Regulators of BCL6 proteolysis and related uses

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

[0003]

[0001] Cross - Reference to Related Applications This disclosure claims priority and benefit to U.S. Provisional Application No. 63 / 175,678, filed April 16, 2021, entitled MODULATORS OF BCL6 PROTEOLYSIS AND ASSOCIATED METHODS OF USE, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Incorporation by Reference U.S. Patent Application No. 17 / 073,135, filed October 16, 2020; U.S. Patent Application No. 15 / 730,728, filed October 11, 2017, published as U.S. Patent Application Publication No. 2018 / 0099940; 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 hereby incorporated by reference in their entirety. Further, all references cited herein are hereby incorporated by reference in their entirety.

[0003] This disclosure provides bifunctional compounds comprising a target protein - binding moiety and an E3 ubiquitin ligase - binding moiety, as well as related methods of use. The bifunctional compounds are useful as regulators of target ubiquitination and as regulators such as B - cell lymphoma 6 protein (BCL6) that are degraded by and / or inhibited by other means by the bifunctional compounds according to the disclosure.

Background Art

[0004] Most small molecule drugs bind tightly to enzymes or receptors in clearly defined pockets. On the other hand, targeting protein-protein interactions using small molecules is well known to be difficult due to the large protein contact surface and the shallow groove-like or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) are even more attractive therapeutic targets than general proteasome inhibitors because they confer substrate specificity to ubiquitination and therefore have specificity for specific protein substrates. Developing ligands for E3 ligases has proven challenging in part due to the fact that it inevitably disrupts protein-protein interactions. However, recent developments have yielded specific ligands that bind to these ligases. For example, since the discovery of nathrin, the first small molecule E3 ligase inhibitor, further compounds targeting E3 ligases have been reported, although much of this field remains undeveloped.

[0005] Cereblon is a protein encoded by the CRBN gene in humans. The orthologs of CRBN are highly conserved from plants to humans, clearly indicating its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and cullin-1 regulator (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism not yet 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 ear vesicle formation. It has ultimately been concluded that this ubiquitin ligase complex is crucial for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

[0006] Difunctional compounds, such as those described in U.S. Patent Publications 2015-0291562 and 2014-0356322 (incorporated herein by reference), function to recruit and degrade endogenous proteins into E3 ubiquitin ligases. In particular, these publications describe difunctional or proteolytic targeting chimeric (PROTAC) compounds, which have been found to be useful as regulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or inhibited by other means by these difunctional compounds.

[0007] There is a continuing need in this field for effective treatments for diseases associated with (i) abnormal expression and / or activity of BCL6, and / or (ii) overexpression or aggregation of B-cell lymphoma 6 protein (BCL6). However, nonspecific action and the inability to target and modulate BCL6 remain obstacles to the development of effective therapies. Therefore, small molecule therapeutics that target BCL6 and utilize or enhance the substrate specificity of E3 ubiquitin ligases (e.g., cereblon) are of great value. [Overview of the Initiative]

[0008] This disclosure describes bifunctional compounds that function to recruit and degrade endogenous proteins into E3 ubiquitin ligases, and methods of using them. In particular, this disclosure provides bifunctional or proteolytic chimeric molecular compounds that have been found useful as regulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or inhibited by other means by the bifunctional compounds described herein. The advantages of the compounds provided herein are that they may have broad pharmacological activity and are compatible with the degradation / inhibition of target polypeptides derived from virtually all protein species or families. Furthermore, this specification provides methods for using effective amounts of the compounds described herein for the treatment or improvement of disease conditions such as cancer, including lymphoma, B-cell non-Hodgkin lymphoma, large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

[0009] Accordingly, in one embodiment, the disclosure provides a bifunctional compound comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for E3 ubiquitin ligase, or "ULM" group) and a target protein binding moiety (i.e., a protein / polypeptide targeting ligand, or "PTM" group), thereby positioning the target protein / polypeptide in close proximity to the ubiquitin ligase and exerting a degradation (and inhibition) effect on the protein. In a preferred embodiment, the ULM (ubiquitination ligase regulator) may be a cereblon E3 ubiquitin ligase binding moiety (CLM). For example, the structure of a bifunctional compound may be shown as follows. [ka]

[0010] The positions and numbers of the PTM and ULM moieties (e.g., CLM) exemplified herein are provided as examples only and are not intended to limit the compounds. As will be understood by those skilled in the art, the bifunctional compounds described herein can be synthesized such that the number and positions 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 may be shown as follows: [ka] In the formula, PTM is the protein / polypeptide targeting moiety, L is a linker, for example, a bond or chemical group that binds PTM to ULM, and ULM is the cereblon E3 ubiquitin ligase binding moiety (CLM).

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

[0013] In certain embodiments, the compounds described herein include a plurality of compounds independently selected from ULMs, 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, thioimide, amide, or thioamide. In a particular embodiment, the chemical group is a phthalimide group, or an analog or derivative thereof. In a particular embodiment, the CLM is thalidomide, lenalidomide, pomalidomide, its analog, its isoster, or a derivative thereof. Other anticipated CLMs include those described in U.S. Patent Application Publication No. 2015 / 0291562, which is incorporated herein by reference 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" may, but is not limited to, functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may include aromatic, aromatic heterocyclic, cyclic, bicyclic, and tricyclic parts. Substitutions with halogens such as Cl, F, Br, and I may be included in the linker. In the case of fluorine substitution, one or more fluorines may be included.

[0016] In certain embodiments, 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 CN bond or a CC bond. Examples of CLM include, but are not limited to, pomalidomide, lenalidomide, and thalidomide, and their derivatives.

[0017] In additional embodiments, this specification provides therapeutic compositions comprising an effective amount of a compound or a salt form thereof described herein and a pharmaceutically acceptable carrier. The therapeutic compositions can be used to modulate the degradation and / or inhibition of a protein in a patient or subject, such as an animal such as a human, and to treat or improve a pathological condition or state modulated by the degraded and / or inhibited protein. In certain embodiments, the therapeutic compositions described herein may be used to induce the degradation of a target protein for the purpose of treating or improving a disease, such as cancer. In yet another embodiment, this 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, comprising a PTM and a CLM, preferably bound via a linker moiety, as otherwise described herein, wherein the CLM is bound to the PTM via a linker to target a protein bound to the PTM, and degradation occurs. Similarly, the PTM may be bound to the CLM via a linker to target a protein or polypeptide, and degradation may occur. The degradation of a target protein occurs when that target protein is positioned in close proximity to an E3 ubiquitin ligase, thus resulting in the degradation / inhibition of the effect of the target protein and regulation of protein levels. The regulation of protein levels brought about by this disclosure provides a therapeutic effect on a pathological condition or state, which is regulated via the target protein by reducing its level in patient cells.

[0018] In yet another embodiment, this specification provides a method for treating or improving a disease, disorder or its symptoms in a subject or patient, such as an animal or human, the method comprising administering a composition to the subject in need of such treatment or improvement, in which case the composition is effective in treating or improving a disease or disorder or its symptoms in the subject.

[0019] In another aspect, the present specification provides a method for identifying the degradation effect of a target protein in a biological system using a compound according to the present disclosure.

[0020] The foregoing general description of the utility is presented for illustrative purposes only and is not intended to limit the present disclosure and the appended claims. Additional objects and advantages related to 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 explicitly contemplated herein. These additional aspects and embodiments are explicitly included within the scope of the present disclosure. The published documents and other materials used herein to explain the background of the present disclosure and, in certain cases, to provide additional details regarding implementation are incorporated by reference.

Brief Description of the Drawings

[0021] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate some embodiments of the present disclosure and serve to explain the principles of the present disclosure together with the description herein. The drawings are for the purpose of illustrating embodiments of the present disclosure only 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 in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure.

[0022] [Figure 1]Figures 1A and 1B. Diagrams of the general principles of the heterobifunctional degrading compounds of the present disclosure. (A) An exemplary heterobifunctional degrading compound includes a protein targeting moiety (PTM; darkly shaded rectangle), a ubiquitin ligase binding moiety (TLM; lightly shaded triangle), and an optional linker moiety (L; black line) that binds or connects the PTM to the ULM. (B) Illustrates the functional use of the heterobifunctional degrading compounds described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds to and recruits the target protein, bringing it into proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and catalyzes ubiquitin binding to lysine on the target protein via an isopeptide bond, either alone or through the E2 protein (dark circles). The polyubiquitinated protein (right end) is then targeted for degradation by the cell's proteasome machinery.

Modes for Carrying Out the Invention

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

[0024] This disclosure describes compositions and methods relating to the surprising and unexpected discovery that when an E3 ubiquitin ligase protein (e.g., cereblon E3 ubiquitin ligase) and a target protein are positioned in close proximity by a bifunctional or chimeric construct, and the E3 ubiquitin ligase binds to the target protein, the E3 ubiquitin ligase protein ubiquitinates the target protein. Accordingly, this disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety (ULM) bound to a protein target binding moiety (PTM), which result in ubiquitination of a selected target protein and subsequent degradation of the target protein by the proteasome (see Figures 1A and 1B). This disclosure also provides a library of compositions and their uses.

[0025] In certain embodiments, the Disclosure provides compounds comprising ligands such as low molecular weight ligands (i.e., having molecular weights less than 2,000, 1,000, 500, or 200 Daltons) that can bind to ubiquitin ligases such as cereblon. The compounds also include a moiety that can bind to the target protein in such a manner that it positions the target protein in close proximity to the ubiquitin ligase, resulting in the degradation (and / or inhibition) of the protein. In addition to the foregoing, low molecular weight may mean that the molecule is non-peptidyl; that is, it is not often considered a peptide, for example, containing fewer than 4, 3, or 2 amino acids. According to this Specification, PTMs, ULMs, or bifunctional degradation molecules may also be low molecular weight molecules.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art of the field to which this disclosure pertains. The technical terms used herein are for illustrative purposes only of specific embodiments and are not intended to limit this disclosure.

[0027] Where a range of values ​​is provided, unless otherwise explicitly stated by the context (for example, in the case of a group containing a certain number of carbon atoms, the number of carbon atoms that fall within that range is provided), it should be understood that each intervening value between that range and any other specified range, up to one-tenth of the lower limit unit, or intervening value within that specified range, is included within the scope of the invention. The upper and lower limits of these smaller ranges may independently be included within even smaller ranges, which are also included in this disclosure and constitute any specifically excluded boundary values ​​within a specified range. Where a specified range includes one or both of the boundary values, ranges excluding one or both of those included boundary values ​​are also included in this disclosure.

[0028] The following terms are used to describe this disclosure. If a term is not specifically defined herein, it shall be given the meaning that is known in the art to those skilled in the art to the extent that the term is used in describing this disclosure.

[0029] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) of the grammatical objects of the article, unless the context clearly indicates otherwise. For example, “element” means one or more elements.

[0030] When used herein in this specification and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements that are thus combined. That is, in some examples the elements exist together, and in other examples they exist separately. Multiple elements listed using “and / or” should be interpreted similarly; that is, “one or more” of the elements are thus combined. Other elements other than those specifically identified by the “and / or” clause may exist, whether or not they are related to those specifically identified elements. Therefore, as a non-restrictive example, a reference to “A and / or B” when used in conjunction with open-ended language such as “including” may, in one embodiment, refer to A only (optionally including elements other than B), in another embodiment, refer to B only (optionally including elements other than A), in yet another embodiment, refer to both A and B (optionally including other elements), and so on.

[0031] As used herein and in the 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” should be interpreted as inclusive; that is, including many elements, or at least one of a list of elements, but also including two or more, and optionally additional items not listed. Only terms that clearly suggest the opposite, such as “exactly one of ~,” or “exactly one of ~,” or, as used in a claim, “consisting of ~,” refer to the inclusion of many elements, or exactly one of a list of elements. Generally as used herein, the term “or” should be interpreted as indicating an exclusive choice (i.e., “one or the other, but not both”) only when preceded by an exclusive term such as “either,” “one of ~,” “only one of ~,” or “exactly one of ~.”

[0032] In the claims and the above-mentioned specification, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood as non-restrictive, meaning they include but are not limited to them. Only the transitional phrases “consisting of” and “consisting essentially of” are considered restrictive or semi-restrictive transitional phrases, respectively, as stated in Section 2111.03 of the U.S. Patent Examination Guidelines.

[0033] Where used herein, in the specification and claims, the phrase "at least one" with respect 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 element list, but not necessarily including at least one of all elements specifically listed in the element list, nor excluding any combination of elements in the element list. Furthermore, this definition allows for the existence of elements other than those specifically identified in the element list referred to by the phrase "at least one," regardless of whether those specifically identified elements are related or not. Therefore, as a non-restrictive 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”) may mean, in one embodiment, at least one, optionally comprising two or more A's and no B (and optionally comprising elements other than B); in another embodiment, at least one, optionally comprising two or more B's and no A (and optionally comprising elements other than A); and in yet another embodiment, at least one, optionally comprising two or more A's and at least one, optionally comprising two or more B's (and optionally comprising other elements).

[0034] In any particular method described herein that includes two or more steps or operations, the order of the steps or operations of the method is not necessarily limited to the order in which the steps or operations of the method are listed, unless otherwise suggested by the context.

[0035] The terms “co-administration” and “co-administering” or “combination therapy” refer to both co-administration (simultaneous administration of two or more therapeutic agents) and administration at different times (administering one or more therapeutic agents at different times than the administration of additional therapeutic agents) while the therapeutic agents are present in the patient’s body to a certain extent, preferably in an effective amount, at the same time. In a particular preferred embodiment, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly an anticancer agent. In a particularly preferred embodiment, the co-administration of the compounds results in synergistic activity and / or therapy, including anticancer activity.

[0036] Where used herein, unless otherwise indicated, the term “compound” means any specific chemical compound disclosed herein, including tautomers, positional isomers, geometric isomers, and stereoisomers, including, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives, including, where appropriate in context, its prodrug and / or deuterated forms. An expected deuterated small molecule is a small molecule in which one or more hydrogen atoms contained in the drug molecule are substituted with deuterium.

[0037] In its contextual use, the term "compound" generally refers to a single compound, but may also include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as specific enantiomers or mixtures enriched with specific enantiomers. The term also, in context, refers to prodrug forms of compounds modified to facilitate administration and deliver the compound to the active site. Note that the description of the compounds includes many substituents and, in particular, related variables. Those skilled in the art will understand that the molecules described herein are stable compounds, as outlined below. Where bonds are shown, both double and single bonds are represented or understood in the context of the compounds shown and known rules regarding valency interactions.

[0038] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, making those substrate proteins targets for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with E2 ubiquitin conjugate enzymes, attaches ubiquitin to lysine on target proteins, subsequently making specific protein substrates targets for proteasomal degradation. Thus, E3 ubiquitin ligases, either alone or in complex with E2 ubiquitin conjugate enzymes, are involved in ubiquitin transfer to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, and a third ubiquitin is attached to a second ubiquitin. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which case only one ubiquitin molecule is attached to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targets for proteasome degradation, but instead may alter their intracellular location or function through binding to other proteins that have domains capable of binding ubiquitin. Further complicating matters is the fact that other lysines on ubiquitin can be targeted by E3 and form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to generate polyubiquitin recognized by the proteasome.

[0039] The terms “patient” or “subject” are used throughout this specification to describe animals, preferably humans or livestock, to which treatment, including prophylactic treatment with the compositions of this disclosure, is provided. In relation to the treatment of infections, conditions, or pathologies specific to certain animals, such as human patients, the term “patient” refers to certain animals, including, for example, domestic animals such as dogs or cats, or agricultural animals such as horses, cattle, or sheep. Generally, in this disclosure, the term “patient” refers to human patients unless otherwise suggested 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 the amount of a compound, composition, or component that produces the intended result. The term "effective" includes all other terms for effective quantity or effective concentration, which are described or used separately in this application.

[0041] Compounds and compositions

[0042] In one embodiment, this specification provides a compound comprising an E3 ubiquitin ligase binding moiety (ULM), where the ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM). In exemplary embodiments, 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 In the formula, L is a binding or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number of moieties in the compounds described herein, and / or their relative positions, are provided for illustrative purposes only. As will be understood by those skilled in the art, the compounds described herein can be synthesized using any desired number of each functional group moiety and / or at the relative positions of each functional group moiety.

[0043] The terms ULM and CLM are used in their comprehensive sense unless otherwise indicated by the context. For example, the term ULM encompasses all ULMs, including those that bind to cereblon (i.e., CLMs). Furthermore, the term CLM encompasses all cereblon binding parts.

[0044] In another embodiment, the present disclosure provides bifunctional or polyfunctional compounds useful for regulating protein activity by inducing the degradation of target proteins. In certain embodiments, the compound comprises a CLM bound to a target protein-binding portion (i.e., a protein-targeting portion or "PTM"), for example, covalently, directly, or indirectly. In certain embodiments, the CLM and PTM are bound or linked via a chemical linker (L). The CLM binds to a cereblon E3 ubiquitin ligase, the PTM recognizes the target protein, and the interaction between each portion and its target positions the target protein in close proximity to the ubiquitin ligase protein, thereby promoting the degradation of the target protein. Exemplary bifunctional compounds may be shown 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 described as follows: (C) PTM-L-CLM In the formula, PTM is the protein / polypeptide targeting portion, L is the chemical linker, and CLM is the cereblon E3 ubiquitin ligase binding portion.

[0046] In certain embodiments, ULM (e.g., CLM) exhibits activity toward or binds to E3 ubiquitin ligase (e.g., cereblon E3 ubiquitin ligase) with an IC50 of less than approximately 200 μM. The IC50 can be determined according to any method known in the art, such as 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., multiple / different E3 ubiquitin ligases, e.g., cereblon-specific moieties), or combinations thereof. In any of the embodiments or models described herein, the PTMs and ULMs (e.g., CLMs) may be linked directly, via one or more chemical linkers, or in combination thereof. In additional embodiments, if the compound has multiple ULMs, those ULMs may be for the same E3 ubiquitin ligase, or each ULM may specifically bind to a different E3 ubiquitin ligase. In further embodiments, if the compound has multiple PTMs, those PTMs may bind to the same target protein, or each PTM may specifically bind to a different target protein.

[0049] In certain embodiments, if the compound contains multiple ULMs, those ULMs are identical. In additional embodiments, the compound contains multiple ULMs (e.g., ULM, ULM'), at least one PTM bound to the ULMs directly, via a chemical linker (L), or both. In certain additional embodiments, the compound containing multiple ULMs further contains multiple PTMs. In yet additional embodiments, the PTMs are identical or optionally different. In further embodiments, if the PTMs are different, each PTM may bind to the same protein target or may bind specifically to different protein targets.

[0050] In certain embodiments, the compound may contain multiple ULMs and / or multiple ULM'. In further embodiments, a compound containing at least two different ULMs, multiple ULMs, and / or multiple ULM' further comprises at least one PTM bound to the ULM or ULM' directly, via a chemical linker, or both. In any of the embodiments described herein, a compound containing at least two different ULMs may further comprise multiple PTMs. In even further embodiments, the PTMs may be identical or optionally different. In even further embodiments, if the PTMs are different, each PTM may bind to the same protein target or may bind specifically to different protein targets. In even further embodiments, the PTM itself is a ULM (or ULM'), such as a CLM and / or CLM'.

[0051] In additional embodiments, this specification provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, and their pharmaceutically acceptable salt forms, such as acid salt forms and base salt forms.

[0052] In this specification, the term “independently” is used to indicate that variables applied independently change independently from one application to the next.

[0053] The term "alkyl" in this context should mean a linear, branched, or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a C1-C10, more preferably a C1-C6, or C1-C3 alkyl group, which may be optionally substituted. Examples of alkyl groups include, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl group is terminally capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to this disclosure may be used to covalently bond to a dehalogenase enzyme. These compounds generally contain side chains (often linked via polyethylene glycol groups), the distal end of which is terminated with an alkyl group having a halogen substituent (often chlorine or bromine), thereby creating a covalent bond between the compound containing that portion and the protein.

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

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

[0056] When the term "alkylene" is used, it refers to an optionally substituted -(CH2)n- group (where n is generally an integer from 0 to 6). If substituted, the alkylene group is preferably substituted with one or more methylene groups, with a C1-C6 alkyl group (including a cyclopropyl group or a 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, O-(C1-C6 alkyl) groups, or amino acid side chains as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which is further 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 is substituted (but not limited to, preferably on the distal end of the polyethylene glycol chain), and the alkyl chain is substituted with a halogen group, preferably a chlorine group. In further embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as 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" shall mean that only hydrogen atoms are substituted. The range of carbon atoms including C0 means that there are no carbon atoms and they are replaced by H. Therefore, the range of carbon atoms C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with H instead of carbon in the case of C0.

[0058] The terms “substituted” or “optionally substituted” mean independently one or more substituents at any carbon (or nitrogen) position on the molecule in the context (up to five substituents independently on a portion of the compounds in the present disclosure, preferably up to three substituents, often one or two substituents, which may include substituents that can be further substituted themselves) (i.e., if there are multiple substituents, each substituent is independent of the other substituents), and substituents include hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (particularly alkyl, particularly one, two or three halogens on a methyl group such as trifluoromethyl), alkyl (particularly C1-C10, more preferably C1-6), aryl (particularly phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy group (particularly C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (particularly C1-C6 acyl), ester or thioester (particularly C1 Examples include alkylene esters (where the bond is on an alkylene group rather than an ester functional group, and is preferably substituted with a C1-C6 alkyl or aryl group), preferably containing a C1-C6 alkyl or aryl group, halogens (preferably F or Cl), amines (including five- or six-membered cyclic alkyleneamines, further containing C1-C6 alkylamines or C1-C6 dialkylamines, where the alkyl group may be substituted with one or two hydroxyl groups), or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) groups (which may be optionally substituted with polyethylene glycol chains to which one halogen, preferably an alkyl group containing a chlorine substituent, is further bonded), hydrazines, amides, which are preferably substituted with one or two C1-C6 alkyl groups (including carboxamides optionally substituted with one or two C1-C6 alkyl groups), alkanols (preferably C1-C6 alkyl or aryl), or alkanoic acids (preferably C1-C6 alkyl or aryl).The substituents according to this disclosure may include, for example, a -SiR1R2R3 group, 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 bonded to the substituted moiety, or the substituents may be bonded to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via optionally substituted (CH2)m- or optionally substituted -(OCH2)m-, -(OCH2CH2)m- or -(CH2CH2O)m- groups, which may be substituted with any or more of the above substituents. The -(CH2)m- or -(CH2)n- group of the alkylene group or other chains, such as the ethylene glycol chain specified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogens or C1-C6 (preferably C1-C3) alkyl groups, 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 amino acid side chains as otherwise described herein, and optionally substituted amides (preferably substituted carboxamides as described above) or urethane groups (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 amino acid side chains as otherwise described herein. The molecular portions in this disclosure may optionally be substituted with up to five substituents, preferably up to three substituents. In most cases, the substituted portions in this disclosure are substituted with one or two substituents.

[0059] The term "substituted" (each substituent independent of any other substituent) also means, in the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (in particular C1-C6 alkylene-NR1R2, mono or di-C1-C6 alkyl-substituted amines which may be optionally substituted with one or two hydroxyl groups). Each of these groups, unless otherwise indicated, contains 1 to 6 carbon atoms in the context. In certain embodiments, preferred substituents include, depending on the context of the substituent's use, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2)m- (where m and n are 1, 2, 3, 4, 5, or 6 in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2)nOH, -(CH2)nSH, -(CH2)nCOOH, C1-C6alkyl, -(CH2)nO-(C1-C6alkyl), -(CH2)nC(O)-(C1-C6alkyl), -(CH2)nOC(O)-(C1-C6alkyl), -(CH2)nC(O)O-( The group will contain C1-C6 alkyl, -(CH2)nNHC(O)-R1, -(CH2)nC(O)-NR1R2, -(OCH2)nOH, -(CH2O)nCOOH, C1-C6 alkyl, -(OCH2)nO-(C1-C6 alkyl), -(CH2O)nC(O)-(C1-C6 alkyl), -(OCH2)nNHC(O)-R1, -(CH2O)nC(O)-NR1R2, -S(O)2-RS, -S(O)-RS (RS is a C1-C6 alkyl or -(CH2)m-NR1R2 group), NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl). R1 and R2 are, in context, H or C1-C6 alkyl groups (which may be optionally substituted with one or two hydroxyl groups, or up to three halogen groups, preferably fluorine).The term “substituted” also means an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group, as otherwise described herein, within the chemical background of the specified compound and the substituents used. The alkylene group may also be substituted as otherwise disclosed herein, preferably an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl, which in turn provide a chiral center), a side chain of an amino acid group as otherwise described herein, the aforementioned amide group, or a urethane group, or an OC(O)-NR1R2 group, where R1 and R2 are as otherwise described herein, but many other groups can also be used as substituents. Various optionally substituted portions may be substituted with three or more substituents, preferably three or fewer substituents, and preferably one or two substituents. Note that in a compound, substitution is required at a particular position of the molecule (primarily for valency reasons), but if the substitution is not shown, the substituent is considered or understood to be H unless otherwise suggested in the context of that substitution.

[0060] The terms “aryl” or “aromatic” in context refer to a substituted (as otherwise specified herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or a fused ring (e.g., naphthyl, anthracenylphenyl, phenantrenyl, etc.), which can be attached to a compound at any available stable position on the ring or as otherwise specified in the presented chemical structure, in accordance with this disclosure. Other examples of aryl groups in context include heterocyclic aromatic ring systems, such as “heteroaryl” groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, etc., or fused ring systems, such as indole, quinoline, indidine, azaindridine, benzofurazan, etc., which may be optionally substituted as described above.Heteroaryl groups that may be mentioned include, in particular, nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indidine, azaindidine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinoridine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanacene, oxadiazole, and benzyl Examples include imidazoles, pyrrolopyridines, pyrrolopyrimidines and pyridopyrimidines, sulfur-containing aromatic heterocycles, such as thiophenes and benzothiophenes, oxygen-containing aromatic heterocycles, such as furans, pyrans, cyclopentapyrans, benzofurans and isobenzofurans, and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazoles, thiadizols, isothiazoles, benzoxazoles, benzothiazoles, benzothiadiazoles, phenothiazines, isoxazoles, furazans, phenoxazines, pyrazoleoxazoles, imidazothiazoles, thienofurans, phlopyrroles, pyridoxazines, phlopyridines, phlopyrimidines, thienopyrimidines and oxazoles, all of which may be optionally substituted.

[0061] The term "substituted aryl" refers to an aromatic carbon ring composed of at least one aromatic ring, or a plurality of fused rings, at least one of which are aromatic, where the ring is substituted with one or more substituents. For example, the aryl group may include 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, where the alkyl group on the amine is optionally 1 or 2 hydroxyls A group, or up to three halos (preferably F, Cl), OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (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 (preferably the phenyl group itself is bonded to a PTM group containing a ULM group via a linker group), and / or F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, N O2, or at least one of a CN group (ortho, meta, and / or para, preferably para, of the phenyl ring), optionally substituted naphthyl group, optionally substituted heteroaryl, optionally substituted isoxazole, preferably methyl-substituted isoxazole, optionally substituted oxazole, optionally substituted thiazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted pyrrole, optionally substituted imidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oxyimidazole or methyloxyimidazole, optionally substituted diazole group, optionally substituted triazole group, optionally substituted pyridine group, optionally substituted pyridine group, preferably halo(preferably F)-substituted or methyl-substituted pyridine group or oxapyridine group (in the formula,The pyridine group is bonded to the phenyl group by oxygen, optionally substituted with furan, optionally substituted with benzofuran, optionally substituted with dihydrobenzofuran, optionally substituted with indole, indidine or azaindridine (2,3, or 4-azandridine), optionally substituted with 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 defined herein for the corresponding groups.

[0063] The terms "heteroaryl" or "hetaryl" are not limited to, but may include, optionally substituted quinolines (which may be added to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indoles (including dihydroindole), optionally substituted indridines, optionally substituted azaindridines (2, 3, or 4-azindridines), optionally substituted benzimidazoles, benzodiazoles, benzoxofrans, optionally substituted imidazoles, optionally substituted isoxazoles, optionally substituted oxazoles (preferably methyl-substituted), and optionally substituted diazoles. This may mean a triazole, tetrazole, optionally substituted, benzofuran, optionally substituted, thiophene, optionally substituted (preferably methyl-substituted and / or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole (preferably substituted with a methyl group, triisopropylsilyl group, optionally substituted -(CH2)mO-C1-C6 alkyl group, or optionally substituted -(CH2)mC(O)-O-C1-C6 alkyl group, or 1,2,3-triazole), optionally substituted pyridine (2,3, or 4-pyridine), or a group with the following chemical structures: [ka] During the ceremony, Sc is CHRSS, NRURE, or O; RHET is H, 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 optionally substituted acetylene group-C≡C-Ra, where Ra is an acetylene group that is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group); 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); RURE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), where each group is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or optionally substituted heterocycles, 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 optionally substituted acetylene group-C≡C-Ra, where Ra is an acetylene group that is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group).

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

[0065] As used herein, the term "arylalkyl" refers to the aryl group defined above that is attached to the alkyl group defined above. The arylalkyl group is attached to the parent part via an alkyl group, in this case having 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be substituted as described above.

[0066] The term "heterocyclic" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, which may be aromatic (heteroaryl) or non-aromatic. Therefore, heteroaryl moieties are included under the definition of heterocyclic, depending on their context of use. Exemplary heteroaryl groups are described above in this specification.

[0067] Exemplary heterocycles include, in particular, azetididine, 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, isoqui Examples include sazolidinil, isoxazolyl, morpholinil, naphthilidinil, oxazolidinil, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinil, N-methylpiperazinil, piperidinil, phthalimide, succinimide, pyrazinil, pyrazolinil, pyridyl, pyrimidinil, pyrrolidinil, pyrrolinil, pyrrolyl, quinolinil, tetrahydrofuranil, tetrahydropyranil, tetrahydroquinoline, thiazolidinil, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanil, oxathiolanil, and thian.

[0068] The heterocyclic group may be optionally substituted with a group selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl. Such a heterocyclic group may have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenantholidine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and N-alkoxy nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which either heterocyclic ring is condensed with a benzene ring, a cyclohexane ring, or another heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0069] The term "cycloalkyl" means, but is not limited to, monovalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes as defined herein, such as saturated monocyclic hydrocarbon groups having 3 to 20 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "substituted cycloalkyl" means, but is not limited to, monocyclic or polycyclic alkyl groups substituted with one or more substituents such as amino, halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto, or sulfo, and these generic substituents have the same meaning as the definitions of the corresponding groups as defined herein.

[0070] "Hypercycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S, or P. "Substitutive heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is substituted with a heteroatom selected from the group consisting of N, O, S, or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto, or sulfo, but these generic substituents have the same meaning as the definition of the corresponding group as defined in this explanation.

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

[0072] In this specification, the term “independently” is used to indicate that variables applied independently change independently from one application to the next.

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

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

[0075] Exemplary CLM

[0076] Neo-imide compounds

[0077] In one embodiment, this specification provides compounds useful for binding to and / or inhibiting cereblon. In a particular embodiment, the compound is selected from the group consisting of the following chemical structures: [ka] During the ceremony, In formulas (a) to (f), W is selected from the group consisting of CH2, O, CHR, C=O, SO2, NH, N, optionally substituted cyclopropyl groups, optionally substituted cyclobutyl groups, and N-alkyl groups; W3 is either C or N; In equations (a) to (f), X is independently selected from the non-existent group of O, S, and CH2; In formulas (a) to (f), Y is independently selected from the group CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S; In equations (a) to (f), Z is independently selected from the groups O, S, and CH2, provided that both X and Z cannot be nonexistent or CH2; In formulas (a) to (f), G and G' are independently selected from the group consisting of H, optionally substituted linear or branched alkyl groups, OH, R'OCOOR, R'OCONRR'', optionally substituted CH2-heterocyclyl groups, and optionally and selectively substituted benzyl groups; In formulas (a) to (f), Q1 to Q4 each independently represent carbon (C) or nitrogen substituted with a group independently selected from H, R, N, or N-oxide, or in formulas (a) to (f), Q1 to Q4 each independently represent N, CH, or CR; In formulas (a) to (f), A is selected from the group consisting of H, linear or branched alkyl, cycloalkyl, Cl, and F, which can be optionally substituted; In equations (a) and (f), n represents an integer between 1 and 10 (for example, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulas (a) to (f) is not limited to but includes: H, -C(=O)R' (e.g., carboxyl group), -CONR'R” (e.g., amide group), -OR' (e.g., OH or OCH3), -NR'R” (e.g., amine group), -SR', -SO2R', -SO2NR'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., optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or at least one of a combination thereof). alkyl-aryl), optionally substituted heteroaryl, optionally substituted alkyl (e.g., C1-C6 linear 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 group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; in this case, the alkoxyl may 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] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls)), optionally substituted [ka] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls)), optionally substituted cycloalkyls, optionally substituted heterocyclines, -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; In formulas (a) through (f), R' and R'' are independently selected from H, an optionally substituted linear or branched alkyl (e.g., methyl or ethyl), an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic, -C(=O)A, and an optionally substituted heterocycline; In equations (a) and (f), n' represents an integer between 1 and 10 (for example, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); [ka] represents a single bond or a double bond; and Equations (a) to (f) [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific.

[0078] Exemplary CLM

[0079] In any of the compounds described herein, CLM comprises a chemical structure selected from the following group: [ka] During the ceremony, In formulas (a) to (f), W is selected from the group consisting of CH2, O, CHR, C=O, SO2, NH, N, optionally substituted cyclopropyl groups, optionally substituted cyclobutyl groups, and N-alkyl groups; W3 is either C or N; In equations (a) to (f), X is independently selected from the non-existent group of O, S, and CH2; In formulas (a) to (f), Y is independently selected from the group CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetalyl, N-cycloalkyl, N-heterocyclyl, O, and S; In equations (a) to (f), Z is independently selected from the groups O, S, and CH2, provided that both X and Z cannot be nonexistent or CH2; In formulas (a) to (f), G and G' are independently selected from the group consisting of H, optionally substituted linear or branched alkyl groups, OH, R'OCOOR, R'OCONRR'', optionally substituted CH2-heterocyclyl groups, and optionally and selectively substituted benzyl groups; In formulas (a) to (f), Q1 to Q4 each independently represent carbon (C) or nitrogen substituted with a group independently selected from H, R, N, or N-oxide, or in formulas (a) to (f), Q1 to Q4 each independently represent N, CH, or CR; In formulas (a) to (f), A is selected from the group consisting of H, linear or branched alkyl, cycloalkyl, Cl, and F, which can be optionally substituted; In equations (a) and (f), n represents an integer between 1 and 10 (for example, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulas (a) to (f) is not limited to but includes: H, -C(=O)R' (e.g., carboxyl group), -CONR'R” (e.g., amide group), -OR' (e.g., OH), -NR'R” (e.g., amine group), -SR', -SO2R', -SO2NR'R”, -CR'R”-, -CR'NR'R”-, (-CR'O)n'R”, optionally substituted aryls (e.g., optionally substituted C5-C7 aryls), optionally substituted alkylaryls (e.g., alkylaryls containing at least one of optionally substituted C1-C6 alkyls, optionally substituted C5-C7 aryls, or combinations thereof), optionally Substituted hetalil, optionally substituted linear or branched alkyl (e.g., C1-C6 linear or branched alkyl optionally substituted with one or more halogens, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls)), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; in this case, the alkoxyl may be substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls)), optionally substituted [ka] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls)), optionally substituted [ka] (For example, optionally substituted with one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls)), optionally substituted cycloalkyls, optionally substituted heterocyclines, -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; In formulas (a) through (f), R' and R'' are independently selected from a bond, H, an optionally substituted linear or branched alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, -C(=O)A, and an optionally substituted heterocycline; In equations (a) and (f), n' represents an integer between 1 and 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and Equations (a) to (f) [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific.

[0080] In any aspect or embodiment described herein, CLM or ULM comprises a chemical structure selected from the following group: [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 non-existent O, S, and CH2; Z is selected from the group consisting of O, S, and CH2, which do not exist; Z is selected from the group consisting of H, methyl, and OH; Each of Q1, Q2, Q3, and Q4 independently represents N or C substituted with a group independently selected from H, R, N, or N-oxide, or each of Q1, Q2, Q3, and Q4 independently represents N, CH, or CR; A is independently selected from the group consisting of H, unsubstituted or substituted linear or branched alkyl, cycloalkyl, Cl, and F; n is an integer between 1 and 4 (for example, 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 linear or branched alkyl (e.g., C1-C3 alkyl and / or optionally substituted with one or more halogens), unsubstituted or substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, where the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), optionally substituted 4- to 6-membered cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, and NO2, where one R is covalently bonded to L; R' and R'' are independently selected from the group consisting of a bond, H, and a substituted or unsubstituted C1-C4 alkyl group (e.g., methyl or ethyl); [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific.

[0081] In any aspect or embodiment described herein, CLM or ULM comprises a chemical structure selected from the following group: [ka] During the ceremony, In formula (g), W is selected from the group CH2, O, C=O, NH, and N-alkyl; In formula (g), A is H, methyl, or a linear or branched alkyl group that is optionally substituted; n is an integer between 1 and 4; R in formula (g) is independently selected from H, O, OH, N, NH, NH2, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), C1-C6 alkoxy, alkyl-aryl (e.g., alkyl-aryl containing at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, in which case one R or W is optionally modified to be covalently bonded to a PTM, chemical linker group (L), ULM, CLM (or CLM') or a combination thereof; and Equation (g) [ka] This represents a binding that may 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 the non-existent O, S, and CH2; Z is O, S, or CH2; G is H, methyl, or OH; Each of Q1, Q2, Q3, and Q4 independently represents N or C which is substituted with H or R; A is H, an unsubstituted or substituted linear or branched alkyl group, Cl, or F; n is an integer between 1 and 4 (for example, 1 or 2, 1 to 3, 1, 2, 3 or 4); Each R is independently a bond, H, -OR', -NR'R'', -CR'R''-, an unsubstituted or substituted linear or branched C1-C6 linear or branched alkyl group (e.g., optionally substituted with C1-C3 alkyl and / or one or more halogens), an unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, where the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), an optionally substituted 4- to 6-membered cycloalkyl, an optionally substituted 4- to 6-membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or NO2, where one R is covalently bonded to L; R' and R'' are each independently selected from the bond, H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); and [ka] This represents a binding that may 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 CH2, O, CH(C1-3 alkyl) (e.g., CH(CH3)), C=O; G is H, methyl, or OH; Each of Q1, Q2, Q3, and Q4 independently represents N, CH, or CR; A is H, an unsubstituted or substituted linear or branched alkyl group, Cl, or F; n is an integer between 1 and 4; R is a bond, H, -OR', -NR'R'', -CR'R''-, unsubstituted or substituted linear or branched C1-C6 linear or branched alkyl (e.g., optionally substituted with C1-C3 alkyl and / or one or more halogens), unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, where the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), optionally substituted 4- to 6-membered cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or NO2, where one R is covalently bonded to L; R' and R'' are each independently selected from the bond, H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); and [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific.

[0084] In any embodiment or configuration described herein, R is selected from: O, OH, N, NH, NH2, C1-C6 alkyl, C1-C6 alkoxy, alkyl-aryl (e.g., alkyl-aryl containing at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof), aryl (e.g., C5-C7 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, NH2, C1-C6 alkyl, C1-C6 alkoxy, alkyl-aryl (e.g., alkyl-aryl including at least one of C1-C6 alkyl, C4-C7 aryl or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy) or W is modified to be covalently bonded to a PTM, a chemical linker group (L), a ULM, a CLM' (e.g., a CLM' is an additional CLM having the same or a different structure as 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 be independently covalently bonded to a linker and / or covalently bonded to a linker bonded to one or more PTM, ULM, CLM, or CLM' groups.

[0087] In any of the embodiments or models described herein, Rn comprises 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 including 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, and optionally one of these is modified to be covalently bonded to a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0088] More specifically, non-limiting examples of CLMs include those listed below, as well as "hybrid" molecules resulting from one or more combinations of the different properties shown in the following molecules. [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 coupled to a linker and / or to one or more PTM, ULM, ULM', CLM, or CLM' bases.

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

[0091] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and Rn may independently be covalently bonded to a linker and / or 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 bonded to a linker group (L), a second CLM, CLM', a second linker having the same chemical structure as PTM, ULM, or CLM, or any combination thereof.

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

[0094] In any aspect or embodiment described herein, the CLM is selected from the following: [ka] During the ceremony, CLM [ka] This indicates the connection point with L; and N* is a nitrogen atom shared with the chemical linker group.

[0095] In any aspect or embodiment described herein, the CLM is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, CLM [ka] This indicates the connection point with L; and N* is a nitrogen atom shared with the chemical linker group.

[0096] In any aspect or embodiment described herein, the CLM is selected from the following: [ka] [ka] [ka] [ka] During the ceremony, ULM [ka] This indicates a linker group or a bonding site with PTM, and N* is a nitrogen atom shared with a chemical linker group or PTM.

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

[0098] Exemplary linker In certain embodiments, the compounds described herein include one or more PTMs that are chemically linked or bonded 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 comprising one or more covalently bonded structural units (e.g., -AL1…(AL)q- or -(AL)q-), where AL1 is a group bonded to the PTM and (AL)q is a group bonded 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 ULM are connected via a heteroatom, any subsequent heteroatom, if present, is separated by at least one single carbon atom (e.g., -CH2-), such as an acetal group or aminal group. As a further example, in any aspect or embodiment described herein, when the linker (L) and ULM are connected via a heteroatom, the heteroatom is not part of the 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 part 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, 4 L is covalently bonded to PTM and ULM, providing sufficient binding between PTM and the protein target, and sufficient binding between ULM and the E3 ubiquitin ligase, thereby causing target protein ubiquitination.

[0101] In any aspect or embodiment described herein, the linker group L is -(AL)q-, where, (AL)q is a group linked to at least one of the following: ULM (e.g., CLM), PTM part, or combination thereof. Linker's q is an integer greater than or equal to 1. Each AL independently consists of a bond, CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(=NCN)NRL4, NRL3C(=NCN), NRL3C(=CNO2)NRL4, monocyclic or bicyclic C3-11 cycloalkyls optionally substituted with 0-6 RL1 and / or RL2 groups, C5-13 spirocycloalkyls optionally substituted with 1-9 RL1 and / or RL2 groups, and 0-6 Selected from the group consisting of monocyclic or bicyclic C3-11 heterocyclils optionally substituted with 1 RL1 and / or RL2 groups, C5-13 spiroheterocyclils optionally substituted with 1 to 8 RL1 and / or RL2 groups, aryls optionally substituted with 1 to 6 RL1 and / or RL2 groups, and heteroaryls optionally substituted with 1 to 6 RL1 and / or RL2 groups, wherein each RL1 or RL2 is independently optionally linked to another group to form a cycloalkyl and / or heterocyclil moiety optionally substituted with 1 to 4 RL5 groups. RL1, RL2, RL3, RL4, and RL5 are each independently H, halogen, C1-8 alkyl, OC1-8 alkyl, SC1-8 alkyl, NHC1-8 alkyl, N(C1-8 alkyl)2, C3-11 cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, C3-11 heterocyclyl, OC3-8 cycloalkyl, SC3-8 cycloalkyl, NHC3-8 cycloalkyl, N(C3-8 cycloalkyl)2, N(C3-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2C1-8 alkyl, P(O)(OC1-8 alkyl)(C1-8 alkyl), P(O)(OC1-8 alkyl)2, CC-C1-8 alkyl, CCH, CH=CH(C1-8 alkyl), C(C1-8 alkyl)=CH(C1-8 alkyl) HCl), C(C1-8alkyl)=C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl)SO2N(C1-8alkyl)2, NH These are SO2NH(C1-8 alkyl), NH SO2N(C1-8 alkyl)2, or NH SO2NH2.

[0102] In any embodiment or configuration described herein, preferably each A is independently CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2, C≡C, a C3-11 monocyclic or bicyclic cycloalkyl group optionally substituted with 1 to 6 RL1 and / or RL2 groups, or optionally substituted with 1 to 9 RL1 and / or RL2 groups. The following are selected: a C5-13 spirocycloalkyl to be replaced, a C3-11 monocyclic or bicyclic heterocycline optionally substituted with 1 to 6 RL1 and / or RL2 groups, a C5-13 spiroheterocycline optionally substituted with 1 to 8 RL1 and / or RL2 groups, an aryl optionally substituted with 1 to 6 RL1 and / or RL2 groups, and a heteroaryl optionally substituted with 1 to 6 RL1 and / or RL2 groups.

[0103] In any aspect or embodiment described herein, each of RL1, RL2, RL3, RL4, and RL5 is independently H, halogen, C1-8 alkyl, OC1-8 alkyl, SC1-8 alkyl, NHC1-8 alkyl, N(C1-8 alkyl)2, C3-11 cycloalkyl, 5-membered or 6-membered aryl, 5-membered or 6-membered heteroaryl, C3-11 heterocyclyl, OC3-8 cycloalkyl, SC3-8 cycloalkyl, NHC3-8 cycloalkyl, N(C3-8 cycloalkyl)2, N(C3-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2C1-8 alkyl, CC-C1-8 alkyl, CCH, CH=CH(C1-8 alkyl), C(C1-8 alkyl) 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)SO2NH(C1-8 alkyl), N(C1-8 alkyl)SO2N(C1-8 alkyl)2, NH These are SO2NH(C1-8 alkyl), NH SO2N(C1-8 alkyl)2, or NH SO2NH2.

[0104] In any aspect or embodiment described herein, the linker q 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 linker q is greater than 2, (AL)q is a group that is AL1 and (AL)q, and unit AL is a bond of PTM and ULM.

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

[0107] In any aspect or embodiment described herein, for example, when the linker q is 1, the structure of the linker group L is -AL1-, and AL1 is a group connected to the ULM portion and the PTM portion.

[0108] In any aspect or embodiment described herein, the linker (L) unit AL 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(CH2CH2O)n-(lower alkyl)-O-CH2-, -NR(CH2CH2O)n-(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O)n-(aryl-O-CH2-, -NR(CH2CH2O)n-(heteroaryl)-O-CH2-, -NR(CH2CH2O)n-(cyclo Alkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O)n-(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O)n-(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O)n-(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O)n-cycloalkyl-O-aryl-, -NR(CH2CH2O)n-cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2)n-(cycloalkyl)-O-(heterocyclyl)-CH2, -NR(CH2CH2)n-(heterocyclyl)-(heterocyclyl)-CH2, -N(R1R2)-(heterocyclyl)-CH2; in the formula, The linker n can be anywhere from 0 to 10; The linker's R may be H, or a low alkyl group; Linkers R1 and R2 may form rings having N bonds.

[0109] In any embodiment or configuration described herein, the linker (L) is optionally substituted with a C1-C50 alkyl group (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 The C50 alkyl group comprises, in this case each carbon is optionally substituted with (1) a heteroatom selected from N, S, P, or Si atoms having an appropriate number of hydrogen atoms, substituents, or both, to complete the valence; (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl group; (3) an optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl group; (4) an optionally substituted aryl or bicyclic aryl group; or (5) an optionally substituted heteroaryl or bicyclic heteroaryl group. In any aspect or embodiment described herein, the linker (L) does not have a heteroatom-heteroatom bond (for example, the heteroatoms are not covalent linkers or are not located adjacent to each other).

[0110] In any embodiment or configuration described herein, the linker (L) comprises 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), in which case, Each carbon is optionally substituted with CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(=NCN)NRL4, NRL3C(=NCN), NRL3C(=CNO2)NRL4, monocyclic or bicyclic C3-11 cycloalkyls optionally substituted with 1 to 6 RL1 and / or RL2 groups, C5-13 spirocycloalkyls optionally substituted with 1 to 9 RL1 and / or RL2 groups, optionally substituted with 1 to 6 RL1 and / or a monocyclic or bicyclic C3-11 heterocyclil substituted with RL2 groups, a C5-13 spiroheterocyclil optionally substituted with 1 to 8 RL1 and / or RL2 groups, a monocyclic or bicyclic aryl optionally substituted with 1 to 6 RL1 and / or RL2 groups, or a monocyclic or bicyclic heteroaryl optionally substituted with 1 to 6 RL1 and / or RL2 groups, in which case RL1 or RL2 are each independently and optionally bonded to other groups to form a cycloalkyl moiety and / or heterocyclil moiety optionally substituted with 1 to 4 RL5 groups; and, RL1, RL2, RL3, RL4, and RL5 are each independently H, halogen, C1-8 alkyl, OC1-8 alkyl, SC1-8 alkyl, NHC1-8 alkyl, N(C1-8 alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C3-11 heterocyclyl, OC1-8 cycloalkyl, SC1-8 cycloalkyl, NHC1-8 cycloalkyl, N(C1-8 cycloalkyl)2, N(C1-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2C1-8 alkyl, P(O)(OC1-8 alkyl)(C1-8 alkyl), P(O)(OC1-8 alkyl)2, CC-C1-8 alkyl, CCH, CH=CH(C1-8 alkyl), C(C1-8 alkyl)=CH(C1-8 alkyl), C(C1 -8alkyl)=C(C1-8alkyl)2,Si(OH)3,Si(C1-8alkyl)3,Si(OH)(C1-8alkyl)2,COC1-8alkyl,CO2H,CN,CF3,CHF2,CH2F,NO2,SF5,SO2NHC1-8alkyl,SO2N(C1-8alkyl)2,SONHC1-8alkyl,SON(C1-8alkyl)2,CONHC1-8alkyl,CON(C1-8alkyl)2,N(C1-8alkyl)CONH(C1-8alkyl),N(C1-8alkyl)CON(C1-8alkyl)2,NHCONH(C1-8alkyl),NHCON(C1-8alkyl)2,NHCONH2,N(C1-8alkyl)SO2NH(C1-8alkyl),N(C1-8alkyl)SO2N(C1-8alkyl)2,NH The linker(L) is SO2NH(C1-8 alkyl), NH2SO2N(C1-8 alkyl)2, or NH2SO2NH2. In any embodiment or configuration described herein, the linker(L) does not have a heteroatom-heteroatom bond (for example, the heteroatom is not a covalent linker or is not located adjacent to it).

[0111] In any embodiment or configuration described herein, each carbon of the optionally substituted C1-C50 alkyl (and subordinate groups described herein) of the linker may optionally be CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, CO, CRL1=CRL2, C≡C, or optionally a monocyclic or bicyclic cycloalkyl of C3-11 substituted with 1 to 6 RL1 and / or RL2 groups. Substitutions include C5-13 spirocycloalkyls selectively substituted with 1 to 9 RL1 and / or RL2 groups, monocyclic or bicyclic C3-11 heterocyclils optionally substituted with 1 to 6 RL1 and / or RL2 groups, C5-13 spiroheterocyclils optionally substituted with 1 to 8 RL1 and / or RL2 groups, aryls optionally substituted with 1 to 6 RL1 and / or RL2 groups, or heteroaryls optionally substituted with 1 to 6 RL1 and / or RL2 groups.

[0112] In any embodiment or configuration 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) alkylene glycol units that are optionally substituted, in which case carbon or oxygen may be substituted with heteroatoms selected from N, S, P, or Si atoms having an appropriate number of hydrogens to complete the valence. For example, in any embodiment or configuration described herein, the linker (L) has a chemical structure selected from: [ka] [ka] In this case, carbon or oxygen may be substituted with a heteroatom selected from N, S, P, or Si atoms having an 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 linker (L) unit AL comprises a group represented by a general structure selected from the group consisting of: [ka] During the ceremony, [ka] Each of these is independently a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl (e.g., a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl), and the overlapping rings represent a spirocyclic ring; Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; RL is selected from H and C1-3 alkyl groups; The linker is optionally substituted with (i)=O and (ii) 1 to 4 substituents (e.g., 1, 2, 3, or 4) independently selected from C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); and [ka] This indicates the connection point with 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] Each of these is independently a 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl (e.g., a 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl), and the overlapping rings represent a spirocyclic ring; [ka] These are 8-10 member cross-linked cycloalkyls, 8-10 member cross-linked heterosylcoalkyls, 3-7 member heterocyclines having one or two double bonds (e.g., 3-7 member heterocyclines having one or two double bonds), or 7-10 member condensed bicyclic heterocycloalkyls (e.g., 7-9 member condensed bicyclic heterocycloalkyls); Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; RL is selected from H and C1-3 alkyl groups; The linker is optionally substituted with at least one of (i)=O and (ii)1 to 4 substituents (e.g., 1, 2, 3, or 4) independently selected from C1-3 alkyl (e.g., methyl), OH, and halogen (e.g., F, Cl, or Br); and [ka] This indicates the junction with PTM or CLM.

[0115] In any embodiment or aspect described herein, the chemical linker group is [ka] Selected from, in this case * indicates an atom (e.g., carbon or nitrogen) that is covalently bonded to or shared with CLM or PTM, [ka] Each of these indicates a junction point with the CLM or PTM.

[0116] In any embodiment or aspect described herein, the chemical linker group is [ka] Selected from, in this case * indicates an atom (e.g., carbon or nitrogen) that is covalently bonded to or shared with CLM or PTM, [ka] Each of these indicates a junction point with the CLM or PTM.

[0117] In any embodiment or aspect described herein, the chemical linker group is [ka] And, During the ceremony, The above chemical linker group, which does not contain substituents, is optionally substituted with at least one of (i)=O and (ii)1 to 4 substituents (e.g., 1, 2, 3, or 4) independently selected from C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * is an atom (e.g., nitrogen, carbon, or oxygen) that is covalently bonded to or shared with the CLM or PTM; [ka] This indicates the junction with 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, the substituents independently selected from C1-3 alkyl (preferably methyl), where p and o are 0 and m is 1.

[0119] In any embodiment or aspect described herein, the chemical linker group is [ka] [ka] And, During the ceremony, The above chemical linker group, which does not contain substituents, is optionally substituted with at least one of (i)=O and (ii)1 to 4 substituents (e.g., 1, 2, 3, or 4) independently selected from C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) that is covalently bonded to or shared with CLM or PTM; [ka] This indicates the junction with 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 embodiment or aspect described herein, the chemical linker group is [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] and wherein The above chemical linker group without substituents 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 C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * represents an atom (e.g., nitrogen or carbon) that is covalently bonded to CLM or PTM, or shared with CLM or PTM; [Chemistry] represents a bonding point with 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 embodiment or aspect described herein, the chemical linker group is [ka] [ka] [ka] [ka] And, During the ceremony, The above chemical linker group, which does not contain substituents, is optionally substituted with at least one of (i)=O and (ii)1 to 4 substituents (e.g., 1, 2, 3, or 4) independently selected from C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) that is covalently bonded to or shared with CLM or PTM; [ka] This indicates the junction with 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 linker (L) includes a group represented by a general structure selected from the following: [ka] [ka] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] <00​​​​​​​​​​​​​​​​​​​​​This indicates the connection point with 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 either 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) that is covalently bonded to or shared with CLM or PTM; [ka] This indicates the junction with PTM or CLM; and The chemical linker contains 0 to 4 substituents (preferably 0, 1, or 2 substituents), and each substituent 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 either an N or CH group; [ka] This represents a stereospecific bond, where one side has a (R) structure and the other side has an (S) structure; * indicates an atom (e.g., nitrogen or carbon) that is covalently bonded to or shared with CLM or PTM; [ka] This indicates the junction with PTM or CLM; and The chemical linker contains 0 to 4 substituents (preferably 0, 1, or 2 substituents), and each substituent is independently a C1-3 alkyl (preferably methyl).

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

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

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

[0128] The ULM and PTM groups may be covalently bonded to the linker group via any stable group suitable for the chemical properties of the linker, and in a preferred embodiment of this disclosure, the linker may be independently covalently bonded to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which may be inserted onto either the ULM or PTM group to provide maximum binding of the ULM group to the ubiquitin ligase and maximum binding of the PTM group to the target protein to be degraded. (Note that in a particular embodiment where the PTM group is a ULM group, the target protein to be degraded may be the ubiquitin ligase itself). In a particular preferred embodiment, the linker may be bonded to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group, or heterocyclic group on the ULM and / or PTM groups.

[0129] Exemplary PTM In preferred embodiments of this disclosure, the PTM group is a group that binds to a target protein. The targets of the PTM group are diverse, and targets are selected from intracellularly expressed proteins whose sequence is present in the cell and capable of binding to the PTM group. The term “protein” includes oligonucleotide and polypeptide sequences of sufficient length to bind to the PTM group in accordance with this disclosure. Any protein of a eukaryotic cell line or a microbial line including viruses, bacteria, or fungi is a target of ubiquitination regulated by the compounds of this disclosure, as otherwise described herein. The target protein is preferably a protein of a eukaryotic cell.

[0130] PTM groups according to this disclosure include, for example, any moiety that specifically binds to a protein (bounds to a target protein) and include non-limiting examples of small target protein moieties such as: 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 that particularly target aryl hydrocarbon receptors (AHRs). The compositions described below exemplify some of a range of small target protein binding moieties. Such small target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target the protein of interest. These binding moieties are preferably bound to a ubiquitin ligase binding moiety via a linker to present the target protein (to which the protein target moiety is bound) in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0131] Any protein that can bind to a protein target moiety or PTM group and is acted upon or degraded by a ubiquitin ligase is a target protein according to this disclosure. Generally, target proteins include, for example, structural proteins, receptors, enzymes, and cell surface proteins, as well as proteins involved in cellular integration functions, including proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, kinase activity, redox activity, transferase activity, hydrolysis activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transduction activity, structural molecular activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell transmission, 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 activity, iron transport activity, channel transport activity, carrier activity, permeabilization activity, secretory activity, and electron transport activity), phagocytosis, chaperone regulatory activity, nucleic acid binding activity, transcriptional regulatory activity, extracellular integration and biosynthesis activity, and translational regulatory activity. Target proteins include those derived from eukaryotes and prokaryotes, including humans and other animals, as targets for drug therapy. Animals include livestock, microorganisms for determining targets for antibiotics and other antimicrobial agents, plants, and especially viruses.

[0132] Many pathological conditions and / or states may be treated using this disclosure, including any pathological conditions and / or states in which proteins are in a disregulated state and the patient would benefit from the degradation and / or inhibition of proteins.

[0133] In additional embodiments, this specification provides therapeutic compositions comprising an effective amount of a compound or a salt thereof described herein, and a pharmaceutically acceptable carrier, additive or excipient, and optionally additional bioactive agents. The therapeutic compositions can be used to modulate protein degradation in a patient or subject, such as an animal such as a human, and to treat or improve a disease or condition modulated via the degraded protein. In certain embodiments, the therapeutic compositions described herein may be used to induce the degradation of a target protein for the purpose of treating or improving a disease, such as cancer. In certain additional embodiments, the diseases are lymphoma, B-cell non-Hodgkin lymphoma, large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

[0134] In another aspect, the present disclosure relates to a method for treating a pathological condition of a subject requiring such treatment, or a method for improving the symptoms of a disease or condition, by degrading a protein or polypeptide, wherein the pathological condition or condition is regulated via the protein or polypeptide, and the method comprises administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one of the compounds described herein, in combination with optionally pharmaceutically acceptable carriers, additives or excipients, and optionally additional bioactive agents, wherein the composition is effective in treating or improving the disease or disorder or symptoms thereof of the subject. By using the methods of the present disclosure, many conditions or conditions, including cancer, can be treated by administering an effective amount of at least one of the compounds described herein. The pathological condition or condition may be a disease caused by a microbial body or other exogenous entity such as a virus, bacteria, fungi, protozoa or other microorganism, or it may be a pathological condition caused by the overexpression of a protein that gives rise to the pathological condition and / or condition.

[0135] In another embodiment, this specification provides a method for identifying the degradation effect of a target protein in a biological system using the compounds of this disclosure.

[0136] The term “target protein” is used herein to describe a protein or polypeptide that is a target to which the disclosed compounds bind and which is degraded by a ubiquitin ligase. Such small target protein binding sites include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target the protein of interest. These binding sites are bound to at least one ULM group (e.g., CLM) via at least one linker group L.

[0137] Target proteins, which can be bound to a protein target moiety and to a ubiquitin ligase-binding moiety that can be degraded by ligase, include any protein or peptide, including fragments thereof, analogues thereof, and / or homologs thereof. Target proteins include any proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, conservative, transport, and signaling. More specifically, many drug targets for human therapeutics are protein targets, to which a protein target moiety can be bound and incorporated into a compound according to this disclosure. These proteins include those that can be used for functional recovery in many polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partner factors of the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalane cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 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 receptor, JAW STAT, RXR and analogues, and 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, CD4, CD5, IL-2 Receptor, BCL6, IL-1 Receptor, TNF-αR, ICAM1, Cat+ Channel, VCAM, VLA-4 Integrins, Selectins, CD40 / CD40L, Neurokinin and Receptors, 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 transport 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 NGF receptor, beta-amyloid, tyrosine kinase Examples of target proteins include Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytoplasmic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABAergic chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel proteins, calcium release channels, and chloride channels. Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvirshikimate-phosphate synthase.

[0138] These various protein targets may be used in screening to identify compound portions that bind to the protein, and by incorporating these portions into the disclosed compounds, the activity level of the protein can be altered for the ultimate therapeutic outcome.

[0139] The terms “protein target moiety” or “PTM” are used to describe small molecules that bind to a target protein or another protein or polypeptide of interest and position / present the protein or polypeptide in close proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase may occur. The compositions described below exemplify some of the components of small target proteins. Exemplary protein target moieties in this disclosure include haloalkane halide 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 aryl hydrocarbon receptors (AHRs).

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

[0141] In any aspect or embodiment described herein, PTM is a small molecule that binds to BCL6. For example, in any aspect or embodiment described herein, PTM is represented by the following chemical structures: PTMI, PTMII, PTMIII, or PTMIV: [ka] During the ceremony, Each RPTM1 independently consists of: 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 optionally substituted with an OH or isopropyl group C1-C8 alkyl); O- optionally substituted linear or branched C1-C4 alkyl; optionally substituted C1-C4 alkynyl; optionally C1-C4 alkynes substituted with; optionally substituted linear or branched hydroxyalkyls (e.g., optionally substituted linear or branched C1-C7 hydroxyalkyls); optionally substituted alkylcycloalkyls (e.g., optionally substituted C1-C6 alkyls, optionally substituted C3-C10 cycloalkyls; or both); optionally substituted alkyl-aryls (e.g., optionally substituted linear or branched C1-C6 alkyls, optionally substituted 5-10 member alkyls) (including teloaryls, or both); optionally substituted alkyl-heteroaryls (e.g., optionally substituted linear or branched C1-C6 alkyls, optionally substituted 5- to 10-membered heteroaryls, or both); optionally substituted alkyl-heteroaryls (e.g., C1-C6 alkyls, optionally substituted 5- or 6-membered heteroaryls, which are optionally substituted with C1-C4 alkyls; heteroaryls include oxazole-4-yl, 1,3,4-triazole-2-yl) , and imidazole-1-yl selected; or combination thereof; including); optionally substituted -NH-alkyl-heteroaryl (e.g., optionally substituted linear or branched C1-C5 alkyl, optionally substituted 5- to 8-membered heteroaryl, which are optionally substituted with C1-C4 alkyl, N-CH2-pyrazole-4-yl, or combination thereof); optionally substituted alkoxy (e.g., optionally substituted linear or branched C1-C6 alkyl or -OCH3);Optionally substituted O-heterocyclines (e.g., optionally substituted 3-12 member or 4-7 member heterocyclines; optionally substituted heterocycloalkyls; optionally substituted C3-12 monocyclic or bicyclic heterocycloalkyls; they include those optionally substituted with at least one OH, C1-C5 alkyl (e.g., methyl), =O, NH2; or a combination thereof); optionally substituted S-heterocyclines (e.g., optionally substituted 4-7 member heterocyclines; optionally substituted heterocycloalkyls; they include those optionally substituted with at least one C1-C4 alkyl (e.g., methyl), =O, or a combination thereof); optionally substituted; [ka] (For example, optionally substituted with linear or branched C1-C4 alkyl groups; -(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] (For example, optionally substituted with linear or branched C1-C4 alkyl groups; -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 u, v, w, and x are independently selected from 1, 2, 3, 4, or 5); optionally substituted [ka] (For example, optionally substituted with linear or branched C1-C4 alkyl groups; -(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] (For example, optionally substituted with linear or branched C1-C4 alkyl groups; -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] (For example, optionally substituted with linear or branched C1-C4 alkyl groups; -(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] (For example, optionally substituted with linear or branched C1-C4 alkyl groups; -NH-(CH2)uCO(CH2)vNRPTM1aRPTM2a or -NH-CH2CONRPTM1aRPTM2a, where each u and v is independently selected from 1, 2, 3, 4 or 5); fluoroalkoxys (for example, mono-, di- and / or tri-fluoroalkoxys); optionally substituted monocyclic or bicyclic cycloalkyls (for example, optionally substituted with 3- to 12-membered cycloalkyl groups; optionally substituted with at least one of OH, =O, linear or branched C1-C6 alkyl groups (e.g., methyl, ethyl, or butyl) or NH2; or a combination thereof); optionally substituted hydroxycycloalkyl groups; optionally substituted aryl groups (for example, optionally substituted C5-C10 aryl groups; optionally substituted 5- to 7-membered aryl groups; they are at least one halogen or C1-C3 alkyl group (e.g.) , methyl or ethyl) optionally substituted; or combination thereof, optionally substituted heteroaryls (e.g., optionally substituted 5-10 member heteroaryls, optionally substituted 5-7 member heteroaryls; optionally substituted 5 member heteroaryls; they optionally substituted with at least one halogen or C1-C3 alkyl (e.g., methyl or ethyl); or combination thereof), they are bonded to Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, or Q15 via the C or N atom of the heteroaryl (e.g., at least one of those optionally bonded to Q16 via optionally substituted -(CH2)uO(CH2)vO(CH2)x-, or combination thereof); optionally substituted monocyclic or bicyclic heterocyclines (e.g., optionally substituted 3-12 member heterocyclines;C3-C12 monocyclic or bicyclic heterocycloalkyl groups, azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, or morpholine-4-yl, or homopiperazine-1-yl, each optionally substituted with OH, a linear or branched C1-C5 alkyl group (methyl, ethyl, or butyl group), or NH2, which are optionally bonded to Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, or Q15 via the C or N atom of the heterocyclyl (for example, at least one or both of which are optionally bonded via optionally substituted -(CH2)uO(CH2)vO(CH2)x-, or optionally bonded to Q16); 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, an optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), an optionally substituted C1-C4 alkoxy (e.g., -OCH2 or -CH2CH3), CH2OCH3, or RPTM1a and RPTM2a are bonded together to form a 3- to 10-membered ring; Q6, Q7, Q8, Q9, Q12, Q13, Q14, and Q15 are each independently N, O, or C, and each is optionally substituted with one or more independently selected RPTM1 (e.g., 1, 2, or 3 independently selected RPTM1 depending on the valence); Q16 is C, preferably substituted with H, a 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 optionally substituted with an OH or isopropyl group), 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); X is O, S, or CH2; [ka] It is either a single bond or a double bond; n is an integer between 0 and 10; and PTM [ka] This indicates a bonding site with a chemical linker group or ULM.

[0142] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] During the ceremony, RPTM5 is H, optionally substituted linear or branched C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl group), 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 independently either N or CH; Q7 and Q14 are independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] These are single or double bonds, When Q8 and Q9 are connected by a single bond, Q8 is CH2; and Q9 is either CH(RPTM3) or N(RPTM3); When Q8 and Q9 are connected by a double bond, Q8 is CH; and Q9 is C(RPTM3); RPTM3 consists of: -OH;-Cl;-F;-CN; optionally substituted linear or branched C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy groups (e.g., -OCH3 or -OCH2CH3); optionally substituted [ka] (For example, optionally substituted with linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl;-F, -CN, or -OH); or optionally substituted [ka] (For example, it can be optionally substituted with linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH); RPTM1a and RPTM2a are 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 composed of H, OH, CN, -F, -Cl, optionally substituted linear or branched C1-C4 alkyl groups, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl)2 or -NH(C1-C3 alkyl)), optionally substituted linear or branched -O-C1-C4 alkyl groups, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyl groups (e.g., azetidine-1-yl, azetidine-1-yl-3-ol, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, or morpholine-4-yl, homopiperazine-1-yl). [ka] Each is optionally substituted with one or more of the following: OH, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyl (for example, optionally substituted with one or more OH, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C3-C12 cycloalkyl (for example, OH, linear or branched C1-C6 alkyl (Optionally substituted with one or more of C1-C6 alkoxy, -CN, -F, -Cl or NH2), optionally substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more linear or branched 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 linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl or NH2); and PTM [ka] This indicates the connection point with L.

[0143] In any aspect or embodiment described herein, Q8 and Q9 [ka] It 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 any other PTM structure described herein, is modified to be covalently bonded to a linker group (L) or ULM. In any aspect or embodiment described herein, at least one of Q6 to Q15 of PTMII, or a relevant position of any other PTM structure described herein, is modified to be covalently bonded to a chemical linker group (L) or ULM.

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

[0146] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] During the ceremony, PTM [ka] This indicates a bonding site with a chemical linker group or ULM.

[0147] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] During the ceremony, PTM [ka] This indicates a bonding site with a chemical linker group or ULM.

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

[0149] In any aspect or embodiment described herein, PTM has the following chemical structure: [ka] [ka] [ka] [ka] During the ceremony, RPTM5 contains H, optionally substituted linear or branched alkyl groups (e.g., optionally substituted linear or branched 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 groups (e.g., optionally substituted C1-C6 alkyl, optionally substituted C5-C10 aryl, or both), optionally substituted alkyl-heteroaryl groups (e.g., optionally substituted C1-C6 alkyl, optionally A C5-C10 heteroaryl (substituted for or both), an aryl (e.g., an aryl that is optionally substituted for a C5-C10 aryl), an optional heteroaryl (e.g., an optional heteroaryl), an optional cycloalkyl (e.g., an optional cycloalkyl that is optionally substituted for a C3-C10 cycloalkyl), an optional alkyl-cycloalkyl (e.g., an optional C1-C6 alkyl, an optional C3-C10 cycloalkyl, or both), or an optional heterocyclyl (e.g., an optional C3-C10 heterocyclyl); Q6 is N, CH, C(NO2), or C(CN); Q7 and Q14 are independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] Q8 does not exist if there is no single bond, double bond, or Q8; If Q8 does not exist, [ka] It does not exist, and neither does Q10; 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 optionally substituted C(NH-alkyl-heteroaryl) (e.g., optionally substituted C1-C5 alkyl, optionally substituted 5-7 member heteroaryl, or both); Q9 is CH, C(RPTM3), N, or N(RPTM3); and RPTM3 is: -OH;-Cl;-F;-CN; optionally substituted linear or branched C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., optionally substituted linear or branched C1-C4 alkyl, -OCH3 or -OCH2CH3); optionally substituted [ka] (For example, linear or branched C1-C4 alkyl groups; optionally substituted with -(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] (For example, linear or branched C1-C4 alkyl groups; can be optionally substituted with -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); can be optionally substituted. [ka] (For example, linear or branched C1-C4 alkyl; optionally substituted with -(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] (For example, optionally substituted with linear or branched C1-C4 alkyl;C1-C4 alkoxy;-Cl;-F;-CN;-OH;-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] (For example, linear or branched C1-C4 alkyl; optionally substituted with -(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] (For example, a linear or branched C1-C4 alkyl;C1-C4 alkoxy;-Cl;-F;-CN;-OH;-NH-(CH2)uCO(CH2)vNRPTM1aRPTM2a or -NH-CH2CONRPTM1aRPTM2a, where each u and v is independently selected from 1, 2, 3, 4 or 5); an optionally substituted -alkyl-heteroaryl (for example, a C1-C4 alkyl;-(CH2)t2-optionally substituted with an optionally substituted 5-membered or 6-membered heteroaryl, where the heteroaryl The yl is selected from oxazole-4-yl, 1,3,4-triazole-2-yl, and imidazole-1-yl; and combinations thereof); optionally substituted -NH-alkyl-heteroaryl (e.g., C1-C4 alkyl or combination thereof, optionally substituted with -NH-(CH2)t2-optionally substituted 5- or 6-membered heteroaryl, optionally substituted with N-CH2-pyrazole-4-yl); optionally substituted alkyl-cycloalkyl, or alkyl-heterocycloalkyl (e.g., C1-C4 alkyl -(CH2)t2- 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 with an 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;It is at least one C1-C4 alkyl group (e.g., methyl), which is optionally substituted with =O or a combination thereof; or a combination thereof. RPTM1a and RPTM2a are each independently H, an optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), an optionally substituted C1-C4 alkoxy (e.g., -OCH3 or -CH2CH3 or -OCH2CH3), CH2OCH3, or RPTM1a and RPTM2a are bonded together to form a 3- to 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 composed of H, OH, CN, optionally substituted linear or branched C1-C4 alkyl groups, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl) or -NH(C1-C3 alkyl)), optionally substituted linear or branched -O-C1-C4 alkyl groups, optionally substituted linear or branched C1-C4 alkyl groups, optionally substituted C1-C4 alkynyl groups, and optionally substituted C1-C4 groups. Alkynes, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyls (e.g., optionally substituted C3-C12 monocyclic or bicyclic heterocycloalkyls, e.g., C3-C12 monocyclic or bicyclic heterocycloalkyls, azetidine 1-yl, azetidine 1-yl-3-ol, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, or morpholine-4-yl, homopiperazine-1-yl, [ka] Each is optionally substituted with one or more of the following: OH, linear or branched C1-C5 alkyl, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted -O-C3-12 monocyclic or bicyclic heterocyclils (for example, optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyls, for example, -O-C3-12 monocyclic or bicyclic heterocycloalkyls optionally substituted with one or more OH, linear or branched C1-C5 alkyl, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optional A selectively substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or an optionally substituted C5-C6 aryl (e.g., optionally substituted with one or more linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or an optionally substituted C3-C12 membered ring (e.g., an optionally substituted non-aryl C3-C12 membered ring optionally substituted with one or more of OH, linear or branched C1-C5 alkyl, or NH2), wherein the formula, if RPTM2 is a ring structure, it is optionally covalently bonded to Q16 via C or N of the RPTM2 ring; and PTM [ka] This indicates a bonding site with a chemical linker group (L) or ULM.

[0150] In any aspect or embodiment described herein, PTM has the following chemical structure: [ka] During the ceremony, RPTM5 is H, optionally substituted linear or branched C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl group), 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 either N or CH; Q7 and Q14 are independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] These are single or double bonds, 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 consists of: -OH;-Cl;-F;-CN; optionally substituted linear or branched C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy groups (e.g., -OCH3 or -OCH2CH3); optionally substituted [ka] (For example, optionally substituted with linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl;-F, -CN, or -OH); or optionally substituted [ka] (For example, it can be optionally substituted with linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH); RPTM1a and RPTM2a are 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 composed of H, OH, CN, -F, -Cl, optionally substituted linear or branched C1-C4 alkyl groups, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl)2 or -NH(C1-C3 alkyl)), optionally substituted linear or branched -O-C1-C4 alkyl groups, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyl groups (e.g., azetidine-1-yl, azetidine-1-yl-3-ol, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, or morpholine-4-yl, homopiperazine-1-yl). [ka] Each is optionally substituted with one or more of the following: OH, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted -O-C3-12 monocyclic or bicyclic heterocycloalkyl (for example, optionally substituted with one or more OH, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C3-C12 cycloalkyl (for example, OH, linear or branched C1-C6 alkyl C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl or NH2 (optionally substituted), optionally substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more linear or branched 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 linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl or NH2); and PTM [ka] This indicates a junction with L or ULM.

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

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

[0153] In any aspect or embodiment described herein, the corresponding positions of RPTM5 or any PTM described herein (e.g., PTMII and its derivatives) are: H, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched 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- These include C6 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); and optionally substituted heterocyclyl (e.g., optionally substituted C3-C10 heterocyclyl).

[0154] In any embodiment or configuration described herein, the corresponding positions of RPTM5 or PTM described herein (e.g., PTMII and its derivatives) are H, methyl, CFH2, CF2H, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, hexyl, -CH2CH2OCH3, -CH2CH(CH3)2, -CH2CHN(CH3)2, -CH2-cyclopropyl, -CH2-CH2-cyclopropyl, [ka] Selected from, in the formula, [ka] This indicates the binding site between the nitrogen of the biheteroaryl or biheterocyclic PTM and RPTM5.

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

[0156] In any aspect or embodiment described herein, the corresponding position of 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 PTM described herein (e.g., PTMII and its derivatives) is selected from: H, OH, ethyl, NH2, -N(CH3)2, methyl, ethyl, [ka] During the ceremony, [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific. [ka] This indicates the binding site between the aryl or heteroaryl group of PTM and RPTM2.

[0158] In any aspect or embodiment described herein, the corresponding position of RPTM2 or PTM described herein (e.g., PTMII and its derivatives) is selected from: H, OH, NH2, -N(CH3)2, methyl, ethyl, [ka] During the ceremony, [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific. [ka] This indicates the binding site between the aryl or heteroaryl group of PTM and RPTM2.

[0159] In any aspect or embodiment described herein, the corresponding positions of RPTM3 or any PTM described herein (e.g., PTMI, PTMIII, and its derivatives) are: -OH; optionally substituted linear or branched alkyl, optionally substituted alkoxy (e.g., optionally substituted with linear or branched C1-C4 alkyl or -OCH3); optionally substituted [ka] (For example, linear or branched C1-C4 alkyl groups; optionally substituted with -(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] (For example, linear or branched C1-C4 alkyl groups; -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] (For example, linear or branched C1-C4 alkyl; optionally substituted with -(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] (For example, linear or branched 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] (For example, linear or branched C1-C4 alkyl; optionally substituted with -(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] (For example, a linear or branched 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); an optionally substituted -alkyl-heteroaryl (for example, a C1-C4 alkyl;-(CH2)t2-optionally substituted with an optionally substituted 5-membered or 6-membered heteroaryl, where the heteroaryl is oxazole-4-yl, 1,3, 4-triazole-2-yl and imidazole-1-yl; and combinations thereof selected); optionally substituted -NH-alkyl-heteroaryl (e.g., C1-C4 alkyl or combination thereof, -NH-(CH2)t2-optionally substituted 5- or 6-membered heteroaryl, optionally substituted with N-CH2-pyrazole-4-yl); optionally substituted alkyl-cycloalkyl or alkyl-heterocycloalkyl (e.g., C1-C4 alkyl, -(CH2)t2-optionally selected Optionally substituted with 3- to 6-membered cycloalkyl or heterocycloalkyl groups); optionally substituted with -NH-alkyl-cycloalkyl or -NH-alkyl-heterocycloalkyl groups (e.g., C1-C4 alkyl, -NH-(CH2)t2-optionally substituted with 3- to 6-membered cycloalkyl or heterocycloalkyl groups); optionally substituted with -O-cycloalkyl or -O-heterocycloalkyl groups (e.g., optionally substituted with 3- to 5-membered cycloalkyl groups) is a 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;It is at least one C1-C4 alkyl group (e.g., methyl), which is optionally substituted with =O or a combination thereof; or a combination thereof.

[0160] In any aspect or embodiment described herein, the corresponding position of RPTM3, or any PTM described herein (e.g., PTMII and its derivatives), is [ka] Selected from, in the formula, [ka] This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific. [ka] The ∫ represents the binding site between the biheteroaryl or biheterocyclic ring of PTM and RPTM3, where XPTM3 is selected from CH2, O, and S.

[0161] In any aspect or embodiment described herein, the corresponding position of RPTM5 or any PTM described herein is selected from: H, methyl, CFH2, CF2H, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, hexyl [ka] Selected from, in the formula, [ka] This indicates the binding site between the nitrogen of the biheteroaryl or biheterocyclic PTM and RPTM5.

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

[0163] In any aspect or embodiment described herein, the corresponding positions of RPMT2 or any PTM described herein (e.g., PTMII and its derivatives) are H, OH, CN, optionally substituted linear or branched C1-C4 alkyl, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl) or -NH(C1-C3 alkyl) or -N(CH3)2), O-optionally substituted linear or branched 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, azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, etc.) (or morpholin-4-yl, or homopiperazine-1-yl, each optionally substituted with one or more of OH, linear or branched C1-C5 alkyl, or NH2), or optionally substituted monocyclic or bicyclic -O-C3-12 heterocyclils (for example, optionally substituted monocyclic or bicyclic -O-C3-12 heterocycloalkyls, for example, at least one OH, linear or branched C1-C5 alkyl, or Q16 is a monocyclic or bicyclic heterocycloalkyl group (-O-C3-12) or a ring (-O-C3-12) that is optionally substituted with NH2, or an optionally substituted C3-C12 member ring (e.g., optionally substituted with one or more of an optionally substituted C3-C12 member nonaryl ring, OH, a linear or branched C1-C5 alkyl group, or NH2), wherein the formula, if RPTM2 is a ring structure, it is optionally covalently bonded to Q16 via the C or N of the RPTM2 ring.

[0164] In any aspect or embodiment described herein, 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, PTM is [ka] Represented by PTM [ka] This indicates the connection point with L.

[0171] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] [ka] [ka] [ka] During the ceremony, PTM [ka] This indicates the connection point with L.

[0172] In any aspect or embodiment described herein, the PTM is selected from the following: [ka] [ka] [ka] [ka] During the ceremony, PTM [ka] This indicates a bond site with a linker group (L) or ULM.

[0173] A difunctional compound represented by the following: [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-heterocycline (e.g., an optionally substituted 3-12 member or 4-7 member heterocycline, an optionally substituted heterocycloalkyl, an optionally substituted C3-12 monocyclic or bicyclic heterocycloalkyl, or a combination thereof, which are 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 CLM as described herein, modified to be covalently bonded to L, such group is selected from -C(=O)-, -CONR'-, -O-, -NR'-, a carbon shared with a cyclic group of L, or a nitrogen shared with a cyclic group of L.

[0174] therapeutic composition A pharmaceutical composition comprising an effective amount of at least one bifunctional compound described herein, and a combination of one or more effective amounts of compounds separately described herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient represents a further aspect of this disclosure.

[0175] This disclosure includes, where applicable, compositions comprising pharmaceutically acceptable salts, in particular acid-added salts or base-added salts, of the compounds described herein. Acids used to prepare pharmaceutically acceptable acid-added salts of the above-mentioned base compounds useful according to this embodiment are non-toxic acid-added salts, i.e., salts containing pharmaceutically acceptable anions, such as, in particular among many other acids, acids that form hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, superphosphates, acetates, lactates, citrates, percitric acids, tartrates, bisulfates, succinates, maleates, fumarates, glucons, saccharates, benzoates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)].

[0176] A pharmaceutically acceptable base addition salt may also be used to produce a pharmaceutically acceptable salt form of the compound or derivative of the present disclosure. Chemical bases that can be used as reagents for preparing a pharmaceutically acceptable base salt of the compound, which is acidic in nature, are bases that form a non-toxic base salt with such compound. 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 base salts of other pharmaceutically acceptable organic amines.

[0177] The compounds described herein may be administered orally, parenterally, or topically, in single doses or in divided doses, in accordance with this disclosure. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (e.g., QID), and may include administration by oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include osmotic enhancers), oral, sublingual, and suppository means, among other routes of administration. Enteric-coated oral tablets may be used to enhance the bioavailability of the compound from the oral route. The most effective dosage form will depend on the pharmacokinetics of the selected particular drug, as well as the severity of the patient's disease. The compounds according to this disclosure may be administered as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration. Therefore, this disclosure also aims to provide pharmaceutical compositions containing an effective amount of the compounds described herein, optionally combined with pharmaceutically acceptable carriers, excipients, or additives. The compounds according to this disclosure may be administered as immediate-release, intermediate-release, sustained-release, or controlled-release agents. Sustained-release or controlled-release formulations are preferably administered orally, but they can also be administered via suppositories and transdermal or other topical formulations. Intramuscular injection in liposomal form may be used to control or maintain 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 may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0179] The compositions described herein may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, orally, vaginally, or via implantation container. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intraarachnoid, intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally, or intravenously.

[0180] The sterile injection forms of the compositions described herein may be aqueous suspensions or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents, according to art known techniques. The sterile injection preparations may be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as 1,3-butanediol solution. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oils are conventionally used as solvents or suspension media. For this purpose, any brand of fixative oil, including synthetic monoglycerides or diglycerides, may be employed. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, as there are naturally pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. 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 administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or aqueous solutions. For tablets intended for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, lactose and dried corn starch are useful diluents. If an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners, flavorings, or colorants may also be added, if desired.

[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 suitable non-irritating excipients that are solid at room temperature but become liquid at rectal temperature and thus melt in the rectum to release the drug. Examples of such substances include cocoa butter, beeswax, and polyethylene glycol.

[0183] The pharmaceutical compositions described herein may also be administered topically. Appropriate topical formulations can be readily prepared for each of these areas or organs. Topical application to the lower intestine can be achieved with rectal suppositories (see above) or appropriate enemas. Topically acceptable transdermal patches may also be used.

[0184] With regard to topical application, the pharmaceutical composition may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Examples of carriers for topical administration of the disclosed compounds 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 disclosed, the compounds may be coated onto a stent surgically implanted in a patient, thereby suppressing or reducing the likelihood of occlusion occurring in the stent within the patient.

[0185] Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

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

[0187] The pharmaceutical compositions described herein may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques known in the field of pharmaceutical formulation, and may be prepared as a solution of physiological saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

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

[0189] It should be understood that the specific dosage and treatment regimen for any particular patient depends on various factors, including the activity of the specific compound used, age, weight, general health status, sex, diet, administration time, excretion rate, drug combinations, the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0190] Patients or subjects requiring treatment with compounds described herein may be treated by administering an effective amount of the compound described herein, including pharmaceutically acceptable salts, solvates, or polymorphs thereof, to the patient (subject) either alone or in combination with other known therapeutic agents separately specified herein, optionally in a pharmaceutically acceptable carrier or diluent.

[0191] These compounds can be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically, and can be administered 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 a therapeutically effective dose to the patient for the desired indication without causing serious toxicity to the patient being treated. Preferred doses of the active compound for all conditions referred to herein range from about 10 ng / kg to 300 mg / kg, preferably from 0.1 to 100 mg / kg per day, and more generally from 0.5 to about 25 mg per kg of recipient / patient body weight per day. Typical topical doses may range from 0.01 to 5% wt / wt in a suitable carrier.

[0193] The compound is conveniently administered in any suitable dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of the active ingredient per unit dosage form, but is not limited to this. An oral dose of approximately 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 approximately 0.00001 to 30 mM, more preferably approximately 0.1 to 30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient in physiological saline solution or an aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active drug.

[0195] The concentration of the active compound in the drug composition will depend on the absorption, distribution, inactivation, and elimination rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage will also vary depending on the severity of the condition being alleviated. Furthermore, it should be understood that for any particular subject, a specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or managing the composition, and that the concentration ranges described herein are merely illustrative and not intended to limit the scope or implementation of the claimed composition. The active ingredient may be administered in a single dose or divided into a number of smaller doses administered at various time intervals.

[0196] Oral compositions will generally contain an inert diluent or food carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound or its prodrug derivative can be combined with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition.

[0197] Tablets, pills, capsules, lozenges, 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 Sterotes; fluids such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring, or compounds of similar properties. If the unit dosage form is a capsule, in addition to the above-mentioned types of substances, it may also contain a liquid carrier such as fatty acids. In addition, the unit dosage form may contain various other substances that modify the physical shape of the physical dosing unit, such as sugar coatings, shellac, or enteric coatings.

[0198] The active compound or a pharmaceutically acceptable salt thereof may be administered as a component of elixirs, suspensions, syrups, wafers, chewing gum, etc. In addition to the active compound, the syrup may contain sucrose as a sweetener, or certain preservatives, dyes and colorants, and flavorings.

[0199] The active compound or a pharmaceutically acceptable salt thereof may also be mixed with other active substances that do not impair the desired effect, or with substances that complement the desired effect, such as anticancer agents, as described herein in particular. In certain preferred embodiments of this disclosure, one or more compounds according to this disclosure may be co-administered with other bioactive agents, such as anticancer agents or wound healing agents, including antibiotics, as described herein separately.

[0200] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain the following components: sterile diluents such as, for example, water for injection, saline solution, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as, for example, benzyl alcohol or methylparaben; antioxidants such as, for example, ascorbic acid or sodium bisulfite; chelating agents such as, for example, ethylenediaminetetraacetic acid; buffering agents such as, for example, acetates, citrates, or phosphates; and tension-modulating agents such as, for example, sodium chloride or dextrose. Parenteral preparations may be sealed in ampoules, disposable syringes, or multi-dosage vials made of glass or plastic.

[0201] When administered intravenously, the preferred carrier is physiological saline or phosphate-buffered saline (PBS).

[0202] In one embodiment, the active compound is prepared on a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation including implants and microencapsulation delivery systems. Biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art.

[0203] Liposome suspensions can also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, a liposome formulation may be prepared by dissolving a suitable lipid (e.g., stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, then evaporating the solution to leave a dry lipid film on the surface of a container. An aqueous solution of the active compound is then placed in the container. The container is then rotated by hand to detach the lipid material from the sides of the container, disperse the lipid clumps, and form a liposome suspension.

[0204] Treatment method In additional embodiments, this specification provides therapeutic compositions comprising an effective amount of a compound or a salt form thereof described herein and a pharmaceutically acceptable carrier. The therapeutic compositions can be used to modulate protein degradation in a patient or subject, such as an animal such as a human, and to treat or improve a disease or condition regulated by such degraded protein.

[0205] Where used herein, the terms “to treat,” “to treat,” and “treatment” refer to any effect that benefits a patient, and the compound may be administered for such benefit, including the treatment of any pathological condition or state regulated via the protein to which the compound binds. Disease conditions or states, including cancer, that may be treated using the compounds of this disclosure are described above herein.

[0206] This specification provides therapeutic compositions described herein for causing degradation of a target protein for the purpose of treating or improving a disease, such as cancer. In a particular additional embodiment, the disease is multiple myeloma. Thus, in another embodiment, this specification provides a method for ubiquitinating / degrading a target protein in cells. In a particular embodiment, the method comprises administering a bifunctional compound described herein, the compound comprising, for example, a ULM and a PTM, preferably linked via a linker moiety, as otherwise described herein, the ULM bound to the PTM, and the ULM recognizes a ubiquitin pathway protein (a ubiquitin ligase such as E3 ubiquitin ligase, e.g., cereblon), and the PTM recognizes the target protein such that degradation of the target protein occurs when the target protein is positioned in close proximity to the ubiquitin ligase, thereby resulting in degradation / inhibition of the effect of the target protein and control of protein levels. The control of protein levels brought about by this disclosure provides a treatment for a pathological condition or state which is regulated via the target protein by reducing the level of that protein in cells, such as patient cells. In certain embodiments, the method involves administering an effective amount of the compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0207] In additional embodiments, this specification provides methods for treating or improving a disease, disorder or its symptoms in subjects or patients, such as animals or humans, the methods comprising administering to a subject in need a composition comprising an effective amount, such as a therapeutic effective amount, of a compound or a salt thereof described herein, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, the composition being effective in treating or improving a disease or disorder or its symptoms in the subject.

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

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

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

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

[0212] In another embodiment, this specification provides a method for identifying the degradation effect of a target protein in a biological system using the compounds of this disclosure.

[0213] In another embodiment, the present disclosure aims to provide a method for treating a human patient in need of a pathological condition or state regulated by a protein, wherein the degradation of the protein produces a therapeutic effect in the patient, and the method comprises administering an effective amount of the compound of the present disclosure to the patient in need, optionally in combination with another bioactive agent. The pathological condition or state may be a disease caused by a microbial body or other exogenous entity such as a virus, bacteria, fungi, protozoa or other microorganism, or it may be a pathological condition caused by the overexpression of a protein that gives rise to the pathological condition and / or state.

[0214] The term “pathological condition or state” is used to describe any pathological condition or state in which a protein dysregulation occurs (i.e., an increased amount of a protein is expressed in the patient) and the degradation of one or more proteins in the patient results in a beneficial treatment or symptom relief for the patient in need. In certain cases, the pathological condition or state may be treatable.

[0215] Conditions or states that may be treated with compounds according to this disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavani syndrome, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromocytic disorders, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome (PKD1) or 4(PDK2), sickle cell anemia, Tay-Sachs disease, and Turner syndrome.

[0216] The terms “neoplasm” or “cancer” are used throughout this specification to refer to cancerous or malignant neoplasms, that is, pathological processes resulting in the formation and growth of abnormal tissues, which often grow by the proliferation of cells much faster than normal and continue to grow even after a stimulus has been stimuli to stop the newly initiated growth. Malignant neoplasms exhibit a partial or complete absence of structural organization and a lack of functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, recur after attempted removal, and have a high probability of causing death if not properly treated. As used herein, the term neoplasm is used to describe all cancerous conditions and encompasses pathological processes associated with malignant hematopoietic cells, ascites, and solid tumors. Examples of cancers that can be treated with the compounds of the present invention alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer; leukemia; benign lymphoma, malignant lymphoma, Burkitt lymphoma, non-Hodgkin 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, gliablastoma, neuroblastoma, ganglioblastoma These include cystic tumors, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and schwannomas, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratomas, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, progenitor B-cell ALL, progenitor 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 agents other than the compounds described herein, which are used in combination with the Compound as bioactive agents to assist the therapeutic, inhibitory, and / or preventive / preventive effects for which the Compound is used. Preferred bioactive agents for use herein include agents having pharmacological activity similar to the activity in which the Compound is used or administered, such as anticancer agents, antiviral agents, particularly anti-HIV and anti-HCV agents, antimicrobial agents, and antifungal agents.

[0218] The term “additional anticancer agent” is used to describe an anticancer agent that may be used in combination with a compound relating to this disclosure to treat cancer. These drugs 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 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, and 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, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegovomab, Lep-etu, noratexide, azd2171, batablin, ofatumumab, zanorimumab, edtecarin, tetrandrin, rubitecan, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silenditide, Jaimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanton, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vinclinstine, Temozolomide, ZK-304709, Sericiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamate,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazine methyl)-indoyl-quinolone Batalanib, AG-013736, AVE-0005, Goserelin acetate, Leuprolide acetate, Triptorelyn pamoate, Medroxyprogesterone acetate, Hydroxyprogesterone caproate, Megestrol acetate, Raloxifene, Bicalutamide, Flutamide, Niltamide, Megestrol acetate, CP-724714;TAK-165, HKI-272, Erlotinib, Lapatanib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ronafarnib, BMS-214662, Tipifal Nib; Amifostine, NVP-LAQ824, Suberoylanalide Hydroxamic Acid, Valproic Acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutethimide, Amsacrin, Anagrelide, L-Asparaginase, Calmette-Guéranbacillus (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, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed,Rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cisretinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimasut, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, i Centaleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezomib, Paclitaxel, Cremophore-free Paclitaxel, Docetaxel, Epitiron B, BMS-247550, BMS-310705, Doroxifene, 4-Hydroxytamoxifene, Pipendoxifene, ERA-923, Alzoxifene, Fulvestrant, Acorbifen, 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, Waltmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoietin, Granulocyte colony stimulant Child, Zolendronate, 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, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwiner-asparaginase, strontium-89, casopitant, netsupitant, NK-1 receptor Examples include antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0219] The terms “anti-HIV agents” or “additional anti-HIV agents” include, for example, nucleotide reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., agents not representative of the Disclosure), protease inhibitors, and fusion inhibitors, the exemplary compounds of which include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), and ddC (zalcita). bine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate) Examples of fusion inhibitors include mesylates, RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), and fusions and mixtures thereof, such as T20, including anti-HIV compounds currently in clinical trials or development.

[0220] Other anti-HIV agents that may be used in co-administration with compounds pursuant to this disclosure include, for example, nevirapine (BI-R6-587), delavirdin (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl3-francarbotiamide), etravirine (TMC125), trovirdin (Ly300046.HCl), MKC-442 (emivirin, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, and HBY. 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 (alkenyldiarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), Caplavillin (AG-1549, S-1153), Atevildine (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-indoyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC633001), caranolide A (NSC675451), caranolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidine-4-one (DABO-546), DPC961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscarvir), HEPT(1-[(2-H [(Droxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), Inophyllam P, L-737,126, Mikelamin A (NSC650898), Mikelamin B (NSC649324), Mikelamin F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-Dimethylbenzyl)-1-(ethioxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC648400), Ortiplasm (4-methyl-5-(pyradinyl)-3H-1,2-dithiol-3-thion), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), 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-difluorobenzoxazole-2-yl)ethyl]-5-ethyl-6-methyl(pipridine-2(1H)-thion (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pipridine-2(1H)-thion, R82150, R82913, R87232, R88703, R89439 (Roviride), R90385, S-2720, Suramin sodium, TBZ (thiazolobenzimidazole, NSC Other NNRTIs (i.e., NNRTIs other than those covered by this disclosure) may be selected from the group consisting of 625487), thiazoloisoindole-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindole-5(9bH)-one, tibirapine (R86183), UC-38, and UC-84.

[0221] The term “pharmaceutically acceptable salt” is used throughout this specification to describe, where appropriate, one or more salt forms of the compounds described herein, which exhibit increased solubility of the compounds in gastric juice of the patient’s digestive tract and promote the dissolution and bioavailability of the compounds. Examples of pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include, among many other acids and bases known in the pharmaceutical field, those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, and ammonium salts. Salts of sodium and potassium are particularly preferred as neutralized salts of phosphates according to this disclosure.

[0222] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., esters, amides, other prodrugs, etc.) that, when administered to a patient, directly or indirectly produce the Compound or its active metabolites.

[0223] General synthesis methods The realization and optimization of the synthesis of the bifunctional molecules described herein may be undertaken in a stepwise or modular manner. For example, the identification of compounds that bind to a target molecule may include high-throughput or medium-throughput screening campaigns if a suitable ligand is not immediately available. It is not uncommon for iterative design and cycle optimization to be required for initial ligands to improve upon suboptimal embodiments identified by appropriate in vitro pharmacological assay and / or ADMET assay data. Part of the optimization / SAR campaign is to probe ligand positions that are tolerable for substitution and may be suitable positions for binding the linker chemicals referenced herein above. If crystallographic or NMR structural data are available, these can be used to focus on such synthetic efforts.

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

[0225] Those skilled in the art can use known synthesis methods for combinations of PTMs and ULMs (e.g., CLMs), with or without the presence of a linker moiety, by utilizing PTMs and ULMs (e.g., CLMs) that they possess. Linker moieties can be synthesized and functionalized within a range of compositions, lengths, and flexities, so that PTM and ULM groups can be continuously bonded to the distal end of the linker. Therefore, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. Similar to PTM and ULM groups, the final bifunctional molecules can be iteratively designed and optimized to identify molecules with desired properties.

[0226] In some cases, protecting group strategies and / or functional group interconversion (FGI) may be required to facilitate the preparation of the desired material. Such chemical processes are known to synthetic organic chemists, and many of these processes can be found in books such as, for example, “Greene's Protective Groups in Organic Synthesis” by Peter GMWuts 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 readily prepared using standard reaction techniques known to those skilled in the art) can be reacted with a compound of formula II (also commercially available or readily prepared 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 in compound II may be a leaving group such as a halogen, and Q6 and Q7 are expected to undergo the selective substitutions shown herein. A non-limiting example is X=Cl, where both Q6 and Q7 are N. The 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 PROTAC® of formula V. The compound of formula IV is a highly complex component, with the ULM, linker, and part of the PTM forming a complete subunit. In the formula, [ka] L' represents a 4- to 8-membered cyclic amine or spirocyclic amine (a combination of any two rings from 4,4;4,5;4,6;5,4;5,5;5,6;6,4;6,5; and 6,6), and optionally includes a second nitrogen 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 in Scheme I can be prepared using a procedure found and / or adapted in 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 K2CO3 (but not limited), and alkylated with RPTM1-X. In this case, X can be a leaving group such as iodine or bromo (but not limited). Generally, RPTM1-X is commercially available or readily prepared by those skilled in the art. Alternatively, the boronic acid analog of RPTM1 can be attached to the compound of formula VI using a Chan-Lam coupling reaction (see Chen et al., 2020, Advanced Synthesis and Catalysis 62(16), 3311-3331 for an overview), in which case the boronic acid and the compound of formula VI are mixed in a solvent such as DCE with a copper salt such as Cu(OAc)2 and a base such as Na2CO3, and heated. In this case, it may be preferable to carry out 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 is skipped when the alkylation of 5-nitroisatin (VI with G1=NO2) is carried out directly using RPTM1-X as the compound of formula VIII. The compound 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 in that literature) to produce the ring-extended compound of formula IX. The hydroxyl group of the compound of formula X can be exposed by treating the compound of formula IX with BBR3. The compound of formula I can be obtained in two additional steps by alkylating the hydroxyl group of X with 2-haloacetamide, followed by reduction of the nitro group. Those skilled in the art can utilize many methods for carrying out the nitro reduction.

[0231] Scheme 3 [ka]

[0232] The compound of formula I obtained from the scheme can also be obtained using the method shown in scheme 3. The compound of formula XII (either commercially available or readily available by methods known to those skilled in the art) can be treated with nitric acid in sulfuric acid to form the compound of formula XIII. By heating the compound of formula XIII in a sodium bromate / HBr mixture, the compound of formula XIV can be obtained. Similarly, as shown in scheme 2, the compound of formula XIV can be alkylated with RPTM1-X under basic conditions to obtain the compound of formula XV. By heating this compound with BrettPhos Palladacycle Gen4 in a mixture of dioxane, water, and KOH, the compound of formula X can be obtained. The last 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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}propan-2-yl)piperazine-1-yl]pyrimidine-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl]oxy}-N-methylacetamide (compound 13)

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

[0236] To a 50 mL solution of 5-nitroindoline-2,3-dione (5.00 g, 26.02 mmol, 1.00 equivalent) in N,N-dimethylformamide, potassium carbonate (7.19 g, 52.05 mmol, 2.00 equivalent) and 2-iodopropane (6.64 g, 39.04 mmol, 3.90 mL, 1.50 equivalent) were added. 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 x 3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-isopropyl-5-nitro-indoline-2,3-dione (4.00 g, 17.08 mmol, yield 66%) 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-nitroquinoline-2-one [ka]

[0238] To a 400 mL ethanol solution of 1-isopropyl-5-nitro-indoline-2,3-dione (25.00 g, 106.74 mmol, 1.00 equivalent) that was stirred, triethylamine (234.83 mmol, 33 mL, 2.20 equivalents), followed by a hexane solution of TMS-diazomethane (2 M, 117 mL, 2.20 equivalents), was added at 25°C. After stirring at 25°C for 12 hours, the reaction mixture was poured into water (1500 mL) and extracted with dichloromethane (500 mL x 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 filtered cake was dried under reduced pressure to obtain 1-isopropyl-3-methoxy-6-nitroquinoline-2-one (45.00 g, crude) as a yellow solid. LC-MS (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-nitroquinoline-2-one [ka]

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

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

[0242] This compound was prepared in the same manner as 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methylacetamide. LC-MS (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-oxoquinoline-3-yl)oxy]-N-methylacetamide [ka]

[0244] 2-[(1-isopropyl-6-nitro-2-oxoquinoline-3-yl)oxy]-N-methylacetamide (300.00 mg, 0.94 mmol, 1.00 equivalent) was added to 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 equivalent), the flask was evacuated and flushed with hydrogen. The mixture was stirred at room temperature for 4 hours, then filtered through a Celite bed and concentrated under reduced pressure to obtain 253 mg of 2-[(6-amino-1-isopropyl-2-oxoquinoline-3-yl)oxy]-N-methylacetamide as a bright yellow solid (92%). LC-MS (ES+): m / z 290.00 [M+H+], tR = 0.59 min (run of 1.20 min).

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

[0246] In a 50 mL round-bottom flask, DIEA (268.01 mg, 2.07 mmol, 3 equivalents) and 2,4,5-trichloropyrimidine (152.14 mg, 0.83 mmol, 1.2 equivalents) were added to a mixture of 2-[(6-amino-1-isopropyl-2-oxoquinoline-3-yl)oxy]-N-methylacetamide (200.00 mg, 0.69 mmol, 1.00 equivalent) and DMSO (5 mL). The resulting solution was stirred at 100 °C for 2 hours. The crude product was purified by flash preparative HPLC under the following conditions: column, C18 silica gel; mobile phase, H2O:ACN=100:0 to H2O:ACN=60:40 within 30 minutes; detector: 254 nm. 183 mg (60%) of 2-([6-[(2,5-dichloropyrimidine-4-yl)amino]-1-isopropyl-2-oxoquinoline-3-yl]oxy)-N-methylacetamide was obtained as a bright yellow solid. LC-MS (ES+): m / z 436.00 [M+H+], tR = 0.81 min (run of 1.20 min).

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

[0248] A 500 mL solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (70.68 g, 268.45 mmol, 1 equivalent) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (153.11 g, 402.68 mmol, 1.5 equivalents) in N,N-dimethylformamide was added at 25°C to tert-butylpiperazine-1-carboxylate (50 g, 268.45 mmol, 1 equivalent) and N,N-diisopropylethylamine (104.09 g, 805.36 mmol, 140.3 mL, 3 equivalents), and the mixture was then stirred at 25°C for 2 hours. LC-MS showed the desired m / z, indicating that 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*100 mm*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, yield 86.32%) 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 equivalents) and tetrahydrofuran (200 mL), a solution of tert-butyl 4-(1-benzyloxycarbonyl piperidine-4-carbonyl)piperazine-1-carboxylate (21 g, 48.66 mmol, 1 equivalent) in tetrahydrofuran (600 mL) was added dropwise over 30 minutes at -60°C under nitrogen. Then, methylmagnesium bromide (3 M, 64.9 mL, 4 equivalents) was 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), extracted with ethyl acetate (2 L x 3), and 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, yield 46%) 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 equivalent) in trifluoroethanol (100 mL) and tetrahydrofuran (300 mL) was added at 30°C to palladium activated carbon catalyst (5 g, 10% purity) and palladium hydroxide activated carbon catalyst (10 g, 20% purity). The mixture was then stirred under hydrogen (Psi = 50 Psi) at 30°C for 12 hours. TLC (dichloromethane / methanol = 10 / 1) indicated that the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the crude product. Tert-butyl 4-[1-methyl-1-(4-piperidyl)ethyl]piperazine-1-carboxylate (25 g, 80.27 mmol, yield 89%) 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-isoindorin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-carboxylate [ka]

[0254] A mixture of 3-(5-bromo-1-oxo-isoindorin-2-yl)piperidine-2,6-dione (6 g, 18.57 mmol, 1 equivalent), tert-butyl 4-[1-methyl-1-(4-piperidyl)ethyl]piperazine-1-carboxylate (6.94 g, 22.28 mmol, 1.2 equivalents), cesium carbonate (12.10 g, 37.14 mmol, 2 equivalents), and Pd-PEPPSI-IPentCl-O-picoline (903 mg, 0.93 mmol, 0.05 equivalents) in N,N-dimethylformamide (60 mL) was stirred under nitrogen at 100°C for 8 hours. LC-MS showed the desired m / z, indicating the reaction was complete. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 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%~40%, 25 min). Tert-butyl 4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-carboxylate (3.5 g, 6.32 mmol, yield 34%) was obtained as a yellow solid. (ESI) m / z: 554.2[M+1]+.

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

[0256] To a 50 mL solution of dichloromethane containing tert-butyl 4-[1-[1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-carboxylate (4.00 g, 7.22 mmol, 1 equivalent), trifluoroacetic acid (30.80 g, 270.12 mmol, 20.00 mL, 37.39 equivalents) was added, and the mixture was stirred at 25°C for 1 hour. LC-MS showed the desired m / z. The mixture was concentrated under vacuum. The residue was triturated with methyl tert-butyl ether (50 mL). 3-[5-[4-(1-methyl-1-piperazine-1-yl-ethyl)-1-piperidyl]-1-oxo-isoindorin-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-isoindoline-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-yl]pyrimidine-4-yl]amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide [ka]

[0258] To an 80 mL dimethyl sulfoxide solution of 3-[5-[4-[1-methyl-1-(4-piperidyl)ethyl]piperazin-1-yl]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione (4.10 g, 7.22 mmol, 1 equivalent, trifluoroacetic acid), N,N-diisopropylethylamine (5.60 g, 43.34 mmol, 7.6 mL, 6 equivalents) and 2-[[6-[(2,5-dichloropyrimidine-4-yl)amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methylacetamide (2.84 g, 6.50 mmol, 0.9 equivalents) were added. The mixture was stirred at 120 °C for 3 hours. LC-MS showed the desired m / z, indicating that the reaction was complete. The mixture was diluted with ethyl acetate (200 mL). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was first purified by silica gel chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1), and then purified by preparative HPLC (column: Phenomenex luna C18 (250 × 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-isoindorin-5-yl]-4-piperidyl]-1-methyl-ethyl]piperazine-1-yl]pyrimidine-4-yl]amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (4.3 g, 4.99 mmol, yield 71%, purity 99%) 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-dioxopiperidine-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl]oxy}-N-methylacetamide (compound 15)

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

[0261] NBS (1.2 g, 6.8 mmol, 1.2 equivalents) was added to a mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.4 g, 5.7 mmol, 1.0 equivalent) and AIBN (0.1 g, 0.9 mmol, 0.2 equivalents) in CCl4. The resulting mixture was stirred overnight at 70°C under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with CH2Cl2. The combined organic layers were 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 under the following conditions: Column: C18 silica gel; Mobile phase: Acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increasing to 80:20 within 30 minutes; 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-isoindole-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 equivalent) and 3-aminopiperidine-2,6-dione (0.6 g) in acetonitrile, TEA (0.7 g) was added. 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 a further 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 yielded 635.0 mg (48%) of 3-(5-bromo-6-fluoro-1-oxo-3H-isoindole-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-dioxopiperidine-3-yl)-6-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-carboxylate [ka]

[0265] To a mixture of DMF containing 3-(5-bromo-6-fluoro-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione (350.0 mg, 1.0 mmol, 1.0 equivalent) and tert-butyl 4-(piperidine-4-ylmethyl)piperazine-1-carboxylate (348.9 mg, 1.2 mmol, 1.2 equivalents), Pd-PEPPSI-pent Cl-O-picoline (86.2 mg, 0.1 mmol, 0.1 equivalent) and Cs2CO3 (1002.9 mg, 3.0 mmol, 3.0 equivalents) were added. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 4 hours. The resulting mixture was diluted with CH2Cl2. HOAc was added to the above mixture. The resulting mixture was extracted with CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash preparative HPLC under the following conditions: Column: C18 silica gel; Mobile phase: Acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increased to 80:20 within 30 minutes; Detector: 254 nm. Tert-butyl 4-({1-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-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-(piperazine-1-ylmethyl)piperidine-1-yl]-3H-isoindole-2-yl}piperidine-2,6-dione [ka]

[0267] A mixture of tert-butyl 4-({1-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-carboxylate (145.0 mg, 0.3 mmol, 1.0 equivalent) and hydrogen chloride (2 mL) was stirred overnight at room temperature under an air atmosphere. The resulting mixture was concentrated under reduced pressure. 3-{6-fluoro-1-oxo-5-[4-(piperazine-1-ylmethyl)piperidine-1-yl]-3H-isoindole-2-yl}piperidine-2,6-dione (118.3 mg, 100%) was obtained 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-dioxopiperidine-3-yl)-6-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide [ka]

[0269] In a 10 mL sealed tube, 3-{6-fluoro-1-oxo-5-[4-(piperazine-1-ylmethyl)piperidine-1-yl]-3H-isoindole-2-yl}piperidine-2,6-dione (117.6 mg, 0.3 mmol, 1.3 equivalents), 2-({6-[(2,5-dichloropyrimidine-4-yl)amino]-1-isopropyl-2-oxoquinoline-3-yl}oxy)-N-methylacetamide (89.0 mg, 0.2 mmol, 1.0 equivalent), DMSO, and DIEA (2 mL) were added. The resulting solution was stirred at 100°C for 6 hours. The crude product was purified by flash preparative HPLC under the following conditions: Column: C18 silica gel; Mobile phase: Acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increased to acetonitrile / water (10 mmol / L NH4HCO3) = 80:20 within 30 minutes; Detector: 254 nm. This yielded 54.7 mg (31.8%) of 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-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-dioxopiperidine-3-yl)-1-oxo-3H-isoindole-5-yl]-4-fluoropiperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide (compound 113)

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

[0272] [ka]

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

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

[0275] To a stirred solution of 4-{[1-(tert-butoxycarbonyl)-4-hydroxypiperidine-4-yl]methyl}piperazine-1-carboxylate benzyl (3.6 g, 8 mmol, 1 equivalent) in CH2Cl2, DAST (2 g, 12 mmol, 1.5 equivalents) was added 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 CH2Cl2. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 30 minutes; detector, UV 254 nm. This yielded 4-{[1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-yl]methyl}piperazine-1-carboxylate benzyl (1.2 g, 33%) as an off-white solid. MS(ES+): m / z 436.20, [MH+].

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

[0277] 900 mg, 2 mmol, 1 equivalent) of 4-{[1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-yl]methyl}piperazine-1-carboxylate benzyl was mixed in DCM, to which 2 mL of TFA was added dropwise at room temperature. The resulting mixture was stirred at room temperature for a further 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was neutralized to pH 7 with saturated Na2CO3 (aqueous solution). The aqueous layer was extracted with CH2Cl2. This yielded 4-[(4-fluoropiperidine-4-yl)methyl]piperazine-1-carboxylate benzyl (660 mg, 95%) as an off-white solid. MS(ES+): m / z 336.20, [MH+].

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

[0279] To a 10 mL DMF solution of benzyl 4-[(4-fluoropiperidine-4-yl)methyl]piperazine-1-carboxylate (300 mg, 0.89 mmol, 1 equivalent) and 3-(5-bromo-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione (289 mg, 0.89 mmol, 1 equivalent), Cs2CO3 (582 mg, 1.78 mmol, 2 equivalents) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline (75 mg, 0.089 mmol, 0.1 equivalent) were added. After stirring at 80°C for 4 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The aqueous layer was separated into CH2Cl2 and acid water (10 mL H2O + 0.5 mL Extraction was performed using HOAc). The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 30 minutes; detector, UV 254 nm. This yielded 4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-3H-isoindole-5-yl]-4-fluoropiperidine-4-yl}methyl)piperazine-1-carboxylate benzyl (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-(piperazine-1-ylmethyl)piperidine-1-yl]-1-oxo-3H-isoindole-2-yl}piperidine-2,6-dione [ka]

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

[0282] Step 7.2 - Preparation of {[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-3H-isoindole-5-yl]-4-fluoropiperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide [ka]

[0283] 3-{5-[4-fluoro-4-(piperazine-1-ylmethyl)piperidine-1-yl]-1-oxo-3H-isoindole-2-yl}piperidine-2,6-dione (182 mg, 0.4 mmol, 1.5 equivalents) and 2-({6-[(2,5-dichloropyrimidine-4-yl)amino]-1-isopropyl-2-oxoquinoline-3-yl}oxy)-N-methylacetamide (120 mg, 0.2 mmol, 1 equivalent) were mixed in DMSO, to which 0.5 mL of DIEA was added dropwise at room temperature. The resulting mixture was further stirred at 100°C for 2 hours. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 30 minutes; detector, UV 254 nm. This yielded 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-3H-isoindole-5-yl]-4-fluoropiperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl]-4-fluoropiperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl]oxy}-N-methylacetamide (compound 114) [ka]

[0285] Example 4 was prepared in the same manner as Example 3, by substituting 3-(5-bromo-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione with 3-(4-bromo-1-oxoisoindorin-2-yl)piperidine-2,6-dione. ¹H NMR (400 MHz, DMSO-d6, 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 .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-dioxopiperidine-3-yl)-7-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl]oxy}-N-methylacetamide (compound 18)

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

[0288] NBS (1.3g, 7.3 mmol, 1.2 equivalents) was added to a mixture of methyl 4-bromo-2-fluoro-6-methylbenzoate (1.5g, 6.0 mmol, 1.0 equivalent) and AIBN (0.2g, 1.2 mmol, 0.2 equivalents) in CCl4. The resulting mixture was stirred overnight at 65°C under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with CH2Cl2. The combined organic layers were 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 under the following conditions: Column: C18 silica gel; Mobile phase: Acetonitrile / water (10 mmol / L NH4HCO3) = 0:100, increasing to 80:20 within 30 minutes; Detector: 254. Methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (1.4 g, 68%) was obtained as a yellow oily substance. MS (ES+): m / z 324.05 [MH+].

[0289] Step 2: Preparation of 3-(5-bromo-7-fluoro-1-oxo-3H-isoindole-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 equivalent) and 3-amino-2,6-dioxopiperidine hydrochloride (0.5 g, 4.1 mmol, 1.0 equivalent) in acetonitrile, TEA (0.8 g, 8.3 mmol, 2.0 equivalents) was added. 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 a further 3 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 yielded 718.0 mg (51%) of 3-(5-bromo-7-fluoro-1-oxo-3H-isoindole-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-dioxopiperidine-3-yl)-7-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide [ka]

[0292] Example 5 was prepared in the same manner as in Example 2, by substituting 3-(5-bromo-6-fluoro-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione with 3-(5-bromo-7-fluoro-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione in step 3. The crude product was purified by flash preparative HPLC under the following conditions: Column: C18 silica gel; Mobile phase, acetonitrile / water (10 mmol / L NH4HCO3) = 0:100 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-dioxopiperidine-3-yl)-7-fluoro-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-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-dioxopiperidine-3-yl)-4-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl]oxy}-N-methylacetamide (Compound 26)

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

[0296] In a 250 mL round-bottom flask, 2.00 g (8.847 mmol, 1.00 equivalent) of 4-bromo-2-methoxy-6-methylbenzonitrile, 50 mL of MeOH, 50 mL of H2O, and 1.06 g (26.540 mmol, 3.00 equivalent) of NaOH were added. The resulting solution was stirred in an oil bath at 100°C for 20 hours. The resulting solution was extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 1.56 g (72%) of 4-bromo-2-methoxy-6-methylbenzamide as a yellow solid.

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

[0298] In a 100 mL round-bottom flask, 1.50 g (6.145 mmol, 1.00 equivalent) of 4-bromo-2-methoxy-6-methylbenzamide, 30 mL of dichloromethane, 10 mL of H2O, and 10 mL of nitrosyl sulfate were added. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with 2 × 40 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 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] In a 100 mL round-bottom flask, 4-bromo-2-methoxy-6-methylbenzoic acid (1.20 g, 4.897 mmol, 1.00 equivalent), DMF (15 mL), K2CO3 (2.03 g, 14.690 mmol, 3.00 equivalent), and CH3I (1.04 g, 7.345 mmol, 1.50 equivalent) were added. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 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 on anhydrous sodium sulfate. The residue was traced on a silica gel column with ethyl acetate / petroleum ether (1 / 2). The collected fractions were combined and concentrated under vacuum. This yielded 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] In a 100 mL round-bottom flask, methyl 4-bromo-2-methoxy-6-methylbenzoate (1.10 g, 4.245 mmol, 1.00 equivalent), carbon tetrachloride (15 mL), NBS (831.19 mg, 4.670 mmol, 1.10 equivalent), and 2,2-azobisisobutyronitrile (69.71 mg, 0.425 mmol, 0.10 equivalent) were added. The resulting solution was stirred overnight in an oil bath at 70°C. The reaction was then quenched by adding water (20 mL). The resulting solution was extracted with dichloromethane (2 x 30 mL). The resulting mixture was washed with brine (2 x 20 mL). The mixture was dried on anhydrous sodium sulfate. The residue was traced on a silica gel column with ethyl acetate / petroleum ether (1 / 2). The collected fractions were combined and concentrated under vacuum. This yielded 1.3 g (91%) of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate as a yellow oily substance. MS(ES+): m / z 338.95[MH+]

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

[0304] In a 100 mL round-bottom flask, 3-aminopiperidine-2,6-dione hydrochloride (949.57 mg, 5.769 mmol, 1.50 equivalents), acetonitrile (15 mL), diisopropylethylamine (1.49 g, 11.539 mmol, 3.00 equivalents), and 4-bromo-2-(bromomethyl)-6-methoxybenzoate methyl (1.30 g, 3.846 mmol, 1.00 equivalent) were added. The resulting solution was stirred in an oil bath at 60°C for 1 hour. Next, HOAC (15 mL) was added to the mixture, and the resulting solution was reacted for another hour while stirring, maintaining the temperature at 120°C in the oil bath. The reaction was then quenched by adding water (50 mL). The solid was collected by filtration. This yielded 1.1 g (81%) of 3-(5-bromo-7-methoxy-1-oxo-3H-isoindole-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-dioxopiperidine-3-yl)-7-methoxy-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide [ka]

[0306] Example 6 was prepared in the same manner as in Example 2, by substituting 3-(5-bromo-6-fluoro-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione with 3-(5-bromo-7-methoxy-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione in step 3. The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), gradient from 0% to 60% over 30 minutes; detector, UV 254 nm. 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-7-methoxy-1-oxo-3H-isoindole-5-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-isopropyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide (58.0 mg) was obtained as a bright 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 prepared using the same procedure as in Examples 1-6. [ka] [ka] [ka]

[0308] Example 21: 2-{[6-({5-chloro-2-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-methyl-2-oxo-1,2-dihydroquinoline-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 equivalents) and butyllithium (100.5 mL, 100.5 mmol, 2.2 equivalents) in THF was stirred under a nitrogen atmosphere at -20°C for 30 minutes. 3-bromo-4-fluorobenzoic acid (10.0 g, 45.7 mmol, 1.0 equivalent) was added to the mixture at -50°C. The resulting mixture was stirred for a further 1 hour at -50°C. Methyl iodide (25.9 g, 182.6 mmol, 4.0 equivalents) was added to the mixture. The resulting mixture was stirred overnight at room temperature. The reaction was then quenched by adding 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 under the following conditions (column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L TFA) = 0:100, increasing to MeCN:H2O (10 mmol / L TFA) = 80:20 within 30 minutes; detector, 254 nm), yielding 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 equivalents) and NaOH (0.5 g, 12.9 mmol, 3.0 equivalents) in water, 3-bromo-4-fluoro-2-methylbenzoic acid (1.0 g, 4.3 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at 100°C for 2 hours. 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-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione [ka]

[0314] 3-aminopiperidine-2,6-dione hydrochloride (1.4 g, 8.6 mmol, 1.5 equivalents) and 3-bromo-4-fluorobenzene-1,2-dicarboxylic acid (3.0 g, 5.7 mmol, 1.0 equivalent) were stirred in AcOH, to which NaOAc (2.3 g, 17.1 mmol, 3.0 equivalents) was added. The resulting mixture was stirred under a nitrogen atmosphere at 120°C for 5 hours. The resulting mixture was concentrated under reduced pressure. Cold water was added to the mixture. The precipitated solid was collected by filtration. The obtained solid was dried. This yielded 4-bromo-2-(2,6-dioxopiperidine-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-dioxopiperidine-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-yl]oxy}-N-methylacetamide

[0316] In Example 21, replace 3-(5-bromo-6-fluoro-1-oxo-3H-isoindole-2-yl)piperidine-2,6-dione with 4-bromo-2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione, and in the final step, replace 2-({6-[(2,5-dichloropyrimidine-4-yl)amino]-1-isopropyl-2-oxoquinoline-3-yl}oxy)-N-methylacetamide with 2-({6-[(2,5-dichloropyrimidine-4-yl)amino]-1-methyl-2-oxoquinoline-3-yl}oxy)-N-methylacetamide The preparation was carried out in the same manner as in steps 3-5 of Example 2, with 2-({6-[(2,5-dichloropyrimidine-4-yl)amino]-1-methyl-2-oxoquinoline-3-yl}oxy)-N-methylacetamide. The crude product was purified by preparative HPLC under 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-dioxopiperidine-3-yl)-5-fluoro-1,3-dioxoisoindole-4-yl]piperidine-4-yl}methyl)piperazine-1-yl]pyrimidine-4-yl}amino)-1-methyl-2-oxoquinoline-3-yl]oxy}-N-methylacetamide (17.5 mg, 39%) was obtained 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-isoindoline-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidine-4-yl]amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (compound 5)

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

[0319] To a mixture of 1H-quinoline-2-one (3.50 g, 24.11 mmol, 1.00 equivalent) and concentrated sulfuric acid (15 mL), concentrated nitric acid (11.11 mmol, 0.5 mL, 0.46 equivalents) was added dropwise at 0°C. The mixture was stirred at 0°C for 3 hours. Next, nitric acid (22.22 mmol, 1 mL, 0.92 equivalents) was added to the mixture. The reaction mixture was stirred at 0°C for 1 hour. LC-MS indicated that 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 obtain 6-nitro-1H-quinoline-2-one (2.50 g, 13.15 mmol, yield 55%) 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-quinoline-2-one [ka]

[0321] To a suspension of 6-nitro-1H-quinoline-2-one (12.00 g, 63.11 mmol, 1.00 equivalent), sodium bromate (12.38 g, 82.04 mmol, 1.30 equivalent), and water (100 mL), hydrogen bromide (2120 mmol, 240 mL, 48% purity, 33.62 equivalents) was added, and the reaction mixture was heated at 100°C for 4 hours. LC / MS indicated that the reaction was complete. The reaction mixture was then poured into water (300 mL). The mixture was filtered. The filtered cake was concentrated under reduced pressure to obtain 3-bromo-6-nitro-1H-quinoline-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-nitroquinoline-2-one [ka]

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

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

[0325] To a solution of 3-bromo-1-ethyl-6-nitroquinoline-2-one (3.00 g, 10.10 mmol, 1.00 equivalent) in dioxane (50 mL) and water (100 mL), potassium hydroxide (1.70 g, 30.29 mmol, 3.00 equivalent) 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 equivalent) were added. The mixture was heated at 100°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH 6 with hydrochloric acid (1 M), and the mixture was filtered. The filtered cake was concentrated under reduced pressure to obtain 1-ethyl-3-hydroxy-6-nitroquinoline-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-methylacetamide [ka]

[0327] To a 5 mL acetonitrile solution of 1-ethyl-3-hydroxy-6-nitroquinoline-2-one (1.00 g, 4.27 mmol, 1.00 equivalent), potassium carbonate (1.77 g, 12.81 mmol, 3.00 equivalent) and 2-bromo-N-methylacetamide (0.65 g, 4.27 mmol, 1.00 equivalent) were added. The reaction mixture was stirred at 80°C for 0.5 hours. Water (50 mL) was added to the mixture. The mixture was filtered. The filtered cake was concentrated under reduced pressure to obtain 2-[(1-ethyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methylacetamide (1.20 g, 3.93 mmol, 92% yield) as a yellow solid. LC-MS (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-methylacetamide (1.00 g, 3.28 mmol, 1.00 equivalent) in tetrahydrofuran (25 mL) and methanol (30 mL), palladium carbon (0.15 g, 10% purity) was added. The mixture was stirred at 25°C for 12 hours under a hydrogen atmosphere at 1 atm. The reaction mixture was then filtered. The filtrate was concentrated under reduced pressure to obtain 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methylacetamide (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-dichloropyrimidine-4-yl)amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methylacetamide [ka]

[0331] To a dimethyl sulfoxide solution (30 mL) of 2-[(6-amino-1-ethyl-2-oxo-3-quinolyl)oxy]-N-methylacetamide (1.00 g, 3.63 mmol, 1.00 equivalent) and diisopropylethylamine (10.90 mmol, 1.90 mL, 3.00 equivalent), 2,4,5-trichloropyrimidine (1.33 g, 7.26 mmol, 2.00 equivalent) was added. The mixture was stirred at 100°C for 1 hour, poured into ice water (50 mL), and filtered. The filtered cake was treated with a solution of petroleum ether (50 mL) and ethyl acetate (10 mL), filtered, and 2-[[6-[(2,5-dichloropyrimidine-4-yl)amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methylacetamide (1.20 g, 2.84 mmol, yield 78%) was obtained as a white solid and 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] Synthesis of tert-butyl 4-[(1R,3R)-3-[4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-1-yl]cyclobutoxy]piperidine-1-carboxylate salt [ka]

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

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

[0335] In a 25 mL round-bottom flask, tert-butyl 4-[(1r,3r)-3-[4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-1-yl]cyclobutoxy]piperidine-1-carboxylate (60 mg, 0.1 mmol, 1.0 equivalent), DCM (10 mL), and TFA (3 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. This yielded 55 mg (99%) of 2-(2,6-dioxopiperidine-3-yl)-5-[1-[(1r,3r)-3-(piperidine-4-yloxy)cyclobutyl]piperidine-4-yl]isoindole-1,3-dione as a yellow oily substance. 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-isoindoline-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidine-4-yl]amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide [ka]

[0337] To a dimethyl sulfoxide solution (6 mL) of 2-[[6-[(2,5-dichloropyrimidine-4-yl)amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methylacetamide (120 mg, 0.28 mmol, 1 equivalent) and N,N-diisopropylethylamine (110 mg, 0.85 mmol, 0.1 mL, 3 equivalents), 2-(2,6-dioxo-3-piperidyl)-5-[1-[3-(4-piperidyloxy)cyclobutyl]-4-piperidyl]isoindorin-1,3-dione (190 mg, 0.31 mmol, 1.1 equivalents, trifluoroacetate) was added at 25°C, and the mixture was then stirred at 120°C for 12 hours. LCMS showed the desired m / z, indicating that the reaction was complete. Water (10 mL) was added to the mixture, and the mixture was 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). Then, it was 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-isoindoline-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidine-4-yl]amino]-1-ethyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (35.08 mg, 0.04 mmol, yield 13%, purity 96.5%) 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-isoindoline-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidine-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-methylbenzoate [ka]

[0340] To a 40 mL dichloromethane solution of 2-methylpropan-2-amine (440 mg, 6.02 mmol, 0.6 mL, 1 equivalent) at -70°C, a 2 mL dichloromethane solution of bromine (961 mg, 6.02 mmol, 0.3 mL, 1 equivalent) was added dropwise, and the mixture was stirred at -70°C for 1 hour. Next, a 2 mL dichloromethane solution of 3-hydroxy-2-methylbenzoate (1 g, 6.02 mmol, 1 equivalent) was added dropwise, and the resulting mixture was heated to 25°C and stirred for 11 hours. 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 under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0~150 / 1). The compound 4-bromo-3-hydroxy-2-methylbenzoate methyl (780 mg, 3.18 mmol, yield 52%) 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-methylbenzoate [ka]

[0342] To a 6 mL solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (780 mg, 3.18 mmol, 1 equivalent) in acetonitrile, potassium carbonate (527 mg, 3.82 mmol, 1.2 equivalents) and iodomethane (1.36 g, 9.55 mmol, 0.5 mL, 3 equivalents) were added. The mixture was stirred at 50°C for 5 hours. Several new peaks were observed on LC-MS, and the desired compound was detected. 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 under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1). The compound 4-bromo-3-methoxy-2-methylbenzoate methyl (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-3,4-bromo-2-(bromomethyl)-3-methoxybenzoate methyl [ka]

[0344] To a solution (1 mL) of methyl 4-bromo-3-methoxy-2-methylbenzoate (145 mg, 0.55 mmol, 1 equivalent) in carbon tetrachloride, n-bromosuccinimide (119 mg, 0.67 mmol, 1.2 equivalents) and AIBN (2 mg, 0.02 mmol, 0.03 equivalents) were added. The mixture was stirred at 70°C for 3 hours under a nitrogen atmosphere. 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 under vacuum. 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, yield 89%). 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-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0346] To a solution (7 mL) of methyl 4-bromo-2-(bromomethyl)-3-methoxybenzoate (750 mg, 2.22 mmol, 1 equivalent) and tert-butyl 4,5-diamino-5-oxopentanoate (673 mg, 3.33 mmol, 1.5 equivalents) in N,N-dimethylformamide, N,N-diisopropylethylamine (860 mg, 6.66 mmol, 1.16 mL, 3 equivalents) was added. The mixture was stirred at 110°C for 1 hour. 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 under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0~1 / 2). The compound tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindorin-2-yl)-5-oxopentanoate (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 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindorin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate benzyl [ka]

[0348] A mixture of tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (780 mg, 1.83 mmol, 1 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate benzyl (751 mg, 2.19 mmol, 1.2 equivalents), ditert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (118 mg, 0.18 mmol, 0.1 equivalent), and cesium fluoride (831 mg, 5.48 mmol, 0.2 mL, 3 equivalents) in dioxane (10 mL) and water (1 mL) was degassed and purged three times with nitrogen. The mixture was then stirred under a nitrogen atmosphere at 90°C for 6 hours. The reaction mixture was diluted with water (200 mL). The organic layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna c18 (250 mm x 70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 50%~75%, 17 min). The compound 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindorin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate benzyl (900 mg, 1.60 mmol, yield 87%) 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)isoindorin-2-yl]-5-oxopentanoate [ka]

[0350] 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindorin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate benzyl (900 mg, 1.60 mmol, 1 equivalent) was dissolved in 2,2,2-trifluoroethanol (10 mL) and tetrahydrofuran (10 mL). Palladium activated carbon catalyst (200 mg, 10% purity) and palladium hydroxide activated carbon catalyst (200 mg, 20% purity) were added under a nitrogen atmosphere. The suspension was degassed and purged three times with hydrogen. The mixture was stirred under hydrogen (50 Psi) at 30°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the 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)isoindorin-2-yl]-5-oxopentanoate (680 mg, 1.58 mmol, yield 98%) 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 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate benzyl [ka]

[0352] A mixture of cis-3-benzyloxycyclobutanol (100 g, 561.08 mmol, 1 equivalent) and benzyl 4-oxopiperidine-1-carboxylate (143.97 g, 617.19 mmol, 123.1 mL, 1.1 equivalents) in acetonitrile (2000 mL) was degassed and purged three times with nitrogen. Then chloro(dimethyl)silane (53.09 g, 561.08 mmol, 1 equivalent) was added at 0°C. The mixture was stirred under a nitrogen atmosphere at 25°C for 12 hours. LC-MS 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 x 2). The combined organic layers were washed with brine (500 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1, 20 / 1) to obtain 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 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate benzyl [ka]

[0354] To a solution of 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate benzyl (65 g, 164.35 mmol, 1 equivalent) in ethanol (300 mL) and tetrahydrofuran (300 mL), palladium on an activated carbon catalyst (6 g, 1.44 mmol, 10% purity), palladium hydroxide on an activated carbon catalyst (6 g, 8.54 mmol, 20% purity), and di-tert-butyl dicarbonate (53.80 g, 246.53 mmol, 56.6 mL, 1.5 equivalents) were added under a nitrogen atmosphere. The suspension was degassed and purged three times with hydrogen. The mixture was stirred under hydrogen (50 Psi) at 40°C for 16 hours. Thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) showed that the starting material was completely consumed and two new spots were formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the 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 (30.8 g, 113.51 mmol, yield 69%). 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 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate benzyl [ka]

[0356] 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate benzyl (4 g, 14.74 mmol, 1 equivalent) and triethylamine (4.47 g, 44.22 mmol, 6.16 mL, 3 equivalents) were dissolved in dichloromethane (120 mL). Trifluoromethanesulfonyl anhydride (4.57 g, 16.22 mmol, 2.68 mL, 1.1 equivalents) was added at 0°C. The mixture was stirred at 25°C for 0.5 hours. TLC indicated that the reaction was complete. The reaction was quenched with water (20 mL). The solution was extracted with dichloromethane (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (in petroleum ether, 2-5% ethyl acetate). 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-oxoisoindorin-5-yl)piperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0358] To a 10 mL acetonitrile solution of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindorin-2-yl]-5-oxopentanoate (330 mg, 0.76 mmol, 1 equivalent) and 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate benzyl (339 mg, 0.84 mmol, 1.1 equivalents), N,N-diisopropylethylamine (296 mg, 2.29 mmol, 0.3 mL, 3 equivalents) was added. 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 x 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 the 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%~40%, 20 min) to obtain the title compound as a yellow oil (290 mg, 0.42 mmol, yield 55%). MS(ESI) m / z: 685.3[M+1]+.

[0359] Step 11: Preparation of 3-(4-methoxy-1-oxo-5-(1-((1r,3r)-3-(piperidine-4-yloxy)cyclobutyl)piperidine-4-yl)isoindorin-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)piperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate (290 mg, 0.42 mmol, 1 equivalent) and [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (245 mg, 1.06 mmol, 2.5 equivalents) in acetonitrile (10 mL) was stirred at 80°C for 12 hours. The reaction mixture was basicized with N,N-diisopropylethylamine and then concentrated under reduced pressure to obtain the residue. The crude product was used in the next step without further purification. The title compound was obtained as a colorless, rubbery substance (260 mg, 0.41 mmol, 98% yield, trifluoroacetate). 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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-1-ethyl-2-oxo-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide [ka]

[0362] N,N-diisopropylethylamine (161 mg, 1.25 mmol, 0.2 mL, 3 equivalents) was added to a dimethyl sulfoxide solution (3 mL) of 3-(4-methoxy-1-oxo-5-(1-((1r,3r)-3-(piperidine-4-yloxy)cyclobutyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (260 mg, 0.41 mmol, 1 equivalent, trifluoroacetate) and 2-[[6-[(2,5-dichloropyrimidine-4-yl)amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methylacetamide (181 mg, 0.41 mmol, 1 equivalent). The mixture was stirred at 120°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the 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 (47.8 mg, 0.05 mmol, 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-dioxopiperidine-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide (compound 79)

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

[0365] To a dimethylformamide solution (110 mL) of 4-bromo-5-fluoro-2-methylbenzoic acid (10.50 g, 45.06 mmol, 1.00 equivalent), potassium carbonate (15.57 g, 112.64 mmol, 2.50 equivalents) and iodomethane (19.19 g, 135.17 mmol, 8.4 mL, 3.00 equivalents) were added at 20°C, and the mixture was stirred at 20°C for 2 hours. Thin-layer chromatography (dichloromethane:methanol = 10:1) indicated 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 x 2) and brine (600 mL x 2), dried on sodium sulfate, and then concentrated under reduced pressure to obtain methyl 4-bromo-5-fluoro-2-methylbenzoate (11.00 g, 44.52 mmol, yield 99%) as a yellow oil. ¹H NMR (400 MHz, CDCl3) 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-fluorobenzoate [ka]

[0367] To a 150 mL solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (11 g, 44.52 mmol, 1.00 equivalent) in dichloroethane, N-bromosuccinimide (8.72 g, 48.98 mmol, 1.10 equivalent) and 2,2-azobisisobutyronitrile (731 mg, 4.45 mmol, 0.10 equivalent) were added at 20°C, and the mixture was heated to 80°C. The mixture was stirred at 80°C for 6 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete. The mixture was filtered, 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) and brine (500 mL x 2), dried on sodium sulfate, and then concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1~20:1) to obtain methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (13.00 g, 39.88 mmol, 90% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl3) 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-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

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

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

[0371] The title compound was prepared in the same manner as in step 5 of Example 23. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 0:1) to obtain 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-6-fluoro-1-oxo-isoindorin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate benzyl (2.20 g, 3.91 mmol, yield 81%, purity 98%) 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)isoindorin-2-yl]-5-oxopentanoate [ka]

[0373] The title compound was prepared in the same manner as in 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-oxoisoindorin-5-yl)piperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

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

[0376] Step 7: Preparation of 3-(6-fluoro-1-oxo-5-(1-((1r,3r)-3-(piperidine-4-yloxy)cyclobutyl)piperidine-4-yl)isoindorin-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%~32%, 7 min) to obtain the title product as a white solid (200 mg, 0.33 mmol, yield 56%, trifluoroacetate). 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-dioxopiperidine-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-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%~41%, 10 min) to obtain the title product as a white solid (77.4 mg, yield 25%). 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-dioxopiperidine-3-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide (compound 81)

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

[0382] 4-bromo-3-fluorobenzoic acid (20.00 g, 91.32 mmol, 1.00 equivalent) was added to a tetrahydrofuran solution (200 mL) at -70°C with lithium isopropylamide (2 M, 96.0 mL, 2.10 equivalents). The mixture was stirred at -70°C for 1 hour. Then iodomethane (38.89 g, 273.96 mmol, 17.1 mL, 3.00 equivalents) was added at -70°C. The mixture was then warmed to 20°C and 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 obtain 4-bromo-3-fluoro-2-methylbenzoic 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-methylbenzoate [ka]

[0384] To a methanol solution (100 mL) of 4-bromo-3-fluoro-2-methylbenzoic acid (14.00 g, 60.08 mmol, 1.00 equivalent), thionyl chloride (42.88 g, 360.46 mmol, 26.1 mL, 6.00 equivalent) was added at 20°C, and the mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to obtain the 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 obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain methyl 4-bromo-3-fluoro-2-methylbenzoate (6.00 g, 24.09 mmol, yield 40%) 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-fluorobenzoate [ka]

[0386] To a 70 mL solution of methyl 4-bromo-3-fluoro-2-methylbenzoate (6.20 g, 25.10 mmol, 1.00 equivalent) in dichloroethane, N-bromosuccinimide (4.91 g, 27.60 mmol, 1.10 equivalent) and 2,2-azobisisobutyronitrile (412.09 mg, 2.51 mmol, 0.10 equivalent) 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 x 2) and brine (100 mL), dried on sodium sulfate, and then concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 20:1) to obtain 4-bromo-2-(bromomethyl)-3-fluorobenzoic acid methylu (7.00 g, 21.48 mmol, yield 86%) 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-dioxopiperidine-3-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide [ka]

[0388] Example 25 was prepared in the same manner as Example 24, after 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 obtain the title product as a white solid (83.5 mg, yield 22%, formate). 1H 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-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide (compound 103)

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

[0391] To a solution of 2-cyano-6-methoxy-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyl)methyl benzoate (4 g, 8.45 mmol, 1 equivalent) and 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 equivalent) in 40 mL of dioxane and 8 mL of water, cesium fluoride (3.21 g, 21.13 mmol, 2.5 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (618 mg, 0.84 mmol, 0.1 equivalent) were added under nitrogen. The reaction mixture was stirred at 80°C for 6 hours. Water (100 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain the title product as a yellow solid (2.9 g, 7.79 mmol, yield 92%). 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-methoxycarbonylphenyl)piperidine-1-carboxylate [ka]

[0393] To a solution of tert-butyl 4-(3-cyano-5-methoxy-4-methoxycarbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.9 g, 7.79 mmol, 1 equivalent) in tetrahydrofuran (20 mL) and ethanol (60 mL), palladium activated carbon catalyst (300 mg, 10% purity) was added 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 under vacuum. 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-(piperidine-4-yl)benzoate [ka]

[0395] Trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL, 10.99 equivalents) was added to a 20 mL dichloromethane solution of tert-butyl 4-(3-cyano-5-methoxy-4-methoxycarbonylphenyl)piperidine-1-carboxylate (2.3 g, 6.14 mmol, 1 equivalent). The reaction mixture was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum. Methyl 2-cyano-6-methoxy-4-(piperidine-4-yl)benzoate (2.3 g, 5.92 mmol, yield 96%, trifluoroacetate) 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-methoxycarbonylphenyl)piperidine-1-carboxylate [ka]

[0397] To a solution of 2-cyano-6-methoxy-4-(4-piperidyl)methyl benzoate (2.3 g, 5.92 mmol, 1 equivalent, trifluoroacetate) in tetrahydrofuran (20 mL) and water (20 mL), sodium bicarbonate (2.49 g, 29.61 mmol, 5 equivalents) and (2,5-dioxopyrrolidine-1-yl)2-trimethylsilylethyl carbonate (1.84 g, 7.11 mmol, 1.2 equivalents) were added. The reaction mixture was stirred at 20°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), dried over sodium sulfate, filtered, and concentrated under vacuum. 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-methoxycarbonylphenyl)piperidine-1-carboxylate [ka]

[0399] To a solution of 2-trimethylsilylethyl 4-(3-cyano-5-methoxy-4-methoxycarbonylphenyl)piperidine-1-carboxylate (1.3 g, 3.11 mmol, 1 equivalent) in pyridine (10 mL), ethyl acid (5 mL), and water (4 mL), sodium dihydrogen phosphate hydrate (2.14 g, 15.53 mmol, 5 equivalents) and Raney-Ni (266 mg, 3.11 mmol, 1 equivalent) were added. The reaction mixture was stirred under nitrogen at 50°C for 2 hours. The mixture was filtered, and the filtrate was diluted with water (50 mL). 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 under vacuum. 2-trimethylsilylethyl 4-(3-formyl-5-methoxy-4-methoxycarbonyl-phenyl)piperidine-1-carboxylate (1.3 g, crude) was obtained as a yellow oily substance. 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-isoindoline-5-yl]piperidine-1-carboxylate [ka]

[0401] 2-trimethylsilylethyl 4-(3-formyl-5-methoxy-4-methoxycarbonylphenyl)piperidine-1-carboxylate (1.3 g, 3.08 mmol, 1 equivalent) and tert-butyl 4,5-diamino-5-oxopentanoate (624 mg, 3.08 mmol, 1 equivalent) were dissolved in methanol (10 mL) and 1,2-dichloroethane (10 mL). Acetic acid (185 mg, 3.08 mmol, 1 equivalent) was added to the mixture, and the mixture was stirred at 40°C for 0.5 hours. Then sodium borohydride (387 mg, 6.17 mmol, 2 equivalents) was added to the mixture, and the reaction mixture was stirred at 40°C for 11.5 hours. 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 under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1 to 0:1) to obtain the desired product as a bright yellow solid (660 mg, 1.09 mmol, yield 35%, purity 95%). 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)isoindorin-2-yl]-5-oxopentanoate [ka]

[0403] 2-Trimethylsilylethyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-7-methoxy-1-oxo-isoindorin-5-yl]piperidine-1-carboxylate (660 mg, 1.15 mmol, 1 equivalent) was added to tetrabutylammonium fluoride (1 M, 3 mL, 2.62 equivalents). 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 layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol = 100:1~8:1) to obtain the title product as a yellow oil (400 mg, 0.92 mmol, yield 80%). 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-dioxopiperidine-3-yl)-7-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide [ka]

[0405] Using tert-butyl 5-amino-4-[7-methoxy-1-oxo-5-(4-piperidyl)isoindorin-2-yl]-5-oxopentanoate, Example 26 was prepared in the same manner as Example 24 by steps 6-8 of Example 24. 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%~45%, 10 min) to obtain Example 26 as a yellow solid (36.5 mg, yield 4%, formate). 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-dioxopiperidine-3-yl)-7-fluoro-4-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide (compound 128)

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

[0408] A mixture of 2-fluoro-5-methoxybenzoic acid (1 g, 5.88 mmol, 1 equivalent) and thionyl chloride (5 mL) was stirred at 85°C for 1 hour. The mixture was then concentrated under reduced pressure to obtain 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 equivalents) 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 obtain a residue. The residue was dissolved in ethyl acetate, filtered, and the filtrate was washed with 10% hydrogen chloride, water, and brine. The filtrate was dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1:1) to obtain the desired product as a yellow oily substance (1.35 g, 5.60 mmol, 95% yield).

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

[0410] 2-Fluoro-N-(2-hydroxy-1,1-dimethyl-ethyl)-5-methoxybenzamide (1.2 g, 4.97 mmol, 1 equivalent) was dissolved in dichloromethane (5 mL), to which thionyl chloride (2.38 g, 1.5 mL) was added at 0°C. The mixture was stirred at 25°C for 20 minutes. TLC indicated that 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 x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without further purification. The compound 2-(2-fluoro-5-methoxyphenyl)-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-methylphenyl)-4,4-dimethyl-5H-oxazole [ka]

[0412] To a tetrahydrofuran solution (30 mL) of 2-(2-fluoro-5-methoxyphenyl)-4,4-dimethyl-5H-oxazole (1 g, 4.48 mmol, 1 equivalent), n-butyllithium (2.5 M, 2.3 mL, 1.3 equivalents) was added at -78°C. The mixture was stirred at -78°C for 0.5 hours. Next, methyl iodide (3.18 g, 22.40 mmol, 1.4 mL, 5 equivalents) was added at -78°C, and the mixture was stirred at -78°C for 20 minutes. The reaction mixture was quenched by adding 100 mL of hydrogen chloride (4N), and then extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the 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%~45%, 20 min). The compound 2-(6-fluoro-3-methoxy-2-methylphenyl)-4,4-dimethyl-5H-oxazole (530 mg, 2.23 mmol, yield 50%) 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-methylbenzoic acid [ka]

[0414] To a solution of 2-(6-fluoro-3-methoxy-2-methylphenyl)-4,4-dimethyl-5H-oxazole (10 g, 42.15 mmol, 1 equivalent) in acetone (50 mL), potassium carbonate (17.47 g, 126.44 mmol, 3 equivalents) and methyl iodide (59.82 g, 421.46 mmol, 26.2 mL, 10 equivalents) were added. The mixture was stirred at 25°C for 15 hours. The mixture was then filtered and concentrated under reduced pressure to obtain the residue. The residue was dissolved in methanol (50 mL) and an aqueous solution of 1N sodium hydroxide (200 mL). The mixture was stirred at 75°C for 3 hours. The reaction mixture was quenched by adding 100 mL of hydrogen chloride (6N) and then extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without further purification. 6-fluoro-3-methoxy-2-methylbenzoic acid (5.1 g, 27.69 mmol, 66% yield) of the compound was obtained as a white solid. ¹H NMR (400 MHz, CDCl3) 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-methylbenzoate [ka]

[0416] To a 2 mL solution of 6-fluoro-3-methoxy-2-methylbenzoic acid (8.5 g, 46.15 mmol, 1 equivalent) in N,N-dimethylformamide, potassium carbonate (19.14 g, 138.46 mmol, 3 equivalents) and methyl iodide (19.65 g, 138.46 mmol, 8.6 mL, 3 equivalents) were added. The mixture was stirred at 25°C for 0.5 hours. 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 layer was washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1~20:1) to obtain the desired product as a colorless oil (7.6 g, 38.35 mmol, yield 83%). 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-methylbenzoate [ka]

[0418] To a 20 mL solution of methyl 6-fluoro-3-methoxy-2-methylbenzoate (1.9 g, 9.59 mmol, 1 equivalent) in N,N-dimethylformamide, n-bromosuccinimide (1.71 g, 9.59 mmol, 1 equivalent) was added at 0°C. The mixture was stirred at 70°C for 12 hours. 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 obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1~20:1) to obtain the desired product as a yellow oily substance (0.9 g, 3.25 mmol, yield 17%). MS(ESI) m / z: 279.0[M+1]+.

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

[0420] To a perbromomethane solution (3 mL) of 4-bromo-6-fluoro-3-methoxy-2-methyl methyl benzoate (200 mg, 0.72 mmol, 1 equivalent), n-bromosuccinimide (167 mg, 0.94 mmol, 1.3 equivalents) and azobisisobutyronitrile (50 mg, 0.29 mmol, 0.4 equivalents) 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 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 obtain the residue, which was purified by preparative TLC (in petroleum ether, 20% ethyl acetate) to obtain the desired product as a yellow oily substance (150 mg, 0.42 mmol, yield 58%). 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-dioxopiperidine-3-yl)-7-fluoro-4-methoxy-1-oxo-2,3-dihydro-1H-isoindole-5-yl]piperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide [ka]

[0422] Example 27 was prepared in the same manner as Example 24, after steps 3-8 using the material prepared in step 7 of Example. 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%~45%, 10 min) to obtain the desired product as an off-white solid (50.1 mg, 0.05 mmol, yield 30%, formate). 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 prepared using a method similar to that described in Examples 22-27: [ka]

[0424] Example 30: 2-((6-((5-chloro-2-(4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide, and 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide (compound 118)

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

[0426] A mixture of 4-bromobenzene-1,2-dicarboxylate dimethyl (5 g, 18.31 mmol, 1 equivalent), 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 equivalents), ditert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (1 g, 1.53 mmol, 8.38 e-2 equivalents), and cesium fluoride (8.34 g, 54.93 mmol, 3 equivalents) in dioxane (50 mL) and water (5 mL) was degassed and purged three times with nitrogen. The mixture was then stirred at 100°C for 3 hours 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 layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain the desired product as yellow (6 g, 15.98 mmol, yield 87%). MS (ESI) m / z: 376.4[M+1]+.

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

[0428] To a tetrahydrofuran solution (30 mL) of dimethyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-4-yl)benzene-1,2-dicarboxylate (3.3 g, 8.79 mmol, 1 equivalent), boron;methylsulfanylmethane (10 M, 1.9 mL, 2.2 equivalents) was added dropwise at 0°C. The mixture was then stirred at 25°C for 2 hours. Subsequently, an aqueous solution (20 mL) of sodium;3-oxidedioxavorilane;tetrahydrate (4.06 g, 26.37 mmol, 5.1 mL, 3 equivalents) was added at 0°C, and the mixture was then 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 under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1~1 / 1). The desired product was isolated as a yellow oily substance containing a mixture of trans isomers (2.8 g, 7.12 mmol, yield 81%). 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 4-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-yl)dimethyl phthalate and 4-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-yl)dimethyl phthalate [ka]

[0430] To a 40 mL dichloromethane solution (2.3 g, 5.85 mmol, 1 equivalent) of dimethyl 4-((3R,4R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine-4-yl)phthalate and dimethyl 4-((3S,4S)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine-4-yl)phthalate, 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethaneamine (1.94 g, 8.77 mmol, 1.9 mL, 1.5 equivalents) was added dropwise at -78°C, and the mixture was then 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 x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1~1 / 1) to obtain the desired product as a yellow oily substance containing a mixture of cis isomers (1.8 g, 4.55 mmol, yield 78%). 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 4-((3S,4R)-3-fluoropiperidine-4-yl)dimethyl phthalate and 4-((3R,4S)-3-fluoropiperidine-4-yl)dimethyl phthalate [ka]

[0432] Dimethyl 4-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-yl)phthalate and dimethyl 4-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-yl)phthalate (4.00 g, 10.12 mmol, 1 equivalent) were dissolved in dichloromethane (20 mL), to which trifluoroacetic acid (30.80 g, 270.13 mmol, 20 mL, 26.70 equivalents) was added, and the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under vacuum, the residue was quenched with saturated sodium bicarbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The desired product mixture was obtained as a yellow oily substance (2.5 g, 8.47 mmol, 84% yield). MS(ESI)m / z: 296.2[M+1]+.

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

[0434] A solution of tert-butyl 4-[3-(trifluoromethylsulfonyloxy)cyclobutoxy]piperidine-1-carboxylate (2.66 g, 6.60 mmol, 1.3 equivalents), 4-((3S,4R)-3-fluoropiperidine-4-yl)dimethyl phthalate, and 4-((3R,4S)-3-fluoropiperidine-4-yl)dimethyl phthalate (1.50 g, 5.08 mmol, 1 equivalent), and N,N-diisopropylethylamine (1.97 g, 15.24 mmol, 2.7 mL, 3 equivalents) in acetonitrile (20 mL) was stirred at 35°C for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1~1 / 1) to obtain the desired product as a yellow oily substance (1.6 g, 2.92 mmol, yield 57%). 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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0436] Lithium iodide (1.37 g, 10.21 mmol, 8 equivalents) was added at 25°C to a pyridine solution (10 mL) of 4-((3S,4R)-1-((1r,3S)-3-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)cyclobutyl)-3-fluoropiperidine-4-yl)dimethyl phthalate (700 mg, 1.28 mmol, 1 equivalent) and 3-aminopiperidine-2,6-dione hydrochloride (420 mg, 2.55 mmol, 2 equivalents), and the mixture was then stirred at 130°C for 12 hours. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain the desired product as a yellow oily substance (500 mg, 0.82 mmol, yield 64%). 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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamine Preparation of 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide [ka]

[0438] Example 30 was prepared in the same manner as Example 24, after 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 obtain the desired product as an off-white solid (40.9 mg, 0.04 mmol, yield 31%, purity 95%). 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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]-3,3-difluoropiperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-yl}oxy)-N-methylacetamide (compound 137)

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

[0441] 4-(1-tert-butoxycarbonyl-3-hydroxy-4-piperidyl)benzene-1,2-dicarboxylate dimethyl (2 g, 5.08 mmol, 1 equivalent) was added to a 40 mL dichloromethane solution to which Dess-Martin reagent (3.23 g, 7.63 mmol, 1.5 equivalents) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with a 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 under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to obtain 4-(1-tert-butoxycarbonyl-3-oxo-4-piperidyl)benzene-1,2-dicarboxylate dimethyl (1.4 g, 3.58 mmol, yield 70%) as a yellow oily substance. 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 4-(1-tert-butoxycarbonyl-3,3-difluoro-4-piperidyl)benzene-1,2-dicarboxylate dimethyl [ka]

[0443] To a 40 mL solution of dimethyl 4-(1-tert-butoxycarbonyl-3-oxo-4-piperidyl)benzene-1,2-dicarboxylate (1.40 g, 3.58 mmol, 1 equivalent) in dichloromethane, 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethaneamine (1.98 g, 8.94 mmol, 2.0 mL, 2.5 equivalents) 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 x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Welch Ultimate XB-SiOH 250*50*10um; mobile phase: [hexane-EtOH (0.1% FA)]; B%: 1%~30%, 15 min), and the desired product was obtained as a yellow oily substance (650 mg, 1.57 mmol, yield 44%). 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 4-8: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]-3,3-difluoropiperidine-1-yl}cyclobutoxy]piperidine-1-yl}pyrimidine-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-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 Example) with dimethyl 4-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-yl)phthalate and dimethyl 4-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-yl)phthalate from step 4 of Example 30. 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 obtain 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-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide, and 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide (compound 131)

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

[0448] To a 10 mL acetic acid solution of tert-butyl 4-((1S,3r)-3-((3S,4R)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate (Example 30, Step 6; 450 mg, 0.73 mmol, 1 equivalent), powdered zinc (816 mg, 12.49 mmol, 17 equivalents) was added. 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 layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture of the desired products was obtained as a yellow oil (400 mg, 0.6 mmol, yield 88%). MS(ESI)m / z: 615.2[M+1]+.

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

[0450] In Example 32, triethylsilane (378 mg, 3.25 mmol, 5 equivalents) and trifluoroacetic acid (1.48 g, 13.01 mmol, 1.0 mL, 20 equivalents) were added to a 5 mL dichloromethane solution of the product from Step 1 at 0°C, and the mixture was then stirred at 25°C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 μm; 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, yield 46%, 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, yield 46%, 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-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0452] To a 5 mL solution of dichloromethane containing fraction 1 (150 mg, 0.30 mmol, 1 equivalent) from step 2 and triethylamine (91 mg, 0.90 mmol, 0.1 mL, 3 equivalents), tert-butyl(2-methylpropan-2-yl)oxycarbonyl carbonate (131 mg, 0.60 mmol, 0.1 mL, 2 equivalents) was added at 25°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative TLC (dichloromethane / methanol = 15 / 1) to obtain 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-(piperidine-4-yloxy)cyclobutyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione and 3-(5-((3R,4S)-3-fluoro-1-((1r,3R)-3-(piperidine-4-yloxy)cyclobutyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0454] To a 3 mL solution of tert-butyl 4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]-3-fluoro-1-piperidyl]cyclobutoxy]piperidine-1-carboxylate (100 mg, 0.17 ml, 1.0 equivalent) in dichloromethane, trifluoroacetic acid (3.85 g, 33.74 mmol, 2.5 mL, 202.02 equivalents) was added, and the mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain the desired crude product as a yellow oily substance (80 mg, 0.16 mmol, yield 96%). 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-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide, Preparation of 2-((6-((5-chloro-2-(4-((1R,3r)-3-((3R,4S)-4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidine-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide [ka]

[0456] Example 32 was prepared in the same manner as in step 12 of Example 23. 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%: 17%~47%, 10 min) to obtain 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-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)-3-fluoropiperidine-1-yl)cyclobutoxy)piperidine-1-yl)pyrimidin...

Claims

1. The compound shown below. 【Chemistry 101】

2. A pharmaceutically acceptable salt of the compound shown below. 【Chemical Engineering 102】

3. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt according to claim 2, and a pharmaceutically acceptable carrier.

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

5. The pharmaceutical composition according to claim 4, wherein the additional bioactive agent is an anticancer agent.

6. A pharmaceutical composition for use in the treatment of a disease or disorder in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of the compound described in claim 1 or the pharmaceutically acceptable salt described in claim 2, The aforementioned diseases or disorders include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer; leukemia; benign lymphoma, malignant lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myasthenia sarcoma, peripheral epithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, gliablastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, medulloblastoma A pharmaceutical composition that is a siphonomas, meningiosarcomas, neurofibromas, and schwannomas, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratoma, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, progenitor B-cell ALL, progenitor 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, or non-small cell lung cancer.

7. A pharmaceutical composition for use in the treatment of a disease or disorder in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt according to claim 2, A pharmaceutical composition in which the disease or disorder is lymphoma, B-cell non-Hodgkin lymphoma, large B-cell lymphoma, Burkitt 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.

8. A pharmaceutical composition for use in the treatment of a disease or disorder in a subject, comprising a pharmaceutically acceptable carrier and an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt according to claim 2, A pharmaceutical composition in which the disease or disorder is lymphoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, large B-cell lymphoma, Burkitt lymphoma, or follicular lymphoma.

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