Modulators of BCL6 protein degradation and related methods of use

Abstract

Described herein are bifunctional compounds that find utility as regulators of B-cell lymphoma 6 protein (BCL6; target protein). In particular, the bifunctional compounds of the present disclosure contain a cereblon ligand that binds to each E3 ubiquitin ligase on one end and a moiety that binds to the target protein on the other end, such that the target protein is placed in close proximity to the ubiquitin ligase, resulting in degradation (and inhibition) of the target protein. The bifunctional compounds of the present disclosure exhibit a wide range of pharmacological activities related to the degradation / inhibition of the target protein. Diseases or disorders resulting from the aggregation or accumulation of the target protein are treated or prevented using the compounds and compositions of the present disclosure.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to and the benefit of U.S. Provisional Application No. 63 / 175,678, filed April 16, 2021, entitled MODULATORS OF BCL6 PROTEOLYSIS AND ASSOCIATED METHODS OF USE, which is incorporated herein in its entirety for all purposes.

[0002] Incorporation by Reference U.S. Patent Application No. 17 / 073,135, filed October 16, 2020, and U.S. Patent Application No. 15 / 730,728, filed October 11, 2017, published as U.S. Patent Application Publication No. 2018 / 0099940, and U.S. Patent Application No. 14 / 686,640, filed April 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562, and U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application Publication No. 2016 / 0058872, are incorporated herein by reference in their entireties. Additionally, all references cited herein are incorporated herein by reference in their entireties.

[0003] Provided herein are bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of use, that are useful as modulators of target ubiquitination, such as B-cell lymphoma 6 protein (BCL6), which is degraded and / or otherwise inhibited by the bifunctional compounds of the present disclosure. [Background technology]

[0004] Most small molecule drugs bind closely to enzymes or receptors in well-defined pockets. However, targeting protein-protein interactions using small molecules is notoriously challenging due to the large protein contact surfaces and shallow, groove-like, or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and are therefore more attractive therapeutic targets than general proteasome inhibitors due to their specificity for specific protein substrates. Developing ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutrin, additional compounds targeting E3 ligases have been reported, but the field remains largely unexplored.

[0005] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, underscoring its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates numerous developmental processes, such as limb and otic vesicle formation. It has been conclusively concluded that this ubiquitin ligase complex is important for limb development in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

[0006] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, these patent publications describe bifunctional or proteolysis targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds.

[0007] There is a continuing need in the art for effective treatments for diseases associated with (i) aberrant BCL6 expression and / or activity and / or (ii) overexpression or aggregation of the B-cell lymphoma 6 protein (BCL6). However, nonspecific effects and the inability to target and modulate BCL6 remain obstacles to the development of effective therapies. Therefore, small molecule therapeutics that target BCL6 and exploit or enhance the substrate specificity of E3 ubiquitin ligases (e.g., cereblon) would be highly useful. Summary of the Invention

[0008] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis-inducing chimeric molecular compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they may have a broad range of pharmacological activity, consistent with the degradation / inhibition of target polypeptides from virtually any protein species or family. Additionally, the present disclosure provides methods of using an effective amount of a compound described herein for treating or ameliorating a disease state, such as, for example, cancer, e.g., lymphoma, B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, non-small cell lung cancer, and the like.

[0009] Thus, in one aspect, the present disclosure provides bifunctional compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase, or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand, or "PTM" group), thereby bringing the target protein / polypeptide into proximity with the ubiquitin ligase, thereby effecting its degradation (and inhibition). In a preferred embodiment, the ULM (ubiquitination ligase modulator) may be a cereblon E3 ubiquitin ligase binding moiety (CLM). For example, the structure of a bifunctional compound may be depicted as follows: [ka]

[0010] The respective positions of the PTM and ULM moieties (e.g., CLM), as well as their numbers, exemplified herein are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by one of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0011] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). In this example, the structure of the bifunctional compound can be represented as follows: [ka] wherein PTM is a protein / polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group, that connects the PTM to ULM, and ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM).

[0012] For example, the structure of a bifunctional compound can be shown as follows: [ka] where PTM is a protein / polypeptide targeting moiety, "L" is a linker (e.g., a bond or chemical linker group) that connects the PTM and CLM, and CLM is a cereblon E3 ubiquitin ligase binding moiety that binds to cereblon.

[0013] In certain embodiments, the compounds described herein comprise a plurality independently selected from a ULM, a plurality of PTMs, a plurality of chemical linkers, or a combination thereof.

[0014] In one embodiment, the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. Other contemplated CLMs include those in U.S. Patent Application Publication No. 2015 / 0291562, which is incorporated herein in its entirety.

[0015] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a connector having a linear number of non-hydrogen atoms ranging from 1 to 20. The connector "L" can include functional groups such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker can include aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Substitution with halogens such as Cl, F, Br, and I can be included in the linker. Fluorine substitution can include single or multiple fluorines.

[0016] In certain embodiments, the CLM is a derivative of piperidine-2,6-dione, which may be substituted at the 3-position, and the 3-position substitution may be a bicyclic heteroaromatic compound with a bond as a C-N or C-C bond. Examples of CLMs include, but are not limited to, pomalidomide, lenalidomide, and thalidomide, and derivatives thereof.

[0017] In an additional aspect, the present disclosure provides therapeutic compositions comprising an effective amount of a compound described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic compositions modulate protein degradation and / or inhibition in a patient or subject, e.g., an animal such as a human, and can be used to treat or ameliorate a disease state or condition regulated through the degraded and / or inhibited protein. In certain embodiments, the therapeutic compositions described herein can be used to cause target protein degradation for the treatment or amelioration of a disease, e.g., cancer. In yet another aspect, the present disclosure provides methods for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein, preferably comprising a PTM and a CLM linked via a linker moiety, as described elsewhere herein, wherein the CLM is linked to the PTM via the linker to target the protein bound to the PTM for degradation. Similarly, the PTM may be linked to the CLM via a linker to target a protein or polypeptide for degradation. Degradation of a target protein occurs when the target protein is placed in proximity to an E3 ubiquitin ligase, thus resulting in degradation of the target protein / inhibition of the effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a disease state or condition that is regulated via the target protein by reducing the level of that protein in the patient's cells.

[0018] In yet another aspect, the present specification provides a method of treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal, e.g., a human, the method comprising administering to a subject in need thereof a composition comprising an effective, e.g., a therapeutically effective amount, of a compound as described herein, or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

[0019] In another aspect, the present specification provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0020] The foregoing general description of utility is presented for illustrative purposes only and is not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be understood by those skilled in the art in view of the claims, detailed description, and examples. For example, the various aspects and embodiments of the present disclosure can be used in many combinations, all of which are expressly contemplated by this specification. These additional aspects and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to describe the background of the disclosure and, in particular cases, to provide additional details regarding the implementation are incorporated by reference. [Brief explanation of the drawings]

[0021] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description herein, serve to explain the principles of the present disclosure. The drawings are solely for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which show exemplary embodiments of the present disclosure.

[0022] [Figure 1]1A and 1B. Diagram of the general principle of the heterobifunctional degradation compounds of the present disclosure. (A) An exemplary heterobifunctional degradation compound includes a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (TLM; light shaded triangle), and, optionally, a linker moiety (L; black line) that attaches or connects the PTM to the ULM. (B) Illustrates the functional uses of the heterobifunctional degradation compounds described herein. Briefly, the ULM recognizes and binds a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein, bringing it into proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and, alone or through the E2 protein, catalyzes the attachment of ubiquitin via an isopeptide bond to a lysine on the target protein (dark circle). Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteasome machinery. DETAILED DESCRIPTION OF THE INVENTION

[0023] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned herein are expressly incorporated by reference in their entirety.

[0024] Described herein are compositions and methods related to the surprising and unexpected discovery that when an E3 ubiquitin ligase protein (e.g., cereblon E3 ubiquitin ligase) and a target protein are placed in close proximity via a bifunctional or chimeric construct, and upon binding of the E3 ubiquitin ligase to the target protein, the E3 ubiquitin ligase protein ubiquitinates the target protein. Accordingly, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety (ULM) conjugated to a protein target binding moiety (PTM), which result in ubiquitination of a selected target protein, leading to degradation of the target protein by the proteasome (see Figures 1A and 1B). The present disclosure also provides libraries of compositions and uses thereof.

[0025] In certain aspects, the present disclosure provides compounds that include a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons), that can bind to a ubiquitin ligase, such as cereblon. The compound also includes a moiety that can bind to a target protein in such a way as to bring the target protein into proximity with the ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. In addition to the above, small molecule can mean that the molecule is nonpeptidyl, i.e., often not considered a peptide, e.g., containing fewer than 4, 3, or 2 amino acids. According to the present specification, a PTM, ULM, or bifunctional degradation molecule can be a small molecule.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0027] Where a range of values ​​is provided, unless the context clearly dictates otherwise (e.g., in the case of a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided), it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated range, or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, as are any specifically excluded limits in the stated range. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0028] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art who apply the term in the context of its use in describing this disclosure.

[0029] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0030] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so conjoined. That is, in some instances, the elements are present conjunctively and in other instances, they are present disjointly. Multiple elements listed with "and / or" should be construed in the same manner, that is, "one or more" of the elements are so conjoined. Other elements other than the elements specifically identified by the "and / or" clause can optionally be present, whether related or not to those specifically identified elements. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[0031] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., the inclusion of at least one, but also two or more, of a number or list of elements, and optionally additional unlisted items. Only terms clearly implied to the contrary, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," shall refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" should be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by exclusive terms, such as "either," "one of," "only one of," or "exactly one of."

[0032] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Examining Guidelines.

[0033] As used herein, in the specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. Furthermore, this definition allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether or not related to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally, two or more A, and no B (and, optionally, including elements other than B); in another embodiment to at least one, optionally, two or more B, and no A (and, optionally, including elements other than A); and in yet another embodiment to at least one, optionally, two or more A, and at least one, optionally, two or more B (and, optionally, including other elements).

[0034] In certain methods described herein that include more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless the context indicates otherwise.

[0035] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a time different from the administration of an additional therapeutic agent) while still providing some, preferably effective, amount of the therapeutic agents present in the patient's body at the same time. In certain preferred embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, including, particularly, anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer activity.

[0036] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, and includes tautomers, positional isomers, geometric isomers, and, where appropriate, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives thereof, including prodrugs and / or deuterated forms, where appropriate in the context. Contemplated deuterated small molecules are small molecules in which one or more of the hydrogen atoms contained in the drug molecule have been replaced with deuterium.

[0037] Within its use in context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as specific enantiomers or mixtures enriched in a specific enantiomer. In context, the term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. Note that in describing the compounds, many substituents and, in particular, variables associated therewith are described. It will be understood by those skilled in the art that the molecules described herein are stable compounds, as outlined below. Where bonds are depicted, both double and single bonds are depicted or understood within the context of the depicted compounds and known rules regarding valency interactions.

[0038] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, thereby targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein, which, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to lysine on target proteins, subsequently targeting specific protein substrates for proteasomal degradation. Thus, E3 ubiquitin ligases, either alone or in complex with an E2 ubiquitin conjugating enzyme, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, and a third ubiquitin is attached to the second ubiquitin. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation but may instead change their cellular location or function, for example, through binding to other proteins that contain domains capable of ubiquitin binding. Further complicating the issue, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to generate polyubiquitin that is recognized by the proteasome.

[0039] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of an infection, condition, or pathology specific to a particular animal, e.g., a human patient, the term patient refers to the particular animal, including domestic animals, e.g., dogs or cats, or agricultural animals, e.g., horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise indicated or implied by the context in which the term is used.

[0040] The term "effective," when used within the context of its intended use, is used to describe an amount of a compound, composition, or component that produces an intended result. The term effective includes all other effective amount or effective concentration terms that are otherwise described or used in this application.

[0041] Compounds and Compositions

[0042] In one aspect, the present disclosure provides a compound comprising an E3 ubiquitin ligase binding moiety (ULM), wherein the ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM). In an exemplary embodiment, the ULM is linked to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure: (A) PTM-L-ULM wherein L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of moieties in the compounds described herein are provided for illustrative purposes only. As will be understood by those skilled in the art, the compounds described herein can be synthesized with any desired number of functional moieties and / or relative positions of each functional moiety.

[0043] The terms ULM and CLM are used in their inclusive sense unless the context indicates otherwise. For example, the term ULM encompasses all ULMs, including those that bind to cereblon (i.e., CLMs). Further, the term CLM encompasses all cereblon-binding moieties.

[0044] In another aspect, the present disclosure provides bifunctional or multifunctional compounds useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compound comprises a CLM attached, for example, covalently, directly, or indirectly, to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the CLM and PTM are attached or linked via a chemical linker (L). The CLM binds to cereblon E3 ubiquitin ligase, the PTM recognizes the target protein, and interaction between each moiety and its target brings the target protein into close proximity with the ubiquitin ligase protein, facilitating degradation of the target protein. Exemplary bifunctional compounds can be depicted as follows: (B) PTM-CLM

[0045] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). For example, the bifunctional compound can be depicted as follows: (C) PTM-L-CLM where PTM is a protein / polypeptide targeting moiety, L is a chemical linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety.

[0046] In certain embodiments, ULM (e.g., CLM) exhibits activity against or binds to an E3 ubiquitin ligase (e.g., cereblon E3 ubiquitin ligase) with an IC50 of less than about 200 μM. IC50 can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay.

[0047] In certain additional embodiments, the bifunctional compounds described herein exhibit an IC50 activity of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0048] In certain embodiments, the compounds described herein include multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., moieties that specifically bind to multiple / different E3 ubiquitin ligases, e.g., cereblon), or combinations thereof. In any of the aspects or embodiments described herein, the PTMs and ULMs (e.g., CLMs) may be linked directly, via one or more chemical linkers, or by a combination thereof. In additional embodiments, when a compound has multiple ULMs, the ULMs may be directed to the same E3 ubiquitin ligase, or each ULM may specifically bind to a different E3 ubiquitin ligase. In yet further embodiments, when a compound has multiple PTMs, the PTMs may bind to the same target protein, or each PTM may specifically bind to a different target protein.

[0049] In certain embodiments, when a compound comprises multiple ULMs, the ULMs are the same. In additional embodiments, a compound comprises multiple ULMs (e.g., ULM, ULM'), at least one PTM linked to the ULM directly, via a chemical linker (L), or both. In certain additional embodiments, a compound comprising multiple ULMs further comprises multiple PTMs. In even further embodiments, the PTMs are the same or, optionally, different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0050] In certain embodiments, a compound may comprise multiple ULMs and / or multiple ULMs'. In further embodiments, a compound comprising at least two different ULMs, multiple ULMs, and / or multiple ULMs' further comprises at least one PTM linked to a ULM or ULM' directly, via a chemical linker, or both. In any of the embodiments described herein, a compound comprising at least two different ULMs may further comprise multiple PTMs. In still additional embodiments, the PTMs are the same or, optionally, different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets. In still further embodiments, the PTM itself is a ULM (or ULM'), e.g., a CLM and / or CLM'.

[0051] In additional embodiments, the present disclosure provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutically acceptable salt forms, e.g., acid and base salt forms.

[0052] As used herein, the term "independently" is used to indicate that the variables that are independently applied vary independently from application to application.

[0053] The term "alkyl," within its context, shall mean a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical or alkyl group, preferably a C1-C10, more preferably a C1-C6, or alternatively a C1-C3 alkyl group, which may be optionally substituted. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, cyclo-propyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl, among others. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, compounds according to the present disclosure may be used to covalently bind to dehalogenase enzymes. These compounds generally contain a side chain (often attached via a polyethylene glycol group) that terminates in an alkyl group with a halogen substituent (often chlorine or bromine) at its distal end, thereby forming a covalent bond between the compound containing the moiety and the protein.

[0054] The term "alkenyl" refers to a straight-chain, branched-chain or cyclic C2-C10 (preferably C2-C6) hydrocarbon radical containing at least one C=C bond.

[0055] The term "alkynyl" refers to a straight-chain, branched-chain or cyclic C2-C10 (preferably C2-C6) hydrocarbon radical containing at least one C≡C bond.

[0056] The term "alkylene," when used, refers to an optionally substituted --(CH)-- group, where n is generally an integer from 0 to 6. When substituted, the alkylene group is preferably substituted at one or more of the methylene groups with a C-C alkyl group (including a cyclopropyl or t-butyl group), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, an O-(C-C alkyl) group, or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which in turn is substituted with a polyethylene glycol chain (a chain of 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to which an alkyl group (preferably, but not exclusively, on the distal end of the polyethylene glycol chain) is substituted, and the alkyl chain is substituted with a single halogen group, preferably a chlorine group. In still other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as the side chain group of a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0057] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with an H. Thus, a range of carbon atoms from C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with an H replacing the carbon for C0.

[0058] The terms "substituted" or "optionally substituted" refer independently to one or more substituents (independently up to five substituents, preferably up to three substituents, often one or two substituents on a moiety in a compound according to the present disclosure, which may include substituents that may themselves be further substituted) at any carbon (or nitrogen) position on the molecule within the context (i.e., when there are multiple substituents, each substituent is independent of the other substituents), and include as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably one, two, or three halogens, especially on alkyl, especially methyl groups such as trifluoromethyl), alkyl group (preferably C1-C10, more preferably C1-6), aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy group (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1 and optionally substituted —N(C0-C6 alkyl)C(O)(O—C1-C6 alkyl) groups (optionally substituted with a polyethylene glycol chain further bonded to an alkyl group containing one halogen, preferably chlorine, substituent), hydrazine, amide, preferably substituted with one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl).Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as otherwise described herein, and R3 is H or a C1-C6 alkyl group, preferably in this context R1, R2, and R3 are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly attached to the substituted moiety, or the substituent may be attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via an optionally substituted (CH2)m- or an optionally substituted -(OCH2)m-, -(OCH2CH2)m-, or -(CH2CHO)m- group, which may be substituted with any one or more of the above-mentioned substituents. -(CH2)m- or -(CH2)n- groups of alkylene groups or other chains, such as the ethylene glycol chains identified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen or a C1-C6 (preferably C1-C3) alkyl group, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or an amino acid side chain as otherwise described herein, and an optionally substituted amide (preferably a carboxamide substituted as described above) or urethane group (often having one or two C0-C6 alkyl substituents, which may also be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or an amino acid side chain as otherwise described herein. Moieties in the molecules of the present disclosure may optionally be substituted with up to five substituents, preferably up to three substituents. In most cases, substituted moieties in the present disclosure are substituted with one or two substituents.

[0059] The term "substituted" (each substituent independent of any other substituent) is intended to mean, within the context of its use, C-C alkyl, C-C alkoxy, halogen, amide, carboxamide, sulfone, including sulfonamide, keto, carboxy, C-C ester (oxyester or carbonylester), C-C keto, urethane-O-C(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly C-C alkylene-NR1R2, mono- or di-C-C alkyl-substituted amines, which may be optionally substituted with one or two hydroxyl groups). Each of these groups, unless otherwise indicated, contains from 1 to 6 carbon atoms within the context. In certain embodiments, preferred substituents include, for example, —NH—, —NHC(O)—, —O—, ═O, —(CH)— (where m and n are 1, 2, 3, 4, 5, or 6, in context), —S—, —S(O)—, SO—, or —NH—C(O)—NH—, —(CH)OH, —(CH)SH, —(CH)COOH, C-C alkyl, —(CH)O—(C-C alkyl), —(CH)C(O)—(C-C alkyl), —(CH)OC(O)—(C-C alkyl), —(CH)C(O)O—( and -S(O)-RS (where RS is a C-C alkyl or a -(CH)-NRR group), NO, CN, or a halogen (F, Cl, Br, I, preferably F or Cl). R1 and R2 are each, in context, H or a C1-C6 alkyl group (optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine).The term "substituted" also refers to an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group as otherwise described herein, within the chemical context of the compound specified and the substituents used. Alkylene groups may also be substituted as otherwise disclosed herein, preferably with an optionally substituted C-C alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thereby providing a chiral center), the side chain of an amino acid group as otherwise described herein, an amide group as described above, or a urethane group, an O-C(O)-NR group, where R and R are as otherwise described herein, although many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer, and preferably one or two substituents. Note that in compounds where substitution is required at certain positions of the molecule (primarily for valence reasons), but where no substitution is indicated, the substituent is assumed or understood to be H unless the context of the substitution indicates otherwise.

[0060] The terms "aryl" or "aromatic," in context, refer to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenylphenyl, phenanthrenyl, etc.), which may be attached to a compound in accordance with the present disclosure at any available stable position on the ring or as otherwise specified in the provided chemical structure. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as heteroaromatic ring systems, e.g., imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, among others, which may be optionally substituted as described above.Heteroaryl groups which may be mentioned in particular are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanacene, oxadiazole, benzyl Examples include imidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine, sulfur-containing aromatic heterocycles such as thiophene and benzothiophene, oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran, and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoleoxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0061] The term "substituted aryl" refers to an aromatic carbocycle composed of at least one aromatic ring or composed of multiple fused rings, at least one of which is aromatic, in which the ring is substituted with one or more substituents. For example, an aryl group may contain substituents selected from -(CH2)nOH, -(CH2)nO-(C1-C6)alkyl, -(CH2)nO-(CH2)n-(C1-C6)alkyl, -(CH2)nC(O)(C0-C6)alkyl, -(CH2)nC(O)O(C0-C6)alkyl, -(CH2)n-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein the alkyl group on the amine optionally contains one or two hydroxyl groups. a group, or up to three halo (preferably F, Cl), OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), an optionally substituted phenyl group (which itself is preferably attached to a PTM group, including a ULM group, via a linker group), and / or F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, N at least one of O, or CN groups (at the ortho, meta, and / or para positions of the phenyl ring, preferably at the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole including a methyl-substituted isoxazole, an optionally substituted oxazole including a methyl-substituted oxazole, an optionally substituted thiazole including a methyl-substituted thiazole, an optionally substituted isothiazole including a methyl-substituted isothiazole, an optionally substituted pyrrole including a methyl-substituted pyrrole, an optionally substituted imidazole including a methylimidazole, an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted oximidazole or methyloximidazole, an optionally substituted diazole group including a methyldiazole group, an optionally substituted triazole group including a methyl-substituted triazole group, an optionally substituted pyridine group including a halo (preferably F)-substituted or methyl-substituted pyridine group or an oxapyridine group,The pyridine group is attached to the phenyl group by an oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[0062] "Carboxyl" means --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, while these generic substituents have the same meaning as in the corresponding group definitions defined herein.

[0063] The term "heteroaryl" or "hetaryl" includes, but is not limited to, optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole , optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl- and / or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole (preferably 1,2,3-triazole substituted with a methyl group, a triisopropylsilyl group, an optionally substituted —(CH)O—C1-C6 alkyl group, or an optionally substituted —(CH)C(O)—O—C1-C6 alkyl group), optionally substituted pyridine (2, 3, or 4-pyridine), or a group according to the following chemical structure: [ka] During the ceremony, Sc is CHRSS, NRURE, or O; RHET is H, CN, NO, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl); RSS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R is H, C-C alkyl (preferably H or C-C alkyl), or —C(O)(C-C alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and YC is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0064] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing aryl or heteroaryl, respectively, as defined above, and alkyl, and / or heteroalkyl, and / or carbocyclic and / or heterocycloalkyl ring systems.

[0065] As used herein, the term "arylalkyl" refers to an aryl group, as defined above, appended to an alkyl group, as defined above. An arylalkyl group is attached to the parent moiety via an alkyl group, where the alkyl group is 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as described above.

[0066] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Heteroaryl moieties are therefore encompassed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described herein above.

[0067] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolyl, and benzothiazolyl. Examples include sazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thiane.

[0068] Heterocyclic groups can be optionally substituted with groups selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which either heterocyclic ring is fused to a benzene ring or a cyclohexane ring or to another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0069] The term "cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, such as a saturated monocyclic hydrocarbon group having from 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" refers to a monocyclic or polycyclic alkyl group substituted with one or more substituents, such as, but not limited to, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these generic substituents have the same meaning as the definition of the corresponding group defined in this Description.

[0070] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P, and which groups contain one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these generic substituents have the same meaning as the definition of the corresponding group provided in this Description.

[0071] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0072] As used herein, the term "independently" is used to indicate that the variables that are independently applied vary independently from application to application.

[0073] The term "lower alkyl" refers to methyl, ethyl, or propyl.

[0074] The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

[0075] Exemplary CLM

[0076] Neo-imide compounds

[0077] In one aspect, the present disclosure provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures: [ka] During the ceremony, W in formulas (a)-(f) is selected from the group consisting of CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl; W3 is C or N; X in formulas (a)-(f) is independently selected from the group consisting of absent, O, S, and CH; Y in formulas (a)-(f) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a)-(f) is independently selected from the group of absent, O, S, and CH2, provided that both X and Z cannot be absent or CH2; G and G' in formulae (a) to (f) are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (f) each independently represent carbon C or N substituted with a group independently selected from H, R, N, or N-oxide, or Q1 to Q4 in formulas (a) to (f) each independently represent N, CH, or CR; A in formulas (a) to (f) is selected from the group consisting of H, optionally substituted straight or branched chain alkyl, cycloalkyl, Cl, and F; n in formulas (a) and (f) represents an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulas (a) to (f) includes, but is not limited to, H, -C(=O)R' (e.g., a carboxy group), -CONR'R" (e.g., an amide group), -OR' (e.g., OH or OCH), -NR'R" (e.g., an amine group), -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O)n, R", optionally substituted heterocyclyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., an optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or an alkyl group containing at least one of a combination thereof). alkyl-aryl), optionally substituted heteroaryl, optionally substituted alkyl (e.g., C1-C6 straight or branched alkyl optionally substituted with one or more halogens, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; in which case the alkoxyl can be substituted with one or more halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl, optionally substituted heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3,-CN,-NR'SO2NR'R",-NR'CONR'R",-CONR'COR",-NR'C(=N-CN)NR'R",-C(=N-CN)NR'R",-NR'C(=N-CN)R",-NR'C( =C-NO2)NR'R",-SO2NR'COR",-NO2,-CO2R',-C(C=N-OR')R",-CR'=CR'R",-CCR',-S(C=O)(C=N-R')R",-SF5 and -OCF3; each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6; R' and R'' of formulas (a) through (f) are each independently selected from H, optionally substituted straight or branched chain alkyl (e.g., methyl or ethyl), optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -C(=O)A, optionally substituted heterocyclyl; n' in formulas (a) and (f) represents an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); [ka] represents a single or double bond; and Equations (a) to (f) [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0078] Exemplary CLM

[0079] In any of the compounds described herein, the CLM comprises a chemical structure selected from the following group: [ka] During the ceremony, W in formulas (a)-(f) is selected from the group consisting of CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl; W3 is C or N; X in formulas (a)-(f) is independently selected from the group consisting of absent, O, S, and CH; Y in formulas (a)-(f) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a)-(f) is independently selected from the group of absent, O, S, and CH2, provided that both X and Z cannot be absent or CH2; G and G' in formulae (a) to (f) are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (f) each independently represent carbon C or N substituted with a group independently selected from H, R, N, or N-oxide, or Q1 to Q4 in formulas (a) to (f) each independently represent N, CH, or CR; A in formulas (a) to (f) is selected from the group consisting of H, optionally substituted straight or branched chain alkyl, cycloalkyl, Cl, and F; n in formulas (a) and (f) represents an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulas (a) to (f) includes, but is not limited to, H, -C(=O)R' (e.g., a carboxy group), -CONR'R" (e.g., an amide group), -OR' (e.g., OH), -NR'R" (e.g., an amine group), -SR', -S02R', -S02NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O)n'R", optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl including at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally Substituted hetaryl, optionally substituted straight or branched alkyl (e.g., C1-C6 straight or branched alkyl optionally substituted with one or more halogens, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl)), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; in which case the alkoxyl can be substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted cycloalkyl, optionally substituted heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3,-CN,-NR'SO2NR'R",-NR'CONR'R",-CONR'COR",-NR'C(=N-CN)NR'R",-C(=N-CN)NR'R",-NR'C(=N-CN)R",-NR'C( =C-NO2)NR'R",-SO2NR'COR",-NO2,-CO2R',-C(C=N-OR')R",-CR'=CR'R",-CCR',-S(C=O)(C=N-R')R",-SF5 and -OCF3; each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6; R' and R'' of formulas (a) through (f) are each independently selected from a bond, H, optionally substituted straight or branched chain alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -C(=O)A, and optionally substituted heterocyclyl; n' in formulas (a) and (f) represents an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and Equations (a) to (f) [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0080] In any aspect or embodiment described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of: [ka] During the ceremony, W is selected from the group consisting of CH2, O, CHR, C=O, NH, and N; each X is independently selected from the group consisting of: absent, O, S, and CH; Z is selected from the group consisting of absent, O, S and CH; Z is selected from the group consisting of H, methyl, and OH; Q1, Q2, Q3, and Q4 each independently represent N or C substituted with a group independently selected from H, R, N, or N-oxide, or Q1, Q2, Q3, and Q4 each independently represent N, CH, or CR; A is independently selected from the group of H, unsubstituted or substituted straight or branched chain alkyl, cycloalkyl, Cl, and F; n is an integer from 1 to 4 (e.g., 1 or 2, 1 to 3, 1, 2, 3, or 4); R includes a bond, H, -OR', -NR'R", -CR'R"-, unsubstituted or substituted linear or branched C1-C6 straight or branched alkyl (e.g., C1-C3 alkyl, and / or optionally substituted with one or more halogens), unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, wherein the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), optionally substituted 4-6 membered cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, and NO2, and one R is covalently bonded to L; R' and R" are independently selected from the group consisting of a bond, H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0081] In any aspect or embodiment described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of: [ka] During the ceremony, W in formula (g) is selected from the group of CH2, O, C=O, NH and N-alkyl; A in formula (g) is H, methyl, or optionally substituted straight or branched chain alkyl; n is an integer from 1 to 4; R of formula (g) is independently selected from H, O, OH, N, NH, NH, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C-C alkyl), C-C alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy, wherein one R or W is optionally modified to be covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof; and In equation (g), [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0082] In any aspect or embodiment described herein, the CLM or ULM has the following structure: [ka] During the ceremony, W is CH2, O, CHR (e.g., CH(CH3)), C=O, NH, or N; each X is independently selected from absent, O, S, and CH; Z is O, S or CH2; G is H, methyl or OH; Each of Q1, Q2, Q3 and Q4 independently represents N or C substituted with H or R; A is H, unsubstituted or substituted straight or branched chain alkyl, Cl, or F; n is an integer from 1 to 4 (e.g., 1 or 2, 1 to 3, 1, 2, 3, or 4); each R is independently a bond, H, -OR', -NR'R", -CR'R"-, unsubstituted or substituted linear or branched C1-C6 straight or branched alkyl (e.g., C1-C3 alkyl, and / or optionally substituted with one or more halogens), an unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, wherein the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), an optionally substituted 4-6 membered cycloalkyl, an optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or NO2, and one R is covalently bonded to L; R' and R" are each independently selected from a bond, H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); and [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0083] In any aspect or embodiment described herein, the CLM or ULM has the following structure: [ka] During the ceremony, W is CH, O, CH(C alkyl) (e.g., CH(CH)), C=O; G is H, methyl or OH; Each of Q1, Q2, Q3, and Q4 independently represents N, CH, or CR; A is H, unsubstituted or substituted straight or branched chain alkyl, Cl, or F; n is an integer from 1 to 4; R is a bond, H, -OR', -NR'R", -CR'R"-, unsubstituted or substituted linear or branched C1-C6 straight or branched alkyl (e.g., C1-C3 alkyl, and / or optionally substituted with one or more halogens), unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, wherein the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), optionally substituted 4-6 membered cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or NO2, and one R is covalently bonded to L; R' and R" are each independently selected from a bond, H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); and [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0084] In any aspect or embodiment described herein, R is selected from: O, OH, N, NH, NH, C-C alkyl, C-C alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy).

[0085] In any aspect or embodiment described herein, at least one R (e.g., an R group selected from the following: O, OH, N, NH, NH, C-C alkyl, C-C alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy), or W is modified to be covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM′ (e.g., a CLM′ is an additional CLM having the same structure or a different structure from the first CLM), or a combination thereof.

[0086] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, A, and Rn of formulas (a)-(g) may independently be covalently bonded to a linker and / or to a linker that is bonded to one or more PTM, ULM, CLM, or CLM' groups.

[0087] In any of the aspects or embodiments described herein, Rn includes 1 to 4 independently selected functional groups or atoms, e.g., O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, on the aryl or heteroaryl of the CLM, optionally one of which is modified to be covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0088] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules that result from combining one or more of the different properties shown in the molecules below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0089] In any of the embodiments described herein, W, R1, R2, Q1, Q2, Q3, Q4 and Rn can independently be covalently linked to a linker and / or a linker connecting one or more PTM, ULM, ULM', CLM or CLM' groups.

[0090] In any of the embodiments described herein, R1, R2, Q1, Q2, Q3, Q4 and Rn can independently be covalently linked to a linker and / or a linker connecting one or more PTM, ULM, ULM', CLM or CLM' groups.

[0091] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and Rn may independently be covalently linked to a linker and / or a linker that is attached to one or more PTM, ULM, ULM', CLM, or CLM' groups.

[0092] In any aspect or embodiment described herein, Rn is modified to be covalently attached to a linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0093] In certain instances, the "CLM" may be an imide that binds to cereblon E3 ligase. These imides and linker attachment points may be, but are not limited to, the following structures: [ka]

[0094] In any aspect or embodiment described herein, the CLM is selected from: [ka] During the ceremony, CLM's [ka] indicates the point of attachment to L; and N* is the nitrogen atom shared with the chemical linker group.

[0095] In any aspect or embodiment described herein, the CLM is selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, CLM's [ka] indicates the point of attachment to L; and N* is the nitrogen atom shared with the chemical linker group.

[0096] In any aspect or embodiment described herein, the CLM is selected from: [ka] [ka] [ka] [ka] During the ceremony, ULM's [ka] indicates the point of attachment to the linker group or PTM, and N* is a nitrogen atom that is shared with a chemical linker group or a PTM.

[0097] In any aspect or embodiment described herein, the ULM is selected from the group consisting of: [ka] [ka] During the ceremony, ULM's [ka] indicates the point of attachment to the chemical linker group or PTM; and N* is a nitrogen atom that is shared with a chemical linker group or a PTM.

[0098] Exemplary Linkers In certain embodiments, compounds described herein include one or more PTMs that are chemically linked or attached to one or more ULMs (e.g., at least one CLM) via a chemical linker (L). In certain embodiments, the linker group, L, is a group that includes one or more covalently linked structural units (e.g., -AL1...(AL)q- or -(AL)q-), where AL1 is a group attached to the PTM and (AL)q is a group attached to the ULM.

[0099] In any aspect or embodiment described herein, the connection or bond between the linker (L) and the ULM (e.g., CLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, any subsequent heteroatom, if present, is separated by at least one single carbon atom (e.g., —CH—), such as, for example, an acetal or aminal group. By way of further example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

[0100] In any aspect or embodiment described herein, the linker group, L, is a bond or chemical linker group represented by the formula -(AL)q-, where A is a chemical moiety and q is an integer from 1 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 1 2,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79, or 80), where L is covalently linked to the PTM and ULM, providing sufficient binding of the PTM to the protein target and sufficient binding of the ULM to the E3 ubiquitin ligase to result in target protein ubiquitination.

[0101] In any aspect or embodiment described herein, the linker group L is -(AL)q-, wherein: (AL)q is a group linked to at least one of a ULM (e.g., a CLM), a PTM moiety, or a combination thereof; q of the linker is an integer of 1 or greater, each AL is independently a bond, CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SON2NRL4, CO, CRL1=CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(=NCN)NRL4, NRL3C(=NCN), NRL3C(=CNO2)NRL4, mono- or bicyclic C3-11 cycloalkyl optionally substituted with 0-6 R1 and / or R2 groups, C5-13 spirocycloalkyl optionally substituted with 1-9 R1 and / or R2 groups, and R1 or R2 are each independently selected from the group consisting of: monocyclic or bicyclic C3-11 heterocyclyl optionally substituted with 1 to 8 R1 and / or R2 groups; C5-13 spiroheterocyclyl optionally substituted with 1 to 8 R1 and / or R2 groups; aryl optionally substituted with 1 to 6 R1 and / or R2 groups; and heteroaryl optionally substituted with 1 to 6 R1 and / or R2 groups, wherein R1 or R2 are each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety optionally substituted with 1 to 4 R5 groups; R, R, R, R, R and R are each independently H, halogen, C alkyl, OC alkyl, SC alkyl, NHC alkyl, N(C alkyl), C cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C heterocyclyl, OC cycloalkyl, SC cycloalkyl, NHC cycloalkyl, N(C cycloalkyl), N(C cycloalkyl)(C alkyl), OH, NH, SH, SO C alkyl, P(O)(OC alkyl)(C alkyl), P(O)(OC alkyl), CC-C alkyl, CCH, CH=CH(C alkyl), C(C alkyl)=CH(C alkyl). alkyl), C(C1-8 alkyl)=C(C1-8 alkyl)2, Si(OH)3, Si(C1-8 alkyl)3, Si(OH)(C1-8 alkyl)2, COC1-8 alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8 alkyl, SON(C1-8 alkyl)2, SONHC1-8 alkyl, SON(C1-8 alkyl)2, CONHC1-8 alkyl, CON(C1-8 alkyl)2, N(C1-8 alkyl)CONH(C1-8 alkyl), N(C1-8 alkyl)CON(C1-8 alkyl)2, NHCONH(C1-8 alkyl), NHCON(C1-8 alkyl)2, NHCONH2, N(C1-8 alkyl)SON2NH(C1-8 alkyl), N(C1-8 alkyl)SON2N(C1-8 alkyl)2, NH SO2NH(C1-8 alkyl), NH2SO2N(C1-8 alkyl)2, or NH2SO2NH2.

[0102] In any aspect or embodiment described herein, preferably each A is independently CRL1R2, O, S, SO, SO2, NRL3, SO2NR3, SONRL3, CONRL3, NRL3CONRL4, NRL3SON2NR4, CO, CRL1=CRL2, C≡C, C3-11 monocyclic or bicyclic cycloalkyl optionally substituted with 1-6 R1 and / or R2 groups, optionally substituted with 1-9 R1 and / or R2 groups. C5-13 spirocycloalkyl optionally substituted with 1-6 R1 and / or R2 groups, C3-11 monocyclic or bicyclic heterocyclyl optionally substituted with 1-6 R1 and / or R2 groups, C5-13 spiroheterocyclyl optionally substituted with 1-8 R1 and / or R2 groups, aryl optionally substituted with 1-6 R1 and / or R2 groups, and heteroaryl optionally substituted with 1-6 R1 and / or R2 groups.

[0103] In any aspect or embodiment described herein, each of R, R2, R3, R4, and R5 independently is H, halogen, C alkyl, OC alkyl, SC alkyl, NHC alkyl, N(C alkyl), C cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, C heterocyclyl, OC cycloalkyl, SC cycloalkyl, NHC cycloalkyl, N(C cycloalkyl), N(C cycloalkyl)(C alkyl), OH, NH, SH, SO C alkyl, CC—C alkyl, CCH, CH═CH(C alkyl), C(C aryl). C(C1-8 alkyl)=CH(C1-8 alkyl), C(C1-8 alkyl)=C(C1-8 alkyl)2, COC1-8 alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8 alkyl, SO2N(C1-8 alkyl)2, SONHC1-8 alkyl, SON(C1-8 alkyl)2, CONHC1-8 alkyl, CON(C1-8 alkyl)2, N(C1-8 alkyl)CONH(C1-8 alkyl), N(C1-8 alkyl)CON(C1-8 alkyl)2, NHCONH(C1-8 alkyl), NHCON(C1-8 alkyl)2, NHCONH2, N(C1-8 alkyl)SON2NH(C1-8 alkyl), N(C1-8 alkyl)SON2N(C1-8 alkyl)2, NH SO2NH(C1-8 alkyl), NH2SO2N(C1-8 alkyl)2, or NH2SO2NH2.

[0104] In any aspect or embodiment described herein, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0105] In any aspect or embodiment described herein, for example, when the linker's q is greater than 2, (AL)q is a group that is AL1 and (AL)q, and the unit AL is the bond between the PTM and ULM.

[0106] In any aspect or embodiment described herein, for example, when q of the linker is 2, (AL)q is a group connecting AL1 and ULM.

[0107] In any aspect or embodiment described herein, for example, when the linker's q is 1, the structure of the linker group L is -AL1-, and AL1 is the group connecting the ULM and PTM moieties.

[0108] In any aspect or embodiment described herein, the unit AL of the linker (L) comprises a group represented by a general structure selected from the group consisting of: -NR(CH2)n-(lower alkyl)-, -NR(CH2)n-(lower alkoxyl)-, -NR(CH2)n-(lower alkoxyl)-OCH2-, -NR(CH2)n-(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2)n-(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2)n-(heterocycloalkyl)-, -NR(CH2CHO)n-(lower alkyl)-O-CH2-, -NR(CH2CHO)n-(heterocycloalkyl)-O-CH2-, -NR(CH2CHO)n-aryl-O-CH2-, -NR(CH2CHO)n-(heteroaryl)-O-CH2-, -NR(CH2CHO)n-(cyclo alkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CHO)n-(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CHO)n-(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CHO)n-(lower alkyl)-O-aryl-CH2, -NR(CH2CHO)n-cycloalkyl-O-aryl-, -NR(CH2CHO)n-cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2)n-(cycloalkyl)-O-(heterocyclyl)-CH2, -NR(CH2CH2)n-(heterocyclyl)-(heterocyclyl)-CH2, -N(R1R2)-(heterocyclyl)-CH2; n in the linker may be 0 to 10; R of the linker can be H, lower alkyl; The linkers R1 and R2 may form a ring with an N bond.

[0109] In any aspect or embodiment described herein, the linker (L) can be an optionally substituted C1-C50 alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, or C alkyl), where each carbon is optionally substituted with (1) a heteroatom selected from N, S, P, or Si atoms bearing the appropriate number of hydrogens, substituents, or both to complete the valence, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) does not have a heteroatom-to-heteroatom bond (e.g., the heteroatoms are not a covalent linker or are not adjacently positioned).

[0110] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C50 alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, or C50 alkyl), wherein: Each carbon is optionally selected from the group consisting of CRL1R2, O, S, SO, SO2, NRL3, SO2NR3, SONRL3, CONRL3, NRL3CONRL4, NRL3SON2NR4, CO, CRL1=CR2, C≡C, SiRL1R2, P(O)RL1, P(O)ORL1, NRL3C(=NCN)NR4, NRL3C(=NCN), NRL3C(=CNO2)NR4, monocyclic or bicyclic C3-11 cycloalkyl optionally substituted with 1-6 R1 and / or R2 groups, C5-13 spirocycloalkyl optionally substituted with 1-9 R1 and / or R2 groups, C5-13 cycloalkyl optionally substituted with 1-6 R1 and monocyclic or bicyclic C3-11 heterocyclyl optionally substituted with 1-8 R1 and / or R2 groups, C5-13 spiroheterocyclyl optionally substituted with 1-8 R1 and / or R2 groups, monocyclic or bicyclic aryl optionally substituted with 1-6 R1 and / or R2 groups, or monocyclic or bicyclic heteroaryl optionally substituted with 1-6 R1 and / or R2 groups, wherein R1 or R2 are each independently optionally joined to other groups to form a cycloalkyl and / or heterocyclyl moiety optionally substituted with 1-4 R5 groups; and R, R, R, R, R and R each independently represent H, halogen, C alkyl, OC alkyl, SC alkyl, NHC alkyl, N(C alkyl), C cycloalkyl, aryl, heteroaryl, C heterocyclyl, OC cycloalkyl, SC cycloalkyl, NHC cycloalkyl, N(C cycloalkyl), N(C cycloalkyl)(C alkyl), OH, NH, SH, SO C alkyl, P(O)(OC alkyl)(C alkyl), P(O)(OC alkyl), CC-C alkyl, CCH, CH=CH(C alkyl), C(C alkyl)=CH(C alkyl), C(C -8 alkyl)=C(C1-8 alkyl)2, Si(OH)3, Si(C1-8 alkyl)3, Si(OH)(C1-8 alkyl)2, COC1-8 alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8 alkyl, SON2N(C1-8 alkyl)2, SONHC1-8 alkyl, SON(C1-8 alkyl)2, CONHC1-8 alkyl, CON(C1-8 alkyl)2, N(C1-8 alkyl)CONH(C1-8 alkyl), N(C1-8 alkyl)CON(C1-8 alkyl)2, NHCONH(C1-8 alkyl), NHCON(C1-8 alkyl)2, NHCONH2, N(C1-8 alkyl)SON2NH(C1-8 alkyl), N(C1-8 alkyl)SON2N(C1-8 alkyl)2, NH SO2NH(C1-8 alkyl), NH2SO2N(C1-8 alkyl), or NH2SO2NH2. In any aspect or embodiment described herein, the linker (L) does not have a heteroatom-to-heteroatom bond (e.g., the heteroatoms are not covalent linkers or are not adjacently positioned).

[0111] In any aspect or embodiment described herein, each carbon of the optionally substituted C1-C50 alkyl (and subgroups described herein) of the linker can optionally be selected from the group consisting of CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SON2NRL4, CO, CRL1=CRL2, C≡C, C3-11 monocyclic or bicyclic cycloalkyl optionally substituted with 1-6 R1 and / or R2 groups, optionally substituted with a C5-13 spirocycloalkyl optionally substituted with 1 to 9 R1 and / or R2 groups; a monocyclic or bicyclic C3-11 heterocyclyl optionally substituted with 1 to 6 R1 and / or R2 groups; a C5-13 spiroheterocyclyl optionally substituted with 1 to 8 R1 and / or R2 groups; an aryl optionally substituted with 1 to 6 R1 and / or R2 groups; or a heteroaryl optionally substituted with 1 to 6 R1 and / or R2 groups.

[0112] In any aspect or embodiment described herein, the linker (L) comprises about 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units, where carbon or oxygen can be replaced with a heteroatom selected from N, S, P, or Si atoms having the appropriate number of hydrogens to complete the valence. For example, in any aspect or embodiment described herein, the linker (L) has a chemical structure selected from the following: [ka] [ka] In this case, carbon or oxygen may be replaced with a heteroatom selected from N, S, P, or Si atoms having the appropriate number of hydrogens to complete the valence, and m, n, o, p, q, r, and s are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0113] In any aspect or embodiment described herein, the unit A L of the linker (L) comprises a group represented by a general structure selected from the group consisting of: [ka] During the ceremony, [ka] are each independently a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl (e.g., a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl), and overlapping rings represent a spirocyclic ring; each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; R is selected from H and C alkyl; The linker is optionally substituted with at least one of: (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); and [ka] indicates the point of attachment to PTM or ULM.

[0114] In any aspect or embodiment described herein, the linker (L) has a chemical structure selected from the following: [ka] [ka] During the ceremony, [ka] are each independently a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl (e.g., a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl), and overlapping rings represent a spirocyclic ring; [ka] is an 8- to 10-membered bridged cycloalkyl, an 8- to 10-membered bridged heterosylcoalkyl, a 3- to 7-membered heterocyclyl having one or two double bonds (e.g., a 3- to 7-membered heterocyclyl having one or two double bonds), or a 7- to 10-membered fused bicyclic heterocycloalkyl (e.g., a 7- to 9-membered fused bicyclic heterocycloalkyl); each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; R is selected from H and C alkyl; The linker is optionally substituted with at least one of: (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl), OH, and halogen (e.g., F, Cl, or Br); and [ka] indicates the point of attachment to the PTM or CLM.

[0115] In any aspect or embodiment described herein, the chemical linker group may be: [ka] where * indicates an atom (e.g., carbon or nitrogen) covalently bonded to or shared with the CLM or PTM; [ka] Each of these indicates a point of attachment to a CLM or PTM.

[0116] In any aspect or embodiment described herein, the chemical linker group may be: [ka] where * indicates an atom (e.g., carbon or nitrogen) covalently bonded to or shared with the CLM or PTM; [ka] Each of these indicates a point of attachment to a CLM or PTM.

[0117] In any aspect or embodiment described herein, the chemical linker group may be: [ka] and During the ceremony, The above-described chemical linker group that does not contain a substituent is optionally substituted with at least one of: (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * is an atom (e.g., nitrogen, carbon, or oxygen) covalently bound to or shared with the CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0118] In any aspect or embodiment described herein, the chemical linker group is optionally substituted with one or two substituents, which are independently selected from C alkyl (preferably methyl), p and o are each 0, and m is 1.

[0119] In any aspect or embodiment described herein, the chemical linker group may be: [ka] [ka] and During the ceremony, The above-described chemical linker group that does not contain a substituent is optionally substituted with at least one of: (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0120] In any aspect or embodiment described herein, the chemical linker group may be: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and During the ceremony, The above-described chemical linker group that does not contain a substituent is optionally substituted with at least one of: (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, and o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0121] In any aspect or embodiment described herein, the chemical linker group may be: [ka] [ka] [ka] [ka] and During the ceremony, The above-described chemical linker group that does not contain a substituent is optionally substituted with at least one of: (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0122] In any aspect or embodiment described herein, the unit AL of the linker (L) comprises a group represented by a general structure selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, The linker (L) above, which does not contain any substituent, is optionally substituted with at least one of (i) =O and (ii) 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from C alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * is an atom (e.g., nitrogen, carbon, or oxygen) covalently bound to or shared with a ULM or PTM; [ka] indicates the point of attachment to the PTM or ULM; and Each of m, n, and o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0123] In any aspect or embodiment described herein, the linker has the following chemical structure: [ka] During the ceremony, XL is an N group or a CH group; each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3); * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and The chemical linker comprises 0 to 4 substituents (preferably 0, 1, or 2 substituents), each of which is independently a C1-3 alkyl (preferably methyl).

[0124] In any aspect or embodiment described herein, the linker has the following chemical structure: [ka] During the ceremony, XL is an N or CH group; [ka] represents a stereospecific bond, one having the (R) configuration and the other having the (S) configuration; * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and The chemical linker comprises 0 to 4 substituents (preferably 0, 1, or 2 substituents), each of which is independently a C1-3 alkyl (preferably methyl).

[0125] In any aspect or embodiment described herein, a unit AL of the linker (L) comprises a group represented by a structure selected from the group consisting of: [ka] wherein * indicates an atom (e.g., carbon, nitrogen, or oxygen) covalently bonded to or shared with a ULM or PTM; [ka] Each indicates a point of attachment to a ULM or PTM.

[0126] In any aspect or embodiment described herein, a unit AL of the linker (L) comprises a group represented by a structure selected from the group consisting of: [ka] [ka] [ka] wherein * indicates an atom (e.g., carbon, nitrogen, or oxygen) covalently bonded to or shared with the CLM or PTM; [ka] Each of these indicates a point of attachment to a CLM or PTM.

[0127] In any aspect or embodiment described herein, the unit A L of the linker (L) comprises a group represented by a general structure selected from the group consisting of: [ka] [ka] wherein * is a nitrogen or carbon atom covalently bonded to or shared with a ULM or PTM; [ka] indicates the point of attachment to ULM or PTM.

[0128] The ULM and PTM groups may be covalently attached to the linker group via any stable group appropriate to the linker chemistry; in preferred embodiments of the present disclosure, the linker is independently covalently attached to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which groups may be inserted either on the ULM or PTM group to provide for maximal binding of the ULM group to the ubiquitin ligase and maximal binding of the PTM group to the target protein to be degraded. (Note that in certain embodiments where the PTM group is a ULM group, the target protein to be degraded may also be the ubiquitin ligase itself.) In certain preferred embodiments, the linker may be attached to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group, or heterocyclic group on the ULM and / or PTM group.

[0129] Exemplary PTMs In a preferred embodiment of the present disclosure, the PTM group is a group that binds to a target protein. The targets of the PTM group are diverse, and the target is selected from proteins expressed in cells, at least a portion of whose sequence is present in the cell and can be bound to the PTM group. The term "protein" includes oligonucleotide sequences and polypeptide sequences of sufficient length to be able to be bound to a PTM group according to the present disclosure. As otherwise described herein, any protein in a eukaryotic cell system or a microbial system, including viruses, bacteria, or fungi, is a target for ubiquitination regulated by the disclosed compounds. Preferably, the target protein is a eukaryotic cell protein.

[0130] PTM groups according to the present disclosure include, for example, any moiety that specifically binds to a protein (binds to a target protein), and include the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, BCL6 inhibitors, HDM2 & MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds specifically targeting the aryl hydrocarbon receptor (AHR). The compositions described below exemplify some of the range of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. These binding moieties are attached to ubiquitin ligase binding moieties, preferably through a linker, to present the target protein (to which the protein target moiety is attached) in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0131] Any protein that can be bound to a protein target moiety or PTM group and that can be acted upon or degraded by a ubiquitin ligase is a target protein in accordance with the present disclosure. In general, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, and proteins involved in cellular integration functions, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, redox activity, transferase activity, hydrolytic activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, iron transport activity, channel transport activity, carrier activity, permeability activity, secretion activity, electron transport activity), phagocytosis, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular integration and biosynthetic activity, and translation regulatory activity. Proteins of interest include proteins from eukaryotes and prokaryotes, including humans and other animals as targets for drug therapy, including livestock animals, microorganisms for determining targets for antibiotics and other antimicrobial agents, and plants, and especially viruses.

[0132] The present disclosure may be used to treat many disease states and / or conditions, including any disease state and / or condition in which a protein is deregulated and in which the patient would benefit from protein degradation and / or inhibition.

[0133] In a further aspect, the present disclosure provides therapeutic compositions comprising an effective amount of a compound described herein or a salt form thereof, a pharmaceutically acceptable carrier, additive, or excipient, and, optionally, an additional bioactive agent. The therapeutic compositions can be used to regulate protein degradation in a patient or subject, e.g., an animal, such as a human, and treat or ameliorate a disease state or condition mediated by the degraded protein. In certain embodiments, the therapeutic compositions described herein can be used to induce target protein degradation for the treatment or amelioration of a disease, e.g., cancer. In certain additional embodiments, the disease is lymphoma, B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, or non-small cell lung cancer.

[0134] In another aspect, the present disclosure relates to a method for treating a pathology or ameliorating the symptoms of a disease or condition in a subject in need thereof by degrading a protein or polypeptide, wherein the pathology or condition is regulated via the protein or polypeptide, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described above, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle, and optionally an additional bioactive agent, wherein the composition is effective in treating or ameliorating the disease or disorder or symptoms thereof in the subject. Using the disclosed methods, many conditions or symptoms can be treated by administering an effective amount of at least one compound described herein. The pathology or condition may be a disease caused by a microbial organism or other foreign agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a pathology caused by overexpression of a protein resulting in the pathology and / or condition.

[0135] In another aspect, the present specification provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0136] The term "target protein" is used hereinafter to describe a protein or polypeptide to which the disclosed compounds bind and are targeted for degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target proteins of interest. These binding moieties are attached to at least one ULM group (e.g., CLM) via at least one linker group, L.

[0137] Target proteins that can be bound to a protein targeting moiety and to which a ubiquitin ligase binding moiety can bind and be degraded by the ligase include any protein or peptide, including fragments, analogs, and / or homologs thereof. Target proteins include proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, conservation, transport, and signal transduction. More specifically, many drug targets for human therapy are protein targets to which a protein targeting moiety can be bound and incorporated into compounds according to the present disclosure. These proteins include proteins that can be used to restore function in many polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners of the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalane cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza neuraminidase, hepatitis B virus reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, BCL6, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor for NGF, beta-amyloid tyrosine kinase Included are Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytosolic phospholipase A2, and EGF receptor tyrosine kinase.Additional protein targets include, for example, ecdysone 20-monooxygenase, GABA-activated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel.Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0138] These various protein targets may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into the disclosed compounds, the activity level of the protein can be altered for therapeutic end results.

[0139] The term "protein targeting moiety" or "PTM" is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. The compositions described below exemplify some of the components of small molecule target proteins. Exemplary protein targeting moieties according to the present disclosure include haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, BCL6 inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0140] The compositions described herein exemplify some of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. The references cited herein below are incorporated by reference in their entirety.

[0141] In any aspect or embodiment described herein, the PTM is a small molecule that binds to BCL6. For example, in any aspect or embodiment described herein, the PTM is represented by the following chemical structure of PTM1, PTMII, PTMIII, or PTMIV: [ka] During the ceremony, Each RPTM1 is independently: H; halogen (e.g., Cl or F); -CN; -OH; -NO2; -NH2; optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-C6 alkyl, or optionally substituted straight or branched chain C1-C4 alkyl, or C1-C8 alkyl optionally substituted with an OH or isopropyl group); O-optionally substituted straight or branched chain C1-C4 alkyl; optionally substituted C1-C4 alkynyl; optionally optionally substituted C1-C4 alkynes; optionally substituted straight or branched chain hydroxyalkyl (e.g., optionally substituted straight or branched chain C1-C7 hydroxyalkyl); optionally substituted alkylcycloalkyl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl; or both); optionally substituted alkyl-aryl (e.g., optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted 5-10 membered cycloalkyl ... optionally substituted alkyl-heteroaryl (e.g., optionally substituted straight or branched C1-C6 alkyl, optionally substituted 5- to 10-membered heteroaryl, or both); optionally substituted alkyl-heteroaryl (e.g., C1-C6 alkyl, optionally substituted 5- or 6-membered heteroaryl, which are optionally substituted with C1-C4 alkyl; heteroaryl is oxazol-4-yl, 1,3,4-triazol-2-yl, and imidazol-1-yl; or combinations thereof; optionally substituted -NH-alkyl-heteroaryl (e.g., optionally substituted straight or branched chain C1-C5 alkyl, optionally substituted 5-8 membered heteroaryl, which are optionally substituted with C1-C4 alkyl, N-CH2-pyrazol-4-yl, or combinations thereof); optionally substituted alkoxy (e.g., optionally substituted straight or branched chain C1-C6 alkyl or -OCH3);Optionally substituted O-heterocyclyl (e.g., optionally substituted 3-12-membered or 4-7-membered heterocyclyl; optionally substituted heterocycloalkyl; optionally substituted C3-12 monocyclic or bicyclic heterocycloalkyl; which are optionally substituted with at least one OH, C1-C5 alkyl (e.g., methyl), ═O, NH2; or combinations thereof); optionally substituted S-heterocyclyl (e.g., optionally substituted 4-7-membered heterocyclyl; optionally substituted heterocycloalkyl; which are optionally substituted with at least one C1-C4 alkyl (e.g., methyl), ═O, or combinations thereof); optionally substituted; [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; -(CH2)uCO(CH2)vCH3, -COCH3, or -CH2CH2COCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; -O(CH2)uCO(CH2)vCH3, -O(CH2)uCH((CH2)xCH3)(CH2)wCO(CH2)vCH3, -O-CH2COCH3, -O-CH2COCH2CH3, -O-CH(CH3)COCH3, -OCH2COCH3, or -OCH2(CH3)COCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; —(CH2)uCO(CH2)vNRPTM1aRPTM2a, —CONRPTM1aRPTM2a, —CH2CONRPTM1aRPTM2a, —CH2CH2CONRPTM1aRPTM2a, —CONHCH3, or —CH2CONHCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; —O(CH2)uCO(CH2)vNRPTM1aRPTM2a, —O(CH2)uCH((CH2)xCH3)(CH2)wCO(CH2)vNRPTM1aRPTM2a, —O—CH(CH3)CONRPTM1aRPTM2a, —O—CH2CONRPTM1aRPTM2a, or —OCH2C(O)NHOCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCHCH(CH2)wCO(CH2)vNRPTM1aRPTM2a or -CHCHCONRPTM1aRPTM2a, where each u, v, and w is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; -NH-(CH2)uCO(CH2)vNRPTMIaRPTM2a or -NH-CH2CONRPTM1aRPTM2a, where each u and v is independently selected from 1, 2, 3, 4, or 5); fluoroalkoxy (e.g., mono-, di-, and / or tri-fluoroalkoxy); optionally substituted monocyclic or bicyclic cycloalkyl (e.g., optionally substituted with at least one of 3-12 membered cycloalkyl; OH, =O, straight or branched chain C1-C6 alkyl (e.g., methyl, ethyl, or butyl), or NH2; or combinations thereof); optionally substituted hydroxycycloalkyl; optionally substituted aryl (e.g., optionally substituted C5-C10 aryl, optionally substituted 5-7 membered aryl; which are substituted with at least one halogen or C1-C3 alkyl (e.g., , methyl, or ethyl); or a combination thereof), optionally substituted heteroaryl (e.g., optionally substituted 5- to 10-membered heteroaryl, optionally substituted 5- to 7-membered heteroaryl; optionally substituted 5-membered heteroaryl; which are optionally substituted with at least one halogen or C1-C3 alkyl (e.g., methyl or ethyl); or a combination thereof), which are bonded to Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, or Q15 via a C atom or N atom of the heteroaryl (e.g., at least one of optionally bonded to Q16 via optionally substituted -(CH2)uO(CH2)vO(CH2)x-, or a combination thereof); optionally substituted monocyclic or bicyclic heterocyclyl (e.g., optionally substituted 3- to 12-membered heterocyclyl;C3-C12 monocyclic or bicyclic heterocycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, or homopiperazin-1-yl, each optionally substituted with OH, straight or branched C1-C5 alkyl (methyl, ethyl, or butyl), or NH2, which are optionally bonded to Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, or Q15 via a C or N atom of the heterocyclyl (e.g., at least one of optionally bonded via optionally substituted -(CH2)uO(CH2)vO(CH2)x-, optionally bonded to Q16, or both); each t1 is independently 1, 2, 3, 4, or 5; each t2 is independently 0, 1, 2, 3, 4, or 5; RPTM1a and RPTM2a are each independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alkoxy (e.g., -OCH2 or -CH2CH3), CHOCH3, or RPTM1a and RPTM2a are joined together to form a 3-10 membered ring; Q6, Q7, Q8, Q9, Q12, Q13, Q14, and Q15 are each independently N, O, or C, each optionally substituted with one or more independently selected RPTM1 (e.g., 1, 2, or 3 independently selected RPTM1, depending on valency); Q16 is H, halogen (e.g., Cl or F), -CN, -OH, -NO2, -NH2, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl, or optionally substituted linear or branched C1-C4 alkyl, or C1-C8 alkyl optionally substituted with OH or isopropyl groups), O-optionally substituted linear or branched C1-C4 alkyl, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4 alkyne, or optionally substituted linear or branched hydroxyalkyl (e.g., optionally substituted linear or branched C1-C7 hydroxyalkyl), preferably substituted with H, halogen, -CN, -OH, -NO2, -NH2, or optionally substituted linear or branched alkyl; X is O, S, or CH; [ka] is a single or double bond; n is an integer from 0 to 10; and PTM [ka] indicates the chemical linker group or point of attachment to ULM.

[0142] In any aspect or embodiment described herein, the PTM is selected from: [ka] During the ceremony, RPTM5 is H, optionally substituted straight or branched C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C1-C4 alkyl-O(C1-C3 alkyl), C1-C4 alkyl-O—, C1-C4 alkyl-NH(C1-C3 alkyl), C1-C4 alkyl-N(C1-C3 alkyl)2, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C3-C10 cycloalkyl, or optionally substituted C3-C10 heterocyclyl; Q6 and Q16 are each independently N or CH; Q7 and Q14 are each independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] is a single or double bond, When Q8 and Q9 are connected by a single bond, Q8 is CH2; and Q9 is CH(RPTM3) or N(RPTM3); When Q8 and Q9 are connected by a double bond, Q8 is CH; and Q9 is C(RPTM3); RPTM3 is: -OH; -Cl; -F; -CN; optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., -OCH3 or -OCH2CH3); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, -Cl; -F, -CN, or -OH); or optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH); RPTM1a and RPTM2a are each independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alkoxy (e.g., -OCH3 or -OCH2CH3), or CH2OCH3; each t1 is independently 1, 2, 3, 4, or 5; and each t2 is independently 0, 1, 2, 3, 4, or 5; RPMT2 is H, OH, CN, -F, -Cl, optionally substituted straight or branched chain C1-C4 alkyl, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl)2 or -NH(C1-C3 alkyl)), optionally substituted straight or branched chain -O-C1-C4 alkyl, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyl (e.g., azetidin 1-yl, azetidin 1-yl-3-ol, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, homopiperazin-1-yl, [ka] optionally substituted with one or more of OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyl (e.g., optionally substituted with one or more OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C3-C12 cycloalkyl (e.g., OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2). , C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C5-C6 aryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2); and PTM [ka] indicates the point of attachment to L.

[0143] In any aspect or embodiment described herein, Q8 and Q9 [ka] is a double bond, Q8 is CH, and Q9 is C(RPTM3).

[0144] In any aspect or embodiment described herein, at least one RPMT1 of PTMII, or a relevant position of other PTM structures described herein, is modified to be covalently attached to a linker group (L) or a ULM. In any aspect or embodiment described herein, at least one of Q6-Q15 of PTMII, or a relevant position of other PTM structures described herein, is modified to be covalently attached to a chemical linker group (L) or a ULM.

[0145] In any aspect or embodiment described herein, X of the PTM (e.g., PTMII, or the relevant position of other PTM structures described herein) is O.

[0146] In any aspect or embodiment described herein, the PTM is selected from: [ka] In the formula, PTM [ka] indicates the chemical linker group or point of attachment to ULM.

[0147] In any aspect or embodiment described herein, the PTM is selected from: [ka] In the formula, PTM [ka] indicates the chemical linker group or point of attachment to ULM.

[0148] In any aspect or embodiment described herein, at least one RPTM1 is [ka] is selected from.

[0149] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] [ka] [ka] [ka] During the ceremony, RPTM5 is selected from the group consisting of H, optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-C6 alkyl, methyl, ethyl, or isopropyl groups, C1-C4 alkyl-O(C1-C3 alkyl), C1-C4 alkyl-O—, C1-C4 alkyl-NH(C1-C3 alkyl) or C1-C4 alkyl-N(C1-C3 alkyl)2, optionally substituted -alkyl-aryl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C5-C10 aryl, or both), optionally substituted -alkyl-hetero ... optionally substituted C5-C10 heteroaryl, or both), optionally substituted aryl (e.g., optionally substituted C5-C10 aryl), optionally substituted heteroaryl (e.g., optionally substituted C5-C10 heteroaryl), optionally substituted cycloalkyl (e.g., optionally substituted C3-C10 cycloalkyl), optionally substituted -alkyl-cycloalkyl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, or both), optionally substituted heterocyclyl (e.g., optionally substituted C3-C10 heterocyclyl); Q6 is N, CH, C(NO2), or C(CN); Q7 and Q14 are each independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] is absent when there is a single bond, a double bond, or Q8; If Q8 does not exist, [ka] is absent, and Q10 is also absent; When Q8 and Q9 are connected by a single bond, Q8 is CH2, O, CH(RPTM3), NH, N(RPTM3), or N(CH3); and Q9 is CH2, O, CH(RPTM3), NH, N(RPTM3), N(CH3), N(CH2CH2CONHCH3), or N(CH2CH2COCH3); When Q8 and Q9 are connected by a double bond, Q8 is CH, C(RPTM3), N(RPTM3), N, or an optionally substituted C(NH-alkyl-heteroaryl) (e.g., an optionally substituted C1-C5 alkyl, an optionally substituted 5-7 membered heteroaryl, or both); Q9 is CH, C(RPTM3), N, or N(RPTM3); and RPTM3 is: -OH; -Cl; -F; -CN; optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., straight or branched chain C1-C4 alkyl, optionally substituted with -OCH3 or -OCH2CH3); optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCO(CH2)vCH3, -COCH3, or -CH2CH2COCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -O(CH2)uCO(CH2)vCH3, -O(CH2)uCH((CH2)xCH3)(CH2)wCO(CH2)vCH3, -O-CH2COCH3, -O-CH2COCH2CH3, -O-CH(CH3)COCH3, -OCH2COCH3, or -OCH2(CH3)COCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCO(CH2)vNRPTM1aRPTM2a, -CONRPTM1aRPTM2a, -CH2CONRPTM1aRPTM2a, -CH2CH2CONRPTM1aRPTM2a, -CONHCH3, or -CH2CONHCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; C1-C4 alkoxy; -Cl; -F; -CN; -OH; -O(CH2)uCO(CH2)vNRPTMIaRPTM2a, -O(CH2)uCH((CH2)xCH3)(CH2)wCO(CH2)vNRPTMIaRPTM2a, -O-CH(CH3)CONRPTM1aRPTM2a, -O-CH2CONRPTM1aRPTM2a, or -OCH2C(O)NHOCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCHCH(CH2)wCO(CH2)vNRPTM1aRPTM2a, or -CHCHCONRPTM1aRPTM2a, where each u, v, and w is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; C1-C4 alkoxy; -Cl; -F; -CN; -OH; -NH-(CH2)uCO(CH2)vNRPTMIaRPTM2a or -NH-CH2CONRPTM1aRPTM2a, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted -alkyl-heteroaryl (e.g., C1-C4 alkyl; -(CH2)t2- optionally substituted with an optionally substituted 5- or 6-membered heteroaryl, where the heteroaryl and combinations thereof); optionally substituted -NH-alkyl-heteroaryl (e.g., C-C alkyl or combinations thereof, -NH-(CH)- optionally substituted 5- or 6-membered heteroaryl, N-CH-pyrazol-4-yl); optionally substituted alkyl-cycloalkyl, or alkyl-heterocycloalkyl (e.g., C-C alkyl, , -(CH2)t2-optionally substituted 3- to 6-membered cycloalkyl or heterocycloalkyl); optionally substituted -NH-alkyl-cycloalkyl or -NH-alkyl-heterocycloalkyl (e.g., C1-C4 alkyl, -NH-(CH2)t2-optionally substituted 3- to 6-membered cycloalkyl or heterocycloalkyl); optionally substituted -O-cycloalkyl or -O-heterocycloalkyl (e.g., optionally substituted 3- to 5-membered cyclo alkyl or heterocycloalkyl; -O-(oxetan-3-yl); optionally substituted -O-alkyl-cycloalkyl or -O-alkyl-heterocycloalkyl (e.g., O-(CH2)t2-optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl; optionally substituted with at least one of =O, OH, and C1-C4 alkyl); optionally substituted S-heterocyclyl (e.g., optionally substituted 4- to 7-membered heterocyclyl; optionally substituted heterocycloalkyl;optionally substituted with at least one C1-C4 alkyl (e.g., methyl), ═O, or combinations thereof; RPTM1a and RPTM2a are each independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alkoxy (e.g., -OCH3 or -CH2CH3 or -OCH2CH3), CHOCH3, or RPTM1a and RPTM2a are joined together to form a 3-10 membered ring; each t1 is independently selected from 1, 2, 3, 4, or 5; and each t2 is independently selected from 0, 1, 2, 3, 4, or 5; RPMT2 is H, OH, CN, optionally substituted straight or branched chain C1-C4 alkyl, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl) or -NH(C1-C3 alkyl)), optionally substituted straight or branched chain -O-C1-C4 alkyl, O-optionally substituted straight or branched chain C1-C4 alkyl, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4 alkyne, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyl (e.g., optionally substituted C3-C12 monocyclic or bicyclic heterocycloalkyl, e.g., C3-C12 monocyclic or bicyclic heterocycloalkyl, azetidin 1-yl, azetidin 1-yl-3-ol, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, homopiperazin-1-yl, [ka] each optionally substituted with one or more of OH, straight-chain or branched C1-C5 alkyl, straight-chain or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted -O-C3-12 monocyclic or bicyclic heterocyclyl (e.g., optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyl, e.g., -O-C3-12 monocyclic or bicyclic heterocycloalkyl optionally substituted with one or more of OH, straight-chain or branched C1-C5 alkyl, straight-chain or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, straight-chain or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally optionally substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C5-C6 aryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C3-C12 membered ring (e.g., a non-aryl optionally substituted C3-C12 membered ring optionally substituted with one or more of OH, straight or branched chain C1-C5 alkyl, or NH2), wherein when RPTM2 is a ring structure, it is optionally covalently bonded to Q16 via the C or N of the RPTM2 ring; and PTM [ka] indicates the point of attachment to the chemical linker group (L) or ULM.

[0150] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] During the ceremony, RPTM5 is H, optionally substituted straight or branched C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C1-C4 alkyl-O(C1-C3 alkyl), C1-C4 alkyl-O—, C1-C4 alkyl-NH(C1-C3 alkyl), C1-C4 alkyl-N(C1-C3 alkyl)2, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C3-C10 cycloalkyl, or optionally substituted C3-C10 heterocyclyl; Q6 is N or CH; Q7 and Q14 are each independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] is a single or double bond, When Q8 and Q9 are connected by a single bond, Q8 is CH2, CH(RPTM3), NH, or N(RPTM3); and Q9 is CH2, O, CH(RPTM3), NH, or N(RPTM3); When Q8 and Q9 are connected by a double bond, Q8 is CH, C(RPTM3), N(RPTM3), or N; Q9 is CH, C(RPTM3), N, or N(RPTM3); and RPTM3 is: -OH; -Cl; -F; -CN; optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., -OCH3 or -OCH2CH3); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, -Cl; -F, -CN, or -OH); or optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH); RPTM1a and RPTM2a are each independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alkoxy (e.g., -OCH3 or -OCH2CH3), or CH2OCH3; each t1 is independently 1, 2, 3, 4, or 5; and each t2 is independently 0, 1, 2, 3, 4, or 5; RPMT2 is H, OH, CN, -F, -Cl, optionally substituted straight or branched chain C1-C4 alkyl, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl)2 or -NH(C1-C3 alkyl)), optionally substituted straight or branched chain -O-C1-C4 alkyl, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyl (e.g., azetidin 1-yl, azetidin 1-yl-3-ol, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, homopiperazin-1-yl, [ka] optionally substituted with one or more of OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyl (e.g., optionally substituted with one or more of OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C3-C12 cycloalkyl (e.g., OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2). optionally substituted with one or more of straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C5-C6 aryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2); and PTM [ka] indicates the point of attachment to L or ULM.

[0151] In any aspect or embodiment described herein, at least one (e.g., 1, 2, or 3) of RPTM1, RPTM2, Q6, Q7, Q8, Q9, XPTM1, XPTM2 of PTMII, or relevant positions of other PTM structures described herein, is covalently linked directly or indirectly to a ULM or a chemical linker group (L).

[0152] In any aspect or embodiment described herein, RPTM2 or the corresponding position of a PTM described herein (e.g., PTMII and its derivatives) may be substituted with one or more groups selected from the following: OH, straight or branched chain C1-C5 alkyl, or NH2.

[0153] In any aspect or embodiment described herein, RPTM5 or the corresponding position of any PTM described herein (e.g., PTMII and derivatives thereof) can be: H, optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C1-C6 alkyl, or C1-C4 alkyl-NH(C1-C3 alkyl), or C1-C4 alkyl-N(C1-C3 alkyl)2), optionally substituted -alkyl-aryl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C5-C10 aryl, or both), optionally substituted -alkyl-heteroaryl (e.g., optionally substituted C1- C alkyl, optionally substituted C5-C10 heteroaryl, or both), optionally substituted aryl (e.g., optionally substituted C5-C10 aryl), optionally substituted heteroaryl (e.g., optionally substituted C5-C10 heteroaryl), optionally substituted cycloalkyl (e.g., optionally substituted C3-C10 cycloalkyl), optionally substituted -alkyl-cycloalkyl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C3-C10 cycloalkyl, or both), optionally substituted heterocyclyl (e.g., optionally substituted C3-C10 heterocyclyl).

[0154] In any aspect or embodiment described herein, the corresponding position of RPTM5 or a PTM described herein (e.g., PTMII and its derivatives) can be H, methyl, CFH, CFH, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, hexyl, -CHCHOCH, -CHCH(CH), -CHCHN(CH), -CH-cyclopropyl, -CH-CH-cyclopropyl, [ka] is selected from: [ka] indicates the point of attachment of the nitrogen of the biheteroaryl or biheterocycle of the PTM to RPTM5.

[0155] In any aspect or embodiment described herein, the corresponding position in XPTM1 or any PTM described herein (eg, PTMII and its derivatives) is H or F.

[0156] In any aspect or embodiment described herein, the corresponding position in XPTM2 or any PTM described herein (e.g., PTMII and its derivatives) is H, Cl, F, or CN.

[0157] In any aspect or embodiment described herein, the corresponding position of RPTM2 or a PTM described herein (e.g., PTMII and derivatives thereof) is selected from the following: H, OH, ethyl, NH2, —N(CH3)2, methyl, ethyl, [ka] During the ceremony, [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; [ka] indicates the attachment point of the aryl or heteroaryl of the PTM to RPTM2.

[0158] In any aspect or embodiment described herein, the corresponding position of RPTM2 or a PTM described herein (e.g., PTMII and derivatives thereof) is selected from the following: H, OH, NH, —N(CH), methyl, ethyl, [ka] During the ceremony, [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; [ka] indicates the attachment point of the aryl or heteroaryl of the PTM to RPTM2.

[0159] In any aspect or embodiment described herein, the corresponding position of RPTM3 or any PTM described herein (e.g., PTMI, PTMIII, and derivatives thereof) can be: -OH; optionally substituted straight or branched chain alkyl, optionally substituted alkoxy (e.g., optionally substituted with straight or branched chain C1-C4 alkyl or -OCH3); optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCO(CH2)vCH3, -COCH3, or -CH2CH2COCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -O(CH2)uCO(CH2)vCH3, -O(CH2)uCH((CH2)xCH3)(CH2)wCO(CH2)vCH3, -O-CH2COCH3, -O-CH2COCH2CH3, -O-CH(CH3)COCH3, -OCH2COCH3, or -OCH2(CH3)COCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCO(CH2)vNRPTM1aRPTM2a, -CONRPTM1aRPTM2a, -CH2CONRPTM1aRPTM2a, -CH2CH2CONRPTM1aRPTM2a, -CONHCH3, or -CH2CONHCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; -O(CH2)uCO(CH2)vNRPTMLRPTM2a, -O(CH2)uCH((CH2)xCH3)(CH2)wCO(CH2)vNRPTMLRPTM2a, -O-CH(CH3)CONNRPTMLRPTM2a, -O-CH2CONNRPTMLRPTM2a, or -OCH2C(O)NHOCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5; optionally substituted [ka] (e.g., optionally substituted with straight or branched C1-C4 alkyl; -(CH2)uCHCH(CH2)wCO(CH2)vNRPTM1aRPTM2a or -CHCHCONRPTM1aRPTM2a, where each u, v, and w is independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl; —NH—(CH2)uCO(CH2)vNRPTM1aRPTM2a or —NH—CH2CONRPTM1aRPTM2a, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted -alkyl-heteroaryl (e.g., C1-C4 alkyl; —(CH2)t2- optionally substituted with an optionally substituted 5- or 6-membered heteroaryl, where the heteroaryl is oxazol-4-yl, 1,3, 4-triazol-2-yl, and imidazol-1-yl; and combinations thereof; optionally substituted -NH-alkyl-heteroaryl (e.g., C1-C4 alkyl or combinations thereof, -NH-(CH2)t2-optionally substituted 5- or 6-membered heteroaryl, optionally substituted with N-CH2-pyrazol-4-yl); optionally substituted alkyl-cycloalkyl, or alkyl-heterocycloalkyl (e.g., C1-C4 alkyl, -(CH2)t2-optionally substituted optionally substituted with an optionally substituted 3- to 6-membered cycloalkyl or heterocycloalkyl; optionally substituted -NH-alkyl-cycloalkyl or -NH-alkyl-heterocycloalkyl (e.g., C1-C4 alkyl, -NH-(CH2)t2-optionally substituted with an optionally substituted 3- to 6-membered cycloalkyl or heterocycloalkyl); optionally substituted -O-cycloalkyl or -O-heterocycloalkyl (e.g., optionally substituted 3- to 5-membered cycloalkyl or is heterocycloalkyl; -O-(oxetan-3-yl)); optionally substituted -O-alkyl-cycloalkyl or -O-alkyl-heterocycloalkyl (e.g., O-(CH2)t2- optionally substituted 3- to 5-membered cycloalkyl or heterocycloalkyl; =O, OH, and C1-C4 alkyl optionally substituted); optionally substituted S-heterocyclyl (e.g., optionally substituted 4- to 7-membered heterocyclyl; optionally substituted heterocycloalkyl;optionally substituted with at least one C1-C4 alkyl (e.g., methyl), ═O, or combinations thereof;

[0160] In any aspect or embodiment described herein, RPTM3, or the corresponding position of any PTM described herein (e.g., PTMII and its derivatives), is [ka] is selected from: [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; [ka] indicates the point of attachment of the biheteroaryl or biheterocycle of the PTM to RPTM3, and XPTM3 is selected from CH2, O, and S.

[0161] In any aspect or embodiment described herein, RPTM5 or the corresponding position of any PTM described herein is selected from the following: H, methyl, CFH2, CF2H, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, hexyl, [ka] is selected from: [ka] indicates the point of attachment of the nitrogen of the biheteroaryl or biheterocycle of the PTM to RPTM5.

[0162] In any aspect or embodiment described herein, RPTM4 or the corresponding position of any PTM described herein (e.g., PTMII and its derivatives) is a straight or branched chain C1-C8 alkyl optionally substituted with OH.

[0163] In any aspect or embodiment described herein, the corresponding position of RPMT2 or any PTM described herein (e.g., PTMII and derivatives thereof) can be selected from the group consisting of H, OH, CN, optionally substituted straight or branched chain C1-C4 alkyl, optionally substituted —NH2 (e.g., —N(C1-C3 alkyl) or —NH(C1-C3 alkyl) or —N(CH3)2), O-optionally substituted straight or branched chain C1 -C4 alkyl, optionally substituted C1-C4 alkynyl, optionally substituted C1-C4 alkyne, optionally substituted monocyclic or bicyclic C3-C12 heterocyclyl (e.g., optionally substituted C3-C12 monocyclic or bicyclic heterocycloalkyl, e.g., C3-C12 monocyclic or bicyclic heterocycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or or morpholin-4-yl, or homopiperazin-1-yl, each optionally substituted with one or more of OH, straight or branched chain C1-C5 alkyl, or NH2), or optionally substituted -O-C3-12 monocyclic or bicyclic heterocyclyl (e.g., optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyl, e.g., optionally substituted with at least one of OH, straight or branched chain C1-C5 alkyl, or is —O—C3-12 monocyclic or bicyclic heterocycloalkyl optionally substituted with NH2), or an optionally substituted C3-C12 membered ring (e.g., an optionally substituted C3-C12 membered non-aryl ring, optionally substituted with one or more of OH, straight or branched C1-C5 alkyl, or NH2), wherein when RPTM2 is a ring structure, it is optionally covalently bonded to Q16 via a C or N of the RPTM2 ring.

[0164] In any aspect or embodiment described herein, the PTM is represented by a chemical structure selected from the following: [ka] [ka] [ka] [ka]

[0165] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] [ka]

[0166] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] [ka]

[0167] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] [ka]

[0168] In any aspect or embodiment described herein, the PTM is selected from the following: [ka]

[0169] In any aspect or embodiment described herein, the PTM is selected from the following: [ka]

[0170] In any aspect or embodiment described herein, the PTM is [ka] and PTMs are represented by [ka] indicates the point of attachment to L.

[0171] In any aspect or embodiment described herein, the PTM is selected from: [ka] [ka] [ka] [ka] In the formula, PTM [ka] indicates the point of attachment to L.

[0172] In any aspect or embodiment described herein, the PTM is selected from: [ka] [ka] [ka] [ka] In the formula, PTM [ka] indicates the point of attachment to the linker group (L) or ULM.

[0173] A bifunctional compound represented by: [ka] During the ceremony, each of RPTM1, Q6, Q7, Q8, Q9, Q12, Q13, Q14, Q15, Q16, n, W, and L is as described in any aspect or embodiment described herein; A is an optionally substituted N-heterocyclyl (e.g., an optionally substituted 3-12-membered or 4-7-membered heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted C3-12 monocyclic or bicyclic heterocycloalkyl, or a combination thereof, which is optionally substituted with at least one OH, halo (e.g., F, Cl, Br), C1-C5 alkyl (e.g., methyl), ═O, NH2, or a combination thereof). Z1 is an R group of a CLM described in any aspect or embodiment described herein modified to covalently link to L, where such group is selected from -C(=O)-, -CONR'-, -O-, -NR'-, a carbon shared with the cyclic group of L, or a nitrogen shared with the cyclic group of L.

[0174] therapeutic composition Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein, and a combination of effective amounts of one or more of the compounds described elsewhere herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent a further aspect of the present disclosure.

[0175] The present disclosure includes compositions containing pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein, where applicable. The acids used to prepare pharmaceutically acceptable acid addition salts of the above-described base compounds useful according to this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as, in particular, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, perphosphate, acetate, lactate, citrate, percitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts, among many other acids.

[0176] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives disclosed herein. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds, which are acidic in nature, are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium, as well as other pharmaceutically acceptable organic amine base salts.

[0177] The compounds described herein may be administered orally, parenterally, or topically in single or divided doses in accordance with the present disclosure. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository administration, among other routes of administration. Enteric-coated oral tablets may be used to enhance the bioavailability of the compound from oral administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected and the severity of the patient's disease. Administration of the compounds according to the present disclosure as a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration may also be used. Accordingly, the present disclosure also contemplates pharmaceutical compositions comprising an effective amount of the compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle. The compounds according to the present disclosure may be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Slow-release or controlled-release forms are preferably administered orally, but also via suppositories and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0178] The compositions described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may be administered in controlled-release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0179] The compositions described herein may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted container. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0180] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions 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. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0181] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Typically, lubricants such as magnesium stearate are also added.For oral administration in 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 sweeteners, flavorings or coloring agents may also be added.

[0182] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0183] The pharmaceutical compositions described herein may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically acceptable transdermal patches may also be used.

[0184] For topical application, pharmaceutical compositions can be formulated with suitable ointments, which contain the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include but are not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.In certain preferred embodiments of the present disclosure, the compound can be coated on the stent that is surgically implanted into patients, thereby preventing or reducing the possibility of stent blockage occurring in patients.

[0185] Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0186] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0187] The pharmaceutical compositions described herein may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the pharmaceutical formulation art 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.

[0188] The amount of compound in the pharmaceutical compositions described herein that can be combined with carrier materials to produce a single dosage form will vary depending on the host and disease being treated, and the particular mode of administration. Preferably, the compositions should be formulated to contain about 0.05 milligrams to about 750 milligrams or more of active ingredient, alone or in combination with at least one other compound according to the present disclosure, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams.

[0189] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, 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 or condition being treated.

[0190] A patient or subject in need of treatment using a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, including a pharmaceutically acceptable salt, solvate or polymorph thereof, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known therapeutic agents as otherwise specified herein.

[0191] These compounds can be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically, for example, transdermally in liquid, cream, gel, or solid form, or in aerosol form.

[0192] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication, but which does not cause serious toxic effects in the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein range from about 10 ng / kg to 300 mg / kg, preferably from 0.1 to 100 mg / kg per day, and more usually from 0.5 to about 25 mg per kg of recipient / patient body weight per day. Typical topical dosages can range from 0.01 to 5% wt / wt in a suitable carrier.

[0193] The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of about 25 to 250 mg is often convenient.

[0194] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30 mM, preferably about 0.1 to 30 μM. This may be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline solution or aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0195] The concentration of the active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be alleviated. It should further be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at once, or may be divided into multiple smaller doses to be administered at varying time intervals.

[0196] Oral compositions generally will contain an inert diluent or an edible carrier. They may be enclosed in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be combined with an excipient and used in the form of a tablet, troche, or capsule. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition.

[0197] Tablets, pills, capsules, troches, etc. may contain any of the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterols; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring, or compounds of a similar nature. When the unit dosage form is a capsule, in addition to the above-mentioned types of materials, it can contain a liquid carrier such as a fatty acid. In addition, the unit dosage form can contain various other materials that modify the physical form of the physical dosage unit, such as sugar coating, shellac, or enteric coating.

[0198] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and / or certain preservatives, dyes and colorings, and flavors.

[0199] The active compounds or pharmaceutically acceptable salts thereof can also be mixed with other active substances that do not impair the desired action, or with substances that complement the desired action, such as anti-cancer agents, especially as described herein. In certain preferred embodiments of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anti-cancer agent, or a wound healing agent, including an antibiotic, as otherwise described herein.

[0200] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0201] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0202] In one embodiment, active compound is prepared with a carrier that protects compound from rapid excretion from the body, for example, controlled release formulations, including implants and microencapsulated delivery systems.For example, biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.The preparation method of such formulations will be clear to those skilled in the art.

[0203] Liposomal suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (incorporated herein in its entirety by reference). For example, liposomal preparations can be prepared by dissolving suitable lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation, leaving a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then added to the container. The container is then rotated by hand to remove lipid material from the sides of the container, disperse lipid mass, and form a liposomal suspension.

[0204] Treatment method In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to modulate protein degradation in a patient or subject, e.g., an animal such as a human, and to treat or ameliorate a disease state or condition mediated by the degraded protein.

[0205] As used herein, the terms "treat," "treating," and "treatment" refer to any action that benefits a patient, including the treatment of any disease state or condition for which the compounds may be administered that is modulated via the protein to which the compounds bind. Disease states or conditions, including cancer, that may be treated using compounds according to the present disclosure are described herein above.

[0206] The present disclosure provides therapeutic compositions described herein for causing degradation of a target protein for the purpose of treating or ameliorating a disease, e.g., cancer. In certain additional embodiments, the disease is multiple myeloma. Accordingly, in another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein, wherein the compound comprises a ULM and a PTM, preferably linked via a linker moiety, e.g., as described elsewhere herein, wherein the ULM binds to the PTM and the ULM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, such as an E3 ubiquitin ligase, including cereblon), and the PTM recognizes the target protein such that, when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, thereby resulting in degradation / inhibition of the effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a disease state or condition that is regulated via the target protein by reducing the level of that protein in a cell, e.g., a patient cell. In certain embodiments, the methods comprise administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0207] In additional embodiments, the present specification provides methods for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal, e.g., a human, the method comprising administering to a subject in need thereof a composition comprising an effective, e.g., therapeutically effective, amount of a compound as described herein, or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

[0208] In any aspect or embodiment described herein, the disease or disorder is associated with aberrant BCL6 expression and / or activity.

[0209] In any aspect or embodiment described herein, the disease or disorder is cancer associated with aberrant BCL6 expression and / or activity.

[0210] In any aspect or embodiment described herein, the disease or disorder is associated with accumulation and aggregation of BCL6.

[0211] In any aspect or embodiment described herein, the disease or disorder is a cancer associated with accumulation and aggregation of BCL6.

[0212] In another aspect, the present specification provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0213] In another embodiment, the present disclosure is directed to a method of treating a human patient in need for a disease state or condition regulated through a protein, where degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial organism or other foreign agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease caused by overexpression of a protein resulting in the disease state and / or condition.

[0214] The term "disease state or condition" is used to describe any disease state or condition in which dysregulation of a protein occurs (i.e., the amount of protein expressed in the patient is increased) and degradation of one or more proteins in the patient results in beneficial treatment or symptomatic relief to the patient in need thereof. In certain instances, the disease state or condition may be treated.

[0215] Disease states or conditions that may be treated using compounds according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4(PDK2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0216] The terms "neoplasm" or "cancer" are used throughout this specification to refer to cancerous or malignant neoplasms, i.e., pathological processes that result in the formation and growth of abnormal tissue that grows by cell proliferation, often much faster than normal, and continues to grow after stimuli that would otherwise have stopped the new growth that has been initiated. Malignant neoplasms exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, recur after attempted removal, and have a high probability of patient death unless appropriately treated. As used herein, the term neoplasm is used to describe all cancerous conditions and includes pathological processes associated with malignant hematopoietic cells, ascites, and solid tumors. Examples of cancers that may be treated with the compounds of the present invention alone, or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral epithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, and ganglionic cell carcinoma. These include: fistula, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratocarcinoma, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

[0217] The term "bioactive agent" is used to describe an agent other than a compound according to the present disclosure, which is used in combination with the present compound as an agent having biological activity to supplement the therapeutic, inhibitory, and / or preventative / prophylactic effects for which the present compound is used. Preferred bioactive agents for use herein include agents having pharmacological activity similar to that for which the present compound is used or administered, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, anti-microbial agents, anti-fungal agents, etc.

[0218] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that can be used in combination with a compound according to the present disclosure to treat cancer. These agents include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jamatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indoyl-quinolone , vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifar Nibs; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin , diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed,Rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, ibuprofen Interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor child, zoledronate, prednisolone, cetuximab, granulocyte-monocyte colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,All-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor agonist These include steroid antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0219] The term "anti-HIV agent" or "additional anti-HIV agent" includes, for example, among others, nucleotide reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., agents not representative of the present disclosure), protease inhibitors, fusion inhibitors, exemplary compounds of which include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), ddD (zalcitabine), ddE (zalcitabine), ddF ... bine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate) mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, and mixtures thereof, including anti-HIV compounds currently in clinical trials or development.

[0220] Other anti-HIV agents that may be used for co-administration with compounds according to the present disclosure include, for example, nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothiamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY, among others. 097, DMP266, baicalin (TJN-151), ADAM-II (methyl 3',3'-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-6,6-diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hupto-1-enyl)-2-methoxybenzoate (alkenyl diarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), capravirin (AG-1549, S-1153), atevirdine (U-87201E), aurintricarboxylic acid (SD-095345 ), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1 -[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscarbil), HEPT(1-[(2-hydroxybenzoyl)methyl]pyrimidin-4-one) HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), Inophylum P, L-737,126, Michelamine A (NSC650898), Michelamine B (NSC649324), Michelamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC648400), oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivative), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pipridine-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pipridine-2(1H)-thione), R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, suramin sodium, TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, tivirapine (R86183), UC-38, and UC-84.

[0221] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, where appropriate, one or more salt forms of the compounds described herein, which salt forms increase the solubility of the compound in the gastric juices of a patient's digestive tract, facilitating the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium and magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0222] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., esters, amides, other prodrug groups, etc.) which, upon administration to a patient, yields, directly or indirectly, the compound, or an active metabolite of the compound.

[0223] General synthesis method The synthesis and optimization of the bifunctional molecules described herein may be approached in a stepwise or modular manner. For example, identifying compounds that bind to a target molecule may involve a high-throughput or medium-throughput screening campaign if a suitable ligand is not readily available. It is not uncommon for initial ligands to require iterative design and cycle optimization to improve suboptimal aspects identified by appropriate in vitro pharmacological and / or ADMET assay data. Part of the optimization / SAR campaign is to probe ligand positions that tolerate substitution and may be suitable locations for attaching the linker chemistry referenced herein above. When crystallographic or NMR structural data are available, they can be used to focus such synthetic efforts.

[0224] In a very similar manner, ligands for E3 ligases, i.e., ULM / CLM, can be identified and optimized.

[0225] Those skilled in the art can utilize known synthetic methods for combining PTMs and ULMs (e.g., CLMs) with or without linker moieties using proprietary PTMs and ULMs. Linker moieties can be synthesized and functionalized with a range of compositions, lengths, and flexibility so that PTM and ULM groups can be sequentially attached to the distal ends of the linker. Thus, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. As with PTM and ULM groups, the final bifunctional molecule can be subjected to iterative design and optimization cycles to identify molecules with desired properties.

[0226] In some cases, protecting group strategies and / or functional group interconversions (FGI) may be required to facilitate the preparation of the desired materials. Such chemical processes are known to synthetic organic chemists, and many of these chemical processes can be found in books such as "Greene's Protective Groups in Organic Synthesis" by Peter G.M.Wuts and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection Approach" by Stuart Warren and Paul Wyatt (Wiley).

[0227] Scheme 1 [ka]

[0228] A compound of Formula I (commercially available or easily made using standard reaction techniques known to those skilled in the art) can be reacted with a compound of Formula II (also commercially available or easily made by those skilled in the art) in a solvent such as DMSO or DMF, reacted with a base such as triethylamine or DIEA, and heated to produce a compound of Formula III. In this case, X of Compound II can be a leaving group such as a halogen, and Q6 and Q7 are expected to undergo selective substitution as shown herein. A non-limiting example is X=Cl, and Q6 and Q7 are both N. A compound of Formula III can be reacted with a compound of Formula IV by heating in a solvent such as DMSO in the presence of a base such as DIEA to produce a PROTAC™ of Formula V. The compound of Formula IV is an advanced building block, where the ULM, linker, and a portion of the PTM form a complete subunit. In this case, X of Compound II can be a leaving group such as a halogen, and Q6 and Q7 are expected to undergo selective substitution as shown herein. A non-limiting example is X=Cl, and Q6 and Q7 are both N. A compound of Formula III can be reacted with a compound of Formula IV by heating in a solvent such as DMSO in the presence of a base such as DIEA to produce a PROTAC™ of Formula V. [ka] represents a 4-8 membered cyclic or spirocyclic amine (4,4; 4,5; 4,6; 5,4; 5,5; 5,6; 6,4; 6,5; and 6,6 combination of any two rings), optionally including a second N if there are more than two carbons between them. L' can be a bond, a linker, or part of a linker.

[0229] Scheme 2 [ka]

[0230] The compound of Formula I of Scheme I can be made using procedures found and / or adapted from Kerres et al., 2017, Cell Reports 20, 2860-2875, and is shown in Scheme 2. When G1 is NO2, the compound of Formula VI can be dissolved in a solvent such as DMF, treated with a base such as, but not limited to, K2CO3, and alkylated with RPTM1-X. In this case, X can be a leaving group such as, but not limited to, iodo or bromo. Generally, RPTM1-X is commercially available or easily made by one skilled in the art. Alternatively, the boronic acid analog of RPTM1 can be attached to a compound of Formula VI using the Chan-Lam coupling reaction (see Chen et al., 2020, Advanced Synthesis and Catalysis 62(16), 3311-3331 for a review), in which the boronic acid and compound of Formula VI are combined with a copper salt, e.g., Cu(OAc)2, and a base, e.g., Na2CO3, in a solvent, e.g., DCE, and heated. In this case, it may be preferable to perform nitration with G1 = H, as shown in the third step of Scheme 2, using KNO3 under acidic conditions. Those skilled in the art will recognize that the nitration step can be skipped if alkylation of 5-nitroisatin (VI with G1 = NO2) with RPTM1-X is carried out directly as a compound of Formula VIII. Compounds of formula VIII can be reacted with TMS-diazomethane under basic conditions (Duplantier et al., 2009, J. Med. Chem. 52, 3576-3585 and references cited therein) to produce ring-expanded compounds of formula IX. The hydroxy group of compounds of formula X can be exposed by treating compounds of formula IX with BBR3. Compounds of formula I can be obtained in two additional steps by alkylating the hydroxy group of X with a 2-haloacetamide, followed by reduction of the nitro group. Many methods for performing nitro reduction are available to those skilled in the art.

[0231] Scheme 3 [ka]

[0232] Compounds of Formula I obtained from the scheme can also be obtained using the method shown in Scheme 3. Compounds of Formula XII (commercially available or easily made by methods known to those skilled in the art) can be treated with nitric acid in sulfuric acid to form compounds of Formula XIII. Compounds of Formula XIV can be obtained by heating compounds of Formula XIII in a mixture of sodium bromate / HBr. Similarly, as shown in Scheme 2, compounds of Formula XIV can be alkylated with RPTM1-X under basic conditions to give compounds of Formula XV. Compounds of Formula X can be obtained by heating this compound with BrettPhos Palladacycle Gen 4 in a mixture of dioxane, water, and KOH. The final two steps are as shown in Scheme 2.

[0233] Synthesis procedure

[0234] Example 1: 2-{[6-({5-chloro-2-[4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}propan-2-yl)piperazin-1-yl]pyrimidin-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide (Compound 13)

[0235] Step 1: Synthesis of 1-isopropyl-5-nitro-indoline-2,3-dione [ka]

[0236] To a solution of 5-nitroindoline-2,3-dione (5.00 g, 26.02 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added potassium carbonate (7.19 g, 52.05 mmol, 2.00 equiv) and 2-iodopropane (6.64 g, 39.04 mmol, 3.90 mL, 1.50 equiv). The mixture was stirred at 25° C. for 48 hours. The mixture was poured into water (300 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-isopropyl-5-nitro-indoline-2,3-dione (4.00 g, 17.08 mmol, 66% yield) as a yellow solid, which was used directly in the next step. H NMR (400MHz, DMSO-d6) δ=8.46(dd,J=8.8,2.4Hz,1H),8.21(d,J=2.4Hz,1H),7.52(d,J=8.8Hz,1H),4.60-4.45(m,1H),1.46(d,J=6.8Hz,6H).

[0237] Step 2: Synthesis of 1-isopropyl-3-methoxy-6-nitro-quinolin-2-one [ka]

[0238] To a stirred solution of 1-isopropyl-5-nitro-indoline-2,3-dione (25.00 g, 106.74 mmol, 1.00 equiv.) in ethanol (400 mL) was added triethylamine (234.83 mmol, 33 mL, 2.20 equiv.) followed by a hexane solution of TMS-diazomethane (2 M, 117 mL, 2.20 equiv.) at 25° C. After stirring for 12 hours at 25° C., the reaction mixture was poured into water (1500 mL) and extracted with dichloromethane (500 mL×3). The organic layers were combined and concentrated under reduced pressure. The residue was stirred in a mixture of ethyl acetate (50 mL) and petroleum ether (500 mL) at 25° C. for 2 hours and then filtered. The filter cake was dried under reduced pressure to give 1-isopropyl-3-methoxy-6-nitro-quinolin-2-one (45.00 g, crude) as a yellow solid. LCMS (ESI) m / z: 263.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.6, 2.8 Hz, 1H), 7.52 (d, J = 9.6 Hz, 1H), 7.49 (s, 1H), 5.45-5.28 (m, 1H), 3.84 (s, 3H), 1.55 (d, J = 6.8 Hz, 6H).

[0239] Step 3: Synthesis of 3-hydroxy-1-isopropyl-6-nitro-quinolin-2-one [ka]

[0240] A solution of boron tribromide (46.14 mmol, 4.5 mL, 1.10 equiv.) in dichloromethane (40 mL) was added dropwise to a mixture of 1-isopropyl-3-methoxy-6-nitro-quinolin-2-one (11.00 g, 41.94 mmol, 1.00 equiv.) in 400 mL of dichloromethane at 0 °C. After stirring at 0 °C for 2 hours, the mixture was poured into saturated sodium bicarbonate (1000 mL) and extracted with dichloromethane (500 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was stirred with a mixture of ethyl acetate (50 mL), petroleum ether (500 mL), and acetonitrile (50 mL) at 25 °C for 12 hours and then filtered. The filtrate was concentrated under reduced pressure to give 3-hydroxy-1-isopropyl-6-nitro-quinolin-2-one (28.00 g, 112.80 mmol, 90% yield) as a brown solid. LCMS (ESI) m / z: 280.2 [M+23]. 1H NMR (400 MHz, DMSO-d6) δ = 9.95 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.14 (dd, J = 9.2, 2.4 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.33 (s, 1H), 5.58-5.14 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H).

[0241] Step 4: Synthesis of 2-[(1-isopropyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide [ka]

[0242] This compound was prepared similarly to 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide. LCMS (ESI) m / z: 320.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ = 8.60 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.6, 2.8 Hz, 1H), 8.01-7.88 (m, 2H), 7.48 (s, 1H), 5.70-5.15 (m, 1H), 4.57 (s, 2H), 2.68 (d, J = 4.8 Hz, 3H), 1.58 (d, J = 7.2 Hz, 6H).

[0243] Step 5: Synthesis of 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide [ka]

[0244] 2-[(1-isopropyl-6-nitro-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (300.00 mg, 0.94 mmol, 1.00 equiv.) was placed in a 50 mL round-bottom flask under nitrogen and dissolved in DMF (15 mL) and MeOH (15 mL). After adding Pd / C (30.00 mg, 0.28 mmol, 0.30 equiv.), the flask was evacuated and flushed with hydrogen. The mixture was stirred at room temperature for 4 h, then filtered through a bed of Celite and concentrated under reduced pressure to give 253 mg of 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide as a light yellow solid (92%). LC-MS (ES+): m / z 290.00 [M+H+], tR = 0.59 min (1.20 min run).

[0245] Step 6: Synthesis of 2-([6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl]oxy)-N-methylacetamide [ka]

[0246] In a 50 mL round-bottom flask, DIEA (268.01 mg, 2.07 mmol, 3 equiv.), 2,4,5-trichloropyrimidine (152.14 mg, 0.83 mmol, 1.2 equiv.) were added to a mixture of 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (200.00 mg, 0.69 mmol, 1.00 equiv.), and DMSO (5 mL). The resulting solution was stirred at 100 °C for 2 h. The crude product was purified by flash preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, HO:ACN = 100:0 increasing to HO:ACN = 60:40 within 30 min; detector, 254 nm. Obtained 183 mg (60%) of 2-([6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl]oxy)-N-methylacetamide as a light yellow solid. LC-MS (ES+): m / z 436.00 [M+H+], tR=0.81 min (1.20 min run).

[0247] Step 7: Preparation of tert-butyl 4-(1-benzyloxycarbonylpiperidine-4-carbonyl)piperazine-1-carboxylate [ka]

[0248] A solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (70.68 g, 268.45 mmol, 1 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (153.11 g, 402.68 mmol, 1.5 equiv.) in N,N-dimethylformamide (500 mL) was added to tert-butyl piperazine-1-carboxylate (50 g, 268.45 mmol, 1 equiv.) and N,N-diisopropylethylamine (104.09 g, 805.36 mmol, 140.3 mL, 3 equiv.) at 25° C., and the mixture was stirred for 2 h at 25° C. LCMS showed the desired m / z and the reaction was complete. The mixture was poured into water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 mm x 100 mm x 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%-60%, 18 min). tert-Butyl 4-(1-benzyloxycarbonylpiperidine-4-carbonyl)piperazine-1-carboxylate (100 g, 231.74 mmol, 86.32% yield) was obtained as a white solid. MS (ESI) m / z: 432.2 [M+1]+. 1H NMR:(400MHz,DMSO-d6)δ:7.37-7.15(m,5H),5.07(s,2H),4.02-3.95(m,2H),3.66-3.55(m,1H),3.52- 3.47(m,2H),3.35-3.25(m,5H),2.95-2.80(m,3H),1.70-1.57(m,2H),1.40(s,9H),1.28-1.22(m,2H).

[0249] Step 8: Synthesis of tert-butyl 4-[1-(1-benzyloxycarbonyl-4-piperidyl)-1-methyl-ethyl]piperazine-1-carboxylate [ka]

[0250] To a mixture of zirconium tetrachloride (18.15 g, 77.86 mmol, 6.5 mL, 1.6 equiv) in tetrahydrofuran (200 mL), a solution of tert-butyl 4-(1-benzyloxycarbonyl piperidine-4-carbonyl)piperazine-1-carboxylate (21 g, 48.66 mmol, 1 equiv) in tetrahydrofuran (600 mL) was added dropwise over 30 minutes at −60° C. under nitrogen. Methylmagnesium bromide (3 M, 64.9 mL, 4 equiv) was then added to the mixture at −60° C. and stirred for 30 minutes. The resulting mixture was warmed to 25° C. and stirred for 6 hours. The mixture was quenched with saturated ammonium chloride solution (2 L) and extracted with ethyl acetate (2 L×3). The combined organic layer was washed with brine (2 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-55%, 20 min). tert-Butyl 4-[1-(1-benzyloxycarbonyl-4-piperidyl)-1-methyl-ethyl]piperazine-1-carboxylate (10 g, 22.44 mmol, 46% yield) was obtained as a yellow oil. MS(ESI) m / z: 446.1 [M+1]+.

[0251] Step 9: Preparation of tert-butyl 4-[1-methyl-1-(4-piperidyl)ethyl]piperazine-1-carboxylate [ka]

[0252] A solution of tert-butyl 4-[1-(1-benzyloxycarbonyl-4-piperidyl)-1-methyl-ethyl]piperazine-1-carboxylate (40 g, 89.77 mmol, 1 equiv.) in trifluoroethanol (100 mL) and tetrahydrofuran (300 mL) was added to palladium on activated carbon catalyst (5 g, 10% purity) and palladium hydroxide on activated carbon catalyst (10 g, 20% purity) at 30 °C. The mixture was then stirred under hydrogen (50 Psi) at 30 °C for 12 h. TLC (dichloromethane / methanol = 10 / 1) indicated the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the crude product. tert-Butyl 4-[1-methyl-1-(4-piperidyl)ethyl]piperazine-1-carboxylate (25 g, 80.27 mmol, 89% yield) was obtained as a white solid. MS(ESI) m / z: 312.3 [M+1]+.

[0253] Step 10: Preparation of tert-butyl 4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-carboxylate [ka]

[0254] A mixture of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (6 g, 18.57 mmol, 1 equiv.), tert-butyl 4-[1-methyl-1-(4-piperidyl)ethyl]piperazine-1-carboxylate (6.94 g, 22.28 mmol, 1.2 equiv.), cesium carbonate (12.10 g, 37.14 mmol, 2 equiv.), and Pd-PEPPSI-IPentCl-O-picoline (903 mg, 0.93 mmol, 0.05 equiv.) in N,N-dimethylformamide (60 mL) was stirred at 100° C. under nitrogen for 8 hours. LCMS showed the desired m / z and the reaction was complete. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 5% to 40%, 25 min). tert-Butyl 4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-carboxylate (3.5 g, 6.32 mmol, 34% yield) was obtained as a yellow solid. (ESI) m / z: 554.2 [M+1]+.

[0255] Step 11: Preparation of 3-[5-[4-(1-methyl-1-piperazin-1-yl-ethyl)-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione [ka]

[0256] To a solution of tert-butyl 4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-carboxylate (4.00 g, 7.22 mmol, 1 equiv.) in dichloromethane (50 mL), trifluoroacetic acid (30.80 g, 270.12 mmol, 20.00 mL, 37.39 equiv.) was added and stirred at 25 °C for 1 h. LCMS showed the desired m / z. The mixture was concentrated in vacuo. The residue was triturated with methyl tert-butyl ether (50 mL). 3-[5-[4-(1-methyl-1-piperazin-1-yl-ethyl)-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (4.10 g, 7.22 mmol, 100% yield, trifluoroacetic acid) was obtained as a yellow solid. MS (ESI) m / z: 454.5 [M+1]+.

[0257] Step 12: Preparation of 2-[[6-[[5-chloro-2-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazin-1-yl]pyrimidin-4-yl]amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide [ka]

[0258] To a solution of 3-[5-[4-[1-methyl-1-(4-piperidyl)ethyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (4.10 g, 7.22 mmol, 1 equiv., trifluoroacetic acid) in dimethyl sulfoxide (80 mL) was added N,N-diisopropylethylamine (5.60 g, 43.34 mmol, 7.6 mL, 6 equiv.) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (2.84 g, 6.50 mmol, 0.9 equiv.). The mixture was stirred at 120 °C for 3 hours. LCMS showed the desired m / z and the reaction was complete. The mixture was diluted with ethyl acetate (200 mL). The combined organic layer was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was first purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) and then by preparative HPLC (column: Phenomenex Luna C18 (250 x 70 mm, 10 μm), mobile phase: [water (0.1% TFA)-ACN], B%: 15% to 45%, 20 min). 2-[[6-[[5-chloro-2-[4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazin-1-yl]pyrimidin-4-yl]amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (4.3 g, 4.99 mmol, 71% yield, 99% purity) was obtained as an off-white solid. MS (ESI) m / z: 853.3 [M]+.1H NMR:(400MHz,DMSO-d6)δ:10.94(s,1H),8.82(s,1H),8.05(s,1H),8.02-7.95(m,2H),7.75-7.65(m,2H),7.52-7.45(m, 1H),7.10-7.00(m,3H),5.50-5.11(m,1H),5.04(dd,J=13.2,5.2Hz,1H),4.55(s,2H),4.36-4.28(m,1H),4.25-4.15(m, 1H),3.95(d,J=11.6Hz,2H),3.65-3.60(m,3H),2.97-2.85(m,1H),2.82-2.72(m,2H),2.66(d,J=4.8Hz,3H),2.63-2.52 (m,6H),2.45-2.27(m,1H),2.00-1.90(m,1H),1.85-1.75(m,3H),1.57(d,J=6.8Hz,6H),1.38-1.20(m,2H),0.89(s,6H).

[0259] Example 2: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide (Compound 15)

[0260] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate [ka]

[0261] To a mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.4 g, 5.7 mmol, 1.0 equiv.) and AIBN (0.1 g, 0.9 mmol, 0.2 equiv.) in CCl4 was added NBS (1.2 g, 6.8 mmol, 1.2 equiv.). The resulting mixture was stirred overnight at 70 °C under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq.). The resulting mixture was extracted with CHCl2. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash preparative HPLC using the following conditions: column: C18 silica gel; mobile phase: acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increasing to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 min; detector: 254 nm. Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (1.3 g, 68%) was obtained as a black solid.

[0262] Step 2: Preparation of 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0263] To a mixture of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (1.3 g, 3.9 mmol, 1.0 equiv.) and 3-aminopiperidine-2,6-dione (0.6 g) in acetonitrile was added TEA (0.7 g). The resulting mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. HOAC (5 mL) was added to the above mixture. The resulting mixture was stirred for an additional 4 hours at 120° C. The resulting mixture was concentrated under reduced pressure. Cold water was added to the above mixture. The precipitated solid was collected by filtration and washed with cold water. This gave 635.0 mg (48%) of 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a black solid. MS (ES+): m / z 341.05 [MH+].

[0264] Step 3: Synthesis of tert-butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazine-1-carboxylate [ka]

[0265] To a mixture of 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (350.0 mg, 1.0 mmol, 1.0 equiv.) and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (348.9 mg, 1.2 mmol, 1.2 equiv.) in DMF, Pd-PEPPSI-pent Cl-O-picoline (86.2 mg, 0.1 mmol, 0.1 equiv.) and CsCO (1002.9 mg, 3.0 mmol, 3.0 equiv.) were added. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours. The resulting mixture was diluted with CHCl. ​​HOAc was added to the above mixture. The resulting mixture was extracted with CHCl. ​​The combined organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash preparative HPLC using the following conditions: column: C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increasing to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 minutes; detector: 254 nm. tert-Butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazine-1-carboxylate (145.0 mg, 26%) was obtained as a yellow solid. MS (ES+): m / z 544.25 [MH+]

[0266] Step 4: Synthesis of 3-{6-fluoro-1-oxo-5-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione [ka]

[0267] A mixture of tert-butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazine-1-carboxylate (145.0 mg, 0.3 mmol, 1.0 equiv.) and hydrogen chloride (2 mL) in dioxane was stirred overnight at room temperature under air. The resulting mixture was concentrated under reduced pressure to give 3-{6-fluoro-1-oxo-5-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (118.3 mg, 100%) as a solid. MS (ES+): m / z 444.25 [MH+]

[0268] Step 5: Synthesis of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0269] A 10 mL sealed tube was charged with 3-{6-fluoro-1-oxo-5-[4-(piperazin-1-ylmethyl)piperidin-1-yl]-3H-isoindol-2-yl}piperidine-2,6-dione (117.6 mg, 0.3 mmol, 1.3 equiv.), 2-({6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (89.0 mg, 0.2 mmol, 1.0 equiv.), DMSO, and DIEA (2 mL). The resulting solution was stirred at 100° C. for 6 hours. The crude product was purified by flash preparative HPLC using the following conditions: column: C18 silica gel; mobile phase: acetonitrile / water (10 mmol / L NH4HCO3) = 0:100 increasing to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 min; detector: 254 nm. This gave 54.7 mg (31.8%) of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide as an off-white solid. 1HNMR(400MHz,DMSO-d6,ppm):δ 10.98(s,1H),8.86(s,1H),8.06(s,1H),7.96(s,2H),7.70(s,2H),7.42-7.39(m,1H),7.24-7.22(m ,1H),7.03(s,1H),5.09-5.05(m,1H),4.55(s,2H),4.33(s,1H),4.25(s,1H),3.65(s,4H),3.47(s,2 H),2.87-2.90(m,1H),2.77-2.74(m,2H),2.67-2.66(m,3H),2.51-2.49(m,1H),2.40(s,6H),2.22-2 .08(m,2H),1.99-1.96(m,1H),1.85-1.82(m,3H),1.60-1.50(m,6H),1.35-1.20(m,2H)MS(ES+):m / z 843.15[MH+].

[0270] Example 3: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoropiperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (Compound 113)

[0271] Step 1: Preparation of benzyl 4-{[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]methyl}piperazine-1-carboxylate

[0272] [ka]

[0273] To a stirred solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (3.9 g, 18 mmol, 1.5 equiv.) and benzyl piperazine-1-carboxylate (2.7 g, 12 mmol, 1 equiv.) in ethanol was added DIEA (4 mL). The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This afforded benzyl 4-{[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]methyl}piperazine-1-carboxylate (3.6 g, 67%) as a brown oil. MS(ES+): m / z 434.10, [MH+]

[0274] Step 2: Preparation of benzyl 4-{[1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl]methyl}piperazine-1-carboxylate [ka]

[0275] To a stirred solution of benzyl 4-{[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]methyl}piperazine-1-carboxylate (3.6 g, 8 mmol, 1 equiv.) in CHCl was added DAST (2 g, 12 mmol, 1.5 equiv.) dropwise at −78°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The aqueous layer was extracted with CHCl. ​​The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, acetonitrile / water (10 mmol / L NHHCO), 10% to 50% gradient in 30 minutes; detector, UV 254 nm. This gave benzyl 4-{[1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl]methyl}piperazine-1-carboxylate (1.2 g, 33%) as an off-white solid. MS (ES+): m / z 436.20, [MH+].

[0276] Step 3: Preparation of benzyl 4-[(4-fluoropiperidin-4-yl)methyl]piperazine-1-carboxylate [ka]

[0277] To a stirred solution of benzyl 4-{[1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl]methyl}piperazine-1-carboxylate (900 mg, 2 mmol, 1 equiv.) in DCM was added TFA (2 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was neutralized to pH 7 with saturated NaCO (aq.). The aqueous layer was extracted with CHCl. ​​This afforded benzyl 4-[(4-fluoropiperidin-4-yl)methyl]piperazine-1-carboxylate (660 mg, 95%) as an off-white solid. MS (ES+): m / z 336.20, [MH+].

[0278] Step 4: Preparation of benzyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoropiperidin-4-yl}methyl)piperazine-1-carboxylate [ka]

[0279] To a solution of benzyl 4-[(4-fluoropiperidin-4-yl)methyl]piperazine-1-carboxylate (300 mg, 0.89 mmol, 1 equiv.) and 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (289 mg, 0.89 mmol, 1 equiv.) in DMF (10 mL) was added CsCO (582 mg, 1.78 mmol, 2 equiv.) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (75 mg, 0.089 mmol, 0.1 equiv.). After stirring at 80 °C under nitrogen for 4 h, the resulting mixture was concentrated under reduced pressure. The aqueous layer was separated using CHCl and aqueous acid (10 mL HO + 0.5 mL H O). The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This gave benzyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoropiperidin-4-yl}methyl)piperazine-1-carboxylate (280 mg, 54%) as an off-white solid. MS (ES+): m / z 578.25, [MH+].

[0280] Step 5: Preparation of 3-{5-[4-fluoro-4-(piperazin-1-ylmethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione [ka]

[0281] To a solution of benzyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoropiperidin-4-yl}methyl)piperazine-1-carboxylate (280 mg, 0.48 mmol, 1 equiv.) in 10 mL of i-PrOH and 5 mL of THF was added Pd(OH) / C (100 mg) (10%) in a 50 mL round-bottom flask under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at room temperature for 4 hours, filtered through a bed of Celite, and concentrated.

[0282] Step 7. Preparation of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoropiperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0283] To a stirred solution of 3-{5-[4-fluoro-4-(piperazin-1-ylmethyl)piperidin-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (182 mg, 0.4 mmol, 1.5 equiv.) and 2-({6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (120 mg, 0.2 mmol, 1 equiv.) in DMSO, DIEA (0.5 mL) was added dropwise at room temperature. The resulting mixture was stirred for an additional 2 h at 100° C. The residue was purified by reverse-phase flash chromatography using the following conditions: column, silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. This gave 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-4-fluoropiperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (55.3 mg, 23%) as an off-white solid. NMR(400MHz,DMSO-d6,ppm)10.93(s,1H),8.84(s,1H),8.05(s,1H),7.94-7.89(m,2H),7.70-7.67(m,2H),7 .53-7.51(m,1H),7.08-7.05(m,3H),5.06-5.02(m,1H),4.53(s,2H),4.34-4.30(m,1H),4.22-4.18(m,1H),3 .64-3.33(m,5H),3.18-3.13(m,2H),2.90-2.89(m,1H),2.66-2.60(m,3H),2.53-2.50(m,2H),2.50-2.34(m ,7H),2.33-2.32(m,1H),1.97-1.94(m,3H),1.81-1.73(m,2H),1.57-1.55(m,6H).MS(ES+):m / z=843.40[M+]

[0284] Example 4: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoropiperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide (Compound 114) [ka]

[0285] Example 4 was prepared similarly to Example 3, substituting 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione for 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione. H NMR (400 MHz, DMSO-d, ppm) 10.97 (s, 1H), 8.84 (s, 1H), 8.05 (s, 1H), 7.94-7.89 (m, 2H), 7.72-7.70 (m, 2H), 7.43-7.42 (m, 1H), 7.32-7.31 (m, 1H), 7.22-7.20 (m, 1H), 7.05 (s, 1H), 5.11-5.10 (m, 1H), 4.53 (s, 2H), 4.0 ... .47-4.43(m,1H),4.32-4.28(m,1H),3.64-3.63(m,4H),3.31-3.30(m,2H),2.97-2.89(m,3H),2.67-2 .62(m,5H),2.55-2.50(m,7H),2.03-1.98(m,3H),1.97-1.94(m,2H),1.57-1.55(m,6H).MS(ES+):m / z 843.45[M+]

[0286] Example 5: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide (Compound 18)

[0287] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate [ka]

[0288] To a mixture of methyl 4-bromo-2-fluoro-6-methylbenzoate (1.5 g, 6.0 mmol, 1.0 equiv.) and AIBN (0.2 g, 1.2 mmol, 0.2 equiv.) in CCl4 was added NBS (1.3 g, 7.3 mmol, 1.2 equiv.). The resulting mixture was stirred overnight at 65 °C under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq.). The resulting mixture was extracted with CHCl2. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash preparative HPLC using the following conditions: column: C18 silica gel; mobile phase: acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increasing to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 min; detector: 254. Methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (1.4 g, 68%) was obtained as a yellow oil. MS (ES+): m / z 324.05 [MH+].

[0289] Step 2: Preparation of 3-(5-bromo-7-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0290] To a mixture of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (1.4 g, 4.1 mmol, 1.0 equiv.) and 3-amino-2,6-dioxopiperidine hydrochloride (0.5 g, 4.1 mmol, 1.0 equiv.) in acetonitrile was added TEA (0.8 g, 8.3 mmol, 2.0 equiv.). The resulting mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. HOAc (5 mL) was added to the above mixture. The resulting mixture was stirred at 120° C. for an additional 3 hours. The resulting mixture was concentrated under reduced pressure. Cold water was added to the above mixture. The precipitated solid was collected by filtration and washed with cold water. This gave 718.0 mg (51%) of 3-(5-bromo-7-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a black solid. MS (ES+): m / z 341.05 [MH+]

[0291] Steps 3-5: Preparation of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0292] Example 5 was prepared similarly to Example 2, replacing 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione with 3-(5-bromo-7-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione in step 3. The crude product was purified by flash preparative HPLC using the following conditions: column: C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3) = 0:100 increasing to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 minutes; detector: 254 nm. 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy

[0293] y}-N-methylacetamide (57.4 mg, 30%) was obtained as a brown solid. 1H NMR(400MHz,DMSO-d6,ppm):δ 10.93(s,1H),8.83(s,1H),8.04-7.95(m,3H),7.69(s,2H),7.03(s,1H) ),6.85(m,2H),5.10-4.90(m,1H),4.54(s,2H),4.40-4.21(m,2H),4.00 -3.80(m,2H),3.64(s,4H),2.95-2.86(m,3H),2.65(s,4H),2.38(s,5H) ,2.17(s,2H),2.00-1.80(m,4H),1.70-1.55(m,7H),1.35-1.20(m,2H). MS(ES+): m / z 843.35 [MH+].

[0294] Example 6: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-4-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide (Compound 26)

[0295] Step 1: Synthesis of 4-bromo-2-methoxy-6-methylbenzamide [ka]

[0296] A 250 mL round-bottom flask was charged with 4-bromo-2-methoxy-6-methylbenzonitrile (2.00 g, 8.847 mmol, 1.00 equiv), MeOH (50 mL), HO (50 mL), and NaOH (1.06 g, 26.540 mmol, 3.00 equiv). The resulting solution was stirred for 20 hours at 100 °C in an oil bath. The resulting solution was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded 1.56 g (72%) of 4-bromo-2-methoxy-6-methylbenzamide as a yellow solid.

[0297] Synthesis of 2,4-bromo-2-methoxy-6-methylbenzoic acid [ka]

[0298] A 100 mL round-bottom flask was charged with 4-bromo-2-methoxy-6-methylbenzamide (1.50 g, 6.145 mmol, 1.00 equiv.), dichloromethane (30 mL), HO (10 mL), and nitrosylsulfuric acid (10 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with dichloromethane (2 × 40 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded 1.2 g (80%) of 4-bromo-2-methoxy-6-methylbenzoic acid as a yellow solid.

[0299] Step 3: Synthesis of methyl 4-bromo-2-methoxy-6-methylbenzoate [ka]

[0300] A 100 mL round-bottom flask was charged with 4-bromo-2-methoxy-6-methylbenzoic acid (1.20 g, 4.897 mmol, 1.00 equiv), DMF (15 mL), K2CO3 (2.03 g, 14.690 mmol, 3.00 equiv), and CHCl (1.04 g, 7.345 mmol, 1.50 equiv). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (2 x 40 mL). The resulting mixture was washed with brine (1 x 30 mL). The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1 / 2). The collected fractions were combined and concentrated in vacuo. This gave 1.1 g (87%) of methyl 4-bromo-2-methoxy-6-methylbenzoate as a yellow solid.

[0301] Step 4: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate [ka]

[0302] A 100 mL round-bottom flask was charged with methyl 4-bromo-2-methoxy-6-methylbenzoate (1.10 g, 4.245 mmol, 1.00 equiv.), carbon tetrachloride (15 mL), NBS (831.19 mg, 4.670 mmol, 1.10 equiv.), and 2,2-azobisisobutyronitrile (69.71 mg, 0.425 mmol, 0.10 equiv.). The resulting solution was stirred overnight at 70 °C in an oil bath. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with dichloromethane (2 × 30 mL). The resulting mixture was washed with brine (2 × 20 mL). The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1 / 2). The collected fractions were combined and concentrated under vacuum. This gave 1.3 g (91%) of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate as a yellow oil. MS (ES+): m / z 338.95 [MH+]

[0303] Step 5: Synthesis of 3-(5-bromo-7-methoxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0304] A 100 mL round-bottom flask was charged with 3-aminopiperidine-2,6-dione hydrochloride (949.57 mg, 5.769 mmol, 1.50 equiv.), acetonitrile (15 mL), diisopropylethylamine (1.49 g, 11.539 mmol, 3.00 equiv.), and methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (1.30 g, 3.846 mmol, 1.00 equiv.). The resulting solution was stirred in an oil bath at 60° C. for 1 hour. HOAC (15 mL) was then added to the mixture, and the resulting solution was allowed to react with stirring for an additional hour while the temperature was maintained at 120° C. in the oil bath. The reaction was then quenched by the addition of water (50 mL). The solid was collected by filtration. This gave 1.1 g (81%) of 3-(5-bromo-7-methoxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione as a dark blue solid. MS (ES+): m / z 353.05 [MH+]

[0305] Steps 6-8: Preparation of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0306] Example 6 was prepared similarly to Example 2, substituting 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione for 3-(5-bromo-7-methoxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione in step 3. The crude product was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), gradient from 0% to 60% in 30 min; detector, UV 254 nm. 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-3H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (58.0 mg) was obtained as a light yellow solid. 1H NMR (400 MHz, DMSO-d6, ppm): δ 10.91(s,1H),8.86(s,1H),8.06(s,1H),7.97(s,2H),7.69(d,J=1.6Hz,2H),7.03(s,1H),6.59(s,1H),6 .45(s,1H),4.99(d,J=13.2,5.2Hz,1H),4.55(s,2H),4.22(s,1H),4.09(s,1H),3.89(s,2H),3.82(s,3H) ),3.64(s,4H),3.29(s,1H),2.99-2.86(m,3H),2.66(s,3H),2.56(d,J=16.6Hz,1H),2.40(s,4H),2.35- 2.24(m,1H),2.18(s,2H),1.91(s,1H),1.80(d,J=12.4Hz,3H),1.56(d,J=6.8Hz,6H),1.25-1.14(m,2H). MS(ES+):m / z 855.25[MH+].

[0307] The following compounds were made using procedures similar to those in Examples 1-6. [ka] [ka] [ka]

[0308] Example 21: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide (Compound 35)

[0309] Step 1: Preparation of 3-bromo-4-fluoro-2-methylbenzoic acid [ka]

[0310] A mixture of 2,2,6,6-tetramethylpiperidine (14.2 g, 100.5 mmol, 2.2 equiv.) and butyllithium (100.5 mL, 100.5 mmol, 2.2 equiv.) in THF was stirred at -20 °C for 30 minutes under a nitrogen atmosphere. 3-Bromo-4-fluorobenzoic acid (10.0 g, 45.7 mmol, 1.0 equiv.) was added to the mixture at -50 °C. The resulting mixture was stirred for another hour at -50 °C. Methyl iodide (25.9 g, 182.6 mmol, 4.0 equiv.) was added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of water. The pH of the solution was adjusted to 3-4 using HCl (1 mol / L). The resulting solution was extracted with 100 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L TFA) = 0:100, increasing to MeCN:HO (10 mmol / L TFA) = 80:20 within 30 min; detector, 254 nm) to give 3-bromo-4-fluoro-2-methylbenzoic acid (14.0 g) as a brown solid. MS (ES+): m / z 233.65 [MH+].

[0311] Step 2: Synthesis of 3-bromo-4-fluorobenzene-1,2-dicarboxylic acid [ka]

[0312] To a mixture of KMnO4 (5.4 g, 34.4 mmol, 8.0 equiv.) and NaOH (0.5 g, 12.9 mmol, 3.0 equiv.) in water was added 3-bromo-4-fluoro-2-methylbenzoic acid (1.0 g, 4.3 mmol, 1.0 equiv.). The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was filtered. The filtrate was neutralized with HCl (3 M) and concentrated under reduced pressure. 3-Bromo-4-fluorobenzene-1,2-dicarboxylic acid (3.0 g) was obtained as a white solid. MS (ES+): m / z 263.15 [MH+].

[0313] Step 3: Preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione [ka]

[0314] To a stirred mixture of 3-aminopiperidine-2,6-dione hydrochloride (1.4 g, 8.6 mmol, 1.5 equiv.) and 3-bromo-4-fluorobenzene-1,2-dicarboxylic acid (3.0 g, 5.7 mmol, 1.0 equiv.) in AcOH was added NaOAc (2.3 g, 17.1 mmol, 3.0 equiv.). The resulting mixture was stirred at 120° C. under a nitrogen atmosphere for 5 hours. The resulting mixture was concentrated under reduced pressure. Cold water was added to the above mixture. The precipitated solid was collected by filtration. The resulting solid was dried. This afforded 4-bromo-2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (600.0 mg, 30%) as a black solid. MS (ES+): m / z 355.00 [MH+].

[0315] Steps 4-6: Preparation of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl]oxy}-N-methylacetamide

[0316] Example 21 was prepared by substituting 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione for 4-bromo-2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione in the final step to prepare 2-({6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide and 2-({6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide This was prepared similarly to steps 3 to 5 of Example 2, substituting 2-({6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide. The crude product was purified by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increasing to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 min; detector, 254 nm. Obtained 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxoisoindol-4-yl]piperidin-4-yl}methyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-methyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (17.5 mg, 39%) as a yellow solid.1H NMR(400MHz,DMSO-d6,ppm):δ 11.10(s,1H),8.87(s,1H),8.06(s,1H),7.99(s,1H),7.94(m,1H),7.75(m,1H),7.54 -7.48(m,2H),7.38(m,1H),7.13(s,1H),5.08(m,1H),4.59(s,2H),3.68(s,3H),3.64( s,4H),3.48(m,1H),3.45(s,1H),3.20(s,2H),2.93-2.80(m,1H),2.66(m,4H),2.61( s,1H),2.40(s,4H),2.21(s,2H),2.02(m,1H),1.78(m,3H),1.32(m,2H).MS(ES+):m / z 829.35[MH+].

[0317] Example 22: 2-[[6-[[5-chloro-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidin-4-yl]amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (Compound 5)

[0318] Step 1: Synthesis of 6-nitro-1H-quinolin-2-one. Synthesis of 3-bromo-1-ethyl-6-nitroquinolin-2-one. [ka]

[0319] To a mixture of 1H-quinolin-2-one (3.50 g, 24.11 mmol, 1.00 equiv) and concentrated sulfuric acid (15 mL) was added concentrated nitric acid (11.11 mmol, 0.5 mL, 0.46 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 3 hours. Nitric acid (22.22 mmol, 1 mL, 0.92 equiv) was then added to the mixture. The reaction mixture was stirred at 0° C. for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was then poured into water (100 mL). The formed precipitate was filtered and washed with water (100 mL). The solid was concentrated under reduced pressure to give 6-nitro-1H-quinolin-2-one (2.50 g, 13.15 mmol, 55% yield) as a yellow solid, which was used directly in the next step. LC / MS(ESI)m / z:191.2[M+1]+. 1H NMR:(400MHz,DMSO-d6)δ=8.67(s,1H),8.31(dd,J=9.2,2.4Hz,1H),8.11(d,J=9.6Hz,1H),7.44(d,J=9.2Hz,1H),6.66(d,J=9.6Hz,1H).

[0320] Step 2: Synthesis of 3-bromo-6-nitro-1H-quinolin-2-one [ka]

[0321] To a suspension of 6-nitro-1H-quinolin-2-one (12.00 g, 63.11 mmol, 1.00 equiv.), sodium bromate (12.38 g, 82.04 mmol, 1.30 equiv.), and water (100 mL) was added hydrogen bromide (2120 mmol, 240 mL, 48% purity, 33.62 equiv.), and the reaction mixture was heated at 100 °C for 4 h. LCMS indicated the reaction was complete. The reaction mixture was then poured into water (300 mL). The mixture was filtered. The filter cake was concentrated under reduced pressure to give 3-bromo-6-nitro-1H-quinolin-2-one (15.00 g, 55.75 mmol, 88% yield) as a yellow solid, which was used directly in the next step. LC / MS (ESI) m / z: 269.0 [M+1]+. 1H NMR:(400MHz,DMSO-d6)δ=12.77(brs,1H),8.76(s,1H),8.68(d,J=2.8Hz,1H),8.34(dd,J=9.6,2.8Hz,1H),7.47(d,J=9.2Hz,1H).

[0322] Step 3: Synthesis of 3-bromo-1-ethyl-6-nitro-quinolin-2-one [ka]

[0323] To a solution of 3-bromo-6-nitro-1H-quinolin-2-one (6.00 g, 22.30 mmol, 1.00 equiv) in N,N'-dimethylformamide (50 mL) was added potassium carbonate (10.90 g, 78.86 mmol, 3.54 equiv) and iodoethane (44.60 mmol, 3.57 mL, 2.00 equiv). The reaction was stirred at 25°C for 0.5 hours. LCMS showed the reaction was complete. The reaction mixture was then poured into water (100 mL) and filtered. The filter cake was treated with a solution of petroleum ether (300 mL) and ethyl acetate (30 mL). The mixture was stirred at 25°C for 0.5 hours and filtered. The filter cake was collected and dried under reduced pressure to give 3-bromo-1-ethyl-6-nitro-quinolin-2-one (4.00 g, 13.46 mmol, 30% yield) as a yellow solid, which was used directly in the next step. LCMS (ESI) m / z: 299.0 [M+1]+. 1H NMR: (400 MHz, DMSO-d6) δ = 8.79-8.74 (m, 2H), 8.42 (dd, J = 9.6, 2.8 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0324] Step 4: Synthesis of 1-ethyl-3-hydroxy-6-nitro-quinolin-2-one [ka]

[0325] To a solution of 3-bromo-1-ethyl-6-nitro-quinolin-2-one (3.00 g, 10.10 mmol, 1.00 equiv.) in dioxane (50 mL) and water (100 mL) was added potassium hydroxide (1.70 g, 30.29 mmol, 3.00 equiv.) and methanesulfonate (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium(II) (0.92 g, 1.01 mmol, 0.10 equiv.). The mixture was heated at 100 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 M hydrochloric acid, and the mixture was filtered. The filter cake was concentrated under reduced pressure to give 1-ethyl-3-hydroxy-6-nitro-quinolin-2-one (2.20 g, 9.39 mmol, 93% yield) as a yellow solid. LCMS: (ESI) m / z: 235.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ = 10.10 (s, 1H), 8.59 (s, 1H), 8.21 (dd, J = 9.6, 2.8 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.38 (s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0326] Step 5: Synthesis of 2-[(1-ethyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide [ka]

[0327] To a solution of 1-ethyl-3-hydroxy-6-nitro-quinolin-2-one (1.00 g, 4.27 mmol, 1.00 equiv) in acetonitrile (5 mL) was added potassium carbonate (1.77 g, 12.81 mmol, 3.00 equiv) and 2-bromo-N-methyl-acetamide (0.65 g, 4.27 mmol, 1.00 equiv). The reaction was stirred at 80 °C for 0.5 h. Water (50 mL) was added to the mixture. The mixture was filtered. The filter cake was concentrated under reduced pressure to give 2-[(1-ethyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (1.20 g, 3.93 mmol, 92% yield) as a yellow solid. LCMS (ESI) m / z: 328.2 [M+23]+. HNMR(400MHz,DMSO-d6)δ=8.64(d,J=2.8Hz,1H),8.27(dd,J=9.2,2.8Hz,1H),7.96(d,J=3.6Hz,1H),7.77(d, J=9.6Hz,1H),7.53(s,1H),4.60(s,2H),4.38(q,J=7.2Hz,2H),2.68(d,J=4.8Hz,3H),1.26(t,J=7.2Hz,3H).

[0328] Step 6: 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide [ka]

[0329] To a mixture of 2-[(1-ethyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (1.00 g, 3.28 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) and methanol (30 mL) was added palladium on carbon (0.15 g, 10% purity). The mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere at 1 atmosphere pressure. The reaction mixture was then filtered. The filtrate was concentrated under reduced pressure to give 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (1.00 g, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI) m / z: 276.1 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ=7.99(d,J=4.0Hz,1H),7.25(d,J=8.8Hz,1H),7.04(s,1H),6.81(dd,J=9.2,2.8Hz,1H),6. 71(d,J=2.8Hz,1H),5.06(s,2H),4.51(s,2H),4.24(q,J=7.2Hz,2H),2.67(d,J=4.8Hz,3H),1.20(t,J=7.2Hz,3H).

[0330] Step 7: Synthesis of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide [ka]

[0331] To a solution of 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide (1.00 g, 3.63 mmol, 1.00 equiv) and diisopropylethylamine (10.90 mmol, 1.90 mL, 3.00 equiv) in dimethyl sulfoxide (30 mL) was added 2,4,5-trichloropyrimidine (1.33 g, 7.26 mmol, 2.00 equiv). The mixture was stirred at 100° C. for 1 hour, poured into ice water (50 mL), and filtered. The filter cake was treated with a solution of petroleum ether (50 mL) and ethyl acetate (10 mL) and filtered to give 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (1.20 g, 2.84 mmol, 78% yield) as a white solid, which was used directly in the next step. LCMS (ESI) m / z: 422.3 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ=9.66(s,1H),8.39(s,1H),7.97(d,J=4.0Hz,1H),7.77(d,J=2.4Hz,1H),7.68(dd,J=9.6,2.4Hz, 1H),7.59(d,J=9.2Hz,1H),7.23(s,1H),4.59(s,2H),4.35(q,J=7.2Hz,2H),2.68(d,J=4.8Hz,3H),1.25(t,J=7.2Hz,3H).

[0332] Step 8:1 Synthesis of tert-butyl 4-[(1R,3R)-3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0333] A 20 mL sealed tube purged with and maintained under an inert nitrogen atmosphere was charged with 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindole-1,3-dione (200 mg, 0.6 mmol, 1.0 equiv.), DMF (20 mL), DIEA (227 mg, 1.8 mmol, 3.0 equiv.), and tert-butyl 4-[(1S,3S)-3-[(4-nitrobenzenesulfonyl)oxy]cyclobutoxy]piperidine-1-carboxylate (WO2018102725, 267.5 mg, 0.6 mmol, 1.0 equiv.). The resulting solution was stirred in an oil bath at 65° C. for 36 hours. The crude product was purified by flash preparative HPLC using the following conditions: column: C18 silica gel; mobile phase, acetonitrile / water = 10, increasing to acetonitrile / water = 70 within 25 minutes; detector: 254 nm. This gave 60 mg (17%) of tert-butyl 4-[(1R,3R)-3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-1-yl]cyclobutoxy]piperidine-1-carboxylate as a yellow oil. MS (ES+): m / z 595.30 [MH+].

[0334] Step 9: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-[1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl]isoindole-1,3-dione [ka]

[0335] A 25 mL round-bottom flask was charged with tert-butyl 4-[(1r,3r)-3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-1-yl]cyclobutoxy]piperidine-1-carboxylate (60 mg, 0.1 mmol, 1.0 equiv.), DCM (10 mL), and TFA (3 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. This afforded 55 mg (99%) of 2-(2,6-dioxopiperidin-3-yl)-5-[1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl]isoindole-1,3-dione as a yellow oil. LC-MS(ES+): m / z 495.30 [MH+].

[0336] Step 10: 2-[[6-[[5-chloro-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidin-4-yl]amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide [ka]

[0337] To a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (120 mg, 0.28 mmol, 1 equiv.) and N,N-diisopropylethylamine (110 mg, 0.85 mmol, 0.1 mL, 3 equiv.) in dimethyl sulfoxide (6 mL), 2-(2,6-dioxo-3-piperidyl)-5-[1-[3-(4-piperidyloxy)cyclobutyl]-4-piperidyl]isoindoline-1,3-dione (190 mg, 0.31 mmol, 1.1 equiv., trifluoroacetate salt) was added at 25° C., and the mixture was stirred at 120° C. for 12 h. LCMS showed the desired m / z and the reaction was complete. The mixture was added with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was first purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [hexane-EtOH]; B%: 20%-60%, 15 min). It was then further purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 12%-42%, 7 min). 2-[[6-[[5-chloro-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidin-4-yl]amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (35.08 mg, 0.04 mmol, 13% yield, 96.5% purity) was obtained as an off-white solid.1H NMR(400MHz,DMSO-d6)δ:11.13(s,1H),8.85(s,1H),8.04(s,1H),8.03-7.99(m,1H),7.95(d,J=2.4Hz,1H),7.87-7.82(m,1H),7.79-7. 76(m,2H),7.74-7.69(m,1H),7.55-7.49(m,1H),7.08(s,1H),5.13(dd,J=12.8,5.2Hz,1H),4.57(s,2H),4.37-4.27(m,2H),4.20-4.05( m,3H),3.25-3.22(m,2H),3.02-2.95(m,2H),2.92-2.80(m,2H),2.77-2.70(m,1H),2.67(d,J=4.8Hz,3H),2.63-2.53(m,3H),2.20-2.1 0(m,2H),2.08-1.95(m,3H),1.85-1.75(m,6H),1.72-1.60(m,2H),1.43-1.30(m,2H),1.23(t,J=7.2Hz,3H).MS(ESI)m / z:880.3[M+1]+.

[0338] Example 23: 2-[[6-[[5-chloro-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidin-4-yl]amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (Compound 72)

[0339] Step 1: Preparation of methyl 4-bromo-3-hydroxy-2-methyl-benzoate [ka]

[0340] To a solution of 2-methylpropan-2-amine (440 mg, 6.02 mmol, 0.6 mL, 1 equiv.) in dichloromethane (40 mL) at -70 °C, a solution of bromine (961 mg, 6.02 mmol, 0.3 mL, 1 equiv.) in dichloromethane (2 mL) was added dropwise and stirred at -70 °C for 1 h. Then, a solution of methyl 3-hydroxy-2-methylbenzoate (1 g, 6.02 mmol, 1 equiv.) in dichloromethane (2 mL) was added dropwise, and the resulting mixture was warmed to 25 °C and stirred for 11 h. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (200 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 150 / 1). The compound, methyl 4-bromo-3-hydroxy-2-methylbenzoate (780 mg, 3.18 mmol, 52% yield), was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 2.38 (s, 3H). MS (ESI) m / z: 246.9 [M+1]+

[0341] Step 2: Preparation of methyl 4-bromo-3-methoxy-2-methyl-benzoate [ka]

[0342] To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (780 mg, 3.18 mmol, 1 equiv.) in acetonitrile (6 mL), potassium carbonate (527 mg, 3.82 mmol, 1.2 equiv.) and iodomethane (1.36 g, 9.55 mmol, 0.5 mL, 3 equiv.) were added. The mixture was stirred at 50 °C for 5 h. LCMS showed several new peaks, indicating the desired compound. The reaction mixture was filtered, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1). The compound methyl 4-bromo-3-methoxy-2-methyl-benzoate (740 mg, 2.86 mmol, 89% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.58-7.50 (m, 1H), 7.50-7.43 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 2.58 (s, 3H). MS (ESI) m / z: 259.0 [M+1]+

[0343] Step 3: Preparation of WX-ARV-DS-021F-3, methyl 4-bromo-2-(bromomethyl)-3-methoxy-benzoate [ka]

[0344] To a solution of methyl 4-bromo-3-methoxy-2-methylbenzoate (145 mg, 0.55 mmol, 1 equiv.) in carbon tetrachloride (1 mL), n-bromosuccinimide (119 mg, 0.67 mmol, 1.2 equiv.) and AIBN (2 mg, 0.02 mmol, 0.03 equiv.) were added. The mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1). The title compound was obtained as a white solid (170 mg, 0.50 mmol, 89% yield). 1H NMR(400MHz,CDCl3)δ:7.62(dd,J=8.4,13.6Hz,2H),5.11(s,2H),4.04(s,3H),3.06(s,3H)

[0345] Step 4: Preparation of tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate [ka]

[0346] To a solution of methyl 4-bromo-2-(bromomethyl)-3-methoxybenzoate (750 mg, 2.22 mmol, 1 equiv.) and tert-butyl 4,5-diamino-5-oxo-pentanoate (673 mg, 3.33 mmol, 1.5 equiv.) in N,N-dimethylformamide (7 mL) was added N,N-diisopropylethylamine (860 mg, 6.66 mmol, 1.16 mL, 3 equiv.). The mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 2). The compound tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (880 mg, 2.06 mmol, 92% yield) was obtained as a white solid. MS (ESI) m / z: 427.1 [M+1]+.

[0347] Step 5: Preparation of benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0348] A mixture of tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (780 mg, 1.83 mmol, 1 equiv.), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (751 mg, 2.19 mmol, 1.2 equiv.), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (118 mg, 0.18 mmol, 0.1 equiv.), and cesium fluoride (831 mg, 5.48 mmol, 0.2 mL, 3 equiv.) in dioxane (10 mL) and water (1 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 90 °C under a nitrogen atmosphere for 6 h. The reaction mixture was diluted with water (200 mL). The organic layer was extracted with ethyl acetate (100 mL × 2). The combined organic layer was washed with brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 mm * 70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 50% to 75%, 17 min). The compound benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (900 mg, 1.60 mmol, 87% yield) was obtained as a white solid. 1H NMR(400MHz,CDCl3)δ:7.56-7.49(m,1H),7.46-7.32(m,5H),7.30-7.23(m,1H),6.54(s,1H),5.96-5.78(m,1H),5.69(br s,1H),5.21(m,2H),4.93(dd,J=6.4,8.4Hz,1H),4.58(d,J=17.2Hz,2H),4.23-4.14(m,2H),3.84(s,3H),3.72(t,J=5.2Hz,2H),2.53(br s,2H),2.42-2.14(m,4H),1.42(s,9H).MS(ESI)m / z:564.4[M+1]+.

[0349] Step 6: Preparation of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate [ka]

[0350] To a solution of benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (900 mg, 1.60 mmol, 1 equiv.) in 2,2,2-trifluoroethanol (10 mL) and tetrahydrofuran (10 mL) was added palladium on activated carbon catalyst (200 mg, 10% purity) and palladium hydroxide on activated carbon catalyst (200 mg, 20% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 Psi) at 30 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. The compound tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate (680 mg, 1.58 mmol, 98% yield) was obtained as a white solid. ).1H NMR(400MHz,CDCl3)δ:7.47(br d,J=7.6Hz,1H),7.28(d,J=7.6Hz,1H),4.82(br t,J=7.2Hz,1H),4.62-4.41(m,2H),3.96-3.96(m,2H),3.85(s,3H),3.65(q,J=7.2Hz,2H) ,2.81-2.63(m,2H),2.36-2.08(m,4H),1.75-1.65(m,2H),1.62-1.56(m,1H),1.34(s,9H).

[0351] Step 7: Preparation of benzyl 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate [ka]

[0352] A mixture of cis-3-benzyloxycyclobutanol (100 g, 561.08 mmol, 1 equiv.) and benzyl 4-oxopiperidine-1-carboxylate (143.97 g, 617.19 mmol, 123.1 mL, 1.1 equiv.) in acetonitrile (2000 mL) was degassed and purged with nitrogen three times. Chloro(dimethyl)silane (53.09 g, 561.08 mmol, 1 equiv.) was then added at 0° C. The mixture was stirred at 25° C. for 12 hours under a nitrogen atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was diluted with water (2 L). The organic layer was extracted with ethyl acetate (1 L × 2). The combined organic layers were washed with brine (500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=30 / 1, 20 / 1) to give the product. The title compound was obtained as a colorless oil (89 g, 225.04 mmol, 40% yield). MS (ESI) m / z: 396.3 [M+1]+.

[0353] Step 8: Preparation of benzyl 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate [ka]

[0354] To a solution of benzyl 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate (65 g, 164.35 mmol, 1 equiv.) in ethanol (300 mL) and tetrahydrofuran (300 mL), palladium on activated carbon (6 g, 1.44 mmol, 10% purity), palladium hydroxide on activated carbon (6 g, 8.54 mmol, 20% purity), and di-tert-butyl dicarbonate (53.80 g, 246.53 mmol, 56.6 mL, 1.5 equiv.) were added under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 Psi) at 40 °C for 16 h. Thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1, 0 / 1). The title product was obtained as a white solid (30.8 g, 113.51 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ: 3.94-3.85 (m, 1H), 3.82-3.71 (m, 2H), 3.68-3.57 (m, 1H), 3.49-3.35 (m, 1H), 3.08-2.92 (m, 2H), 2.76-2.64 (m, 2H), 1.96-1.88 (m, 2H), 1.84-1.72 (m, 2H), 1.54-1.37 (m, 11H).

[0355] Step 9: Preparation of benzyl 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate [ka]

[0356] To a solution of benzyl 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate (4 g, 14.74 mmol, 1 equiv.) and triethylamine (4.47 g, 44.22 mmol, 6.16 mL, 3 equiv.) in dichloromethane (120 mL) was added trifluoromethanesulfonyl anhydride (4.57 g, 16.22 mmol, 2.68 mL, 1.1 equiv.) at 0° C. The mixture was stirred at 25° C. for 0.5 h. TLC showed the reaction was complete. The reaction was quenched with water (20 mL). The solution was extracted with dichloromethane (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (2-5% ethyl acetate in petroleum ether). The title compound was obtained as a yellow solid (2.5 g, 6.20 mmol, 42% yield). 1H NMR(400MHz,CDCl3)δ:4.83(quin,J=7.2Hz,1H),3.76-3.61(m,3H),3.43-3.34(m,1H),2.99(ddd,J= 3.6,9.6,13.2Hz,2H),2.88-2.74(m,2H),2.48-2.21(m,2H),1.74-1.65(m,2H),1.45-1.36(m,11H).

[0357] Step 10: Preparation of tert-butyl 4-((1r,3r)-3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0358] To a solution of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate (330 mg, 0.76 mmol, 1 equiv.) and benzyl 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate (339 mg, 0.84 mmol, 1.1 equiv.) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (296 mg, 2.29 mmol, 0.3 mL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (100 mL). The organic layer was extracted with ethyl acetate (100 mL × 2). The combined organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue.The residue was purified by preparative HPLC (column: Phenomenex luna c18 (250 mm * 70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 10% to 40%, 20 min) to obtain the title compound as a yellow oil (290 mg, 0.42 mmol, 55% yield).MS (ESI) m / z: 685.3 [M+1]+.

[0359] Step 11: Preparation of 3-(4-methoxy-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0360] A mixture of tert-butyl 4-((1r,3r)-3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate (290 mg, 0.42 mmol, 1 equiv.) and [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonate (245 mg, 1.06 mmol, 2.5 equiv.) in acetonitrile (10 mL) was stirred at 80° C. for 12 hours. The reaction mixture was basified with N,N-diisopropylethylamine and then concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. The title compound was obtained as a colorless gum (260 mg, 0.41 mmol, 98% yield, trifluoroacetate salt). MS (ESI) m / z: 529.3 [M+18]+.

[0361] Step 12: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-ethyl-2-oxo-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0362] To a solution of 3-(4-methoxy-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (260 mg, 0.41 mmol, 1 equiv., trifluoroacetate salt) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (181 mg, 0.41 mmol, 1 equiv.) in dimethyl sulfoxide (3 mL) was added N,N-diisopropylethylamine (161 mg, 1.25 mmol, 0.2 mL, 3 equiv.). The mixture was stirred at 120° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 18%~48%, 10 min). The title compound was obtained as a white solid (47.8mg, 0.05mmol, yield 12%, purity 98%). 1H NMR(400MHz,DMSO-d6)δ:10.9(s,1H),8.83(s,1H),8.05(s,1H),8.01-7.92(m,2H),7.69(s,2H),7.40(s,2H),7.03(s,1H),5.59-5. 19(m,1H),5.10(dd,J=5.2,13.2Hz,1H),4.70-4.60(m,1H),4.55(s,2H),4.50-4.42(m,1H),4.24-4.11(m,2H),3.91(s,3H),3.54(br s,1H),3.30(s,3H),3.27-3.19(m,2H),3.05-2.86(m,4H),2.68(d,J=4.4Hz,3H),2.65-2.59(m,2H),2.16(br s,2H),2.04-19.6(m,3H),1.88-1.76(m,4H),1.72-1.66(m,3H),1.58(d,J=7.2Hz,6H),1.43-1.33(m,2H).MS(ESI)m / z:910.2[M+1]+.

[0363] Example 24: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 79)

[0364] Step 1: Preparation of methyl 4-bromo-5-fluoro-2-methyl-benzoate [ka]

[0365] To a solution of 4-bromo-5-fluoro-2-methylbenzoic acid (10.50 g, 45.06 mmol, 1.00 equiv) in dimethylformamide (110 mL) was added potassium carbonate (15.57 g, 112.64 mmol, 2.50 equiv) and iodomethane (19.19 g, 135.17 mmol, 8.4 mL, 3.00 equiv) at 20 °C, and the mixture was stirred at 20 °C for 2 hours. Thin layer chromatography (dichloromethane:methanol = 10:1) showed that the reaction was complete. The mixture was filtered, and the filtrate was diluted with water (600 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (600 mL × 2), brine (600 mL × 2), dried over sodium sulfate, and then concentrated under reduced pressure to give methyl 4-bromo-5-fluoro-2-methyl-benzoate (11.00 g, 44.52 mmol, 99% yield) as a yellow oil. H NMR (400 MHz, CDCl) δ: 7.68 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 3.91 (s, 3H), 2.56 (s, 3H).

[0366] Step 2: Preparation of methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate [ka]

[0367] To a solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (11 g, 44.52 mmol, 1.00 equiv.) in dichloroethane (150 mL), N-bromosuccinimide (8.72 g, 48.98 mmol, 1.10 equiv.) and 2,2-azobisisobutyronitrile (731 mg, 4.45 mmol, 0.10 equiv.) were added at 20 °C, and the mixture was warmed to 80 °C. The mixture was stirred at 80 °C for 6 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The mixture was filtered, and the filtrate was diluted with saturated sodium thiosulfate (500 mL) and extracted with dichloromethane (300 mL). The organic layer was washed with water (500 mL x 2), brine (500 mL x 2), dried over sodium sulfate, and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 30:1 to 20:1) to give methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (13.00 g, 39.88 mmol, 90% yield) as a colorless oil. H NMR (400 MHz, CDCl) δ: 7.75-7.67 (m, 2H), 4.89 (s, 2H), 3.95 (s, 3H).

[0368] Step 3: Preparation of tert-butyl 5-amino-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate [ka]

[0369] To a solution of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (2.00 g, 6.14 mmol, 1.00 equiv.) in dimethylformamide (20 mL), diisopropylethylamine (3.17 g, 24.54 mmol, 4.3 mL, 4.00 equiv.) and tert-butyl 4,5-diamino-5-oxo-pentanoate (1.24 g, 6.14 mmol, 1.00 equiv.) were added at 80 °C, and the mixture was stirred at 80 °C for 12 hours. Thin layer chromatography (dichloromethane:methanol = 20:1) showed the reaction was complete. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL x 2), brine (100 mL), dried over sodium sulfate, and then concentrated under reduced pressure to give a light yellow solid. The solid was triturated with petroleum ether:ethyl acetate (80 mL, 3:1) to give tert-butyl 5-amino-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (4.50 g, 10.84 mmol, 88% yield) as a white solid, δ: 8.02 (d, J = 6.0 Hz, 1H), 7.72-7.54 (m, 2H), 7.24 (s, 1H), 4.79-4.67 (m, 1H), 4.65-4.55 (m, 1H), 4.52-4.35 (m, 1H), 2.23-2.09 (m, 3H), 2.05-1.90 (m, 1H), 1.33 (s, 9H).

[0370] Step 4: Preparation of benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-6-fluoro-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0371] The title compound was prepared in a similar manner to Step 5 of Example 23. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=5:1 to 0:1) to afford benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-6-fluoro-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.20 g, 3.91 mmol, 81% yield, 98% purity) as a light brown solid. 1H NMR(400MHz,CDCl3)δ:7.47(d,J=9.6Hz,1H),7.44-7.28(m,6H),6.40(s,1H),5.97(d,J=9.6Hz,1H),5.54(s,1H),5.19(s,2 H),4.90(dd,J=6.4,8.4Hz,1H),4.58-4.48(m,1H),4.45-4.36(m,1H),4.18(d,J=2.4Hz,2H),3.72(t,J=5.2Hz,2H),2.53(br s,2H),2.43-2.09(m,4H),1.42(s,9H).MS(ESI)m / z:552.2[M+1]+.

[0372] Step 5: Preparation of tert-butyl 5-amino-4-[6-fluoro-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate [ka]

[0373] The title compound was made analogously to Step 6 of Example 23. The crude product (720 mg, 1.72 mmol, 95% yield) was used in the next step without further purification. 1H NMR(400MHz,DMSO-d6)δ:7.66-7.51(m,2H),7.42(d,J=9.2Hz,1H),7.20(s,1H),4.76-4.67(m,1H),4.62-4.51(m,1H),4.47-4.36(m,1H) ,3.12-2.93(m,3H),2.66(t,J=11.2Hz,2H),2.16(s,3H),2.00-1.94(m,1H),1.78-1.55(m,4H),1.32(s,9H).MS(ESI)m / z:420.2[M+1]+.

[0374] Step 6: Preparation of tert-butyl 4-((1r,3r)-3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0375] The title compound was prepared in a similar manner to Step 10 of Example 23. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1 to dichloromethane:methanol=20:1) to give the title product as a pale yellow oil (600 mg, 0.89 mmol, 53% yield). MS (ESI) m / z: 673.3 [M+1]+.

[0376] Step 7: Preparation of 3-(6-fluoro-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0377] The title compound was prepared in the same manner as in Step 11 of Example 23. The crude product was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 2% to 32%, 7 min) to give the title product as a white solid (200 mg, 0.33 mmol, 56% yield, trifluoroacetate salt). MS (ESI) m / z: 613.2 [M+1]+.

[0378] Step 8: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0379] The title compound was prepared in the same manner as in Step 12 of Example 23. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 11% to 41%, 10 min) to give the title product as a white solid (77.4 mg, 25% yield). NMR(400MHz,DMSO-d6)δ:11.00(s,1H),8.83(s,1H),8.16(s,1H),8.05(s,1H),7.99-7.90(m,2H),7.69(s,2H),7.62(d,J=6.0Hz,1H),7.50-7 .43(m,1H),7.03(s,1H),5.64-5.18(m,1H),5.16-5.05(m,1H),4.61-4 .50(m,2H),4.47-4.39(m,1H),4.33-4.26(m,1H),4.22-4.16(m,1H),4 .15-4.07(m,2H),3.57-3.50(m,1H),3.24(t,J=10.4Hz,2H),3.02(d,J=10.4Hz,2H),2.94-2.86(m,2H),2.68(d,J=4.8Hz,3H),2.64-2.58(m, 2H),2.42-2.36(m,2H),2.21-2.14(m,2H),2.03-1.98(m,2H),1.86-1. 79(m,4H),1.77-1.69(m,4H),1.57(d,J=6.8Hz,6H),1.43-1.34(m,2H).

[0380] Example 25: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 81)

[0381] Step 1: Preparation of 4-bromo-3-fluoro-2-methyl-benzoic acid [ka]

[0382] To a solution of 4-bromo-3-fluorobenzoic acid (20.00 g, 91.32 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) was added lithium triisopropylamide (2 M, 96.0 mL, 2.10 equiv) at -70 °C. The mixture was stirred at -70 °C for 1 hour. Iodomethane (38.89 g, 273.96 mmol, 17.1 mL, 3.00 equiv) was then added at -70 °C. The mixture was then warmed to 20 °C, and the mixture was stirred at 20 °C for 12 hours. The mixture was quenched with saturated ammonium chloride solution (400 mL) and extracted with ethyl acetate (400 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give 4-bromo-3-fluoro-2-methyl-benzoic acid (16.00 g, 68.66 mmol, 75% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.55-7.47 (m, 1H), 7.46-7.36 (m, 1H), 2.42 (d, J = 2.0 Hz, 3H).

[0383] Step 2: Preparation of methyl 4-bromo-3-fluoro-2-methyl-benzoate [ka]

[0384] To a solution of 4-bromo-3-fluoro-2-methyl-benzoic acid (14.00 g, 60.08 mmol, 1.00 equiv.) in methanol (100 mL) was added thionyl chloride (42.88 g, 360.46 mmol, 26.1 mL, 6.00 equiv.) at 20 °C, and the mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated sodium bicarbonate solution (1000 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give methyl 4-bromo-3-fluoro-2-methyl-benzoate (6.00 g, 24.09 mmol, 40% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ:7.58-7.52(m,1H),7.45-7.39(m,1H),3.90(s,3H),2.53(d,J=2.6Hz,3H).

[0385] Step 3: Preparation of methyl 4-bromo-2-(bromomethyl)-3-fluoro-benzoate [ka]

[0386] To a solution of methyl 4-bromo-3-fluoro-2-methylbenzoate (6.20 g, 25.10 mmol, 1.00 equiv.) in dichloroethane (70 mL), N-bromosuccinimide (4.91 g, 27.60 mmol, 1.10 equiv.) and 2,2-azobisisobutyronitrile (412.09 mg, 2.51 mmol, 0.10 equiv.) were added at 20 °C, and the mixture was heated to 80 °C. The mixture was stirred at 80 °C for 6 hours. The mixture was filtered, and the filtrate was diluted with saturated sodium thiosulfate solution (100 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with water (100 mL × 2), brine (100 mL), dried over sodium sulfate, and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 30:1 to 20:1) to give 4-bromo-2-(bromomethyl)-3-fluorobenzoic acid metiru (7.00 g, 21.48 mmol, 86% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.71-7.62 (m, 1H), 7.62-7.51 (m, 1H), 5.00 (s, 2H), 3.96 (s, 3H).

[0387] Steps 4-9: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0388] Example 25 was prepared similarly to Example 24, following steps 3-8 using the material prepared in step 3 of this example. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 min) to give the title product as a white solid (83.5 mg, 22% yield, formate salt). NMR(400MHz,DMSO-d6)δ:11.00(s,1H),8.83(s,1H),8.18(s,1H),8.04(s,1H),7.99-7.91(m,2H),7.69(s,2H),7.61-7.47(m,2H),7.03(s ,1H),5.58-5.15(m,1H),5.11(dd,J=5.2,13.2Hz,1H),4.59-4.50(m,3H),4.37(d,J=17.4Hz,1H),4.24-4.06(m,3H),3.56-3.51(m,1H),3. 24(t,J=10.4Hz,2H),3.01(d,J=10.0Hz,2H),2.97-2.82(m,3H),2.68(d,J=4.8Hz,3H),2.60(d,J=16.0Hz,1H),2.46-2.39(m,1H),2.21-2 .13(m,2H),2.05-1.96(m,3H),1.87-1.79(m,4H),1.78-1.69(m,4H),1.57(d,J=6.8Hz,6H),1.43-1.34(m,2H).MS(ESI)m / z:748.2[M+1]+.

[0389] Example 26: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 103)

[0390] Step 1: Preparation of tert-butyl 4-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0391] To a solution of methyl 2-cyano-6-methoxy-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyl)benzoate (4 g, 8.45 mmol, 1 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.87 g, 9.30 mmol, 1.1 equiv.) in dioxane (40 mL) and water (8 mL), cesium fluoride (3.21 g, 21.13 mmol, 2.5 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (618 mg, 0.84 mmol, 0.1 equiv.) were added under nitrogen. The reaction mixture was stirred at 80 °C for 6 h. Water (100 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give the title product as a yellow solid (2.9 g, 7.79 mmol, 92% yield). 1HNMR(400MHz,CDCl3)δ:7.21(s,1H),7.06(s,1H),6.09(br s,1H),4.09-4.02(m,2H),3.91(s,3H),3.85(s,3H),3.58(br t,J=5.6Hz,2H),2.43(br s,2H),1.42(s,9H).MS(ESI)m / z:373.1[M+1]+.

[0392] Step 2: Preparation of tert-butyl 4-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate [ka]

[0393] To a solution of tert-butyl 4-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.9 g, 7.79 mmol, 1 equiv.) in tetrahydrofuran (20 mL) and ethanol (60 mL) was added palladium-on-charcoal catalyst (300 mg, 10% purity) under nitrogen. The reaction mixture was stirred under hydrogen (50 psi) at 30°C for 12 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The desired product was obtained as a yellow oil (2.8 g, 7.48 mmol, 96% yield). MS (ESI) m / z: 375.1 [M+1]+.

[0394] Step 3: Preparation of methyl 2-cyano-6-methoxy-4-(piperidin-4-yl)benzoate [ka]

[0395] To a solution of tert-butyl 4-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate (2.3 g, 6.14 mmol, 1 equiv.) in dichloromethane (20 mL) was added trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL, 10.99 equiv.). The reaction mixture was stirred at 20 °C for 1 hour. The mixture was concentrated in vacuo. Methyl 2-cyano-6-methoxy-4-(piperidin-4-yl)benzoate (2.3 g, 5.92 mmol, 96% yield, trifluoroacetate salt) was obtained as a yellow oil. MS (ESI) m / z: 275.4 [M+1]+.

[0396] Step 4: Preparation of 2-trimethylsilylethyl 4-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate [ka]

[0397] To a solution of methyl 2-cyano-6-methoxy-4-(4-piperidyl)benzoate (2.3 g, 5.92 mmol, 1 equiv., trifluoroacetate salt) in tetrahydrofuran (20 mL) and water (20 mL) was added sodium bicarbonate (2.49 g, 29.61 mmol, 5 equiv.) and (2,5-dioxopyrrolidin-1-yl)2-trimethylsilylethyl carbonate (1.84 g, 7.11 mmol, 1.2 equiv.). The reaction mixture was stirred at 20 °C for 12 h. Water (20 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1). The desired product was obtained as a light yellow oil (1.3 g, 3.11 mmol, 52% yield). δ:7.14(s,1H),7.00(s,1H),4.34(br d,J=12.0Hz,2H),4.25-4.18(m,2H),3.98(s,3H),3.90(s,3H),2.86(br t,J=12.4Hz,2H),2.73(tt,J=3.6,12.0Hz,1H),1.85(br d,J=12.8Hz,2H),1.64-1.56(m,2H),1.12-0.99(m,2H),0.06(s,9H)

[0398] Step 5: Preparation of 2-trimethylsilylethyl 4-(3-formyl-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate [ka]

[0399] To a solution of 2-trimethylsilylethyl 4-(3-cyano-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate (1.3 g, 3.11 mmol, 1 equiv.) in pyridine (10 mL), ethyl acetate (5 mL), and water (4 mL) was added sodium dihydrogen phosphate hydrate (2.14 g, 15.53 mmol, 5 equiv.) and Raney-Ni (266 mg, 3.11 mmol, 1 equiv.). The reaction mixture was stirred at 50° C. for 2 hours under nitrogen. The mixture was filtered, and the filtrate was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 2-Trimethylsilylethyl 4-(3-formyl-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate (1.3 g, crude) was obtained as a yellow oil. MS(ESI) m / z: 444.1 [M+23]+.

[0400] Step 6: Preparation of 2-trimethylsilylethyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperidine-1-carboxylate [ka]

[0401] To a solution of 2-trimethylsilylethyl 4-(3-formyl-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate (1.3 g, 3.08 mmol, 1 equiv.) and tert-butyl 4,5-diamino-5-oxo-pentanoate (624 mg, 3.08 mmol, 1 equiv.) in methanol (10 mL) and 1,2-dichloroethane (10 mL), acetic acid (185 mg, 3.08 mmol, 1 equiv.) was added and the mixture was stirred at 40 °C for 0.5 h. Sodium cyanoborohydride (387 mg, 6.17 mmol, 2 equiv.) was then added and the reaction mixture was stirred at 40 °C for 11.5 h. Water (50 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1 to 0:1) to give the desired product (660 mg, 1.09 mmol, 35% yield, 95% purity) as a light yellow solid. 1HNMR(400MHz,CDCl3)δ:6.91(s,1H),6.78-6.63(m,2H),5.71(br s,1H),4.81(br t,J=7.2Hz,1H),4.54-4.45(m,1H),4.42-4.27(m,3H),4.25-4.18(m,2H),3.96(s,3H),2.95-2.70(m,3H),2.38-2.05(m,5H),1.85(br d,J=11.6Hz,2H),1.64(br d,J=11.2Hz,2H),1.39(s,9H),1.07-0.99(m,2H),0.05(s,9H). MS(ESI) m / z: 576.4 [M+1]+.

[0402] Step 7: Preparation of tert-butyl 5-amino-4-[7-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate [ka]

[0403] 2-Trimethylsilylethyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperidine-1-carboxylate (660 mg, 1.15 mmol, 1 equiv.) in tetrabutylammonium fluoride (1 M, 3 mL, 2.62 equiv.) was added. The reaction mixture was stirred at 30 °C for 12 hours. Water (20 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 100:1 to 8:1) to give the title product as a yellow oil (400 mg, 0.92 mmol, 80% yield). MS(ESI)m / z:432.2[M+1]+

[0404] Steps 7-9: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0405] Example 26 was prepared in the same manner as Example 24 by steps 6 to 8 using tert-butyl 5-amino-4-[7-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 15% to 45%, 10 min) to give Example 26 as a yellow solid (36.5 mg, 4% yield, formate salt). 1H NMR(400MHz,DMSO-d6)δ:10.95(s,1H),8.85(s,1H),8.05(s,1H),7.96(s ,2H),7.70(s,2H),7.02(d,J=9.6Hz,2H),6.92(s,1H),5.56-5.52(m,1H), 5.02(dd,J=5.2,13.2Hz,1H),4.55(s,2H),4.37-4.29(m,1H),4.25-4.08 (m,4H),3.90-3.84(m,3H),3.59-3.40(m,1H),3.29-3.16(m,2H),3.07(br d,J=8.8Hz,2H),3.01-2.84(m,2H),2.71-2.53(m,4H),2.48-2.35(m,1H),2.33-2.32(m,1H),2.23-2.10(m,2H),2.04(br s, 2H), 2.00-1.89 (m, 2H), 1.89-1.68 (m, 7H), 1.58 (d, J=6.8Hz, 6H), 1.45-1.37 (m, 2H). MS(ESI)m / z:910.3[M+1]+.

[0406] Example 27: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 128)

[0407] Step 1: Preparation of 2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide [ka]

[0408] A mixture of 2-fluoro-5-methoxy-benzoic acid (1 g, 5.88 mmol, 1 equiv) and thionyl chloride (5 mL) was stirred at 85° C. for 1 hour. The mixture was then concentrated under reduced pressure to give a residue. The residue was dissolved in dichloromethane (15 mL), and then a solution of 2-amino-2-methyl-propan-1-ol (1.05 g, 11.76 mmol, 1.1 mL, 2 equiv) in dichloromethane (12 mL) was added at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate, filtered, and the filtrate was washed with 10% hydrogen chloride, water, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 1:1) to give the desired product as a yellow oil (1.35 g, 5.60 mmol, 95% yield).

[0409] Step 2: 2-(2-fluoro-5-methoxy-phenyl)-4,4-dimethyl-5H-oxazole [ka]

[0410] To a solution of 2-fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxy-benzamide (1.2 g, 4.97 mmol, 1 eq.) in dichloromethane (5 mL) was added thionyl chloride (2.38 g, 1.5 mL) at 0° C. The mixture was stirred at 25° C. for 20 minutes. TLC showed the reaction was complete. The reaction mixture was quenched by adding 50 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was used in the next step without further purification. The compound 2-(2-fluoro-5-methoxy-phenyl)-4,4-dimethyl-5H-oxazole (1.1 g, 4.93 mmol, 99% yield) was obtained as a white solid.

[0411] Step 3: 2-(6-fluoro-3-methoxy-2-methyl-phenyl)-4,4-dimethyl-5H-oxazole [ka]

[0412] To a solution of 2-(2-fluoro-5-methoxy-phenyl)-4,4-dimethyl-5H-oxazole (1 g, 4.48 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was added n-butyllithium (2.5 M, 2.3 mL, 1.3 equiv.) at −78° C. The mixture was stirred at −78° C. for 0.5 h. Then, methyl iodide (3.18 g, 22.40 mmol, 1.4 mL, 5 equiv.) was added at −78° C., and the mixture was stirred at −78° C. for 20 min. The reaction mixture was quenched by adding 100 mL of hydrogen chloride (4 N) and then extracted with ethyl acetate (100 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 mm * 70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 10% to 45%, 20 min). The compound 2-(6-fluoro-3-methoxy-2-methyl-phenyl)-4,4-dimethyl-5H-oxazole (530 mg, 2.23 mmol, 50% yield) was obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 7.28-7.08 (m, 2H), 4.07 (s, 2H), 3.79 (s, 3H), 2.13 (s, 3H), 1.30 (s, 6H). MS (ESI) m / z: 237.9 [M+1]+

[0413] Step 4: Preparation of WX-ARV-DS-021L-4,6-fluoro-3-methoxy-2-methyl-benzoic acid [ka]

[0414] To a solution of 2-(6-fluoro-3-methoxy-2-methyl-phenyl)-4,4-dimethyl-5H-oxazole (10 g, 42.15 mmol, 1 equiv.) in acetone (50 mL) was added potassium carbonate (17.47 g, 126.44 mmol, 3 equiv.) and methyl iodide (59.82 g, 421.46 mmol, 26.2 mL, 10 equiv.). The mixture was stirred at 25° C. for 15 hours. The mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in methanol (50 mL) and a 1N aqueous solution of sodium hydroxide (200 mL). The mixture was stirred at 75° C. for 3 hours. The reaction mixture was quenched by adding 100 mL of 6N hydrogen chloride and then extracted with ethyl acetate (100 mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was used in the next step without further purification. The compound 6-fluoro-3-methoxy-2-methyl-benzoic acid (5.1 g, 27.69 mmol, 66% yield) was obtained as a white solid. H NMR (400 MHz, CDCl) δ: 7.08-6.81 (m, 2H), 3.91 (s, 1H), 3.86 (s, 2H), 2.36 (s, 3H). (ESI) m / z: 185.1 [M+1]+.

[0415] Step 5: Preparation of methyl 6-fluoro-3-methoxy-2-methyl-benzoate [ka]

[0416] To a solution of 6-fluoro-3-methoxy-2-methylbenzoic acid (8.5 g, 46.15 mmol, 1 equiv.) in N,N-dimethylformamide (2 mL) was added potassium carbonate (19.14 g, 138.46 mmol, 3 equiv.) and methyl iodide (19.65 g, 138.46 mmol, 8.6 mL, 3 equiv.). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with 500 mL of saturated ammonium chloride solution and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50:1 to 20:1) to give the desired product as a colorless oil (7.6 g, 38.35 mmol, 83% yield). 1HNMR (400MHz, CDCl3) δ:7.02-6.78(m,2H),3.96(s,3H),3.83(s,3H),2.23(s,3H).

[0417] Step 6: Preparation of methyl 4-bromo-6-fluoro-3-methoxy-2-methyl-benzoate [ka]

[0418] To a solution of methyl 6-fluoro-3-methoxy-2-methylbenzoate (1.9 g, 9.59 mmol, 1 equiv.) in N,N-dimethylformamide (20 mL) was added n-bromosuccinimide (1.71 g, 9.59 mmol, 1 equiv.) at 0 °C. The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with 100 mL of saturated sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20:1) to give the desired product as a yellow oil (0.9 g, 3.25 mmol, 17% yield). MS (ESI) m / z: 279.0 [M+1]+.

[0419] Step 7: Preparation of methyl 4-bromo-2-(bromomethyl)-6-fluoro-3-methoxy-benzoate [ka]

[0420] To a solution of methyl 4-bromo-6-fluoro-3-methoxy-2-methylbenzoate (200 mg, 0.72 mmol, 1 equiv.) in perbromomethane (3 mL), n-bromosuccinimide (167 mg, 0.94 mmol, 1.3 equiv.) and azobisisobutyronitrile (50 mg, 0.29 mmol, 0.4 equiv.) were added. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was diluted with 100 mL of saturated sodium bicarbonate and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative TLC (20% ethyl acetate in petroleum ether) to give the desired product as a yellow oil (150 mg, 0.42 mmol, 58% yield). 1HNMR (400MHz, CDCl3) δ: 7.28 (d, J = 8.4 Hz, 1H), 4.69 (s, 2H), 3.90 (d, J = 7.6Hz, 6H).

[0421] Steps 8-13: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-4-methoxy-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0422] Example 27 was prepared similarly to Example 24 following steps 3-8 using the material prepared in step 7 of this example. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10 min) to give the desired product as an off-white solid (50.1 mg, 0.05 mmol, 30% yield, formate salt). 1HNMR(400MHz,DMSO-d6)δ:11.01(s,1H),8.84(s,1H),8.25(s,1H),8.05(s,1H),8.00-7.89(m,2H),7.70(s,2H),7.21(br d,J=10.4Hz,1H),7.03(s,1H),5.33(br s,1H),5.07(br dd,J=4.8,13.2Hz,1H),4.64-4.51(m,3H),4.42(br d,J=17.6Hz,1H),4.23-4.06(m,3H),3.84(s,3H),3.54(br s,1H),3.29-3.24(m,1H),3.04-2.80(m,6H),2.69(d,J=4.8Hz,3H),2.62(br s,2H),2.40(br s,1H),2.21-2.10(m,2H),2.01(br d,J=7.2Hz,3H),1.89-1.77(m,3H),1.73-1.65(m,4H),1.58(d,J=6.8Hz,6H),1.46-1.36(m,2H). MS(ESI)m / z:928.4[M+1]+.

[0423] The following examples were made using methods similar to those described in Examples 22-27: [ka]

[0424] Example 30: 2-((6-((5-chloro-2-(4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide, and and 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (Compound 118).

[0425] Step 1: Preparation of dimethyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,2-dicarboxylate [ka]

[0426] A mixture of dimethyl 4-bromobenzene-1,2-dicarboxylate (5 g, 18.31 mmol, 1 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.79 g, 21.97 mmol, 1.2 equiv.), ditert-butyl(cyclopentyl)phosphane, dichloropalladium, iron (1 g, 1.53 mmol, 8.38 e-2 equiv.), and cesium fluoride (8.34 g, 54.93 mmol, 3 equiv.) in dioxane (50 mL) and water (5 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction mixture was filtered, diluted with 400 mL of water, and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give the desired product as a yellow solid (6 g, 15.98 mmol, 87% yield). MS (ESI) m / z: 376.4 [M+1]+.

[0427] Step 2: Preparation of dimethyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)phthalate and dimethyl 4-((3S,4S)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)phthalate [ka]

[0428] To a solution of dimethyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,2-dicarboxylate (3.3 g, 8.79 mmol, 1 equiv.) in tetrahydrofuran (30 mL), boron methylsulfanylmethane (10 M, 1.9 mL, 2.2 equiv.) was added dropwise at 0°C. The mixture was stirred at 25°C for 2 hours. Then, an aqueous solution (20 mL) of sodium 3-oxidedioxaborilane tetrahydrate (4.06 g, 26.37 mmol, 5.1 mL, 3 equiv.) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with saturated sodium sulfite solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). The desired product was isolated as a yellow oil containing a mixture of trans isomers (2.8 g, 7.12 mmol, 81% yield). 1NMR(400MHz,CDCl3)δ:7.74(d,J=8.0Hz,1H),7.61(s,1H),7.44(d,J=8.0Hz,1H),4.50-4.35(m,1H),4.27-4.17(m,1H),3.91 (d,J=3.2Hz,6H),3.80-3.67(m,1H),2.85-2.71(m,1H),2.70-2.60(m,2H),1.88-1.77(m,1H),1.65-1.60(m,1H),1.49(s,9H).

[0429] Step 3: Preparation of dimethyl 4-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)phthalate and dimethyl 4-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)phthalate [ka]

[0430] To a solution of dimethyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)phthalate and dimethyl 4-((3S,4S)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)phthalate (2.3 g, 5.85 mmol, 1 equiv.) in dichloromethane (40 mL), 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethanamine (1.94 g, 8.77 mmol, 1.9 mL, 1.5 equiv.) was added dropwise at −78° C., and the mixture was stirred for 2 hours at 25° C. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give the desired product as a yellow oil containing a mixture of cis isomers (1.8 g, 4.55 mmol, 78% yield). 1HNMR(400MHz,DMSO-d6)δ:7.73(d,J=8.0Hz,1H),7.61(s,1H),7.47-7.40(m,1H),4.70-4.40(m,2H),4.30 -4.15(m,1H),3.92(d,J=3.6Hz,6H),3.00-2.70(m,3H),1.95-1.85(m,1H),1.84-1.70(m,1H),1.49(s,9H). MS(ESI)m / z:418.2[M+23]+.

[0431] Step 4: Preparation of dimethyl 4-((3S,4R)-3-fluoropiperidin-4-yl)phthalate and dimethyl 4-((3R,4S)-3-fluoropiperidin-4-yl)phthalate [ka]

[0432] To a solution of dimethyl 4-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)phthalate and dimethyl 4-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)phthalate (4.00 g, 10.12 mmol, 1 equiv.) in dichloromethane (20 mL), trifluoroacetic acid (30.80 g, 270.13 mmol, 20 mL, 26.70 equiv.) was added, and the mixture was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated in vacuo, and the residue was quenched with saturated sodium bicarbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The desired product mixture was obtained as a yellow oil (2.5 g, 8.47 mmol, 84% yield). MS (ESI) m / z: 296.2 [M+1]+.

[0433] Step 5: Preparation of dimethyl 4-((3S,4R)-1-((1r,3S)-3-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)cyclobutyl)-3-fluoropiperidin-4-yl)phthalate and dimethyl 4-((3R,4S)-1-((1r,3R)-3-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)cyclobutyl)-3-fluoropiperidin-4-yl)phthalate [ka]

[0434] A solution of tert-butyl 4-[3-(trifluoromethylsulfonyloxy)cyclobutoxy]piperidine-1-carboxylate (2.66 g, 6.60 mmol, 1.3 equiv.), dimethyl 4-((3S,4R)-3-fluoropiperidin-4-yl)phthalate, and dimethyl 4-((3R,4S)-3-fluoropiperidin-4-yl)phthalate (1.50 g, 5.08 mmol, 1 equiv.), and N,N-diisopropylethylamine (1.97 g, 15.24 mmol, 2.7 mL, 3 equiv.) in acetonitrile (20 mL) was stirred at 35° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give the desired product as a yellow oil (1.6 g, 2.92 mmol, 57% yield). MS(ESI) m / z: 571.2 [M+23]+.

[0435] Step 6: Preparation of tert-butyl 4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0436] To a pyridine solution (10 mL) of dimethyl 4-((3S,4R)-1-((1r,3S)-3-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)cyclobutyl)-3-fluoropiperidin-4-yl)phthalate, and dimethyl 4-((3R,4S)-1-((1r,3R)-3-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)cyclobutyl)-3-fluoropiperidin-4-yl)phthalate (700 mg, 1.28 mmol, 1 equivalent), 3-aminopiperidine-2,6-dione hydrochloride (420 mg, 2.55 mmol, 2 equivalents), lithium iodide (1.37 g, 10.21 mmol, 8 equivalents) was added at 25° C., and the mixture was then stirred at 130° C. for 12 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give the desired product as a yellow oil (500 mg, 0.82 mmol, 64% yield). MS (ESI) m / z: 613.3 [M+1]+.

[0437] Steps 7 and 8: 2-((6-((5-chloro-2-(4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamine and 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide [ka]

[0438] Example 30 was prepared similarly to Example 24 following steps 7-8 using the material prepared in step 6 of this example. The crude product was purified by preparative HPLC (Column: Phenomenex Synergi C18 150*25mm*10um; Mobile phase: [water (0.225% FA)-ACN]; B%: 13%-43%, 10 min) to give the desired product as an off-white solid (40.9 mg, 0.04 mmol, 31% yield, 95% purity). 1HNMR(400MHz,DMSO-d6)δ:11.29(s,1H),8.84(s,1H),8.06(s,1H),7.98-7.92(m,2H),7.91-7.88(m,1H), 7.87-7.83(m,2H),7.72-7.62(m,2H),7.02(s,1H),5.60-5.10(m,2H),5.00-4.70(m,1H)4.54(s,2H),4.22 -4.05(m,3H),3.60-3.45(m,1H),3.25-3.20(m,1H),3.05-2.80(m,4H),2.67(d,J=4.8Hz,3H),2.64-2.56( m,2H),2.25-2.13(m,2H),2.10-1.96(m,4H),1.92-1.69(m,7H),1.57(d,J=6.8Hz,6H),1.42-1.31(m,2H). MS(ESI)m / z:912.5[M]+.

[0439] Example 31: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3,3-difluoropiperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 137)

[0440] Step 1: Preparation of dimethyl 4-(1-tert-butoxycarbonyl-3-oxo-4-piperidyl)benzene-1,2-dicarboxylate [ka]

[0441] To a solution of dimethyl 4-(1-tert-butoxycarbonyl-3-hydroxy-4-piperidyl)benzene-1,2-dicarboxylate (2 g, 5.08 mmol, 1 equiv.) in dichloromethane (40 mL) was added Dess-Martin reagent (3.23 g, 7.63 mmol, 1.5 equiv.) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1 to 1 / 1) to give dimethyl 4-(1-tert-butoxycarbonyl-3-oxo-4-piperidyl)benzene-1,2-dicarboxylate (1.4 g, 3.58 mmol, 70% yield) as a yellow oil. 1HNMR(400MHz,CDCl3)δ:7.74(d,J=8.0Hz,1H),7.52-7.48(m,1H),7.35-7.30(m,1H),4.32-4.22(m,1H),4.1 0-3.98(m,2H),3.91(d,J=1.6Hz,6H),3.77-3.68(m,1H),3.59-3.50(m,1H),2.38-2.17(m,2H),1.49(s,9H). MS(ESI)m / z:336.1[M-55]+.

[0442] Step 2: Preparation of dimethyl 4-(1-tert-butoxycarbonyl-3,3-difluoro-4-piperidyl)benzene-1,2-dicarboxylate [ka]

[0443] To a solution of dimethyl 4-(1-tert-butoxycarbonyl-3-oxo-4-piperidyl)benzene-1,2-dicarboxylate (1.40 g, 3.58 mmol, 1 equiv.) in dichloromethane (40 mL), 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethanamine (1.98 g, 8.94 mmol, 2.0 mL, 2.5 equiv.) was added dropwise at −78° C., and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10um; mobile phase: [hexane-EtOH (0.1% FA)]; B%: 1% to 30%, 15 min) to give the desired product as a yellow oil (650 mg, 1.57 mmol, 44% yield). 1HNMR(400MHz,CDCl3)δ:7.73(d,J=8.0Hz,1H),7.67(s,1H),7.50(d,J=7.6Hz,1H),4.38-4.25(m,2H), 3.92(s,6H),3.20-3.10(m,1H),3.05-2.70(m,2H),2.30-2.10(m,1H),1.95-1.80(m,1H),1.49(s,9H). MS(ESI)m / z:436.3[M+23]+.

[0444] Steps 4 to 8: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-3,3-difluoropiperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0445] Example 31 was prepared in the same manner as Example 30 by replacing dimethyl 4-(1-tert-butoxycarbonyl-3,3-difluoro-4-piperidyl)benzene-1,2-dicarboxylate (prepared in Step 2 of this Example) with dimethyl 4-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)phthalate in Step 4 of Example 30 and dimethyl 4-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)phthalate. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 25%~55%, 10 min) to give the desired product as a white solid (19.3 mg, 0.02 mmol, yield 14%, purity 100%). 1HNMR(400MHz,DMSO-d6)δ:11.12(s,1H),8.84(s,1H),8.04(s,1H),7.98-7.92(m,3H),7.86-7.80(m,2H) ,7.69(s,2H),7.02(s,1H),5.70-5.23(m,1H),5.20-5.10(m,1H),4.54(s,2H),4.25-4.05(m,3H),3.60-3 .40(m,2H),3.25-3.14(m,3H),3.07-2.97(m,2H),2.95-2.82(m,1H),2.67(d,J=4.8Hz,3H),2.64-2.56(m ,1H),2.28-2.09(m,5H),2.08-1.96(m,4H),1.91-1.77(m,3H),1.57(d,J=6.8Hz,6H),1.45-1.31(m,2H). MS(ESI)m / z:930.6[M]+.

[0446] Example 32: 2-((6-((5-chloro-2-(4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide, and and 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (Compound 131).

[0447] Step 1: Preparation of tert-butyl 3-(5-(3-fluoro-1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-3-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-(3-fluoro-1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-hydroxy-3-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0448] To a solution of tert-butyl 4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate (Example 30, Step 6; 450 mg, 0.73 mmol, 1 equiv.) in acetic acid (10 mL) was added powdered zinc (816 mg, 12.49 mmol, 17 equiv.). The mixture was stirred at 90°C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (500 mL), and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The desired product mixture was obtained as a yellow oil (400 mg, 0.6 mmol, 88% yield). MS (ESI) m / z: 615.2 [M+1]+.

[0449] Step 2: Preparation of 3-(5-((cis)-3-fluoro-1-((1r,3s)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-((cis)-3-fluoro-1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0450] To a solution of the product from Example 32, Step 1 (400 mg, 0.64 mmol, 1 equiv.) in dichloromethane (5 mL), triethylsilane (378 mg, 3.25 mmol, 5 equiv.) and trifluoroacetic acid (1.48 g, 13.01 mmol, 1.0 mL, 20 equiv.) were added at 0° C., and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 8%-38%, 10 min), and two impure fractions were isolated. Fraction 1: 3-[5-[3-fluoro-1-[3-(4-piperidyloxy)cyclobutyl]-4-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (150 mg, 0.30 mmol, 46% yield, Rt = 0.233 min, also containing the second peak) was obtained as a yellow oil. Fraction 2: 3-[6-[3-fluoro-1-[3-(4-piperidyloxy)cyclobutyl]-4-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (150 mg, 0.30 mmol, 46% yield, Rt = 0.317 min, also containing peak 1) was obtained as a yellow oil. MS (ESI) m / z: 499.3 [M+1]+.

[0451] Step 3: Preparation of tert-butyl 4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0452] To a solution of fraction 1 (150 mg, 0.30 mmol, 1 equiv) from step 2 and triethylamine (91 mg, 0.90 mmol, 0.1 mL, 3 equiv) in dichloromethane (5 mL) was added tert-butyl(2-methylpropan-2-yl)oxycarbonyl carbonate (131 mg, 0.60 mmol, 0.1 mL, 2 equiv) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane / methanol = 15 / 1) to give the desired product as a white solid. 1HNMR(400MHz,CDCl3)δ:8.00(s,1H),7.90-7.80(m,1H),7.45-7.35(m,2H),5.27-5.17(m,1H ),4.85-4.60(m,1H),4.55-4.45(m,1H),4.40-4.30(m,1H),4.25-4.15(m,1H),3.90-3.75(m,2 H),3.50-3.40(m,1H)3.39-3.30(m,1H),3.10-2.95(m,4H),2.90-2.70(m,3H),2.45-2.30(m, 1H), 2.25-2.10 (m, 5H), 1.97-1.80 (m, 5H), 1.67-1.55 (m, 2H), 1.54-1.47 (m, 2H), 1.45 (s, 9H). MS(ESI)m / z:599.3[M+1]+.

[0453] Step 4: Preparation of 3-(5-((3S,4R)-3-fluoro-1-((1r,3S)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(5-((3R,4S)-3-fluoro-1-((1r,3R)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0454] To a solution of tert-butyl 4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3-fluoro-1-piperidyl]cyclobutoxy]piperidine-1-carboxylate (100 mg, 0.17 μmol, 1.0 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (3.85 g, 33.74 mmol, 2.5 mL, 202.02 equiv), and the mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give the crude desired product as a yellow oil (80 mg, 0.16 mmol, 96% yield). MS (ESI) m / z: 499.3 [M+1]+.

[0455] Step 5: 2-((6-((5-chloro-2-(4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide, and preparation of 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide [ka]

[0456] Example 32 was prepared similarly to step 12 of Example 23. The crude product was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [water (0.225% FA)-ACN]; B%: 17%-47%, 10 min) to give the desired product as an off-white solid (56.6 mg, 0.06 mmol, yield 38%, purity 98%). 1HNMR(400MHz,DMSO-d6)δ:10.98(s,1H),8.04(s,1H),7.98-7.92(m,2H),7.71-7.62(m,3H),7.60-7.54(m,1H),7.50-7.42(m, 1H),7.02(s,1H),5.57-5.25(m,1H),5.15-5.05(m,1H),4.88-4.65(m,1H),4.54(s,2H),4.48-4.40(m,1H),4.35-4.25(m,1H),4 .22-4.07(m,3H),3.58-3.50(m,1H),3.26-3.18(m,1H),3.00-2.80(s,4H),2.67(d,J=4.8Hz,3H),2.63-2.53(m,1H),2.45-2.3 0(m,3H),2.25-2.15(m,2H),2.05-1.95(m,3H),1.90-1.80(m,5H),1.77-1.67(m,1H),1.57(d,J=6.8Hz,6H),1.45-1.31(m,2H). MS(ESI)m / z:898.4[M]+.

[0457] Example 33: 2-((6-((5-chloro-2-(4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide, and and 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide (Compound 132).

[0458] Step 1: Preparation of tert-butyl 4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3-fluoropiperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0459] To a solution of Fraction 2 from Step 2 of Example 32 (150 mg, 0.30 mmol, 1 equiv.) and triethylamine (91 mg, 0.90 mmol, 3 equiv.) in dichloromethane (5 mL), tert-butyl(2-methylpropan-2-yl)oxycarbonyl carbonate (131 mg, 0.60 mmol, 2 equiv.) was added at 25° C., and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methanol=15:1, Rf=0.43) to give the desired product as a white solid (110 mg, 0.18 mmol, 61% yield). 1HNMR(400MHz,CDCl3)δ:8.00(s,1H),7.90-7.80(m,1H),7.55-7.35(m,2H),5.25-5.20(m,1H ),4.82-4.57(m,1H),4.55-4.45(m,1H),4.40-4.30(m,1H),4.25-4.15(m,1H),3.90-3.75(m,2 H),3.50-3.40(m,1H)3.39-3.30(m,1H),3.10-2.95(m,4H),2.90-2.70(m,3H),2.45-2.30(m, 1H), 2.25-2.10 (m, 5H), 1.97-1.80 (m, 5H), 1.67-1.55 (m, 2H), 1.54-1.47 (m, 2H), 1.45 (s, 9H). MS(ESI)m / z:599.3[M+1]+.

[0460] Steps 2-3: Preparation of 3-(6-((3S,4R)-3-fluoro-1-((1r,3S)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and 3-(6-((3R,4S)-3-fluoro-1-((1r,3R)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0461] Example 33 was prepared similarly to steps 4 and 5 of Example 32. The crude product was purified by preparative HPLC {Column: Unisil 3-100 C18 Ultra 150*50mm*3um; Mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10 min} to give the desired product as an off-white solid (52.2 mg, 54.17 umol, 38.58% yield, 98% purity, formate salt). 1HNMR(400MHz,DMSO-d6)δ:11.05(s,1H),8.81(s,1H),8.23(s,1H),8.04(s,1H),7.98-7.92(m,2H),7.71-7.66(m,2H),7.65-7.4 5(m,3H),7.03(s,1H),5.57-5.25(m,1H),5.15-5.05(m,1H),4.88-4....

Claims

1. A compound of the following formula: 【Chemistry 101】

2. A pharma- ceutically acceptable salt of a compound of the formula: 【Chemistry 102】

3. A pharmaceutical composition comprising an effective amount of a compound described in claim 1 or a pharma- ceutically acceptable salt described in claim 2, and a pharma- ceutically acceptable carrier.

4. The composition of claim 3 , wherein the pharmaceutical composition further comprises at least one additional bioactive agent.

5. The composition of claim 4 , wherein the additional bioactive agent is an anti-cancer agent.

6. 10. A pharmaceutical composition comprising a pharma- ceutical carrier and an effective amount of a compound of claim 1 or a pharma- ceutical acceptable salt of claim 2 for use in treating a disease or disorder in a subject, wherein the disease or disorder is associated with aberrant BCL6 expression and / or activity.

7. The pharmaceutical composition of claim 6, wherein the disease or disorder is a cancer associated with aberrant BCL6 expression and / or activity.

8. The disease or disorder is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral epithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, myeloma, leukemia, leukemia, leukemia, leukemia, leukemia, The pharmaceutical composition according to claim 6, wherein the cancer is selected from the group consisting of membranous sarcoma, neurofibroma, and neurilemmoma, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratocarcinoma, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

9. 7. The pharmaceutical composition of claim 6, wherein the disease or disorder is lymphoma, B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, large intravascular B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, or non-small cell lung cancer.

10. The pharmaceutical composition of claim 6, wherein the disease or disorder is lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, or follicular lymphoma.

11. The disease or disorder is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral epithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, myeloma, leukemia, leukemia, leukemia, leukemia, leukemia, The pharmaceutical composition according to claim 7, wherein the cancer is selected from the group consisting of membranous sarcoma, neurofibroma, and neurilemmoma, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratocarcinoma, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

12. 8. The pharmaceutical composition of claim 7, wherein the disease or disorder is lymphoma, B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, large intravascular B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, or non-small cell lung cancer.

13. The pharmaceutical composition of claim 7, wherein the disease or disorder is lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, or follicular lymphoma.

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