BRM targeting compounds and associated methods of use

Abstract

To provide bifunctional compounds which find utility as modulators of SMARCA2 or BRM (target protein).SOLUTION: The present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds target protein, so that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the target protein. The present disclosure exhibits broad pharmacological activity associated with degradation / inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 651,186, filed April 1, 2018, and entitled "BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE," and U.S. Provisional Patent Application No. 62 / 797,754, filed January 28, 2019, and entitled "BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE," both of which are incorporated herein by reference in their entireties.

[0002] The present description provides bifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, and related methods of use. The bifunctional compounds are useful as regulators of targeted ubiquitination, particularly with respect to switch / sucrose non-fermentable (SWI / SNF)-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) (i.e., BRAHMA or BRM), which is degraded and / or alternatively inhibited by the bifunctional compounds according to the present disclosure. [Background technology]

[0003] Most small molecule drugs bind to enzymes or receptors in precise, well-defined pockets. Protein-protein interactions, on the other hand, are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and, in turn, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. Developing ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of nutrin, the first small molecule E3 ligase inhibitor, additional compounds have been reported to target E3 ligases, but this field remains underdeveloped. For example, since the discovery of nutrin, the first small molecule E3 ligase mouse double minute 2 homologue (MDM2) inhibitor, additional compounds have been reported to target MDM2 (i.e., human double minute 2 or HDM2) E3 ligase (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

[0004] One E3 ligase with exciting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate-recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2, and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the vascular endothelial growth factor (VEGF) and the erythropoiesis-inducing cytokine (erythropoietin) in response to low oxygen levels. We generated the first small molecule ligand of VHL to the substrate-recognition subunit of the E3 ligase, obtained its crystal structure, and confirmed that the compound mimics the binding mode of the transcription factor HIF-1α, a primary substrate of VHL.

[0005] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015 / 0291562 and 2014 / 0356322 (herein incorporated by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Generally, these publications describe bifunctional or proteolysis-targeting chimeric (PROTAC) compounds that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins, which are then degraded and / or alternatively inhibited by the bifunctional compounds.

[0006] Switch / sucrose nonfermentable (SWI / SNF) is a multisubunit complex that regulates pigment structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2, BRAHMA, or BRM) and SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4 or BRG1). The core and regulatory subunits couple ATP hydrolysis to perturbations of histone-DNA contacts, thereby providing attachment points to transcription factors and cognate DNA elements that promote gene activation and repression.

[0007] Mutations in the genes encoding 20 canonical SWI / SNF subunits are observed in nearly 20% of all cancers, with the most frequent mutations observed in rhabdoid tumors, female cancers (including ovarian cancer, uterine cancer, cervical cancer and endometrial cancer), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer and renal clear cell carcinoma.Despite having a high degree of homology and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported to have different roles in cancer.For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is rare in tumorigenesis.In fact, various types of cancer have been shown to be SMARCA4-related (for example, SMARCA4 mutation or SMARCA4 deficiency, such as lack of expression), including lung cancer (for example, non-small cell lung cancer).

[0008] SMARCA2 has been demonstrated to be one of the most essential genes in SMARCA4-related or mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells rely solely on SMARCA2 activity, i.e., SMARCA2 is more highly incorporated into the complex to compensate for SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The co-occurrence of the lack of expression of two (or more) genes that leads to cell death is known as synthetic lethality. Therefore, synthetic lethality can be exploited in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0009] There is a continuing need for effective therapies for diseases treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecific effects and the inability to target and regulate SMARCA2 continue to hinder the development of effective treatments. Therefore, small molecule therapeutics that target SMARCA2 and exploit or enhance the substrate specificity of VHL would be extremely useful. Summary of the Invention

[0010] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods for their use. Specifically, the present disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins, which are then degraded and / or alternatively inhibited by the bifunctional compounds described herein. The advantage of the compounds provided herein is that they are capable of a wide range of pharmacological activity, consistent with the degradation / inhibition of target polypeptides from virtually any protein class or family. In addition, the present description provides a novel therapeutic approach for the treatment of cancer, for example, SM, such as lung cancer or non-small cell lung cancer. Methods are provided using effective amounts of the compounds described herein for the treatment or amelioration of disease conditions such as ARCA4-associated / deficient cancers.

[0011] Thus, in one aspect, the present disclosure provides bifunctional or PROTAC compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand or "PTM" group), thereby placing the target protein / polypeptide in proximity to the ubiquitin ligase, resulting in degradation (and inhibition) of that protein. In a preferred embodiment, the ULM (ubiquitination ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM). For example, the structure of a bifunctional compound can be represented as follows:

[0012] [ka]

[0013] The respective positions of the PTM and ULM moieties, as well as their numbers, exemplified herein are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by one of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0014] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be represented as follows:

[0015] [ka]

[0016] where PTM is a protein / polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group, that connects the PTM to ULM, and ULM is a von Hippel-Lindau E3 ubiquitin ligase (VHL)-binding moiety (VLM).

[0017] For example, the structure of a bifunctional compound can be represented as follows:

[0018] [ka]

[0019] where PTM is a protein / polypeptide targeting moiety, "L" is a linker (e.g., a bond or chemical linker group) that connects the PTM to the VLM, and VLM is a von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3 ligase.

[0020] In certain embodiments, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0021] In additional embodiments, the VLM can be hydroxyproline or a derivative thereof. Additionally, other contemplated VLMs are included in U.S. Patent Application Publication No. 2014 / 03022523, which is incorporated herein in its entirety, as discussed above.

[0022] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a connector having a linear number of non-hydrogen atoms ranging from 1 to 20. The connector "L" can contain functional groups such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker can contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Substitution with halogens such as Cl, F, Br, and I can be included in the linker. Fluorine substitution can include single or multiple fluorines.

[0023] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, in which both the nitrogen and the carboxylic acid in trans-3-hydroxyproline are functionalized as amides.

[0024] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic composition can be used to regulate protein degradation and / or inhibition in a patient or subject, e.g., an animal such as a human, and treat or ameliorate a disease state or condition regulated by the degraded / inhibited protein. In certain embodiments, the therapeutic composition described herein can be used to cause degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer, such as lung cancer (e.g., non-small cell lung cancer), including at least one of SWI / SNF-associated cancer, cancer with SMARCA4 mutation, cancer with SMARCA4 deficiency, or a combination thereof. In yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein, preferably comprising a VLM linked via a linker moiety, as described elsewhere herein, wherein the VLM is linked to a PTM via the linker to target the protein for degradation. Degradation of the target protein occurs when the target protein is placed in proximity to an E3 ubiquitin ligase, thus resulting in degradation / inhibition of the effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment of disease states or conditions regulated by the target protein by reducing the level of the protein in the patient's cells.

[0025] In yet another aspect, the description provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, the method comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease, disorder, or symptom thereof in the subject.

[0026] In another aspect, the description provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0027] The foregoing general areas of utility are offered by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be recognized by those skilled in the art in light of the claims, description, and examples of the present disclosure. For example, various aspects and implementations of the present disclosure may be practiced in various ways. The embodiments can be utilized in numerous combinations, all of which are expressly contemplated by this description. These additional aspects and embodiments are expressly included within the scope of this disclosure. Publications and other materials used herein to illustrate the background of the disclosure and, in particular cases, to provide further details regarding the implementation are incorporated by reference.

[0028] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating one embodiment of the present disclosure and are not to be construed as limiting the disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure. [Brief explanation of the drawings]

[0029] [Figure 1A]Diagram of the general principle of PROTAC function. (A) An exemplary PROTAC includes a protein-targeting moiety (PTM; dark rectangle), a ubiquitin ligase-binding moiety (ULM; light triangle), and, optionally, a linker moiety (L; black line) that couples or tethers the PTM to the ULM. (B) Illustrates the functional use of the PROTACs 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 with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin (dark circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. [Figure 1B] Diagram of the general principle of PROTAC function. (A) An exemplary PROTAC includes a protein-targeting moiety (PTM; dark rectangle), a ubiquitin ligase-binding moiety (ULM; light triangle), and, optionally, a linker moiety (L; black line) that couples or tethers the PTM to the ULM. (B) Illustrates the functional use of the PROTACs 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 with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin (dark circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. DETAILED DESCRIPTION OF THE INVENTION

[0030] The following is a detailed description of the invention, provided to aid those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0031] Described herein are compositions and methods related to the surprising and unexpected discovery that an E3 ubiquitin ligase protein (e.g., von Hippel-Lindau E3 ubiquitin ligase (VHL)) will ubiquitinate a target protein once the two proteins are brought into close proximity via a bifunctional or chimeric construct that links the E3 ubiquitin ligase protein and the target protein. Accordingly, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") linked to a protein target binding moiety ("PTM"), which results in ubiquitination of a selected target protein and the target protein's uptake by the proteasome. This leads to degradation (see Figure 1). The present disclosure also provides libraries of compositions and uses thereof.

[0032] In certain aspects, the present disclosure provides compounds comprising a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons), capable of binding to a ubiquitin ligase such as VHL. The compound also comprises a moiety capable of binding to a target protein such that the target protein is positioned in proximity to the ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. Small molecule, in addition to the above, can mean that the molecule is non-peptidyl, i.e., not generally considered a peptide, and contains, for example, fewer than 4, 3, or 2 amino acids. According to this description, a PTM, ULM, or PROTAC molecule can be a small molecule.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in this description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0034] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, to the nearest tenth of the lower limit (e.g., in the case of a group containing a number of carbon atoms, each number of carbon atoms falling within the range is provided), and any other stated or intervening value in that stated range, is encompassed within the disclosure, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0035] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by one of ordinary skill in the art applying the term in the context in which it is used in describing this disclosure.

[0036] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an" means one element or more than one element.

[0037] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are sometimes conjunctively present and other times disjunctively present. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0038] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" are inclusive. It should be construed as including at least one, but also two or more, of a number or list of elements, and optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" shall only be construed as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by exclusive terms such as "either," "one of," "only one of," or "exactly one of."

[0039] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," and the like, are understood to be open-ended, i.e., to mean "including, but not limited to." Only the transitional phrases "consisting of" and "consisting essentially of" must be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0040] As used herein in the specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of every element specifically recited in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer to, in one embodiment, at least one, optionally, two or more A, and no B (and, optionally, including elements other than B); in another embodiment, at least one, optionally, two or more B, and no A (and, optionally, including elements other than A); in yet another embodiment, at least one, optionally, two or more A, and at least one, optionally, two or more B (and, optionally, including other elements).

[0041] It should also be understood that, in certain methods described herein that include more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless the context dictates otherwise.

[0042] The terms "co-administration" and "co-administering" or "combination therapy" refer to both combined administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a different time than the administration of the additional therapeutic agent(s)), so long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, an anti-cancer agent. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0043] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, including, where context requires, its tautomers, regioisomers, The present invention includes isomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives, where applicable, including prodrugs and / or deuterated forms thereof. Contemplated deuterated small molecules are those in which one or more hydrogen atoms contained in a drug molecule have been replaced with deuterium.

[0044] In its use in context, the term "compound" generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers to prodrug forms of compounds that are modified to facilitate administration and delivery of the compound to the active site. When describing the present compounds, it should be noted that, among other things, numerous substituents and variables associated therewith are described. It is understood by those skilled in the art that the molecules described herein are stable compounds, as outlined herein below. When bonds are shown, both double and single bonds are represented or understood within the context of the compounds shown and the well-known rules of valence interactions.

[0045] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-conjugating enzymes, cause the attachment of ubiquitin to lysines on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-conjugating enzymes, are responsible for the transfer of ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin binds to the first, and a third ubiquitin binds to the second. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may be modified in their cellular location or function, for example, by binding to other proteins that have domains capable of binding to ubiquitin. A further complication is that different lysines on ubiquitin can be targeted by E3s to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin that is recognized by the proteasome. As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise specified, a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8means 1 to 8 carbons). When no specific number of carbon atoms is present, the alkyl groups provided herein are assumed to have 1 to 12 carbons, 1 to 8 carbons, 1 to 6 carbons, or 1 to 4 carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups can be optionally substituted as provided herein. In some embodiments, an alkyl group is selected from the group consisting of C 1-6 alkyl, and in some embodiments the alkyl group is C 1-4 It is alkyl.

[0046] No. 15 / 230,354, filed August 5, 2016, and U.S. Patent Application No. 14 / 371,956, filed July 11, 2014 (published as U.S. Patent Application Publication No. 2014 / 0356322), and U.S. Patent Application No. 15 / 074,820, filed March 18, 2016 (published as U.S. Patent Application Publication No. 2016 / 027263 No. 9, filed February 24, 2016 (published as International Patent Application Publication No. WO2016 / 138114), and International Patent Application No. PCT / US2016 / 023258, filed March 18, 2016 (published as International Patent Application Publication No. WO2016 / 149668), and U.S. Nonprovisional Patent Application No. 15 / 885,671, filed January 31, 2018 (published as U.S. Patent Application Publication No. 2018 / 0215731), all of which are incorporated herein by reference in their entireties. Additionally, all references cited herein are incorporated herein by reference in their entireties.

[0047] The term "optionally substituted," when used in combination with a substituent defined herein, means that the substituent may, but need not, be substituted with one or more suitable functional groups or other substituents as provided herein. For example, the substituent may be halo, cyano, C1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo(C 1-6 ) Alkyl, C 1-6 Alkoxy, Halo(C 1-6 Alkoxy), C 1-6 Alkylthio, C 1-6 Alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, NH(C 1-6 Alkoxy), N(C 1-6 Alkoxy)2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NH2, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -S(O)C 1-6 Alkyl, -S(O)2C 1-6 It may be optionally substituted with one or more alkyl, oxo, phenyl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5- to 6-membered heteroaryl groups. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0048] The term "cycloalkyl" as used herein refers to a C 3-12 "Cycloalkyl" refers to cyclic alkyl groups, including bridged and spirocyclic (e.g., adamantine). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, the cycloalkyl group is C 3-6 It is cycloalkyl.

[0049] The term "alkenyl," as used herein, refers to a C alkyl group in which at least two of the carbon atoms are sp2 hybridized to form a carbon-carbon double bond therebetween. 2-12 The term "alkenyl" refers to an alkyl group. The alkenyl groups provided herein may contain two or more carbon-carbon double bonds, but one is preferred. The alkyl portion of the alkenyl groups provided herein may be substituted as provided above. In some embodiments, the alkenyl group is a C 2-6 It is alkenyl.

[0050] The term "alkynyl" as used herein refers to an alkynyl group having a small number of carbon atoms. At least two Cs are sp hybridized to form a carbon-carbon triple bond between them 2-12 The alkynyl group provided herein may contain two or more carbon-carbon triple bonds, but one is preferred. The alkyl portion of the alkynyl group provided herein may be substituted as provided above. In some embodiments, the alkynyl group is C 2-6 It is alkynyl.

[0051] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group. The term "alkylamino" includes mono- and di-alkylamino groups, where the alkyl portions can be the same or different. obtain.

[0052] The term "halo," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine or chlorine.

[0053] "Haro (C 1-xThe term "halo(C1-C6 alkyl)" refers to an alkyl having 1 to x carbon atoms and substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halo groups. For example, this term includes an alkyl group having 1 to 6 carbon atoms substituted with one or more halo groups. Non-limiting examples of the term halo(C1-C6 alkyl) include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0054] "Haro (C 1-x The term "halo(C1-C6 alkyl)" refers to an alkoxy group having 1 to x carbon atoms and substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halo groups. For example, the term includes an alkoxy group having 1 to 6 carbon atoms substituted with one or more halo groups. Non-limiting examples of the term halo(C1-C6 alkyl) include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, and 2,2,2-trifluoroethoxy.

[0055] The term "heteroalkyl" refers to a straight or branched chain alkyl group, e.g., having 2 to 14 carbons, e.g., 2 to 10 carbons, in the chain, where one or more of the carbons is replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl amides, alkyl sulfides, and the like. The group can be a terminal group or a bridging group. As used herein, reference to a normal chain when used in the context of a bridging group refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

[0056] The term "aryl," as used herein, refers to a single all-carbon aromatic ring or a multiple condensed all-carbon ring system, in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 12 carbon atoms. Aryl includes the phenyl radical. Aryl also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 12 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic. Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the multiple condensed ring system. The rings of a multiple condensed ring system can be connected to each other via fused bonds, spiro bonds, and bridged bonds, as permitted by valency requirements. It is understood that the point of attachment of a multiple condensed ring system can be at any position on the ring system, including the aromatic or carbocyclic portions of the ring, as defined above. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.

[0057] The term "heteroaryl," as used herein, refers to a single aromatic ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, so long as the ring is aromatic. Exemplary heteroaryl ring systems include pyridyl, pyrimidinyl, oxazolyl, or furyl, although these may also be substituted or unsubstituted. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where the heteroaryl group is fused to one or more groups selected from heteroaryl (e.g., to form naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl), as defined above, to form the multiple condensed ring system. Thus, a heteroaryl (single aromatic ring or multiple condensed ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. A heteroaryl (single aromatic ring or multiple condensed ring system) can also have about 5 to 12 or about 5 to 10 members in the heteroaryl ring. The multiple condensed ring system can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of the multiple condensed ring system can be connected to each other via fused bonds, spiro bonds, and bridged bonds, where permitted by valency requirements. It is understood that the individual rings of the multiple condensed ring system can be connected to each other in any order. It is also understood that the point of attachment of the multiple condensed ring system (as defined above for heteroaryl) can be at any position of the multiple condensed ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portions of the multiple condensed ring system. It is also understood that the point of attachment of the heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen).Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, this term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms. Non-limiting examples of heteroaryls include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0058] The term "heterocyclyl" or "heterocycle," as used herein, refers to a single saturated or partially unsaturated ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur; the term also includes multiple condensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) of about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a single heterocycle (as defined above) can be fused with one or more groups selected from heterocycle (e.g., to form 1,8-decahydronapthyridinyl), carbocycle (e.g., to form decahydroquinolyl), and aryl to form multiple condensed ring systems. Thus, a heterocycle (a single saturated or single partially unsaturated ring, or a multiple condensed ring system) has about 2 to 20 carbon atoms and 1 to 6 heteroatoms in the heterocycle. Such multiple condensed ring systems are also contemplated. Fused ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the multiple fused ring. The rings of a multiple fused ring system can be connected to each other through fused, spiro, and bridged bonds, where permitted by valency requirements. It is understood that the individual rings of a multiple fused ring system can be connected to each other in any order. Thus, a heterocyclic ring (a single saturated or single partially unsaturated ring, or a multiple fused ring system) has about 3 to 20 atoms, including about 1 to 6 heteroatoms in the heterocyclic ring system. It is also understood that the point of attachment of a multiple fused ring system (as defined above for heterocyclic rings) can be anywhere in the multiple fused ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring. It is also understood that the point of attachment of a heterocyclic or heterocyclic multiple fused ring system can be at any suitable atom in the heterocyclic or heterocyclic multiple fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). In one embodiment, the term heterocycle refers to a C 2-20 In one embodiment, the term heterocycle includes C 2-7 In one embodiment, the term heterocycle includes C 2-5 In one embodiment, the term heterocycle includes C 2-4Exemplary heterocycles include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, and imidazolidin-2-one. These include, but are not limited to, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidin-2-one. In one embodiment, the term "heterocycle" refers to a monocyclic, saturated, or partially unsaturated 3- to 8-membered ring containing at least one heteroatom. For example, this term includes monocyclic, saturated, or partially unsaturated 4-, 5-, 6-, or 7-membered rings containing at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperazine, oxirane, morpholine, and thiomorpholine. As used herein, the term "9- or 10-membered heterocycle" refers to a partially unsaturated or aromatic fused bicyclic ring system containing at least one heteroatom. For example, the term 9- or 10-membered heterocycle includes bicyclic ring systems containing a benzo ring fused to a 5- or 6-membered saturated, partially unsaturated, or aromatic ring containing one or more heteroatoms.

[0059] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Nitrogen and sulfur may be in the oxidized form, where possible.

[0060] As used herein, the term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0061] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0062] [ka]

[0063] indicates a mixture of E and Z stereoisomers. As used herein, a wavy line crossing a bond in a chemical structure

[0064] [ka]

[0065] or dashed line

[0066] [ka]

[0067] indicates the point of attachment of the bond to which it is attached in a chemical structure to the rest of the molecule. "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical techniques such as electrophoresis and chromatography.

[0068] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0069] Stereochemical definitions and conventions used herein generally follow those in S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about the chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by a compound; (-) or 1 means the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0070] When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g., flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a prescribed stereochemical manner (e.g., bold, bold wedge, dashed line, or dashed wedge), unless otherwise stated, the atom to which the stereochemical bond is attached includes all stereochemical possibilities as depicted. It is understood that the compound is enriched in the enantiomeric form. In one embodiment, the compound may be at least 51% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 80% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 90% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 95% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 97% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 98% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 99% of the absolute stereoisomer shown.

[0071] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0072] As used herein, the term "solvate" refers to the association or complex of one or more solvent molecules and the compound of the present invention.The examples of solvents that form solvates include but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.The term "hydrate" refers to the complex where the solvent molecule is water.

[0073] As used herein, the term "protecting group" refers to a substituent commonly used to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For a general overview of protecting groups and their uses, see P. G. M. Buts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006.

[0074] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl Examples include morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginine acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups, allowing the compounds to be converted into either base or acid addition salts.

[0075] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of the present invention.

[0076] In addition to salt forms, the present invention also provides compounds in prodrug form. As used herein, the term "prodrug" refers to a compound that easily undergoes chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0077] Prodrugs of the present invention include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino, hydroxy, or carboxylic acid group of a compound of the present invention via an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by their three-letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, gamma-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0078] Additional types of prodrugs are also encompassed. For example, free carboxyl groups of the compounds of the invention can be derivatized as amides or alkyl esters. As another example, compounds of the invention containing free hydroxy groups can be prepared as described in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, As outlined in J. Med. Chem., (1996), 39:115, hydroxy groups can be derivatized as prodrugs by converting them to groups such as, but not limited to, phosphate esters, hemisuccinates, dimethylaminoacetates, or phosphoryloxymethyloxycarbonyl groups. Carbamate prodrugs of hydroxy and amino groups also include sulfonate and sulfate esters of hydroxy groups, as do carbonate prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also encompassed, where the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. A more specific example involves converting the hydrogen atom of an alcohol group to a (C 1-6 ) alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, alpha-amino (C 1-4) alkanoyl, aryl acyl, and alpha-amino acyl, or alpha-amino acyl-alpha-amino acyl groups, each alpha-amino acyl group independently being a natural L-amino acid, P(O)(OH), -P(O)(O(C 1-6 ) alkyl) 2, or glycosyl (the radical resulting from removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

[0079] For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985), and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al. al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0080] Furthermore, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced through metabolism in the body of a specific compound or its salt. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

[0081] The metabolites are typically radiolabeled (e.g., 14 C or 3 H) isotopes are prepared and identified by parenteral administration to animals such as rats, mice, guinea pigs, monkeys, or humans at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed similarly to conventional drug metabolism studies well known to those skilled in the art. Metabolites, unless otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

[0082] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of those infections, conditions, or disease states specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals such as dogs or cats, or livestock such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise specified or implied from the context of the use of the term.

[0083] The term "effective," when used within the context of its intended use, is used to describe the amount of a compound, composition, or ingredient that affects an intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0084] Compounds and Compositions In one aspect, the description provides compounds that include an E3 ubiquitin ligase binding moiety ("ULM") that is a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM). In an exemplary embodiment, the ULM is attached to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure: (A) PTM-L-ULM wherein L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of the moieties in the compounds exemplified herein are provided as examples only. As will be understood by those skilled in the art, the compounds described herein can be synthesized with any desired number and / or relative positions of the respective functional moieties.

[0085] In another aspect, the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) useful for regulating protein activity by inducing target protein degradation. In certain embodiments, the compounds include a VLM attached, e.g., covalently, directly, or indirectly, to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the VLM and PTM are linked or connected via a chemical linker (L). The VLM binds to VHL, and the PTM recognizes the target protein, and the interaction of each moiety with their target promotes degradation of the target protein by placing the target protein in close proximity to a ubiquitin ligase protein. An exemplary bifunctional compound can be represented as a PTM-VLM.

[0086] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be represented as follows: PTM-L-VLM where PTM is a protein / polypeptide targeting moiety, L is a chemical linker, and VLM is a VHL binding moiety.

[0087] In certain embodiments, ULM (e.g., VLM) has an IC of less than about 200 μM. 50 exhibit activity towards or bind to E3 ubiquitin ligases (e.g., VHL) in IC 50 can be determined according to any method known in the art, for example, a fluorescence polarization assay.

[0088] In certain additional embodiments, the bifunctional compounds described herein have a concentration 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. IC<5, 0.1, 0.05, 0.01, 0.005, 0.001 pM 50 It exhibits activity having the following properties:

[0089] In certain embodiments, a compound comprises multiple ULMs, the ULMs are the same. In additional embodiments, a compound comprises multiple ULMs (e.g., ULM, ULM', etc.), at least one PTM attached to a ULM directly or via a chemical linker (L), or both. In certain additional embodiments, a compound comprising multiple ULMs further comprises multiple PTMs. In even further embodiments, the PTMs are the same or, optionally, different. In still further embodiments, where the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

[0090] In certain embodiments, a compound comprises multiple ULMs and / or multiple ULMs'. In further embodiments, a compound comprising at least two different ULMs, multiple ULMs, and / or multiple ULMs' further comprises at least one PTM attached to the ULM or ULM' directly or via a chemical linker, or both. In any of the embodiments described herein, a compound comprising at least two different ULMs can further comprise multiple PTMs. In yet additional embodiments, the PTMs are the same or optionally different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0091] In additional embodiments, the present description provides the compounds described herein, including their pharmaceutically acceptable salt forms, e.g., acid and base salt forms, including their enantiomers, diastereomers, solvates, and polymorphs.

[0092] Exemplary VLM In certain embodiments, the compounds described herein comprise a means for binding to an E3 ubiquitin ligase, e.g., a von Hippel-Lindau E3 ubiquitin ligase. In certain embodiments, the ULM is a VLM and comprises a chemical structure selected from the ULM-a group:

[0093] [ka]

[0094] During the ceremony, the dashed line indicates the attachment of at least one PTM, another ULM or VLM (VLM'), or a chemical linker moiety connecting at least one PTM, ULM', or VLM' to the other end of the linker; X in the formula ULM-a 1 , X 2 each independently represents a bond, O, or NR Y3 , C.R. Y3 RY4 , C=O, C=S, SO, and SO; R in the formula ULM-a Y3 , R Y4 each independently represents a straight or branched chain C optionally substituted with H, one or more halo 1-6 alkyl, optionally substituted (e.g., 0-3 R P Optionally substituted with a C group 1-6 is selected from the group consisting of alkoxyl, R in the formula ULM-a P is 0, 1, 2, or 3 groups, each independently selected from H, halo, —OH, C 1-3 Alkyl, C=O, alkyl, alkoxy, or a combination thereof selected from a group of Formula ULM-a W 3 is optionally substituted T, optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-biheteroaryl, optionally substituted -T-heterocyclyl, optionally substituted -T-biheterocyclyl, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl, or optionally substituted -NR 1 -T-heterocyclyl, X in the formula ULM-a 3 But C=O, R 1 , R 1a , R 1b and R 1 , R 1a , R 1b each independently represents H, a straight or branched chain C-C alkyl group optionally substituted with one or more halo, or an —OH group, R Y3 C=O, R Y3 C=S, R Y3 SO, R Y3 SO2, N(R Y3 RY4 )C=O, N(R Y3 R Y4 )C=S,N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO2, T of formula ULM-a is optionally substituted alkyl, —(CH) n - group, optionally substituted straight or branched chain -(CH2) n -O-C1-C6 alkyl, or optionally substituted -(CH2) n -O-heterocyclyl, wherein each methylene group is substituted with one or two substituents selected from the group of halogen, methyl, a straight or branched C1-C6 alkyl group optionally substituted with one or more halogens, or an -OH group, an optionally substituted amino acid side chain, or an optionally substituted heterocyclyl; Formula ULM-a W 4 is an optionally substituted -NR1-T-aryl, wherein the aryl group can be an optionally substituted 5-6 membered heteroaryl, or an optionally substituted aryl, an optionally substituted -NR1-T-heteroaryl group, wherein the heteroaryl is optionally substituted with an optionally substituted aryl, or an optionally substituted heteroaryl, or an optionally substituted -NR1-T-heterocyclyl, wherein -NR1 is X 2 covalently bonded to R 1 is H or CH3, preferably H.

[0095] In certain embodiments, R P is modified to form a prodrug, including an ester or ether bond.

[0096] In any of the embodiments described herein, T is optionally substituted alkyl, —(CH) n - groups, wherein each methylene group is selected from the group consisting of halogen, methyl, optionally substituted alkoxy, straight or branched C1-C6 alkyl groups optionally substituted with one or more halogens, C(O)NR 1 R1a , or NR 1 R 1a or R 1 and R 1a are attached to form an optionally substituted heterocyclyl, or an —OH group, or an optionally substituted amino acid side chain, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

[0097] In certain embodiments, W of formula ULM-a 4 teeth,

[0098] [ka]

[0099] where R 14a , R 14b are each independently H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine.

[0100] In any of the embodiments, W of formula ULM-a 5is selected from the group of optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 membered heteroaryl; R in the formula ULM-a 15 H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl.

[0101] In additional embodiments, W for use in the present disclosure 4 Substituents may also be any of the W groups found in certain compounds disclosed herein. 4 These W groups are specifically included (and are not limited to the particular compounds disclosed). 4 Each of the substituents may be any number of W as also disclosed herein. 3 It may be used in conjunction with a substituent.

[0102] In certain additional embodiments, ULM-a has 0 to 3 R in the pyrrolidine moiety. P Each R is optionally substituted by a group. P are independently H, halo, —OH, C1-3 alkyl, or C═O.

[0103] In any of the embodiments described herein, W of formula ULM-a 3 , W 4 can be independently covalently attached to a linker that is attached to one or more PTM groups; wherein the dashed lines indicate the attachment site for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0104] In certain embodiments, the ULM is VHL and is represented by the following structure:

[0105] [ka]

[0106] During the ceremony, W in formula ULM-b 3 is optionally substituted aryl, optionally substituted heteroaryl, or

[0107] [ka]

[0108] is selected from the group R9 and R of formula ULM-b 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R in formula ULM-b 11 optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0109] [ka]

[0110] is selected from the group R in formula ULM-b 12 is selected from the group of H or optionally substituted alkyl; R in formula ULM-b 13 is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in formula ULM-b 14a , R 14b are each independently H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CONR 27a R 27b , CH2NHCOR 26 , or (CH2)N(CH3)COR 26 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; W in formula ULM-b 5 is selected from the group of phenyl, naphthyl, or 5-10 membered heteroaryl; R in formula ULM-b 15 H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; Each R in formula ULM-b 16 is independently selected from the group of halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; are selected from o of formula ULM-b is 0, 1, 2, 3, or 4; R in formula ULM-b 18 is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; Each R 26 are independently H, optionally substituted alkyl, or NR 27a R 27b is selected from Each R 27a and R 27b are independently H, optionally substituted alkyl, or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; The p of formula ULM-b is 0, 1, 2, 3, or 4, where the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0111] In certain embodiments, R of formula ULM-b 15 teeth,

[0112] [ka]

[0113] where R 17 is H, halo, optionally substituted C 3-6Cycloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl, and C 1-6 haloalkyl, and Xa is S or O.

[0114] In certain embodiments, R of formula ULM-b 17 is selected from the group of methyl, ethyl, isopropyl, and cyclopropyl.

[0115] In certain additional embodiments, R of formula ULM-b 15 is selected from the group consisting of:

[0116] [ka]

[0117] In certain embodiments, R of formula ULM-b 11 is selected from the group consisting of:

[0118] [ka]

[0119] [ka]

[0120] In certain embodiments, R of formula ULM-b 14a , R 14b are each independently H, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CHOR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R27b , CH2CONR 27a R 27b , CH2NHCOR 26 , or CH2NCH3COR 26 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine, and the spirocycloalkyl or spiroheterocyclyl itself is an alkyl, haloalkyl, or -COR 33 wherein R 33 is alkyl or haloalkyl, In the formula, R 30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or further optionally substituted heteroarylalkyl; R 26 and R 27 However, as stated above.

[0121] In certain embodiments, R of formula ULM-b 15 H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl (e.g., optionally substituted fluoroalkyl), optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl. wherein the optional substitutions of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of CH2OR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , CH2NCH3COR 26 ,or

[0122] [ka]

[0123] wherein R 26 , R 27 , R 30 , and R 14 a is as described above. In certain embodiments, R of formula ULM-b 14a , R 14b each independently represents H, optionally substituted haloalkyl, optionally substituted alkyl, CHOR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , or CH2NCH3COR 26 R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered spirocycloalkyl or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine, and the spirocycloalkyl or spiroheterocyclyl itself is not an alkyl, haloalkyl, or -COR 33 wherein R 33is alkyl or haloalkyl, wherein R 30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or further optionally substituted heteroarylalkyl; R in formula ULM-b 15 H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein the optional substitutions of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from CHOR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , CH2NCH3COR 26 ,or

[0124] [ka]

[0125] wherein R 26 , R 27 , R 30 , and R 14 a is as described above. In certain embodiments, ULM has a chemical structure selected from the group consisting of:

[0126] [ka]

[0127] During the ceremony, R1 of formulae ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R for formulas ULM-c, ULM-d, and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R for formulas ULM-c, ULM-d, and ULM-e 15 is selected from the group consisting of H, halogen, CN, OH, NO, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; X of formula ULM-c, ULM-d, and ULM-e is C, CH, or C=O; R3 of formulae ULM-c, ULM-d, and ULM-e is absent or an optionally substituted 5- or 6-membered heteroaryl; Dashed lines indicate attachment sites for at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0128] In certain embodiments, a ULM comprises a group according to the following chemical structure:

[0129] [ka]

[0130] During the ceremony, R in the formula ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 of formula ULM-f is H; R in the formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R in the formula ULM-f 11 but,

[0131] [ka]

[0132] or optionally substituted heteroaryl; of the formula ULM-f, p is 0, 1, 2, 3, or 4; Each R in the formula ULM-f 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; R in the formula ULM-f 12 is H, C=O, R in the formula ULM-f 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in the formula ULM-f 15 is H, halogen, Cl, CN, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl,

[0133] [ka]

[0134] and wherein the dashed line in formula ULM-f indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0135] In certain embodiments, ULM is selected from the following structures:

[0136] [ka]

[0137] In the formula, n is 0 or 1. In certain embodiments, ULM is selected from the following structures:

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] wherein the phenyl rings in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to ULM.

[0143] In one embodiment, the phenyl rings in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 can be functionalized as esters to become part of a prodrug.

[0144] In certain embodiments, the hydroxyl group on the pyrrolidine ring of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 each comprises an ester-linked prodrug moiety.

[0145] In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0146] [ka]

[0147] or a pharmaceutically acceptable salt thereof, wherein: ULM-g R 1’ optionally substituted C1-C6 alkyl groups, optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6) alkyl group, optionally substituted (CH2) containing an epoxide moiety WCOCW, where each W is independently H or a C1-C3 alkyl group. n-WCOCW-(C0-C6) alkyl group, optionally substituted -(CH2) n COOH, optionally substituted -(CH2) n C(O)—(C1-C6 alkyl), optionally substituted —(CH2) n NHC(O)-R″, optionally substituted —(CH2) n C(O)-N(R")2, optionally substituted -(CH2) n OC(O)-N(R″)2, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), optionally substituted —(CH2) n C(O)—O—(C1-C6 alkyl), optionally substituted —(CHO) n COOH, optionally substituted -(OCH2) n O—(C1-C6 alkyl), optionally substituted —(CHO) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2) n NHC(O)-R″, optionally substituted —(CHO) n C(O)-N(R″)2, -(CH2CH2O) n H, optionally substituted -(CH2CH2O) n COOH, optionally substituted -(OCH2CH2) n O-(C1-C6 alkyl), optionally substituted -(CH2CH2O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2CH2) n NHC(O)-R″, optionally substituted —(CH2CH2O) n C(O)-N(R″)2, optionally substituted -SO2R S , optionally substituted S(O)R S , NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl), each R″ of ULM-g is independently H or a C1-C6 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine); ULM-g R Sis a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or -(CH2) m N(R″)2 group, X and X' of ULM-g are each independently C=O, C=S, -S(O), or S(O)2 (preferably, both X and X' are C=O); ULM-g R 2’ is an optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w Alkyl groups, optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w NR 1N R 2N group, optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -(C=O) v NR″(SO2) w -heterocyclyl, optionally substituted -NR"-(CH2) n -C(O) u (NR″) v (SO2) w -Alkyl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -NR 1N R 2N , optionally substituted -NR"-(CH2) n -C(O) u (NR″) v (SO2) w -NR″C(O)R 1N , optionally substituted -NR"-(CH2) n-(C=O) u (NR″) v (SO2) w -aryl, Optionally substituted -NR"-(CH2) n -(C=O) u (NR″) v (SO2) w -heteroaryl or optionally substituted -NR"-(CH2) n -(C=O) v NR″(SO2) w -heterocyclyl, optionally substituted -X R2’ -Alkyl group, optionally substituted -X R2’ -aryl group, optionally substituted -X R2’ -heteroaryl group, optionally substituted -X R2’ -heterocyclyl group, ULM-g R 3’ optionally substituted alkyl, optionally substituted -(CH2) n -(O) u (NR″) v (SO2) w -alkyl, optionally substituted -(CH2) n -C(O) u (NR″) v (SO2) w -NR 1N R 2N , optionally substituted -(CH2) n -C(O) u (NR″) v (SO2) w -NR″C(O)R 1N , optionally substituted -(CH2) n -C(O) u (NR″) v (SO2) w -C(O)(R″)2, optionally substituted -(CH2) n -C(O) u (NR″) v (SO2) w -aryl, optionally substituted -(CH2) n -C(O) u (NR″) v (SO2) w-heteroaryl, optionally substituted -(CH2) n -C(O) u (NR″) v (SO2) w -heterocyclyl, optionally substituted -NR"-(CH2) n -C(O) u (NR″) v (SO2) w -Alkyl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -NR 1N R 2N , optionally substituted -NR"-(CH2) n -C(O) u (NR″) v (SO2) w -NR″C(O)R 1N , optionally substituted -NR"-(CH2) n -C(O) u (NR″) v (SO2) w -aryl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR″) v (SO2) w -heterocyclyl, optionally substituted -O-(CH2)n-(C=O) u (NR″) v (SO2) w -Alkyl, optionally substituted -O-(CH2)n-(C=O) u (NR″) v (SO2) w -NR 1N R 2N , optionally substituted -O-(CH2)n-(C=O) u (NR″) v (SO2) w -NR″C(O)R 1N, optionally substituted -O-(CH2)n-(C=O) u (NR″) v (SO2) w -aryl, optionally substituted -O-(CH2) n -(C=O) u (NR″) v (SO2) w -heteroaryl or optionally substituted -O-(CH2) n -(C=O) u (NR″) v (SO2) w -heterocyclyl, -(CH2) n -(V) n’ -(CH2) n -(V) n’ -Alkyl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -heterocyclyl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -Alkyl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclyl group, optionally substituted -X R3’-alkyl group, optionally substituted -X R3’ -aryl group, optionally substituted -X R3’ -heteroaryl group, optionally substituted -X R3’ -heterocyclyl group, ULM-g R 1N and R 2N are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups and up to three halogen groups, or optionally substituted -(CH2) n -aryl, -(CH2) n -heteroaryl, or -(CH2) n -heterocyclyl group, V of ULM-g is O, S, or NR1; Each R of ULM-g 1’ are independently H or a C1-C3 alkyl group; ULM-g X R2’ and X R3’ each independently represents an optionally substituted —CH2) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group, wherein X v is H, halo, or an optionally substituted C1-C3 alkyl group; each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; each m' of ULM-g is independently 0 or 1; each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; each n' of ULM-g is independently 0 or 1; each u in ULM-g is independently 0 or 1; each v of ULM-g is independently 0 or 1; each w of ULM-g is independently 0 or 1; If the PTM is not ULM', the R of ULM-g1’ , R 2’ , R 3’ any one or more of X, X, and X′ are optionally modified to be covalently attached to the PTM group via a linker group, or, when the PTM is a ULM′, R of each of the ULM and ULM′ 1’ , R 2’ , R 3’ Any one or more of X, X, and X' are optionally modified to be a group, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, covalently bonded to each other directly or through a linker group.

[0148] In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0149] [ka]

[0150] During the ceremony, Each R of ULM-h 1’ , R 2’ , and R 3’ is the same as above, and X is a C=O, C=S, -S(O) or S(O) group, more preferably a C=O group; If the PTM is not ULM', the R of ULM-h 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to further covalently link to the PTM group, or when the PTM is a ULM′, R of each of the ULM and ULM′ 1’ , R 2’ , R 3’ any one or more of which are optionally modified to be covalently linked to each other directly or via a linker group; or A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof.

[0151] In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0152] [ka]

[0153] During the ceremony, If the PTM is not ULM', the R of ULM-I 1’ , R 2’ , and R 3’ any one or more of which are optionally modified to further covalently link to the PTM group, or when the PTM is a ULM′, R of each of the ULM and ULM′ 1’ , R 2’ , R 3’ any one or more of which are optionally modified to be covalently linked to each other directly or via a linker group; or A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof.

[0154] In a further preferred embodiment of the present disclosure, R of ULM-g to ULM-i 1’ is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxylic acid group such that the compound represents a prodrug form of the active compound. Exemplary preferred R 1’ Examples of the group include -(CH2) n OH, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CHO) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), or optionally substituted -(CH2) n C(O)—O—(C1-C6 alkyl), where n is 0 or 1. R 1’is or contains a carboxylic acid group, a hydroxyl group, or an amine group, the hydroxyl group, carboxylic acid group, or amine (each of which may be optionally substituted) may be further chemically modified to provide a covalent bond to a linker group to which a PTM group (including a ULM' group) is attached.

[0155] X and X′ of ULM-g and ULM-h, when present, are preferably C═O, C═S, —S(O), or —S(O) groups, more preferably C═O groups.

[0156] ULM-g~ULM-i R 2’ is preferably an optionally substituted -NH-T-aryl, an optionally substituted -N(CH3)-T-aryl, an optionally substituted -NH-T-heteroaryl group, an optionally substituted -N(CH3)-T-heteroaryl, an optionally substituted -NH-T-heterocyclyl, or an optionally substituted -N(CH3)-T-heterocyclyl, preferably H, and T is an optionally substituted -(CH2) n - group, each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, an amino acid side chain as described elsewhere herein, or a C1-C3 alkyl group, preferably one or two methyl groups, which may be optionally substituted, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T may also be -(CHO) n -group, a-(OCH2) n - group, a-(CH2CH2O) n - group, -(OCH2CH2) n - groups, all of which are optionally substituted.

[0157] ULM-g~ULM-i R 2’ Preferred aryl groups for include optionally substituted aryl groups. and optionally a halogen (preferably F or Cl), an amine, a monoalkyl, or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group, each of which may be at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position. and / or a naphthyl group substituted with at least one of F, Cl, OH, COOH, CH, CF, OMe, OCF, NO, or CN groups (at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), which may be optionally substituted; an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole; optionally substituted oxazoles including methyl-substituted oxazoles, optionally substituted thiazoles including methyl-substituted thiazoles, optionally substituted isothiazoles including methyl-substituted isothiazoles, optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl-substituted pyridine groups, or oxapyridine groups (where the pyridine group is attached to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines, or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines, optionally substituted groups according to the following chemical structure:

[0158] [ka]

[0159] During the ceremony, ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), (C1-C6 alkyl), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or is an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran; ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or an optionally substituted heterocyclyl, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, or morpholine (each of which groups, when substituted, is preferably substituted with methyl or halo (F, Br, Cl), each of which groups may optionally be attached to a PTM group (including a ULM' group) via a linker group.

[0160] In certain preferred embodiments, ULM-g to ULM-i

[0161] [ka]

[0162] teeth,

[0163] [ka]

[0164] It is the basis, In the formula, R of ULM-g to ULM-i PRO and n is the same as above.

[0165] ULM-g~ULM-i R 2’ Preferred heteroaryl groups for include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran (including optionally substituted benzofuran), optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3, or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oximidazole, or a group according to the following chemical structure:

[0166] [ka]

[0167] During the ceremony, ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a wherein R of ULM-g to ULM-i a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups contains one or two hydroxyl groups or up to three halogens, preferably fluorine. optionally substituted with a substituted or optionally substituted heterocyclyl, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), each of which groups can be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0168] ULM-g~ULM-i R 2’Preferred heterocyclyl groups for include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, each of which groups may be optionally substituted or is a group according to the chemical structure:

[0169] [ka]

[0170] Preferably,

[0171] [ka]

[0172] It is the basis, During the ceremony, ULM-g~ULM-i R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclyl group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of these groups can optionally be linked to a PTM group (including a ULM′ group) via a linker group.

[0173] Preferred R of ULM-g to ULM-i 2’ Substituents also include the R groups found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and its accompanying drawings. 2’ These R 2’ Each of the substituents may be any number of R 3’It may be used in conjunction with a substituent.

[0174] ULM-g~ULM-i R 3’ is preferably an optionally substituted -NH-T-aryl, an optionally substituted -N(C1-C3 alkyl)-T-aryl, an optionally substituted -NH-T-heteroaryl group, an optionally substituted -N(C1-C3 alkyl)-T-heteroaryl, an optionally substituted -NH-T-heterocyclyl, or an optionally substituted -N(C1-C3 alkyl)-T-heterocyclyl, where T is an optionally substituted -(CH2) n - group, each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, a C1-C3 alkyl group, or the side chain of an amino acid as otherwise described herein, preferably an optionally substituted methyl, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T may also be -(CHO) n -group, a-(OCH2) n - group, a-(CH2CH2O) n - group, -(OCH2CH2) n - groups, each of which is optionally substituted.

[0175] ULM-g~ULM-i R 3’ Preferred aryl groups for include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, which are optionally linked to a PTM group (including a ULM′ group) via a linker group, and / or are selected from the group consisting of halogen (preferably F or Cl), amine, monoalkyl- or dialkylamine (preferably dimethylamine), amide group (preferably —(CH) m -NR1C(O)R2 group (where m, R1, and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN, or S(O)2R S Group (R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or -(CH2)m and (R″) groups), each of which may be substituted at the ortho, meta, and / or para positions on the phenyl ring (preferably the para position), or is aryl (preferably phenyl), heteroaryl, or heterocyclyl. Preferably, the substituted phenyl group is an optionally substituted phenyl group (i.e., the substituted phenyl group itself is preferably substituted with at least one of F, Cl, OH, SH, COOH, CH, CF, OMe, OCF, NO, CN, or a linker group attached to a PTM group (including a ULM′ group), where the substitution occurs at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), a naphthyl group which may be optionally substituted, including as described above, an optionally substituted heteroaryl (preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, an optionally substituted oxazole, including methyl-substituted oxazole, a methyl-substituted thiazolinone ... optionally substituted thiazoles including azoles, optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazoles, benzylimidazole or methoxybenzylimidazole, oximidazole or methyloximidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, pyridine groups including halo- (preferably F) or methyl-substituted pyridine groups, or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen), or optionally substituted heterocyclyl (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane. Each of the aryl, heteroaryl, heterocyclyl groups may optionally be linked to a PTM group (including a ULM' group) via a linker group.

[0176] ULM-g~ULM-i R 3’Preferred heteroaryl groups for include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazo benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted -(CH2) m -O-C1-C6 alkyl group, or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl group), optionally substituted pyridine (2-, 3, or 4-pyridine), or a group according to the following chemical structure:

[0177] [ka]

[0178] During the ceremony, ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl). Each of the heteroaryl groups is The PTM group may optionally be linked to a PTM group (including a ULM' group) via a -.

[0179] ULM-g~ULM-i R 3’ Preferred heterocyclyl groups for include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiene, oxane, and thiane, each of which groups may be optionally substituted or is a group according to the chemical structure:

[0180] [ka]

[0181] Preferably,

[0182] [ka]

[0183] It is the basis, During the ceremony, ULM-g~ULM-i R PROis H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of the heterocyclyl groups can optionally be linked to a PTM group (including a ULM′ group) via a linker group.

[0184] Preferred R of ULM-g to ULM-i 3’ Substituents also include the R groups found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and its accompanying drawings. 3’ These R 3’ Each of the substituents may be any number of R 2’ It may be used in conjunction with a substituent.

[0185] In certain alternative preferred embodiments, the R of ULM-g to ULM-i 2’ is an optionally substituted -NR1-X R2’ -Alkyl group, -NR1-X R2’ -aryl group, optionally substituted -NR1-X R2’ -HET, optionally substituted -NR1-X R2’ -Ali -HET, or optionally substituted -NR1-X R2’ -HET-aryl, wherein R1 of ULM-g to ULM-i is H or a C1-C3 alkyl group (preferably H), ULM-g~ULM-i X R2’ optionally substituted -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group; ULM-g~ULM-i X v is H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; The alkyl of ULM-g to ULM-i is optionally substituted C1-C 10 an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is end-capped with a halo group, often Cl or Br); Aryl in ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET of ULM-g through ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), or a group according to the following chemical structure:

[0186] [ka]

[0187] ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted (preferably 1 or 2 hydroxyl groups or up to 3 optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), O(C-C alkyl), or optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), —C(O)(C-C alkyl); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

[0188] Each of the groups may optionally be linked to a PTM group (including a ULM' group) via a linker.

[0189] In certain alternative preferred embodiments of the present disclosure, the R of ULM-g to ULM-i 3’ is an optionally substituted -(CH2) n -(V) n’ -(CH2) n-(V) n’ -R S3’ group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -R S3’ group, optionally substituted -X R3’ -alkyl group, optionally substituted -X R3’ -aryl group, optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group, or optionally substituted -X R3’ -HET-aryl group, During the ceremony, R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), an optionally substituted aryl group, or a HET group; R 1’ is H or a C1-C3 alkyl group (preferably H), V is O, S, or NR 1’ and X R3’ But -(CH2) n -, -(CH2CH2O) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, or a C3-C6 cycloalkyl group, all of which are optionally substituted; X v is H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; alkyl is optionally substituted C-C 10 an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is end-capped with a halo group, often Cl or Br); aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each of which, if substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), or a group according to the following chemical structure:

[0190] [ka]

[0191] ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidin and piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R PROis H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each m' in ULM-g to ULM-i is 0 or 1, Each n' of ULM-g to ULM-i is 0 or 1, wherein the compound, preferably each alkyl, aryl, or Het group, is optionally linked to a PTM group (including a ULM′ group) via a linker.

[0192] In an alternative embodiment, R of ULM-g to ULM-i 3 ' is -(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET, or -(CH2CH2O) n -HET, During the ceremony, The aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, and the substituent(s) is preferably —(CH) n OH, C1-C6 alkyl (itself optionally further substituted with CN), halo (up to 3 halo groups), OH, -(CH2)n selected from O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups; or The aryl group of ULM-g to ULM-i is —(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl) amine, where the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, CN, NO2, optionally substituted -(CH2) n -(V) m’ -CH2) n -(V) m’ -(C1-C6) alkyl group, -(V) m’ -(CH2CH2O) n -R PEG group, wherein V is O, S, or NR 1’ and R 1’ is H or a C1-C3 alkyl group (preferably H), and R PEG is H or an optionally substituted C1-C6 alkyl group (including optionally substituted with a carboxyl group), or The aryl group of ULM-g to ULM-i is oxazole, isoxazole, thiazoline, optionally substituted with heterocyclyl, including heteroaryl, selected from the group consisting of aryl, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (each of which, if substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), or a group according to the following chemical structure:

[0193] [ka]

[0194] ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) C-C alkyl (e.g., CF), optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) C≡CR, an optionally substituted acetylenic group, or an optionally substituted acetylenic group, -C≡CR, substituted with a silyl group or up to three halo groups. a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R PROis H, optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; HET of ULM-g through ULM-i is preferably oxazole, isoxazole, thiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl or halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the following chemical structure:

[0195] [ka]

[0196] ULM-g~ULM-i S c But CHR SS , N.R. URE , or O, ULM-g~ULM-i R HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted (preferably 1 or 2 hydroxyl groups or up to 3 optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), O(C-C alkyl), or optionally substituted (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), —C(O)(C-C alkyl); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C But N or CR YC where R YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡CR a where R a is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl), ULM-g~ULM-i R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclyl group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; each m' of ULM-g to ULM-i is independently 0 or 1; each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); wherein the compound, preferably each of the aryl or HET groups, is optionally linked to a PTM group (including a ULM′ group) via a linker group.

[0197] In yet additional embodiments, preferred compounds include compounds according to the following chemical structure:

[0198] [ka]

[0199] During the ceremony, ULM-i R 1’ is OH or a group that is metabolized to OH in the patient or subject, ULM-i R 2’is -NH-CH-aryl-HET (preferably phenyl directly attached to a methyl substituted thiazole); ULM-i R 3’ But -CHR CR3’ -NH-C(O)-R 3P1 group or -CHR CR3’ -R 3P2 It is the basis, ULM-i R CR3’ is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl; ULM-i R 3P1 is C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted), -(CH2) n OCH3 group, where n is 1 or 2 (preferably 2), or

[0200] [ka]

[0201] group (the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (attached to the carbonyl at the 2- or 3-position), ULM-i R 3P2 but,

[0202] [ka]

[0203] It is the basis, the aryl of ULM-i is phenyl, HET of ULM-i is an optionally substituted thiazole or isothiazole; ULM-i R HET is H or a halo group (preferably H), or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, each of which is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0204] In certain embodiments, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure:

[0205] [ka]

[0206] During the ceremony, each R5 and R6 of ULM-i is independently OH, SH, or optionally substituted alkyl, or R5, R6 and the carbon atom to which they are attached form a carbonyl; R7 of ULM-j is H or optionally substituted alkyl; E of ULM-j is a bond, C=O, or C=S, G of ULM-j is a bond, optionally substituted alkyl, —COOH, or C═J; J of ULM-j is O or N-R8, R8 of ULM-j is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or

[0207] [ka]

[0208] and Each R9 and R of ULM-j 10 are independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, a disulfide bonded to a ULM, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; ULM-j R11 is optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

[0209] [ka]

[0210] and ULM-j R 12 is H or optionally substituted alkyl; ULM-j R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate; Each R of ULM-j 14 are independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, azetidine, optionally substituted alkoxy, or optionally substituted heterocyclyl; ULM-j R 15 is H, CN, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; Each R of ULM-j 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted CN, or optionally substituted haloalkoxy; Each R of ULM-j 25 are independently H or optionally substituted alkyl, or both R 25 the groups can be taken together to form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23 is H or OH, Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; ULM-j is a bifunctional compound or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, wherein o of ULM-j is 0, 1, 2, 3, or 4.

[0211] In certain embodiments where G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and o is 0.

[0212] In certain embodiments where G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and R 15 is an optionally substituted heteroaryl and o is 0. In other instances, E is C=O and M is

[0213] [ka]

[0214] is. In certain embodiments, E of ULM-j is C=O. 11 is an optionally substituted heterocyclyl or

[0215] [ka]

[0216] and M is

[0217] [ka]

[0218] is. E of ULM-j is C=O and M is

[0219] [ka]

[0220] and R 11 but,

[0221] [ka]

[0222] In certain embodiments, each R 18 is independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0223] In certain embodiments, each R 14 is independently substituted with at least one of H, hydroxyl, halo, amine, amido, alkoxy, alkyl, haloalkyl, or heterocycle.

[0224] In certain embodiments, the R of ULM-j 15 teeth,

[0225] [ka]

[0226] , CN, or haloalkyl, and each R 18 is independently H, halo, optionally substituted alkoxy, cyano, aminoalkyl, amidoalkyl, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0227] In certain embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0228] [ka]

[0229] During the ceremony, G of ULM-k is C=J and J is O, R7 of ULM-k is H, Each R of ULM-k 14 are independently H, amido, alkyl, e.g., methyl optionally substituted with one or more C1-C6 alkyl groups or C(O)NR'R"; R' and R" are each independently H, optionally substituted alkyl, or cycloalkyl; o of ULM-k is 0, ULM-k R 15 is as defined above for ULM-j, ULM-k R 16 is as defined above for ULM-j, ULM-k R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

[0230] In other cases, the R of ULM-k 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

[0231] In other embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0232] [ka]

[0233] During the ceremony, G of ULM-k is C=J and J is O, R7 of ULM-k is H, Each R of ULM-k 14 is H, o of ULM-k is 0, ULM-k R 15is selected from the group consisting of optionally substituted:

[0234] [ka]

[0235] [ka]

[0236] (Wherein, R of ULM-k 30 is H or optionally substituted alkyl. In other embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0237] [ka]

[0238] During the ceremony, E of ULM-k is C=O, The M in ULM-k is

[0239] [ka]

[0240] and ULM-k R 11 is selected from the group consisting of optionally substituted:

[0241] [ka]

[0242] In yet another embodiment, a compound of the following chemical structure:

[0243] [ka]

[0244] During the ceremony, E of ULM-k is C=O, ULM-k R 11 but,

[0245] [ka]

[0246] and The M in ULM-k is

[0247] [ka]

[0248] and q of ULM-k is 1 or 2, ULM-k R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

[0249] [ka]

[0250] and ULM-k R 21 is H or optionally substituted alkyl; ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

[0251] In any embodiment described herein, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0252] [ka]

[0253] [ka]

[0254] [ka]

[0255] In certain embodiments, R of ULM-j or ULM-k 11 is selected from the group consisting of:

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] In certain embodiments, ULM (or ULM′, if present) is a group according to the following chemical structure:

[0260] [ka]

[0261] During the ceremony, X of ULM-1 is O or S; Y of ULM-l is H, methyl, or ethyl; ULM-l R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or

[0262] [ka]

[0263] and R9 of ULM-1 is H, ULM-l R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, or cycloalkyl; R11 of ULM-l is optionally substituted heteroaromatic, optionally substituted heterocyclyl, optionally substituted aryl, or

[0264] [ka]

[0265] and ULM-l R 12 is H or optionally substituted alkyl; ULM-l R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl, optionally substituted (oxoalkyl)carbamate.

[0266] In some embodiments, ULM, and if present, ULM′, are each independently a group according to the following chemical structure:

[0267] [ka]

[0268] During the ceremony, Y of ULM-m is H, methiol, or ethyl; R9 of ULM-m is H, R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, an optionally substituted heterocyclyl.

[0269] In other preferred embodiments of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0270] [ka]

[0271] During the ceremony, ULM-n R 17 is methyl, ethyl, or cyclopropyl; ULM-n R9, R 10 , and R 11 is as defined above. In other instances, R9 is H; ULM-n R 10 is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0272] In other preferred embodiments of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0273] [ka]

[0274] or a pharmaceutically acceptable salt thereof, wherein: R1 is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R3 is an optionally substituted 5- to 6-membered heteroaryl; W 5 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted pyridinyl; R 14a and R 14b is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 and;R 14a and R 14b the other of which is H; or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; R 15 is CN, optionally substituted fluoroalkyl,

[0275] [ka]

[0276] , optionally substituted

[0277] [ka]

[0278] (for example,

[0279] [ka]

[0280] where R 28a is halo, optionally substituted alkyl, or fluoroalkyl, or

[0281] [ka]

[0282] and Each R 16 is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy; Each R 26 are independently H, optionally substituted alkyl, or NR 27a R 27b and Each R 27a and R 27b are independently H, optionally substituted alkyl, optionally substituted or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R 28 are independently H, halogen, CN, optionally substituted aminoalkyl, optionally substituted amidoalkyl, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted alkylamine, optionally substituted hydroxyalkyl, amine, optionally substituted alkynyl, or optionally substituted cycloalkyl; o is 0, 1, or 2; p is 1, 2, 3, or 4.

[0283] In any of the aspects or embodiments described herein, ULM is of the formula:

[0284] [ka]

[0285] During the ceremony, X 4 , X 5 , and X 6 are each selected from CH and N, and no more than two are N; R 1 is C1-6 alkyl, R 3 is the same as defined for ULM-o and ULM-p, R 14a and R 14b is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 and;R 14a and R 14b the other of which is H; or R 14a and R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; Each R 27a and R 27b However, independently, H, C 1-6 alkyl, or cycloalkyl; q is 1, 2, 3, or 4; R 15 is arbitrarily replaced

[0286] [ka]

[0287] , or CN, R 28 H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 Archi (O)C 1-4 Alkyl, NH2,

[0288] [ka]

[0289] and R 28C is H, methyl, fluoro, or chloro; R 16 But H, C 1-4 Alkyl, fluoro, chloro, CN, or C 1-4 It is an alkoxy.

[0290] In any aspect or embodiment described herein, R 14a and R 14b is H, C 1-4 Alkyl, C 1-4 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyloxyalkyl, C 1-4 Alkyl-NR 27a R 27b , and CONR 27a R 27b is selected from.

[0291] In any aspect or embodiment described herein, R 14a and R 14b At least one of is H (e.g., R 14a and R 14b Both are H).

[0292] In any aspect or embodiment described herein, R 14a and R 14b at least one of which is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkylheterocycloalkyl, optionally substituted alkoxyheterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 Alternatively, in any aspect or embodiment described herein, R 14a and R 14b one of which is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkylheterocycloalkyl, optionally substituted alkoxyheterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 and R 14a and R 14b The other of these is H.

[0293] In any aspect or embodiment described herein, R 14a and R 14b together with the carbon atoms to which they are attached,

[0294] [ka]

[0295] wherein R 23 But H, C 1-4 Alkyl, -C(O)C 1-4 alkyl.

[0296] In other preferred embodiments of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

[0297] [ka]

[0298] or a pharmaceutically acceptable salt thereof, wherein X is CH or N; R1, R3, and R of ULM-q and ULM-r 14a , R 14b , and R 15 is the same as defined for ULM-o and ULM-p.

[0299] In any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any of the aspects or embodiments described herein, the ULM described herein (or ULM', if present) may be attached to a PTM directly via a bond or by a chemical linker.

[0300] In certain aspects of the disclosure, the ULM moiety is selected from the group consisting of:

[0301] [ka]

[0302] [ka]

[0303] [ka]

[0304]

change

[0305]

change

[0306]

change

[0307]

change

[0308]

change

[0309]

change

[0310]

change

[0311]

change

[0312]

change

[0313]

change

[0314]

change

[0315]

change

[0316]

change

[0317]

change

[0318]

change

[0319]

change

[0320]

change

[0321]

change

[0322]

change

[0323]

change

[0324]

change

[0325] wherein the VLM can be linked to the PTM via a linker as described herein, optionally via any suitable functional group, e.g., an amine, ester, ether, alkyl, or alkoxy, at any suitable location, including, e.g., an aryl, heteroaryl, phenyl, or phenyl of an indole group. Exemplary Linkers In certain embodiments, compounds described herein include one or more PTMs chemically bonded or coupled to one or more ULMs (e.g., at least one of the VLMs) via a means for chemically linking the PTM to the ULM, e.g., a chemical linker (L). In certain embodiments, the linker group L is a linker group consisting of one or more covalently linked structural units (e.g., -A L 1… (A L ) q -or-(A L ) q -), and A L 1 is a group attached to the PTM, (A L ) q is a group attached to ULM.

[0326] In any aspect or embodiment described herein, the linkage or bond of the linker (L) to a ULM (e.g., a VLM, an ILM, a CLM, or an MLM) is a stable L-ULM linkage. For example, in any aspect or embodiment described herein, when the linker (L) and a ULM are linked via a heteroatom, any subsequent heteroatom (if present) is separated by at least one single carbon atom (e.g., —CH—), e.g., an acetal or aminal group. By way of further example, in any aspect or embodiment described herein, when the linker (L) and a ULM are linked via a heteroatom, the heteroatom is not part of an ester.

[0327] In any aspect or embodiment described herein, the linker group L is of the formula -(A L ) q-, where A is a chemical moiety, q is an integer between 1 and 100, and L is covalently attached to the PTM and ULM and provides sufficient binding of the PTM to a protein target and of the ULM to E3 ubiquitin to result in target protein ubiquitination.

[0328] In any aspect or embodiment described herein, the linker group L is -(A L ) q - in which (A L ) q may contain a ULM (e.g., VLM), a PTM moiety, or a combination thereof. a group linked to at least one of q of the linker is an integer of 1 or more, Each A L However, independently, combined, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 0 to 9 R L1 and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 0 to 6 R L1 and / or R L2C optionally substituted with a group 3-11 Heterocyclyl, 0 to 8 R L1 and / or R L2 C optionally substituted with a group 5-13 Spiroheterocyclyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 heteroaryl optionally substituted with a group, wherein R L1 or R L2 are each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, and optionally 0 to 4 R L5 is substituted with a group, R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[0329] In certain embodiments, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0330] For example, in certain embodiments where the linker q is greater than 2, (A L ) q is A L 1 and (A L ) q A group in which the unit A L conjugates a PTM to ULM.

[0331] For example, in certain embodiments where the linker q is 2, (A L ) q is A L1 and to a ULM or PTM.

[0332] For example, in certain embodiments where the linker q is 1, the structure of the linker group L is -A L 1- and A L 1 is a group linking the ULM moiety and the PTM moiety.

[0333] In certain embodiments, the unit A of the linker (L) L includes groups represented by the general structure selected from the group consisting of: -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy )-, -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 -(cycloalkyl)-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)-CH, -N(R1R2)-(heterocyclyl)-CH, wherein n of the linker can be 0 to 10; R of the linker can be H, lower alkyl, The linker R1 and R2 can form a ring with the N to which they are connected.

[0334] In certain embodiments, the unit A of the linker (L) L includes groups represented by the general structure selected from the group consisting of: -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-, -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-, -(CH2) m -O(CH2) n -O(CH2) o-O(CH2) p -O(CH2) q -O(CH2) r -O-, -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-,

[0335] [ka]

[0336] [ka]

[0337] [ka]

[0338] During the ceremony, m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20; If the number is zero, there are no NO or OO bonds, R of the linker is H, methyl, and ethyl; X of the linker is H and F;

[0339] [ka]

[0340] wherein m of the linker can be 2, 3, 4, or 5;

[0341] [ka]

[0342] [ka]

[0343] [ka]

[0344] [ka]

[0345] [ka]

[0346] [ka]

[0347] [ka]

[0348] [ka]

[0349] [ka]

[0350] wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, or 6.

[0351] In any aspect or embodiment described herein, the unit A of the linker (L) L is selected from the group consisting of:

[0352] [ka]

[0353] [ka]

[0354] [ka]

[0355] [ka]

[0356] wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6. In any aspect or embodiment described herein, the unit A of the linker (L) L is selected from the group consisting of:

[0357] [ka]

[0358] [ka]

[0359] [ka]

[0360] [ka]

[0361] [ka]

[0362] [ka]

[0363]

change

[0364]

change

[0365]

change

[0366]

change

[0367]

change

[0368]

change

[0369]

change

[0370]

change

[0371]

change

[0372]

change

[0373]

change

[0374]

change

[0375]

change

[0376]

change

[0377]

change

[0378]

change

[0379]

change

[0380]

change

[0381]

change

[0382]

change

[0383]

change

[0384] [ka]

[0385] [ka]

[0386] [ka]

[0387] [ka]

[0388] [ka]

[0389] wherein each m, n, o, p, q, r, and s is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0390] In any aspect or embodiment described herein, the unit A of the linker (L) L is selected from the group consisting of:

[0391] [ka]

[0392] [ka]

[0393] [ka]

[0394]

change

[0395]

change

[0396]

change

[0397]

change

[0398]

change

[0399]

change

[0400]

change

[0401]

change

[0402]

change

[0403]

change

[0404]

change

[0405] [ka]

[0406] [ka]

[0407] [ka]

[0408] [ka]

[0409] [ka]

[0410] In any aspect or embodiment described herein, the linker unit or linker (L) comprises a group represented by a structure selected from the group consisting of: -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O(CH2) t -, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O-, -(CH2) m -O(CH2) n -O(CH2)o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O(CH2) t -、 -CH=CH(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O(CH2) t -、

[0411]

change

[0412]

change

[0413]

change

[0414]

change

[0415]

change

[0416]

change

[0417]

change

[0418] wherein m, n, o, p, q, r, s, and t are each independently selected from the integers 0, 1, 2, 3, and 4.

[0419] In any aspect or embodiment described herein, the linker (L) is selected from the group consisting of:

[0420] [ka]

[0421] [ka]

[0422] In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety:

[0423] [ka]

[0424] During the ceremony, W L1 and W L2 are each independently absent or optionally R Q and each R is a 4- to 8-membered ring having 0 to 4 heteroatoms substituted with Q are independently H, halo, OH, CN, CF, optionally substituted straight or branched chain C-C alkyl, optionally substituted straight or branched chain C-C alkoxy, or two R Q groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, a (linear, branched, optionally substituted) C1-C6 alkyl (or C1-C6 alkoxy) optionally with one or more C atoms replaced by O, or a (linear, branched, optionally substituted) C1-C6 alkoxy; n is 0 to 10,

[0425] [ka]

[0426] indicates the point of attachment to the PTM or ULM moiety. In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety:

[0427] [ka]

[0428] During the ceremony, W L1 and W L2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclyl, C, optionally with one or more C atoms replaced by O or N, 1-6 Alkyl, optionally with one or more C atoms replaced by O 1-6 alkenyl, optionally 1 C in which one or more C atoms are replaced by O 1-6 alkynyl, bicyclic, biaryl, biheteroaryl, or biheterocyclyl, each of which is R Q and each R Q are independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more F), OH, NH2, NR Y1 R Y2 , CN or two R Q groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; YL1 each independently represents a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, (linear, branched, optionally substituted) C1-C6 alkyl, (linear, branched, optionally substituted) C1-C6 alkoxy, optionally with one or more C atoms replaced by O; Q L is optionally bridged, and optionally has 0 to 6 R Q and each R is a 3- to 6-membered alicyclic or aromatic ring having 0 to 4 heteroatoms, substituted with Q are independently H, optionally one or more halo or C 1-6 Alkoxy-substituted, straight or branched chain C 1-6 alkyl or two R Q groups, together with the atoms to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 each independently represents H, OH, (linear, branched, optionally with one or more halo, C 1-6 Alkoxy-substituted)C 1-6 alkyl or R 1 , R 2 together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms; n is 0 to 10,

[0429] [ka]

[0430] indicates the point of attachment to the PTM or ULM moiety. In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, or an optionally substituted alkyl group interdispersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclyl group. In certain embodiments, the linker can be asymmetric or symmetric.

[0431] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0432] In another embodiment, the disclosure is directed to compounds comprising a PTM group as described above, wherein the PTM group binds to a target protein or polypeptide (e.g., SMARCA2, BRAHMA, or BRM) that has been ubiquitinated by a ubiquitin ligase and chemically linked to a ULM group, either directly or via a linker moiety, L; or the PTM is alternatively a ULM' group that is also a ubiquitin ligase-binding moiety, wherein the ULM' group is a ULM' group as described above. and L is a linker moiety, as defined above, which may be present or absent and which chemically (covalently) bonds ULM to the PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

[0433] In certain embodiments, the linker group, L, is a group comprising one or more covalently linked structural units independently selected from the group consisting of:

[0434] [ka]

[0435] X is selected from the group consisting of O, N, S, S(O), and SO2, n is an integer from 1 to 5, and R L1 is hydrogen or alkyl,

[0436] [ka]

[0437] is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano;

[0438] [ka]

[0439] is a monocyclic or bicyclic cycloalkyl or heterocyclyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano, and the phenyl ring fragment may be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano. In one embodiment, the linker group L comprises up to 10 covalently linked structural units as described above.

[0440] While the ULM and PTM groups can be covalently attached to the linker group via any group that is appropriate and stable for the linker chemistry, in preferred embodiments of the present disclosure, the linkers are independently covalently attached to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, and each of these groups can be inserted anywhere on the ULM and PTM groups to provide maximal coupling between the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself.) In certain embodiments, the linker is It can be attached to an optionally substituted alkyl, alkylene, alkenyl, or alkynyl group, aryl group, or heterocyclyl group on the ULM and / or PTM group.

[0441] Exemplary PTMs In any aspect or embodiment of the present disclosure, the PTM group is a moiety that binds to a target protein, e.g., switch / sucrose non-fermenting (SWI / SNF)-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) or BRM. Thus, in any aspect or embodiment described herein, the PTM group is any moiety that specifically binds to a SMARCA 2 or BRM protein (binds to the target protein SMARCA 2, BRAHMA, or BRM).

[0442] In certain embodiments, the compounds described herein comprise a means for binding to a target protein, for example, Brm. Thus, in certain aspects, the present disclosure provides bifunctional compounds having a means for binding to Brm and a means for binding to VHL, and a means for chemically binding the means for binding to Brm to the means for binding to VHL.

[0443] The compositions described below exemplify some of the components of small molecule target protein binding moieties.Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target SMARCA2.These binding moieties are preferably linked to ubiquitin ligase binding moieties via a linker to present the target protein (to which the protein target moiety is bound) in proximity to ubiquitin ligase for ubiquitination and degradation.Any protein (e.g., SMARCA2, BRAHMA, or BRM) that can be bound to a protein target moiety or PTM group and act on or be degraded by ubiquitin ligase is a target protein according to the present disclosure.

[0444] The present disclosure may be used to treat numerous disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated (e.g., SMARCA4 deficiency / mutation) and in which the patient would benefit from the degradation and / or inhibition of a protein such as SMARCA2, BRAHMA, or BRM.

[0445] In a further aspect, the present description provides a therapeutic composition comprising an effective amount of the compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally additional bioactive agents.The therapeutic composition can be used to regulate protein degradation in a patient or subject, for example, an animal, such as a human, and treat or improve a disease state or condition regulated by degraded protein.In certain embodiments, the therapeutic composition described herein can be used to cause the degradation of a target protein for the treatment or improvement of a disease, including lung cancer or non-small cell lung cancer, for example, at least one of SWI / SNF-associated cancer, SMARCA4 mutation-associated cancer, SMARCA4-deficient cancer, or cancer in which SMARCA4 expression is reduced compared to normal SMARCA4 expression (for example, reduced expression compared to non-mutated SMARCA4 or SMARCA4 expression in non-cancerous cells in a similar location with wild-type SMARCA4). In any aspect or embodiment described herein, the cancer is at least one of a SWI / SNF-associated cancer, a cancer with a SMARCA4 mutation, a cancer with a SMARCA4 deficiency, or a combination thereof, and may be lung cancer or non-small cell lung cancer.

[0446] In certain additional embodiments, the therapeutic compositions described herein are used to treat diseases, For example, degradation of a protein of interest may be effected to treat or ameliorate cancer, such as at least one of SWI / SNF-associated cancer, SMARCA2-associated cancer, or cancer with normal or overexpression of SMARCA2.

[0447] In an alternative aspect, the present disclosure relates to a method for treating a disease state or ameliorating the symptoms of a disease or condition in a subject in need thereof by degrading a protein or polypeptide that regulates the disease state or condition, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described herein above, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent, wherein the composition is effective for treating or ameliorating a disease or disorder or its symptoms in the subject. Using the method according to the present disclosure, numerous disease states or conditions, including cancer, can be treated by administering an effective amount of at least one compound described herein. The disease state or condition can be a disease caused by a microbial pathogen or other exogenous pathogen, such as a virus, bacteria, fungus, protozoan, or other microorganism, or can be a disease state caused by overexpression of a protein that leads to the disease state and / or condition.

[0448] In another aspect, the description provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0449] The term "target protein" is used to describe a protein or polypeptide that is targeted for conjugation to a compound in accordance with the present disclosure and subsequent degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target the protein of interest. These binding moieties are attached to at least one ULM group (e.g., VLM) via at least one linker group, L.

[0450] Protein targets can be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into compounds according to the present disclosure, can alter the activity level of the protein for a therapeutic end result.

[0451] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest, such as SMARCA2 or BRM, and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. The compositions described below exemplify some of the components of small molecule target proteins.

[0452] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by:

[0453] [ka]

[0454] During the ceremony, W PTM1 is an optionally substituted 5- to 6-membered aryl or heteroaryl ring (e.g., a 5- to 6-membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano, or combinations thereof); W PTM2 is an optionally substituted 5- to 6-membered aryl or heteroaryl ring (e.g., a 5- to 6-membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM3is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), or an optionally substituted 4-9 cycloalkyl or heterocyclyl, such as an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring (e.g., a 4-9 cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM5 does not exist (e.g., W PTM3 is directly linked to L (linker) or ULM), or an optionally substituted alkyl, an optionally substituted 5-6 membered cycloalkyl, heterocycle, aryl, or heteroaryl ring (e.g., a 5-6 membered cycloalkyl, heterocycle, aryl, or heteroaryl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);

[0455] [ka]

[0456] is the point of attachment to the linker, ULM group, ULM′ group, VLM group, VLM′ group. In any aspect or embodiment described herein, W PTM5 is piperidine.

[0457] In certain embodiments, W PTM1 contains a phosphate substitution. In any aspect or embodiment described herein, the PTM of a PROTAC of the disclosure is represented by Formula I, wherein: W PTM1is optionally substituted phenyl or pyridyl (e.g., substituted as described herein, e.g., substituted with hydroxy or phosphate substituents, with or without additional optional substituents selected as described herein, e.g., hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkyla, phenyl substituted with 0, 1, 2, or 3 substituents selected from amino, cyano, or combinations thereof; W PTM2 is an optionally substituted 6-membered heteroaryl ring (e.g., substituted as described herein, e.g., pyridazine substituted with an amino group); W PTM3 is an optionally substituted 5-6 membered heteroaryl (e.g., pyrazole, pyrrole, imidazole, oxazole, oxadiazole, or triazole); W PTM5 as described in any aspect or embodiment described herein (e.g., W PTM5 may be absent or a pyridine ring), or At least one of these combinations.

[0458] In any aspect or embodiment described herein, e.g., an embodiment comprising a PTM of Formula I, W PTM3 is pyrazole or a 6- to 8-membered heterocyclyl (e.g., piperazine or diazabicyclooctane).

[0459] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by:

[0460] [ka]

[0461] During the ceremony, W PTM1 , W PTM2 , and WPTM5 as described in any other aspect or embodiment described herein (e.g., W PTM5 may be present or absent because WPTM4 can be directly linked to L (linker) or ULM), W PTM4 But, W PTM2 an optionally substituted 5- to 7-membered cycloalkyl or heterocyclyl (e.g., a 5- to 7-membered cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a ring;

[0462] [ka]

[0463] is the point of attachment to the linker, ULM group, ULM′ group, VLM group, VLM′ group. In any aspect or embodiment described herein, the PTM of the disclosure is represented by Formula II, wherein W PTM1 , W PTM2 , and W PTM5 is as described in any of the aspects or embodiments described herein, and W PTM4 is a piperazine ring. For example, in any aspect or embodiment described herein, W of Formula II PTM2 and W PTM4 together form the dihydropyrazino[2,3-e]pyridazine shown below.

[0464] [ka]

[0465] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by:

[0466] [ka]

[0467] During the ceremony, W PTM1 and W PTM2 as described in any aspect or embodiment described herein; W PTM6 and W PTM7 is independently optionally 4-7 cycloalkyl or heterocyclyl (e.g., 4-7 cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents each independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), and W PTM6 and W PTM7 are fused or joined via a spiro linkage;

[0468] [ka]

[0469] is the point of attachment to the linker, ULM group, ULM′ group, VLM group, VLM′ group. In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by Formula III, wherein W PTM1 and W PTM2 are each independently selected as described in any aspect or embodiment described herein (e.g., W PTM1 is phenyl substituted with a hydroxy substituent, with or without any additional substituents described herein; W PTM2 is a pyridazine substituted with an amino group), W PTM6 and W PTM7 is a spirocyclic ring system, for example a spirocyclic ring selected from:

[0470] [ka]

[0471] In any aspect or embodiment described herein, the PTM of the disclosure is represented by:

[0472] [ka]

[0473] In the formula, W PTM1 , W PTM2 , and W PTM5 as described in any other aspect or embodiment described herein.

[0474] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by Formula IV, wherein: W PTM1 is phenyl substituted with a hydroxy or phosphate substituent, with or without any additional substituents described herein; W PTM2 is an amino-substituted pyridazine, W PTM5 is absent or is a pyrazole ring or a pyridine ring, or At least one of these combinations.

[0475] In any aspect or embodiment described herein, the PTM of the disclosure is represented by:

[0476] [ka]

[0477] Formula V or a pharmaceutically acceptable salt thereof, wherein: W PTM3 is absent or is an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 4- to 9-membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring; W PTM5 is an optionally substituted 5-6 membered heteroaryl or aryl, for example, pyridine, or pyridazine.

[0478] In any aspect or embodiment described herein, the PTM of the disclosure is represented by:

[0479] [ka]

[0480] Formula Vb or a pharmaceutically acceptable salt thereof, wherein: W PTM3 is an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 4- to 9-membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring; W PTM5 is an optionally substituted 5- to 6-membered heteroaryl or aryl, e.g., pyridine, or pyridazine; Rv is 0, 1, 2, or 3 substituents independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano, or combinations thereof.

[0481] In certain embodiments, the hydroxyl groups are modified with phosphate groups (ie, phosphoester groups).

[0482] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by:

[0483] [ka]

[0484] W PTM1 and W PTM2as described in any other aspect or embodiment described herein (e.g., W PTM5 may be present or absent because WPTM4 can be directly linked to L (linker) or ULM), W PTM3 But, W PTM2 an optionally substituted 5-7 cycloalkyl or heterocyclyl (e.g., a 5-7 cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a ring; W PTM4 is an optionally substituted 5-7 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), or an optionally substituted 4-9 cycloalkyl or heterocyclyl, such as an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring (e.g., a 4-9 cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM5 does not exist (e.g., W PTM3 is directly linked to L (linker) or ULM), or an optionally substituted alkyl, an optionally substituted 5-6 membered cycloalkyl, heterocycle, aryl, or heteroaryl ring (e.g., a 5-6 membered cycloalkyl, heterocycle, aryl, or heteroaryl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), such as an optionally substituted pyrazole ring, or pyridine ring;

[0485] [ka]

[0486] is the point of attachment to the linker, ULM group, ULM′ group, VLM group, VLM′ group. In any aspect or embodiment described herein, the PTM is selected from the following:

[0487] [ka]

[0488] [ka]

[0489] In any aspect or embodiment described herein, the PTM is selected from the following:

[0490] [ka]

[0491] [ka]

[0492] In any aspect or embodiment described herein, the PTM is selected from the group consisting of:

[0493] [ka]

[0494] The compositions described herein exemplify some of the components of these types of small molecule target protein binding moieties.Such small molecule target protein binding moieties also include the pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, and other small molecules that can target target proteins.The references cited below in this specification are incorporated herein by reference in their entirety.

[0495] therapeutic composition an effective amount of at least one bifunctional compound described herein and an effective amount of one Pharmaceutical compositions comprising a combination of one or more compounds as otherwise described herein in combination with a pharmaceutically effective amount of a carrier, excipient, or vehicle represent a further aspect of the disclosure.

[0496] The present disclosure includes, where applicable, compositions containing pharmaceutically acceptable salts, particularly acid or base addition salts of the compounds described herein. The acids used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful according to this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), among others.

[0497] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present disclosure.Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to, water-soluble amine addition salts, such as alkali metal cations (e.g., potassium and sodium), and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium, or N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0498] The compounds described herein may be administered in single or divided doses via oral, parenteral, or topical routes in accordance with the present disclosure. Administration of the active compounds may range from continuous administration (intravenous infusion) to several oral doses per day (e.g., QID), and include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository administration, among other routes. Enteric-coated oral tablets may also be used to enhance the bioavailability of the compounds from oral administration. The most effective dosage form will depend on the pharmacokinetics of the specific agent selected and the severity of the disease in the patient. Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intranasal, intratracheal, or intrapulmonary administration may also be used. Accordingly, the present disclosure is also directed to pharmaceutical compositions comprising an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. Compounds according to the present disclosure may be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Sustained or controlled release forms are preferably administered orally, but also via suppositories and transdermal or other topical forms. Intramuscular injection of liposomal forms may also be used to control or sustain the release of the compound at the injection site.

[0499] Compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in controlled release formulations.The pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat. However, the present invention is not limited to these.

[0500] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0501] The sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, including natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0502] The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or aqueous solutions.For tablets 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, useful diluents include lactose and dried corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or colorings can also be added.

[0503] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration.These can be prepared by mixing the drug with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and thus melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycol.

[0504] The pharmaceutical compositions described herein can also be administered topically.Suitable topical formulations can be easily prepared for each of these areas or organs.Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation.Topically acceptable transdermal patches can also be used.

[0505] For topical application, pharmaceutical compositions can be formulated into suitable ointment, which contains the active ingredient suspended or dissolved in one or more carriers.The carrier for topical administration of the compound of the present disclosure includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In a certain preferred embodiment of the present disclosure, compound can be coated on the stent that is surgically implanted in patient, so as to prevent or reduce the possibility of stent blockage occurring in patient.

[0506] Alternatively, the pharmaceutical compositions may be suspended or dispersed in one or more pharmaceutically acceptable carriers. It can be formulated into a suitable lotion or cream containing the dissolved active ingredient.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0507] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated into an ointment such as petrolatum.

[0508] The pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation.Such compositions can be prepared according to the techniques well known in the field of pharmaceutical formulation, and can be prepared as a solution in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0509] The amount of the compounds in the pharmaceutical compositions described herein that can be combined with the carrier materials to produce a single dosage form will vary depending on the host and disease being treated, as well as the particular mode of administration. Preferably, the compositions should be formulated 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, alone or in combination with at least one other compound according to the present disclosure.

[0510] It is also understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, dietary restrictions, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0511] Patients or subjects in need of therapy using compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, and pharmaceutically acceptable salts, solvates, or polymorphs thereof, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known therapeutic agents as otherwise specified herein.

[0512] These compounds can be administered by any suitable route, including, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel, or solid form, or by aerosol form.

[0513] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing significant toxic effects to the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein are in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, and more commonly 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical dosages will be in the range of 0.01 to 5% w / w in a suitable carrier.

[0514] The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, those containing less than 1 mg, 1 mg to 3000 mg, and preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of about 25 to 250 mg is often convenient.

[0515] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30 mM, preferably about 0.1 to 30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0516] The concentration of active compound in the drug composition will depend on the absorption, distribution, inactivation and excretion rate of the drug, and other factors known to those skilled in the art.It should be noted that dosage value will also vary depending on the severity of the condition to be alleviated.It should be further understood that the specific dosage regimen for any specific subject should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed compositions.The active ingredient can be administered at once or divided into several smaller doses that are administered at various time intervals.

[0517] Oral compositions generally contain an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition.

[0518] Tablets, pills, capsules, troches, etc. can contain the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterols; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring, or any of the compounds of similar nature.When the unit dosage form is a capsule, it can contain a liquid carrier such as fatty oil in addition to the above-mentioned materials.In addition, the unit dosage form can contain various other materials that modify the physical form of the dosage unit, such as sugar, shellac, or enteric coating.

[0519] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes, colorings, and flavors.

[0520] The active compounds or pharmaceutically acceptable salts thereof can also be mixed with other active substances that do not impair the desired action, or substances that complement the desired action, such as anti-cancer agents, including pembrolizumab, among others. In certain preferred embodiments of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anti-cancer agent or a therapeutic agent, including an antibiotic, as described elsewhere herein.

[0521] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical use can contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations can be packaged in glass or plastic ampoules, disposable syringes, or Alternatively, it may be packaged in a multi-dose vial.

[0522] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0523] In one embodiment, active compound is prepared with carrier that can prevent compound from rapid excretion from body, for example, comprises implant and microencapsulated delivery system, controlled release formulation.Biodegradable biocompatible polymer can be used, for example, ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester and polylactic acid.The method of preparing such formulation will be clear to those skilled in the art.

[0524] Liposomal suspensions can also be pharmaceutically acceptable carriers.They can be prepared according to methods known to those skilled in the art, for example, the method described in United States Patent No. 4,522,811 (its entirety is incorporated herein by reference).For example, liposomal preparations can be prepared by dissolving suitable lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, aracadyl phosphatidylcholine and cholesterol) in an inorganic solvent, and then evaporating it to leave a thin film of dry lipid on the surface of the container.Then, an aqueous solution of active compound is introduced into the container.Then, the container is swirled by hand to release lipid material from the side of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0525] Treatment method In an additional aspect, the present description provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to modulate protein degradation in a patient or subject, e.g., an animal, such as a human, and to treat or ameliorate a disease state or condition modulated by degraded proteins.

[0526] As used herein, the terms "treat," "treating," and "treatment" refer to any action that provides benefit to a patient to which the compound may be administered, including the treatment of any disease state or condition that is regulated by the protein to which the compound binds. Disease states or conditions, including cancers such as lung cancer, including non-small cell lung cancer, that may be treated using compounds according to the present disclosure are described herein above.

[0527] The present description provides therapeutic compositions described herein for causing degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In certain additional embodiments, the disease is multiple myeloma. Accordingly, in another aspect, the present description provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound described herein, wherein the compound comprises a ULM and a PTM, preferably linked via a linker moiety, e.g., as described elsewhere herein, wherein the ULM binds to the PTM and the ULM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase such as VHL E3 ubiquitin ligase), and the PTM recognizes the target protein such that, when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, thereby resulting in degradation / inhibition of the effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a disease state or condition regulated by the target protein by reducing the level of the protein in a cell, e.g., a patient's cell. In certain embodiments, the methods include administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0528] In additional embodiments, the present description provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, the method comprising administering to a subject in need thereof an effective amount, e.g., a therapeutically effective amount, of a composition comprising a compound described herein or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or combination thereof, wherein the composition is effective to treat or ameliorate the disease, disorder, or symptom thereof in the subject.

[0529] In another aspect, the description provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0530] In another embodiment, the present disclosure is directed to a method of treating a human patient in need of treatment for a disease state or condition regulated by a protein, where degradation of the protein would provide a therapeutic benefit in the patient, the method comprising administering to the patient in need an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial pathogen, or other exogenous pathogen, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that leads to the disease state and / or condition.

[0531] The term "disease state or condition" is used to describe any disease state or condition in which protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and degradation of one or more proteins in the patient can provide beneficial therapy or symptom relief to a patient in need thereof. In certain cases, the disease state or condition can be cured.

[0532] Disease states or conditions that may be treated using compounds according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related disorders, cleft palate, diabetes, heart disease, high blood pressure, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0533] The term "tumor" or "cancer" is used throughout this specification to refer to a cancerous or malignant tumor, i.e., a pathological process that results in the formation and growth of abnormal tissue that grows by cellular proliferation, often more rapidly than normal, and continues to grow after the stimulus that initiated the new growth has ceased. Malignant tumors exhibit a partial or complete lack of structural organization and functional connection with normal tissue, most invade surrounding tissues, metastasize to several sites, and unless properly treated, are likely to recur after attempted removal and cause patient death. As used herein, the term tumor is used to describe all cancerous disease states and encompasses or encompasses the pathological processes associated with malignant hematologic, ascites, and solid tumors. Exemplary cancers that may be treated with the present compounds, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, Sarcomas, including neuroma, neuronal glioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that may be treated using compounds according to the present disclosure include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell acute lymphoblastic leukemia, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell acute lymphoblastic leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, and Philadelphia chromosome-positive chronic myeloid leukemia.

[0534] The term "bioactive agent" is used to describe an agent other than a compound according to the present disclosure, which is used in combination with the present compound as a biologically active agent to help achieve the intended therapeutic, inhibitory, and / or prophylactic / preventative method for which the present compound is used. Preferred bioactive agents for use herein include agents with similar pharmacological activity to that for which the present compound is used or administered, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, antibacterial agents, anti-fungal agents, etc.

[0535] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that may be combined with a compound according to the present disclosure to treat cancer. These agents include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jaimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indoyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin; Lympamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trimethoprim-400 Costatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxime Testosterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, Thiotepa, tretinoin, vindesine, 13-cis retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974,Interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisolone, cetuximab, granulocyte-monocyte colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab Mab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol,Dexamethasone, methyl, These include prednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0536] The terms "anti-HIV agent" or "additional anti-HIV agent" include, for example, inter alia, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., not representative of the present disclosure), protease inhibitors, fusion inhibitors, exemplary compounds of which include anti-HIV compounds currently in clinical trials or development, e.g., 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), These include tenofovir (PMPA), D-D4FC (Reverset), D4T (stavudine), rasibir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesylate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), fusion inhibitors such as T20, Fuseon, and mixtures thereof, among others.

[0537] Other anti-HIV agents that may be used for co-administration with compounds according to the present disclosure include, for example, nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothiamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY, among others. 097, DMP266, baicalin (TJN-151), ADAM-II (methyl 3',3'-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-6,6-diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hupto-1-enyl)-2-methoxybenzoate (alkenyl diarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), capravirin (AG-1549, S-1153), atevirdine (U-87201E), aurintricarboxylic acid (SD-09534 5), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine , 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl) sulfone (NSC633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscarbil), HEPT(1-[( 2-hydroxyethoxy)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), Inophylum P, L-737,126, Michelamine A (NSC650898), Michelamine B (NSC649324), Michelamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6, -(3,5-dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC648400), oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivative), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pipridine-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pipridine-2(1H)-thione), R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, suramin sodium, TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, tivirapine (R86183), UC-38, and UC-84.

[0538] The term "pharmaceutically acceptable salt" is used throughout this specification to describe one or more salt forms of the compounds described herein, which are provided to increase the solubility of the compound in the gastric acid of the patient's gastrointestinal tract, where applicable, to promote the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases, and, where applicable, acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, among many acids and bases well known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0539] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (such as an ester, amide, other prodrug group, etc.) that, upon administration to a patient, directly or indirectly provides the compound or an active metabolite of the compound.

[0540] General synthetic approach The synthesis and optimization of the bifunctional molecules described herein can be approached in a stepwise or modular manner. For example, identifying compounds that bind to a target molecule can involve a high- or medium-throughput screening campaign if a suitable ligand is not readily available. It is not uncommon for the initial ligand to require iterative design and optimization cycles to improve non-optimal aspects, as identified by data from appropriate in vitro pharmacological and / or ADMET assays. Part of the optimization / SAR campaign will explore positions in the ligand that are tolerant to substitution and may be suitable for attaching the linker chemistry previously mentioned herein. When crystallographic or NMR structural data are available, they can be used to focus such synthetic efforts.

[0541] A very similar approach was used to identify ligands for E3 ligases, i.e., ULM / VLM. , can be optimized.

[0542] Given PTMs and ULMs (e.g., VLMs), one skilled in the art can use known synthetic methods for their combination, with or without a linker moiety. Linker moieties can be synthesized with various compositions, lengths, and flexibility and can be functionalized to allow sequential attachment of PTM and ULM groups to the distal ends of the linker. Thus, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. As with the PTM and ULM groups, the final bifunctional molecules can be subjected to iterative design and optimization cycles to identify molecules with desired properties.

[0543] In some cases, protecting group strategies and / or functional group interconversions (FGI) may be required to facilitate the preparation of the desired materials. Such chemical processes are well known to synthetic organic chemists, and many of these are described in "Greene's Protective Groups" by Peter G.M. Wuts and Theodora W. Greene. in Organic Synthesis" (Wiley), and Stuart Warren and Paul Wyatt's "Organic Synthesis: The Disconnection Approach" (Wiley).

[0544] Abbreviation: ACN: acetonitrile ADDP: 1,1'-(azodicarbonyl)dipiperidine BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride BPO: Benzoyl peroxide Cbz: carbonylbenzyloxy DAST: Diethylaminosulfur trifluoride DBE: 1,2-dibromoethane DCM: dichloromethane DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DIBAL: Diisobutylaluminum hydride DIEA or DIPEA: Diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane EA: Ethyl acetate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HBTU: N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HMDS: Bis(9-trimethylsilyl)amine HMPA: hexamethylphosphoramide LDA: Lithium diisopropylamide MCPBA: meta-chloroperoxybenzoic acid MsCl: methanesulfonyl chloride MW: Microwave NBS: N-bromobromosuccinimide NMP: N-methylpyrrolidone PCC: Pyridinium chlorochromate Pd-118 or Pd(dtpf)Cl2: 1,1'-bis(di-tert-butyl Phosphino)ferrocenedichloropalladium Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium Pd(dba)2: Bis(dibenzylideneacetone)palladium Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium PPTS: Pyridinium p-toluenesulfonate PTSA: p-toluenesulfonic acid RuPhos-Pd-G3: XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate RuPhos-Pd-G2: chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) SFC: Supercritical Fluid Chromatography t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA: Trimethylamine TFA: Trifluoroacetic acid TLC: Thin Layer Chromatography TMP: 2,2,6,6-tetramethylpiperidine TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide TosCl or TsCl: p-toluenesulfonyl chloride TsOH: p-toluenesulfonic acid XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate 12354-85-7: Bis(pentamethylcyclopentadienylrhodium dichloride)

[0545] [ka]

[0546] As shown in Scheme 1, W PTM5 The compound bearing the moiety contains a linking group L containing a nucleophilic group, such as an amino group. When reacted with a compound bearing a good leaving group LG (e.g., the perfluorosulfonyl group C4F9SO3-), a coupling product is formed. The coupling product can be converted to a monoprotected amine molecule W under palladium-catalyzed conditions. PTM3 In response, W PTM3 Following amine deprotection, W PTM5 -W PTM3 The more reactive halogen atom selected from Z' and Z'' in W is nucleophilically substituted with a free amino group. PTM5 -W PTM3 -W PTM2 and then W PTM2 Reaction with boronic acid to give W PTM5 -W PTM3 -W PTM2 -W PTM1 After base-catalyzed ester hydrolysis, the resulting acid is conjugated to a ULM moiety bearing an amino group, combining the PTM and ULM binding moieties into one molecule.

[0547] [ka]

[0548] As shown in Scheme 2, a Mitsunobu reaction between a hydroxyl-containing moiety R3 and a monoprotected diol containing a linking group L provides the coupling product. Following O deprotection, the free hydroxyl group is activated, for example as a sulfonate, and then reacted with W PTM5 In the above, the moiety W having an amino group PTM5 -W PTM3 -W PTM2 -W PTM1 After ester hydrolysis, the resulting acid is conjugated to a ULM moiety bearing an amino group, combining the PTM and ULM binding moieties into one molecule.

[0549] [ka]

[0550] As shown in Scheme 3, the vinyl group is first converted to the bis-halogenated derivative W PTM2 The resulting product is then introduced into a halogenated moiety W bearing a linking group L' containing an optionally protected amino group. PTM2 undergo a palladium-catalyzed Heck coupling reaction with W PTM1 To introduce the part, W PTM2 -W PTM5 The halide moiety of is coupled with an appropriate boronic acid under Suzuki conditions, and the resulting amine is reacted with a ULM-containing aldehyde to provide the PTM-ULM coupled product.

[0551] [ka]

[0552] Scheme 4 shows the PTM binding moiety W PTM5 -W PTM3 -W PTM2 -W PTM1 Illustrated are exemplary coupling reactions utilized to link a ULM-containing moiety to a ULM-containing moiety. Such reactions may include reductive amination using sodium cyanoborohydride as a reducing agent, or a condensation coupling reaction between a carboxylic acid and a diamine. One of skill in the art would be able to select appropriate reagents and conditions to effect the desired transformation.

[0553] [ka]

[0554] As shown in Scheme 5, the hydroxyl-containing moiety R3 and W PTM5 A Mitsunobu-type reaction between W PTM5 The halogen atoms in the monoprotected diamine W can be converted to the monoprotected diamine W under Suzuki or Buchwald conditions. PTM3 Following deprotection of the second amino group, W PTM2By replacing the more reactive halogen atom attached to the W moiety, PTM5 -W PTM3 -W PTM2 The resulting monohalide is then reacted with an appropriate boronic acid under Suzuki conditions to form the PTM binding moiety W PTM5 -W PTM3 -W PTM2 -W PTM2 After ester hydrolysis, the resulting acid is then conjugated with a ULM moiety bearing an amino group, combining the PTM and ULM binding moieties into one molecule.

[0555] [ka]

[0556] As shown in Scheme 6, the acetal-containing ULM moiety can undergo acid-catalyzed hydrolysis under sufficiently mild conditions to form an aldehyde, which can then be converted to a W-type ULM moiety with an amino group-containing linker L' under reductive amination conditions. PTM5 -W PTM3 -W PTM2 -W PT M2 The fragment is reacted with the PTM-ULM coupling product to form a PTM-ULM coupled product. One of skill in the art would be able to select appropriate reagents and conditions to effect the desired transformation.

[0557] [ka]

[0558] As shown in Scheme 7, a Mitsunobu-type reaction between a hydroxyl-containing moiety R3 and a monoprotected fluorinated diol provides a fluorine-containing intermediate. Following O deprotection, the free hydroxyl group is activated (e.g., as a sulfonate), and then W PTM5 In the above, the moiety W having an amino group PTM5 -W PTM3 -W PTM2 -W PTM1After ester hydrolysis, the resulting acid is conjugated to a ULM moiety bearing an amino group, combining the PTM and ULM binding moieties into one molecule.

[0559] [ka]

[0560] As shown in Scheme 8, nucleophilic displacement of the leaving group in L'-OLG with a hydroxyl-containing ester containing R3 affords a coupled product combining linkers L' and L". Subsequent base hydrolysis and coupling of the resulting acid with a ULM moiety bearing an amino group provides a ULM fragment with two consecutive linking groups L' and L". N-deprotection of the amino group of L', followed by W PTM5 -W PTM3 -W PTM2 -W PTM1 -L'" aldehyde reductive amino acid conversion, or W PTM5 -W PTM3 -W PTM2 -W PTM1 Condensation with -L'" carboxylic acid provides the PTM-ULM coupled product.

[0561] [ka]

[0562] As shown in Scheme 9, the moiety W in a hydroxyl group-containing compound having R PTM5 Nucleophilic substitution of the fluorine atom in W PTM5 -L-R3 halides, which can be reacted with monoprotected diamines W under Suzuki or Buchwald conditions. PTM5 Following deprotection of the second amino group, W PTM3 -W PTM5 -L-R3 moiety is bishalogenated by aromatic nucleophilic substitution. PTM2 Subsequent Suzuki reaction with an appropriate boronic acid affords the monohalide W PTM1 -W PTM2-W PTM3 -W PTM5 -L-R3 ester. Base hydrolysis and coupling with a ULM moiety bearing an amino group provides the PTM-ULM coupled product.

[0563] One possible approach to synthesizing exemplary compounds of the present disclosure is to follow the general synthetic route detailed in the following scheme.

[0564] [ka]

[0565] Those skilled in the art will appreciate that modified approaches can be utilized to attach PTMs via different chemical linkers. For example, W PTM5 When is linked to L' via a CH2 group (X = CH2 in the above scheme), the approach depicted in the following scheme can be envisaged.

[0566] [ka]

[0567] Or W PTM5 If not present, the PTM of exemplary compounds represented by Formula I can be synthesized according to the following general scheme:

[0568] [ka]

[0569] Those skilled in the art will be able to modify the general approach described herein to produce W PTM1 , W PTM2 , W PTM3 , W PTM4 , W PTM5 , W PTM6 , and W PTM7It will be understood that the specific nature of the ring can be adapted. For example, in some embodiments, exemplary compounds represented by Formula II can be prepared as described in the following general synthetic scheme, where one skilled in the art will recognize that additional protection / deprotection steps may be required depending on the specific chemical nature of the exemplary compound.

[0570] [ka]

[0571] In one embodiment where X represents NH, exemplary compounds are PTM5 Depending on whether is present, it can be prepared according to one of the two schemes shown below.

[0572] [ka]

[0573] Exemplary PTMs represented by general formula III include W PMT5 If not present, it can be prepared according to the general approach described for compounds of formula I.

[0574] Exemplary PTMs represented by general formula IV can be prepared according to the following general scheme:

[0575] [ka]

[0576] Exemplary Synthesis of Exemplary Compound 11 Step 1

[0577] [ka]

[0578] To a mixture of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate (1.5 g, 6.8 mmol) and TEA (2.07 g, 20.5 mmol) in DCM (5 mL) was added TsCl (1.95 g, 10.23 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 3 h. The solution was quenched with water (20 mL) and extracted with DCM. The organic phase was washed with brine (20 mL × 2). The organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (CHCl:MeOH 40:1) to give tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (2.14 g, mmol, 84% yield).

[0579] Step 2

[0580] [ka]

[0581] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.11 g, 5.722 mmol), tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (2.14 g, 5.722 mmol), and CsCO (3.73 g, 11.444 mmol) in dry DMF (10 mL) was heated to 75 °C for 3 h. The reaction mixture was then cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water (10 mL) and brine (10 mL × 2), dried (NaSO), filtered, and concentrated. The crude residue (2.8 g) was used in the next reaction without further purification.

[0582] Step 3

[0583] [ka]

[0584] A mixture of tert-butyl 2-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (1.5 g, 3.79 mmol), 4-bromo-6-chloropyridazin-3-amine (1.1 g, 5.69 mmol), PdCl(dppf) (555 mg, 0.758 mmol), tBuPHBF (441 mg, 1.52 mmol), and CsCO (3.09 g, 9.48 mmol) in dioxane (10 ml) and water (1 ml) was heated to 100 °C with stirring under N for 3 h. The solids were filtered, and the filtrate was concentrated. The residue was purified by chromatography (CH2Cl2:MeOH 30:1) to give tert-butyl 2-(2-(2-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (800 mg, 53% yield).

[0585] Step 4

[0586] [ka]

[0587] tert-Butyl 2-(2-(2-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (800 mg, 2.02 mmol), (2-hydroxyphenyl)boronic acid (418 mg, 3.03 mmol), cesium carbonate (1.65 g, 5.05 mmol), PdCl(dppf) (444 mg, 0.606 mmol), and tert-butyl ...hydroxyphenyl)boronic acid (418 mg, 3.03 mmol) in dioxane (10 mL) and water (1 mL). tA suspension of BuPHBF (352 mg, 1.212 mmol) was heated to 100 °C under nitrogen for 3 h. The mixture was cooled to room temperature, and the solid was filtered. The filtrate was concentrated and purified by chromatography (CHCl:MeOH 40:1) to give tert-butyl 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (400 mg, 44% yield).

[0588] Step 5

[0589] [ka]

[0590] To a solution of tert-butyl 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (400 mg, 0.88 mmol) in THF / HO (5 mL, 2:1) was added LiOH (111 mg, 2.64 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction solution was quenched with 1 M HCl. The solution was dried (NaSO), filtered, and concentrated under reduced pressure to give crude 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetic acid (600 mg), which was used in the next step without further purification.

[0591] Step 6

[0592] [ka]

[0593] 2-(2-(2-(4-(3-amino-6-(2-hydroxybenzoyl)methyl)-2-hydroxybenzoyl)methyl)-2-hydroxybenzoyl)methyl) To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (430 mg, 1 mmol), and DIPEA (516 mg, 4 mmol) was added HATU (570 mg, 1.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (8 mL × 2), dried (NaSO), and filtered. The organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (6% MeOH in DCM) to give (2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (22 mg).

[0594] 1 HNMR (400MHz, MeOD): δ8.83(s, 1H), 8.32(s, 1H), 8.04(d, J=9.6Hz, 2H), 7.78(d, J=7.6Hz, 1H), 7.65(d, J=10.0Hz, 1H), 7.39(d, J=8.0Hz, 2H), 7.32~7.34(m, 2H), 7.28(m, 1H), 6.95(d, J=7.6Hz 2H), 4.69(d, J=9.6Hz 1H), 4.44~4.57(m, 6H), 4.25~4.35(m, 1H), 3.60~3.99(m, 11H), 2.46(s, 3H), 2.23(m, 1H), 2.08(m, 1H), 1.01(s, 9H).

[0595] Exemplary compound 5 was prepared according to the following scheme using procedures similar to those described above for exemplary compound 11, as well as procedures known and understood by those skilled in the art.

[0596] [ka]

[0597] Using the procedures described for Exemplary Compound 11 and Exemplary Compound 5, Exemplary Compound 1, Exemplary Compound 2, Exemplary Compound 3, Exemplary Compound 4 were prepared.

[0598] Exemplary Synthesis of Exemplary Compound 9 Step 1

[0599] [ka]

[0600] To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (13.5 g, 56.8 mmol) in anhydrous DMF (30 mL) was added 60% NaH (1.25 g, 31.2 mmol) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. Then, 4-bromo-2-fluoropyridine (5 g, 28.4 mmol) was added dropwise to the mixture, and the mixture was heated to 75° C. for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (200 mL). The organic phase was washed with brine (10 mL), dried (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel column to give 14-((4-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (9.0 g, 22.9 mmol, 81% yield).

[0601] Step 2

[0602] [ka]

[0603] To a solution of 14-((4-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol (5.0 g, 12.7 mmol) in anhydrous THF (50 mL) was added 60% NaH (660 mg, 16.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 40 min. Then, tert-butyl 2-bromoacetate (4.9 g, 25.4 mmol) was added dropwise to the mixture and stirred at room temperature overnight. The reaction mixture was quenched with 2 N NH4Cl (10 mL) and extracted with EA (200 mL). The organic phase was then washed with brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column to give tert-butyl 17-((4-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (2.6 g, 5.13 mmol, 40% yield).

[0604] Step 3

[0605] [ka]

[0606] A mixture of tert-butyl 17-((4-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (250 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (718 mg, 1.4 mmol), cesium carbonate (769 mg, 2.36 mmol), Pd(dba) (110 mg, 0.12 mmol), and Xantphos (138 mg, 0.24 mmol) in dioxane (5 mL) in a sealed tube was heated to 110 °C overnight under nitrogen. The mixture was extracted with EA (100 mL). The organic phase was then washed with water (10 mL), brine (10 mL), dried (NaSO), and concentrated under reduced pressure. The residue was purified by silica gel column to give tert-butyl 8-(2-( (19,19-dimethyl-17-oxo-3,6,9,12,15,18-hexaoxaicosyl)oxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (550 mg, 0.86 mmol, 73% yield) was obtained.

[0607] Step 4

[0608] [ka]

[0609] To a solution of tert-butyl 8-(2-((19,19-dimethyl-17-oxo-3,6,9,12,15,18-hexaoxaicosyl)oxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (550 mg, 0.86 mmol) in MeOH (15 mL) was added HCl in dioxane (6N in dioxane) (5 ml, 30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give crude methyl 17-((4-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (0.55 g).

[0610] Step 5

[0611] [ka]

[0612] To a solution of crude methyl 17-((4-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (550 mg, crude) in DMSO (5 mL) was added 5-bromo-6-chloropyridazin-3-amine (526 mg, 2.71 mmol) and DIPEA (1.87 g, 14.5 mmol). The solution was stirred at 150° C. overnight. The mixture was extracted with EA (60 mL). The organic phase was washed with water (8 mL) and brine (8 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 17-((4-((1R,5S)-3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (400 mg).

[0613] Step 6

[0614] [ka]

[0615] Methyl 17-((4-((1R, To a solution of 5S)-3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (325 mg, 0.52 mmol) and (2-hydroxyphenyl)boronic acid (93 mg, 0.68 mmol), cesium carbonate (542 mg, 1.66 mmol), PdCl(dppf) (73.2 mg, 0.1 mmol), and t-BuPHBF (58 mg, 0.2 mmol) were added. The solution was stirred at 100 °C under a nitrogen atmosphere for 4 hours. The pH of the solution was adjusted to 5 with 1 N HCl. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 17-((4-((1R,5S)-3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoic acid (300 mg), which was used in the next step without further purification.

[0616] Step 7

[0617] [ka]

[0618] To a solution of crude 17-((4-((1R,5S)-3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoic acid (80 mg, 0.12 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (108 mg, 0.24 mmol) in DMF (5 mL) was added DIPEA (124 mg, 0.96 mmol) and HATU (92 mg, 0.24 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was extracted with EA (50 mL). The organic phase was washed with water (8 mL) and brine (8 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (6% MeOH in DCM) to give (2S,4R)-1-((S)-20-((4-((1R,5S)-3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12,15,18-pentaoxa-3-azaicosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (20 mg, 0.018 mmol, 15.0% yield).

[0619] 1 H NMR (400MHz, MeOD): δ8.74(s, 1H), 7.68~7.66(m, 2H), 7.34~7.28(m, 5H), 7.18~7 .10(m, 1H), 6.80~6.78(m, 2H), 6.43~6.40(m, 1H), 6.10(s, 1H), 4.60~4.20(m, 9H) , 3.92~3.89(m, 2H), 3.80~3.64(m, 4H), 3.71~3.45(m, 16H), 3.10~3.00(m, 1H), 3. 00~2.90(m, 2H), 2.37~2.34(m, 1H), 2.35(s, 3H), 2.18~1.99(m, 6H), 0.92(s, 9H).

[0620] Using similar procedures, exemplary compounds 7, 8, 10, and 35 were prepared. Exemplary Synthesis of Exemplary Compound 6 Step 1

[0621] [ka]

[0622] To a solution of 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (3.49 g, 10 mmol) [prepared using a procedure similar to that described for Example A2979] in DCM (50 mL) and HO (25 mL) was added PhI(OAc) (9.66 g, 30 mmol) and TEMPO (312 mg, 2 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (100 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid (3.5 g, 9.64 mmol, 96% yield).

[0623] Step 2

[0624] [ka]

[0625] To a solution of 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid (3.0 g, 8.26 mmol) in MeOH (30 mL) was added SOCl (4.0 g, 33.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The pH of the solution was adjusted to about 8 with saturated NaHCO. The mixture was extracted with DCM (100 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure to give methyl 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetate (2.9 g, 7.69 mmol, 93% yield).

[0626] Using a procedure similar to that described for exemplary compound 9, methyl 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetate was converted to the final compound (2S,4R)-1-((2S)-14-((4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (exemplary compound 6).

[0627] 1 HNMR (400MHz, MeOD): δ8.82(s, 1H), 7.76~7.74(m, 2H), 7.42~7.34(m, 5H), 7.22~7.18(m, 1H), 6.89~6.86(m, 2H), 6.53~ 6.52(m, 1H), 6.16(s, 1H), 4.66~4.28(m, 9H), 4.01~4.00(m, 2H), 3.82~3.60(m, 12H), 3.31~3.29(m, 1H), 3.10~3.08(m, 2H), 2.51~2.50(m, 1H), 2.49(s, 3H), 2.29~2.05(m, 6H), 2.42~2.29(m, 2H), 1.01(s, 9H).

[0628] Exemplary Synthesis of Exemplary Compound 20 Step 1

[0629] [ka]

[0630] To a solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (4 g, 14.2 mmol) and EtN (8.6 g, 85.2 mmol) in DCM (50 mL) was added TsCl (8.1 g, 42.6 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc (100 mL) and water (10 mL). The organic phase was washed with brine (10 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis(4-methylbenzenesulfonate) (6.0 g, 10.2 mmol, 72% yield).

[0631] Step 2

[0632] [ka]

[0633] To a solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis(4-methylbenzenesulfonate) (3.5 g, 5.93 mmol) in anhydrous DMF (20 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.15 g, 5.93 mmol) and CsCO (3.87 g, 11.86 mmol). The reaction mixture was stirred at 75 °C for 0.5 h. The mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and water (20 mL). The organic phase was washed with brine (20 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (0.6 g, 0.98 mmol, 16.5% yield).

[0634] Step 3

[0635] [ka]

[0636] To a solution of 17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (0.3 g, 0.49 mmol) and (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (268 mg, 0.49 mmol) in DMF (5 mL) was added KCO (135 mg, 0.98 mmol). The mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was extracted with EA (80 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-((17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl). A mixture of pyrrolidine-2-carboxamide and (1-(17-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)-1H-pyrazol-4-yl)boronic acid (270 mg, 0.27 mmol, 56% yield) was obtained.

[0637] Step 4

[0638] [ka]

[0639] (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-((17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl)pyrrolidine-2-carboxamide and (1-(17-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-((17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl)pyrrolidine-2-carboxamide in dioxane (20 mL) and water (2 mL). To a mixture of (xoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)-1H-pyrazol-4-yl)boronic acid (270 mg, 0.27 mmol) and a solution of 5-bromo-6-chloropyridazin-3-amine (85 mg, 0.41 mmol) was added cesium carbonate (220 mg, 0.68 mmol), PdCl(dppf) (40 mg, 0.054 mmol), and t-BuPHBF (31 mg, 0.11 mmol). The solution was stirred at 100° C. under a nitrogen atmosphere for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S,4R)—N-(2-((17-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (175 mg, 0.18 mmol, 67% yield).

[0640] Step 5

[0641] [ka]

[0642] (2S,4R)-N-(2-((17-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoin) in dioxane (15 mL) and water (1.5 mL). To a solution of (2-hydroxyphenyl)pyrrolidine-2-carboxamide (175 mg, 0.18 mmol) and (2-hydroxyphenyl)boronic acid (32 mg, 0.23 mmol) was added cesium carbonate (176 mg, 0.54 mmol), PdCl(dppf) (53 mg, 0.072 mmol), and t-BuPHBF (42 mg, 0.144 mmol). The solution was stirred at 100 °C under a nitrogen atmosphere for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S,4R)—N-(2-((17-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (24 mg, 0.023 mmol, 13% yield).

[0643] 1 HNMR (400MHz, MeOD): δ8.84(s, 1H), 8.28(s, 1H), 8.05(d, J=12.4Hz, 2H), 7.38~7.81(m , 6H), 7.36~7.37(m, 1H), 6.98~7.00(m, 2H), 6.92(d, J=7.6Hz, 2H), 4.37~4.59(m, 9H), 4 .15~4.16(m, 2H), 3.83~3.96(m, 6H), 3.46~3.56(m, 16H), 2.46(s, 3H), 2.44~2.45(m, 1 H), 2.21~2.22(m, 1H), 2.09~2.10(m, 1H), 1.03(d, J=6.4Hz, 3H), 0.82(d, J=6.4Hz, 3H).

[0644] Using procedures similar to those described for exemplary compound 20, exemplary compounds 12, 13, and 21 were prepared.

[0645] Exemplary Synthesis of Exemplary Compound 14 Step 1

[0646] [ka]

[0647] A 250 mL round-bottom flask was charged with a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.73 mmol, 1.00 equiv.), 4-bromo-6-chloropyridazin-3-amine (1.7 g, 8.16 mmol, 1.20 equiv.), Pd(PPh3)4 (800 mg, 0.69 mmol, 0.10 equiv.), and potassium carbonate (2.9 g, 20.98 mmol, 3.00 equiv.) in dioxane / HO (1:1) (60 mL). The resulting solution was stirred overnight at 100 °C in an oil bath. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). This gave 1.0 g (66%) of 6-chloro-4-(1H-pyrazol-4-yl)pyridazin-3-amine as a white solid.

[0648] Step 2

[0649] [ka]

[0650] A 10 mL sealed tube was charged with a solution of 6-chloro-4-(1H-pyrazol-4-yl)pyridazin-3-amine (390 mg, 1.99 mmol, 1.00 equiv.) in dioxane (4 mL), [2-(methoxymethoxy)phenyl]boronic acid (546 mg, 3.00 mmol, 1.50 equiv.), Pd(PPh3)4 (300 mg, 0.26 mmol, 0.20 equiv.), and a solution of potassium carbonate (552 mg, 3.99 mmol, 2.00 equiv.) in water (2 mL). The resulting solution was stirred in an oil bath at 100 °C for 12 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). This gave 120 mg (20%) of 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine as a yellow solid.

[0651] Step 3

[0652] [ka]

[0653] A 50 mL round-bottom flask was charged with a solution of 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (100 mg, 0.34 mmol, 1.00 equiv.), 2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]ethan-1-ol (100 mg, 0.33 mmol, 1.00 equiv.), and potassium carbonate (91 mg, 0.66 mmol, 2.00 equiv.) in N,N-dimethylformamide (10 mL). The resulting solution was stirred at 70 °C in an oil bath for 12 hours. The resulting solution was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). This gave 100 mg (69%) of 2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethan-1-ol as a yellow oil.

[0654] Step 4

[0655] [ka]

[0656] A 100 mL round-bottom flask was charged with a solution of 2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethan-1-ol (100 mg, 0.23 mmol, 1.00 equiv.) in dichloromethane (20 mL), 4-toluenesulfonyl chloride (66.0 mg, 0.35 mmol, 1.50 equiv.), triethylamine (47 mg, 0.46 mmol, 2.00 equiv.), and 4-dimethylaminopyridine (10 mg, 0.08 mmol, 0.30 equiv.). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were concentrated under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). This gave 100 mg (74%) of 2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate as a yellow oil.

[0657] Step 5

[0658] [ka]

[0659] In a 50 mL round-bottom flask was added a solution of 2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate (120 mg, 0.2 mmol, 1.00 equiv.), (2S,4R)-4-hydroxy-1-[2-(3- [hydroxy-1,2-oxazol-5-yl]-3-methylbutanoyl-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (130 mg, 0.2 mmol, 1.00 equiv.) [prepared as described by Qian, Y et al. in WO 2017 / 030814] and potassium carbonate (100 mg, 0.4 mmol, 2.00 equiv.) were added. The resulting solution was stirred at 70 °C for 12 h. The resulting solution was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were concentrated under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). This gave 90 mg of (2S,4R)-1-[2-[3-(2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a colorless oil.

[0660] Step 6

[0661] [ka]

[0662] A 50 mL round-bottom flask was charged with a solution of (2S,4R)-1-[2-[3-(2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (90.0 mg, 0.10 mmol, 1.00 equiv) in i-propanol (2 mL) and tetrahydrofuran (2 mL), and concentrated hydrogen chloride solution (12 N, 2 mL) was added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 32% B to 41% B in 8 min; 254 nm; Retention time: 70 min. This afforded 56 mg (65%) of (2S,4R)-1-[2-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid.

[0663] The product was purified by chiral preparative HPLC using the following conditions: column, CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase, Hex-HPLC and ethanol-HPLC (hold 50% ethanol-HPLC in 24 min); detector, UV 220 / 254 nm. This gave 17.8 mg (34%) of (2S,4R)-1-[(2S)-2-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [ 1 H NMR (300MHz, CD3OD): δ8.82 (d, J=11.1Hz, 1H), 8.29~8.18 (m, 1H), 8.11~7.89 (m, 2H), 7.80 (d, J=8.2Hz) , 1H), 7.48~7.41(m, 1H), 7.37~7.30(m, 3H), 7.30~7.19(m, 1H), 6.95~6.83 (m, 2H), 5.89(s, 1H), 4.59~4.41(m, 2H), 4.40~4.30(m, 4H), 4.27~4.11(m, 2H), 3.86(q, J=5.3Hz, 2H), 3.75~3.59(m, 6H), 3.56(s, 3H), 2.42(d, J=5.0 Hz, 3H), 2.36~2.10(m, 2H), 2.04~2.01(m, J=13.1, 8.1, 4.7Hz, 1H), 1.26(s , 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H)] and 24.4 mg (47%) of (2S,4R)-1-[(2R)-2-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide[ 1H NMR (300MHz, CD3OD): δ8.82 (d, J=6.6Hz, 1H), 8.26 (dd, J=3.1, 0.8Hz, 1H), 8.10~7.96 (m, 2H), 7.86~7.75 (m, 1H), 7.4 5~7.30(m, 4H), 7.25~7.22(m, 1H), 6.96~6.84(m, 2H), 5.88(s, 1H), 4.70~4.42(m, 3H), 4.41~4.33(m, 3H), 4.28~4.17( m, 2H), 3.87 (t, J = 5.0 Hz, 3H), 3.85–3.63 (m, 2H), 3.59–3.57 (m, 6H), 2.41 (d, J = 12.2 Hz, 3H), 2.38–2.33 (m, 1H), 2.25–2.12 (m, 1H), 2.06–2.02 (m, 1H), 1.26 (s, 1H), 0.97 (dd, J = 6.6, 1.8 Hz, 3H), 0.80 (dd, J = 6.6, 1.8 Hz, 3H)] was obtained as a white solid.

[0664] Exemplary compounds 16, 17, 18, and 19 were prepared using the procedures described above for exemplary compound 14 and exemplary compound 15.

[0665] Exemplary Synthesis of Exemplary Compound 22 Step 1

[0666] [ka]

[0667] A 250 mL round-bottom flask was charged with (Z)-4-(benzyloxy)-N-hydroxybutocarbonimidoyl chloride (8.7 g, 38.21 mmol, 1.00 equiv.), but-3-yn-1-ol (3.3 g, 47.08 mmol, 1.23 equiv.), ethyl acetate (70 mL), water (70 mL), and sodium bicarbonate (4.0 g, 47.61 mmol, 1.25 equiv.). The resulting solution was stirred at 25 °C for 2 h. The resulting solution was extracted with ethyl acetate and washed with saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). This afforded 5.9 g (59%) of 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]ethan-1-ol as a yellow oil.

[0668] Step 2

[0669] [ka]

[0670] A 100 mL round-bottom flask was charged with 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]ethan-1-ol (550.0 mg, 2.10 mmol, 1.00 equiv), acetone (30 mL), CrO (100.0 mg), sulfuric acid (0.25 mL), and water (1 mL). The resulting solution was stirred at 25 °C for 1 hour. The resulting solution was diluted with water. The resulting solution was extracted with ethyl acetate and washed with saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 420 mg (72%) of 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetic acid as a yellow oil.

[0671] Step 3

[0672] [ka]

[0673] A 250 mL round-bottom flask was charged with ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetate (8.0 g, 26.37 mmol, 1.00 equiv.), ethanol (50 mL), and sulfuric acid (0.1 mL). The resulting solution was stirred at 70 °C for 1.5 h. The resulting mixture was concentrated in vacuo. The crude product was purified by flash preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, acetonitrile:water = 0:100 increasing to acetonitrile:water = 60:40 within 49 min; detector, UV 220 nm. This afforded 4.5 g (56%) of ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetate as a pale yellow oil.

[0674] Step 4

[0675] [ka]

[0676] A 250 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetate (4.5 g, 14.83 mmol, 1.00 equiv.) and tetrahydrofuran (70 mL). Following this, a solution of t-BuOK (2.0 g, 17.82 mmol, 1.20 equiv.) in tetrahydrofuran (17.8 mL) was added dropwise with stirring at 0° C. for 20 minutes. To this was added 2-iodopropane (3.01 g, 17.71 mmol, 1.19 equiv.) dropwise with stirring at 0° C. for 2 minutes. The resulting solution was stirred at 25° C. for 2 hours. The reaction was then quenched with water. The resulting solution was extracted with ethyl acetate. The mixture was filtered and washed with saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 4.3 g (84%) of ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]-3-methylbutanoate as an orange oil.

[0677] Step 5

[0678] [ka]

[0679] A 250 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]-3-methylbutanoate (4.2 g, 12.16 mmol, 1.00 equiv.) and dichloromethane (100 mL). Following this, a solution of BBr3 (5.17 g, 20.64 mmol, 1.70 equiv.) in dichloromethane (20.7 mL) was added dropwise with stirring at −78° C. for 30 minutes. The resulting solution was stirred at −78° C. for 2 hours. The reaction was then quenched. The resulting solution was extracted with dichloromethane and washed with saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash preparative HPLC using the following conditions: Column: C18 silica gel; Mobile phase: acetonitrile:water = 0:100, increasing to acetonitrile:water = 23:76 within 25 min; Detector: UV 220 nm. This afforded 2.6 g (84%) of ethyl 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoate as an orange oil.

[0680] Step 6

[0681] [ka]

[0682] A 100 mL round-bottom flask was charged with ethyl 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoate (1.2 g, 4.70 mmol, 1.00 equiv.), ethanol (20 mL), water (10 mL), and sodium hydroxide (1.9 g, 47.50 mmol, 10.0 equiv.). The resulting solution was stirred at room temperature overnight. The pH of the solution was adjusted to 6 with hydrogen chloride (2 M). The resulting solution was extracted with ethyl acetate and washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This afforded 800 mg (75%) of 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoic acid as a yellow oil.

[0683] Step 7

[0684] [ka]

[0685] A 100 mL round-bottom flask was charged with 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoic acid (800 mg, 3.52 mmol, 1.00 equiv.), (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (1.24 g, 3.50 mmol, 1.00 equiv.), N,N-dimethylformamide (15 mL), N-ethyl-N-isopropylpropan-2-amine (1.82 g, 14.08 mmol, 4.00 equiv.), and T3P (1.77 g, 1.20 equiv.). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched with water. The resulting solution was extracted with ethyl acetate and washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (5:1). The collected fractions were combined and concentrated under vacuum. This afforded 870 mg (53%) of (2S,4R)-4-hydroxy-1-[[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]carbonyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a yellow solid.

[0686] Step 8

[0687] [ka]

[0688] A 50 mL round-bottom flask was charged with (2S,4R)-4-hydroxy-1-[2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (870 mg, 1.65 mmol, 1.00 equiv.), dichloromethane (10 mL), 4-methylbenzene-1-sulfonyl chloride (377 mg, 1.98 mmol, 1.20 equiv.), triethylamine (334.0 mg, 3.30 mmol, 2.00 equiv.), and 4-dimethylaminopyridine (40 mg, 0.33 mmol, 0.20 equiv.). The resulting solution was stirred at room temperature for 4 hours. The resulting solution was extracted with dichloromethane and washed with water and saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated in vacuo. This gave 600 mg (53%) of 3-(5-[1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)propyl 4-methylbenzene-1-sulfonate as a yellow solid.

[0689] Step 9

[0690] [ka]

[0691] A 50 mL round-bottom flask was charged with 2-(2-hydroxyethoxy)ethan-1-ol (273.0 mg, 2.57 mmol, 5.00 equiv.) and N,N-dimethylformamide (5 mL). Sodium hydride (41.0 mg, 1.71 mmol, 2.00 equiv.) was added at 0° C., followed 20 min later by the addition of 3-(5-[1-[(4S)-4-hydroxy-1-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-2-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)propyl 4-methylbenzene-1-sulfonate (350.0 mg, 0.51 mmol, 1.00 equiv.). The resulting solution was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over sodium sulfate, concentrated, and the residue was subjected to flash chromatography to give 160 mg (51%) of (4S)-4-hydroxy-2-[2-(3-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-1-carboxamide as a yellow oil.

[0692] Step 10

[0693] [ka]

[0694] In a 50 mL round-bottom flask was added (2S,4R)-4-hydroxy-1-[2-(3-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (160 mg, 0.26 mmol, 1.00 equiv), dichloromethane (5 mL), 4-methylbenzene-1-sulfonyl chloride (59 mg, 0.31 mmol, 1.20 equiv), triethylamine (53 mg, 0.52 mmol, 2.00 equiv), 4-dimethylaminopyridine (6 mg, 0.5 mL), and HCl (1 mL). 0.05 mmol, 0.20 equiv. The resulting solution was stirred at room temperature for 5 hours. The resulting solution was extracted with dichloromethane and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (12:1). The collected fractions were combined and concentrated under vacuum. This afforded 72 mg (36%) of 2-[2-[3-(5-[1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)propoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate as a yellow oil.

[0695] Step 11

[0696] [ka]

[0697] A 50 mL round-bottom flask was charged with 2-[2-[3-(5-[1-[(2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-1,2-oxazol-3-yl)propoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate (70 mg, 0.09 mmol, 1.00 equiv), 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (27 mg, 0.09 mmol, 1.00 equiv), acetonitrile (2 mL), and potassium carbonate (38 mg, 0.27 mmol, 3.00 equiv). The resulting solution was stirred at 80 °C overnight. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum. This gave 30 mg (37%) of (2S,4R)-1-[2-[3-(3-[ 2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]propyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide was obtained as a yellow oil.

[0698] Step 12

[0699] [ka]

[0700] A 50 mL round-bottom flask was charged with (2S,4R)-1-[2-[3-(3-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]propyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (27.0 mg, 0.03 mmol, 1.00 equiv), methanol (2 mL), and hydrogen chloride (aq) (0.5 mL). The resulting solution was stirred at room temperature overnight. The resulting solution was diluted with water. The pH of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Shield RP18 OBD column, 5um, 19*150mm; Mobile phase A: water (0.05% NH3H2O), Mobile phase B: acetonitrile; Flow rate: 20mL / min; Gradient: 34%B to 47%B in 8min; 220nm. This gave 7.6 mg (30%) of (2S,4R)-1-[2-(3-[3-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]propyl]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid.

[0701] 1H-NMR: (400MHz, CD3OD) δ8.89~8.83(m, 1H), 8.31~8.26(m, 1H), 8.08~8.03(m, 2H), 7.85~7.81(m, 1H) ,7.46~7.21(m,5H),6.96~6.87(m,2H),6.15(s,1H),4.52~4.44(m,5H),4.41~4.31(m,3H),3.91~3.8 0(m, 2H), 3.72~3.65(m, 1H), 3.61~3.35(m, 6H), 2.62~2.51(m, 2H), 2.45~2.33(m, 3H), 2.22~2.15(m, 1H), 2.10~2.01(m, 1H), 1.84~1.72(m, 2H), 1.30~1.24(m, 1H), 1.03~0.97(m, 3H), 0.91~0.75(m, 3H).

[0702] Exemplified NA compound 23 and exemplified NA compound 24. Exemplified NA synthesis.

[0703]

change

[0704] A 25 mL round-bottom flask was charged with (2S,4R)-1-[2-[3-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]propyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (87 mg, 0.10 mmol, 1.00 equiv) [prepared as described for exemplary compound 22] and methanol (10 mL). The resulting solution was stirred at 25° C. for 1 hour. The crude product was purified by chiral preparative HPLC using the following conditions: Column: CHIRALPAK ID-3; Mobile phase: MtBE (0.1% DEA):EtOH = 80:20; Size: 0.46*10cm; 3um; Detector: UV-254nm. This gave 17mg (20%) of (2S,4R)-1-[(2S)-2-[3-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]propyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as an off-white solid [ 1H NMR (300MHz, CD3OD, ppm):δ 8.83(s, 1H), 8.33(s, 1H), 8.23(s, 1H), 7.99(s, 1H), 7.70~7.67(d, J=9Hz, 1H), 7.48~ 7.45(d, J=9Hz, 1H), 7.37~7.32(m, 4H), 7.00~6.97(m, 2H), 6.19(s, 1H), 4.61~4.58(m, 1H), 4.50~4.38(m, 5H), 3.91~3.86(m, 3H), 3.60~3.51(m, 8H), 3.50~3.43(m, 2H), 3.4 0~3.34(m, 2H), 2.57~2.52(m, 2H), 2.46~2.43(m, 4H), 2.30~2.23(m, 1H), 2.10~2.04(m , 1H), 1.73–1.69 (m, 2H), 1.07–1.05 (d, J = 6.6 Hz, 3H), 0.88–0.86 (d, J = 6.9 Hz, 3H)] and 21 mg (24%) of (2S,4R)-1-[(2R)-2-[3-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]propyl)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [ 1 H NMR (300 MHz, C D3OD, ppm):δ 8.88(s, 1H), 8.37(s, 1H), 8.31(s, 1H), 8.04(s, 1H), 7.69~7.67(d, J=8.1Hz, ppm), 7.43~7.39(m, 5H), 7.03~ 6.99(m, 2H), 6.21~6.00(m, 1H), 4.53~4.48(m, 3H), 4.44~4.40(m, 3H), 3.92~3.89(m, 3H), 3.79~3.76(m, 1H), The diols obtained were 3.62–3.54 (m, 7H), 3.50–3.48 (m, 2H), 3.42–3.40 (m, 2H), 2.64–2.61 (m, 2H), 2.46–2.44 (m, 4H), 2.26–2.18 (m, 1H), 2.13–2.04 (m, 1H), 1.82–1.78 (m, 2H), 1.05–1.02 (d, J = 6.6 Hz, 3H), and 0.85–0.82 (d, J = 6.9 Hz, 3H).

[0705] Exemplary compounds 25 and 26 were prepared using procedures similar to those described above for exemplary compounds 22, 23, and 24.

[0706] Exemplary Synthesis of Exemplary Compound 27 Step 1

[0707] [ka]

[0708] A 50 mL round-bottom flask was charged with 2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol (257 mg, 1.71 mmol, 3.00 equiv.) and N,N-dimethylformamide (5 mL). This was followed by the addition of sodium hydride (34 mg, 1.42 mmol, 1.50 equiv.) at 0° C. for 10 minutes. To this was added 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol, 1.00 equiv.). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 5 mL of water / ice. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This gave 90 mg (52%) of 2-(2-[2-[(4-bromopyridin-2-yl)oxy]ethoxy]ethoxy)ethan-1-ol as a pale yellow liquid.

[0709] Step 2

[0710] [ka]

[0711] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 2-(2-[2-[(4-bromopyridin-2-yl)oxy]ethoxy]ethoxy)ethan-1-ol (500 mg, 1.63 mmol, 1.00 equiv.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (347 mg, 1.64 mmol), ... ol, 1.00 equiv.), Cs2CO3 (1599 mg, 4.91 mmol, 3.00 equiv.), toluene (8 mL), and Ruphos (69 mg, 0.05 equiv.) were added. The resulting solution was stirred in an oil bath at 100 °C for 5 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with dichloromethane / MeOH, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated in vacuo. This gave 419 mg (59%) of tert-butyl 8-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow oil.

[0712] Step 3

[0713] [ka]

[0714] A 50 mL round-bottom flask was charged with tert-butyl 8-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (419 mg, 0.96 mmol, 1.00 equiv) and 1 M HCl in methanol (8 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. This afforded 319 mg (99%) of 2-(2-[2-[(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethan-1-ol as a yellow oil.

[0715] Step 4

[0716] [ka]

[0717] A 10 mL microwave tube was charged with 2-(2-[2-[(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethan-1-ol (319 mg, 0.95 mmol, 1.00 equiv), 4-bromo-6-chloropyridazin-3-amine (780 mg, 3.74 mmol, 4.00 equiv), DMSO (10 mL), and DIEA (2 mL). The final reaction mixture was irradiated with microwave radiation at 130° C. for 3 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum to give 260 mg (59%) of 2-[2-[2-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxa C)Ethoxy]ethoxy]ethan-1-ol was obtained as a yellow solid.

[0718] Step 5

[0719] [ka]

[0720] A 10 mL microwave tube purged and maintained under an inert atmosphere of nitrogen was charged with 2-[2-[2-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)ethoxy]ethoxy]ethan-1-ol (295 mg, 0.63 mmol, 1.00 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (223 mg, 1.23 mmol, 2.00 equiv.), potassium carbonate (254 mg, 1.84 mmol, 3.00 equiv.), dioxane (4 mL), water (1 mL), and Pd(PPh) (70 mg, 0.06 mmol, 0.10 equiv.). The resulting solution was stirred at 100 °C overnight. The reaction was then quenched by the addition of water. The resulting solution was extracted with dichloromethane / MeOH, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum. This gave 221 mg (61%) of 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethan-1-ol as a yellow solid.

[0721] Step 6

[0722] [ka]

[0723] In a 50 mL round-bottom flask, 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethan-1-ol (100 mg, 0.18 mmol, 1.00 equiv.), TsCl (50 mg, 0.26 mmol, 1.50 equiv.), dichloromethane (5 mL), triethylamine (0.3 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.10 (equivalent). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum. This gave 97 mg (76%) of 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate as a yellow solid.

[0724] Step 7

[0725] [ka]

[0726] In a 50 mL round-bottom flask, add 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethyl 4-Methylbenzene-1-sulfonate (87 mg, 0.12 mmol, 1.00 equiv.), N,N-dimethylformamide (54 mg, 0.75 mmol, 1.00 equiv.), (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylpyrrolidine-2-carboxamide (79 mg, 0.16 mmol, 2.00 equiv.), and CsCO (5 g, 15.35 mmol, 127.15 equiv.) were added to a solution. The resulting solution was stirred at room temperature for 4 hours. The resulting solution was extracted with dichloromethane / MeOH, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (5:1). The collected fractions were combined and concentrated under vacuum to give 124 mg (99%) of (2S,4R)-1-[2-(3-[2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a yellow solid.

[0727] Step 8

[0728] [ka]

[0729] A 50 mL round-bottom flask was charged with (2S,4R)-1-[2-(3-[2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (131 mg, 0.13 mmol, 1.00 equiv), methanol (5 mL), and 1 M HCl in MeOH (1.5 mL). The resulting solution was stirred at room temperature for 7 hours. The resulting solution was diluted with 5 mL of HO. The pH value of the solution was adjusted to 7 with aqueous Na2CO3 (2M). The resulting solution was extracted with dichloromethane, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (39.0% acetonitrile, maximum 50.0% in 9 minutes); detector, UV 220nm. This afforded 60 mg (48%) of (2S,4R)-1-(2-[3-[2-(2-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a yellow solid, which was further purified by chiral preparative HPLC using the following conditions: Column: Chiralpak ID-2, 2*25cm, 5um; Mobile phase: (0.1% DEA) and ethanol (hold 30% ethanol for 30 minutes); Detector: UV254 / 220nm.This gave 13.9 mg (23%) of (2S,4R)-1-[(2S)-2-[3-[2-(2-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [. 1 H NMR (400MHz, CD3OD): δ8.85 (m, 1H), 7.78~7.72 (m, 2H), 7.47~7.45 (m, 2H), 7.40~7. 34(m, 3H), 7.23~7.22(m, 1H), 6.92~6.88(m, 2H), 6.55~6.53(m, 1H), 6.23(s, 1H), 5 .97(s, 1H), 4.64~4.59(m, 2H), 4.50(s, 3H), 4.40(s, 2H), 4.33~4.24(m, 4H), 3.81~ 3.79(m, 2H), 3.75~3.65(m, 8H), 3.29(m, 1H), 3.10~3.07(m, 2H), 2.48~2.46(m, 3H), 2.23–2.20 (m, 1H), 2.13–2.06 (m, 6H), 1.05 (s, 1H), 0.90–0.89 (d, J = 6.8 Hz, 3H), 0.78–0.76 (d, J = 8 Hz, 3H)] and 17.9 mg (29%) of (2S,4R)-1-[(2R)-2-[3-[2-(2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)-2-methyl-2-propanol]-2-hydroxyphenyl]-2-methyl-2-propanol]-2-hydroxy-1 ... )pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [ 1H NMR (400MHz, CD3OD): δ8.88 (m, 1H), 7.79~7.75 (m, 2H), 7.49~7.39 (m, 5H), 7.24 (m, 1H), 6.92 ~6.90(m, 2H), 6.56~6.54(m, 1H), 6.25~6.24(M, 1H), 6.00(s, 1H), 4.53~4.29(m, 10H), 3.88~3 0.81 (m, 5H), 3.70–3.63 (m, 6H), 3.33 (m, 2H), 3.14–3.12 (m, 2H), 2.48–2.44 (m, 3H), 2.42–2.29 (m, 1H), 2.25–2.12 (m, 6H), 1.04–1.02 (d, J = 6.4 Hz, 3H), 0.88–0.86 (d, J = 6.4 Hz, 3H)].

[0730] Exemplary compounds 29 and 30 were prepared using procedures similar to those described for exemplary compounds 27 and 28.

[0731] Exemplary Synthesis of Exemplary Compound 31 Step 1

[0732] [ka]

[0733] A 50 mL round-bottom flask was charged with 2-(oxan-2-yloxy)ethan-1-ol (4.5 g, 30.78 mmol, 1.00 equiv.), tetrahydrofuran (10 mL), and a solution of t-BuOK (3.6 g, 32.08 mmol, 2.00 equiv.) in tetrahydrofuran (60 mL). Following this, 3-bromoprop-1-yne (2.61 mL, 1.00 equiv.) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding water / ice. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:5). The collected fractions were combined and concentrated in vacuo. This gave 2.8 g (49%) of 2-[2-(prop-2-yn-1-yloxy)ethoxy]oxane as a yellow oil.

[0734] Step 2

[0735] [ka]

[0736] In a 10 mL microwave tube purged and maintained under an inert atmosphere of nitrogen, 2-[ 2-(prop-2-yn-1-yloxy)ethoxy]oxane (2.8 g, 15.20 mmol, 1.00 equiv.), ZrCpHCl (390 mg, 0.10 equiv.), triethylamine (153 mg, 1.52 mmol, 0.10 equiv.), and pinacolborane (2.5 mL) were added. The resulting solution was stirred overnight at 68 °C in an oil bath. The reaction was then quenched by adding NH Cl. The reaction mixture was cooled to 0 °C in a water / ice bath. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:5). The collected fractions were combined and concentrated in vacuo. This gave 3.01 g (63%) of 4,4,5,5-tetramethyl-2-[(1E)-3-[2-(oxan-2-yloxy)ethoxy]prop-1-en-1-yl]-1,3,2-dioxaborolane as a yellow liquid.

[0737] Step 3

[0738] [ka]

[0739] A 10 mL microwave tube purged and maintained under an inert atmosphere of nitrogen was charged with 4,4,5,5-tetramethyl-2-[(1E)-3-[2-(oxan-2-yloxy)ethoxy]prop-1-en-1-yl]-1,3,2-dioxaborolane (1 g, 3.20 mmol, 1.00 equiv.), Pd(PPh3)4 (800 mg, 0.69 mmol, 1.00 equiv.), potassium carbonate (8 g, 57.88 mmol, 18.07 equiv.), dioxane (2 g), tert-butyl 8-(2-bromopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (902 mg, 2.45 mmol, 3.00 equiv.), and water (252 mg, 0.10 equiv.). The resulting solution was stirred overnight at 100°C in an oil bath. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum. This afforded 639 mg (42%) of tert-butyl 8-[2-[(1E)-3-[2-(oxan-2-yloxy)ethoxy]prop-1-en-1-yl]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow oil.

[0740] Step 4

[0741] [ka]

[0742] A 50 mL round-bottom flask was charged with tert-butyl 8-[2-[(1E)-3-[2-(oxan-2-yloxy)ethoxy]prop-1-en-1-yl]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (639 mg, 1.35 mmol, 1.00 equiv.), palladium on carbon (200 mg), and methanol (15 mL). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solids were filtered, and the filtrate was concentrated. This afforded 639 mg (100%) of tert-butyl 8-(2-[3-[2-(oxan-2-yloxy)ethoxy]propyl]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow oil.

[0743] Step 5

[0744] [ka]

[0745] A 50 mL round-bottom flask was charged with tert-butyl 8-(2-[3-[2-(oxan-2-yloxy)ethoxy]propyl]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (639 mg, 1.34 mmol, 1.00 equiv.) and methanol (15 mL), and hydrogen chloride gas was bubbled through the solution. The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. This afforded 387 mg (100%) of 2-[3-(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethan-1-ol as a yellow oil.

[0746] Step 6

[0747] [ka]

[0748] A 10 mL microwave tube was charged with 2-[3-(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethan-1-ol (387 mg, 1.85 mmol, 1.00 equiv.), 4-bromo-6-chloropyridazin-3-amine (1.54 g, 7.39 mmol, 4.00 equiv.), DMSO (8 mL), and DIEA (1.53 mL, 5.00 equiv.). The final reaction mixture was irradiated with microwave radiation at 130° C. for 3 hours. The reaction was then quenched by adding water. The resulting solution was extracted with dichloromethane / MeOH=10:1, and the aqueous layers were combined and concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (7:3). The collected fractions were combined and concentrated under vacuum. This gave 519 mg (67%) of 2-(3-[4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]propoxy)ethan-1-ol as a yellow oil.

[0749] Step 7

[0750] [ka]

[0751] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 2-(3-[4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]propoxy)ethan-1-ol (650 mg, 1.55 mmol, 1.00 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (566 mg, 3.11 mmol, 2.00 equiv.), dioxane (8 mL), water (2 mL), potassium carbonate (644 mg, 4.66 mmol, 3.00 equiv.), and Pd(PPh) (180 mg, 0.16 mmol, 0.10 equiv.). The resulting solution was stirred in an oil bath at 100 °C for 3 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with methanol / HO (85:15). The collected fractions were combined and concentrated in vacuo to give 400 mg (50%) of 2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethan-1-ol as a yellow oil.

[0752] Step 8

[0753] [ka]

[0754] A 50 mL round-bottom flask was charged with 2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethan-1-ol (400 mg, 0.77 mmol, 1.00 equiv.), dichloromethane (15 mL), TsCl (219 mg, 1.15 mmol, 1.50 equiv.), triethylamine (155 mg, 1.53 mmol, 2.00 equiv.), and 4-dimethylaminopyridine (9.4 mg, 0.08 mmol, 0.10 equiv.). The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding water. The resulting solution was extracted with dichloromethane, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated under vacuum to give 330 mg (64%) of 2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl 4-methylbenzene-1-sulfonate as a yellow solid.

[0755] Step 9

[0756] [ka]

[0757] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with methyl 2-(6-chloropyridin-3-yl)acetate (500 mg, 2.69 mmol, 1.00 equiv.), tert-butyl piperazine-1-carboxylate (502 mg, 2.70 mmol, 1.00 equiv.), CsCO (2.63 g, 8.07 mmol, 3.00 equiv.), toluene (10 mL), and RuPhosPd (115 mg, 0.05 equiv.). The resulting solution was stirred overnight at 100 °C in an oil bath. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This gave 319 mg (35%) of tert-butyl 4-[5-(2-methoxy-2-oxoethyl)pyridin-2-yl]piperazine-1-carboxylate as a yellow solid.

[0758] Step 10

[0759] [ka]

[0760] A 50 mL round-bottom flask was charged with tert-butyl 4-[5-(2-methoxy-2-oxoethyl)pyridin-2-yl]piperazine-1-carboxylate (319 mg, 0.95 mmol, 1.00 equiv.), dichloromethane (8 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. This afforded 223 mg (100%) of methyl 2-[6-(piperazin-1-yl)pyridin-3-yl]acetate as a yellow oil.

[0761] Step 11

[0762] [ka]

[0763] A 50 mL round-bottom flask was charged with methyl 2-[6-(piperazin-1-yl)pyridin-3-yl]acetate (101 mg, 0.43 mmol, 1.00 equiv), 2-3-[4-(3-3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxyethyl 4-methylbenzene-1-sulfonate (320 mg, 0.47 mmol, 1.10 equiv), acetonitrile (4 mL), potassium carbonate (298 mg, 2.16 mmol, 5.00 equiv), and NaI (193 mg, 3.00 equiv). The resulting solution was stirred at 60 °C overnight. The resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and water, and the organic layer was separated and washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with dichloromethane / methanol (5:1). The collected fractions were combined and concentrated under vacuum. This afforded 94 mg (30%) of methyl 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl)piperazin-1-yl]pyridin-3-yl]acetate as a yellow solid.

[0764] Step 12

[0765] [ka]

[0766] A 50 mL round-bottom flask was charged with methyl 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl)piperazin-1-yl]pyridin-3-yl]acetate (94 mg, 0.13 mmol, 1.00 equiv), methanol (5 mL), water (2 mL), and LiOH (15 mg, 0.64 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 10 mL of HO. The resulting solution was extracted with dichloromethane, and the aqueous layers were combined and concentrated in vacuo. The residue was dissolved in 10 mL of methanol. The solids were filtered. The resulting mixture was concentrated under vacuum to give 72 mg (78%) of 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl)piperazin-1-yl]pyridin-3-yl]acetic acid as a yellow solid.

[0767] According to the following scheme and using the procedures described above for the preceding examples, 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl)piperazin-1-yl]pyridin-3-yl]acetic acid was prepared from the final compound (2S,4R)-1-((2S)-2-(2-( 6-(4-(2-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)propoxy)ethyl)piperazin-1-yl)pyridin-3-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0768] [ka]

[0769] Exemplary compound 50 was prepared using the procedure described for exemplary compound 31.

[0770] Exemplary Synthesis of Exemplary Compound 32 Step 1

[0771] [ka]

[0772] A 250 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol (10.0 g, 66.59 mmol, 1.00 equiv.), (diethyloxonio)trifluoroborate (1.9 g, 13.33 mmol, 0.20 equiv.), and ethyl 2-diazoacetate (3.8 g, 0.50 equiv.) in dichloromethane (100 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This resulted in 3.6 g (23%) of ethyl 2-[2-[2-(hydroxyethoxy) )Ethoxy]ethoxy]acetate was obtained as a yellow oil.

[0773] Step 2

[0774] [ka]

[0775] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with a solution of ethyl 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]acetate (1.0 g, 4.23 mmol, 1.00 equiv.) in dichloromethane (20 mL), 4-methylbenzene-1-sulfonyl chloride (970 mg, 5.09 mmol, 1.20 equiv.), and triethylamine (860.0 mg, 8.50 mmol, 2.00 equiv.). The resulting solution was stirred at room temperature for 5 hours. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This gave 1.1 g (65%) of ethyl 2-[2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]ethoxy]acetate as a yellow oil.

[0776] Step 3

[0777] [ka]

[0778] A 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with a solution of ethyl 2-[2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]ethoxy]acetate (1.0 g, 2.56 mmol, 1.20 equiv.) in N,N-dimethylformamide (20 mL), 6-bromopyridin-2-ol (370 mg, 2.13 mmol, 1.00 equiv.), and CsCO (2.1 g, 6.45 mmol, 3.00 equiv.). The resulting solution was stirred at 80 °C for 12 h. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This gave 800 mg (96%) of ethyl 1-(6-bromopyridin-2-yl)-1,4,7,10-tetraoxadodecane-12-ate as a yellow solid.

[0779] According to the following scheme and using procedures similar to those described for other examples above, ethyl 1-(6-bromopyridin-2-yl)-1,4,7,10-tetraoxadodecane-12-oate was converted to the final compound (2S,4R)-1-[(2S)-2-(1-[6-[(1R,4R)-5-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-2,5-diazabicyclo[2.2.1heptan-2-yl]pyridin-2-yl]-1,4,7,10-tetraoxadodecane-12-amido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazolinone] This was converted to]pyrrolidine-2-carboxamide.

[0780] [ka]

[0781] Exemplary Synthesis of Exemplary Compound 33 Step 1

[0782] [ka]

[0783] A 250 mL round-bottom flask was charged with 1-bromo-4-ethylbenzene (5.5 g, 29.8 mmol, 1.0 equiv), CCl4 (100 mL), AIBN (490 mg, 3.0 mmol, 0.1 equiv), and N-bromosuccinimide (5.34 g, 30.0 mmol, 1.0 equiv). The resulting solution was stirred at 90 °C for 3 h. The resulting mixture was concentrated in vacuo to afford 5.4 g (68%) of 1-bromo-4-(1-bromoethyl)benzene as a yellow oil.

[0784] Step 2

[0785] [ka]

[0786] A 100 mL round-bottom flask was charged with 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (300 mg, 1.0 mmol, 1.0 equiv.), N,N-dimethylformamide (5.0 mL), 1-bromo-4-(1-bromoethyl)benzene (400.0 mg, 1.5 mmol, 1.5 equiv.), and potassium carbonate (414 mg, 3.0 mmol, 3.0 equiv.). The resulting solution was stirred at 60 °C for 3 hours. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with ethyl acetate (20.0 mL × 3), and the combined organic layers were concentrated under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (1:10). This gave 300 mg (62%) of 4-[1-[1-(4-bromophenyl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine as a brown solid.

[0787] Step 3

[0788] [ka]

[0789] A 250 mL round-bottom flask was charged with prop-2-yn-1-ol (10 g, 178.4 mmol, 1.0 equiv.), tetrahydrofuran (100.0 mL), sodium hydride (6.4 g, 266.7 mmol, 0.9 equiv.), and tert-butyl 2-bromoacetate (28 g, 143.6 mmol, 0.8 equiv.). The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 20 mL of aqueous ammonium chloride. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate (3 The organic layers were combined and concentrated in vacuo to give 24.0 g (90%) of tert-butyl 2-(prop-2-yn-1-yloxy)acetate as a yellow solid.

[0790] Step 4

[0791] [ka]

[0792] A 250 mL round-bottom flask was charged with tert-butyl 2-(prop-2-yn-1-yloxy)acetate (6.6 g, 38.8 mmol, 1.0 equiv.), triethylamine (400.0 mg, 3.9 mmol, 0.1 equiv.), pinacolborane (20.0 mL), and ZrCpHCl (1 g, 0.1 equiv.). The resulting solution was stirred at 60 °C for 12 minutes. The reaction was then quenched by adding 10 mL of ice / water. The resulting solution was extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:5). This gave 5.0 g (43%) of tert-butyl 2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]acetate as a yellow oil.

[0793] Step 5

[0794] [ka]

[0795] A 10 mL sealed tube was charged with 4-[1-[1-(4-bromophenyl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (300 mg, 0.6 mmol, 1.0 equiv.), tert-butyl 2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]acetate (279 mg, 0.9 mmol, 1.5 equiv.), Pd(PPh3)4 (72 mg, 0.06 mmol, 0.1 equiv.), potassium carbonate (259 mg, 1.9 mmol, 3.0 equiv.), dioxane (4.0 mL), and HO (1.0 mL). The resulting solution was stirred at 90 °C for 5 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1) to give 200 mg (56%) of tert-butyl 2-[[(2E)-3-[4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]prop-2-en-1-yl]oxy]acetate as a yellow solid.

[0796] Step 6

[0797] [ka]

[0798] A 100 mL round-bottom flask was charged with tert-butyl 2-[[(2E)-3-[4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]prop-2-en-1-yl]oxy]acetate (93 mg, 0.2 mmol, 1.0 equiv), methanol (5.0 mL), and palladium on carbon (100 mg). The resulting solution was stirred under a hydrogen atmosphere at room temperature for 1 hour. The solids were filtered off. The resulting mixture was concentrated in vacuo. This afforded 56 mg (60%) of tert-butyl 2-(3-[4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]propoxy)acetate as a yellow solid.

[0799] Step 7

[0800] [ka]

[0801] A 100 mL round-bottom flask was charged with tert-butyl 2-(3-[4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]propoxy)acetate (56 mg, 0.1 mmol, 1.0 equiv), dichloromethane (10.0 mg), and trifluoroacetic acid (5 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. This afforded 45 mg (90%) of 2-(3-[4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]propoxy)acetic acid as a brown solid.

[0802] Step 8

[0803] [ka]

[0804] A 25 mL round-bottom flask was charged with 2-[3-[4-(1-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethyl)phenyl]propoxy]acetic acid (26 mg, 0.06 mmol, 1.0 equiv.), N,N-dimethylformamide (5 mL), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylpyrrolidine-2-carboxamide (30 mg, 0.07 mmol, 1.2 equiv.), DIEA (21 mg, 0.2 mmol, 3.0 equiv.), and T3P (53 mg, 1.2 equiv.). The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by adding 0.5 mL of water. The solid was filtered. The crude product (5 mL) was purified by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD column, 150 mm 5 μm; Mobile phase: water (10 mmol / L amine bicarbonate) and ACN (45.0% ACN, maximum 52.0% in 7 min); Detector: UV 254 / 220 nm. This gave 6 mg (12%) of (2S,4R)-1-[(2S)-2-(2-[3-[4-(1-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethyl)phenyl]propoxy]acetamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a gray solid.

[0805] 1H NMR (300MHz, methanol-d4) δ8.79(s, 1H), 8.35~8.23(m, 1H), 8.09~7.97(m, 2H), 7.80(d, J=7.7Hz, 1H), 7.43~7.37(m, 2H), 7.31(d, J= 8.1Hz, 2H), 7.24(d, J=8.1Hz, 1H), 7.20(s, 4H), 6.89(t, J=7.6Hz, 2H), 5.64~5.52(m, 1H), 4.66(s, 1H), 4.60~4.44(m, 3H), 4.27(d , J=15.5Hz, 1H), 3.92(d, J=4.6Hz, 2H), 3.88~3.74(m, 2H), 3.52(d, J=6.2Hz, 2H), 2.71(t, J=7.6Hz, 2H), 2.37(s, 3H), 2.18(d, J=7 .7Hz, 1H), 2.07(dd, J=9.4, 4.2Hz, 1H), 1.89(dd, J=7.3, 1.2Hz, 6H), 1.26(s, 1H), 1.10~0.95(d, J=1.6Hz, 9H), 0.95~0.90(m, 1H).

[0806] Exemplary Synthesis of Exemplary Compound 34 Exemplary compound 34 was prepared according to the following scheme using procedures described for other examples above, as well as procedures known and appreciated by those skilled in the art.

[0807] [ka]

[0808] Exemplary Synthesis of Exemplary Compound 36 and Exemplary Compound 37 Exemplary compounds 36 and 37 were prepared according to the following scheme using procedures described for other examples above, as well as procedures known and appreciated by those skilled in the art.

[0809] [ka]

[0810] [ka]

[0811] Exemplary Synthesis of Exemplary Compound 38 and Exemplary Compound 39 Step 1

[0812] [ka]

[0813] A 500 mL round-bottom flask was charged with 2-(piperazin-1-yl)ethan-1-ol (26.0 g, 199.7 mmol, 1.0 equiv.), dichloromethane (200.0 mL), triethylamine (40.4 g, 399.3 mmol, 2.0 equiv.), and benzyl carbonochloridate (40.8 g, 239.2 mmol, 1.2 equiv.). The resulting solution was stirred at 0° C. for 2 hours. The reaction was then quenched b...

Claims

1. A bifunctional compound having the following chemical structure: PTM-L-ULM During the ceremony, ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to von Hippel-Lindau E3 ubiquitin ligase; L is a bond or chemical linking moiety connecting the ULM and PTM; the PTM is a small molecule comprising a SMARCA2 protein targeting moiety having a chemical structure represented by Formula I, II, III, IVa, IVb, or VI; 【Chemical 1】 During the ceremony, W ＰＴＭ１ is a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano, or combinations thereof; W ＰＴＭ２ is a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof; W ＰＴＭ３ is absent or a 5- to 6-membered aryl or heteroaryl ring optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or a combination thereof; a 4- to 9-membered cycloalkyl or heterocyclyl optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or a combination thereof; or a bridged bicycloalkyl or bridged biheterocyclyl optionally substituted with 0, 1, or 2 substituents selected from amino, cyano, or combinations thereof; W ＰＴＭ４ is a 5- to 7-membered cycloalkyl or heterocyclyl optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano, or combinations thereof; W ＰＴＭ５ is absent or a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof; W ＰＴＭ６ and W ＰＴＭ７ is a 4- to 7-membered cycloalkyl or heterocyclyl optionally substituted with 0, 1, or 2 substituents independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof; W ＰＴＭ６ and W ＰＴＭ７ are fused or joined via a spiro linkage; 【Chemistry 2】 is the point of attachment to said linker or ULM group, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

2. The PTM is represented by Formula I: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein: W ＰＴＭ１ is optionally substituted phenyl or pyridyl; W ＰＴＭ２ is an optionally substituted 6-membered heteroaryl ring; W ＰＴＭ３ is absent or is an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 4- to 9-membered cycloalkyl or heterocyclyl ring, or an optionally substituted bridged bicycloalkyl or bridged biheterocyclyl ring; W ＰＴＭ５ does not exist (so W ＰＴＭ３ is directly connected to L (linker) or ULM), or is an optionally substituted 5-6 membered aryl or heteroaryl ring.

3. The PTM is represented by the following formula: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein: W ＰＴＭ３ is absent or is an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 4- to 9-membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl or bridged biheterocyclyl ring; W ＰＴＭ５ The compound of claim 2, wherein is an optionally substituted 5-6 membered ring.

4. The PTM is represented by the formula: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof, wherein: W ＰＴＭ５ The compound of claim 3 , wherein is phenyl, pyridine, pyrimidine, or pyrazine.

5. The PTM is represented by the formula: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

6. the PTM is represented by Formula III: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, wherein: W ＰＴＭ１ is phenyl substituted with a hydroxy substituent and optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano, or combinations thereof; W ＰＴＭ２ is an amino-substituted pyridazine; W ＰＴＭ６ and W ＰＴＭ７ 10. The compound of claim 1, wherein is a spirocyclic ring system having a structure selected from: 【Chemistry 8】

7. the PTM is represented by formula IVa or IVb; 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, wherein: W ＰＴＭ１ is phenyl substituted with a hydroxy substituent and optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano, or combinations thereof; W ＰＴＭ２ is an amino-substituted pyridazine; W ＰＴＭ５ The compound of claim 1 , wherein is absent or is a pyrazole ring or a pyridine ring.

8. The compound of any one of claims 1 to 7, wherein the PTM is selected from the group consisting of: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】

9. ULM is a chemical structure represented by: 【Chemistry 11】 During the ceremony, W ３ is optionally substituted aryl, optionally substituted heteroaryl, or 【Chemistry 12】 is selected from the group R ９ and R １０ are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R ９ , R １０ and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R １１ optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, 【Chemistry 13】 is selected from the group R １２ is selected from the group of H or optionally substituted alkyl; R １３ is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R １４ａ , R １４ｂ are each independently H, amine, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR ２６ , C.O.R. ２７ａ R ２７ｂ , NHCOR ２６ , or NHCH ３ COR ２６ R １４ａ and R １４ｂ the other of R is H; or R １４ａ , R １４ｂ together with the carbon atoms to which they are attached form an optionally substituted 3 to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; W ５ is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 membered heteroaryl; R １５ H, halogens, CN, OH, NO ２ , N.R. ２７ａ R ２７ｂ , OR ２７ａ , C.O.R. ２７ａ R ２７ｂ , N.R. ２７ａ COR ２７ｂ , S.O. ２ NR ２７ａ R ２７ｂ , N.R. ２７ａ SO ２ R ２７ｂ , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; Each R １６ is independently selected from the group of halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; R １８ is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; Each R ２６ are independently H, optionally substituted alkyl, or NR ２７ａ R ２７ｂ is selected from Each R ２７ａ and R ２７ｂ are independently H, optionally substituted alkyl, or or R ２７ａ and R ２７ｂ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; 8. The compound of any of claims 1-7, wherein p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety connecting at least one PTM or ULM', or both, to a ULM.

10. the ULM has a chemical structure selected from the group consisting of: 【Chemistry 14-1】 【Chemistry 14-2】 During the ceremony, R １ is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R １４ａ is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R １５ H, halogens, CN, OH, NO ２ , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; X is C, CH ２ or C═O, R ３ is absent or is an optionally substituted 5- or 6-membered heteroaryl; 10. The compound of claim 9, wherein the dashed lines indicate the attachment site of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM', or both, to the ULM.

11. the ULM is of the formula: 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, wherein: R １ is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R ３ is an optionally substituted 5-6 membered heteroaryl; W ５ is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted pyridinyl; R １４ａ and R １４ｂ is H, optionally substituted alkyl, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR ２６ , C.O.R. ２７ａ R ２７ｂ , NHCOR ２６ , or NHCH ３ COR ２６ and R １４ａ and R １４ｂ the other of R is H; or R １４ａ , R １４ｂ together with the carbon atoms to which they are attached form an optionally substituted 3 to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; R １５ CN, fluoroalkyl, 【Chemistry 16】 or optionally substituted 【Chemistry 17】 (e.g., 【Chemistry 18】 wherein R ２８ａ is halo, optionally substituted alkyl, or fluoroalkyl; Each R １６ is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy; Each R ２６ are independently H, optionally substituted alkyl, or NR ２７ａ R ２７ｂ in can be, Each R ２７ａ and R ２７ｂ is independently H, optionally substituted alkyl, or R ２７ａ and R ２７ｂ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; R ２８ is H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted alkylamine, optionally substituted hydroxyalkyl, amine, optionally substituted alkynyl, or optionally substituted cycloalkyl; 11. The compound of claim 10, wherein o is 0, 1, or 2.

12. the ULM is of the formula: 【Chemistry 19】 During the ceremony, X ４ , X ５ , and X ６ are each selected from CH and N, and no more than two are N; R １ is C1-6 alkyl, R １４ａ and R １４ｂ is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR ２６ , C.O.R. ２７ａ R ２７ｂ , NHCOR ２６ , or NHCH ３ COR ２６ and R １４ａ and R １４ｂ the other of R is H; or R １４ａ and R １４ｂ together with the carbon atoms to which they are attached form an optionally substituted 3 to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; Each R ２７ａ and R ２７ｂ are independently H or C １－６ is alkyl, q is 1, 2, 3, or 4; R １５ but, 【Chemistry 20】 , or CN, R ２８ H, methyl, CH ２ N (Me) ２ , C.H. ２ OH, CH ２ O (C １－４ alkyl), CH ２ NHC(O)C １－４ Alkyl, NH ２ , 【Chemical formula 21】 and R ２８Ｃ is H, methyl, fluoro, or chloro; R １６ But H, C １－４ Alkyl, fluoro, chloro, CN, or C １－４ The compound of claim 11 which is alkoxy.

13. R １４ａ and R １４ｂ But H, C １－４ Alkyl, C １－４ Cycloalkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkyloxyalkyl, C １－４ Alkyl-NR ２７ａ R ２７ｂ , and CONR ２７ａ R ２７ｂ 13. The compound of claim 12, selected from:

14. R １４ａ and R １４ｂ together with the carbon atoms to which they are attached, 【Chemical 22】 wherein R ２３ But H, C １－４ Alkyl, —C(O)C １－４ 14. The compound of claim 12 or 13, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

15. the ULM is of the formula: 【Chemical 23】 or a pharmaceutically acceptable salt thereof, wherein X is CH or N.

16. R １ But C １－６ 16. The compound of claim 12 or 15, or a pharmaceutically acceptable salt thereof, wherein:

17. R １４ａ and R １４ｂ One of them is H, C １－６ Alkyl, C １－６ Haloalkyl, optionally substituted C １－４ Alkylamines, C １－６ Alkoxy, (CH ２ ) ｑ C １－６ Alkoxy, (CH ２ ) ｑ C １－６ Alkoxy-C ３ - ７ Heterocycloalkyl, (CH ２ ) ｑ OH, (CH ２ ) ｑ NR ２７ａ R ２７ｂ , (CH ２ ) ｑ NHCOC １－６ Alkyl, C ３－６ cycloalkyl, or NR ２７ａ R ２７ｂ and Each R ２６ However, independently, H, C １－６ alkyl, or NR ２７ａ R ２７ｂ and Each R ２７ａ and R ２７ｂ are independently H or C １－６ is alkyl, 17. Any one of claims 12, 15, or 16, wherein q is 1, 2, 3, or 4. or a pharmaceutically acceptable salt thereof.

18. R １４ａ and R １４ｂ One of them is H, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, optionally substituted C １－４ Alkylamines, (CH ２ ) ｑ C １－６ Alkoxy, (CH ２ ) ｑ C １－６ Alkoxy-C ３ - ７ Heterocycloalkyl, (CH ２ ) ｑ OH, (CH ２ ) ｑ NR ２７ａ R ２７ｂ , (CH ２ ) ｑ NHCOC １－６ Alkyl or C ３－６ cycloalkyl, or NR ２７ａ R ２７ｂ and Each R ２６ However, independently, H, C １－４ alkyl, or NR ２７ａ R ２７ｂ and Each R ２７ａ and R ２７ｂ are independently H or C １－４ is alkyl, 17. The compound of any one of claims 12, 15, or 16, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

19. R ２８ But C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, (CH ２ ) ｑ O.C. １－６ Alkyl, (CH ２ ) ｑ OH, (CH ２ ) ｑ NR ２７ａ R ２７ｂ , (CH ２ ) ｑ NHCOC １－６ alkyl, or 【Chemistry 24】 and R ２９ But H, C １－６ Alkyl, NR ２７ａ R ２７ｂ or ｑ NHCOC １－６ is alkyl, 17. The compound of any one of claims 12, 15, or 16, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

20. R ３ The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein is isoxazolyl, 4-chloroisoxazolyl, 4-fluoroisoxazolyl, or pyrazolyl.

21. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein X is CH.

22. The ULM has the formula: 【Chemistry 25】 or a pharmaceutically acceptable salt thereof; During the ceremony, X is CH or N; R ３０ is H, F, or Cl; R １６ But H, C １－４ Alkyl, fluoro, chloro, CN, or C １－４ is an alkoxy, R ２８ H, methyl, CH ２ N (Me) ２ , C.H. ２ OH, CH ２ O (C １－４ alkyl), CH ２ NHC(O)C １－４ Alkyl, NH ２ , 【Chemical 26】 22. The compound of claim 20, wherein

23. The ULM has the formula: 【Chemical 27】 or a pharmaceutically acceptable salt thereof, wherein R ３０ 23. The compound of claim 22, wherein is H, F, or Cl.

24. 24. The compound of any one of claims 1, 12, 15, or 23, wherein the ULM is a ULM as provided in Table 1A, Table 1B, and Table 1C.

25. The linker (L) comprises a chemical structural unit represented by the following formula: -(A Ｌ ) ｑ - During the ceremony, (A Ｌ ) ｑ is a group linked to at least one of the ULM, PTM, or both; q is an integer of 1 or more, Each A Ｌ However, independently, the bond, CR Ｌ１ R Ｌ２ ,O,S,SO,SO ２ , N.R. Ｌ３ , S.O. ２ NR Ｌ３ , SONR Ｌ３ , C.O.R. Ｌ３ , N.R. Ｌ３ CONR Ｌ４ , N.R. Ｌ３ SO ２ NR Ｌ４ , CO, CR Ｌ１ =CR Ｌ２ , C≡C, SiR Ｌ１ R Ｌ２ , P(O)R Ｌ１ , P(O)OR Ｌ１ , N.R. Ｌ３ C(=NCN)NR Ｌ４ , N.R. Ｌ３ C (=NCN), NR Ｌ３ C (= CNO ２ ) NR Ｌ４ , 0 to 6 R Ｌ１ and / or R Ｌ２ C optionally substituted with a group ３－１１ cycloalkyl, 0 to 6 R Ｌ１ and / or R Ｌ２ C optionally substituted with a group ３－１１ heterocyclyl, 0 to 6 R Ｌ１ and / or R Ｌ２ aryl optionally substituted with a group, 0 to 6 R Ｌ１ and / or R Ｌ２ heteroaryl optionally substituted with a group, wherein R Ｌ１ or R Ｌ２ are each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, and optionally 0 to 4 R Ｌ５ is substituted with a group, R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ and R Ｌ５ each independently represents H, halo, or C １－８ Alkyl, OC １－８ Alkyl, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, OC １－８ Cycloalkyl, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ cycloalkyl) ２ , N(C １－８ cycloalkyl)(C １－８ alkyl), OH, NH ２ , SH, SO ２ C １－８ Alkyl, P(O)(OC １－ ８ alkyl) (C １－８ alkyl), P(O)(OC １－８ alkyl) ２ , CC-C １－８ Alkyl, CCH, CH=CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ alkyl) ２ , Si(OH) ３ , Si(C １－８ alkyl) ３ , Si(OH)(C １－８ alkyl) ２ , COC １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , CHF ２ , C.H. ２ F. NO. ２ , SF ５ , S.O. ２ NHC １－８ Alkyl, SO ２ N (C １－８ alkyl) ２ ,SONHC １－８ Alkyl, SON(C １－８ alkyl) ２ , CONHC １－８ Alkyl, CON(C １－８ alkyl) ２ , N(C １－８ alkyl)CONH(C １－８ alkyl), N(C １－８ alkyl)CON(C １－８ alkyl) ２ , NHCONH(C １－８ alkyl), NHCON(C １－８ alkyl) ２ , NHCONH ２ , N(C １－８ alkyl)SO ２ NH (C １－８ alkyl), N(C １－８ alkyl)SO ２ N (C １－８ alkyl) ２ , NHSO ２ NH (C １－８ alkyl), NHSO ２ N (C １－８ alkyl) ２ , NHSO ２ NH ２ 24. The compound of claim 1, 12, 15, or 23, wherein:

26. 2. The compound of claim 1, wherein L is a means for covalently linking said PTM to said ULM.

27. The linker (L) comprises the following chemical structure: 【Chemical formula 28】 During the ceremony, W Ｌ１ and W Ｌ２ are each independently a 4-8 membered ring having 0-4 heteroatoms optionally substituted with RQ, and each RQ is independently H, halo, OH, CN, CF3, (straight chain, branched, optionally substituted) C1-C6 alkyl, (straight chain, branched, optionally substituted) C1-C6 alkoxy, or two RQ groups together with the atoms to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms; Y Ｌ１ are each independently a bond, a (linear, branched, optionally substituted) C1-C6 alkyl, optionally in which one or more C atoms are replaced by O, or a (linear, branched, optionally substituted) C1-C6 alkoxy; n is 0 to 10; 27. The compound of claim 1 or 26, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety.

28. The linker (L) comprises the following chemical structure: 【Chemical 29】 During the ceremony, W Ｌ１ and W Ｌ２ each independently represents aryl, heteroaryl, cyclic, heterocyclyl, C １－６ alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclyl, each of which is optionally R Ｑ and each R Ｑ are independently H, halo, OH, CN, CF ３ , hydroxyl, nitro, C≡CH, C ２－６ Alkenyl, C ２－６ Alkynyl, (straight chain, branched chain, optionally substituted) C １ -C ６ Alkyl, (straight chain, branched chain, optionally substituted) C １ -C ６ Alkoxy, OC (optionally substituted with one or more —F) １－３ Alkyl, OH, NH ２ , N.R. Ｙ１ R Ｙ２ , CN, or two R Ｑ groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y Ｌ１ each independently represents a bond, NR ＹＬ１ ,O,S,NR ＹＬ２ , C.R. ＹＬ１ R ＹＬ２ , C=O, C=S, SO, SO ２ , (linear, branched, optionally substituted) and optionally one or more C atoms replaced by O １ -C ６ Alkyl, or (linear, branched, optionally substituted) C １ -C ６ is an alkoxy, Q Ｌ is optionally bridged, and optionally has 0 to 6 R Ｑ and each R is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms substituted with Ｑ are independently selected from H, (linear, branched, optionally with one or more halo, C １－６ Alkoxy-substituted)C １－６ alkyl or two R Ｑ groups, together with the atoms to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R ＹＬ１ , R ＹＬ２ each independently represents H, OH, (linear, branched, optionally with one or more halo, C １－６ Alkoxy-substituted)C １－６ alkyl or R １ , R ２ together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms; n is 0 to 10; 27. The compound of claim 1 or 26, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety.

29. The linker (L) is -O-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O(CH ２ ) ｓ -O(CH ２ ) ｔ -、 -O-(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O(CH ２ ) ｓ -O-、 -(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O(CH ２ ) ｓ -O(CH ２ ) ｔ -、 -CH=CH(CH ２ ) ｍ -O(CH ２ ) ｎ -O(CH ２ ) ｏ -O(CH ２ ) ｐ -O(CH ２ ) ｑ -O(CH ２ ) ｒ -O(CH ２ ) ｓ -O(CH ２ ) ｔ -、 【Chemistry 30-1】 【Chemistry 30-2】 【Chemistry 30-3】 【Chemistry 30-4】 【Chemistry 30-5】 【Chemistry 30-6】 【Chemistry 30-7】 27. The compound of claim 1 or 26, comprising a group represented by a structure selected from the group consisting of:

30. L, 【Chemical 31】 27. The compound of any of claims 1 or 26, selected from the group consisting of:

36. i) W ＰＴＭ４ But, W ＰＴＭ２ or ii) is condensed with W ＰＴＭ３ But, W ＰＴＭ２ 2. The compound of claim 1 , wherein

37. W ＰＴＭ３ 3. The compound of claim 2, wherein is an optionally substituted pyrazole, pyrrole, imidazole, oxazole, oxadiazole, or triazole.

38. W ＰＴＭ５ The compound of claim 3 , wherein is an optionally substituted pyridine, pyrimidine, or pyrazine.

39. 27. The compound of any of claims 1 or 26, wherein the compound is a member selected from the compounds of Table 1A, Table 1B, and Table 1C.

40. The compound has a D content of 80% or more 最大 40. The compound of claim 39, having the formula:

41. 30. A composition comprising an effective amount of a bifunctional compound of either claim 1 or 26 and a pharmaceutically acceptable carrier.

42. 42. The composition of claim 41, wherein the composition further comprises at least one of an additional bioactive agent or another compound of claim 1.

43. 43. The composition of claim 42, wherein the additional bioactive agent is an anti-cancer agent.

44. 10. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of claim 1 for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective to treat or ameliorate at least one symptom of the disease or disorder.

45. 45. The composition of claim 44, wherein the disease or disorder is associated with accumulation and aggregation of SMARCA1, BRAHMA, or BRM.

46. 46. ​​The composition of claim 45, wherein the disease or disorder is cancer.

47. 47. The composition of claim 46, wherein the cancer is a SWI / SNF-associated cancer or a cancer with a SMARCA4 mutation (e.g., lung cancer or non-small cell lung cancer).

48. The composition of claim 46, wherein the cancer is a SMARCA4-deficient cancer or a cancer in which expression of SMARCA4 is reduced compared to normal SMARCA4 expression (e.g., compared to expression of non-mutated SMARCA4 or SMARCA4 in similarly located non-cancer cells with wild-type SMARCA4), e.g., lung cancer or non-small cell lung cancer.

Images