BRM targeting compounds and related methods of use

Abstract

The present disclosure relates to bifunctional compounds that are useful as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure relates to bifunctional compounds containing on one end a ligand that binds to the Hilpeer-Linde E3 ubiquitin ligase and on the other end a moiety that binds to a target protein such that the target protein is positioned in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the target protein. The present disclosure exhibits a wide range of pharmacological activities associated with degradation / inhibition of a target protein. The compounds and compositions of the present disclosure are used to treat or prevent diseases or conditions resulting from aggregation or accumulation of target proteins.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of April 1, 2019, application number 201980036295.9, and invention name “BRM targeting compounds and related use methods”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 651,186, filed April 1, 2018, entitled “BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE,” and U.S. Provisional Patent Application Serial No. 62 / 797,754, filed January 28, 2019, entitled “BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE,” both of which are incorporated herein by reference in their entirety. Technical Field

[0004] The present disclosure provides bifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds can be used as modulators of targeted ubiquitination, particularly with respect to yeast mating type switch / sucrose non-fermenting complex (SWI / SNF)-associated chromatin subfamily A member 2 matrix-associated actin-dependent regulator (SMARCA2) (i.e., BRAHMA or BRM), which are degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

[0005] Most small molecule drugs bind enzymes or receptors in a tight and well-defined pocket. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surface and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity for ubiquitination, and therefore, due to their specificity for certain protein substrates, are more attractive therapeutic targets than general proteasome inhibitors. The development of E3 ligase ligands has proven challenging, in part due to the fact that they must destroy protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutlin, other compounds targeting E3 ligases have been reported, but this field is still underdeveloped. For example, since the discovery of Nutlin, the first small molecule E3 ligase inhibitor of mouse double minute 2 homolog (MDM2), additional compounds targeting MDM2 (ie, human double minute 2 or HDM2) E3 ligase have been reported (J. Di et al., Current Cancer Drug Targets (2011), 11(8), 987-994).

[0006] One E3 ligase with exciting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, the substrate-recognition subunit of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2, and Rbx1. VHL's primary substrate is hypoxia-inducible factor 1 (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell-inducing cytokine erythropoietin in response to low oxygen levels. The first small-molecule ligand of VHL that targets the substrate-recognition subunit of the E3 ligase was generated, and a crystal structure was obtained, demonstrating that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0007] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), are used to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Specifically, this disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that are useful as targeted ubiquitination modulators of a variety of polypeptides and other proteins that, following targeted ubiquitination, are degraded and / or otherwise inhibited by the bifunctional compounds.

[0008] The yeast mating-type switch / sucrose non-fermenting complex (SWI / SNF) is a multi-subunit complex that regulates chromatin structure through the activities of two mutually exclusive helicase / ATPase catalytic subunits, SWI / SNF-associated matrix-associated actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2, BRAHMA, or BRM) and SWI / SNF-associated 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 access points for transcription factors and cognate DNA elements, which promote gene activation and repression.

[0009] Mutations in the genes encoding the twenty canonical SWI / SNF subunits are observed in nearly 20% of all cancers, with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer, and characteristic clear cell carcinomas. Although SMARCA2 and SMARCA4 have a high degree of homology and presumed overlapping functions, they are reported to have different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation rarely occurs in tumor development. In fact, many types of cancer have been shown to be SMARCA4-associated (e.g., cancers with SMARCA4 mutations or SMARCA4 defects (such as lack of expression)), including, for example, lung cancer (such as non-small cell carcinoma).

[0010] SMARCA2 has been shown to be one of the most important essential genes in SMARCA4-related or mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells are solely dependent on SMARCA2 activity, i.e., SMARCA2 is more incorporated into the complex to compensate for SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The co-occurrence of two (or more) gene expression defects leading to cell death is called synthetic lethality. Therefore, synthetic lethality can be exploited in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0011] There is a continuing need for effective treatments for diseases that can be treated by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecific effects and the inability to target and modulate SMARCA2 continue to hinder the development of effective therapeutics. Therefore, small molecule therapeutics that target SMARCA2 and utilize or enhance the substrate specificity of VHL would be very useful. Summary of the Invention

[0012] The present disclosure describes bifunctional compounds and methods of use thereof, which are used to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Specifically, the present disclosure provides bifunctional or protein degradation targeting chimeric (PROTAC) compounds that are suitable for use as targeted ubiquitination regulators of a variety of polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds as described herein after targeted ubiquitination. An advantage of the compounds provided herein is that there can be a broad spectrum of pharmacological activity consistent with the degradation / inhibition of targeted polypeptides from almost any protein class or family. In addition, the present specification provides methods of using an effective amount of the compounds as described herein to treat or ameliorate disease conditions, such as cancer, for example, SMARCA4-associated / deficient cancers, such as lung cancer or non-small cell lung cancer.

[0013] Thus, in one aspect, the present disclosure provides bifunctional or PROTAC compounds comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase or "ULM" group) and a target protein binding moiety (i.e., a protein / polypeptide targeting ligand or "PTM" group), such that the target protein / polypeptide is placed in proximity to the ubiquitin ligase to achieve degradation (and inhibition) of the protein. In a preferred embodiment, the ULM (ubiquitination ligase modulator) can be a VHL-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM). For example, the structure of the bifunctional compound can be depicted as:

[0014]

[0015] The corresponding positions and numbers of the PTM and ULM moieties as illustrated herein are provided for illustrative purposes only and are not intended to limit the compounds in any way. As will be appreciated by those skilled in the art, bifunctional compounds as described herein can be synthesized such that the number and positions of the various functional moieties can vary as desired.

[0016] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as:

[0017]

[0018] wherein PTM is a protein / peptide targeting moiety, L is a linker, such as a bond or chemical group that couples PTM and ULM, and ULM is a VHL-binding moiety (VLM).

[0019] For example, the structure of a bifunctional compound can be depicted as:

[0020]

[0021] wherein: PTM is a protein / peptide targeting moiety; "L" is a linker (e.g., a bond or a chemical linker group) coupling PTM and VLM, wherein VLM is a Hippel-Lindau E3 ubiquitin ligase binding moiety that binds VHL E3 ligase.

[0022] In certain embodiments, the compounds as described herein comprise a plurality of independently selected ULMs, a plurality of PTMs, a plurality of chemical linkers, or a combination thereof.

[0023] In further embodiments, the VLM may be hydroxyproline or a derivative thereof. Additionally, other contemplated VLMs are contained in U.S. Patent Application Publication No. 2014 / 03022523, which, as noted above, is incorporated herein in its entirety.

[0024] In certain embodiments, "L" is a bond. In other embodiments, the linker "L" is a linker having a linear number of non-hydrogen atoms in the range of 1 to 20. The linker "L" may include, but is not limited to, functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker may include aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. Halogen substitutions such as Cl, F, Br, and I may be included in the linker. In the case of fluorine substitution, single or multiple fluorines may be included.

[0025] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, wherein both the nitrogen and the carboxylic acid of trans-3-hydroxyproline are functionalized as amides.

[0026] On the other hand, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic composition regulates protein degradation and / or inhibition in a patient or subject (e.g., an animal, such as a human) and can be used to treat or improve a disease state or condition regulated by the protein degradation / inhibition. In certain embodiments, the therapeutic composition as described herein can be used to achieve degradation of a protein of interest to treat or improve a disease, such as cancer (including at least one of SWI / SNF-related cancers, cancers with SMARCA4 mutations, cancers with SMARCA4 defects, or a combination thereof), such as lung cancer (e.g., non-small cell lung cancer). In yet another aspect, the present disclosure provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein, the bifunctional compound comprising a VLM preferably connected by a linker moiety, as described elsewhere herein, wherein the VLM is coupled to a PTM via a linker to target the protein for degradation. When the target protein is placed near an E3 ubiquitin ligase, degradation of the target protein will occur, resulting in degradation / inhibition of the action of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides for the treatment of disease states or conditions that are modulated by the target protein by reducing the levels of that protein in the patient's cells.

[0027] In another aspect, the present disclosure provides a method for treating or improving 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 capable of effectively treating or improving the disease, disorder, or symptom thereof in the subject.

[0028] In another aspect, the present description provides methods of identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0029] The aforementioned general practical areas are given for illustrative purposes only and are not intended to limit the scope of the present disclosure and the appended claims. Based on the claims, description, and examples, one of ordinary skill in the art will understand the additional objects and advantages associated with the compositions, methods, and methods of the present disclosure. For example, various aspects and embodiments of the present disclosure may be utilized in numerous combinations, all of which are explicitly contemplated by this specification. These additional aspects and embodiments are explicitly included within the scope of the present disclosure. Publications and other materials herein that are used to illustrate the background of the present disclosure and to provide additional details about practice in certain circumstances are incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings, which are incorporated into and constitute 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 accompanying drawings are only for the purpose of illustrating the embodiments of the present disclosure and should not be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate exemplary embodiments of the present disclosure, wherein:

[0031] Figure 1A and Figure 1B . Illustration of the general principles of PROTAC function. (A) An exemplary PROTAC comprises a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and an optional linker moiety (L; black line) that couples or tethers the PTM to the ULM. (B) Functional uses of PROTACs as described herein are shown. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and, alone or through an E2 protein, catalyzes the attachment of ubiquitin (dark circles) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein is then targeted (far right) for degradation by the cell's proteasome machinery. DETAILED DESCRIPTION

[0032] The following is a detailed description provided to help those skilled in the art practice 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, drawings, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0033] The present invention describes compositions and methods that relate to the surprising and unexpected discovery that E3 ubiquitin ligase proteins (e.g., VHL) ubiquitinate target proteins upon proximity to them through bifunctional or chimeric constructs that bind the E3 ubiquitin ligase protein and the target protein. Accordingly, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase targeting moiety ("ULM") coupled to a protein target binding moiety ("PTM") that will cause ubiquitination of a selected target protein, thereby resulting in degradation of the target protein by the proteasome (see Figure 1). The present disclosure also provides libraries of compositions and uses thereof.

[0034] In certain aspects, the present disclosure provides compounds comprising a ligand such as a small molecule ligand (i.e., a molecular weight of less than 2,000, 1,000, 500 or 200 Daltons) that is capable of binding to a ubiquitin ligase such as VHL. The compound further comprises a portion capable of binding to a target protein in such a way that the target protein is placed near the ubiquitin ligase to achieve degradation (and / or inhibition) of the protein. In addition to the above, a small molecule can also mean that the molecule is non-peptidyl, i.e., it is not generally considered a peptide, for example, comprising less than 4, 3 or 2 amino acids. According to the present specification, a PTM, ULM or PROTAC molecule can be a small molecule.

[0035] Unless defined otherwise, 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 terms used in this specification are for describing particular embodiments only and are not intended to be limiting of the disclosure.

[0036] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (e.g., in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided), between the upper and lower limits of the range, and any other stated or intervening value within the stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges, which may independently be included in smaller ranges, are also encompassed within the disclosure, subject to any specifically excluded limitations in the stated range. Where the stated range includes one or both of the limits, ranges excluding either of these limits are also included in the disclosure.

[0037] The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the term is given the art-recognized meaning as applied by persons of ordinary skill in the art in the context of its use in describing the present disclosure.

[0038] As used herein and in 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. For example, "an element" means one element or more than one element.

[0039] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" elements so combined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may refer to only A (optionally including elements in addition to B) in one embodiment; to only B (optionally including elements in addition to A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; etc.

[0040] 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 the items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also including more than one of a number of elements or a list of elements, and optionally, additionally unlisted items. Only when the contrary term is clearly indicated, such as "only one" or "exactly one", or, when used in the claims, "consisting of..." refers to exactly one element of a number of elements or a list of elements. In general, when preceded by an exclusive term such as "either", "one of", "only one" or "exactly one", as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both").

[0041] In the claims and the foregoing description, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "having," "consisting of," and the like are to be construed as open-ended, i.e., meaning including, but not limited to, "consisting of." Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures.

[0042] As used herein in the specification and claims, referring to a list of one or more elements, the phrase "at least one" should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that in addition to the elements specifically identified within the list of elements to which the phrase "at least one" refers, elements, whether related or unrelated to those specifically identified, may optionally be present. 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") may, in one embodiment, refer to at least one, optionally including more than one A, without B (and optionally including elements in addition to B); in another embodiment, refer to at least one, optionally including more than one B, without A (and optionally including elements in addition to A); in yet another embodiment, refer to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); etc.

[0043] It should also be understood that in certain methods described herein that include more than one step or action, the order of the steps or actions of the method are not necessarily limited to the order in which the steps or actions of the method are recited unless the context dictates otherwise.

[0044] The term "co-administration" or "combination therapy" refers to concurrent administration (administration of two or more therapeutic agents at the same time) and timed administration (administration of one or more therapeutic agents at a different time than administration of other therapeutic agents or agents), as long as the therapeutic agents are present in the patient simultaneously, preferably in effective amounts, to some extent. In certain preferred aspects, one or more compounds of the invention described herein are co-administered in combination with at least one other biologically active agent (especially including anticancer agents). In particularly preferred aspects, co-administration of the compounds produces synergistic and / or therapeutic (including anticancer) activity.

[0045] Unless otherwise indicated, as used herein, the term "compound" refers to any specific compound disclosed herein and includes its tautomers, regioisomers, geometric isomers and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), and, where applicable, pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). Contemplated deuterated small molecules are those in which one or more hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0046] In its use in this 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. In this context, the term also refers to prodrug forms of the compounds that have been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the compounds herein, many substituents and variables associated therewith are described, among others. It will be understood by those of ordinary skill that the molecules described herein are stable compounds as generally described 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 for valence interaction.

[0047] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins to target them for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin conjugating enzymes, cause the attachment of ubiquitin to lysine on the target protein and subsequently target the specific protein substrate for degradation by the proteasome. Therefore, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin conjugating enzymes, are responsible for the transfer of ubiquitin to the target protein. In general, ubiquitin ligases involve polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines of ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome. As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched hydrocarbon group (i.e., C 1-8 means one to eight carbon atoms). In the absence of a specific number of carbon atoms, the alkyl groups provided herein are assumed to have one to twelve carbon atoms, one to eight carbon atoms, one to six carbon atoms, or one to four carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Alkyl groups can be optionally substituted as provided herein. In some embodiments, the alkyl group is C 1-6 Alkyl; in some embodiments, it is C 1-4 alkyl.

[0048] U.S. patent application serial number 15 / 230,354, filed on August 5, 2016; and U.S. patent application serial number 14 / 371,956, filed on July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322; and U.S. patent application serial number 15 / 074,820, filed on March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639; and International Patent Application No. PCT / US2016, filed on February 24, 2016 016 / 019328, published as International Patent Application Publication No. WO2016 / 138114; and International Patent Application No. PCT / US2016 / 023258, filed on March 18, 2016, published as International Patent Application Publication No. WO2016 / 149668; and U.S. Non-Provisional Patent Application No. 15 / 885,671, filed on January 31, 2018, published as U.S. Patent Application Publication No. 2018 / 0215731, all of which are incorporated herein by reference in their entirety. In addition, all references cited herein are incorporated herein by reference in their entirety.

[0049] As used in conjunction with a substituent as defined herein, the term "optionally substituted" means that the substituent may, but need not, be substituted with one or more suitable functional groups or other substituents provided herein. For example, a substituent may be optionally substituted with one or more of the following groups: halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo (C 1-6 ) alkyl, C 1-6 Alkoxy, halogenated (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)2C 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 1-6Alkyl, oxo, phenyl, benzyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl or other 5-6 membered heteroaryl groups. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0050] As used herein, the term "cycloalkyl" refers to a C 3-12 Cycloalkyl groups, and include bridged rings and spiro rings (e.g., adamantane). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [4.1.0] heptyl, spiro [3.3] heptyl, and spiro [3.4] octyl. In some embodiments, the cycloalkyl group is C 3-6 Cycloalkyl.

[0051] As used herein, the term "alkenyl" refers to a C 2-12 Alkyl, wherein at least two carbon atoms are sp2 hybridized and form a carbon-carbon double bond between them. The alkenyl groups provided herein may contain more than one carbon-carbon double bond, but preferably one. The alkyl portion of the alkenyl groups provided herein may be substituted as described above. In some embodiments, the alkenyl group is C 2-6 Alkenyl.

[0052] As used herein, the term "alkynyl" refers to a C 2-12 Alkyl groups wherein at least two carbon atoms are sp hybridized and form a carbon-carbon triple bond between them. The alkynyl groups provided herein may contain more than one carbon-carbon triple bond, but preferably one. The alkyl portion of the alkynyl groups provided herein may be substituted as described above. In some embodiments, the alkynyl group is C 2-6 Alkynyl.

[0053] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense and refer to those alkyl groups that are attached to the rest of the molecule via an oxygen atom ("oxo"), an amino group ("amino"), or a thio group. The term "alkylamino" includes monoalkylamino groups, dialkylamino groups, and the alkyl portions can be the same or different.

[0054] The term "halo," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, but preferably fluorine or chlorine.

[0055] The term "halogenated (C 1-xThe term "halo(C1-C6 alkyl)" refers to an alkyl group having 1 to x carbon atoms and substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogen groups. For example, the term includes alkyl groups having 1 to 6 carbon atoms substituted with one or more halogen groups. Non-limiting examples of the term halo(C1-C6 alkyl) include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0056] The term "halogenated (C 1-x "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 alkoxy groups 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.

[0057] The term "heteroalkyl" refers to a straight or branched chain alkyl group, for example, having 2 to 14 carbons (e.g., 2 to 10 carbons) in the chain, one or more of which has been substituted with a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkylamides, alkyl sulfides, and the like. The group can be a terminal group or a bridging group. As used herein, when used in the context of a bridging group, a reference to a normal chain refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

[0058] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems, wherein at least one ring is an aromatic ring. For example, in certain embodiments, the aryl group has 6 to 12 carbon atoms. Aryl includes phenyl. Aryl also includes a polycondensed ring system (for example, a ring system comprising 2, 3 or 4 rings) with about 9 to 12 carbon atoms, wherein at least one ring is an aromatic ring, and wherein other rings may be aromatic rings or not aromatic rings. Such polycondensed ring systems are optionally substituted by one or more (for example 1, 2 or 3) oxo groups on any carbocyclic ring portion of the polycondensed ring system. When valence requirements allow, the rings of the polycondensed ring system can be interconnected by fusion, spirocycles and bridge bonds. It should be understood that, as defined above, the attachment point of the polycondensed ring system can be at any position of the ring system, including the aromatic portion or carbocyclic portion of the ring. Non-limiting examples of aryl groups include but are not limited to phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, etc.

[0059] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. If the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized form. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings), wherein a heteroaryl as defined above is fused to one or more rings selected from heteroaryl (forming, for example, naphthyridinyl such as 1,8-naphthyridine), heterocycle (forming, for example, 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8-naphthyridine), carbocycle (forming, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (forming, for example, indazolyl) to form a multiple fused ring system. Thus, the heteroaryl (single aromatic ring or multiple fused ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. The heteroaryl (single aromatic ring or multiple fused ring system) may also have about 5 to 12 or about 5 to 10 members within the heteroaryl ring. The multiple fused ring system may 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. When valence requirements allow, the rings of the polycondensed ring system can be interconnected by fusion, spirocycle and bridge bond. It should be understood that the individual rings of the polycondensed ring system can be connected to each other in any order. It should also be understood that the attachment point of the polycondensed ring system (as defined above for heteroaryl) can be at any position of the polycondensed ring system, including heteroaryl, heterocycle, aryl or carbocyclic ring part of the polycondensed ring system. It should also be understood that the attachment point of heteroaryl or heteroaryl polycondensed ring system can be at any suitable atom of heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thiazolyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, the term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms.Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0060] As used herein, the term "heterocyclyl" or "heterocycle" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen and sulfur; the term also includes a polycondensed ring system having at least one such saturated or partially unsaturated ring, which is further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6 or 7-membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. The ring may be substituted by one or more (e.g., 1, 2 or 3) oxo groups, and the sulfur and nitrogen atoms may also exist in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl and piperidinyl. The term "heterocycle" also includes polycondensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a single heterocycle (as defined above) may be fused to one or more groups selected from heterocycles (forming, for example, 1,8-decahydronaphthyridine), carbocycles (forming, for example, decahydroquinolinyl), and aryl groups to form a polycondensed ring system. Thus, a heterocycle (a single saturated or single partially unsaturated ring or a polycondensed ring system) has approximately 2-20 carbon atoms and 1-6 heteroatoms within the heterocycle. Such a polycondensed ring system may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portions of the polycondensed ring. When valence requirements permit, the rings of the polycondensed ring system may be interconnected by fusions, spirocycles, and bridges. It should be understood that the rings of the polycondensed ring system may be connected to each other in any order. Thus, a heterocycle (a single saturated or single partially unsaturated ring or a polycondensed ring system) has approximately 3-20 atoms, including approximately 1-6 heteroatoms, within the heterocycle system. It is also understood that the point of attachment of a polycondensed ring system (as defined above for heterocycle) can be at any position of the polycondensed ring system, including the heterocycle, aryl, and carbocyclic portions of the ring. It is also understood that the point of attachment of a heterocycle or heterocyclic polycondensed ring system can be at any suitable atom of the heterocycle or heterocyclic polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). In one embodiment, the term heterocycle includes 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 2-4Heterocycle. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxazolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one 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 3-8 membered ring having at least one heteroatom. As used herein, the term "9-yuan or 10-yuan heterobicyclic ring" refers to a partially unsaturated or aromatic fused bicyclic ring system having at least one heteroatom. For example, the term includes monocyclic, saturated or partially unsaturated 4, 5, 6 or 7-membered rings having at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperidine, piperazine, oxirane, morpholine and thiomorpholine. As used herein, the term "9-yuan or 10-membered heterobicyclic ring" refers to a partially unsaturated or aromatic fused bicyclic ring system having at least one heteroatom. For example, the term 9-yuan or 10-membered heterobicyclic ring includes a bicyclic ring system having a benzo ring fused to a 5-yuan or 6-membered saturated, partially unsaturated or aromatic ring containing one or more heteroatoms.

[0061] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Where applicable, the nitrogen and sulfur may be in oxidized form.

[0062] As used herein, the term "chiral" refers to molecules that have the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0063] 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. represents a mixture of E and Z stereoisomers.

[0064] As used herein, a wavy line that intersects a bond in a chemical structure Or a dashed line "----" indicates the point in a chemical structure where a wavy bond intersects the rest of the molecule.

[0065] "Diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical methods (such as electrophoresis and chromatography).

[0066] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0067] The 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. It is intended that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, 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. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of the compound with respect to plane polarized light, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur where there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric substances that is devoid of optical activity.

[0068] When the bond in this paper's compound formula is drawn in a non-stereochemical manner (e.g., flat), the atom connected to the bond includes all stereochemical possibilities. When the bond in this paper's compound formula is drawn in a defined stereochemical manner (e.g., bold, bold-wedge, dotted line, or dotted-wedge), it should be understood that, unless otherwise stated, the atom connected by the stereochemical bond is rich in the absolute stereoisomers being depicted. In one embodiment, the compound can be at least 51% of the absolute stereoisomer being depicted. In another embodiment, the compound can be at least 80% of the absolute stereoisomer being depicted. In another embodiment, the compound can be at least 90% of the absolute stereoisomer being depicted. In another embodiment, the compound can be at least 95% of the absolute stereoisomer being depicted. In another embodiment, the compound can be at least 97% of the absolute stereoisomer being depicted. In another embodiment, the compound can be at least 98% of the absolute stereoisomer being depicted. In another embodiment, the compound can be at least 99% of the absolute stereoisomer being depicted.

[0069] 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 proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0070] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. 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 a complex in which the solvent molecule is water.

[0071] As used herein, the term "protecting group" refers to a substituent that is typically used to block or protect a specific 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, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of the hydroxyl group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a carboxyl group substituent that blocks or protects the carboxyl functionality. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, etc. For a general description of protecting groups and their use, see PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis 4th ed., Wiley-Interscience, New York, 2006.

[0072] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrazine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids (such as arginine salts) and organic acids (such as glucuronic acid or galacturonic acid, etc.) (see, for example, Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain basic and acidic functional groups that allow the compounds to be converted into base or acid addition salts.

[0073] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but for the purposes of the present invention, these salts are equivalent to the parent form of the compound.

[0074] In addition to salt forms, the present invention also provides compounds in prodrug form. As used herein, the term "prodrug" refers to compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, the prodrug can be slowly converted into the compound of the present invention.

[0075] 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 attached to a free amino group, a hydroxyl group, or a carboxylic acid group of the compounds 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 typically represented by three-letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, γ-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0076] Other types of prodrugs are also included. For example, the free carboxyl groups of the compounds of the present invention can be derived into amides or alkyl esters. As another example, the compounds of the present invention comprising free hydroxyl groups can be derived into prodrugs by converting the hydroxyl groups into groups such as, but not limited to, phosphates, hemisuccinates, dimethylaminoacetates or phosphoryloxymethyloxycarbonyl groups, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19: 115. Also included are carbamate prodrugs of hydroxyl and amino groups, and carbonate prodrugs, sulfonates and sulfates of hydroxyl groups. The hydroxyl groups are derived into (acyloxy) methyl and (acyloxy) ethyl ethers, wherein the acyl groups can be alkyl esters optionally substituted by groups including, but not limited to, ethers, amines and carboxylic acid functional groups, or wherein the acyl groups are amino acid esters as also described above. This type of prodrug is described in J. Med. Chem., (1996), 39: 10. More specific examples include replacing the hydrogen atom of the alcohol group with a group such as (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, succinyl, (C 1-6 ) alkanoyl, α-amino (C 1-4 )alkanoyl, aryl acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C 1-6 )alkyl)2 or glycosyl (a group produced by removing a hydroxyl group in the hemiacetal form of a carbohydrate).

[0077] For other examples of prodrug derivatives, see, e.g., 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", written 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., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0078] In addition, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced by the metabolism of a particular compound or its salt in vivo. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

[0079] Metabolites are usually prepared by radiolabeling (e.g. 14 C or 3H) isotopes of the compounds of the present invention are identified and administered parenterally to animals such as rats, mice, guinea pigs, monkeys or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), giving sufficient time for metabolism to occur (usually about 30 seconds to 30 hours), and isolating the conversion products from urine, blood or other biological samples. These products are easy to separate because they have been labeled (other antibodies are separated by using antibodies that can bind to epitopes that survive in metabolites). The structure of the metabolites is determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. Typically, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. As long as no metabolites are found in the body, they can be used for diagnostic determination of therapeutic doses of the compounds of the present invention.

[0080] The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or domesticated animal, to whom treatment, including prophylactic treatment, is provided with a composition according to the present disclosure. For treatment of those infections, conditions, or disease states that are specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domesticated animals such as dogs or cats or farm animals such as horses, cattle, sheep, etc. In general, in this disclosure, unless otherwise specified or implied by the context in which the term is used, the term patient refers to a human patient.

[0081] The term "effective" is used to describe an amount of a compound, composition, or component that, when used in the context of its intended use, achieves the intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0082] Compounds and compositions

[0083] In one aspect, the present disclosure provides a compound comprising an E3 ubiquitin ligase binding moiety ("ULM") that is a VHL binding moiety (VLM). In an exemplary embodiment, the ULM is coupled to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure:

[0084] (A)PTM-L-ULM

[0085] 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 shown herein are provided for example only. As will be appreciated by those skilled in the art, the compounds described herein can be synthesized with any desired number and / or relative positions of the various functional moieties.

[0086] On the other hand, the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) that can be used to modulate protein activity by inducing degradation of a target protein. In certain embodiments, the compound comprises a VLM coupled (e.g., covalently, directly or indirectly connected) to a portion that binds to a target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, VLM and PTM are joined or coupled via a chemical linker (L). VLM binds to VHL, and PTM recognizes the target protein, and the interaction of each portion with its target is beneficial for degrading the target protein by placing the target protein near a ubiquitin ligase protein. Exemplary bifunctional compounds can be described as: PTM-VLM.

[0087] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be depicted as: PTM-L-VLM,

[0088] where PTM is the protein / peptide targeting moiety, L is a chemical linker, and VLM is the VHL binding moiety.

[0089] In certain embodiments, a ULM (eg, VLM) exhibits activity or an IC of less than about 200 μM. 50 Binds to E3 ubiquitin ligases (e.g., VHL). 50 It can be determined according to any method known in the art, such as fluorescence polarization analysis.

[0090] In certain additional embodiments, the bifunctional compounds described herein exhibit IC 50 An activity of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0091] In certain embodiments where the compound comprises multiple ULMs, the ULMs are identical. In other embodiments where the compound comprises multiple ULMs (e.g., ULMs, ULM's, etc.), at least one PTM is coupled to the ULM directly, via a chemical linker (L), or both. In certain other embodiments, the compound comprising multiple ULMs also comprises multiple PTMs. In other embodiments, the PTMs are identical or, optionally, different. In other embodiments where the PTMs are different, each PTM may bind to the same protein target or specifically bind to different protein targets.

[0092] In certain embodiments, a compound may comprise multiple ULMs and / or multiple ULMs'. In further embodiments where the compound comprises at least two different ULMs, the multiple ULMs and / or multiple ULMs' further comprise at least one PTM coupled to the ULMs or ULMs' directly, via a chemical linker, or both. In any of the embodiments described herein, a compound comprising at least two different ULMs may further comprise multiple PTMs. In further embodiments, the PTMs are the same or, optionally, different. In further embodiments where the PTMs are different, each PTM may bind to the same protein target or specifically bind to different protein targets.

[0093] In further embodiments, the present description provides compounds as described herein, including enantiomers, diastereomers, solvates, and polymorphs thereof, including pharmaceutically acceptable salt forms, such as acid and base salt forms.

[0094] Exemplary VLM

[0095] In certain embodiments, the compounds as described herein include a moiety for binding to an E3 ubiquitin ligase (e.g., Hippel-Lindau E3 ubiquitin ligase). In certain embodiments, the ULM is a VLM and comprises a chemical structure selected from group ULM-a:

[0096]

[0097] in:

[0098] Dashed lines indicate at least one PTM, another ULM or VLM (i.e., VLM'), or a chemical linker moiety coupling at least one PTM, ULM', or VLM' to the other end of the linker;

[0099] Formula ULM-a X 1 、X 2 Each independently selected from a bond, O, NR Y3 , CR Y3 R Y4 , C=O, C=S, SO and SO2;

[0100] R of formula ULM-a Y3 、R Y4 Each independently selected from H, a linear or branched C optionally substituted by one or more halogens 1-6 Alkyl, optionally substituted C 1-6 Alkoxy (eg, optionally with 0-3 R P group substitution);

[0101] R of formula ULM-aP is 0, 1, 2 or 3 groups, each independently selected from H, halogen, -OH, C 1-3 alkyl, C=O, alkyl, alkoxy, or a combination thereof;

[0102] W of ULM-a 3 Selected from 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-diheteroaryl, optionally substituted -T-heterocyclyl, optionally substituted -T-diheterocyclyl, optionally substituted -NR 1 -T-aryl, optionally substituted-NR 1 -T-heteroaryl or optionally substituted-NR 1 -T-heterocyclyl;

[0103] Formula ULM-a X 3 C=O、R 1 、R 1a 、R 1b ;

[0104] R 1 、R 1a 、R 1b are each independently selected from H, a linear or branched C1-C6 alkyl group optionally substituted with one or more halogen or -OH groups, R Y3 C=O、R Y3 C=S、R Y3 SO, R Y3 SO2、N(R Y3 R Y4 )C=O、N(R Y3 R Y4 )C=S、N(R Y3 R Y4 )SO and N(R Y3 R Y4 )SO2;

[0105] T of formula ULM-a is selected from optionally substituted alkyl, -(CH2) n -group, optionally substituted straight chain, branched chain –(CH2) n -O-C1-C6 alkyl or optionally substituted –(CH2) n-O-heterocyclyl, wherein each of the methylene groups is optionally substituted by one or two substituents selected from halogen, methyl, linear or branched C1-C6 alkyl optionally substituted by one or more halogen or -OH groups, an optionally substituted amino acid side chain, or an optionally substituted heterocyclyl;

[0106] W of ULM-a 4 is optionally substituted -NR1-T-aryl, wherein aryl may be optionally substituted with optionally substituted 5-6 membered heteroaryl or optionally substituted aryl, optionally substituted -NR1-T-heteroaryl, wherein heteroaryl is optionally substituted with optionally substituted aryl or optionally substituted heteroaryl or optionally substituted -NR1-T-heterocyclyl, wherein -NR1 is covalently bonded to X 2 , and R 1 It is H or CH3, preferably H.

[0107] In certain embodiments, R P modified to form prodrugs, including through ester or ether linkages.

[0108] In any of the embodiments described herein, T is selected from optionally substituted alkyl, -(CH2) n - group, wherein each of the methylene groups is optionally substituted by one or two groups selected from halogen, methyl, optionally substituted alkoxy, linear or branched C1-C6 alkyl optionally substituted by one or more halogens, C(O)NR 1 R 1a or NR 1 R 1a Substituents, or R 1 and R 1a is connected to form an optionally substituted heterocyclic group or an -OH group or an optionally substituted amino acid side chain; and n is 0 to 6, typically 0, 1, 2 or 3, preferably 0 or 1.

[0109] In certain embodiments, W of Formula ULM-a 4 yes where R 14a 、 R 14b are each independently selected from H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 R14b The other one is H; or R 14a 、R 14b Together with the carbon atom to which they are attached, they form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine.

[0110] In any embodiment, W of Formula ULM-a 5 is selected from optionally substituted phenyl, optionally substituted naphthyl or optionally substituted 5-10 membered heteroaryl,

[0111] R of formula ULM-a 15 Selected from H, halogen, CN, OH, NO2, NR 14a R 14b , OR 14a 、CONR 14a R 14b NR 14a COR 14b 、SO2NR 14a R 14b NR 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;

[0112] In another embodiment, W used in the present disclosure 4 Substituents also specifically include (and are not limited to the specific compounds disclosed) W 4 Substituents, which are found in the identified compounds disclosed herein. These W 4 Each of the substituents may be combined with any number of W also disclosed herein. 3 Substituents are used in combination.

[0113] In certain additional embodiments, ULM-a is optionally replaced by 0-3 R P Each R P are independently H, halogen, -OH, C1-3 alkyl, or C=O.

[0114] In any of the embodiments described herein, W 3 、W 4 Can be independently covalently coupled to a linker to which one or more PTM groups are attached.

[0115] and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

[0116] In certain embodiments, the ULM is VHL and is represented by the following structure:

[0117]

[0118] in:

[0119] W of ULM-b 3 is selected from optionally substituted aryl, optionally substituted heteroaryl or

[0120] 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 R9, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group;

[0121] R of formula ULM-b 11 is selected from optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

[0122] R of formula ULM-b 12 is selected from H or optionally substituted alkyl;

[0123] R of formula ULM-b 13 is selected from 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;

[0124] R of formula ULM-b 14a 、R 14b are each independently selected from H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxyalkyl, 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 ; and R 14a and R 14b The other one is H; or R 14a 、R 14btogether 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;

[0125] W of ULM-b 5 is selected from phenyl, naphthyl or 5-10 membered heteroaryl,

[0126] R of formula ULM-b 15 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 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;

[0127] Each R of the formula ULM-b 16 independently selected from halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;

[0128] o of formula ULM-b is 0, 1, 2, 3 or 4;

[0129] R of formula ULM-b 18 is independently selected from H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;

[0130] Each R 26 are independently selected from H, optionally substituted alkyl or NR 27a R 27b ;

[0131] 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, they form a 4-6 membered heterocyclic group;

[0132] and

[0133] p of formula ULM-b 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 coupling at least one PTM or ULM', or both, to the ULM.

[0134] In certain embodiments, R of Formula ULM-b 15 yes where R 17 is H, halogen, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl and C 1-6 haloalkyl; and Xa is S or O.

[0135] In certain embodiments, R of Formula ULM-b 17 Selected from methyl, ethyl, isopropyl and cyclopropyl.

[0136] In certain additional embodiments, R of Formula ULM-b 15 Selected from:

[0137]

[0138] In certain embodiments, R of Formula ULM-b 11 Selected from:

[0139]

[0140]

[0141] In certain embodiments, R of Formula ULM-b 14a 、R 14b are each independently selected from H, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, CH2OR 30 、CH2NHR 30 、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 or CH2NCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14bTogether with the carbon atoms to which they are attached, they 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 optionally substituted with an alkyl, haloalkyl or -COR 33 Substituted, where R 33 is an alkyl group or a haloalkyl group, wherein R 30 R is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl or heteroarylalkyl, which is further optionally substituted; 26 and R 27 As mentioned above.

[0142] In certain embodiments, R of Formula ULM-b 15 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 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 aryl, heteroaryl, cycloalkyl, and heterocycloalkyl include CH2OR 30 、CH2NHR 30 、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 、CH2NCH3COR 26 or where R 26 、R 27 、R 30 and R 14 aAs described above.

[0143] In certain embodiments, R of Formula ULM-b 14a 、R 14b are each independently selected from H, optionally substituted haloalkyl, optionally substituted alkyl, CH2OR 30 、CH2NHR 30 、CH2NCH3R30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 or CH2NCH3COR 26 ; and R 14a and R 14b The other one is H; or R 14a 、R 14b Together with the carbon atoms to which they are attached, they 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 spiroheterocycloalkyl itself is optionally substituted with an alkyl, haloalkyl or -COR 33 Substituted, where R 33 is an alkyl group or a haloalkyl group, wherein R 30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl or heteroarylalkyl, which is further optionally substituted;

[0144] R of formula ULM-b 15 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 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 substitution of aryl, heteroaryl, cycloalkyl and heterocycloalkyl includes CH2OR 30 、CH2NHR 30 、CH2NCH3R 30 、CONR 27a R 27b 、CH2CONR 27a R 27b 、CH2NHCOR 26 、CH2NCH3COR 26 or where R 26 、R 27 、R 30 and R 14 aAs described above.

[0145] In certain embodiments, the ULM has a chemical structure selected from the group consisting of:

[0146]

[0147] in:

[0148] R1 of formula 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;

[0149] R of formula ULM-c, ULM-d and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[0150] R of formula ULM-c, ULM-d and ULM-e 15 is selected from H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl or optionally substituted heterocyclyl;

[0151] X of formula ULM-c, ULM-d and ULM-e is C, CH2 or C=O;

[0152] R3 of formula ULM-c, ULM-d and ULM-e is absent or is an optionally substituted 5- or 6-membered heteroaryl; and

[0153] The dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

[0154] In certain embodiments, a ULM comprises a group according to the following chemical structure:

[0155]

[0156] in:

[0157] R of ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl;

[0158] R9 of formula ULM-f is H;

[0159] R of ULM-f 10is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0160] R of ULM-f 11 yes

[0161]

[0162] or optionally substituted heteroaryl;

[0163] p of the formula ULM-f is 0, 1, 2, 3 or 4;

[0164] Each R of the formula ULM-f 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;

[0165] R of ULM-f 12 It is H, C=O;

[0166] R of 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,

[0167] R of ULM-f 15 is selected from H, halogen, Cl, CN, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl,

[0168] and

[0169] 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 couples at least one PTM or ULM', or both, to the ULM.

[0170] In certain embodiments, the ULM is selected from the following structures:

[0171]

[0172]

[0173] where n is 0 or 1.

[0174] In certain embodiments, the ULM is selected from the following structures:

[0175]

[0176]

[0177]

[0178] wherein the phenyl rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 are optionally substituted with fluorine, lower alkyl, and alkoxy groups, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to ULM-a.

[0179] In one embodiment, the phenyl rings in ULM-a1 to ULM-a15, ULM-b1 to ULM-b12, ULM-c1 to ULM-c15, and ULM-d1 to ULM-d9 can be functionalized as esters so that they become part of a prodrug.

[0180] 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, respectively, comprises an ester-linked prodrug moiety.

[0181] In any aspect or embodiment described herein, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0182]

[0183] or a pharmaceutically acceptable salt thereof, wherein:

[0184] ULM-g R 1’ is an optionally substituted C1-C6 alkyl, an optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n -O-(C1-C6)alkyl, optionally substituted (CH2) n -WCOCW-(C0-C6)alkyl containing an epoxide moiety WCOCW, wherein each W is independently H or C1-C3 alkyl, optionally substituted -(CH2) n COOH, optionally substituted -(CH2) n C(O)-(C1-C6 alkyl), optionally substituted-(CH2) n NHC(O)-R″, optionally substituted-(CH2) nC(O)-N(R″)2, optionally substituted-(CH2) n OC(O)-N(R″)2, -(CH2O) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl), optionally substituted-(CH2) n C(O)-O-(C1-C6 alkyl), optionally substituted-(CH2O) n COOH, optionally substituted -(OCH2) n O-(C1-C6 alkyl), optionally substituted-(CH2O) n C(O)-(C1-C6 alkyl), optionally substituted-(OCH2) n NHC(O)-R″, optionally substituted-(CH2O) 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);

[0185] Each R″ of ULM-g is independently H or C1-C6 alkyl which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

[0186] ULM-g R S is C1-C6 alkyl, optionally substituted aryl, heteroaryl or heterocyclic group or -(CH2) m N(R″)2 group;

[0187] X and X' of ULM-g are each independently C=O, C=S, -S(O), S(O)2, (preferably X and X' are both C=O);

[0188] ULM-g R 2’ is optionally substituted –(CH2) n -(C=O) u (NR″)v (SO2) w Alkyl, 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"-(CH2) 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; optionally substituted -X R2’ -aryl; optionally substituted -XR2’ -heteroaryl; optionally substituted -X R2’ -heterocyclic group;

[0189] ULM-g R 3’ is 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"-(CH2) 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, 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 -heterocyclic group, –(CH2) n -(V) n’ -(CH2) n -(V) n’ -alkyl, optionally substituted –(CH2) n -(V) n’ -(CH2) n -(V) n’-aryl, optionally substituted –(CH2) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl, optionally substituted –(CH2) n -(V) n’ -(CH2) n -(V) n’ -Heterocyclic group ’ , optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -alkyl, optionally substituted-(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -aryl, optionally substituted-(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl, optionally substituted-(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclyl, optionally substituted -X R3’ -alkyl; optionally substituted -X R3’ -aryl; optionally substituted -X R3’ -heteroaryl; optionally substituted -X R3’ -heterocyclic group;

[0190] 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 -heterocyclic group;

[0191] V of ULM-g is O, S or NR1;

[0192] Each R of ULM-g 1’ are independently H or C1-C3 alkyl;

[0193] ULM-gX R2’ and X R3’ each independently optionally substituted -CH2) n -, –CH2)n -CH(X v )=CH(X v )-(cis or trans), –CH2) n -CH≡CH-, -(CH2CH2O) n - or C3-C6 cycloalkyl, wherein X v is H, halogen or optionally substituted C1-C3 alkyl;

[0194] Each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[0195] Each m' of ULM-g is independently 0 or 1;

[0196] Each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;

[0197] Each n' of ULM-g is independently 0 or 1;

[0198] Each u of ULM-g is independently 0 or 1;

[0199] Each v of ULM-g is independently 0 or 1;

[0200] Each w of ULM-g is independently 0 or 1; and

[0201] When the PTM is not ULM', R of ULM-g 1’ 、R 2’ 、R 3’ Any one or more of X, X and X' is optionally modified to be covalently bound to the PTM group through a linker group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ 、R 3’ Any one or more of X, X and X' are optionally modified to be covalently bound to each other directly or through a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0202] In any aspect or embodiment described herein, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0203]

[0204] in:

[0205] ULM-h R 1’ ,R 2’ and R 3Each of ' is the same as above, and X is a C=O, C=S, -S(O) ... group or a S(O) 2 group, more preferably a C=O group, and

[0206] When the PTM is not ULM', the R of ULM-h 1’ 、R 2’ and R 3’ Any one or more of is optionally modified to incorporate a linker group that further covalently binds to the PTM group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ 、R 3’ Any one or more of are optionally modified to be covalently bound to each other directly or through a linker group, or

[0207] or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0208] In any aspect or embodiment described herein, the ULM and any ULM' present are each independently according to the chemical structure:

[0209]

[0210] in:

[0211] When the PTM is not ULM', R of ULM-I 1’ 、R 2’ and R 3’ Any one or more of is optionally modified to incorporate a linker group that further covalently binds to the PTM group, or when the PTM is ULM', R of each of ULM and ULM' 1’ 、R 2’ 、R 3’ Any one or more of are optionally modified to be covalently bound to each other directly or through a linker group, or

[0212] or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0213] In a further preferred aspect of the present disclosure, R of ULM-g to ULM-i 1’ Preferably, it is hydroxy or a group that can be metabolized to a hydroxy or carboxyl group, so that the compound represents a prodrug form of the active compound. 1’ Groups include, for example, -(CH2) n OH, (CH2) n -O-(C1-C6)alkyl, -(CH2) n COOH, -(CH2O) n H, optionally substituted -(CH2)n OC(O)-(C1-C6 alkyl) or optionally substituted-(CH2) n C(O)-O-(C1-C6 alkyl), wherein n is 0 or 1. 1’ When it is or contains a carboxylic acid group, the hydroxyl or amine group, hydroxyl group, carboxylic acid group or amine group (each of which may be optionally substituted) may be further chemically modified to provide a covalent linker group to which the PTM group (including the ULM) is bonded;

[0214] When present, X and X' of ULM-g and ULM-h are preferably C=O, C=S, -S(O) groups or S(O)2 groups, more preferably C=O groups;

[0215] R from ULM-g to ULM-i 2’ It is preferably an optionally substituted -NH-T-aryl, an optionally substituted -N(CH3)-T-aryl, an optionally substituted -NH-T-heteroaryl, 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 are optionally substituted -(CH2) n - group, wherein each of the methylene groups may be optionally substituted by 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, typically 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be -(CH2O) n - group, –(OCH2) n - group, –(CH2CH2O) n - group, –(OCH2CH2) n - groups, all of which are optionally substituted.

[0216] R from ULM-g to ULM-i 2’Preferred aryl groups include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl is linked to the PTM (including the ULM' group) via a linker group and / or is optionally substituted by halogen (preferably F or Cl), amine, mono- or dialkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2 or CN groups (each of which may be substituted in the ortho, meta and / or para positions of the phenyl ring). , preferably para), optionally substituted phenyl (phenyl itself optionally linked to the PTM group, including ULM', via a linker group), and / or optionally substituted with at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN groups (in the ortho, meta and / or para position of the phenyl ring, preferably para), optionally substituted naphthyl, optionally substituted heteroaryl, preferably optionally substituted isoxazole (including isoxazole substituted with methyl), optionally substituted optionally substituted oxazole (including oxazole substituted with methyl), optionally substituted thiazole (including thiazole substituted with methyl), optionally substituted isothiazole (including isothiazole substituted with methyl), optionally substituted pyrrole (including pyrrole substituted with methyl), optionally substituted imidazole (including methylimidazole), optionally substituted benzimidazole or methoxybenzimidazole, optionally substituted oxaimidazole or methyloxaimidazole, optionally substituted diazole group (including methyldiazole group), optionally substituted triazole group (including substituted with methyl), an optionally substituted pyridine group (including a pyridine group or an oxapyridine group substituted with a halo (preferably F) or methyl group, wherein the pyridine group is attached to the phenyl group through an oxygen), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indolizine or azaindolizine (2-azaindolizine, 3-azaindolizine or 4-azaindolizine), an optionally substituted quinoline, an optionally substituted group according to the following chemical structure:

[0217]

[0218] in:

[0219] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0220] R from ULM-g to ULM-i HETis H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0221] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0222] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, preferably for example piperidine, morpholine, pyrrolidine, tetrahydrofuran);

[0223] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0224] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl, or together form a keto group; and

[0225] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), or an optionally substituted heterocyclic group, preferably tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine or morpholine (when substituted, each of said groups is preferably substituted with methyl or halogen (F, Br, Cl), each of which may be optionally linked to a PTM group (including a ULM' group) via a linker group).

[0226] In certain preferred aspects, ULM-g to ULM-i yes

[0227] Group,

[0228] Among them, R PRO and n are the same as above.

[0229] About R of ULM-g to ULM-i 2’ Preferred heteroaryl groups 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 oxamidazole, or a group according to the following chemical structure:

[0230]

[0231] in:

[0232] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0233] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R of ULM-g to ULM-i a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0234] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0235] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocyclic group, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0236] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl), each of which may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0237] For ULM-g to ULM-i R 2’ , preferred heterocyclic groups include tetrahydrofuran, tetrahydrothiophene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane or thiazane, each of which may be optionally substituted, or a group according to the following chemical structure:

[0238]

[0239] Preferably, Group, in which:

[0240] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl or heterocyclyl;

[0241] R from ULM-g to ULM-i PRO1 and RPRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group, and

[0242] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (typically 0 or 1), each of which may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0243] Preferred R for ULM-g to ULM-i 2’ Substituents also specifically include (and are not limited to the specific compounds disclosed) R 2’ Substituents found in the identified compounds disclosed herein (including specific compounds disclosed in this specification and the accompanying drawings). These R 2’ Each of the substituents may be combined with any number of R 3’ Substituents are used in combination.

[0244] ULM-g to ULM-i ULM-g R 3’ Preferably, it is optionally substituted -NH-T-aryl, optionally substituted -N(C1-C3 alkyl)-T-aryl, optionally substituted -NH-T-heteroaryl, optionally substituted -N(C1-C3 alkyl)-T-heteroaryl, optionally substituted -NH-T-heterocyclyl or optionally substituted -N(C1-C3 alkyl)-T-heterocyclyl, wherein T is optionally substituted -(CH2) n - group, wherein each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, C1-C3 alkyl or an amino acid side chain as described elsewhere herein, preferably methyl, which may be optionally substituted; and n is 0 to 6, typically 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T may also be -(CH2O) n - group, –(OCH2) n - group, –(CH2CH2O) n - group, –(OCH2CH2) n - groups, each of which is optionally substituted.

[0245] R from ULM-g to ULM-i 3’ Preferred aryl groups include optionally substituted phenyl or naphthyl, preferably phenyl, wherein the phenyl or naphthyl is optionally linked to the PTM group (including the ULM' group) via a linker group and / or is optionally substituted by halogen (preferably F or Cl), amine, monoalkylamine or dialkylamine (preferably dimethylamine), amide (preferably -(CH2) m-NR1C(O)R2 group, wherein m, R1 and R2 are the same as above), halogen (usually F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN or S(O)2R S Group (R S is C1-C6 alkyl, optionally substituted aryl, heteroaryl or heterocyclic group or -(CH2) m (R ″) 2 groups, each of which may be substituted in the ortho, meta and / or para positions of the phenyl ring, preferably the para position), or aryl (preferably phenyl), heteroaryl or heterocyclic groups. 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 3 , CF 3 , OMe, OCF 3 , NO 2 , CN or a linker group to which a PTM group (including a ULM 'group) is attached, wherein the substitution occurs in the ortho, meta and / or para positions of the phenyl ring, preferably the para position), which may be optionally substituted including naphthyl as described above; optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl-substituted isoxazole; optionally substituted oxazole, including methyl-substituted oxazole ; optionally substituted thiazole, including thiazole substituted with methyl; optionally substituted pyrrole, including pyrrole substituted with methyl; optionally substituted imidazole, including methylimidazole, benzimidazole or methoxybenzimidazole, oxaimidazole or methyloxaimidazole; optionally substituted diazole group, including methyldiazole group; optionally substituted triazole group, including triazole group substituted with methyl; pyridine group, including pyridine group substituted with halo (preferably F) or methyl or oxapyridine group (wherein the pyridine group is linked to the phenyl group through oxygen) or optionally substituted heterocyclic group (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane or thiazane. Each of the aryl, heteroaryl or heterocyclic group can be optionally linked to the PTM group (including the ULM' group) via a linker group.

[0246] R from ULM-g to ULM-i 3’ Preferred heteroaryl groups 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, benzofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably substituted with methyl), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably substituted with methyl and / or thiol), optionally substituted isothiazole, optionally substituted triazole (preferably substituted with methyl, triisopropylsilyl, optionally substituted -(CH2)m -O-C1-C6 alkyl or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl-substituted 1,2,3-triazole), optionally substituted pyridine (2-pyridine, 3-pyridine or 4-pyridine) or a group according to the following chemical structure:

[0247]

[0248] in:

[0249] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0250] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0251] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0252] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocyclic group, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0253] Y for ULM-g to ULM-i C Is N or CR YC , where R YCis H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl). Each of the heteroaryl groups may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0254] R from ULM-g to ULM-i 3’ Preferred heterocyclic groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane and thiazane, each of which may be optionally substituted, or a group according to the following chemical structure:

[0255] Preferably,

[0256] Group,

[0257] in:

[0258] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0259] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group, and

[0260] Each n in ULM-g to ULM-i is 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), wherein each of the heterocyclic groups may be optionally linked to a PTM group (including a ULM' group) via a linker group.

[0261] Preferred R for ULM-g to ULM-i 3’ Substituents also specifically include (and are not limited to the specific compounds disclosed) R 3’Substituents found in the identified compounds disclosed herein (including specific compounds disclosed in this specification and the accompanying drawings). These R 3’ Each of the substituents may be combined with any number of R 2’ Substituents are used in combination.

[0262] In certain alternative preferred embodiments, R of ULM-g to ULM-i 2’ is optionally substituted -NR1-X R2’ -alkyl, -NR1-X R2’ -aryl, optionally substituted-NR1-X R2’ -HET, optionally substituted -NR1-X R2’ -aryl-HET or optionally substituted-NR1-X R2’ -HET-aryl,

[0263] in:

[0264] R1 of ULM-g to ULM-i is H or C1-C3 alkyl (preferably H);

[0265] X for ULM-g to ULM-i R2’ is optionally substituted –CH2) n -, –CH2) n -CH(X v )=CH(X v )-(cis or trans), –(CH2) n -CH≡CH-, -(CH2CH2O) n - or C3-C6 cycloalkyl; and

[0266] X for ULM-g to ULM-i v is H, halogen or C1-C3 alkyl optionally substituted by one or two hydroxyl groups or up to three halogen groups;

[0267] The alkyl groups of ULM-g to ULM-i are optionally substituted C1-C 10 an alkyl (preferably a C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halogen group (typically Cl or Br));

[0268] The aryl group of ULM-g to ULM-i is optionally substituted phenyl or naphthyl (preferably phenyl); and

[0269] HET of ULM-g to ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably substituted by a C1-C3 alkyl group, preferably a methyl group or a halogen group, preferably F or Cl) or a group according to the following chemical structure:

[0270]

[0271] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0272] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0273] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0274] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocyclic group, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0275] Y for ULM-g to ULM-i C Is N or CR YC , where R YCis H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0276] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0277] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl or together form a keto group, and

[0278] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1). Each of the groups may be optionally linked to a PTM group (including a ULM' group) via a linker group. In certain alternative preferred embodiments of the present disclosure, R of ULM-g to ULM-i is 3’ is optionally substituted –(CH2) n -

[0279] (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, optionally substituted-X R3’ -aryl, optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group or optionally substituted -X R3’ -HET-aryl, wherein:

[0280] R S3’ is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), optionally substituted aryl or HET group;

[0281] R 1’ is H or C1-C3 alkyl (preferably H);

[0282] V is O, S, or NR 1’ ;

[0283] X R3’ Yes – (CH2) n -、-(CH2CH2O) n -, –CH2) n -CH(X v )=CH(X v )-(cis or trans), –CH2) n -CH≡CH- or C3-C6 cycloalkyl, all of which are optionally substituted;

[0284] X v is H, halogen or C1-C3 alkyl optionally substituted by one or two hydroxyl groups or up to three halogen groups;

[0285] Alkyl is an optionally substituted C1-C 10 an alkyl (preferably a C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminated with a halogen group (typically Cl or Br));

[0286] Aryl is optionally substituted phenyl or naphthyl (preferably phenyl); and

[0287] HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably by C1-C3 alkyl, preferably methyl or halogen group, preferably F or Cl) or a group according to the following chemical structure:

[0288]

[0289] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0290] R from ULM-g to ULM-i HETis H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0291] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0292] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocyclic group, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0293] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0294] R from ULM-g to ULM-i PROis H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0295] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl, or together form a keto group;

[0296] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1);

[0297] Each m' of ULM-g to ULM-i is 0 or 1; and

[0298] Each n' of ULM-g to ULM-i is 0 or 1;

[0299] Each of the compounds is preferably linked to a PTM group (including a ULM' group) via a linker group, preferably on an alkyl, aryl or Het group.

[0300] In an alternative embodiment, R of ULM-g to ULM-i 3 'Yes – (CH2) n -aryl, –(CH2CH2O) n -aryl, –(CH2) n -HET or –(CH2CH2O) n -HET, where:

[0301] The aryl group of ULM-g to ULM-i is a phenyl group optionally substituted with one or two substituents, wherein the substituents are preferably selected from (CH2) n OH, C1-C6 alkyl which itself is further optionally substituted by CN, halogen (up to three halogen groups), OH, -(CH2) n O(C1-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine, wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, or

[0302] The aryl groups of ULM-g to ULM-i are replaced by -(CH2) 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-C6alkyl)amine, wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halogen (preferably F, Cl) groups, CN, NO2, optionally substituted -(CH2) n -(V) m’ -CH2) n -(V) m’ -(C1-C6)alkyl, –(V) m’ -(CH2CH2O) n -R PEG Group substituted, where V is O, S or NR 1’ , R 1’ is H or C1-C3 alkyl (preferably H), and R PEG is H or optionally substituted (including optionally substituted by carboxyl) C1-C6 alkyl, or

[0303] The aryl groups of ULM-g to ULM-i are optionally substituted with heterocyclic groups, including heteroaryl groups selected from oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (when substituted, each preferably substituted with C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), or a group according to the following chemical structure:

[0304]

[0305] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0306] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R ais H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0307] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0308] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocyclic group, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0309] Y for ULM-g to ULM-i C Is N or CR YC , where R YC is H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0310] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl or optionally substituted aryl (phenyl or naphthyl), a heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxamidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by C1-C3 alkyl, preferably methyl or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;

[0311] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl, or together form a keto group;

[0312] HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxaimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted by a C1-C3 alkyl group, preferably a methyl group or a halogen group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the following chemical structure:

[0313]

[0314] S for ULM-g to ULM-i c It is CHR SS NR URE or O;

[0315] R from ULM-g to ULM-i HET is H, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0316] R from ULM-g to ULM-i SS is H, CN, NO2, halogen (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogen groups);

[0317] R from ULM-g to ULM-i URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C0-C6 alkyl), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluoro groups, or an optionally substituted heterocyclic group, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;

[0318] Y for ULM-g to ULM-i C Is N or CR YC , where R YCis H, OH, CN, NO2, halogen (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g. CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0319] R from ULM-g to ULM-i PRO is H, optionally substituted C1-C6 alkyl, or optionally substituted aryl, heteroaryl or heterocyclyl;

[0320] R from ULM-g to ULM-i PRO1 and R PRO2 are each independently H, optionally substituted C1-C3 alkyl, or together form a keto group;

[0321] Each m' of ULM-g to ULM-i is independently 0 or 1; and

[0322] Each n of ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1),

[0323] Each of the compounds is preferably linked to a PTM group (including a ULM' group) on the alkyl or HET group, optionally via a linker group.

[0324] In further embodiments, preferred compounds include compounds according to the following chemical structure:

[0325]

[0326] in:

[0327] ULM-i R 1’ is OH or a group that metabolizes or undergoes OH in the patient;

[0328] ULM-i R 2’ is -NH-CH2-aryl-HET (preferably a phenyl group directly attached to a methyl-substituted thiazole);

[0329] ULM-i R 3’ Yes – CHR CR3’ -NH-C(O)-R 3P1 group or –CHR CR3’ -R 3P2 group;

[0330] ULM-i R CR3’is C1-C4 alkyl, preferably methyl, isopropyl or tert-butyl;

[0331] ULM-i R 3P1 is a C1-C3 alkyl group (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted, –(CH2) n OCH3 group, wherein n is 1 or 2 (preferably 2), or groups (the ethyl ether group is preferably substituted on the phenyl portion), morpholino groups (attached to the carbonyl group at the 2- or 3-position;

[0332] ULM-i R 3P2 yes group;

[0333] The aryl group of ULM-i is phenyl;

[0334] HET of ULM-i is an optionally substituted thiazole or isothiazole; and

[0335] ULM-i R HET is H or a halogen group (preferably H);

[0336] or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein each of said compounds is optionally linked to a PTM group (including a ULM' group) via a linker group.

[0337] In certain aspects, the bifunctional compound comprises a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure:

[0338]

[0339] in:

[0340] each R5 and R6 of ULM-j is independently OH, SH or an optionally substituted alkyl group, or R5, R6 and the carbon atom to which they are attached form a carbonyl group;

[0341] R7 of ULM-j is H or optionally substituted alkyl;

[0342] E of ULM-j is a bond, C=O, or C=S;

[0343] G of ULM-j is a bond, optionally substituted alkyl, -COOH, or C=J;

[0344] The J of ULM-j is O or N-R8;

[0345] R8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;

[0346] M of ULM-j is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclic group or

[0347] Each R9 and R of ULM-j 10 are independently H; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, disulfide-linked ULM, optionally substituted heteroaryl or haloalkyl; or R9, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group;

[0348] ULM-j R 11 is an optionally substituted heterocyclic group, an optionally substituted alkoxy group, an optionally substituted heteroaryl group, an optionally substituted aryl group or

[0349] ULM-j R 12 is H or optionally substituted alkyl;

[0350] 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,

[0351] Each R of ULM-j 14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, azetidine, optionally substituted alkoxy, or optionally substituted heterocyclyl;

[0352] ULM-j R 15 is H, CN, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy or optionally substituted heterocyclyl;

[0353] Each R of ULM-j 16 is independently halogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted CN, or optionally substituted haloalkoxy;

[0354] Each R of ULM-j 25 are independently H or optionally substituted alkyl; or two R 25 The groups may together form oxo or optionally substituted cycloalkyl;

[0355] ULM-j R 23 is H or OH;

[0356] Z1, Z2, Z3 and Z4 of ULM-j are independently C or N; and

[0357] o of ULM-j is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0358] In certain embodiments, wherein G of ULM-j is C=J, J is O, R7 is H, each R 14 is H, and o is 0.

[0359] In certain embodiments, wherein G of ULM-j is C=J, J is O, R7 is H, each R 14 It's H, R 15 is optionally substituted heteroaryl, and o is 0. In other cases, E is C=O and M is

[0360] In certain embodiments, wherein E of ULM-j is C=O, R 11 is an optionally substituted heterocycle or And M is

[0361] In certain embodiments, wherein E of ULM-j is C=O and M is And R 11 yes Each R 18 is independently halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0362] In certain embodiments, each R 14 are independently substituted with at least one of H, hydroxy, halogen, amine, amide, alkoxy, alkyl, haloalkyl, or heterocyclyl.

[0363] In certain embodiments, R of ULM-j 15 is based on CN or a haloalkyl group, and each R 18 is independently H, halogen, optionally substituted alkoxy, cyano, aminoalkyl, amidoalkyl, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0364] In certain embodiments, ULM and any ULM' present are each independently a group according to the following chemical structure:

[0365]

[0366] in:

[0367] The G of ULM-k is C=J, and J is O;

[0368] R7 of ULM-k is H;

[0369] Each R of ULM-k 14 is independently H, amide, alkyl, such as methyl, optionally substituted with one or more C1-C6 alkyl or C(O)NR'R";

[0370] R' and R" are each independently H, optionally substituted alkyl or cycloalkyl;

[0371] The o of ULM-k is 0;

[0372] R of ULM-k 15 As defined above for ULM-j;

[0373] R of ULM-k 16 As defined above for ULM-j; and

[0374] R of ULM-k 17 is H, halogen, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl and haloalkyl.

[0375] In other cases, the R of ULM-k 17 is an alkyl group (eg, methyl) or a cycloalkyl group (eg, cyclopropyl).

[0376] In other embodiments, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0377]

[0378] in:

[0379] The G of ULM-k is C=J, and J is O;

[0380] R7 of ULM-k is H;

[0381] Each R of ULM-k 14 It is H;

[0382] o of ULM-k is 0; and

[0383] R of ULM-k 15 Selected from optionally substituted:

[0384]

[0385] The R of ULM-k 30is H or optionally substituted alkyl.

[0386] In other embodiments, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0387]

[0388] in:

[0389] The E of ULM-k is C=O;

[0390] The M of ULM-k is and

[0391] R of ULM-k 11 Selected from optionally substituted:

[0392]

[0393] In yet other embodiments, the compound has the chemical structure,

[0394]

[0395] in:

[0396] The E of ULM-k is C=O;

[0397] R of ULM-k 11 yes and

[0398] The M of ULM-k is

[0399] ULM-k's q is 1 or 2;

[0400] R of ULM-k 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or

[0401]

[0402] R of ULM-k 21 is H or optionally substituted alkyl; and

[0403] R of ULM-k 22 is H, optionally substituted alkyl, optionally substituted alkoxy or haloalkyl.

[0404] In any of the embodiments described herein, R of ULM-j or ULM-k 11 Selected from:

[0405]

[0406]

[0407]

[0408] In certain embodiments, R of ULM-j or ULM-k 11 Selected from:

[0409]

[0410]

[0411] In certain embodiments, the ULM (or ULM' where present) is a group according to the following chemical structure:

[0412]

[0413] in:

[0414] X of ULM-l is O or S;

[0415] Y of ULM-1 is H, methyl or ethyl;

[0416] ULM-1 R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl;

[0417] M of ULM-1 is an optionally substituted aryl group, an optionally substituted heteroaryl group or

[0418] R9 of ULM-l is H;

[0419] ULM-1 R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, or cycloalkyl;

[0420] R11 of ULM-1 is an optionally substituted heteroaromatic, an optionally substituted heterocyclic, an optionally substituted aryl or

[0421] ULM-1 R 12 is H or optionally substituted alkyl; and

[0422] ULM-1 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.

[0423] In some embodiments, ULM and any ULM' present are each independently a group according to the following chemical structure:

[0424]

[0425] in:

[0426] Y of ULM-m is H, methyl or ethyl;

[0427] R9 of ULM-m is H;

[0428] R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;

[0429] ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocycle.

[0430] In other preferred embodiments of the present disclosure, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0431]

[0432] in:

[0433] ULM-nR 17 is methyl, ethyl or cyclopropyl; and

[0434] ULM-n R9, R 10 and R 11 As defined above. In other cases, R9 is H; and

[0435] ULM-nR 10 is H, alkyl or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl).

[0436] In other preferred embodiments of the present disclosure, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0437]

[0438] or a pharmaceutically acceptable salt thereof, wherein:

[0439] R1 is H, optionally substituted alkyl or optionally substituted cycloalkyl;

[0440] R3 is an optionally substituted 5-6 membered heteroaryl;

[0441] W 5is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted pyridyl;

[0442] R 14a and R 14b wherein one of the following is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 one 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;

[0443] R 15 is CN, optionally substituted fluoroalkyl, Optionally substituted (For example where R 28a is halogen, optionally substituted alkyl or fluoroalkyl) or

[0444] Each R 16 independently selected from halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy;

[0445] Each R 26 are independently H, optionally substituted alkyl or NR 27a R 27b ;

[0446] Each R 27a and R 27b is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or R 27a and R 27b Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group;

[0447] Each R 28is 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;

[0448] o is 0, 1, or 2; and

[0449] p is 0, 1, 2, 3, or 4.

[0450] In any aspect or embodiment described herein, the ULM has the formula:

[0451]

[0452] in:

[0453] X 4 、X 5 and X 6 are each selected from CH and N, not more than two of which are N;

[0454] R 1 is a C1-6 alkyl group;

[0455] R 3 Same as defined for ULM-o and ULM-p

[0456] R 14a and R 14b wherein one of the following is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 one is H; or R 14a and R 14b together with the carbon atom 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;

[0457] R 27a and R 27b Each independently is H, C 1-6 Alkyl or cycloalkyl;

[0458] q is 1, 2, 3, or 4;

[0459] R 15 is optionally substituted or CN;

[0460] R 28 It is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2,

[0461] R 28C is H, methyl, fluoro or chloro; and

[0462] R 16 It is H, C 1-4 Alkyl, fluorine, chlorine, CN or C 1-4 Alkoxy.

[0463] In any aspect or embodiment described herein, R 14a and R 14b Selected from: H, C 1-4 Alkyl, C 1-4 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxyalkyl, C 1-4 Alkyl-NR 27a R 27b and CONR 27a R 27b .

[0464] In any aspect or embodiment described herein, R 14a and R 14b At least one of them is H (e.g., R 14a and R 14b Both are H).

[0465] In any aspect or embodiment described herein, R 14a and R 14b At least one of them is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 Alternatively, in any aspect or embodiment described herein, R 14a and R 14bAt least one of them is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 one is H.

[0466] In any aspect or embodiment described herein, R 14a and R 14b Together with the carbon atoms to which they are attached, they form where R 23 Selected from H, C 1-4 Alkyl, -C(O)C 1-4 alkyl.

[0467] In other preferred embodiments of the present disclosure, ULM and ULM', if present, are each independently a group according to the following chemical structure:

[0468]

[0469] or a pharmaceutically acceptable salt thereof, wherein:

[0470] X is CH or N; and

[0471] R1, R3, R of ULM-q and ULM-r 14a 、R 14b and R 15 Same as defined for ULM-o and ULM-p.

[0472] In any aspect or embodiment described herein, the ULM as described herein (or ULM' as present) can be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof. In addition, in any aspect or embodiment described herein, the ULM as described herein (or ULM' as present) can be directly coupled to the PTM via a bond or chemical linker.

[0473] In certain aspects of the present disclosure, the ULM moiety is selected from:

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497] Wherein the VLM can be linked to the PTM via a linker as described herein at any suitable position, including, for example, an aryl, heteroaryl, phenyl or phenyl group of an indole group, optionally via any suitable functional group, such as an amine, ester, ether, alkyl or alkoxy group.

[0498] Exemplary linkers

[0499] In certain embodiments, the compounds described herein include a moiety for chemically coupling a PTM to a ULM, e.g., one or more PTMs chemically linked or coupled to one or more ULMs (e.g., at least one of a VLM) via a chemical linker (L). In certain embodiments, the linker group L is a moiety comprising one or more covalently linked structural units (e.g., -A L 1… (A L ) q -or–(A L ) q -) group, where A L 1 is a group coupled to PTM, and (A L ) q is the group coupled to the ULM.

[0500] In any aspect or embodiment described herein, the linker (L) connection or coupling of the ULM (e.g., VLM, ILM, CLM, or MLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, any subsequent heteroatom (if present) is separated by at least one single carbon atom (e.g., -CH2-), such as from an acetal or amino group. For another example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

[0501] In any aspect or embodiment described herein, the linker group L is of formula -(A L ) q -represented by a bond or chemical linker group, wherein A is a chemical moiety and q is an integer from 1 to 100, and wherein L covalently binds to the PTM and the ULM and provides sufficient binding of the PTM to the protein target and the ULM to the E3 ubiquitin ligase, thereby resulting in ubiquitination of the target protein.

[0502] In any aspect or embodiment described herein, the linker group L is -(A L ) q -,in:

[0503] (A L ) q is a group attached to at least one of a ULM (such as a VLM), a PTM moiety, or a combination thereof;

[0504] The linker q is an integer greater than or equal to 1;

[0505] Each A L independently selected from a bond, CR L1 R L2 、O、S、SO、SO2、NRL3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , 0-6 R's can be selected L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted by 0-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 0-8 R L1 and / or R L2 C 5-13 Spiroheterocyclic group, optionally substituted by 0-6 R L1 and / or R L2 substituted aryl, optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently is optionally linked to other groups to form an optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and

[0506] R L1 、R L2 、R L3 、R L4 and R L5 are independently H, halogen, 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, C3-11 Heterocyclic group, 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 1-8 alkyl)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, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

[0507] In certain embodiments, 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.

[0508] In certain embodiments, for example, when q of the linker is greater than 2, (A L ) q Yes to A L 1 and (A L ) q A group wherein unit A L The PTM was coupled to the ULM.

[0509] In certain embodiments, for example, when q of the linker is 2, (A L ) q To connect to A L 1 and ULM or PTM groups.

[0510] In certain embodiments, for example, when q of the linker is 1, the structure of the linker group L is -A L 1–, and A L 1 is a group connected to the ULM moiety and the PTM moiety.

[0511] In certain embodiments, unit A of linker (L) L Contains a group represented by a general structure selected from the following:

[0512] -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy)-, -NR(CH2) n -(lower alkoxy)-OCH2-, -NR(CH2) n -(lower alkoxy)-(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)-CH2, -N(R1R2)-(heterocyclyl)-CH2; wherein

[0513] n of the linker can be 0 to 10;

[0514] The R of the linker can be H, lower alkyl;

[0515] R1 and R2 of the linker may form a ring via the attached N.

[0516] In certain embodiments, unit A of linker (L) L Contains a group represented by a general structure selected from the following:

[0517] -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-,

[0518] in

[0519] 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;

[0520] When the number is zero, there is no NO or OO key

[0521] R of the linker is H, methyl and ethyl;

[0522] The X of the linker is H and F

[0523]

[0524] The m of the linker can be 2, 3, 4, 5

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533] wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, or 6.

[0534] In any aspect or embodiment described herein, unit A of linker (L)L Selected from:

[0535]

[0536]

[0537]

[0538]

[0539] wherein each n and m is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0540] In any aspect or embodiment described herein, unit A of linker (L) L Selected from:

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570] wherein each of 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.

[0571] In any aspect or embodiment described herein, unit A of linker (L) L Selected from:

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587] In any aspect or embodiment described herein, the Linker unit of Linker (L) comprises a group represented by a structure selected from:

[0588] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O(CH2) t -、

[0589] -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O-,

[0590] -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O(CH2) s -O(CH2) t -、

[0591] -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 -

[0592] -O(CH2) n NCH3C(=O)(CH2) m -;

[0593]

[0594]

[0595]

[0596]

[0597] wherein m, n, o, p, q, r, s and t are each independently selected from the integers 0, 1, 2, 3 and 4.

[0598] In any aspect or embodiment described herein, the linker (L) is selected from:

[0599]

[0600] In further embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety:

[0601]

[0602] in:

[0603] W L1 and W L2 Each independently does not exist, is a 4-8 membered ring having 0-4 heteroatoms, optionally replaced by R Q Replace, each R Q are independently H, halogen, OH, CN, CF3, optionally substituted linear or branched C1-C6 alkyl, optionally substituted linear or branched C1-C6 alkoxy, or 2 R Q The groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

[0604] Y L1 each independently a bond, C1-C6 alkyl (straight chain, branched chain, optionally substituted) and optionally one or more C atoms are replaced by O; or C1-C6 alkoxy (straight chain, branched chain, optionally substituted);

[0605] n is 0-10; and

[0606] Indicates the point of attachment to the PTM or ULM portion.

[0607] In further embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, wherein the dashed line indicates the point of attachment to the PTM or ULM moiety:

[0608]

[0609] in:

[0610] W L1 and W L2 Each independently does not exist, is an aryl, heteroaryl, cyclic group, heterocyclic group, C 1-6 Alkyl and optionally one or more C atoms are replaced by O or N, C 1-6 Alkenyl and optionally one or more C atoms are replaced by O, C 1-6 Alkynyl and optionally one or more C atoms are replaced by O, bicyclic, biaryl, biheteroaryl or biheterocyclic, each optionally replaced by R Q Replace, each R Q are independently H, halogen, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight chain or branched C1-C6 alkyl, optionally substituted straight chain or branched C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with 1 or more -F), OH, NH2, NR Y1 R Y2 , CN, or 2 R Q The groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms;

[0611] Y L1 Each independently is a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (straight chain, branched chain, optionally substituted), and optionally one or more C atoms are replaced by O; C1-C6 alkoxy (straight chain, branched chain, optionally substituted);

[0612] Q L is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally surrounded by 0-6 R Q Replace, each R Q are independently H, linear or branched C 1-6 Alkyl (optionally substituted by one or more halogen or C 1-6 alkoxy substituted), or 2 R QThe groups, together with the atoms to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms;

[0613] R YL1 、R YL2 are independently H, OH, C 1-6 Alkyl (straight chain, branched, optionally substituted with one or more halogens, C 1-6 alkoxy substituted), or R 1 、R 2 Together with the atoms to which they are attached, they form a 3-8 membered ring system containing 0-2 heteroatoms);

[0614] n is 0-10; and

[0615] Indicates the point of attachment to the PTM or ULM portion.

[0616] In other 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 interspersed 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.

[0617] In any embodiment 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, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units.

[0618] In another embodiment, the present disclosure relates to a compound comprising a PTM group as described above that is bound to a target protein or polypeptide (e.g., SMARCA2, BRAHMA or BRM), the PTM group being ubiquitinated by a ubiquitin ligase and being chemically linked directly or through a linker moiety L to a ULM group, or the PTM is alternatively a ULM' group, which is also a ubiquitin ligase binding moiety that can be the same or different from the ULM group as described above and is directly linked to the ULM group or through a linker moiety; and L is a linker moiety as described above that can be present or absent and that chemically (covalently) links the ULM to the PTM; or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

[0619] In certain embodiments, the linker group L is a group comprising one or more covalently linked structural units independently selected from:

[0620]

[0621] X is selected from O, N, S, S(O) and SO2; n is an integer from 1 to 5; R L1 is hydrogen or an alkyl group, is a monocyclic or bicyclic aryl or heteroaryl group optionally substituted by 1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy or cyano; is a monocyclic or bicyclic cycloalkyl or heterocyclic group optionally substituted with 1-3 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 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.

[0622] Although the ULM group and the PTM group can be covalently linked to the linker group through any group that is suitable and stable for the linker chemistry, in preferred aspects of the present disclosure, the linker is independently covalently bound to the ULM group and the PTM group, preferably through an amide, ester, thioester, keto, carbamate (urethane), carbon, or ether, each of which can be inserted anywhere on the ULM group and the PTM group to maximize binding of the ULM group on the ubiquitin ligase to the PTM group on the target protein to be degraded. (Note that in certain aspects where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself). In certain preferred aspects, the linker can be attached to an optionally substituted alkyl, alkylene, alkenyl or alkynyl, aryl, or heterocyclic group on the ULM and / or PTM group.

[0623] Exemplary PTMs

[0624] In any aspect or embodiment of the present disclosure, the PTM group is a moiety that binds to a target protein, such as yeast mating type switch / sucrose non-fermenting complex (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 SMARCA2 or BRM protein (binding to a target protein SMARCA2, BRAHMA or BRM).

[0625] In certain embodiments, the compounds described herein include a moiety for binding to a target protein, such as Brm. Thus, in certain aspects, the present disclosure provides a bifunctional compound having a moiety for binding to Brm, a moiety for binding to VHL, and a moiety for chemically coupling the moiety for binding to Brm to the moiety for binding to VHL.

[0626] The compositions described below illustrate some members of the small molecule target protein binding moiety. 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 connected to the ubiquitin ligase binding moiety via a linker so as to present the target protein (protein target moiety binds thereto) near the ubiquitin ligase for ubiquitination and degradation. According to the present disclosure, a target protein is any protein (i.e., SMARCA2, BRAHMA or BRM) that can bind to a protein target moiety or a PTM group and act on or be degraded by a ubiquitin ligase.

[0627] The present disclosure can 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 a patient would benefit from degradation and / or inhibition of a protein (such as SMARCA2, BRAHMA, or BRM).

[0628] In another aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition modulates protein degradation in a patient or subject (e.g., an animal, such as a human) and can be used to treat or ameliorate a disease state or condition mediated by the degraded protein. In certain embodiments, the therapeutic compositions described herein can be used to achieve degradation of a protein of interest to treat or ameliorate a disease, such as a cancer, such as a SWI / SNF-associated cancer, a SMARCA4 mutation-associated cancer, a SMARCA4-deficient cancer, or a cancer in which SMARCA4 expression is reduced relative to normal SMARCA4 expression (e.g., relative to non-mutated SMARCA4 or SMARCA4 expression in a noncancerous cell with a similar location of wild-type SMARCA4), including lung cancer or non-small cell lung cancer. In any aspect or embodiment described herein, the disease 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, which can be lung cancer or non-small cell lung cancer.

[0629] In certain additional embodiments, the therapeutic compositions as described herein can be used to effect degradation of a protein of interest to treat or ameliorate a disease, e.g., a cancer, such as at least one of a SWI / SNF-associated cancer, a SMARCA2-associated cancer, or a cancer in which SMARCA2 is normally expressed or overexpressed.

[0630] In an alternative aspect, the present disclosure relates to a method for treating a disease state in a subject in need thereof or ameliorating the symptoms of a disease or condition by degrading a protein or polypeptide used to modulate 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 as described above, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient and optionally an additional bioactive agent, wherein the composition is effective to treat or ameliorate the disease or condition or its symptoms in the subject. The methods according to the present disclosure can be used to treat a variety of disease states or conditions, including cancer, 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 agent or other exogenous agent (e.g., a virus, bacteria, fungus, protozoa, or other microorganism), or can be a disease state caused by overexpression of a protein, which results in the disease state and / or condition.

[0631] In another aspect, the present description provides methods of identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0632] The term "target protein" is used to describe a protein or polypeptide that is a target for binding to a compound according to the present disclosure and for degradation by a ubiquitin ligase as described below. 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 a protein of interest. These binding moieties are linked to at least one ULM group (e.g., VLM) via at least one linker group, L.

[0633] The protein target can be used in screens to identify compound moieties that bind to the protein, and by incorporating such moieties into compounds according to the disclosure, the activity level of the protein can be altered to achieve a therapeutic end result.

[0634] 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 places / 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 illustrate some members of the small molecule target protein.

[0635] In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

[0636]

[0637] in:

[0638] W PTM1 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl ring substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano, or a combination thereof);

[0639] W PTM2 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl ring substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);

[0640] W PTM3 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl ring 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 membered cycloalkyl or heterocyclyl, such as an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring (e.g., a 4-9 membered cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);

[0641] W PTM5 does not exist (so that W PTM3 directly attached to L (Linker) or ULM) or is an optionally substituted alkyl, 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, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano); and

[0642] Is the point of attachment to the linker, ULM group, ULM' group, VLM group, VLM' group.

[0643] In any aspect or embodiment described herein, W PTM5 It's piperidine.

[0644] In certain embodiments, W PTM1 Contains phosphate substitution.

[0645] In any aspect or embodiment described herein, the PTM of the PROTAC of the present disclosure is represented by Formula I, wherein at least one of the following conditions is met:

[0646] W PTM1 is optionally substituted phenyl or pyridyl (e.g., substituted as described herein, such as phenyl substituted with hydroxy or phosphate substituents, with or without additional optional substituents selected as described herein, e.g., substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof);

[0647] W PTM2 is an optionally substituted 6-membered heteroaryl ring (e.g., substituted as described herein, such as a pyridazine substituted with an amino group);

[0648] W PTM3 is an optionally substituted 5-6 membered heteroaryl (eg, pyrazole, pyrrole, imidazole, oxazole, oxadiazole or triazole);

[0649] W PTM5 As described in any aspect or embodiment described herein (e.g., W PTM5 may be absent or be a pyridine ring); or

[0650] A combination of them.

[0651] In any aspect or embodiment described herein, e.g., embodiments including a PTM of Formula I, W PTM3 is pyrazole or a 6- to 8-membered heterocyclic group (eg, piperazine or diazabicyclooctane).

[0652] In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

[0653]

[0654] in:

[0655] W PTM1 、W PTM2 and W PTM5 As described in any other aspect or embodiment described herein (e.g., W PTM5 May be present or absent so that the WPTM4 can be connected directly to the L (connector) or ULM);

[0656] W PTM4 Yes and W PTM2a ring-fused 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); and

[0657] Is the point of attachment to the linker, ULM group, ULM' group, VLM group, VLM' group.

[0658] In any aspect or embodiment described herein, the PTM of the present disclosure is represented by Formula II, wherein W PTM1 、W PTM2 and W PTM5 As described in any aspect or embodiment 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 they form the dihydropyrazino[2,3-e]pyridazine shown below:

[0659]

[0660] In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

[0661]

[0662] in:

[0663] W PTM1 and W PTM2 As described in any aspect or embodiment described herein;

[0664] W PTM6 and W PTM7 is independently an optional C4-7 cycloalkyl or heterocyclyl (e.g., each independently a C4-7 cycloalkyl or heterocyclyl substituted with 0, 1 or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano), and W PTM6 and W PTM7 The rings of are fused or connected via a spiro ring connection; and

[0665] Is the point of attachment to the linker, ULM group, ULM' group, VLM group, VLM' group.

[0666] In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by Formula III, wherein W PTM1 and W PTM2Each is 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 further optional substituents selected as described herein, W PTM2 is a pyridazine substituted with an amino group), and W PTM6 and W PTM7 is a spiro ring system, for example, a spiro ring selected from:

[0667]

[0668] In any aspect or embodiment described herein, the PTM of the present disclosure is represented by the following chemical structure:

[0669]

[0670]

[0671] Where W PTM1 、W PTM2 and W PTM5 As described in any other aspect or embodiment described herein.

[0672] In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by Formula IV, wherein at least one of the following conditions is met:

[0673] W PTM1 is phenyl substituted with hydroxy or phosphate substituents, with or without additional optional substituents as described herein;

[0674] W PTM2 It is a pyridazine substituted with an amino group;

[0675] W PTM5 does not exist, is a pyrazole ring or a pyridine ring; or

[0676] A combination of them.

[0677] In any aspect or embodiment described herein, the PTM of the present disclosure is represented by the following chemical structure:

[0678]

[0679] or a pharmaceutically acceptable salt thereof, wherein:

[0680] W PTM3 is absent or optionally substituted 5-6 membered heteroaryl, optionally substituted 4-9 membered cycloalkyl or heterocyclyl ring, optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring; and

[0681] W PTM5is an optionally substituted 5-6 membered heteroaryl or aryl group, for example pyridine or pyridazine.

[0682] In any aspect or embodiment described herein, the PTM of the present disclosure is represented by the following chemical structure:

[0683]

[0684] or a pharmaceutically acceptable salt thereof, wherein:

[0685] W PTM3 is an optionally substituted 5-6 membered heteroaryl, an optionally substituted 4-9 membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl ring, and a bridged biheterocyclyl ring;

[0686] W PTM5 is an optionally substituted 5-6 membered heteroaryl or aryl group, for example pyridine or pyridazine;

[0687] Rv is 0, 1, 2 or 3 substituents independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano or a combination thereof.

[0688] In certain embodiments, the hydroxyl group is modified with a phosphate group (ie, a phosphate ester group).

[0689] In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

[0690]

[0691] W PTM1 and W PTM2 As described in any other aspect or embodiment described herein (e.g., W PTM5 May be present or absent so that the WPTM4 can be connected directly to the L (connector) or ULM);

[0692] W PTM3 Yes and W PTM2 a ring-fused 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);

[0693] W PTM4is an optionally substituted 5-7 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl ring 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 membered cycloalkyl or heterocyclyl, such as an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring (e.g., a 4-9 membered cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);

[0694] W PTM5 does not exist (so that W PTM3 is directly attached to L (Linker) or ULM) or is an optionally substituted alkyl, 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), e.g., an optionally substituted pyrazole or pyridine ring; and

[0695] Is the point of attachment to the linker, ULM group, ULM' group, VLM group, VLM' group.

[0696] In any aspect or embodiment described herein, the PTM is selected from:

[0697]

[0698]

[0699] In any aspect or embodiment described herein, the PTM is selected from:

[0700]

[0701]

[0702] In any aspect or embodiment described herein, the PTM is selected from the group consisting of the following chemical structures:

[0703]

[0704] The compositions described herein exemplify some members of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. The references cited below are incorporated herein by reference in their entirety.

[0705] Therapeutic compositions

[0706] Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound as described herein in combination with one or more compounds described elsewhere herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient represent further aspects of the present disclosure.

[0707] Where applicable, the present disclosure includes compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts of the compounds described herein. Acids used to prepare pharmaceutically acceptable acid addition salts of the above-mentioned base compounds that can be used according to this aspect are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrose, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)] salts, and the like.

[0708] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of compounds or derivatives according to the present disclosure. Chemical bases that are acidic in nature and can be used as reagents for preparing pharmaceutically acceptable basic salts of compounds herein are those that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), as well as other basic salts of lower alkanolammonium and pharmaceutically acceptable organic amines, and the like.

[0709] Compounds as described herein can be administered orally, parenterally or topically in single doses or divided doses according to the present disclosure. The scope of administration of the active compound can be from continuous (intravenous drip) to oral administration several times a day (e.g., QID), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include a penetration enhancer), buccal, sublingual and suppository administration, and other administration routes. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form depends on the pharmacokinetics of the selected specific agent and the severity of the disease in the patient. It is also possible to use a spray, mist or aerosol according to the present disclosure for intranasal, intratracheal or pulmonary administration. Therefore, the present disclosure also relates to pharmaceutical compositions, which include an effective amount of a compound as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. Compounds according to the present disclosure can be administered in an immediate release, intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but may also be administered as suppositories and transdermal or other topical forms. Intramuscular injection of liposomes may also be used to control or sustain the release of the compound at the injection site.

[0710] The compositions as 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. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0711] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0712] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, may be used to prepare injectables, as may natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helvetic acid or similar alcohols.

[0713] 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 solutions. In the case of 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 dry corn starch. When an aqueous suspension is desired for oral use, the active ingredient is mixed with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or coloring agents may also be added, if desired.

[0714] Alternatively, the pharmaceutical compositions as described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0715] The pharmaceutical compositions described herein can also be administered topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical administration to the lower intestinal tract can be achieved with a rectal suppository formulation (see above) or with a suitable enema formulation. Topically acceptable transdermal patches can also be used.

[0716] For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. In certain preferred aspects of the present disclosure, the compound can be applied to a stent that is to be surgically implanted in a patient in order to inhibit or reduce the likelihood of the stent becoming blocked in the patient.

[0717] Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0718] For ophthalmic use, the pharmaceutical composition can 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 benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0719] The pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0720] The amount of compound in a pharmaceutical composition as described herein that can be combined with a carrier material to prepare a single dosage form will vary depending on the host and disease being treated, as well as the particular mode of administration. Preferably, the composition should be formulated to contain from about 0.05 mg to about 750 mg or more, more preferably from about 1 mg to about 600 mg, even more preferably from about 10 mg to about 500 mg of the active ingredient, alone or in combination with at least one other compound according to the present disclosure.

[0721] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the specific disease or condition being treated.

[0722] A patient or subject in need of treatment with a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, including a pharmaceutically acceptable salt, solvate, or polymorph thereof, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known therapeutic agents as identified elsewhere herein.

[0723] The compounds may be administered by any appropriate route, for example orally, parenterally, intravenously, intradermally, subcutaneously or topically, including transdermally, in liquid, cream, gel or solid form or by aerosol form.

[0724] 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 severe toxic effects in the treated patient. Preferred dosages of the active compound for all conditions mentioned herein are in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg / day, more typically 0.5 to about 25 mg / kg of recipient / patient body weight / day. Typical topical dosages range from 0.01-5% by weight in a suitable carrier.

[0725] The compound is conveniently administered in any suitable unit dosage form, including but not limited to unit dosage forms containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of about 25-250 mg is generally convenient.

[0726] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, preferably about 0.1-30 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 as a bolus injection of the active ingredient. Oral administration is also suitable for generating effective plasma concentrations of the active agent.

[0727] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage value will also change with the severity of the condition to be alleviated. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time based on individual needs and the professional judgment of the individual who administers or oversees the administration of the composition, and the concentration ranges described herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once, or can be divided into many smaller doses, administered at different time intervals.

[0728] Oral compositions will typically contain an inert diluent or edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be mixed with an excipient and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition.

[0729] Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the types mentioned above, a liquid carrier such as a fatty oil. Additionally, the dosage unit form may contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.

[0730] 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 and colorings, and flavors.

[0731] The active compound or its pharmaceutically acceptable salt may also be mixed with other active materials that do not impair the desired effect, or with materials that supplement the desired effect, such as anticancer agents (including pembrolizumab). In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another biologically active agent, such as an anticancer agent or a wound healing agent, including an antibiotic, as described elsewhere herein.

[0732] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may contain the following components: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methyl paraben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate and an agent for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0733] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0734] In one embodiment, the active compound is prepared with a carrier that protects the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0735] Liposomal suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods well known to persons skilled in the art, for example, as described in U.S. Patent number 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome preparations can be prepared by dissolving suitable lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonic acid phosphatidylcholine and cholesterol) in an organic solvent, then evaporating the organic solvent, leaving a thin film of dry lipids on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release lipid material and disperse lipid aggregates from the side of the container, thereby forming a liposome suspension.

[0736] Treatment

[0737] In another aspect, the present disclosure provides therapeutic compositions comprising an effective amount of a compound as described herein or a salt thereof and a pharmaceutically acceptable carrier. The therapeutic compositions regulate protein degradation in a patient or subject (e.g., an animal, such as a human) and can be used to treat or ameliorate a disease state or condition mediated by degraded protein.

[0738] As used herein, the terms "treat," "treating," and "treatment" and the like refer to any action that provides a benefit to a patient to whom the compounds herein can be administered, including the treatment of any disease state or condition modulated by a protein to which the compounds herein bind. Disease states or conditions that can be treated using the compounds according to the present disclosure are described above, including cancers such as lung cancer, including non-small cell lung cancer.

[0739] This specification provides a therapeutic composition as described herein for achieving degradation of a target protein to treat or improve a disease, such as cancer. In certain other embodiments, the disease is multiple myeloma. Therefore, on the other hand, this specification provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound as described herein, the bifunctional compound comprising, for example, a ULM and a PTM preferably connected by a linker moiety as described herein, wherein the ULM is coupled to the PTM and wherein the ULM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, such as a VHL E3 ubiquitin ligase) and the PTM recognizes the target protein, such that when the target protein is placed near the ubiquitin ligase, degradation of the target protein will occur, thereby achieving inhibition of the degradation / target protein effect of the target protein and control of protein levels. The control of the protein levels provided by the present disclosure provides treatment for a disease state or condition, which is 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 method comprises administering an effective amount of a compound as described herein, optionally with a pharmaceutically acceptable excipient, carrier, adjuvant, another biologically active agent, or a combination thereof.

[0740] In another embodiment, the present description provides a method for treating or improving 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 excipient, carrier, adjuvant, another biologically active agent or a combination thereof, wherein the composition is capable of effectively treating or improving the disease, disorder or symptom thereof in the subject.

[0741] In another aspect, the present description provides methods of identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0742] In another embodiment, the present disclosure relates to a method of treating a human patient in need of treatment for a disease state or condition modulated by a protein, wherein degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to the patient in need thereof an effective amount of a compound according to the present disclosure, optionally in combination with another biologically active agent. The disease state or condition can be a disease caused by a microbial agent or other exogenous agent (e.g., a virus, bacteria, fungus, protozoa, or other microorganism), or can be a disease state caused by overexpression of a protein, which results in the disease state and / or condition.

[0743] The term "disease state or condition" is used to describe any disease state or condition in which protein dysregulation occurs (i.e., the amount of protein expressed in a patient is elevated) and in which degradation of one or more proteins in the patient can provide beneficial therapy or relief of symptoms to a patient in need thereof. In some cases, the disease state or condition can be cured.

[0744] Disease states or conditions that can be treated using the compounds according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0745] The term "neoplasia" or "cancer" is used throughout this specification to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors (i.e., abnormal tissue that grows by cell proliferation), which is generally faster than normal tissue and continues to grow after the stimulus that initiated the new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, and may recur after attempted removal and lead to death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated with the compounds of the present invention, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, hemangioendothelioma, Kaposi's sarcoma, and leukemia. sarcoma), liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwannomas; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma. Additional cancers that can be treated using the compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0746] The term "biologically active agent" is used to describe an agent, other than a compound according to the present disclosure, that is used in combination with the compounds of the present invention as an agent having biological activity to help achieve the intended therapy, inhibition and / or prevention / prophylaxis for which the compounds of the present invention are used. Preferred biologically active agents as used herein include those agents that have pharmacological activity similar to that of the compounds of the present invention used or administered, and include, for example, anticancer agents, antiviral agents, particularly including anti-HIV agents and anti-HCV agents, antimicrobial agents, antifungal agents, and the like.

[0747] The term "additional anticancer agent" is used to describe an anticancer agent that can be combined with the compounds 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 modulators, 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 (MEK) inhibitors, VEGF capture antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, ogavuzumab, Lep-ETU, noratriptide, AZD2171, batabulin, ofatumumab, zalimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, tesimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, methionone, 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, celecoxib; 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 estrogen, bevacizumab, IMC-1C11,CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, cinnamaldehyde Diacylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, amine glutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG) vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone acetate, cytarabine, dacarbazine, actinomycin D, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, dichloromethane, Melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neivastat, BMS- 275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezomib, paclitaxel, paclitaxel without hydrogenated castor oil, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipenoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxyfene, 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, zolendronate ate), prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan), androgens, decitabine, hexamethasone, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, daunorubicin liposomal, Edwina asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0748] The term "anti-HIV agent" or "another anti-HIV agent" includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those not representative of the present disclosure), protease inhibitors, fusion inhibitors, and the like, exemplary compounds of which may include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir disoproxil fumarate (PMPA), D-D4FC (Reverset), D 4T (stavudine), Racivir, 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, etc., their fusions and mixtures, including anti-HIV compounds currently in clinical trials or development.

[0749] Other anti-HIV agents that can be co-administered with the compounds according to the present disclosure include, for example, other NNRTIs (i.e., in addition to the NNRTIs according to the present disclosure) that can be selected from 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-furancarboxamide, etravirine (TMC125), treviridine (Ly300046.HCl), MKC-442 (imivirine, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (3',3'-dichloro-4',4"-dimethoxy-5',5"-bis(methoxycarbonyl)-6,6-diphenylhexenoic acid methyl ester), 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoic acid methyl ester (Alkenyldiarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), caprovirine (AG-1549, S-1153), ativiridine (U-87201E), aurintricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[ 3-(Isopropylamino)-2-pyridyl]piperazine, 1-[5-[[N]-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridyl]piperazine, 1-[3-(ethylamino)-2-[pyridyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC 633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, phosphonoformic acid (Foscavir), HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymidine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymidine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)- 2-thiothymine), malusin 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-(ethoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiolene-3-thione), N-{2-(2-chloro-6-fluorophenethyl)-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-difluorophenethyl)-N'-[2-(5-bromopyridyl)]thiourea (PETT derivative), N-{2-(2,6-difluorophenethyl)-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivatives], N-[2-(3-fluorofuryl)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(pyridine-2(1H)-thione (2-pyridine) ketone derivatives), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, suramin sodium, TBZ (thiazolobenzimidazole, NSC625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, tevirapine (R86183), UC-38 and UC-84, etc.

[0750] Where applicable, the term "pharmaceutically acceptable salt" is used throughout this specification to describe a salt form of one or more compounds described herein that is used to increase the solubility of the compound in the gastric fluid of the patient's gastrointestinal tract in order to promote dissolution and bioavailability of the compound. Where applicable, pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include salts derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, as well as numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralized salts of the phosphates according to the present disclosure.

[0751] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., esters, amides, other prodrug groups) that, when administered to a patient, directly or indirectly provides a compound of the invention or an active metabolite of a compound of the invention.

[0752] General synthetic methods

[0753] The synthetic realization and optimization of bifunctional molecules as described herein can be carried out in a step-by-step or modular manner. For example, if a suitable ligand is not immediately available, identifying compounds that bind to the target molecule can involve high-throughput or medium-throughput screening activities. It is not uncommon for an initial ligand to require iterative design and optimization cycles to improve suboptimal aspects, as determined by appropriate in vitro and pharmacological and / or ADMET assays. Part of the optimization / SAR activity will be to probe the position of the ligand for tolerant substitution and possibly for the attachment of the chemical linkers previously mentioned herein. Where crystallographic or NMR structural data are available, these can be used to focus such synthetic tasks.

[0754] In a very similar manner, ligands for E3 ligases, ie ULM / VLM, can be identified and optimized.

[0755] Using PTMs and ULMs (e.g., VLMs), one skilled in the art can combine them with or without linker moieties using known synthetic methods. Linker moieties can be synthesized with a range of compositions, lengths, and flexibilities and functionalized so that PTM and ULM groups can be sequentially attached to the distal end of the linker. Thus, libraries of bifunctional molecules can be realized and analyzed in in vitro and in vivo pharmacology and ADMET / PK studies. As with PTM and ULM groups, the resulting bifunctional molecules can be subjected to iterative design and optimization cycles to identify molecules with desired properties.

[0756] In some cases, protecting group strategies and / or functional group interconversion (FGI) may be necessary to facilitate the preparation of the desired material. Such chemical processes are well known to synthetic organic chemists and many of them can be found in textbooks such as "Greene's Protective Groups in Organic Synthesis," Peter G.M. Wuts and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection Approach," Stuart Warren and Paul Wyatt (Wiley).

[0757] abbreviation:

[0758] ACN: acetonitrile

[0759] ADDP: 1,1'-(azodicarbonyl)dipiperidine

[0760] BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride

[0761] BPO: Benzoyl peroxide

[0762] Cbz: carbonylbenzyloxy

[0763] DAST: Diethylaminosulfur trifluoride

[0764] DBE: 1,2-dibromoethane

[0765] DCM: dichloromethane

[0766] DEAD: diethyl azodicarboxylate

[0767] DIAD: diisopropyl azodicarboxylate

[0768] DIBAL: Diisobutylaluminum hydride

[0769] DIEA or DIPEA: diisopropylethylamine

[0770] DMA: N,N-dimethylacetamide

[0771] DMF: N,N-dimethylformamide

[0772] DMP: Dess-Martin Periodinane

[0773] EA: ethyl acetate

[0774] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0775] HBTU: N,N,N'N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate

[0776] HMDS: bis(trimethylsilyl)amine

[0777] HMPA: Hexamethylphosphoramide

[0778] LDA: lithium diisopropylamide

[0779] MCPBA: meta-chloroperbenzoic acid

[0780] MsCl: methanesulfonyl chloride

[0781] MW: Microwave

[0782] NBS: N-bromosuccinimide

[0783] NMP: N-methylpyrrolidone

[0784] PCC: Pyridinium Chlorochromate

[0785] Pd-118 or Pd(dtpf)Cl2: 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride

[0786] Pd(dppf)Cl2:1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride

[0787] Pd(dba)2:Bis(dibenzylideneacetone)palladium

[0788] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0789] PPTS: Pyridinium p-toluenesulfonate

[0790] PTSA: p-toluenesulfonic acid

[0791] RuPhos-Pd-G3:XPhos-Pd-G3:[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0792] RuPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0793] SFC: Supercritical Fluid Chromatography

[0794] t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0795] TEA: trimethylamine

[0796] TFA: trifluoroacetic acid

[0797] TLC: Thin layer chromatography

[0798] TMP: 2,2,6,6-tetramethylpiperidine

[0799] TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide

[0800] TosCl or TsCl: p-Toluenesulfonyl chloride

[0801] TsOH: p-toluenesulfonic acid

[0802] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0803] XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl

[0804] XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0805] 12354-85-7: Bis(pentamethylcyclopentadienylrhodium dichloride)

[0806] Solution 1

[0807]

[0808] As shown in Scheme 1, with W PTM5 Some compounds contain a linker group L, which includes a nucleophilic group, such as an amino group. When reacted with a compound having a good leaving group LG (e.g., a perfluorosulfonyl group C4F9SO3-), a coupling product is formed. The coupling product reacts with a monoprotected amine molecule W under palladium catalysis. PTM3 Reaction, connect W PTM3 After amine deprotection, selected from W PTM5 -W PTM3 The more reactive halogen atoms of Z' and Z" undergo nucleophilic substitution of the free amino group to form W PTM5 -W PTM3 -W PTM2 , then with W PTM2 Boronic acid reaction yields PTM binding groups, including W PTM5 -W PTM3 -W PTM2 -W PTM1 After base-catalyzed ester hydrolysis, the resulting acid is coupled to a ULM moiety bearing an amino group to combine the PTM and ULM binding moieties in one molecule.

[0809] Option 2

[0810]

[0811] As shown in Scheme 2, a Mitsunobu reaction between a hydroxyl-containing moiety R3 and a monoprotected diol including a linker group L produces a coupling product. After O-deprotection, the free hydroxyl group is activated, for example as a sulfonate, and subsequently used in W PTM5 W with an amino group PTM5 -W PTM3 -W PTM2 -W PTM1 After ester hydrolysis, the resulting acid is coupled to a ULM moiety bearing an amino group to combine the PTM and ULM binding moieties in one molecule.

[0812] Option 3

[0813]

[0814] As shown in Scheme 3, a vinyl group was first introduced into the dihalogenated derivative W. PTM2 Then, the obtained product is combined with the halogenated part W having the linking group L' PTM2 A palladium-catalyzed Heck coupling reaction is performed, wherein the linker L' comprises an optionally protected amino group. PTM1 Part, W PTM2 -W PTM5 The halide moiety is coupled with a suitable boronic acid under Suzuki conditions, and the resulting amine reacts with an aldehyde containing ULM to afford the PTM-ULM coupling product.

[0815] Option 4

[0816]

[0817] Scheme 4 shows the method for combining the PTM binding moiety W PTM5 -W PTM3 -W PTM2 -W PTM1 Exemplary coupling reactions for attachment to ULM-containing moieties. Such reactions may include reductive amination using sodium cyanoborohydride as a reducing agent or condensation coupling reactions between carboxylic acids and diamines. One of ordinary skill in the art will be able to select appropriate reagents and conditions to carry out the desired transformation.

[0818] Option 5

[0819] As shown in Scheme 5, the hydroxyl-containing portion R3 and W PTM5 Mitsuno

[0820]

[0821] The bu-type reaction produces a coupled product. Then, under Suzuki or Buchwald conditions, a monoprotected diamine W PTM3 Replacement in W PTM5 After the second amino group is deprotected, it is connected to W PTM2 Some of the more reactive halogen atoms are replaced to form W PTM5 -W PTM3 -W PTM2 The resulting monohalide is then reacted with an appropriate boronic acid under Suzuki conditions to yield the PTM binding moiety W PTM5 -W PTM3 -W PTM2 -W PTM2 After ester hydrolysis, the resulting acid is then coupled to a ULM moiety bearing an amino group to combine the PTM and ULM binding moieties in one molecule.

[0822] Option 6

[0823]

[0824] As shown in Scheme 6, the acetal-containing ULM moiety can be hydrolyzed under sufficiently mild conditions to form an aldehyde, which can then be ligated to a W having an amino group-containing linker L'. PTM5 -W PTM3 -W PTM2 -W PTM2 The fragments react under reductive amination conditions to form the PTM-ULM coupled product. One of ordinary skill in the art will be able to select appropriate reagents and conditions to carry out the desired transformation.

[0825] Option 7

[0826]

[0827] As shown in Scheme 7, a Mitsunobu-type reaction between the hydroxyl-containing moiety R3 and a mono-protected fluorinated diol affords a fluorinated intermediate. After O-deprotection, the free hydroxyl group is activated (e.g., as a sulfonate) and subsequently used in W PTM5 W with an amino group PTM5 -W PTM3 -W PTM2 -W PTM1 After ester hydrolysis, the resulting acid is coupled to a ULM moiety bearing an amino group to combine the PTM and ULM binding moieties in one molecule.

[0828] Option 8

[0829]

[0830] As shown in Scheme 8, nucleophilic substitution of the leaving group in L'-OLG with an ester containing a hydroxyl group of R3 produces a coupled product to which linkers L' and L" are attached. Subsequent alkaline hydrolysis and coupling of the resulting acid with an amino group-bearing ULM moiety yields a ULM fragment to which two sequentially linked groups L' and L" are attached. The amino group of L' is N-deprotected and then reacted with W PTM5 -W PTM3 -W PTM2 -W PTM1 -L"' aldehyde reductive amination or with W PTM5 -W PTM3 -W PTM2 -W PTM1 -L"' carboxylic acid condensation to obtain PTM-ULM coupling product.

[0831] Option 9

[0832]

[0833] As shown in Scheme 9, W is nucleophilically substituted with a compound having a hydroxyl group in R3. PTM5 The fluorine atoms in the part give W PTM5 -L-R3 halide, which reacts with the monoprotected diamine W under Suzuki or Buchwald conditions PTM5 After the second amino group is deprotected, W is then substituted by nucleophilic aromatic substitution. PTM3 -W PTM5 -L-R3 part and dihalogenated W PTM2 Reaction to obtain a monohalide. Then Suzuki reaction with appropriate boronic acid to obtain W PTM1 -W PTM2 -W PTM3 -W PTM5 -L-R3 ester. Alkaline hydrolysis and coupling with the ULM part with an amino group gave the PTM-ULM coupling product.

[0834] One possible method for synthesizing exemplary compounds of the present disclosure is by following the general synthetic routes detailed in the following schemes:

[0835]

[0836] It will be appreciated by those skilled in the art that improved methods can be employed to link PTMs via different chemical linkers. PTM5 Connected to L via a CH2 group (X=CH2 in the above scheme) ’ In this case, the approach described in the following scenario can be envisaged:

[0837]

[0838] Alternatively, if there is no W PTM5 , the PTM of the exemplary compound represented by Formula I can be synthesized according to the following general scheme:

[0839]

[0840] It will be appreciated by those skilled in the art that the general methods described herein can be modified to suit W PTM1 、W PTM2 、W PTM3 、W PTM4 、W PTM5 、W PTM6 and W PTM7For example, in some embodiments, the exemplary compounds represented by Formula II can be prepared as described in the following general synthetic scheme, wherein those skilled in the art will recognize that additional protection / deprotection steps may be required depending on the specific chemical properties of the exemplary compounds:

[0841]

[0842] In one embodiment, wherein X represents NH, depending on whether W is present PTM5 , exemplary compounds can be prepared according to one of the following two schemes:

[0843]

[0844] When there is no W PMT5 When , the exemplary PTMs represented by formula III can be prepared according to the general methods described for compounds of formula I.

[0845] An exemplary PTM represented by Formula IV can be prepared according to the following general scheme:

[0846]

[0847] Exemplary Synthesis of Exemplary Compound 11

[0848] Step 1

[0849]

[0850] At 0 ℃, to a mixture of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate (1.5g, 6.8mmol) and TEA (2.07g, 20.5mmol) in DCM (5mL), TsCl (1.95g, 10.23mmol) was added. The resulting mixture was warmed to room temperature and stirred for 3 hours. The solution was quenched with water (20mL) and extracted with DCM. The organic phase was washed with salt water (20mLx2). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CH2Cl2: MeOH 40:1) to obtain tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (2.14g, 84% yield).

[0851] Step 2

[0852]

[0853] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.11 g, 5.722 mmol), tert-butyl 2-(2-(tosyloxy)ethoxy)ethoxy)acetate (2.14 g, 5.722 mmol) and CsCO (3.73 g, 11.444 mmol) in anhydrous DMF (10 mL) was heated to 75 ° C for 3 hours. 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 mLx2), dried (NaSO), filtered and concentrated. The crude residue (2.8 g) was used in the next reaction without further purification.

[0854] Step 3

[0855]

[0856] 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), PdCl2(dppf) (555 mg, 0.758 mmol), tBuPHBF4 (441 mg, 1.52 mmol) and Cs2CO3 (3.09 g, 9.48 mmol) in dioxane (10 mL) and water (1 ml) was heated to 100° C. and stirred under N2 for 3 hours. The solid was filtered off 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).

[0857] Step 4

[0858]

[0859] 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), PdCl2(dppf) (444 mg, 0.606 mmol) and tBu PHBF (352 mg, 1.212 mmol) suspension in dioxane (10 mL) and water (1 mL) was heated to 100 ° C under nitrogen for 3 hours. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was concentrated and purified by chromatography (CH Cl : MeOH 40: 1) to give tert-butyl 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl) pyridazine-4-yl)-1H-pyrazoles-1-yl) ethoxy) ethoxy) acetate (400 mg, 44% yield).

[0860] Step 5

[0861]

[0862] 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 hours. The reaction solution was quenched with 1M 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.

[0863] Step 6

[0864]

[0865] To a solution of 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetic acid (200 mg, crude), (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) in DMF (5 mL) 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 phases were washed with brine (8 mL x 2), dried (Na2SO4), 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).

[0866] 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).

[0867] Exemplary Compound 5 was prepared according to the following scheme using methods similar to those described above for Exemplary Compound 11 and methods known and understood by those skilled in the art:

[0868]

[0869] Exemplary Compound 1, Exemplary Compound 2, Exemplary Compound 3, Exemplary Compound 4 were prepared using the methods described for Exemplary Compound 11 and Exemplary Compound 5.

[0870] Exemplary Synthesis of Exemplary Compound 9

[0871] Step 1

[0872]

[0873] At 0 ° C, 60% NaH (1.25 g, 31.2 mmol) was added to a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (13.5 g, 56.8 mmol) in anhydrous DMF (30 mL). The reaction mixture was stirred at room temperature for 0.5 hours. 4-bromo-2-fluoropyridine (5 g, 28.4 mmol) was then added dropwise to the mixture, and the mixture was heated to 75 ° C for 2 hours. 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 (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column to obtain 14-((4-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-ol (9.0 g, 22.9 mmol, 81% yield).

[0874] Step 2

[0875]

[0876] At 0 DEG C, to 14-((4-bromopyridin-2-yl) oxygen base)-3,6,9,12-tetraoxatetradecane-1-ol (5.0g, 12.7mmol) in anhydrous THF (50mL) solution, add 60% NaH (660mg, 16.5mmol).Reactant mixture is stirred at room temperature for 40 minutes.Then 2-bromoacetic acid tert-butyl esters (4.9g, 25.4mmol) are added dropwise into the mixture, and stirred at room temperature overnight.Reactant mixture is quenched with 2N NH4Cl (10mL), and extracted with EA (200mL).Then organic phase is washed with salt water (10mL), dried (Na2SO4), and concentrated under reduced pressure.By silica gel column purification residue, 17-((4-bromopyridin-2-yl) oxygen base)-3,6,9,12,15-five oxaheptadecanoic acid tert-butyl esters (2.6g, 5.13mmol, 40% yield) are obtained.

[0877] Step 3

[0878]

[0879] By tert-butyl 17-((4-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (250mg, 1.18mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (718mg, 1.4mmol), cesium carbonate (769mg, 2.36mmol), Pd(dba) (110mg, 0.12mmol) and XantPhos (138mg, 0.24mmol) in dioxane (5mL) mixture in sealed tube under nitrogen to 110°C overnight.The mixture is extracted with EA (100mL).Then the organic phase is washed with water (10mL), brine (10mL), 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-hexaoxaeicosanyl)oxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (550 mg, 0.86 mmol, 73% yield).

[0880] Step 4

[0881]

[0882] At room temperature, to a solution of 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-carboxylic acid tert-butyl ester (550mg, 0.86mmol) in MeOH (15mL), a dioxane solution of HCl (6N dioxane solution) (5ml, 30mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give crude 17-((4-(3,8-diazabicyclo[3.2.1]octane-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoic acid methyl esters (0.55g).

[0883] Step 5

[0884]

[0885] To a solution of crude 17-((4-(3,8-diazabicyclo[3.2.1]octane-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoic acid methyl ester (550 mg crude product) in DMSO (5 mL) was added 5-bromo-6-chloropyridazine-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).

[0886] Step 6

[0887]

[0888] To a solution of 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 (325 mg, 0.52 mmol) and (2-hydroxyphenyl)boronic acid (93 mg, 0.68 mmol) in dioxane (12 mL) and water (1.2 mL) was added cesium carbonate (542 mg, 1.66 mmol), PdCl2(dppf) (73.2 mg, 0.1 mmol), and t-Bu3PHBF4 (58 mg, 0.2 mmol). The solution was stirred at 100° C. under a nitrogen atmosphere for 4 hours. The pH of the solution was adjusted to 5 with 1N 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.

[0889] Step 7

[0890]

[0891] 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-dimethylbutanoyl)-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). In 40mL 40mL 40mL 40mL 40mL 30mL 40mL 80mL 30mL 30mL 40mL 80mL 20mL 10mL 80mL 20mL 10mL 40mL 80mL 20mL 10mL 40mL 80mL 20mL 10mL 20mL 80mL 20mL 10mL 4 ...

[0892] 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).

[0893] Using similar methods, exemplary compounds 7, 8, 10 and 35 were prepared.

[0894] Exemplary Synthesis of Exemplary Compound 6

[0895] Step 1

[0896]

[0897] To a solution of 2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)ethane-1-ol (3.49 g, 10 mmol) [prepared using a method similar to that described in Example A2979] in DCM (50 mL) and H o (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 hours. 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 (Na sO ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid (3.5 g, 9.64 mmol, 96% yield).

[0898] Step 2

[0899]

[0900] 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 hours. The pH of the solution was adjusted to ~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-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetate (2.9 g, 7.69 mmol, 93% yield).

[0901] Using a method similar to that described for Exemplary Compound 9, methyl 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).

[0902] 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).

[0903] Exemplary Synthesis of Exemplary Compound 20

[0904] Step 1

[0905]

[0906] To 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (4g, 14.2mmol) and Et3N (8.6g, 85.2mmol) in DCM (50mL) is added TsCl (8.1g, 42.6mmol). The reaction mixture is stirred at room temperature for 1 hour. The mixture is distributed between EtOAc (100mL) and water (10mL). The organic phase is washed with salt water (10mL). The combined organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain 3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis(4-methylbenzenesulfonate) (6.0g, 10.2mmol, 72% yield).

[0907] Step 2

[0908]

[0909] To 3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis(4-methylbenzenesulfonate) (3.5g, 5.93mmol) in anhydrous DMF (20mL) solution, add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.15g, 5.93mmol) and CsCO(3.87g, 11.86mmol).The reaction mixture was stirred at 75°C for 0.5 hour.The mixture was cooled to room temperature and distributed between EtOAc (200mL) and water (20mL).The organic phase was washed with salt water (20mL).The combined organic layer was 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-pentaoxaheptadecanol-4-methylbenzenesulfonate (0.6 g, 0.98 mmol, 16.5% yield).

[0910] Step 3

[0911]

[0912] 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-pentaoxaheptadecanol (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 (Na2SO4), 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-pentaoxaheptadecanyl)oxy)benzyl)pyrrole To this mixture was added a mixture of alkane-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-pentaoxaheptadecanyl)-1H-pyrazol-4-yl)boronic acid (270 mg, 0.27 mmol, 56% yield).

[0913] Step 4

[0914]

[0915] To (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-pentaoxaheptadecanyl)oxy)benzyl)pyrrolidine-2-carboxamide and (1-(17-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrole To a solution of a mixture of (4-(4-(4-methylthiazol-5-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanyl)-1H-pyrazol-4-yl)boronic acid (270 mg, 0.27 mmol) and 5-bromo-6-chloropyridazin-3-amine (85 mg, 0.41 mmol) in dioxane (20 mL) and water (2 mL) were added cesium carbonate (220 mg, 0.68 mmol), PdCl2(dppf) (40 mg, 0.054 mmol), and t-Bu3PHBF4 (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-pentaoxaheptadecanyl)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).

[0916] Step 5

[0917]

[0918] To a solution of (2S,4R)-N-(2-((17-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecanyl)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) and (2-hydroxyphenyl)boronic acid (32 mg, 0.23 mmol) in dioxane (15 mL) and water (1.5 mL) were 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-pentaoxaheptadecanyl)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).

[0919] 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).

[0920] Exemplary compounds 12, 13, and 21 were prepared using a method similar to that described for exemplary compound 20.

[0921] Exemplary Synthesis of Exemplary Compound 14

[0922] Step 1

[0923]

[0924] In a 250-mL round-bottom flask was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.73 mmol, 1.00 equiv) in dioxane / HO (1:1) (60 mL), 4-bromo-6-chloropyridazin-3-amine (1.7 g, 8.16 mmol, 1.20 equiv), Pd(PPh) (800 mg, 0.69 mmol, 0.10 equiv), and potassium carbonate (2.9 g, 20.98 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The residue was applied to a silica gel column using dichloromethane / methanol (10:1). This afforded 1.0 g (66%) of 6-chloro-4-(1H-pyrazol-4-yl)pyridazin-3-amine as a white solid.

[0925] Step 2

[0926]

[0927] In a 10-mL sealed tube was placed 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 potassium carbonate (552 mg, 3.99 mmol, 2.00 equiv) in water (2 mL). The resulting solution was stirred at 100°C in an oil bath for 12 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column using 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.

[0928] Step 3

[0929]

[0930] In a 50-mL round-bottom flask was placed a solution of 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (100 mg, 0.34 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), 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). 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 x 3), and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column using dichloromethane / methanol (10:1). 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 were obtained as a yellow oil.

[0931] Step 4

[0932]

[0933] In a 100-mL round-bottom flask was placed a solution of 2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazine-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethane-1-ol (100 mg, 0.23 mmol, 1.00 equivalent) in dichloromethane (20 mL), 4-toluenesulfonyl chloride (66.0 mg, 0.35 mmol, 1.50 equivalents), triethylamine (47 mg, 0.46 mmol, 2.00 equivalents), 4-dimethylaminopyridine (10 mg, 0.08 mmol, 0.30 equivalents). The resulting solution was stirred at room temperature for 16 hours. The resulting solution was extracted with ethyl acetate (20 mLx3), the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). 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 were obtained as a yellow oil.

[0934] Step 5

[0935]

[0936] In a 50-mL round-bottom flask were placed 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) in N,N-dimethylformamide (5 mL), (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) [as described by Qian, Y. et al. in WO 2017 / 030814], potassium carbonate (100 mg, 0.4 mmol, 2.00 equivalents). The resulting solution was stirred at 70 ° C for 12 hours. The resulting solution was extracted with ethyl acetate (20 mLx3), the organic layer was combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10: 1). 90 mg of (2S, 4R) -1- [2- [3- (2- [2- [2- (4- [3-amino-6- [2- (methoxymethoxy) phenyl] pyridazine-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 was obtained as a colorless oil.

[0937] Step 6

[0938]

[0939] 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 isopropanol (2 mL) and tetrahydrofuran (2 mL), followed by the addition of concentrated hydrogen chloride solution (12N, 2 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: Column: XBridge C18 OBD preparative column, 5 μm, 19 mm x 250 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 32% B to 41% B over 8 minutes; 254 nm; Rt: 70 min. 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 was obtained as a white solid.

[0940] The product was purified by chiral-preparative HPLC under the following conditions: chromatographic column, CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase, Hex-HPLC and ethanol-HPLC (maintained at 50% ethanol-HPLC within 24 minutes); detector, UV 220 / 254 nm. 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 was obtained as a white solid. 1H 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, 4.7 Hz, 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 as a white solid. -[(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[ 1 HNMR (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),7.45-7.30(m,4H),7.25-7.22(m,1H),6.96-6.84(m,2H),5.88(s,1H),4.7 0-4.42(m,3H),4.41-4.33(m,3H),4.28-4.17(m,2H),3.87(t,J=5.0Hz,3H),3.85-3.63(m ,2H),3.59-3.57(m,6H),2.41(d,J=12.2Hz,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=6.6,1.8Hz,3H),0.80(dd,J=6.6,1.8Hz,3H)].

[0941] Exemplary Compounds 16, 17, 18, and 19 were prepared using the methods described above for Exemplary Compound 14 and Exemplary Compound 15.

[0942] Exemplary Synthesis of Exemplary Compound 22

[0943] Step 1

[0944]

[0945] In a 250-mL round-bottom flask was placed (Z)-4-(benzyloxy)-N-hydroxybutanecarboimidoyl chloride (8.7 g, 38.21 mmol, 1.00 equivalent), but-3-yn-1-ol (3.3 g, 47.08 mmol, 1.23 equivalent), ethyl acetate (70 mL), water (70 mL), sodium bicarbonate (4.0 g, 47.61 mmol, 1.25 equivalent). The resulting solution was stirred at 25 ° C for 2 hours. The resulting solution was extracted with ethyl acetate and washed with saturated sodium chloride aqueous solution. The mixture was dehydrated over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1: 1). 5.9 g (59%) of 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]ethan-1-ol was obtained as a yellow oil.

[0946] Step 2

[0947]

[0948] In a 100-mL round-bottom flask was placed 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]ethan-1-ol (550.0 mg, 2.10 mmol, 1.00 equivalent), acetone (30 mL), Cr2O3 (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 sodium chloride aqueous solution. The mixture was dehydrated over anhydrous sodium sulfate and concentrated under vacuum. 420 mg (72%) of 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetic acid was obtained as a yellow oil.

[0949] Step 3

[0950]

[0951] In a 250-mL round-bottom flask, 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) were placed. The resulting solution was stirred at 70°C for 1.5 hours. 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, increasing acetonitrile:water = 0:100 to acetonitrile:water = 60:40 over 49 minutes; detector, UV 220 nm. 4.5 g (56%) of ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetate was obtained as a light yellow oil.

[0952] Step 4

[0953]

[0954] In a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 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) were placed. A solution of t-BuOK (2.0 g, 17.82 mmol, 1.20 equiv) in tetrahydrofuran (17.8 mL) was then added dropwise over 20 minutes at 0°C with stirring. 2-iodopropane (3.01 g, 17.71 mmol, 1.19 equiv) was then added dropwise over 2 minutes at 0°C with stirring. 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 and washed with a saturated aqueous sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. 4.3 g (84%) of ethyl 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]-3-methylbutanoate were obtained as an orange oil.

[0955] Step 5

[0956]

[0957] In a 250-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]-3-methylbutanoic acid ethyl ester (4.2 g, 12.16 mmol, 1.00 equivalent) and dichloromethane (100 mL) were placed. Then, over 30 minutes, at -78°C, a solution of BBr (5.17 g, 20.64 mmol, 1.70 equivalent) in dichloromethane (20.7 mL) was added dropwise while stirring. 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 a saturated sodium chloride solution. The mixture was dehydrated 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, increasing from acetonitrile:water = 0:100 to acetonitrile:water = 23:76 over 25 minutes; detector, UV 220 nm. 2.6 g (84%) of ethyl 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoate was obtained as an orange oil.

[0958] Step 6

[0959]

[0960] In a 100-mL round-bottom flask was placed ethyl 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoate (1.2 g, 4.70 mmol, 1.00 equivalent), ethanol (20 mL), water (10 mL), sodium hydroxide (1.9 g, 47.50 mmol, 10.0 equivalent). The resulting solution was stirred at room temperature for 1 night. The pH value 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 dehydrated over anhydrous sodium sulfate and concentrated under vacuum. 800 mg (75%) of 2-[3-(3-hydroxypropyl)-1,2-oxazol-5-yl]-3-methylbutanoic acid was obtained as a yellow oil.

[0961] Step 7

[0962]

[0963] 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-isobutylpropan-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 in vacuo. 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 were obtained as a yellow solid.

[0964] Step 8

[0965]

[0966] In a 50-mL round-bottom flask was placed (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 under vacuum. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10: 1). The collected fractions were combined and concentrated in vacuo. 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-oxobutane-2-yl]-1,2-oxazol-3-yl)propyl 4-methylbenzene-1-sulfonate were obtained as a yellow solid.

[0967] Step 9

[0968]

[0969] 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 by 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) after 20 minutes. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over sodium sulfate and 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.

[0970] Step 10

[0971]

[0972] A 50-mL round-bottom flask was charged with (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), and 4-dimethylaminopyridine (6 mg, 0.05 mmol, 0.20 equiv). The resulting solution was stirred at room temperature for 5 hours. The resulting solution was extracted with dichloromethane. 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 in vacuo. 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-oxobutane-2-yl]-1,2-oxazol-3-yl)propoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate were obtained as a yellow oil.

[0973] Step 11

[0974]

[0975] 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 dehydrated over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane / methanol (10: 1). The collected fractions were combined and concentrated under vacuum. 30 mg (37%) of (2S, 4R) -1- [2- [3- (3- [2- [2- (4- [3-amino-6- [2- (methoxymethoxy) phenyl] pyridazine-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 were obtained as a yellow oil.

[0976] Step 12

[0977]

[0978] 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 (aqueous solution) (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: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (0.05% NH₃H₂O), mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 34% B to 47% B over 8 minutes; HPLC 220 nm. This yielded 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.

[0979] 1 H-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).

[0980] Exemplary Syntheses of Exemplary Compound 23 and Exemplary Compound 24

[0981]

[0982] In a 25-mL round-bottom flask was placed (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 under the following conditions: column, CHIRALPAK ID-3; mobile phase, MtBE (0.1% DEA): EtOH = 80:20, size: 0.46*10 cm; 3 μm; detector, UV-254 nm. 17 mg (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 was obtained as an off-white solid. 1H NMR (300MHz, CD3OD, ppm): δ8.83(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),3.40-3.34(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[ 1 H NMR (300MHz, CD3OD, ppm): δ8.88(s,1H),8.37(s,1H),8.31(s,1H),8.04(s,1H),7.69-7.67(d,J=8.1Hz,ppm),7.4 3-7.39(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),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=6.6Hz,3H),0.85-0.82(d,J=6.9Hz,3H)].

[0983] Exemplary compounds 25 and 26 were prepared using methods similar to those described above for exemplary compounds 22, 23, and 24.

[0984] Exemplary Synthesis of Exemplary Compound 27

[0985] Step 1

[0986]

[0987] 2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol (257 mg, 1.71 mmol, 3.00 equivalents) and N,N-dimethylformamide (5 mL) were placed in a 50-mL round-bottom flask. Then, over 10 minutes, at 0°C, sodium hydride (34 mg, 1.42 mmol, 1.50 equivalents) was added. 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol, 1.00 equivalents) was added thereto. 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 using ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. This gave 90 mg (52%) of 2-(2-[2-[(4-bromopyridin-2-yl)oxy]ethoxy]ethoxy)ethan-1-ol as a light yellow liquid.

[0988] Step 2

[0989]

[0990] In a 50 mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 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, 1.00 equiv), Cs2CO3 (1599 mg, 4.91 mmol, 3.00 equiv), toluene (8 mL), Ruphos (69 mg, 0.05 equiv) were placed. 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 to a silica gel column eluted with dichloromethane / methanol (10:1). The collected fractions were combined and concentrated in vacuo. 419 mg (59%) of 8-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was obtained as a yellow oil.

[0991] Step 3

[0992]

[0993] In a 50 mL round-bottom flask was placed 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. 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 was obtained as a yellow oil.

[0994] Step 4

[0995]

[0996] In a 10 mL microwave tube was placed 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 in vacuo. 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]oxy)ethoxy]ethoxy]ethan-1-ol were obtained as a yellow solid.

[0997] Step 5

[0998]

[0999] In a 10 mL microwave tube purged and maintained with a nitrogen inert atmosphere were placed 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), Pd(PPh 3 ) 4 (70 mg, 0.06 mmol, 0.10 equiv). The resulting solution was stirred at 100° C. overnight. The reaction was then quenched by adding 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 in vacuo. 221 mg (61%) of 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazine-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethane-1-ol were obtained as a yellow solid.

[1000] Step 6

[1001]

[1002] In a 50 mL round-bottom flask was placed 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), and 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.10 equiv). 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 in vacuo. 97 mg (76%) of 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazine-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate were obtained as a yellow solid.

[1003] Step 7

[1004]

[1005] In a 50 mL round-bottom flask were placed 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 The product was purified by HPLC-MS / MS (HPLC-MS / MS) and HPLC-MS / MS (HPLC-MS / MS) to obtain 4-[(2-[(2-(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). 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 in vacuo. 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 were obtained as a yellow solid.

[1006] Step 8

[1007]

[1008] In a 50 mL round-bottom flask was placed (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 a 1 M methanolic solution of HCl (1.5 mL). The resulting solution was stirred at room temperature for 7 hours. The resulting solution was diluted with 5 mL of H2O. The pH of the solution was adjusted to 7 with aqueous Na2CO3 (2 M). 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: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase: water (0.05% NH₃H₂O) and acetonitrile (39.0% acetonitrile to 50.0% over 9 minutes); detector: UV 220 nm. 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 were obtained as a yellow solid and further purified by chiral-preparative HPLC under the following conditions: chromatographic column, Chiralpak ID-2, 2*25 cm, 5 um; mobile phase (0.1% DEA) and ethanol (maintained at 30% ethanol within 30 minutes); detector, UV 254 / 220 nm. 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 was obtained as a white solid. 1H 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-[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 [ 1 HNMR (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),3.8 8-3.81(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=6.4Hz,3H),0.88-0.86(d,J=6.4Hz,3H)].

[1009] Exemplary compounds 29 and 30 were prepared using methods similar to those described for exemplary compounds 27 and 28.

[1010] Exemplary Synthesis of Exemplary Compound 31

[1011] Step 1

[1012]

[1013] In a 50mL round-bottom flask, 2-(oxan-2-yloxy)ethane-1-ol (4.5g, 30.78mmol, 1.00 equivalent), tetrahydrofuran (10mL), and a solution of t-BuOK (3.6g, 32.08mmol, 2.00 equivalent) in tetrahydrofuran (60mL) were placed. Then, at 0°C, 3-bromoprop-1-yne (2.61mL, 1.00 equivalent) was added dropwise while stirring. 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. 2.8 g (49%) of 2-[2-(prop-2-yn-1-yloxy)ethoxy]oxane were obtained as a yellow oil.

[1014] Step 2

[1015]

[1016] 2-[2-(prop-2-yn-1-yloxy)ethoxy]oxane (2.8g, 15.20mmol, 1.00 equivalent), ZrCpHCl (390mg, 0.10 equivalent), triethylamine (153mg, 1.52mmol, 0.10 equivalent), pinacol borane (2.5mL) were placed in a 10-mL microwave tube purged and maintained with a nitrogen inert atmosphere. The resulting solution was stirred overnight in an oil bath at 68°C. The reaction was then quenched by adding NH4Cl. The reaction mixture was cooled to 0°C with 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.

[1017] Step 3

[1018]

[1019] In a 10-mL microwave tube purged and maintained with a nitrogen inert atmosphere were placed 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 in an oil bath at 100°C overnight. 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 in vacuo. 639mg (42%) of 8- [2- [(1E) -3- [2- (oxane -2- yloxy) ethoxy] prop-1-ene-1-yl] pyridin-4-yl] -3,8- diazabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl ester was obtained as a yellow oil.

[1020] Step 4

[1021]

[1022] In a 50-mL round-bottom flask was placed 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-carboxylic acid tert-butyl ester (639 mg, 1.35 mmol, 1.00 equivalent), palladium on carbon (200 mg) and methanol (15 mL), and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The solid was filtered off and the filtrate was concentrated. 639 mg (100%) of 8-(2-[3-[2-(oxan-2-yloxy)ethoxy]propyl]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was obtained as a yellow oil.

[1023] Step 5

[1024]

[1025] In a 50-mL round-bottom flask was placed 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 into the solution. The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated in vacuo. 387 mg (100%) of 2-[3-(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethan-1-ol was obtained as a yellow oil.

[1026] Step 6

[1027]

[1028] In a 10-mL microwave tube was placed 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), 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 in vacuo. The residue was applied to a silica gel column using dichloromethane / methanol (7:3). The collected fractions were combined and concentrated in vacuo. 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 were obtained as a yellow oil.

[1029] Step 7

[1030]

[1031] In a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 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 3 ) 4 (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 using methanol / HO (85:15). The collected fractions were combined and concentrated in vacuo to afford 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.

[1032] Step 8

[1033]

[1034] In a 50-mL round-bottom flask was placed 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 in vacuo. 330 mg (64%) of 2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazine-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-yl)pyridin-2-yl]propoxy]ethyl 4-methylbenzene-1-sulfonate were obtained as a yellow solid.

[1035] Step 9

[1036]

[1037] In a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, 2-(6-chloropyridin-3-yl)methyl acetate (500 mg, 2.69 mmol, 1.00 equivalent), tert-butyl piperazine-1-carboxylate (502 mg, 2.70 mmol, 1.00 equivalent), Cs2CO3 (2.63 g, 8.07 mmol, 3.00 equivalent), toluene (10 mL), RuPhosPd (115 mg, 0.05 equivalent) were placed. The resulting solution was stirred overnight in an oil bath at 100°C. 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.

[1038] Step 10

[1039]

[1040] In a 50-mL round-bottom flask, 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) were placed. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. 223 mg (100%) of methyl 2-[6-(piperazin-1-yl)pyridin-3-yl]acetate was obtained as a yellow oil.

[1041] Step 11

[1042]

[1043] In a 50-mL round-bottom flask were placed 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, 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 in vacuo. 94 mg (30%) of 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-yl)pyridin-2-yl]propoxy]ethyl)piperazine-1-yl]pyridin-3-yl]methyl acetate were obtained as a yellow solid.

[1044] Step 12

[1045]

[1046] In a 50-mL round-bottom flask was placed 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 under vacuum. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with dichloromethane, and the aqueous layers were combined and concentrated under vacuum. The residue was dissolved in 10 mL of methanol. The solid was filtered off. The resulting mixture was concentrated under vacuum. This gives 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.

[1047] 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 converted to 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.

[1048]

[1049] Exemplary compound 50 was prepared using the method described for exemplary compound 31.

[1050] Exemplary Synthesis of Exemplary Compound 32

[1051] Step 1

[1052]

[1053] In a 250-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethan-1-ol (10.0 g, 66.59 mmol, 1.00 equivalent) in dichloromethane (100 mL), (diethyloxy)trifluoroborate (1.9 g, 13.33 mmol, 0.20 equivalent) and ethyl 2-diazoacetate (3.8 g, 0.50 equivalent) were placed. 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 using ethyl acetate / petroleum ether (1: 1). The collected fractions were combined and concentrated in vacuo. 3.6 g (23%) of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl acetate were obtained as a yellow oil.

[1054] Step 2

[1055]

[1056] In a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl acetate (1.0 g, 4.23 mmol, 1.00 equivalent) in dichloromethane (20 mL), 4-methylbenzene-1-sulfonyl chloride (970 mg, 5.09 mmol, 1.20 equivalents), and triethylamine (860.0 mg, 8.50 mmol, 2.00 equivalents) were placed. 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 using ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo. 1.1 g (65%) of ethyl 2-[2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]ethoxy]acetate were obtained as a yellow oil.

[1057] Step 3

[1058]

[1059] In a 50-mL round-bottom flask purged and maintained with a nitrogen inert atmosphere, a solution of ethyl 2-[2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy] ... This gave 800 mg (96%) of ethyl 1-(6-bromopyridin-2-yl)-1,4,7,10-tetraoxadodec-12-oate as a yellow solid.

[1060] According to the following scheme and using methods similar to those described above for other examples, ethyl 1-(6-bromopyridin-2-yl)-1,4,7,10-tetraoxadodec-12-ate 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[2.2.1]heptan-2-yl]pyridin-2-yl]-1,4,7,10-tetraoxadodec-12-amido)-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide.

[1061]

[1062] Exemplary Synthesis of Exemplary Compound 33

[1063] Step 1

[1064]

[1065] In a 250-mL round-bottom flask, 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) were placed. The resulting solution was stirred at 90°C for 3 hours. The resulting mixture was concentrated in vacuo to yield 5.4 g (68%) of 1-bromo-4-(1-bromoethyl)benzene as a yellow oil.

[1066] Step 2

[1067]

[1068] In a 100-mL round-bottom flask was placed 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazine-3-amine (300 mg, 1.0 mmol, 1.0 equivalent), N,N-dimethylformamide (5.0 mL), 1-bromo-4-(1-bromoethyl)benzene (400.0 mg, 1.5 mmol, 1.5 equivalents), potassium carbonate (414 mg, 3.0 mmol, 3.0 equivalents). 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 x 3), the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (1:10). 300 mg (62%) of 4-[1-[1-(4-bromophenyl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine were obtained as a brown solid.

[1069] Step 3

[1070]

[1071] In a 250-mL round-bottom flask, propan-2-yn-1-ol (10g, 178.4mmol, 1.0 equivalent), tetrahydrofuran (100.0mL), sodium hydride (6.4g, 266.7mmol, 0.9 equivalent) and tert-butyl 2-bromoacetate (28g, 143.6mmol, 0.8 equivalent) were placed. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 20mL of aqueous ammonium chloride solution. The resulting mixture was concentrated in vacuo. The resulting solution was extracted with ethyl acetate (30mLx3), the organic layers were combined and concentrated in vacuo. 24.0g (90%) of tert-butyl 2-(propan-2-yn-1-yloxy) acetate was obtained as a yellow solid.

[1072] Step 4

[1073]

[1074] In a 250-mL round-bottom flask was placed tert-butyl 2-(prop-2-yn-1-yloxy)acetate (6.6 g, 38.8 mmol, 1.0 equivalent), triethylamine (400.0 mg, 3.9 mmol, 0.1 equivalent), pinacol borane (20.0 mL), ZrCp2HCl (1 g, 0.1 equivalent). The resulting solution was stirred at 60 ° C for 12 minutes. The reaction was then quenched by adding 10 mL of ice / . The resulting solution was extracted with ethyl acetate (30 mLx3) and the organic layer was combined. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1: 5). 5.0 g (43%) of 2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolane-2-yl)prop-2-ene-1-yl]oxy] tert-butyl acetate was obtained as a yellow oil.

[1075] Step 5

[1076]

[1077] In a 10-mL sealed tube was placed 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 H2O (1.0 mL). The resulting solution was stirred at 90°C for 5 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). This gave 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.

[1078] Step 6

[1079]

[1080] In a 100-mL round-bottom flask were placed 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 at room temperature under a hydrogen atmosphere for 1 hour. The solid was filtered off. The resulting mixture was concentrated in vacuo. 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 was obtained as a yellow solid.

[1081] Step 7

[1082]

[1083] In a 100-mL round-bottom flask was placed 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.

[1084] Step 8

[1085]

[1086] 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 hour. The reaction was then quenched by the addition of 0.5 mL of water. The solid was filtered off. The crude product (5 mL) was purified by preparative HPLC using the following conditions: XBridge Prep C18 OBD column, 150 mm 5 μm; mobile phase: water (10 mmol / L ammonium bicarbonate) and ACN (45.0% ACN to 52.0% over 7 minutes); detector: UV 254 / 220 nm. This yielded 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.

[1087] 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).

[1088] Exemplary Synthesis of Exemplary Compound 34

[1089] Exemplary compound 34 was prepared according to the following scheme using the methods described above for other examples and methods known and understood by those skilled in the art.

[1090]

[1091] Exemplary Syntheses of Exemplary Compound 36 and Exemplary Compound 37

[1092] Exemplary compounds 36 and 37 were prepared according to the following schemes using the methods described above for other examples and methods known and understood by those skilled in the art.

[1093]

[1094]

[1095] Exemplary Syntheses of Exemplary Compound 38 and Exemplary Compound 39

[1096] Step 1

[1097]

[1098] 2-(piperazine-1-yl) ethane-1-ol (26.0 g, 199.7 mmol, 1.0 equivalent), dichloromethane (200.0 mL), triethylamine (40.4 g, 399.3 mmol, 2.0 equivalent), benzyl chloroformate (40.8 g, 239.2 mmol, 1.2 equivalent) were placed in a 500-mL round-bottom flask. The resulting solution was stirred at 0 ° C for 2 h. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with dichloromethane (100 mL x3), the organic layer was combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10: 1). 22 g (42%) of 4-(2-hydroxyethyl)piperazine-1-carboxylic acid benzyl ester was obtained as a yellow oil.

[1099] Step 2

[1100]

[1101] 4-(2-hydroxyethyl)piperazine-1-carboxylic acid benzyl ester (5.3g, 20.1mmol, 1.0 equivalent) and N, N-dimethylformamide (30.0mL) were placed in a 100-mL round-bottom flask. Sodium hydride (1.6g, 66.7mmol, 1.2 equivalents) was then added within 5 minutes. 4-bromo-2-fluoropyridine (3.9g, 22.2mmol, 1.1 equivalents) was added thereto within 20 minutes. The resulting solution was stirred at 0°C for 4 hours. The reaction was then quenched by adding 10mL of ammonium chloride aqueous solution. The resulting solution was extracted with ethyl acetate (50mLx3), the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1). 5.2g (62%) of 4-[2-[(4-bromopyridin-2-yl)oxy]ethyl]piperazine-1-carboxylic acid benzyl ester was obtained as a yellow oil.

[1102] Step 3

[1103]

[1104] In the 250-mL round-bottom flask purged and maintained with nitrogen inert atmosphere, 4-[2-[(4-bromopyridine-2-yl) oxygen base] ethyl] piperazine-1-carboxylic acid benzyl ester (2.1g, 5.0mmol, 1.0 equivalent), RuphosPd II (775.0mg, 1.0mmol, 0.2 equivalent) and Cs solution of (4.89g, 15.0mmol, 3.0 equivalent) in PhMe (100mL) are placed.Gained mixture is stirred in oil bath at 100 ℃ and spend the night.Reaction mixture is quenched with water (100mL), and extracted with ethyl acetate (100mLx2).Organic layer is merged and concentrated under reduced pressure, and residue is applied to the silica gel column using 100% ethyl acetate wash-out. This gave 670 mg (32%) of tert-butyl 8-[2-(2-[4-[(benzyloxy)carbonyl]piperazin-1-yl]ethoxy)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow solid.

[1105] Step 4

[1106]

[1107] A 100-mL round-bottom flask was charged with a solution of 8-[2-(2-[4-[(benzyloxy)carbonyl]piperazine-1-yl]ethoxy)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (670 mg, 1.2 mmol, 1.0 equivalent) in methanol (10.0 mL). A solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL) was then added. The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated in vacuo. 410 mg (69%) of 4-[2-[(4-[3,8-diazabicyclo[3.2.1]octane-8-yl]pyridin-2-yl)oxy]ethyl]piperazine-1-carboxylic acid benzyl ester hydrochloride was obtained as a yellow solid.

[1108] Step 5

[1109]

[1110] In a 10-mL sealed tube was placed 4-[2-[(4-[3,8-diazabicyclo[3.2.1]octane-8-yl]pyridin-2-yl)oxy]ethyl]piperazine-1-carboxylic acid benzyl ester hydrochloride (200.0 mg, 0.4 mmol, 1.0 equivalent), 4-bromo-6-chloropyridazine-3-amine (137.0 mg, 0.7 mmol, 1.5 equivalents), methyl sulfoxide (3.0 mL) and N,N-diisopropylethylamine (1 mL). The final reaction mixture was irradiated with microwave radiation at 130 ° C for 6 hours. The reaction was then quenched by adding 1 mL of water. The resulting solution was extracted with ethyl acetate (20 mLx3), the organic layer was combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10: 1). This gave 100 mg (42%) of benzyl 4-[2-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)ethyl]piperazine-1-carboxylate as a brown solid.

[1111] Step 6

[1112]

[1113] A 100-mL round-bottom flask was charged with benzyl 4-[2-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)ethyl]piperazine-1-carboxylate (390 mg, 0.7 mmol, 1.0 equiv), dioxane (8.0 mL), water (2.0 mL), potassium carbonate (279 mg, 2.0 mmol, 3.0 equiv), [2-(methoxymethoxy)phenyl]boronic acid (184.0 mg, 1.0 mmol, 1.50 equiv), and Pd(PPh3)4 (78 mg, 0.07 mmol, 0.1 equiv). The resulting solution was stirred at 100°C for 2 hours. The resulting solution was extracted with ethyl acetate (20 mL x 3), and the organic layers were combined and concentrated in vacuo. The residue was applied to a silica gel column eluted with dichloromethane / methanol (10:1), yielding 120 mg (26%) of benzyl 4-(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]ethyl)piperazine-1-carboxylate as a brown solid.

[1114] Step 7

[1115]

[1116] Under a nitrogen atmosphere, in a 100-mL round-bottom flask, to a solution of benzyl 4-(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]ethyl)piperazine-1-carboxylate (200 mg, 0.29 mmol, 1.00 equiv) in 10 mL of isopropanol was added palladium hydroxide (100 mg, 0.71 mmol, 2.42 equiv). The flask was then evacuated and flushed with hydrogen. The resulting solution was stirred at room temperature for 12 hours. The solid was filtered off. The resulting mixture was concentrated in vacuo. 70 mg (44%) of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[2-(piperazin-1-yl)ethoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine were obtained as a brown oil.

[1117] Step 8

[1118]

[1119] In a 100-mL round-bottom flask, 4-(tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.9 g, 10.0 mmol, 1.00 e...

Claims

1. A bifunctional compound having the following chemical structure: PTM-L-ULM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof, in: The ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to the Hippel-Lindau E3 ubiquitin ligase; The L is a bond or chemical linking moiety connecting the ULM and the PTM; and 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: in: W PTM1 is a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2 or 3 substituents selected from hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano or a combination thereof; W PTM2 is a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2 or 3 substituents selected from hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano or a combination thereof; W PTM3 a 5-6 membered aryl or heteroaryl ring which is absent or optionally substituted with 0, 1, 2 or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano or a combination thereof; a 4-9 membered cycloalkyl or heterocyclyl group which is 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 group which is optionally substituted with 0, 1 or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano or a combination thereof; W PTM4 is a 5-7 membered cycloalkyl or heterocyclic group optionally substituted with 0, 1, 2 or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano or a combination thereof; W PTM5 a 5-6 membered aryl or heteroaryl ring which is absent or optionally substituted with 0, 1 or 2 substituents selected from hydroxy, halo, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano or a combination thereof; W PTM6 and W PTM7 is independently a 4-7 cycloalkyl or heterocyclyl group optionally substituted with 0, 1 or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano or a combination thereof, wherein W PTM6 and W PTM7 The rings of are fused or connected via a spiro ring connection; and is the point of attachment to the linker or ULM group.

2. The compound according to claim 1, wherein the PTM is represented by formula I: 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 5-6 membered heteroaryl, an optionally substituted 4-9 membered cycloalkyl or heterocyclyl ring, or an optionally substituted bridged bicycloalkyl or bridged biheterocyclyl ring; W PTM5 does not exist (therefore W PTM3 Directly attached to L (linker) or ULM) or to an optionally substituted 5-6 membered aryl or heteroaryl ring.

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

4. The compound according to claim 3, wherein the PTM is represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: W PTM5 is phenyl, pyridine, pyrimidine or pyrazine.

5. The compound according to claim 1, wherein the PTM is represented by the following formula: or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the PTM is represented by Formula III: 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, halo, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano or a combination thereof; W PTM2 is a pyridazine substituted with an amino group; and W PTM6 and W PTM7 is a spirocyclic ring system having a structure selected from the group consisting of:

7. The compound of claim 1, wherein the PTM is represented by Formula IVa or IVb: 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, halo, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano or a combination thereof; W PTM2 is a pyridazine substituted with an amino group; and W PTM5 Not present, is a pyrazole ring or a pyridine ring.

8. The compound according to any one of claims 1 to 7, wherein the PTM is selected from:

9. The compound according to any one of claims 1 to 7, wherein ULM is a chemical structure represented by: in: W 3 is selected from optionally substituted aryl, optionally substituted heteroaryl or R9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl, or R9, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl group; R 11 is selected from optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, R 12 is selected from H or optionally substituted alkyl; R 13 is selected from 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 selected from H, amine, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 one is H; or R 14a 、R 14b together with the carbon atom 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 Selected from H, halogen, CN, OH, NO2, NR 27a R 27b , OR 27a 、CONR 27a R 27b NR 27a COR 27b 、SO2NR 27a R 27b NR 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 16 independently selected from halogen, 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 H, halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; Each R 26 are independently selected from H, optionally substituted alkyl or NR 27a R 27b ; 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, they form a 4-6 membered heterocyclic group; and 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 that couples at least one PTM or ULM', or both, to the ULM.

10. The compound of claim 9, wherein the ULM has a chemical structure selected from the group consisting of: in: R1 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 is selected from H, halogen, CN, OH, NO2, 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, CH2 or C=O; R3 is absent or is optionally substituted 5- or 6-membered heteroaryl; and Dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that couples at least one PTM or ULM', or both, to the ULM.

11. The compound of claim 10, wherein the ULM has the formula: or a pharmaceutically acceptable salt thereof, wherein: R1 is H, optionally substituted alkyl or optionally substituted cycloalkyl; R3 is an optionally substituted 5-6 membered heteroaryl; W 5 is optionally substituted phenyl, optionally substituted naphthyl or optionally substituted pyridyl; R 14a and R 14b wherein one of the following is H, optionally substituted alkyl, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 one is H; or R 14a 、R 14b together with the carbon atom 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 is CN, fluoroalkyl, or optionally substituted (For example where R 28a is halogen, optionally substituted alkyl or fluoroalkyl); Each R 16 independently selected from halogen, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy; Each R 26 are independently H, optionally substituted alkyl or NR 27a R 27b ; 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, they form a 4-6 membered heterocyclic group; 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; and o is 0, 1, or 2.

12. The compound of claim 11, wherein the ULM has the formula: in: X 4 、X 5 and X 6 are each selected from CH and N, not more than two of which are N; R 1 is a C1-6 alkyl group; R 14a and R 14b wherein one of the following is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, 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 one is H; or R 14a and R 14b together with the carbon atom 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 27a and R 27b are each independently H or C 1-6 alkyl; q is 1, 2, 3, or 4; R 15 yes or CN; R 28 It is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, R 28C is H, methyl, fluoro or chloro; and R 16 It is H, C 1-4 Alkyl, fluorine, chlorine, CN or C 1-4 Alkoxy.

13. The compound according to claim 12, wherein R 14a and R 14b Selected from: H, C 1-4 Alkyl, C 1-4 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxyalkyl, C 1-4 Alkyl-NR 27a R 27b and CONR 27a R 27b .

14. The compound according to claim 12 or 13, wherein R 14a and R 14b Together with the carbon atoms to which they are attached, they form where R 23 Selected from H, C 1-4 Alkyl, -C(O)C 1-4 alkyl.

15. The compound of claim 12, wherein the ULM has the formula: or a pharmaceutically acceptable salt thereof, wherein X is CH or N.

16. The compound according to claim 12 or 15, or a pharmaceutically acceptable salt thereof, wherein R1 is C 1-6 alkyl.

17. The compound according to any one of claims 12, 15 or 16, or a pharmaceutically acceptable salt thereof, wherein: R 14a and R 14b One of them is H, C 1-6 Alkyl, C 1-6 Haloalkyl, optionally substituted C 1-4 Alkylamine, C 1-6 Alkoxy, (CH2) q C 1-6 Alkoxy, (CH2) q C 1-6 Alkoxy-C 3-7 Heterocycloalkyl, (CH2) q OH, (CH2) q NR 27a R 27b 、(CH2) q NHCOC 1-6 Alkyl, C 3-6 Cycloalkyl or NR 27a R 27b ; R 26 Each independently is H, C 1-6 Alkyl or NR 27a R 27b ; R 27a and R 27b are each independently H or C 1-6 alkyl; and And q is 1, 2, 3 or 4.

18. The compound according to any one of claims 12, 15 or 16, or a pharmaceutically acceptable salt thereof, wherein: R 14a and R 14b One of them is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, optionally substituted C 1-4 Alkylamine, (CH2) q C 1-6 Alkoxy, (CH2) q C 1-6 Alkoxy-C 3-7 Heterocycloalkyl, (CH2) q OH, (CH2) q NR 27a R 27b 、(CH2) q NHCOC 1-6 Alkyl or C 3-6 Cycloalkyl or NR 27a R 27b ; R 26 Each independently is H, C 1-4 Alkyl or NR 27a R 27b ; R 27a and R 27b are each independently H or C 1-4 alkyl; and q is 1 or 2.

19. The compound according to any one of claims 12, 15 or 16, or a pharmaceutically acceptable salt thereof, wherein: R 28 It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, (CH2) q OC 1-6 Alkyl, (CH2) q OH, (CH2) q NR 27a R 27b 、(CH2) q NHCOC 1-6 Alkyl or R 29 It is H, C 1-6 Alkyl, NR 27a R 27b or q NHCOC 1-6 alkyl; and where q is 1 or 2.

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

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

22. The compound of any one of claims 20 or 21, wherein the ULM has the formula: or a pharmaceutically acceptable salt thereof: in: X is CH or N; R 30 is H, F or Cl; R 16 It is H, C 1-4 Alkyl, fluorine, chlorine, CN or C 1-4 alkoxy; and R 28 It is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, 23. The compound of claim 22, wherein the ULM has the formula: or a pharmaceutically acceptable salt thereof, wherein R 30 It is H, F or Cl.

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 compound according to any one of claims 1, 12, 15 or 23, wherein the linker (L) comprises a chemical structural unit represented by the following formula: -(A L ) q -， in: (A L ) q is a group attached to at least one of the ULM, PTM, or both; q is an integer greater than or equal to 1; Each A L are independently selected from a bond, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , 0-6 R's can be selected L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted with 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 0-6 R L1 and / or R L2 The aryl group is optionally substituted with 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently is optionally linked to other groups to form an optionally 0-4 R L5 substituted cycloalkyl and / or heterocyclyl moieties; and R L1 、R L2 、R L3 、R L4 and R L5 are independently H, halogen, 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 Heterocyclic group, 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 1-8 alkyl)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, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

26. The compound of claim 1, wherein L is a moiety for covalently coupling the PTM to the ULM.

27. The compound according to any one of claims 1 or 26, wherein the linker (L) comprises the following chemical structure: in: W L1 and W L2 Each is independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted by RQ, each RQ is independently H, halogen, OH, CN, CF3, C1-C6 alkyl (straight chain, branched, optionally substituted), C1-C6 alkoxy (straight chain, branched, optionally substituted), 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 each independently a bond, C1-C6 alkyl (straight chain, branched chain, optionally substituted) and optionally one or more C atoms are replaced by O; or C1-C6 alkoxy (straight chain, branched chain, optionally substituted); n is 0-10; and Dashed lines indicate points of attachment to the PTM or ULM moiety.

28. The compound according to any one of claims 1 or 26, wherein the linker (L) comprises the following chemical structure: in: W L1 and W L2 Each is independently an aryl, heteroaryl, cyclic, heterocyclic, C 1-6 Alkyl, bicyclic, biaryl, biheteroaryl or biheterocyclic, each optionally substituted by R Q Replace, each R Q are independently H, halogen, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-C6 alkyl (straight chain, branched chain, optionally substituted), C1-C6 alkoxy (straight chain, branched chain, optionally substituted), OC 1-3 Alkyl (optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , CN, or 2 R Q The 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 is a bond, NR YL1 , O, S, NR YL2 , CR YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (straight chain, branched chain, optionally substituted), and optionally one or more C atoms are replaced by O; C1-C6 alkoxy (straight chain, branched chain, optionally substituted); Q L is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally surrounded by 0-6 R Q Replace, each R Q Independently H, C 1-6 Alkyl (straight chain, branched, optionally substituted with one or more halogen, C 1-6 alkoxy substituted), or 2 R Q The 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 are independently H, OH, C 1-6 Alkyl (straight chain, branched, optionally substituted with one or more halogen, C 1-6 alkoxy substituted), or R 1 、R 2 Together with the atoms to which they are attached, they form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0-10; and Dashed lines indicate points of attachment to the PTM or ULM moiety.

29. The compound according to any one of claims 1 or 26, wherein the linker (L) comprises a group represented by a structure selected from the group consisting of: -O-(CH2)mO(CH2)nO(CH2)oO(CH2)pO(CH2)qO(CH2)rO(CH2)sO(CH2)t-, -O-(CH2)mO(CH2)nO(CH2)oO(CH2)pO(CH2)qO(CH2)rO(CH2)sO-, -(CH2)mO(CH2)nO(CH2)oO(CH2)pO(CH2)qO(CH2)rO(CH2)sO(CH2)t-, -CH=CH(CH2)mO(CH2)nO(CH2)oO(CH2)pO(CH2)qO(CH2)rO(CH2)sO(CH2)t- —O(CH2) n NCH3C(=O)(CH2) m —; wherein m, n, o, p, q, r, s and t are each independently selected from the integers 0, 1, 2, 3 and 4.

30. The compound according to any one of claims 1 or 26, wherein L is selected from:

31. The compound of claim 1, wherein i) W PTM4 With W PTM2 Thick or ii)W PTM3 With W PTM2 Thick.

32. The compound according to claim 2, wherein W PTM3 is an optionally substituted pyrazole, pyrrole, imidazole, oxazole, oxadiazole or triazole.

33. The compound according to claim 3, wherein W PTM5 is optionally substituted pyridine, pyrimidine or pyrazine.

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

35. The compound according to claim 34, wherein D of the compound max Greater than or equal to 80%.

36. A composition comprising an effective amount of the bifunctional compound according to any one of claims 1 or 26, and a pharmaceutically acceptable carrier.

37. The composition of claim 36, wherein the composition further comprises at least one of an additional bioactive agent or another compound of claim 1.

38. The composition of claim 37, wherein the additional bioactive agent is an anti-cancer agent.

39. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to claim 1 for treating a disease or condition 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 condition.

40. The composition of claim 39, wherein the disease or disorder is associated with accumulation and aggregation of SMARCA1, BRAHMA, or BRM.

41. The composition of claim 40, wherein the disease or disorder is cancer.

42. The composition of claim 41, wherein the cancer is a SWI / SNF-associated cancer or a cancer with a SMARCA4 mutation (eg, lung cancer or non-small cell lung cancer).

43. The composition of claim 41, wherein the cancer is a SMARCA4-deficient cancer or a cancer in which SMARCA4 expression is reduced relative to normal SMARCA4 expression (e.g., relative to the expression of non-mutated SMARCA4 or SMARCA4 in a similarly located non-cancerous cell with wild-type SMARCA4), such as lung cancer or non-small cell lung cancer.

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