (8 g, 39.95 mmol, 1 eq) in THF (80 mL), was added LDA (2 M, 39.95 mL, 2 eq). The mixture was stirred at -78 °C for 30 min, then to a solution of 2-bromoethoxybenzene (5.62 g, 27.97 mmol, 0.7 eq) in THF (6 mL) was added to the mixture and stirred for 5 h. Upon completion, the mixture quenched with NH4Cl (100 mL), extrated with EtOAc (50 mL*2), the combined organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (33-50% EtOAc in PE) to give tert-butyl 3-oxo- 2-(2-phenoxyethyl)piperazine-1-carboxylate (1.41 g, 4.3 mmol, 11% yield, 97% purity) as a solid. MS (ESI) m/z 321.2 [M+H] ⁺ . Step 2: methyl 2-[4-tert-butoxycarbonyl-2-oxo-3-(2-phenoxyethyl)piperazin-1 -yl]imidazo[1,2- a]pyridine-6-carboxylate To a solution of methyl A mixture of tert-butyl 3-oxo-2-(2-phenoxyethyl)piperazine-1- carboxylate (300 mg, 936 μmol, 1 eq), methyl 2-bromoimidazo[1,2-a]pyridine-6-carboxylate (239 mg, 936 μmol, 1 eq), CuI (27 mg, 140.5 μmol, 0.15 eq), N,N'-dimethylethane-1,2-diamine (20.6 mg, 234 μmol, 25 μL, 0.25 eq) and K ₂ CO ₃ (259 mg, 1.87 mmol, 2 eq) in dioxane (10 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by EDTA (10 mL), extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (30-50% EtOAc in PE) to give methyl 2-[4-tert- butoxycarbonyl-2-oxo-3-(2-phenoxyethyl)piperazin-1-yl]imidaz o[1,2-a]pyridine-6-carboxylate (100 mg, 137.5 μmol, 15% yield, 68% purity) as a solid. MS (ESI) m/z 495.2 [M+H] ⁺ . Step 3: tert-butyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2-(2 - To a solution of methyl 2-[4-tert-butoxycarbonyl-2-oxo-3-(2-phenoxyethyl)piperazin-1 - yl]imidazo[1,2-a]pyridine-6-carboxylate (100 mg, 202.2 μmol, 1 eq) in EtOH (1 mL), was added MeNH ₂ (1 g, 9.66 mmol, 30% purity, 47.8 eq). The mixture was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl 4-[6- (methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2-(2-phen oxyethyl)piperazine-1- carboxylate (135 mg, crude) as an oil. MS (ESI) m/z 494.2 [M+H] ⁺ . Step 4: N-methyl-2-[2-oxo-3-(2-phenoxyethyl)piperazin-1-yl]imidazo[1 ,2-a]pyridine-6- carboxamide

To a solution of tert-butyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2- (2-phenoxyethyl)piperazine-1-carboxylate (135 mg, 273.5 μmol, 1 eq) in DCM (3 mL), was added TFA (1.54 g, 13.5 mmol, 1 mL, 49.2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-methyl-2-[2-oxo-3-(2- phenoxyethyl)piperazin-1-yl]imidazo[1,2-a]pyridine-6-carboxa mide (87 mg, 221 μmol, 81% yield) as an oil. MS (ESI) m/z 394.2 [M+H] ⁺ . Step 5: N-methyl-2-[2-oxo-3-(2-phenoxyethyl)-4-prop-2-enoyl-piperazi n-1-yl]imidazo[1,2- To a solution of N-methyl-2-[2-oxo-3-(2-phenoxyethyl)piperazin-1-yl]imidazo[1 ,2- a]pyridine-6-carboxamide (77 mg, 195.7 μmol, 1 eq) in DCM (8 mL) was added TEA (99 mg, 978.6 μmol, 391.4 μL, 5 eq). Then was dropwise added prop-2-enoyl chloride (15.9 mg, 176.1 μmol, 14.4 μL, 0.9 eq) in DCM (5 ml) , the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient c) to give N-methyl-2-[2-oxo-3-(2-phenoxyethyl)- 4-prop-2-enoyl-piperazin-1-yl]imidazo[1,2-a]pyridine-6-carbo xamide (Compound 172, 16.8 mg, 38 μmol, 19% yield, 100% purity) as a solid. MS (ESI) m/z 448.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.11 (s, 1H), 8.47 (br s, 2H), 7.67 - 7.62 (m, 1H), 7.60 - 7.53 (m, 1H), 7.32 - 7.21 (m, 2H), 6.91 (br s, 4H), 6.14 (br s, 1H), 5.78 - 5.51 (m, 1H), 5.24 - 4.95 (m, 1H), 4.63 - 4.27 (m, 2H), 4.22 - 3.57 (m, 4H), 2.81 (s, 3H), 2.45 - 2.36 (m, 2H). Example 41: Synthesis of Compound 173 Step 1: tert-butyl 2-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxylate

A solution of tert-butyl 2-(2-methoxy-2-oxoethyl)-3-oxo-piperazine-1-carboxylate (1 g, 3.67 mmol, 1 eq) in THF (15 mL), was cooled to 0 °C and was added LAH (2.5 M, 1.76 mL, 1.2 eq) and was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.2 mL) at 0 °C, then was added 15% NaOH(aq.) (0.2 ml) and then added H ₂ O (0.6 mL) then the mixture was filtered out and the resulting solution was concentrated under vacuum to give tert-butyl 2-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxylate (900 mg, crude) as an oil. MS (ESI) m/z 245.2 [M+H] ⁺ . Step 2: tert-butyl 2-(2-hydroxyethyl)-4-[6-(methylcarbamoyl)imidazo[1,2-a]pyrid in-2-yl]-3-oxo- piperazine-1-carboxylate A solution of tert-butyl 2-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxylate (900 mg, 3.7 mmol, 1.1 eq) and 2-bromo-N-methyl-imidazo[1,2-a]pyridine-6-carboxamide (851 mg, 3.35 mmol, 1 eq) in dioxane (30 mL) was added K2CO3 (926 mg, 6.7 mmol, 2 eq) and DMEDA (236.2 mg, 2.7 mmol, 288 μL, 0.8 eq) then CuI (255.2 mg, 1.34 mmol, 0.4 eq) was added and stirred under N ₂ at 100 °C for 16 h. Upon completion, the solids were filtered out and the resulting solution was concentrated under vacuum. The residue was purified by column chromatography (9% EtOAc in PE to 9% MEOH in EtOAc) to give tert-butyl 2-(2-hydroxyethyl)-4-[6-(methylcarbamoyl) imidazo[1,2-a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (1 g, 2.16 mmol, 64% yield, 90% purity) as an oil. MS (ESI) m/z 418.3 [M+H] ⁺ . Step 3: tert-butyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2-[2 -(p- tolylsulfonyloxy)ethyl]piperazine-1-carboxylate

A solution of tert-butyl 2-(2-hydroxyethyl)-4-[6-(methylcarbamoyl)imidazo[1,2- a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (1 g, 2.40 mmol, 1 eq) in DCM (20 mL) was added TEA (363.59 mg, 3.59 mmol, 500.13 μL, 1.5 eq) and DMAP (29.27 mg, 239.55 μmol, 0.1 eq) was stirred at 0 °C. Then 4-methylbenzenesulfonyl chloride (685.03 mg, 3.59 mmol, 1.5 eq) was added and the mixture was sitrred at 0 °C for 1 h, then the mixture was stirred at 20 °C for 15 h. Upon completion, the reaction mixture was quenched by addition H2O (50 mL) at 0°C, and extracted with DCM (30 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give tert-butyl 4-[6- (methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2-[2-(p-t olylsulfonyloxy)ethyl]piperazine- 1-carboxylate (900 mg, crude) as an oil. MS (ESI) m/z 572.3 [M+H] ⁺ . Step 4: tert-butyl 2-[2-(3-methoxycarbonylphenoxy)ethyl]-4-[6-(methylcarbamoyl) imidazo[1,2- a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate A solution of methyl 3-hydroxybenzoate (95.8 mg, 630 μmol, 1.2 eq) and t-BuOK (88.3 mg, 787 μmol, 1.5 eq) in DMF (3 mL), was added tert-butyl 4-[6-(methylcarbamoyl)imidazo[1,2- a]pyridin-2-yl]-3-oxo-2-[2-(p-tolylsulfonyloxy)ethyl]piperaz ine-1-carboxylate (300 mg x3, 524.8 μmol, 1 eq) and stirred at 20 °C for 16 h. Upon completion, the reaction mixture was poured into H2O (6 mL) at 20 °C, and then extracted with EtOAc (3 mL x3). The combined organic layers were washed with brine 5 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (3-100% EtOAc in PE) to give tert-butyl 2-[2-(3-methoxycarbonylphenoxy)ethyl]-4-[6-(methylcarbamoyl) imidazo[1,2- a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (350 mg, 381 μmol, 24% yield, 60% purity) as an oil. MS (ESI) m/z 552.3 [M+H] ⁺ . Step 5: 3-[2-[1-tert-butoxycarbonyl-4-[6-(methylcarbamoyl)imidazo[1, 2-a]pyridin-2-yl]-3-oxo- piperazin-2-yl]ethoxy]benzoic acid A solution of tert-butyl 2-[2-(3-methoxycarbonylphenoxy)ethyl]-4-[6-(methylcarbamoyl) imidazo[1,2-a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (350 mg, 634.5 μmol, 1 eq) in THF (2 mL), then LiOH.H ₂ O (79.9 mg, 1.9 mmol, 3 eq) in H ₂ O (0.6 mL) was added and stirred at 20 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H2O (2 mL). The reaction mixture was added 1M HCl adjust to pH=3 and extracted with EtOAc (1 mL x3). The combined organic layers were washed with brine (1 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-[2-[1-tert-butoxycarbonyl-4-[6- (methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-piperazin -2-yl]ethoxy]benzoic acid (150 mg, crude) as an oil. MS (ESI) m/z 538.2 [M+H] ⁺ . Step 6: 3-[2-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-ox o-piperazin-2- yl]ethoxy]benzoic acid

A solution of 3-[2-[1-tert-butoxycarbonyl-4-[6-(methylcarbamoyl)imidazo[1, 2-a]pyridin- 2-yl]-3-oxo-piperazin-2-yl]ethoxy]benzoic acid (150 mg, 279 μmol, 1 eq) in DCM (1 mL), was added TFA (0.2 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 3-[2-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-ox o- piperazin-2-yl]ethoxy]benzoic acid (120 mg, crude) as an oil. MS (ESI) m/z 438.3 [M+H] ⁺ . Step 7: 3-[2-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-ox o-1-prop-2-enoyl- piperazin-2-yl]ethoxy]benzoic acid A solution of 3-[2-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-ox o-piperazin- 2-yl]ethoxy]benzoic acid (120 mg, 274.3 μmol, 1 eq) in DCM (1 mL) was added TEA (138.8 mg, 1.4 mmol, 191 μL, 5 eq) and was cooled to 0 °C, then prop-2-enoyl chloride (24.8 mg, 274.3 μmol, 22.3 μL, 1 eq) in DCM (0.5 mL) was added dropwise and was stirred at 0 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 9, Gradient b) to give 3-[2-[4-[6- (methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-1-prop-2- enoyl-piperazin-2-yl]ethoxy]- benzoic acid (Compound 173, 10.1 mg, 20.6 μmol, 7.5% yield, 100% purity) as a solid. MS (ESI) m/z 492.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 13.14 - 12.83 (s, 1H), 9.11 (s, 1H), 8.59 - 8.44 (m, 2H), 7.69 - 7.62 (m, 1H), 7.61 - 7.47 (m, 2H), 7.46 - 7.34 (m, 2H), 7.24 - 7.06 (m, 1H), 6.97 - 6.74 (m, 1H), 6.22 - 6.02 (m, 1H), 5.80 - 5.47 (m, 1H), 5.27 - 4.98 (m, 1H), 4.67 - 4.18 (m, 3H), 4.13 - 3.80 (m, 3H), 2.80 (d, J = 4.5 Hz, 3H), 2.48 - 2.36 (m, 2H). Example 42: Synthesis of Compound 174 Step 1 : dimethyl (2-((tert-butoxycarbonyl)amino)ethyl)glutamate To a solution of tert-butyl N-(2-oxoethyl)carbamate (7 g, 43.97 mmol, 1 eq) in MeOH (100 mL) was added dimethyl 2-aminopentanedioate;hydrochloride (10.9 g, 44 mmol, 1 eq, HCl), NaBH ₃ CN (4.15 g, 66 mmol, 1.5 eq) and AcOH (3.7 g, 61.6 mmol, 3.5 mL, 1.4 eq) at 0 °C, the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was poured into H2O (200 mL), then extracted with DCM (100 mL*3), the combined organic layers were washed with sat. NaCl (100 mL*3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give dimethyl 2-[2-(tert-butoxycarbonylamino)ethylamino]pentanedioate (14 g, crude) as an oil. Step 2 : dimethyl N-((benzyloxy)carbonyl)-N-(2-((tert-butoxycarbonyl)amino)eth yl)glutamate To a solution of dimethyl 2-[2-(tert-butoxycarbonylamino)ethylamino]pentanedioate (14 g, 44 mmol, 1 eq) in DCM (100 mL) was added CbzCl (11.3 g, 66 mmol, 9.4 mL, 1.5 eq) and DIEA (17 g, 131.9 mmol, 23 mL, 3 eq) at 0 °C, the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (150 mL), extracted with DCM (100 mL*2) and washed with sat. NaCl (100 mL*2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-50% EtOAc in PE) to give dimethyl 2-[benzyloxycarbonyl-[2-(tert- butoxycarbonylamino)ethyl]amino]pentanedioate (11.6 g, 26 mmol, 58% yield) as an oil. Step3 : dimethyl N-(2-aminoethyl)-N-((benzyloxy)carbonyl)glutamate A mixture of dimethyl 2-[benzyloxycarbonyl-[2-(tert-butoxycarbonylamino) ethyl]amino]pentanedioate (11.6 g, 25.64 mmol, 1 eq) and HCl/dioxane (4 M, 116 mL, 18.1 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in vacuum to give dimethyl 2-[2-aminoethyl (benzyloxycarbonyl) amino] pentanedioate (9 g, crude) as an oil. Step4 : benzyl 2-(3-methoxy-3-oxopropyl)-3-oxopiperazine-1-carboxylate To a solution of dimethyl 2-[2-aminoethyl(benzyloxycarbonyl)amino]pentanedioate (9 g, 25.5 mmol, 1 eq) in DMF (90 mL) was added Cs2CO3 (20.8 g, 64 mmol, 2.5 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (100 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with sat.NaCl (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give benzyl 2-(3-methoxy-3-oxo-propyl)-3-oxo-piperazine-1-carboxylate (7 g, crude) as a solid. Step5 : 3-(1-((benzyloxy)carbonyl)-3-oxopiperazin-2-yl)propanoic acid To a solution of benzyl 2-(3-methoxy-3-oxo-propyl)-3-oxo-piperazine-1-carboxylate (1 g, 3.1 mmol, 1 eq) in H ₂ O (2.3 mL) and MeOH (7 mL) was added K ₂ CO ₃ (1.3 g, 9.4 mmol, 3 eq). The mixture was stirred at 50 °C for 1 h. Upon completion, the reaction mixture was added 1M HCl adjust to pH~2, then extracted with EtOAc (15 mL*3). The combined organic layers were washed with sat. NaCl (20 mL*2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-(1-benzyloxycarbonyl-3-oxo-piperazin-2-yl) propanoic acid (800 mg, crude) as an oil. Step6 : 3-(1-((benzyloxy)carbonyl)-4-(6-(methoxycarbonyl)imidazo[1,2 -a]pyridin-2-yl)-3- oxopiperazin-2-yl)propanoic acid To a solution of 3-(1-benzyloxycarbonyl-3-oxo-piperazin-2-yl)propanoic acid (100 mg, 327 μmol, 1 eq) and methyl 2-bromoimidazo[1,2-a]pyridine-6-carboxylate (83.3 mg, 326.5 μmol, 1 eq) in dioxane (20 mL) was added K ₂ CO ₃ (90.2 mg, 653 μmol, 2 eq) and DMEDA (7.2 mg, 81.6 μmol, 8.8 μL, 0.25 eq), then exchange N2 (x3), then added CuI (9.33 mg, 49 μmol, 0.15 eq) and exchange N2 (x3), the mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with sat. NaCl (30 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-100% EtOAc in PE) to give 3-[1-benzyloxycarbonyl-4-(6-methoxycarbonylimidazo[1,2-a]pyr idin-2-yl)- 3-oxo-piperazin-2-yl]propanoic acid (110 mg, 229 μmol, 9% yield) as a solid. Step7 : 3-(1-((benzyloxy)carbonyl)-4-(6-(methylcarbamoyl)imidazo[1,2 -a]pyridin-2-yl)-3- oxopiperazin-2-yl)propanoic acid

3-[1-benzyloxycarbonyl-4-(6-methoxycarbonylimidazo[1,2-a]pyr idin-2-yl)-3-oxo- piperazin-2-yl]propanoic acid (110 mg, 229 μmol, 1 eq) was added to MeNH2/EtOH (2 g, 19.3 mmol, 30% purity, 84.4 eq), the mixture was stirred for 12 h at 50 °C. Upon completion, the reaction mixture was concentrated in vacuum to give 3-[1-benzyloxycarbonyl-4-[6- (methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-piperazin -2-yl]propanoic acid (105 mg, crude) as an oil. Step8 : 3-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-p iperazin-2-yl]propanoic acid To a solution of 3-[1-benzyloxycarbonyl-4-[6-(methylcarbamoyl)imidazo[1,2-a]p yridin-2- yl]-3-oxo-piperazin-2-yl]propanoic acid (105 mg, 219 μmol, 1 eq) in EtOH (2 mL) was added H2(15 psi) and Pd/C (105 mg, 219 μmol, 10% purity). The mixture was stirred at 25 °C for 3 h. Upon completion, the residue was filtered and washed by H ₂ O and EtOH, then the filtrate was concentrated in vacuum to give 3-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo- piperazin-2-yl]propanoic acid (70 mg, crude) as a solid. Step 9 : 3-(1-acryloyl-4-(6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2- yl)-3-oxopiperazin-2- yl)propanoic acid To a solution of 3-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-p iperazin- 2-yl]propanoic acid (70 mg, 202.7 μmol, 1 eq) in THF (1 mL) was added KOH (17 mg, 304 μmol, 1.5 eq) in H2O (1 mL) and prop-2-enoyl chloride (18.4 mg, 202.7 μmol, 16.5 μL, 1 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Upon completion, the mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (Condition 9, Gradient c) to give 3-[4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-1 -prop-2-enoyl-piperazin-2- yl]propanoic acid (Compound 174, 12.8 mg, 31.5 μmol, 16% yield, 98.7% purity) as a solid. MS (ESI): m/z 400.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.59 - 11.65 (m, 1H), 9.13 - 9.09 (m, 1H), 8.57 - 8.42 (m, 2H), 7.68 - 7.51 (m, 2H), 6.97 - 6.81 (m, 1H), 6.30 - 6.12 (m, 1H), 5.85 - 5.69 (m, 1H), 5.12 - 4.76 (m, 1H), 4.54 - 4.19 (m, 2H), 4.06 - 3.69 (m, 2H), 2.83 - 2.78 (m, 3H), 2.37 - 2.06 (m, 4H). Example 43: Synthesis of Compound 175 Step 1: benzyl 2-(3-hydroxypropyl)-3-oxo-piperazine-1-carboxylate To a solution of benzyl 2-(3-methoxy-3-oxo-propyl)-3-oxo-piperazine-1-carboxylate (1.2 g, 3.75 mmol, 1 eq) in THF (15 mL) was added LiAlH ₄ (284.32 mg, 7.49 mmol, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H2O (0.3 mL) and 15% NaOH (0.3 mL) and H2O (0.9 mL) at 20 °C, and then diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-9% MeOH in EtOAc) to obtain benzyl 2-(3-hydroxypropyl)-3-oxo-piperazine-1-carboxylate (600 mg, 1.3 mmol, 36% yield, 65% purity) as an oil. MS (ESI) m/z 293.2 [M+H] ⁺ . Step 2: methyl 2-[4-benzyloxycarbonyl-3-(3-hydroxypropyl)-2-oxo-piperazin-1 -yl]imidazo[1,2- a]pyridine-6-carboxylate

To a solution of benzyl 2-(3-hydroxypropyl)-3-oxo-piperazine-1-carboxylate (600 mg, 2.05 mmol, 1 eq) in dioxane (15 mL) was added K ₂ CO ₃ (567.35 mg, 4.10 mmol, 2 eq), methyl 2- bromoimidazo[1,2-a]pyridine-6-carboxylate (575.87 mg, 2.26 mmol, 1.1 eq), N,N'- dimethylethane-1,2-diamine (144.74 mg, 1.64 mmol, 176.73 μL, 0.8 eq) and CuI (156.36 mg, 820.99 μmol, 0.4 eq) under N ₂ atmosphere, the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. Upon completion, the mixture was diluted with H2O (30 mL), extracted with ethyl acetate (20 mL * 3), the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (0-50% EtOAc in PE) to obtained methyl 2-[4-benzyloxycarbonyl-3-(3- hydroxypropyl)-2-oxo-piperazin-1-yl]imidazo[1,2-a]pyridine-6 -carboxylate (400 mg, 772 μmol, 38% yield, 90% purity) as a solid. MS (ESI) m/z 467.2 [M+H] ⁺ . Step 3: benzyl 2-(3-hydroxypropyl)-4-[6-(methylcarbamoyl)imidazo[1,2-a]pyri din-2-yl]-3-oxo- piperazine-1-carboxylate A solution of methyl 2-[4-benzyloxycarbonyl-3-(3-hydroxypropyl)-2-oxo-piperazin-1 - yl]imidazo[1,2-a]pyridine-6-carboxylate (350 mg, 750.3 μmol, 1 eq) in MeNH ₂ (8 mL, 30% purity in EtOH) was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (9% MeOH in EtOAc) to obtained benzyl 2-(3-hydroxypropyl)-4-[6-(methylcarbamoyl)imidazo[1,2-a]pyri din-2- yl]-3-oxo-piperazine-1-carboxylate (210 mg, 406 μmol, 54% yield, 90% purity) as a solid. MS (ESI) m/z 466.2 [M+H] ⁺ . Step 4: benzyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2-[3 -(p- tolylsulfonyloxy)propyl]piperazine-1-carboxylate To a solution of benzyl 2-(3-hydroxypropyl)-4-[6-(methylcarbamoyl)imidazo[1,2- a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (210 mg, 451.1 μmol, 1 eq) and DMAP (5.51 mg, 45.1 μmol, 0.1 eq) in DCM (5 mL) was stirred at 0 °C, was added Et ₃ N (68.5 mg, 676.7 μmol, 94.2 μL, 1.5 eq) and TosCl (129 mg, 676.7 μmol, 1.5 eq) slowly, the mixture was stirred at 20 °C for 8 h. Upon completion, the mixture was diluted with H2O (20 mL) and extracted with DCM (10 mL x3). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtained benzyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3- oxo-2-[3-(p-tolylsulfonyloxy)propyl]piperazine-1-carboxylate (310 mg, crude) as a solid. MS (ESI) m/z 620.2 [M+H] ⁺ . Step 5: benzyl 2-[3-(dimethylamino)propyl]-4-[6-(methylcarbamoyl)imidazo[1, 2-a]pyridin-2- yl]-3-oxo-piperazine-1-carboxylate A mixture of benzyl 4-[6-(methylcarbamoyl)imidazo[1,2-a]pyridin-2-yl]-3-oxo-2-[3 -(p- tolylsulfonyloxy)propyl]piperazine-1-carboxylate (310 mg, 500.3 μmol, 1 eq) in N- methylmethanamine (2 M in THF, 2.5 mL, 50% purity) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 7, Gradient d) to obtained benzyl 2-[3- (dimethylamino)propyl]-4-[6-(methylcarbamoyl)imidazo[1,2-a]p yridin-2-yl]-3-oxo-piperazine-1 carboxylate (230 mg, 444 μmol, 89% yield, 95% purity) as a solid. MS (ESI) m/z 493.2 [M+H] ⁺ . Step 6: 2-[3-[3-(dimethylamino)propyl]-2-oxo-piperazin-1-yl]-N-methy l-imidazo[1,2-a]pyridine- 6-carboxamide To a solution of benzyl 2-[3-(dimethylamino)propyl]-4-[6-(methylcarbamoyl)imidazo[1, 2- a]pyridin-2-yl]-3-oxo-piperazine-1-carboxylate (100 mg, 203 μmol, 1 eq) in EtOH (6 mL) was added Pd/C (108 mg, 101.5 μmol, 10% purity, 0.5 eq), the mixture was stirred at 20 °C for 0.5 h under H ₂ (15 psi) atmosphere. Upon completion, the mixture was filtered and concentrated under reduced pressure to obtained 2-[3-[3-(dimethylamino)propyl]-2-oxo-piperazin-1-yl]-N-methy l- imidazo[1,2-a]pyridine-6-carboxamide (50 mg, crude) as a gum. MS (ESI) m/z 359.3 [M+H] ⁺ . Step 7: 2-[3-[3-(dimethylamino)propyl]-2-oxo-4-prop-2-enoyl-piperazi n-1-yl]-N-methyl- i To a solution of 2-[3-[3-(dimethylamino)propyl]-2-oxo-piperazin-1-yl]-N-methy l- imidazo[1,2-a]pyridine-6-carboxamide (60 mg, 167.4 μmol, 1 eq, 2 batches in parallel) in DCM (10 mL) was added TEA (50.8 mg, 502.2 μmol, 69.9 μL, 3 eq), then the mixture was cooled to 0 °C and was added prop-2-enoyl chloride (18.18 mg, 200.87 μmol, 16.32 μL, 1.2 eq) drop-wised at 0 °C, the mixture was stirred at 0 °C for 1 h. Upon completion, the mixture was quenched by water (0.1 mL) and was dried by blowing N ₂ . The crude product was purified by prep-HPLC (Condition 4, Gradient b) to obtained 2-[3-[3-(dimethylamino)propyl]-2-oxo-4-prop-2-enoyl- piperazin-1-yl]-N-methyl-imidazo[1,2-a]pyridine-6-carboxamid e (Compound 175, 18 mg, 43.6 μmol, 13% yield) as a solid. MS (ESI) m/z 413.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD) δ ppm 8.94 (s, 1H), 8.41 (s, 1H), 7.66 (dd, J = 1.6, 9.4 Hz, 1H), 7.52 (d, J = 9.4 Hz, 1H), 7.01 - 6.78 (m, 1H), 6.41 - 6.24 (m, 1H), 5.85 (dd, J = 1.8, 10.6 Hz, 1H), 5.24 - 5.12 (m, 1H), 4.44 - 4.22 (m, 2H), 4.19 - 3.75 (m, 2H), 2.94 (s, 3H), 2.54 - 2.38 (m, 2H), 2.33 - 2.25 (m, 6H), 2.17 - 1.97 (m, 2H), 1.83 - 1.57 (m, 2H). Example 44: Synthesis of Compound 176 Step 1 : 4-bromo-1-methyl-imidazole-2-carbaldehyde LDA (2 M, 10.25 mL, 1.1 eq) was added to a solution of 4-bromo-1-methyl-imidazole (3 g, 18.6 mmol, 1 eq) in THF (90 mL) at -10 °C, after 1 h, DMF (2.04 g, 28 mmol, 2.15 mL, 1.5 eq) was added, then the mixture was stirred for another 1 h at 0 °C. Upon completion, the reaction mixture was quenched by saturated aqueous citric acid solution (30 Ml), and then extracted with ethyl acetate (30 mL x2). The combined organic layers were washed with aqueous NaCl (30 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to 4-bromo-1-methyl- imidazole-2-carbaldehyde (2.7 g, crude) as a solid. Step 2 : methyl (E)-3-(4-bromo-1-methyl-imidazol-2-yl)prop-2-enoate To a solution of methyl 2-diethoxyphosphorylacetate (3.56 g, 16.93 mmol, 1 eq) in THF (60 mL) was added NaH (1.22 g, 30.60 mmol, 60 % purity, 1.81 eq) at 0 °C for 0.5 h, then a solution of 4-bromo-1-methyl-imidazole-2-carbaldehyde (3.2 g, 16.93 mmol, 1 eq) in THF (60 mL) was added and the mixture was stirred at 0 °C for 2 h. Upon completion, the reaction mixture was poured into H2O 90 mL, and then extracted with ethyl acetate (90 mL * 2). The combined organic layers were washed with aqueous NaCl (60 mL*3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (25-100% EtOAc in PE) to give methyl (E)-3-(4-bromo-1-methyl-imidazol-2- yl)prop-2-enoate (3.11 g, 12.7 mmol, 75% yield) as a solid. Step 3 : tert-butyl 4-[2-[(E)-3-methoxy-3-oxo-prop-1-enyl]-1-methyl-imidazol-4-y l]-3-oxo- piperazine-1-carboxylate A mixture of methyl (E)-3-(4-bromo-1-methyl-imidazol-2-yl)prop-2-enoate (3.11 g, 12.7 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (2.54 g, 12.7 mmol, 1 eq), CuI (362.5 mg, 1.9 mmol, 0.15 eq), DMEDA (279.7 mg, 3.17 mmol, 341.5 μL, 0.25 eq) and K ₂ CO ₃ (3.51 g, 25.4 mmol, 2 eq) in dioxane (50 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by H2O 100 mL, and then extracted with EtOAc (80 mL*2). The combined organic layers were washed with aqueous NaCl (50 mL*3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (18-100% EtOAc in PE) to give tert-butyl 4-[2-[(E)-3-methoxy-3-oxo-prop-1-enyl]-1-methyl- imidazol-4-yl]-3-oxo-piperazine-1-carboxylate (1.7 g, 4.7 mmol, 37% yield) as a solid. Step 4 : tert-butyl 4-[2-(3-methoxy-3-oxo-propyl)-1-methyl-imidazol-4-yl]-3-oxo- piperazine-1- carboxylate To a solution of tert-butyl 4-[2-[(E)-3-methoxy-3-oxo-prop-1-enyl]-1-methyl-imidazol-4- yl]-3-oxo-piperazine-1-carboxylate (500 mg, 1.37 mmol, 1 eq) in EtOH (10 mL) was added Pd/C (500 mg, 10% purity) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ (x3). The mixture was stirred under H2 (15 psi) at 25 °C for 1 h. Upon completion, the mixture was filtered and concentrated in vacuum to give tert-butyl 4-[2-(3-methoxy-3-oxo-propyl)-1- methyl-imidazol-4-yl]-3-oxo-piperazine-1-carboxylate (500 mg, crude) as an oil. Step5 : tert-butyl 4-[1-methyl-2-[3-(methylamino)-3-oxo-propyl]imidazol-4-yl]-3 -oxo- piperazine-1-carboxylate tert-butyl 4-[2-(3-methoxy-3-oxo-propyl)-1-methyl-imidazol-4-yl]-3-oxo- piperazine-1- carboxylate (500 mg, 1.4 mmol, 1 eq) was added to methanamine (12.4 g, 120 mmol, 30% purity, 88 eq) (methylamine ethanol solution), and then the temperature was raised to 50 °C for 16 h. Upon completion, the residue was evaporated to dryness to give tert-butyl 4-[1-methyl-2-[3- (methylamino)-3-oxo-propyl]imidazol-4-yl]-3-oxo-piperazine-1 -carboxylate (500 mg, crude) as an oil. Step6 : N-methyl-3-[1-methyl-4-(2-oxopiperazin-1-yl)imidazol-2-yl]pr opanamide To a solution of tert-butyl 4-[1-methyl-2-[3-(methylamino)-3-oxo-propyl]imidazol-4-yl]- 3-oxo-piperazine-1-carboxylate (500 mg, 1.37 mmol, 1 eq) in TFA (2 mL) and DCM (6 mL), the mixture was stirred for 1 h at 25 °C. Upon completion, the resulting solution was concentrated in vacuum to give N-methyl-3-[1-methyl-4-(2-oxopiperazin-1-yl) imidazol-2-yl] propanamide (400 mg, crude) as an oil. Step 7 : N-methyl-3-[1-methyl-4-(2-oxo-4-prop-2-enoyl-piperazin-1-yl) imidazol-2- yl]propanamide To a solution of N-methyl-3-[1-methyl-4-(2-oxopiperazin-1-yl)imidazol-2- yl]propanamide (400 mg, 1.5 mmol, 1 eq) in DCM (5 mL) was added TEA (610 mg, 6 mmol, 839 μL, 4 eq) and prop-2-enoyl chloride (164 mg, 1.8 mmol, 147.5 μL, 1.2 eq), then the mixture was stirred for 1 h at 0 °C. Upon completion, the resulting solution was quenched with H ₂ O (0.1 mL), then was concentrated in vacuum (25 °C). The residue was purified by prep-HPLC (Condition 4, Gradient b) to give N-methyl-3-[1-methyl-4-(2-oxo-4-prop-2-enoyl-piperazin-1-yl) imidazol-2- yl]propanamide (Compound 176, 206.5 mg, 622 μmol, 41% yield, 96% purity) as a solid. MS (ESI) m/z 320.2 NMR (400 MHz, MeOD) δ = 7.24 (s, 1H), 6.82 (br dd, J = 10.6, 16.9 Hz, 1H), 6.29 (dd, J = 1.6, 16.8 Hz, 1H), 5.82 (dd, J = 1.8, 10.6 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.04 - 3.92 (m, 4H), 3.63 (s, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.60 (s, 3H), 2.63 - 2.51 (m, 2H). Example 45: Synthesis of Compound 177 Step 1: 2-[(2-bromoimidazol-1-yl)methoxy]ethyl-trimethyl-silane To a solution of 2-bromo-1H-imidazole (10.5 g, 71.44 mmol, 1 eq) in THF (100 mL) was added dropwise NaH (3.43 g, 85.73 mmol, 60% purity, 1.2 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h and then was added dropwise SEMCl (15.48 g, 92.87 mmol, 16.44 mL, 1.3 eq). The mixture was stirred at 25 °C for 1.5 h. Upon completion, the reaction mixture was quenched by aqueous NH4Cl 200 mL, and then extracted with EtOAc (200 mL*2). The combined organic ayers were washed with aqueous NaCl (150 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (18-50% EtOAc in PE) to give 2-[(2-bromoimidazol-1-yl)methoxy]ethyl- trimethyl-silane (12 g, 43.3 mmol, 61% yield) as an oil. MS (ESI) m/z 279.1 [M+H] ⁺ . Step 2: 2-bromo-3-(2-trimethylsilylethoxymethyl)imidazole-4-carbalde hyde To a solution of 2-[(2-bromoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (12 g, 43.28 mmol, 1 eq) in THF (250 mL) was added LDA (2 M, 23.81 mL, 1.1 eq). The mixture was stirred at -65 °C for 1 h. Then was added DMF (6.33 g, 86.57 mmol, 6.66 mL, 2 eq). The mixture was stirred at -65 °C for 0.5 h. Upon completion, the reaction mixture was quenched by aqueous 1 M NH ₄ Cl 100 mL and extracted with EtOAc (200 mL*2). The combined organic ayers were washed with aqueous NaCl (150 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (9-50% EtOAc in PE) to give 2-bromo-3-(2-trimethylsilylethoxymethyl)- imidazole-4-carbaldehyde (6.5 g, 21.3 mmol, 49% yield) as an oil. MS (ESI) m/z 307.2 [M+H] ⁺ . Step 3: methyl (E)-3-[2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl ]prop-2-enoate To a solution of methyl 2-diethoxyphosphorylacetate (4.48 g, 21.29 mmol, 1 eq) in THF (60 mL) was added DBU (6.48 g, 42.59 mmol, 6.42 mL, 2 eq). The mixture was stirred at 0 °C for 0.5 h. Then was added 2-bromo-3-(2-trimethylsilylethoxymethyl)imidazole-4-carbalde hyde (6.5 g, 21.29 mmol, 1 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by aqueous NH4Cl 100 mL, and then extracted with EtOAc (150 mL*2). The combined organic ayers were washed with aqueous NaCl (200 mL*3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (9-50% EtOAc in PE) to give methyl (E)-3- [2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]prop- 2-enoate (5 g, 13.8 mmol, 65% yield) as an oil. MS (ESI) m/z 363.1 [M+H] ⁺ . Step 4: methyl (E)-3-(2-bromo-1H-imidazol-5-yl)prop-2-enoate To a solution of methyl (E)-3-[2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4- yl]prop-2-enoate (5 g, 13.84 mmol, 1 eq) in THF (30 mL) was added TBAF (1 M, 37.36 mL, 2.7 eq). The mixture was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was quenched by aqueous H ₂ O 20 mL and then extracted with EtOAc (50 mL * 2). The combined organic ayers were washed with aqueous NaCl (40 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with (9% EtOAc in PE, 10 mL) to give methyl (E)-3-(2-bromo-1H-imidazol-5-yl)prop-2-enoate (2 g, 6.9 mmol, 50% yield, 80% purity) as a solid. MS (ESI) m/z 233.0 [M+H] ⁺ . Step 5: methyl (E)-3-(2-bromo-3-methyl-imidazol-4-yl)prop-2-enoate To a solution of methyl (E)-3-(2-bromo-1H-imidazol-5-yl)prop-2-enoate (2 g, 8.66 mmol, 1 eq) in DMF (25 mL) was added dropwise NaOH (519 mg, 12.98 mmol, 1.5 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h and then was added dropwise CH3I (2.58 g, 18.18 mmol, 1.13 mL, 2.1 eq). The mixture was stirred at 50 °C for 1 h. Upon completion, the reaction mixture was quenched by aqueous H ₂ O 5 mL and then extracted with EtOAc (10 mL * 2). The combined organic ayers were washed with aqueous NaCl (15 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18180*70mm*10um; mobile phase: [H ₂ O (0.01%TFA)- ACN]; gradient: 10%-40% B over 0.1 min) to give methyl (E)-3-(2-bromo-3-methyl-imidazol-4- yl)prop-2-enoate (700 mg, 2.86 mmol, 83% yield) as a solid. MS (ESI) m/z 247.1 [M+H] ⁺ . Step 6: tert-butyl 4-[5-[(E)-3-methoxy-3-oxo-prop-1-enyl]-1-methyl-imidazol-2-y l]-3-oxo- piperazine-1-carboxylate To a solution of methyl (E)-3-(2-bromo-3-methyl-imidazol-4-yl)prop-2-enoate (700 mg, 2.9 mmol, 1 eq) and tert-butyl 3-oxopiperazine-1-carboxylate (1.7 g, 8.6 mmol, 3 eq) in dioxane (50 mL) was added CuI (272 mg, 1.4 mmol, 0.5 eq) 1,10-phenanthroline (360.3 mg, 2 mmol, 0.7 eq) and K2CO3 (395 mg, 2.9 mmol, 1 eq). The mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was quenched by aqueous H ₂ O 60 mL, and then extracted with EtOAc (100 mL * 2). The combined organic ayers were washed with aqueous NaCl (100mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (18-90% EtOAc in PE) to give tert-butyl 4-[5-[(E)-3- methoxy-3-oxo-prop-1-enyl]-1-methyl-imidazol-2-yl]-3-oxo-pip erazine-1-carboxylate (500 mg, 1.37 mmol, 48% yield) as a solid. MS (ESI) m/z 365.2 [M+H] ⁺ . Step 7: tert-butyl 4-[5-(3-methoxy-3-oxo-propyl)-1-methyl-imidazol-2-yl]-3-oxo- piperazine-1- carboxylate To a solution of tert-butyl 4-[5-[(E)-3-methoxy-3-oxo-prop-1-enyl]-1-methyl-imidazol-2- yl]-3-oxo-piperazine-1-carboxylate (500 mg, 1.37 mmol, 1 eq) in EtOH (10 mL) was added Pd/C (706.6 mg, 664 μmol, 10% purity). The suspension was degassed and purged with H ₂ (x3). The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. Upon completion, the solution was filtered and concentrated to give tert-butyl 4-[5-(3-methoxy-3-oxo-propyl)-1-methyl-imidazol-2-yl]-3- oxo-piperazine-1-carboxylate (500 mg, 1.36 mmol, 99.5% yield) as a solid and used directly for the next step. MS (ESI) m/z 367.2 [M+H] ⁺ . Step 8: tert-butyl 4-[1-methyl-5-[3-(methylamino)-3-oxo-propyl]imidazol-2-yl]-3 -oxo- piperazine-1-carboxylate To a solution of tert-butyl 4-[5-(3-methoxy-3-oxo-propyl)-1-methyl-imidazol-2-yl]-3-oxo- piperazine-1-carboxylate (500 mg, 1.36 mmol, 1 eq) in MeNH2/EtOH (15 mL) was stirred for 4 h at 50 °C. Upon completion, the solution was concentrated to dryness to give tert-butyl 4-[1-methyl- 5-[3-(methylamino)-3-oxo-propyl]imidazol-2-yl]-3-oxo-piperaz ine-1-carboxylate (495 mg, 1.35 mmol, 99.3% yield) as an oil and used directly for the next step. MS (ESI) m/z 366.2 [M+H] ⁺ . Step 9: N-methyl-3-[3-methyl-2-(2-oxopiperazin-1-yl)imidazol-4-yl]pr opanamide To a solution of tert-butyl 4-[1-methyl-5-[3-(methylamino)-3-oxo-propyl]imidazol-2-yl]- 3-oxo-piperazine-1-carboxylate (300 mg, 821 μmol, 1 eq) in DCM (7 mL) and TFA (2 mL) was stirred for 2 h at 20 °C. Upon completion, the solution was concentrated to dryness to give N- methyl-3-[3-methyl-2-(2-oxopiperazin-1-yl)imidazol-4-yl]prop anamide (217 mg, 818 μmol, 99.6% yield) as an oil and used directly for the next step. MS (ESI) m/z 266.3 [M+H] ⁺ . Step 10: N-methyl-3-[3-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl) imidazol-4- yl]propanamide To a solution of N-methyl-3-[3-methyl-2-(2-oxopiperazin-1-yl)imidazol-4- yl]propanamide (210 mg, 791.5 μmol, 1 eq) in DCM (6 mL) was added TEA (240.3 mg, 2.4 mmol, 330.5 μL, 3 eq) and then prop-2-enoyl chloride (85.97 mg, 949.8 μmol, 77.2 μL, 1.2 eq) was added at 0 °C. The solution was stirred for 1 h at 0 °C. Upon completion, the solution was quenched with H2O (1 mL) and filtered to give crude. The crude was purified by prep-HPLC (Condition 1, Gradient c) to give N-methyl-3-[3-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl) imidazol-4- yl]propanamide (Compound 177, 55 mg, 172.2 μmol, 22% yield) as a solid. MS (ESI) m/z 320.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD) δ = 6.89 - 6.71 (m, 2H), 6.31 (dd, J = 1.8, 16.8 Hz, 1H), 5.84 (dd, J = 1.7, 12.0 Hz, 1H), 4.55 - 4.41 (m, 2H), 4.06 (br d, J = 2.4 Hz, 2H), 3.75 (br d, J = 3.6 Hz, 2H), 3.42 (s, 3H), 2.97 (t, J = 7.6 Hz, 2H), 2.71 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H). Example 46: Synthesis of Compound 178 Step 1: 2-chlorooxazole-4-carbaldehyde To a solution of ethyl 2-chlorooxazole-4-carboxylate (3 g, 17.09 mmol, 1 eq) in THF (30 mL), was added DIBAL-H (1 M, 68.35 mL, 4 eq), the mixture was stirred at -78 °C for 2 h. Upon completion, the reaction mixture was quenched by addition seignette salt 150 mL at -78 °C, and then diluted with EtOAc 200 mL and extracted with EtOAc (200 mL * 3). The combined organic layers were washed with NaCl aq. (200 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (25-50% EtOAc in PE) to give 2-chlorooxazole-4-carbaldehyde (965 mg, 7.34 mmol, 43% yield, 100% purity) as a solid. Step 2: benzyl (E)-3-(2-chlorooxazol-4-yl)prop-2-enoate To a solution of benzyl 2-diethoxyphosphorylacetate (652.98 mg, 2.28 mmol, 1 eq) in THF (5 mL) was added NaH (165.13 mg, 4.13 mmol, 60% purity, 1.81 eq) at 0 °C for 0.5 h, then a solution of 2-chlorooxazole-4-carbaldehyde (300 mg, 2.28 mmol, 1 eq) in THF (5 mL) was added and the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was poured into NH4Cl 70 mL, and then extracted with EtOAc (100 mL*2). The combined organic layers were washed with aqueous NaCl (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (25-100% EtOAc in PE) to give benzyl (E)-3-(2-chlorooxazol-4-yl)prop-2-enoate (600 mg, 2.07 mmol, 91% yield, 91% purity) as a solid. Step 3: tert-butyl 4-[4-[(E)-3-benzyloxy-3-oxo-prop-1-enyl]oxazol-2-yl]-3-oxo-p iperazine-1- carboxylate To solution of benzyl (E)-3-(2-chlorooxazol-4-yl)prop-2-enoate (600 mg, 2.28 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (546.8 mg, 2.7 mmol, 1.2 eq) in dioxane (15 mL), was added Cs2CO3 (1.48 g, 4.55 mmol, 2 eq), tBuXPhos Pd G3 (180.8 mg, 227.6 μmol, 0.1 eq). The mixture was stirred at 90 °C for 1 h. Upon completion, the mixture was concentrated in vauum. The residue was purified by column chromatography (25-50% EtOAc in PE) to give tert-butyl 4- [4-[(E)-3-benzyloxy-3-oxo-prop-1-enyl]oxazol-2-yl]-3-oxo-pip erazine-1-carboxylate (698 mg, 1.52 mmol, 67% yield, 93% purity) as a solid. Step 4: 3-[2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)oxazol-4-yl ]propanoic acid To a solution of tert-butyl 4-[4-[(E)-3-benzyloxy-3-oxo-prop-1-enyl]oxazol-2-yl]-3-oxo- piperazine-1-carboxylate (698 mg, 1.63 mmol, 1 eq) in EtOH (15 mL) was added Pd/C (608.72 mg, 572 μmol, 10% purity, 0.35 eq) under N2. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 30 min. Upon completion, the reaction mixture is filtered with diatomaceous earth and spin dried. The residue was purified by column chromatography (50-100% EtOAc in PE) to give 3-[2-(4-tert- butoxycarbonyl-2-oxo-piperazin-1-yl)oxazol-4-yl]propanoic acid (320 mg, 698 μmol, 43% yield, 74% purity) as an oil. Step 5: tert-butyl 4-[4-[3-(methylamino)-3-oxo-propyl]oxazol-2-yl]-3-oxo-pipera zine-1- carboxylate To a solution of 3-[2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)oxazol-4-yl ]propanoic acid (310 mg, 913.5 μmol, 1 eq) in DMF (1 mL), was added HATU (416.8 mg, 1.1 mmol, 1.2 eq), DIPEA (354.2 mg, 2.74 mmol, 477.4 μL, 3 eq), the mixture was stirred at 25 °C for 30 min, methanamine; hydrochloride (95 mg, 913.5 μmol, 1 eq, HCl) was added, the mixture was stirred at 25 °C for 30 min. Upon completion, the reaction mixture was diluted with H2O 10 mL and extracted with EtOAc (30 mL*3). The combined organic layers were dried over sat.Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-9% MeOH in EtOAc) to afford tert-butyl 4-[4-[3-(methylamino)-3- oxo-propyl]oxazol-2-yl]-3-oxo-piperazine-1-carboxylate (217 mg, 431 μmol, 47% yield, 70% purity) as an oil. Step 6: N-methyl-3-[2-(2-oxopiperazin-1-yl)oxazol-4-yl]propanamide To solution of tert-butyl 4-[4-[3-(methylamino)-3-oxo-propyl]oxazol-2-yl]-3-oxo- piperazine-1-carboxylate (217 mg, 615.8 μmol, 1 eq) in TFA (1.73 g, 15.2 mmol, 1.13 mL, 24.7 eq), DCM (3 mL), the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated in vacuum. To give N-methyl-3-[2-(2-oxopiperazin-1-yl)oxazol-4-yl]propanamide (150 mg, crude) as an oil. Step 7: N-methyl-3-[2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)oxazol-4- yl]propanamide To solution of N-methyl-3-[2-(2-oxopiperazin-1-yl)oxazol-4-yl]propanamide (120 mg, 475.7 μmol, 1 eq) in ACN (12 mL), was added K ₂ CO ₃ (197.2 mg, 1.43 mmol, 3 eq), then prop-2- enoyl chloride (30 mg, 333 μmol, 27 μL, 0.7 eq) was added, the mixture was stirred at 0 °C for 1 h. Upon completion, the mixture was concentrated in vacuum. The residue was purified by prep- HPLC (Condition 9, Gradient c) to give N-methyl-3-[2-(2-oxo-4-prop-2-enoyl-piperazin-1- yl)oxazol-4-yl]propanamide (Compound 178, 20 mg, 63.4 μmol, 13% yield, 97% purity) as a solid. MS (ESI) m/z= 307.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 7.79 (br d, J = 4.0 Hz, 1H), 7.68 (s, 1H), 6.86 - 6.75 (m, 1H), 6.18 (br d, J = 16.8 Hz, 1H), 5.77 (br d, J = 9.0 Hz, 1H), 4.49 - 4.27 (m, 2H), 3.97 - 3.83 (m, 4H), 2.65 (t, J = 7.6 Hz, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.35 (t, J = 7.7 Hz, 2H). Example 47: Synthesis of Compound 181 Step 1: benzyl 4-hydroxy-3-nitro-benzoate To a solution of 4-hydroxy-3-nitro-benzoic acid (10 g, 54.6 mmol, 1 eq) in DMF (500 mL) was added NaHCO3 (6.88 g, 81.9 mmol, 3.2 mL, 1.5 eq) and bromomethylbenzene (14 g, 81.9 mmol, 9.73 mL, 1.5 eq). The mixture was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 800 mL, and then extracted with EtOAc 2.4 L (800 mL * 3). The combined organic layers were washed with brine (1L x3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (20% EtOAc in PE) to give benzyl 4-hydroxy-3-nitro-benzoate (6.4 g, 23.4 mmol, 43% yield) as a solid. MS (ESI) m/z 272.2 [M-H] ⁺ . Step 2: benzyl 3-amino-4-hydroxy-benzoate A mixture of benzyl 4-hydroxy-3-nitro-benzoate (2 g, 7.32 mmol, 1 eq) and NH4Cl (3.9 g, 73.2 mmol, 10 eq) in EtOH (20 mL) and H2O (4 mL) was degassed and purged with N2 (x3), then added Fe (2 g, 36.6 mmol, 5 eq) at 60 °C. Then the mixture was stirred at 80 °C for 1 h under N ₂ atmosphere. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, then added H2O 30 mL, and then extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine 150 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (18% EtOAc in PE) to give benzyl 3-amino-4-hydroxy-benzoate (940 mg, 3.86 mmol, 53% yield) as a solid. MS (ESI) m/z 244.2 [M+H] ⁺ . Step 3: benzyl 1,3-benzoxazole-5-carboxylate

A solution of benzyl 3-amino-4-hydroxy-benzoate (850 mg, 3.5 mmol, 1 eq) in trimethoxymethane (5.81 g, 54.7 mmol, 6 mL, 15.66 eq) was stirred at 80 °C for 16 h. Upon completion, the solution was concentrated to dryness to give the residue. The residue was purified by column chromatography (10% EtOAc in PE) to give benzyl 1,3-benzoxazole-5-carboxylate (650 mg, 2.57 mmol, 74% yield) as a solid. MS (ESI) m/z 254.1 [M+H] ⁺ . Step 4: benzyl 2-bromo-1,3-benzoxazole-5-carboxylate To a solution of benzyl 1,3-benzoxazole-5-carboxylate (600 mg, 2.37 mmol, 1 eq) in THF (6 mL) was added LiHMDS (1 M, 2.84 mL, 1.2 eq) at -25 °C for 1 h under N ₂ atmosphere. Then added NBS (632.5 mg, 3.6 mmol, 1.5 eq) at -25 °C. The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition NH4CI 15 mL, and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine 60 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (100% PE) to give benzyl 2-bromo-1,3-benzoxazole-5- carboxylate (710 mg, 2.14 mmol, 90% yield) as a solid. MS (ESI) m/z 332.0 [M+H] ⁺ . Step 5: benzyl 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)-1,3-benzoxazo le-5-carboxylate To a solution of benzyl 2-bromo-1,3-benzoxazole-5-carboxylate (200 mg, 602.14 μmol, 1 eq) in ACN (14 mL) was added K ₂ CO ₃ (249.67 mg, 1.81 mmol, 3 eq) and tert-butyl 3- oxopiperazine-1-carboxylate (241.14 mg, 1.20 mmol, 2 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the solution was concentrated to dryness to give crude. The residue was purified by column chromatography (70-40% EtOAc in PE) to give benzyl 2-(4-tert- butoxycarbonyl-2-oxo-piperazin-1-yl)-1,3-benzoxazole-5-carbo xylate (450 mg, 209 μmol, 12% yield, 21% purity) as a solid. MS (ESI) m/z 452.2 [M+H] ⁺ . Step 6: 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)-1,3-benzoxazo le-5-carboxylic acid A mixture of Pd/C (420 mg, 394.7 μmol, 10% purity, 0.4 eq) in i-PrOH (60 mL) was added benzyl 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)-1,3-benzoxazo le-5-carboxylate (420 mg, 930.3 μmol, 1 eq) was degassed and purged with H2 (x3), and then the mixture was stirred at 20 °C for 0.5 h under H ₂ atmosphere. Upon completion, the reaction was filtered and concentrated to dryness to give 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)-1,3-benzoxazo le-5-carboxylic acid (280 mg, crude) as a solid. MS (ESI) m/z 362.1 [M+H] ⁺ . Step 7: tert-butyl 4-[5-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-oxo-piperazine -1-carboxylate To a solution of 2-(4-tert-butoxycarbonyl-2-oxo-piperazin-1-yl)-1,3-benzoxazo le-5- carboxylic acid (280 mg, 774.9 μmol, 1 eq) in DCM (3 mL) was added HATU (353.6 mg, 929.9 μmol, 1.2 eq) and DIEA (300.4 mg, 2.3 mmol, 404.9 μL, 3 eq) at 20 °C for 0.5 h. Then added methanamine;hydrochloride (52.3 mg, 774.9 μmol, 1 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, then added H2O 10 mL, and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 4-[5-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-oxo- piperazine-1-carboxylate (350 mg, crude) as a solid. MS (ESI) m/z 375.2 [M+H] ⁺ . Step 8: N-methyl-2-(2-oxopiperazin-1-yl)-1,3-benzoxazole-5-carboxami de To a solution of tert-butyl 4-[5-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-oxo- piperazine-1-carboxylate (400 mg, 1.07 mmol, 1 eq) in DCM (5 mL) was added TFA (1.23 g, 10.77 mmol, 1 mL, 10.1 eq) .The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-methyl-2-(2-oxopiperazin-1- yl)-1,3-benzoxazole-5-carboxamide (293 mg, crude) as an oil. MS (ESI) m/z 275.2 [M+H] ⁺ . Step 9: N-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-1,3-benzoxa zole-5-carboxamide To a solution of N-methyl-2-(2-oxopiperazin-1-yl)-1,3-benzoxazole-5-carboxami de (293 mg, 534 μmol, 1 eq) in DCM (3 mL) was added TEA (270.2 mg, 2.7 mmol, 371.7 μL, 5 eq) and prop-2-enoyl chloride (43.5 mg, 481 μmol, 39 μL, 0.9 eq) in DCM (0.3 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 9, Gradient d) to give N-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-1,3-benzoxa zole-5-carboxamide (Compound 181, 12.5 mg, 38.1 μmol, 7% yield, 94% purity) as a solid. MS (ESI) m/z 329.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.02 (d, J = 1.0 Hz, 1H), 7.78 (br d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.54 - 6.52 (m, 1H), 6.50 - 6.41 (m, 1H), 6.15 (br d, J = 3.2 Hz, 1H), 5.97 - 5.77 (m, 1H), 4.56 (br s, 2H), 4.28 (br s, 2H), 4.05 (s, 2H), 3.06 ppm (d, J = 4.8 Hz, 3H). An analogous method was followed to obtain the following compound. Example 48: Synthesis of Compound 183 Step 1: methyl 3-(3-iodopyrazol-1-yl)propanoate To a solution of 3-iodo-1H-pyrazole (3 g, 15.47 mmol, 1 eq) in ACN (45 mL) was added DBU (1.18 g, 7.73 mmol, 1.17 mL, 0.5 eq) at 0 °C, followed by methyl prop-2-enoate (2.66 g, 30.93 mmol, 2.79 mL, 2 eq) then was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched with 1 M HCl (30 mL) and extracted with EtOAc (30 mL*2). The combined organic layers were washed with water (20 mL) and brine (20 mL*2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give methyl 3-(3-iodopyrazol-1- yl)propanoate (4 g, crude) as an oil. Step 2: tert-butyl 4-[1-(3-methoxy-3-oxo-propyl)pyrazol-3-yl]-3-oxo-piperazine- 1-carboxylate A mixture of methyl 3-(3-iodopyrazol-1-yl)propanoate (2 g, 7.14 mmol, 1 eq), tert-butyl 3- oxopiperazine-1-carboxylate (1.43 g, 7.14 mmol, 1 eq), iodocopper (204 mg, 1.07 mmol, 0.15 eq), N,N'-dimethylethane-1,2-diamine (157.4 mg, 1.79 mmol, 192.2 uL, 0.25 eq) and dipotassium;carbonate (1.97 g, 14.3 mmol, 2 eq) in dioxane (20 mL) was degassed and purged with N ₂ (x3), and then the mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with aq. EDTA 30 mL and extracted with EtOAc (20 mL*2). The combined organic layers were dried over sat.Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (10-30% EtOAc in PE) to give tert-butyl 4-[1-(3-methoxy-3-oxo-propyl)pyrazol-3-yl]-3-oxo-piperazine- 1- carboxylate (1.9 g, 5.4 mmol, 76% yield) as an oil. Step 3: tert-butyl 4-[1-[3-(methylamino)-3-oxo-propyl]pyrazol-3-yl]-3-oxo-piper azine-1- carboxylate tert-butyl 4-[1-(3-methoxy-3-oxo-propyl)pyrazol-3-yl]-3-oxo-piperazine- 1-carboxylate (1 g, 2.84 mmol, 1 eq) was added to methanamine (25.860 g, 249.80 mmol, 30% purity, 88.03 eq) (methylamine ethanol solution), and then the temperature was raised to 50 °C for 16 h. Upon completion, the residue was evaporated to dryness to give tert-butyl 4-[1-[3-(methylamino)-3-oxo- propyl]pyrazol-3-yl]-3-oxo-piperazine-1-carboxylate (0.9 g, crude) as an oil. Step 4: N-methyl-3-[3-(2-oxopiperazin-1-yl)pyrazol-1-yl]propanamide To a solution of tert-butyl 4-[1-[3-(methylamino)-3-oxo-propyl]pyrazol-3-yl]-3-oxo- piperazine-1-carboxylate (300 mg, 854 μmol, 1 eq) in DCM (5 mL) was added TFA (2.30 g, 20.19 mmol, 1.5 mL, 23.65 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in vacuum (30 °C), then was added DCM (2 mL), and concentrated, and repeat to give N-methyl-3-[3-(2-oxopiperazin-1-yl)pyrazol-1-yl]propanamide (220 mg, crude) as an oil. Step 5: N-methyl-3-[3-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)pyrazol-1 -yl]propanamide To a solution of N-methyl-3-[3-(2-oxopiperazin-1-yl)pyrazol-1-yl]propanamide (210 mg, 835.7 μmol, 1 eq) in DCM (5 mL) was added TEA (422.8 mg, 4.2 mmol, 581.6 μL, 5 eq) and prop- 2-enoyl chloride (83.2 mg, 919.3 μmol, 74.7 μL, 1.1 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 6, Gradient d) to give N-methyl-3-[3-(2-oxo- 4-prop-2-enoyl-piperazin-1-yl)pyrazol-1-yl]propanamide (Compound 183, 130 mg, 426 μmol, 51% yield, 100% purity) as a solid. MS (ESI) m/z 306.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 7.85 (br d, J = 3.9 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 6.82 (dt, J = 10.6, 16.3 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.18 (br d, J = 16.6 Hz, 1H), 5.80 - 5.67 (m, 1H), 4.50 - 4.19 (m, 4H), 4.02 - 3.75 (m, 4H), 2.57 (t, J = 7.0 Hz, 2H), 2.54 - 2.53 (m, 3H). An analogous method was followed to obtain the following compound. Example 49: Synthesis of Compound 185 Step 1: 1-benzyl-3,5-dibromo-1H-pyrazole To a solution of 3,5-dibromo-1H-pyrazole (5 g, 22.1 mmol, 1 eq) in DMF (30 mL) was added NaH (2.2 g, 55.3 mmol, 60% purity, 2.5 eq) and BnBr (4.54 g, 26.6 mmol, 3.16 mL, 1.2 eq) at 0 °C. The mixture was then allowed to 25 °C and stirred for 12 h. Upon completion, the reaction mixture was quenched by addition aq.NH4Cl at 0 °C, and then diluted with water 10 mL and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 200/1) to give 1-benzyl-3,5-dibromo-pyrazole (1.7 g, 5 mmol, 23% yield, 94% purity) was obtained as an oil. MS (ESI) m/z 315.0 [M+H] ⁺ . Step 2: 2-benzyl-5-bromo-pyrazole-3-carbaldehyde To a solution of 1-benzyl-3,5-dibromo-pyrazole (1.5 g, 4.75 mmol, 1 eq) in THF (22.5 mL) was added chloro(isopropyl)magnesium (2 M, 2.85 mL, 1.2 eq) at -78 ℃ and stirred for 30 min. And then DMF (2.43 g, 33.23 mmol, 2.56 mL, 7 eq) was added. The mixture was stirred at 25 ℃ for 4.5 h. Upon completion, the reaction mixture was quenched by addition aq.NH4Cl at 0 ℃, and then diluted with water 30 mL and extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 200/1) to give 2-benzyl-5-bromo-pyrazole-3-carbaldehyde (1.03 g, 3.4 mmol, 72% yield, 88% purity) as a solid. MS (ESI) m/z 265.1 [M+H] ⁺ . Step 3: methyl (E)-3-(2-benzyl-5-bromo-pyrazol-3-yl)prop-2-enoate To a solution of methyl 2-diethoxyphosphorylacetate (575 mg, 2.73 mmol, 1 eq) in THF (32 mL) was added DBU (833 mg, 5.47 mmol, 824 μL, 2 eq) at 25℃ for 30 min. And then 2- benzyl-5-bromo-pyrazole-3-carbaldehyde (870 mg, 3.3 mmol, 1.2 eq) in THF (2 mL) was added. The mixture was stirred at 25 ℃ for 15.5 h. Upon completion, the reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/EtOAc = 200/1 to 30/1) to give methyl (E)-3-(2-benzyl-5-bromo-pyrazol-3-yl)prop-2-enoate (820 mg, 2.5 mmol, 92% yield, 99% purity) as a solid. MS (ESI) m/z 321.1 [M+H] ⁺ . Step 4: tert-butyl 4-[1-benzyl-5-[(E)-3-methoxy-3-oxo-prop-1-enyl]pyrazol-3-yl] -3-oxo- piperazine-1-carboxylate A mixture of methyl (E)-3-(2-benzyl-5-bromo-pyrazol-3-yl)prop-2-enoate (820 mg, 2.6 mmol, 1 eq), tert-butyl 3-oxopiperazine-1-carboxylate (613.5 mg, 3.06 mmol, 1.2 eq), K ₂ CO ₃ (705.7 mg, 5.1 mmol, 2 eq), DMEDA (180 mg, 2.04 mmol, 219.8 μL, 0.8 eq) and CuI (194.5 mg, 1 mmol, 0.4 eq) in dioxane (41 mL) was degassed and purged with N2 (x3), and then the mixture was stirred at 100 ℃ for 16 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with water 30 mL and extracted with EtOAc (30 mL x3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 60/1 to 3/1) to give tert-butyl 4-[1-benzyl-5-[(E)-3-methoxy-3-oxo-prop-1- enyl]pyrazol-3-yl]-3-oxo-piperazine-1-carboxylate (570 mg, 1.3 mmol, 51% yield, 100% purity) as an oil. MS (ESI) m/z 441.2 [M+H] ⁺ . Step 5: tert-butyl 4-[5-(3-methoxy-3-oxo-propyl)-1H-pyrazol-3-yl]-3-oxo-piperaz ine-1- carboxylate A solution of tert-butyl 4-[1-benzyl-5-[(E)-3-methoxy-3-oxo-prop-1-enyl]pyrazol-3-yl] -3- oxo-piperazine-1-carboxylate (450 mg, 1.02 mmol, 1 eq) in AcOH (10 mL) was added Pd/C (450 mg, 10% purity), then the mixture was stirred at 40 ℃ for 16 h under H2 (2.06 mg, 1.02 mmol, 1 eq) (15 Psi). Upon completion, the mixture was filted with MeOH and concentrated under reduced pressure to give the crude. The crude was diluted with NaHCO ₃ 20 mL and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 15/1 to 3/1) to give tert-butyl 4- [5-(3-methoxy-3-oxo-propyl)-1H-pyrazol-3-yl]-3-oxo-piperazin e-1-carboxylate (285 mg, 785 μmol, 77% yield, 97% purity) as a solid. MS (ESI) m/z 353.2 [M+H] ⁺ . Step 6: tert-butyl 4-[5-[3-(methylamino)-3-oxo-propyl]-1H-pyrazol-3-yl]-3-oxo-p iperazine-1- carboxylate A solution tert-butyl 4-[5-(3-methoxy-3-oxo-propyl)-1H-pyrazol-3-yl]-3-oxo-piperaz ine- 1-carboxylate (285 mg, 808.8 μmol, 1 eq) in MeNH ₂ (7.37 g, 71.17 mmol, 30% purity, 88 eq) (ethanol solution) was stirred at 50 ℃ for 2 h. Upon completion, the residue was evaporated to dryness. The crude was used directly. To give crude product tert-butyl 4-[5-[3-(methylamino)-3- oxo-propyl]-1H-pyrazol-3-yl]-3-oxo-piperazine-1-carboxylate (280 mg, crude) as a solid. MS (ESI) m/z 352.2 [M+H] ⁺ . Step 7: N-methyl-3-[3-(2-oxopiperazin-1-yl)-1H-pyrazol-5-yl]propanam ide To a solution of tert-butyl 4-[5-[3-(methylamino)-3-oxo-propyl]-1H-pyrazol-3-yl]-3-oxo- piperazine-1-carboxylate (280 mg, 796.8 μmol, 1 eq) in DCM (10 mL) was added TFA (4.6 g, 40.4 mmol, 3 mL, 50.7 eq). The mixture was stirred at 25 ℃ for 0.5 h. Upon completion, the residue was evaporated to dryness. The crude product N-methyl-3-[3-(2-oxopiperazin-1-yl)-1H- pyrazol-5-yl]propanamide (290 mg, crude, TFA) was obtained as an oil and used the next step without further purification. MS (ESI) m/z 252.3 [M+H] ⁺ . Step 8: N-methyl-3-[3-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)-1H-pyraz ol-5-yl]propanamide To a solution of N-methyl-3-[3-(2-oxopiperazin-1-yl)-1H-pyrazol-5-yl]propanam ide (250 mg, 995 μmol, 1 eq) in DCM (12 mL) was added TEA (403 mg, 3.98 mmol, 554 μL, 4 eq) andprop- 2-enoyl chloride (45 mg, 497.4 μmol, 40.4 μL, 0.5 eq). The mixture was stirred at 0 ℃ for 1 h. Upon completion, the reaction mixture was diluted with water 20 mL and extracted with EtOAc (40 mL x3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 7, Gradient b) to give N-methyl-3-[3-(2-oxo-4-prop-2-enoyl-piperazin-1- yl)-1H-pyrazol-5-yl]propanamide (Compound 185, 16 mg, 51.4 μmol, 5% yield, 98% purity) was obtained as a solid. MS (ESI) m/z 306.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD) δ = 6.86 - 6.68 (m, 1H), 6.50 (s, 1H), 6.29 (dd, J = 1.6, 16.8 Hz, 1H), 5.82 (dd, J = 1.8, 10.6 Hz, 1H), 4.49 - 4.36 (m, 2H), 4.04 - 3.93 (m, 4H), 2.93 (t, J = 7.6 Hz, 2H), 2.70 (s, 3H), 2.51 (t, J = 7.5 Hz, 2H). Example 50: Synthesis of Compound 186 Step 1: methyl 2-[allyl(tert-butoxycarbonyl)amino]acetate To a solution of methyl 2-(tert-butoxycarbonylamino)acetate (3.7 g, 19.6 mmol, 2.9 mL, 1 eq) in DMF (37 mL) was cooled to 0 °C then NaH (938.6 mg, 23.5 mmol, 60% purity, 1.2 eq) was added and stirred at 0 °C for 0.5 h. Then 3-bromoprop-1-ene (2.84 g, 23.5 mmol, 1.2 eq) was added and the mixture was stirred at 0 °C for 1.5 h. Upon completion, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (100 mL x3). The combined organic layers were washed with sat.aq. NaCl (60 mL x3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0-8% EtOAc in PE) to give methyl 2-[allyl(tert-butoxycarbonyl)amino]acetate (3.2 g, 14 mmol, 71% yield) as an oil. Step 2: methyl 2-[tert-butoxycarbonyl(2-oxoethyl)amino]acetate To a solution of methyl 2-[allyl(tert-butoxycarbonyl)amino]acetate (3 g, 13.08 mmol, 1 eq) in MeOH (30 mL), cooled to -60 °C, passed through O ₃ (13.08 mmol, 1 eq) under 0.1 MPa until the solution turn blue, and then pass into the N2 until the reaction solution becomes no color. The mixture was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (0- 20% EtOAc in PE) to give methyl 2-[tert-butoxycarbonyl(2-oxoethyl)amino]acetate (2.1 g, 5.5 mmol, 42% yield, 60% purity) as an oil. Step 3: amino 2,4,6-trimethylbenzenesulfonate To a solution of (tert-butoxycarbonylamino) 2,4,6-trimethylbenzenesulfonate (60 g, 190.2 mmol, 1 eq) in TFA (460.5 g, 4.04 mol, 300 mL, 21.23 eq) was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by ice and water (400 mL) and maintained inter- temperature below 5 °C. The mixture was stirred for 15 min to form a slurry. The slurry was filtered and the filter cake was washed with water (10 mL x3) and air dried to afford amino 2,4,6- trimethylbenzenesulfonate (46 g, crude) as a solid. Step 4: 2-(4-bromo-2-pyridyl)acetonitrile To a solution of 4-bromo-2-fluoro-pyridine (15 g, 85.2 mmol, 1 eq) and acetonitrile (7 g, 170.5 mmol, 8.97 mL, 2 eq) in THF (200 mL) was cooled to -60 °C, then added LiHMDS (1 M, 29.8 mL, 0.35 eq) dropwise for 1 h. The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was saturated ammonium chloride aqueous solution (500 mL) was added thereto, then the mixture was extracted with EtOAc (200 mL x3), the combined organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (10-25% EtOAc in PE) to give 2-(4-bromo-2-pyridyl)acetonitrile (17 g, 69 mmol, 81% yield, 80% purity) as an oil. MS (ESI) m/z 199.2 [M+H] ⁺ . Step 5: 2-(1-amino-4-bromo-pyridin-1-ium-2-yl)acetonitrile To a solution of 2-(4-bromo-2-pyridyl)acetonitrile (23 g, 116.73 mmol, 1 eq) in DCM (100 mL) was cooled to 0 °C, then amino 2,4,6-trimethylbenzenesulfonate (46 g, 213.7 mmol, 1.83 eq) in DCM (150 mL) was added dropwise and stirred at 20 °C for 2 h. Upon completion, the reaction mixture was filtered and the filter cake was washed with DCM (15 ml * 2) and dried to give 2-(1- amino-4-bromo-pyridin-1-ium-2-yl)acetonitrile (10.5 g, crude) as a solid. Step 6: 5-bromopyrazolo[1,5-a]pyridin-2-amine To a solution of 2-(1-amino-4-bromo-pyridin-1-ium-2-yl)acetonitrile (10.5 g, 49.3 mmol, 1 eq) in MeOH (200 mL) was added K2CO3 (27.3 g, 197.1 mmol, 4 eq). The mixture was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (2-50% EtOAc in PE) to give 5-bromopyrazolo[1,5-a]pyridin-2-amine (7 g, 31.4 mmol, 64% yield, 95% purity) as a solid. Step 7: methyl 2-aminopyrazolo[1,5-a]pyridine-5-carboxylate A mixture of 5-bromopyrazolo[1,5-a]pyridin-2-amine (3.5 g, 16.5 mmol, 1 eq), carbon monoxide;molybdenum (871.5 mg, 3.3 mmol, 444.7 μL, 0.2 eq) and TEA (5.01 g, 49.5 mmol, 6.9 mL, 3 eq) in DMF (35 mL) and MeOH (35 mL) was degassed and purged with N2 (x3), and then cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (1.21 g, 1.65 mmol, 0.1 eq) was added under N ₂ atmosphere. The mixture was stirred at 100 °C for 16 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition water 50 mL at 25 °C, and then diluted with ethyl acetate 5 mL and extracted with ethyl acetate (20 mL x3). The combined organic layers were washed with sat. aq. NaCl (6 mL x3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (2-50% EtOAc in PE) to give methyl 2-aminopyrazolo[1,5-a]pyridine-5-carboxylate (1.6 g, 8.4 mmol, 51% yield) as a solid. MS (ESI) m/z 192.4 [M+H] ⁺ . Step 8: 2-amino-N-methyl-pyrazolo[1,5-a]pyridine-5-carboxamide To a solution of methyl 2-aminopyrazolo[1,5-a]pyridine-5-carboxylate (0.3 g, 1.6 mmol, 1 eq) in EtOH (7 mL) was added MeNH ₂ (162.5 mg, 1.6 mmol, 30% purity, 1 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 2-amino-N-methyl-pyrazolo[1,5-a]pyridine-5-carboxamide (1.5 g, crude) as a solid. Step 9: methyl 2-[tert-butoxycarbonyl-[2-[[5-(methylcarbamoyl)pyrazolo[1,5- a]pyridin-2- yl]amino]ethyl]amino]acetate To a mixture of methyl 2-[tert-butoxycarbonyl(2-oxoethyl)amino]acetate (182.4 mg, 788.6 μmol, 1.5 eq) and 2-amino-N-methyl-pyrazolo[1,5-a]pyridine-5-carboxamide (0.1 g, 525.8 μmol, 1 eq) in MeOH (3 mL) under Nitrogen, a drop of AcOH (44.2 mg, 736.1 μmol, 42.14 μL, 1.4 eq) was added and then was stirred at 0 °C for 0.5 h. NaBH3CN (66.1 mg, 1.05 mmol, 2 eq) was then added and the resulting reaction mixture was stirred at 20 °C for 15.5 h under N ₂ . Upon completion, the reaction mixture was quenched by addition water 0.2 mL, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [H ₂ O (0.2% FA) - ACN]; gradient: 30%-60% B in 20 min) to give methyl 2-[tert-butoxycarbonyl-[2-[[5-(methylcarbamoyl)pyrazolo[1,5- a]pyridin-2- yl]amino]ethyl]amino]acetate (0.62 g, 1.45 mmol, 23% yield, 95% purity) as a solid. MS (ESI) m/z 406.4 [M+H] ⁺ . Step 10: tert-butyl 4-[5-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-2-yl]-3-oxo-pip erazine-1- carboxylate To a solution of methyl 2-[tert-butoxycarbonyl-[2-[[5-(methylcarbamoyl)pyrazolo[1,5- a]pyridin-2-yl]amino]ethyl]amino]acetate (0.2 g, 493.3 μmol, 1 eq) in MeOH (3 mL) was added K2CO3 (204.5 mg, 1.5 mmol, 3 eq). The mixture was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was quenched by addition of water (1 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 9, Gradient e) to give tert-butyl 4-[5-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-2-yl]- 3-oxo-piperazine-1-carboxylate (40 mg, 107 μmol, 22% yield) as a solid. MS (ESI) m/z 374.3 [M+H] ⁺ . Step 11: N-methyl-2-(2-oxopiperazin-1-yl)pyrazolo[1,5-a]pyridine-5-ca rboxamide To a solution of tert-butyl 4-[5-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-2-yl]-3-oxo- piperazine-1-carboxylate (30 mg, 80.34 μmol, 1 eq) in TFA (460.50 mg, 4.04 mmol, 0.3 mL, 50.27 eq) and DCM (1 mL) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-methyl-2-(2-oxopiperazin-1-yl)pyrazolo[1,5- a]pyridine-5-carboxamide (20 mg, crude) as an oil. MS (ESI) m/z 274.3 [M+H] ⁺ . Step 12: N-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)pyrazolo[1,5 -a]pyridine-5- carboxamide A solution of N-methyl-2-(2-oxopiperazin-1-yl)pyrazolo[1,5-a]pyridine-5-ca rboxamide (20 mg, 73.18 μmol, 1 eq) in ACN (0.8 mL) and H ₂ O (0.2 mL) was added K ₂ CO ₃ (30.34 mg, 219.55 μmol, 3 eq) and prop-2-enoyl chloride (4.97 mg, 54.89 μmol, 4.46 μL, 0.75 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 9, Gradient c) to give N-methyl-2-(2-oxo-4-prop-2-enoyl-piperazin-1-yl)pyrazolo[1,5 -a]pyridine-5- carboxamide (Compound 186, 18 mg, 53.3 μmol, 73% yield, 97% purity) as a solid. MS (ESI) m/z 328.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.76 - 8.51 (m, 2H), 8.12 (s, 1H), 7.31 - 7.10 (m, 2H), 6.97 - 6.69 (m, 1H), 6.20 (d, J = 17.2 Hz, 1H), 5.89 - 5.66 (m, 1H), 4.52 (s, 1H), 4.35 (s, 1H), 4.17 - 4.07 (m, 2H), 4.01 (s, 1H), 3.91 (d, J = 4.0 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H). Example 51: Synthesis of Compound 187 Step 1: tert-butyl 3-oxo-4-prop-2-ynyl-piperazine-1-carboxylate A solution of tert-butyl 3-oxopiperazine-1-carboxylate (5 g, 24.97 mmol, 1 eq) in DMF (60 mL) was added NaH (1.50 g, 37.46 mmol, 60% purity, 1.5 eq) under N ₂ , stirring at 25 °C for 1 h. And then, 3-bromoprop-1-yne (4.08 g, 27.47 mmol, 2.96 mL, 1.1 eq) was added. The reaction mixture was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (60 mL) at 0 °C, and then extracted with EtOAc (80 mL * 3). The combined organic layers were washed with brine (100 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (5-19% EtOAc in PE) to give tert-butyl 3-oxo-4-prop-2-ynyl-piperazine-1-carboxylate (3.1 g, 13 mmol, 52% yield) as a solid. MS (ESI) m/z 239.2 [M+H] ⁺ . Step 2: tert-butyl 4-[[1-(2-methoxy-2-oxo-ethyl)triazol-4-yl]methyl]-3-oxo-pipe razine-1- carboxylate A solution of tert-butyl 3-oxo-4-prop-2-ynyl-piperazine-1-carboxylate (500 mg, 2.10 mmol, 1 eq) and methyl 2-azidoacetate (241.5 mg, 2.1 mmol, 1 eq) in dioxane (8 mL) was added CuI (119.9 mg, 629.5 μmol, 0.3 eq). The reaction mixture was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was poured into H2O (10 mL) at 20 °C, and then extracted with EtOAc (20 mL x3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column (5-20% EtOAc in PE) to give tert-butyl 4-[[1-(2-methoxy-2-oxo-ethyl)triazol- 4-yl]methyl]-3-oxo-piperazine-1-carboxylate (520 mg, 1.5 mmol, 70% yield) as a solid. MS (ESI) m/z 354.2 [M+H] ⁺ . Step 3: tert-butyl 4-[[1-[2-(methylamino)-2-oxo-ethyl]triazol-4-yl]methyl]-3-ox o-piperazine-1- carboxylate tert-butyl 4-[[1-(2-methoxy-2-oxo-ethyl)triazol-4-yl]methyl]-3-oxo-pipe razine-1- carboxylate (300 mg, 848.96 μmol, 1 eq) was added to MeNH ₂ (4 g, 38.64 mmol, 4 mL, 30% purity, 45.5 eq) (methylamine ethanol solution), and then the mixture was stirred at 50 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl 4-[[1-[2-(methylamino)-2-oxo-ethyl]triazol-4-yl]methyl]-3-ox o-piperazine-1- carboxylate (300 mg, crude) as an oil. MS (ESI) m/z 353.2 [M+H] ⁺ . Step 4: N-methyl-2-[4-[(2-oxopiperazin-1-yl)methyl]triazol-1-yl]acet amide A solution of tert-butyl 4-[[1-[2-(methylamino)-2-oxo-ethyl]triazol-4-yl]methyl]-3-ox o- piperazine-1-carboxylate (300 mg, 851.3 μmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-methyl-2-[4-[(2-oxopiperazin-1-yl)methyl]triazol-1-yl]acet amide (220 mg, crude) as an oil. MS (ESI) m/z 253.2 [M+H] ⁺ . Step 5: N-methyl-2-[4-[(2-oxo-4-prop-2-enoyl-piperazin-1-yl)methyl]t riazol-1-yl]acetamide To a solution of N-methyl-2-[4-[(2-oxopiperazin-1-yl)methyl]triazol-1-yl]acet amide (220 mg, 872.1 μmol, 1 eq) in DCM (3 mL) was added TEA (264.73 mg, 2.6 mmol, 364.1 μL, 3 eq) and then prop-2-enoyl chloride (78.9 mg, 872.1 μmol, 70.9 μL, 1 eq) in DCM (1 mL) was added at 0 °C. The solution was stirred for 0.5 h at 0 °C. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.2 mL) at 0 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Condition 4, Gradient b) to give N-methyl-2- [4-[(2-oxo-4-prop-2-enoyl-piperazin-1-yl)methyl]triazol-1-yl ]acetamide (Compound 187, 44 mg, 133 μmol, 34% yield, 93% purity) as a solid. MS (ESI) m/z 307.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 8.20 (d, J = 3.3 Hz, 1H), 7.97 (s, 1H), 6.87 - 6.70 (m, 1H), 6.15 (dd, J = 1.8, 16.6 Hz, 1H), 5.72 (br d, J = 10.5 Hz, 1H), 5.03 (s, 2H), 4.59 (s, 2H), 4.26 (s, 1H), 4.11 (s, 1H), 3.81 (d, J = 4.6 Hz, 1H), 3.72 (br s, 1H), 3.46 - 3.35 (m, 2H), 2.62 (d, J = 4.6 Hz, 3H). Example 52: Gel-Based Activity-Based Protein Profiling (ABPP) to assess DUB Recruiter binding to OTUB1 Recombinant OTUB1 from Sino Biological (12927-H07E) or produced and purified in- house (0.08μg/sample) was pre-treated with either DMSO vehicle or covalent ligand or bifunctional compounds at 37℃ for 30 min in 49 μL of PBS, and subsequently treated with of IA- Rhodamine (Setareh Biotech) at room temperature for 1 h. The reaction was stopped by addition of 4×reducing Laemmli SDS sample loading buffer (Alfa Aesar). After boiling at 95℃ for 5 min, the samples were separated on precast 4−20% Criterion TGX gels (Bio-Rad). Probe-labeled proteins were analyzed by in-gel fluorescence using an Azure 600 to provide a IC50 value for binding to OTUB1. These results are summarized in Table 3, wherein compounds that compete with IA-rhodamine at 50 µM to show between 100–80% of DMSO control fluorescence intensity are annotated “-“; compounds that show between 80-50% of DMSO control fluorescence intensity are annotated “ ”; compound that show between 50-30% of DMSO control fluorescence intensity are annotated “ ” and compounds that show less than 30% of DMSO control fluorescence intensity are annotated “+++”. Table 3. OTUB1 binding of Exemplary Compounds (IC50) Example 53: Intact-MS Assay via RapidFire-TOF Sample Preparation: Compound (1 μL of 5mM DMSO solution – final concentration 100 μM) was added to recombinant protein (1 μM, 49 μL) in buffer (25 mM Tris HCl; 10 mM NaCl; pH 7.5) in 96 well plates on ice. The reaction was mixed and incubated at 4C for 16 hours. Formic acid solution (1% in water, 50 μL) was added to quench the reaction and the samples were mixed, then centrifuged for 3 minutes at 3000xg and stored at 4C until analysis. Sample Analysis: A volume of 50 μL sample was aspirated from the 96-well plate by using an aspiration time of 300 ms, and 10 μL (limited by the sample loop size) was injected and concentrated on a C4 SPE cartridge (Agilent #G9203A, 20 μm, 4 μL). The sample load/wash time was 8000 ms at a flow rate of 0.6 mL/min (10% acetonitrile with 0.1% formic acid); elution time was 7000 ms at a flow rate of 0.5 mL/min (80% acetonitrile, 0.1% formic acid); re-equilibration time was 500 ms at a flow rate of 0.6 mL/min (10% acetonitrile, 0.1% formic acid). An Agilent 6230 TOF mass spectrometer was operated with a dual Agilent Jet Spray (AJS) ion source in the positive ionization mode and 3200 m/z range. The source parameters were as follows: gas temperature 325 °C, drying gas 8 L/min, nebulizer 35 psi, sheath gas 350 °C, sheath gas flow 11 L/min, capillary 3500V, nozzle 1000 V, fragmentor 175 V, and skimmer 65 V. Data Analysis: Data files were parsed into individual injections using the RapidFire UI software. In Agilent BioConfirm 12.0 TICs for individual injection files were integrated (with only one peak allowed per injection) and MS spectra extracted, using a designated background time range of 0.0 – 0.05 min. Decovolution for OTUB1 samples was performed using the maximum entropy method, filtering for peak signal-to-noise of >30, calculating average mass using the top 25% of peak height, using an explicit output mass range of 28,000 – 40,000 Da and a mass step of 0.2 Da, using a limited input range of 850 – 1800 m/z, and subtracting baseline with a baseline factor of 1.0. Biomolecule filters were set to a minimum consecutive charge states of 4, minimum fit score of 2, and minimum height threshold of 5%. Deconvolution was followed by bulk export of “Biomolecules” csv lists. Peaks present in the Biomolecules lists were compared to expected masses of protein + compound adducts for up to 5 modifications allowing for a window of +/- 2 amu in Excel. Percent modification values were calculated by comparing the peak height for a given species (i.e. a given degree of modification) versus the total peak height of unmodified and modified protein peaks in the deconvoluted spectrum. These results are summarized in Table 4, wherein compounds that demonstrated less than 20% modification for a single cysteine are annotated “ ; and compounds that demonstrated more than 20% modification for a single cysteine are annotated “++”. Table 4. Mass Spectrometry Based Deubiquitinase Screening Assay Example 53: Deubiquitinase Activity Assay Recombinant OTUB1 (500 nM) was pre-incubated with DMSO or Compound 100 (50 mM) for 1 hr. To initiate assay pre-treated OTUB1 enzyme was mixed 1:1 with di-Ub reaction mix for final concentrations of 250 nM OTUB1, 1.5 µM di-Ub, 12.5 µM UBE2D1 and 5 mM DTT. The appearance of mono-Ub was monitored by Western blotting over time by removing a portion of the reaction mix and adding Laemmli’s buffer to terminate the reaction. Blot shown is a representative gel from n=3 biologically independent experiments/group. Additionally, recombinant OTUB1 activity will be assessed using commercially available fluorescently-labeled di-Ubiquitin substrates from LifeSensors (DU0101). Western Blotting Proteins were resolved by SDS/PAGE and transferred to nitrocellulose membranes using the Trans-Blot Turbo transfer system (Bio-Rad). Membranes were blocked with 5% BSA in Tris- buffered saline containing Tween 20 (TBS-T) solution for 30 min at RT, washed in TBS-T, and probed with primary antibody diluted in recommended diluent per manufacturer overnight at 4℃. After 3 washes with TBS-T, the membranes were incubated in the dark with IR680- or IR800- conjugated secondary antibodies at 1:10,000 dilution in 5 % BSA in TBS-T at room temperature for 1 h. After 3 additional washes with TBST, blots were visualized using an Odyssey CLx Li-Cor fluorescent scanner. The membranes were stripped using ReBlot Plus Strong Antibody Stripping Solution (EMD Millipore) when additional primary antibody incubations were performed. Antibodies used in this study were CFTR (Cell Signaling Technologies, Rb mAb #78335), GAPDH (Proteintech, Ms mAb, #60004-1-Ig), OTUB1 (Abcam, Rb mAb, #ab175200, [EPR13028(B)]). Alternatively, target protein (e.g. CFTR) abundance was analyzed via Simple Western on a Jess instrument (Protein Simple) using the same primary antibodies and normalized to total protein abundance using a total protein detection kit (Protein Simple; DMTP01). Example 54: Quantitative TMT Proteomics Analysis Quantitative TMT-based proteomic analysis will be performed to assess relative protein abundance. Acquired MS data will be processed using a standard software package and searched against a protein database. Data analysis will be done to determine relative protein abundance of different target proteins. Example 55. Assessing protein abundance in ΔF508-CFTR human cystic fibrosis bronchial epithelial cells CFBE41o-4.7 with treatment of exemplary bifunctional compounds. CFBE41o-4.7 cells were seeded at 600k cells per 6cm ² plate and were treated with either DMSO vehicle or 10uM DUBTAC (total of 0.1% DMSO) for 24 hours, then harvested, lysed, and cell lysate normalized to total protein content. Proteins were resolved by SDS–PAGE and transferred to nitrocellulose membranes. Membranes were blocked with 5% BSA in Tris-buffered saline containing Tween 20 (TBS-T) solution for 30 min at room temperature, washed in TBS-T and probed with primary antibody against CFTR (Cell Signaling Technologies, rabbit monoclonal antibody 78335, 1:1,000 dilution in 5% BSA) and GAPDH (Proteintech, mouse monoclonal antibody, 1:10,000 dilution in 5% BSA, 60004-1-Ig), and incubated overnight at 4 °C. After three washes with TBS-T, the membranes were incubated in the dark with IR680- or IR800-conjugated secondary antibodies at a 1:10,000 dilution in 5% BSA in TBS-T at room temperature for 1 h. After three additional washes with TBS-T, blots were visualized using an Odyssey CLx Li-Cor fluorescent scanner. CFTR abundance was quantified relative to GAPDH control.