BRM Targeted Compounds and Related Methods of Use

Abstract

The present disclosure relates to bifunctional compounds that find utility as modulators of SMARCA2 or BRM (target proteins). In particular, the present disclosure is directed to bifunctional compounds that contain a ligand that binds to von Hippel-Lindau E3 ubiquitin ligase at one end and a moiety that binds to a target protein at the other end, placing the target protein in close proximity to the ubiquitin ligase, resulting in degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities related to degradation / inhibition of target proteins. The compounds and compositions of the present disclosure treat or prevent diseases or disorders resulting from the aggregation or accumulation of target proteins.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 282,897, filed November 24, 2021. The entire contents of the aforementioned application are expressly incorporated herein by reference.

[0002] Provided herein are bifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, as well as related methods of use. The bifunctional compounds are useful as modulators of target ubiquitination, particularly with respect to switch / sucrose non-fermenting (SWI / SNF)-related matrix-binding actin-dependent chromatin regulator subfamily A member 2 (SMARCA2) (i.e., BRAHMA or BRM), which is degraded and / or otherwise inhibited by the bifunctional compounds disclosed herein. [Background technology]

[0003] Most small molecule drugs bind to enzymes or receptors in tight, well-defined pockets. Protein-protein interactions, on the other hand, are notoriously difficult to target using small molecules because they involve large contact surfaces, shallow grooves, or flat interfaces. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and therefore are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for specific protein substrates. Developing ligands for E3 ligases has proven challenging, in part due to the fact that protein-protein interactions must be blocked. 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, additional compounds targeting E3 ligases have been reported, but this field still remains open for development. 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 (i.e., human double minute 2 or HDM2) E3 ligase have been reported (J. Di, et al. Current Cancer Drug Targets (2011), 11(8), 987-994).

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

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

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

[0007] Mutations in genes encoding the 20 canonical SWI / SNF subunits are observed in nearly 20% of all cancers, with the highest mutation frequencies observed in rhabdoid tumors, female cancers (including ovarian, endometrial, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and clear cell renal carcinoma. SMARCA2 and SMARCA4 share high homology and are thought to have overlapping functions, but have been reported to play distinct roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is rare in tumor development. Indeed, numerous types of cancer, including lung cancer (e.g., non-small cell lung cancer), have been shown to be SMARCA4-associated (e.g., cancers with SMARCA4 mutations or SMARCA4 deficiencies, such as lack of expression). SMARCA2 has been shown to be one of the most important genes in SMARCA4-related or SMARCA4-mutated cancer cell lines because SMARCA4-deficient patient populations or cells rely solely on SMARCA2 activity, i.e., more SMARCA2 is incorporated into the complex to compensate for the SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The coexistence of defective expression of two (or more) genes that leads to cell death is known as synthetic lethality. Therefore, synthetic lethality can be exploited in the treatment of certain SMARCA2 / SMARCA4-related cancers. There is an ongoing need for effective therapies for diseases treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecific effects and the inability to target and modulate SMARCA2 present obstacles to developing effective therapies. Therefore, small molecule therapeutics that target SMARCA2 and exploit or enhance the substrate specificity of VHL may be highly useful. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent Application Publication No. 2015-0291562 [Patent Document 2] U.S. Patent Application Publication No. 2014-0356322 [Non-patent literature]

[0009] [Non-Patent Document 1] J.Di,et al.Current Cancer Drug Targets(2011),11(8),987-994 Summary of the Invention [Means for solving the problem]

[0010] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis-directed chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, thereby allowing these polypeptides and other proteins to be degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they are capable of a broad range of pharmacological activity consistent with degrading / inhibiting target polypeptides from virtually any protein class or family. In addition, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of conditions such as cancer, e.g., SMARCA4-associated / deficient cancers, such as lung cancer or non-small cell lung cancer.

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

[0012] The respective positions of the PTM and ULM moieties and their numbers exemplified herein are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by one of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0013] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be represented as follows: [ka] where PTM is a protein / polypeptide targeting moiety, L is a linker, e.g., a bond or chemical group, that couples the PTM to ULM, and ULM is a von Hippel-Lindau E3 ubiquitin ligase (VHL)-binding moiety (VLM).

[0014] For example, the structure of a bifunctional compound can be represented as follows: [ka] where PTM is a protein / polypeptide targeting moiety, "L" is a linker (e.g., a bond or chemical linker group) that couples the PTM and VLM, and VLM is a von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3 ligase.

[0015] In certain embodiments, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0016] In additional embodiments, the VLM can be hydroxyproline or a derivative thereof. Further, other contemplated VLMs are included in U.S. Patent Application Publication No. 2014 / 03022523, which, as noted above, is incorporated herein by reference in its entirety.

[0017] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a linear connector having 1 to 20 non-hydrogen atoms. The connector "L" can contain functional groups such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker can contain aromatic, heteroaromatic, cyclic, bicyclic, and tricyclic moieties. The linker can include substitution with halogens such as Cl, F, Br, and I. Fluorine substitution can include one or more fluorines.

[0018] In certain embodiments, the VLM is a derivative of trans-3-hydroxyproline, where both the nitrogen and the carboxylic acid of trans-3-hydroxyproline are functionalized to an amide.

[0019] In an additional aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic composition modulates protein degradation and / or inhibition in a patient or subject, e.g., an animal such as a human, and can be used to treat or ameliorate a disease state or condition regulated through the degraded / inhibited protein. In certain embodiments, the therapeutic composition described herein can be used to effect degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer, such as lung cancer (e.g., non-small cell lung cancer), including at least one of SWI / SNF-associated cancer, cancer with a SMARCA4 mutation, cancer with a SMARCA4 deficiency, or a combination thereof. In yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein comprising a VLM linked, preferably via a linker moiety as described elsewhere herein, wherein the VLM is coupled via the linker to a PTM that targets the protein for degradation. Degradation of a target protein occurs when the target protein is placed in proximity to an E3 ubiquitin ligase, resulting in degradation / inhibition of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides for treating a disease state or condition regulated via a target protein by reducing the level of that protein in a patient's cells.

[0020] In yet another aspect, the present specification provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

[0021] In another aspect, the present description provides methods for determining the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0022] The foregoing general description of utility is provided by way of example only and is not intended to limit the scope of the present disclosure and the appended claims. Further objects and advantages associated with the compositions, methods, and processes of the present disclosure will be recognized by those skilled in the art in light of the claims, specification, and examples. For example, the various aspects and embodiments of the present disclosure may be utilized in numerous combinations, all of which are expressly contemplated by the present description. These additional aspects and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to illustrate the context of the present disclosure and, in certain cases, to provide additional details regarding implementation are incorporated herein by reference.

[0023] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure. [Brief explanation of the drawings]

[0024] [Figure 1]Diagram of the general principle of PROTAC function. (A) An exemplary PROTAC includes a protein targeting moiety (PTM; darkly shaded rectangle), a ubiquitin ligase binding moiety (ULM; lightly shaded triangle), and, optionally, a linker moiety (L; black gland) that couples or tethers the PTM to the ULM. (B) illustrates the functional uses of the PROTACs described herein. Briefly, the ULM recognizes and binds a specific E3 ubiquitin ligase, and the PTM binds to and recruits the target protein, bringing it into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin (black circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. DETAILED DESCRIPTION OF THE INVENTION

[0025] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned herein are expressly incorporated by reference in their entirety.

[0026] Described herein are compositions and methods related to the surprising and unexpected discovery that an E3 ubiquitin ligase protein (e.g., von Hippel-Lindau E3 ubiquitin ligase (VHL)) and a target protein ubiquitinate a target protein when the two proteins are placed in close proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein. Accordingly, the present disclosure provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein target binding moiety ("PTM"), thereby resulting in ubiquitination of a selected target protein and its degradation by the proteasome (see FIG. 1). The present disclosure also provides libraries of compositions and uses thereof.

[0027] In certain embodiments, the present disclosure provides compounds comprising a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000 daltons, 1,000 daltons, 500 daltons, or 200 daltons), capable of binding to a ubiquitin ligase such as VHL. The compound also comprises a moiety capable of binding to a target protein in a manner that places the target protein in proximity to a ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. As disclosed herein, the term "small molecule" further means that the molecule is nonpeptidic (i.e., a molecule not generally considered a peptide, e.g., a molecule containing fewer than four amino acids, fewer than three amino acids, or fewer than two amino acids). In accordance with the present disclosure, a PTM, ULM, or bifunctional compound disclosed herein can be a small molecule.

[0028] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in this description is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0029] Where a range of values ​​is provided, unless the context clearly dictates otherwise (such as in the case of a group containing a certain number of carbon atoms, where each carbon atom number falling within the range is provided), it is understood that each value between the upper and lower limit of that range, to the tenth of the unit of the lower limit, and any other stated or intervening value within that stated range, is encompassed within the disclosure. The upper and lower limits of these narrower ranges may independently be included in the narrower ranges and are also encompassed within the disclosure, except for any specifically excluded limit in the stated range. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0030] The following terms are used to describe this disclosure: If a term is not expressly defined herein, the term is given its art-recognized meaning by one of ordinary skill in the art applying the term in the context of its use in describing this disclosure.

[0031] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0032] The term "and / or," as used in the specification and claims, should be understood to mean "either or both" of the elements so combined, i.e., the elements are present conjunctively in some cases and disjunctively in others. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so combined. Other elements than the elements specifically identified by the "and / or" clause may optionally be present, whether or not those elements specifically identified are related. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0033] As used in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be construed as inclusive, i.e., including not only at least one but also two or more of several elements or lists of elements, and optionally including additional items not in the list. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or when used in the claims, "consisting of," shall refer to the inclusion of exactly one element of several elements or lists of elements. In general, the term "or" as used herein shall only be construed as referring to exclusive alternatives (i.e., "one or the other, but not both") when followed by terms indicating exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0034] In the claims and the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., meaning inclusive, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as defined in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0035] As used in this specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also recognizes that elements other than those specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, regardless of the relevance of the specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally more than one, A, and no B (and optionally including elements other than B); in another embodiment to at least one, optionally more than one, B, and no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally more than one, A, and at least one, optionally more than one, B (and optionally including other elements); and so on.

[0036] It should also be understood that in any particular method that includes more than one step or act described herein, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are recited, unless the context otherwise dictates.

[0037] The terms "co-administration," "administering simultaneously," or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a different time than administration of one or more additional therapeutic agents), so long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the present compounds described herein are administered in combination with at least one additional bioactive agent, including, in particular, anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0038] The term "compound," as used herein, unless otherwise specified, refers to any specific chemical compound disclosed herein, including its tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers, e.g., optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as, where appropriate in the context, pharmaceutically acceptable salts and derivatives thereof, e.g., prodrugs and / or deuterated forms. Contemplated deuterated small molecules are those in which one or more of the hydrogen atoms contained in a drug molecule have been replaced with deuterium. The term compound, as used in context, generally refers to a single compound, but may also include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as specific enantiomers or enantiomer-enriched mixtures. The term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the compounds, many substituents and variables, particularly those associated with the compounds, are described. It is understood by those skilled in the art that the molecules described herein are stable compounds. Where bonds are depicted, both double and single bonds are represented or understood within the context of the compound depicted and the known rules of valency interactions.

[0039] The term "ubiquitin ligase" refers to a family of proteins that transfer ubiquitin to specific substrate proteins, facilitating their targeting for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-conjugating enzymes, conjugate ubiquitin to a lysine on a target protein, thereby targeting that specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin-conjugating enzymes, are responsible for transferring ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, and a third ubiquitin is attached to the second ubiquitin. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation and can change their cellular location or function, for example, through binding to other proteins that have domains capable of binding ubiquitin. Further complicating the issue is that different lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to form polyubiquitin that is recognized by the proteasome. As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise indicated, a straight- or branched-chain hydrocarbon radical having the indicated number of carbon atoms (i.e., C 1-8means 1 to 8 carbons). When no specific number of carbon atoms is present, the alkyl groups provided herein are assumed to have 1 to 12 carbons, 1 to 8 carbons, 1 to 6 carbons, or 1 to 4 carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted as provided herein. In some embodiments, an alkyl group is selected from the group consisting of C 1-6 alkyl, and in some embodiments, the alkyl group is C 1-4 It is alkyl.

[0040] The term "optionally substituted," when used in combination with a substituent defined herein, means that the substituent may or may not be substituted with one or more suitable functional groups or other substituents provided herein. For example, the substituent may be halo, 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, Halo(C 1-6 Alkoxy), C 1-6 Alkylthio, C 1-6 Alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, NH(C 1-6 Alkoxy), N(C 1-6 Alkoxy)2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NH2, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -NHCO(C 1-6 alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -S(O)C 1-6 Alkyl, -S(O)2C1-6 It may be optionally substituted with one or more alkyl, oxo, phenyl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5- to 6-membered heteroaryl groups. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0041] The term "cycloalkyl" as used herein refers to a C 3-12 "Cycloalkyl" refers to a cyclic alkyl group, including bridged rings and spiro rings (e.g., adamantine). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, a cycloalkyl group is C 3-6 It is cycloalkyl.

[0042] The term "alkenyl" as used herein refers to an alkyl group in which at least two of the carbon atoms are sp 2 hybridized to form a carbon-carbon double bond between them, C 2-12 The term "alkenyl" refers to an alkyl group. The alkenyl groups provided herein may contain more than one carbon-carbon double bond. The alkyl portion of the alkenyl groups provided herein may be substituted as provided above. In some embodiments, the alkenyl group is a C 2-6 It is alkenyl.

[0043] The term "acynyl," as used herein, refers to a C alkyl group, wherein at least two of the carbon atoms are sp hybridized, forming a carbon-carbon triple bond therebetween. 2-12The term "alkynyl" refers to an alkyl group. The alkynyl groups provided herein may contain more than one carbon-carbon triple bond, but one is preferred. The alkyl portion of the alkynyl groups provided herein may be substituted as provided above. In some embodiments, the alkynyl group is C 2-6 It is alkynyl.

[0044] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group. The term "alkylamino" includes mono- and di-alkylamino groups, where the alkyl portions may be the same or different.

[0045] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine or chlorine.

[0046] "Haro (C 1-x The term "alkyl" refers to an alkyl having 1-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 alkyl groups having 1 to 6 carbon atoms substituted with one or more halo groups. Non-limiting examples of the term halo include (C 1-6 alkyl)fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, and 2,2,2-trifluoroethyl.

[0047] "Haro (C 1-x The term "alkoxy" refers to an alkoxy group having 1-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. 1-6Non-limiting examples of alkyl) groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, and 2,2,2-trifluoroethoxy groups.

[0048] The term "heteroalkyl" refers to a straight or branched chain alkyl group, e.g., having 2 to 14 carbons, e.g., 2 to 10 carbons, one or more of which are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl amides, alkyl sulfides, and the like. The group can be a terminal group or a bridging group. As used herein, reference to a normal chain when used in the context of a bridging group refers to the direct chain of atoms of the bridging group connecting the two terminal moieties.

[0049] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a multiple condensed all-carbon ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 12 carbon atoms. Aryl includes the phenyl radical. Aryl also includes fused polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 12 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic. Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the multiple condensed ring system. Rings in a multiple condensed ring system can be connected to each other via fused bonds, spiro bonds, and bridged bonds, as permitted by valency requirements. It is understood that the point of attachment of a multiple condensed ring system can be at any position on the ring system, including the aromatic or carbocyclic portions of the ring, as defined above. Non-limiting examples of aryl groups include phenyl, indenyl, naphthyl, 1-, 2-, 3-, 4-tetrahydronaphthyl, and the like.

[0050] The term "heteroaryl," as used herein, refers to a single aromatic ring having at least one atom other than carbon within the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, so long as the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where the heteroaryl group is fused to one or more rings selected from heteroaryl (e.g., to form naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl), as defined above, to form a multiple condensed ring system. Thus, a heteroaryl (single aromatic ring or multiple condensed ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. A heteroaryl (single aromatic ring or multiple condensed ring system) can also have about 5 to 12 members or about 5 to 10 members in the heteroaryl ring. A multiple fused ring system may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of a multiple fused ring system may be connected to each other via fused, spiro, and bridged bonds, where permitted by valency requirements. It is understood that the individual rings of a multiple fused ring system may be connected to each other in any order. It is also understood that the point of attachment of a multiple fused ring system (as defined above for heteroaryl) may be at any position on the multiple fused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portions of the multiple fused ring system.It is also understood that the point of attachment of the heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (eg, nitrogen). Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, this term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms. Non-limiting examples of heteroaryls include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0051] The term "heterocyclyl" or "heterocycle," as used herein, refers to a single saturated or partially unsaturated ring having at least one atom other than carbon within the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term also includes multiple condensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) of about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes multiple condensed ring systems (e.g., ring systems containing two, three, or four rings), in which a single heterocycle (as defined above) is fused with one or more groups selected from heterocycle (e.g., to form 1,8-decahydronaphthyridinyl), carbocycle (e.g., to form decahydroquinolyl), and aryl to form the multiple condensed ring system. Thus, a heterocycle (single saturated or single partially unsaturated ring or multiple condensed ring system) has about 2 to 20 carbon atoms and 1 to 6 heteroatoms in the heterocycle. Such multiple condensed ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the multiple condensed ring. The rings of a multiple condensed ring system may be connected to each other via fused, spiro, and bridged bonds, as permitted by valency requirements. It is understood that the individual rings of a multiple condensed ring system may be connected to each other in any order. Thus, a heterocyclic ring (single saturated or single partially unsaturated ring or multiple condensed ring system) has about 3 to 20 atoms, including about 1 to 6 heteroatoms in the heterocyclic ring system. It is also understood that the point of attachment of the multiple condensed ring system (as defined above for heterocyclic rings) can be at any position in the multiple condensed ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring.It is also understood that the point of attachment of the heterocyclic ring or heterocyclic multiple condensed ring system can be at any suitable atom of the heterocyclic ring or heterocyclic multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). In one embodiment, the term heterocyclic ring is defined as C. 2-20 In one embodiment, the term heterocycle includes C 2-7 In one embodiment, the term heterocycle includes C 2-5 In one embodiment, the term heterocycle includes C 2-4Exemplary heterocycles include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one, and the like. The amines and amines used in the present invention include, but are not limited to, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidin-2-one. In one embodiment, the term "heterocycle" refers to a monocyclic, saturated, or partially unsaturated, 3- to 8-membered ring containing at least one heteroatom. For example, this term includes monocyclic, saturated, or partially unsaturated, 4-, 5-, 6-, or 7-membered rings containing at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperazine, oxirane, morpholine, and thiomorpholine. As used herein, the term "9- or 10-membered heterobicycle" refers to a partially unsaturated or aromatic fused bicyclic ring system containing at least one heteroatom. For example, the term 9- or 10-membered heterobicycle includes bicyclic ring systems containing a benzo ring fused to a 5- or 6-membered saturated, partially unsaturated, or aromatic ring containing one or more heteroatoms.

[0052] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Nitrogen and sulfur may be in the oxidized form, where possible.

[0053] As used herein, the term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, and the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0054] 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. [ka] refers to a mixture of E and Z stereoisomers.

[0055] As used herein, a wavy line crossing a bond in a chemical structure [ka] Or a dashed line "----" indicates the point of attachment of the bond that the wavy bond crosses to the rest of the molecule in a chemical structure.

[0056] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers differ in physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0057] Stereochemical definitions and conventions used herein generally follow 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 thus may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the rotation of plane-polarized light by a compound; (-) or l means the compound is levorotatory. Compounds with a (+) or d prefix are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is also referred to as a racemic mixture or racemate, which may occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0058] When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g., planar), the atom to which the bond is attached is intended to include all possible stereochemistries. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g., bold, bold wedge, dashed, or dashed wedge), the atom to which the stereochemical bond is attached is understood to be enriched in the depicted absolute stereoisomer, unless otherwise noted. In one embodiment, a compound can be at least 51% of the depicted absolute stereoisomer. In another embodiment, a compound can be at least 80% of the depicted absolute stereoisomer. In another embodiment, a compound can be at least 90% of the depicted absolute stereoisomer. In another embodiment, a compound can be at least 95% of the depicted absolute stereoisomer. In another embodiment, a compound can be at least 97% of the depicted absolute stereoisomer. In another embodiment, a compound can be at least 98% of the depicted absolute stereoisomer. In another embodiment, a compound can be at least 99% of the depicted absolute stereoisomer.

[0059] 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 transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via rearrangement of some of the bonding electrons.

[0060] As used herein, the term "solvate" refers to the association or complex of one or more solvent molecules with the 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.

[0061] As used herein, the term "protecting group" refers to a substituent commonly employed to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of the hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For an overview of protecting groups and their uses, see P.G.M.Wuts and T.W.Greene, "Greene's Protective Groups in Organic Synthesis" 4 th See, e.g., Wiley-Interscience, New York, 2006.

[0062] As used herein, the term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found 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, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or 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-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginine acid, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al. "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0063] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, the salts are otherwise equivalent to the parent form of the compound for purposes of this invention.

[0064] In addition to salt forms, the present invention provides compounds in prodrug form. As used herein, the term "prodrug" refers to a compound that readily undergoes chemical changes under physiological conditions to provide a compound of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0065] Prodrugs of the present invention include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues is covalently attached via an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of the present invention. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by their three-letter symbols, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, gamma-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, parabenzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine. Additional types of prodrugs are also encompassed. For example, free carboxyl groups of compounds of the invention can be derivatized to amides or alkyl esters. As another example, compounds of the invention containing free hydroxy groups can be derivatized to prodrugs by converting the hydroxy group to groups such as, but not limited to, phosphate esters, hemisuccinate esters, dimethylaminoacetate esters, or phosphoryloxymethyloxycarbonyl groups, as reviewed in Fleisher, D. et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, and sulfate prodrugs of hydroxy groups.Also included are derivatizations of hydroxy groups to (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include those in which the hydrogen atom of the alcohol group is replaced with (C. 1-6 ) alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, alpha-amino (C 1-4 ) alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl groups, where each alpha-aminoacyl group is a naturally occurring L-amino acid, P(O)(OH), -P(O)(O(C 1-6) alkyl) 2 or glycosyl (the radical formed by removing the hydroxyl group of the hemiacetal form of a carbohydrate). Further examples of prodrug derivatives can be found, for example, in: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al. al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0066] Additionally, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced by metabolism in the body of a particular compound or its salt. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Metabolites typically include radiolabeled compounds of the present invention (e.g., 14 C or 3H) isotopes are prepared and identified by parenteral administration to animals such as rats, mice, guinea pigs, monkeys, or humans at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding to epitopes surviving in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed similarly to conventional drug metabolism studies familiar to those skilled in the art. Metabolites, so long as they are not otherwise detectable in vivo, are useful in diagnostic assays for therapeutic administration of the compounds of the invention.

[0067] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of an infection, condition, or pathology specific to a particular animal, such as a human patient, the term patient refers to the particular animal, including domestic animals such as dogs or cats, or livestock animals such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient unless otherwise stated or suggested by the context in which the term is used.

[0068] The term "effective," when used within the context of its intended use, is used to describe the amount of a compound, composition, or component that produces an intended result. The term effective includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0069] compound Disclosed herein are bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of use thereof. In particular, disclosed herein are bifunctional compounds that are modulators of the targeted ubiquitination of various polypeptides and other proteins, thereby degrading and / or otherwise inhibiting these polypeptides and other proteins by the bifunctional compounds. The disclosed bifunctional molecules actively degrade SMARCA2, resulting in potent suppression of cell proliferation and induction of apoptosis. Bifunctional compound-mediated protein degradation offers a promising strategy for targeting pathological proteins that are "untreatable" by conventional approaches.

[0070] Other bifunctional modulators of targeted ubiquitination are described in U.S. Utility Patent Application No. 16 / 590,329, filed October 1, 2020, published as U.S. Patent Application Publication No. 2020 / 0038378A1; U.S. Utility Patent Application No. 16 / 372,345, filed April 1, 2019, published as U.S. Patent Application Publication No. 2019 / 0300521A1; U.S. Provisional Patent Application No. 62 / 651,186, filed April 1, 2018, entitled BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE; and BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF No. 62 / 797,754, filed January 28, 2019, entitled "USE"; U.S. Patent Application No. 15 / 230,354, filed August 5, 2016; and U.S. Patent Application No. 14 / 371,956, filed July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322; and U.S. Patent Application No. 15 / 074,820, filed March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639; and International Patent Application Publication No. WO2016 / 1 and U.S. utility patent application Ser. No. 15 / 885,671, filed Jan. 31, 2018, published as U.S. Patent Application Publication No. 2018 / 0215731, all of which are incorporated herein by reference in their entireties.

[0071] The bifunctional compounds of the present disclosure offer a wide range of pharmacological activity consistent with degrading / inhibiting target polypeptides from many different protein classes and / or families.

[0072] In any aspect or embodiment described herein, the bifunctional compound of the present disclosure includes an E3 ubiquitin ligase binding moiety ("ULM") that is a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM). In an exemplary embodiment, the ULM is coupled to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure: PTM-L-ULM wherein L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and / or relative positions of moieties in the compounds exemplified herein are provided by way of example only. As will be appreciated by one of skill in the art, the compounds described herein can be synthesized with any desired number and / or relative positions of each functional moiety.

[0073] In another aspect, the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compound comprises a VLM coupled to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"), e.g., a VLM linked covalently, directly, or indirectly. In certain embodiments, the VLM and PTM are linked or coupled via a chemical linker (L). The VLM binds to VHL, and the PTM recognizes the target protein, with each moiety interacting with its respective target to promote degradation of the target protein by placing it in proximity to a ubiquitin ligase protein. Exemplary bifunctional compounds can be represented as follows: PTM-VLM.

[0074] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be represented as follows: PTM-L-VLM where PTM is a protein / polypeptide targeting moiety, L is a chemical linker, and VLM is a VHL binding moiety.

[0075] In any aspect or embodiment described herein, the description provides the following exemplary SMARCA2 (i.e., BRAHMA or BRM) heterobifunctional degrader compounds (compounds 1-157 in Table 1), including pharmaceutically acceptable salts thereof. In any aspect or embodiment described herein, the description provides bifunctional compounds having the chemical structure: PTM-L-ULM, or a pharmaceutically acceptable salt thereof, where ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to von Hippel-Lindau E3 ubiquitin ligase, as described in any aspect or embodiment described herein, L is a bond or chemical linking moiety connecting the ULM and the PTM, as described in any aspect or embodiment described herein, and PTM is a small molecule comprising a SMARCA2 protein targeting moiety, as described in any aspect or embodiment described herein.

[0076] In any aspect or embodiment described herein, ULM (e.g., VLM) exhibits activity against an E3 ubiquitin ligase (e.g., VHL) or has an IC of less than about 200 μM. 50 Combine with IC 50 can be determined according to any method known in the art, for example, a fluorescence polarization assay.

[0077] IC of the bifunctional compounds described herein 50 The value can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay.

[0078] In any aspect or embodiment described herein, ULM (e.g., VLM) exhibits activity against an E3 ubiquitin ligase (e.g., VHL) or has an IC of less than about 200 μM. 50For example, in any aspect or embodiment described herein, the bifunctional compounds described herein have an IC of less than about 100 mM, less than about 50 mM, less than about 10 mM, less than about 1 mM, less than about 0.5 mM, less than about 0.1 mM, less than about 0.05 mM, less than about 0.01 mM, less than about 0.005 mM, or less than about 0.001 mM. 50 The activity of

[0079] In any aspect or embodiment described herein, the bifunctional compounds described herein have an IC of less than about 100 μM, less than about 50 μM, less than about 10 μM, less than about 1 μM, less than about 0.5 μM, less than about 0.1 μM, less than about 0.05 μM, less than about 0.01 μM, less than about 0.005 μM, or less than about 0.001 μM. 50 The activity of

[0080] In any aspect or embodiment described herein, the bifunctional compounds described herein have an IC of less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.1 nM, less than about 0.05 nM, less than about 0.01 nM, less than about 0.005 nM, or less than about 0.001 nM. 50 The activity of

[0081] In any aspect or embodiment described herein, the bifunctional compounds described herein have an IC of less than about 100 pM, less than about 50 pM, less than about 10 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.1 pM, less than about 0.05 pM, less than about 0.01 pM, less than about 0.005 pM, or less than about 0.001 pM. 50 The activity of

[0082] In any aspect or embodiment described herein, D of the bifunctional compound described herein max can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay.

[0083] In any aspect or embodiment described herein, the bifunctional compound has a D max It has.

[0084] In any aspect or embodiment described herein, the bifunctional compound has a D max In any aspect or embodiment described herein, the bifunctional compound has a D max In any aspect or embodiment described herein, the bifunctional compound has a D max It has.

[0085] In any aspect or embodiment described herein, the bifunctional compound DC 50 The value can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay.

[0086] In any aspect or embodiment described herein, the bifunctional compound DC 50 In any aspect or embodiment described herein, the DC 50 In any aspect or embodiment described herein, the DC 50 The value is less than 2.5 nM.

[0087] In any aspect or embodiment described herein, the bifunctional compound has a D max and DC of the bifunctional compound 50 is less than 10 nM or less than 2.5 nM.

[0088] In any aspect or embodiment described herein, the bifunctional compound has a DC of less than about 2.5 nM. 50 (i.e., Category A as described herein), wherein DC 50is optionally determined as described herein.

[0089] In any aspect or embodiment described herein, the bifunctional compound has a DC of greater than or equal to about 2.5 nM and less than about 10 nM. 50 (i.e., Category B as described herein), wherein DC 50 is optionally determined as described herein.

[0090] In any aspect or embodiment described herein, the bifunctional compound has a DC of greater than or equal to about 2.5 nM and less than about 30 nM. 50 (i.e., Category C as described herein), wherein DC 50 is optionally determined as described herein.

[0091] In any aspect or embodiment described herein, the bifunctional compound has a DC of about 30 nM or greater. 50 (i.e., Category D as described herein), wherein DC 50 is optionally determined as described herein.

[0092] In any aspect or embodiment described herein, a DC of about 30 nM or greater 50 Compound(s) having a phenotype (i.e., Category D as described herein) are excluded (optionally, DC 50 can be determined as described herein).

[0093] In any aspect or embodiment described herein, the bifunctional compound DC 50 The value can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay, or the methods described herein.

[0094] In any aspect or embodiment described herein, the bifunctional compound has a D of greater than about 75% decomposition. Max (i.e., Category A as described herein), wherein D Max is optionally determined as described herein.

[0095] In any aspect or embodiment described herein, the bifunctional compound has a D Max (i.e., Category B as described herein), wherein DC 50 is optionally determined as described herein.

[0096] In any aspect or embodiment described herein, the bifunctional compound has a D Max (i.e., Category C as described herein), wherein D Max is optionally determined as described herein.

[0097] In any aspect or embodiment described herein, a D Max (i.e., Category C as described herein) are excluded (optionally, D Max can be determined as described herein).

[0098] In any aspect or embodiment described herein, D of the bifunctional compound described herein Max The value can be determined according to any method known in the art, such as, for example, a fluorescence polarization assay, or the methods described herein.

[0099] In any aspect or embodiment described herein, the compound comprises multiple ULMs, and the ULMs are the same. In any aspect or embodiment described herein, the compound comprises multiple ULMs (e.g., ULMs), at least one PTM coupled to the ULM directly or via a chemical linker (L), or both. In any aspect or embodiment described herein, the compound comprising multiple ULMs further comprises multiple PTMs. In any aspect or embodiment described herein, the PTMs are the same or, optionally, different. In any aspect or embodiment described herein, in which the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

[0100] In any aspect or embodiment described herein, a compound may comprise multiple ULMs. In any aspect or embodiment described herein, a compound comprising at least two different ULMs and / or multiple ULMs further comprises at least one PTM coupled to the ULM directly, via a chemical linker, or both. In any aspect or embodiment described herein, a compound comprising at least two different ULMs may further comprise multiple PTMs. In any aspect or embodiment described herein, the PTMs are the same or, optionally, different. In any aspect or embodiment described herein in which the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

[0101] In any aspect or embodiment described herein, the compound has a chemical structure selected from the following: [ka] or a pharmaceutically acceptable salt thereof (wherein PTM, L, X, R 30 , R1, R 28A , R 28B , R 28, R 14a , R 14b , R 15 , and R 16 is as defined in any aspect or embodiment described herein, including different variable names at the same position in a chemical structure).

[0102] In any aspect or embodiment described herein, the compound has a chemical structure selected from the following: [ka] or a pharmaceutically acceptable salt thereof, PTM and L are as defined in any aspect or embodiment described herein; R 14a , R 14b , R 15 , and R 16 is as defined in any aspect or embodiment described herein, including different variable names at the same position in the chemical structure; X is CH or N; R 30 is H, F, or Cl, R1 is C 1-6 is alkyl, R 28A is selected from H or methyl; R 28B is selected from H, methyl, and halogen (e.g., F or Cl); R 28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] (It is).

[0103] In any aspect or embodiment described herein, the compound has a chemical structure selected from the following: [ka] or a pharmaceutically acceptable salt thereof, PTM and L are as defined in any aspect or embodiment described herein; X is CH or N; R 30 is H, F or Cl, R1 is C 1-6 is alkyl, R 28A is selected from H or methyl; R 28B is selected from H, methyl, and halogen (e.g., F or Cl); R 28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] and R 14a and R 14b one of which is H, methyl, C1 fluoroalkyl, CHF2, CF3, and the other is H; R 15 is cyano, halogen (e.g., F or Cl), [ka] is selected from R 16 is H, C 1-4 Alkyl, fluoro, chloro, NH2, CN, or C 1-4 alkoxy).

[0104] In additional embodiments, the present disclosure provides compounds described herein, including enantiomers, diastereomers, solvates, and polymorphs, including pharmaceutically acceptable salt forms thereof, e.g., acid and base salt forms.

[0105] Exemplary VLM In any aspect or embodiment described herein, the ULM has a chemical structure selected from the following: [ka] or a pharmaceutically acceptable salt thereof (wherein X, R 30 , R1, R 28A , R 28B , R 28 , R 14a , R 14b , R 15 , and R 16 is as defined in any aspect or embodiment described herein).

[0106] In any aspect or embodiment described herein, the ULM has a chemical structure selected from the following: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 14a , R 14b , R 15 , and R 16 is as defined in any aspect or embodiment described herein; X is CH or N; R 30 is H, F or Cl, R1 is C 1-6 is alkyl, R 28A is selected from H or methyl; R 28B is selected from H, methyl, and halogen (e.g., F or Cl); R 28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] (It is).

[0107] In any aspect or embodiment described herein, the ULM has a chemical structure selected from the following: [ka] or a pharmaceutically acceptable salt thereof (In the formula, X is CH or N; R 30 is H, F or Cl, R1 is C 1-6 is alkyl, R 28A is selected from H or methyl; R 28B is selected from H, methyl, and halogen (e.g., F or Cl); R 28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] and R 14a and R 14b one of which is H, methyl, C1 fluoroalkyl, CHF2, CF3, and the other is H; R 15 is cyano, halogen (e.g., F or Cl), [ka] is selected from R 16 is H, C 1-4 Alkyl, fluoro, chloro, NH2, CN, or C 1-4 alkoxy).

[0108] In any aspect or embodiment described herein, the ULM is selected from: [ka] [ka] [ka]

[0109] In certain embodiments, the compounds described herein provide a means for binding to an E3 ubiquitin ligase, such as a von Hippel-Lindau E3 ubiquitin ligase. In certain embodiments, the ULM is a VLM and comprises a chemical structure selected from the group ULM-a: [ka] (In the formula, The dashed lines indicate the attachment of at least one PTM, another ULM or VLM (i.e., VLM'), or a chemical linker moiety that couples at least one PTM or VLM' to the other end of the linker; X in the formula ULM-a 1 , X 2 is a bond, O, NR Y3 , C.R. Y3 R Y4 , C=O, C=S, SO, and SO2; R in the formula ULM-a Y3 , R Y4 is a straight or branched chain C optionally substituted with H, one or more halo 1-6 Alkyl, optionally substituted C 1-6 Alkoxyl (e.g., 0 to 3 R P each independently selected from the group consisting of: R in the formula ULM-a P is 0, 1, 2, or 3 groups, H, halo, -OH, C 1-3each independently selected from the group consisting of alkyl, C═O, alkyl, alkoxy, or a combination thereof; Formula ULM-a W 3 is an optionally substituted T, an optionally substituted -TN(R 1a R 1b )X 3 , optionally substituted -TN(R 1a R 1b ), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted -T-biheteroaryl, optionally substituted -T-heterocyclyl, optionally substituted -T-biheterocyclyl, optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl or optionally substituted -NR 1 -T-heterocyclyl; X in the formula ULM-a 3 is C=O, R 1 , R 1a , R 1b and R 1 , R 1a , R 1b each of which is a straight or branched chain C optionally substituted with H, one or more halo or -OH groups 1-6 Alkyl group, 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, T of formula ULM-a is optionally substituted alkyl, —(CH) n - group, optionally substituted straight chain, branched chain -(CH2) n -OC 1-6alkyl, or optionally substituted -(CH2) n -O-heterocyclyl, wherein each one of the methylene groups is selected from the group consisting of halogen, methyl, straight or branched C optionally substituted with one or more halogen or -OH groups. 1-6 optionally substituted with one or two substituents selected from the group consisting of an alkyl group, an optionally substituted amino acid side chain, or an optionally substituted heterocyclyl; Formula ULM-a W 4 is an optionally substituted —NR1-T-aryl (wherein the aryl group can be optionally substituted with an optionally substituted 5- to 6-membered heteroaryl or an optionally substituted aryl), an optionally substituted —NR1-T-heteroaryl group (wherein the heteroaryl is optionally substituted with an optionally substituted aryl or an optionally substituted heteroaryl), or an optionally substituted —NR1-T-heterocyclyl, where —NR1 is selected from the group consisting of X 2 covalently bonded to R 1 is H or CH3, preferably H, The dashed lines indicate the attachment site of at least one PTM or a chemical linker moiety that couples at least one PTM to ULM).

[0110] In any aspect or embodiment described herein, R P is modified to form a prodrug, including an ester or ether linkage.

[0111] In any aspect or embodiment described herein, T is optionally substituted alkyl, —(CH) n - groups, wherein each one of the methylene groups is selected from the group consisting of halogen, methyl, optionally substituted alkoxy, straight or branched chain C optionally substituted with one or more halogens. 1-6 Alkyl group, C(O)NR 1 R 1a, or NR 1 R 1a , or R 1 and R 1a is attached to an optionally substituted heterocyclyl, or an —OH group, or an optionally substituted amino acid side chain, where n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

[0112] In any aspect or embodiment described herein, W of formula ULM-a 4 teeth, [ka] where R 14a , R 14b is H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amido, optionally substituted alkylamido, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphoric acid, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 , alkyl-COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 R 14a and R 14b The other 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, where the spiroheterocyclyl is not an epoxide or an aziridine.

[0113] In any aspect or embodiment described herein, the W 5 is selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 membered heteroaryl.

[0114] In any aspect or embodiment described herein, R of formula ULM-a 15 is H, halogen, CN, C≡CH, OH, NO2, NR 14a R 14b , OR 14a ,CONR 14a R 14b , N.R. 14a COR 14b , SO2NR 14a R 14b , N.R. 14a SO2R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl.

[0115] In additional embodiments, W for use in the present disclosure 4 Substituents also include the W groups found in the identified compounds disclosed herein. 4 Substituents are specifically included (but are not limited to the specific compounds of this disclosure). 4 Each of the substituents may be any number of W as similarly disclosed herein. 3 It may be used with a substituent.

[0116] In certain additional embodiments, ULM-a has 0 to 3 R in the pyrrolidine moiety. P Each R is optionally substituted by a group. P are independently H, halo, -OH, C 1-3 Alkyl, C=O.

[0117] In any of the embodiments described herein, W of formula ULM-a 3 and / or W 4 can be independently covalently coupled to a linker that is attached to one or more PTM groups.

[0118] In certain embodiments, the ULM is VHL and is represented by the following structure: [ka] (In the formula, W in formula ULM-b 3 is an optionally substituted aryl, an optionally substituted heteroaryl, or [ka] is selected from the group consisting of R9 and R of formula ULM-b 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R in formula ULM-b 11 is an optionally substituted heterocyclyl, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, [ka] is selected from the group consisting of R in formula ULM-b 12 is selected from the group consisting of H or optionally substituted alkyl; R in formula ULM-b 13is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in formula ULM-b 14a , R 14b is H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphoric acid, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 , alkyl-COR 26 ,CONR 27a R 27b , CH2NHCOR 26 , or (CH2)N(CH3)COR 26 R 14a and R 14b The other is H or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; W in formula ULM-b 5 is selected from the group consisting of phenyl, naphthyl, or 5-10 membered heteroaryl; R in formula ULM-b 15 is H, halogen, CN, C≡CH, OH, NO2, NR 27a R27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; Each R in formula ULM-b 16 is independently selected from the group consisting of halo, CN, optionally substituted alkyl, optionally substituted alkylamine, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; in the formula ULM-b, o is 0, 1, 2, 3, or 4; R in formula ULM-b 18 is independently selected from the group consisting of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; Each R 26 is H, OH, optionally substituted alkyl or NR 27a R 27b are independently selected from Each R 27a and R 27b are independently H, optionally substituted alkyl, optionally substituted 3- to 5-membered cycloalkyl, or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; p of the formula ULM-b is 0, 1, 2, 3, or 4; Dashed lines indicate binding sites for at least one PTM, another ULM, or a chemical linker moiety that couples at least one PTM or both to ULM).

[0119] In certain embodiments, R of formula ULM-b 15 teeth, [ka] where R 17 is H, halo, 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.

[0120] In certain embodiments, R of formula ULM-b 17 is selected from the group of methyl, ethyl, isopropyl, and cyclopropyl.

[0121] In certain additional embodiments, R of formula ULM-b 15 is selected from: [ka]

[0122] In certain embodiments, R of formula ULM-b 11 is selected from: [ka]

[0123] In any aspect or embodiment described herein, R of formula ULM-b 14a , R 14bis H, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphoric acid, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 , alkyl-COR 26 , CH2OR 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , or CH2NCH3COR 26 R 14a and R 14b The other is H or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine, and the spirocycloalkyl or spiroheterocycloalkyl is itself an alkyl, haloalkyl, or -COR 33 optionally replaced by R 33 is alkyl or haloalkyl, and R 30 is H, optionally further substituted alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl; R 26 and R 27 is as described above.

[0124] In any aspect or embodiment described herein, R of formula ULM-b 15 is H, halogen, CN, C≡CH, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl (e.g., optionally substituted fluoroalkyl), optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein the optional substitutions on the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of CHOR, 30 , CH2NHR 30 , CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , CH2NCH3COR 26 or [ka] Contains R 26 , R 27 , R 30 and R 14 a is as described above.

[0125] In any aspect or embodiment described herein, R of formula ULM-b 14a , R 14b is H, optionally substituted haloalkyl, optionally substituted alkyl, CHOR 30 , CH2NHR 30、 CH2NCH3R 30,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , or CH2NCH3COR 26 R 14a and R 14b The other is H or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered spirocycloalkyl or spiroheterocyclyl, where the spiroheterocyclyl is not an epoxide or an aziridine, and the spirocycloalkyl or spiroheterocycloalkyl is not itself an alkyl, haloalkyl, or -COR 33 optionally replaced by R 33 is alkyl or haloalkyl, and R 30 is H, optionally further substituted alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl; R of formula ULM-b 15 is H, halogen, CN, C≡CH, OH, NO2, NR 27a R 27b , OR 27a ,CONR 27a R 27b , N.R. 27a COR 27b , SO2NR 27a R 27b , N.R. 27a SO2R 27b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein the optional substitutions on the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from the group consisting of CHOR 30 , CH2NHR 30、CH2NCH3R 30 ,CONR 27a R 27b , CH2CONR 27a R 27b , CH2NHCOR 26 , CH2NCH3COR 26 or [ka] where R 26 , R 27 , R 30 and R 14 a is as described above.

[0126] In certain embodiments, ULM has a chemical structure selected from the following: [ka] (In the formula, R1 of formulae ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R of formulas ULM-c, ULM-d, and ULM-e 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R of formulas ULM-c, ULM-d, and ULM-e 15 is selected from the group consisting of H, halogen, CN, C≡CH, 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 of formulae ULM-c, ULM-d, and ULM-e is C, CH, or C=O; R3 of formulae ULM-c, ULM-d, and ULM-e is absent or optionally substituted 5- or 6-membered heteroaryl; Dashed lines indicate binding sites for at least one PTM, another ULM, or a chemical linker moiety that couples at least one PTM or both to ULM).

[0127] In certain embodiments, a ULM includes a group according to the following chemical structure: [ka] (In the formula, R in the formula ULM-f 14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 of formula ULM-f is H; R in the formula ULM-f 10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R in the formula ULM-f 11 teeth, [ka] or optionally substituted heteroaryl; p of the formula ULM-f is 0, 1, 2, 3, or 4; Each R in the formula ULM-f 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker; R in the formula ULM-f 12 is H, C=O, R in the formula ULM-f 13is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R in the formula ULM-f 15 is H, halogen, Cl, CN, C≡CH, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl; [ka] is selected from the group consisting of The dashed lines in formula ULM-f indicate attachment sites for at least one PTM, another ULM, or a chemical linker moiety that couples at least one PTM or both to ULM).

[0128] In certain embodiments, the ULM is selected from: [ka] (wherein n is 0 or 1).

[0129] In certain embodiments, the ULM is selected from: [ka] [ka] [ka] (wherein the phenyl rings in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 are optionally substituted with fluorine, lower alkyl and alkoxy groups, and the dashed lines indicate attachment sites for at least one PTM, another ULM, or a chemical linker moiety coupling at least one PTM or both to ULM-a).

[0130] In certain embodiments, the hydroxyl group on the pyrrolidine ring of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 each comprises an ester-linked prodrug moiety.

[0131] In one embodiment, the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 can be functionalized to an ester to form part of a prodrug.

[0132] In any of the aspects or embodiments described herein, ULM is a group according to the following chemical structure: [ka] or a pharmaceutically acceptable salt thereof, ULM-g R 1’ is an optionally substituted C 1-6 Alkyl groups, optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n -O-(C 1-6 ) alkyl group, optionally substituted (CH2) containing an epoxide moiety WCOCW n -WCOCW-(C 0-6 ) alkyl group (each W is independently H or C 1-3 alkyl group), optionally substituted -(CH2) nCOOH, optionally substituted -(CH) n C(O)-(C 1-6 alkyl), optionally substituted -(CH) n NHC(O)-R″, optionally substituted —(CH2) n C(O)-N(R")2, optionally substituted -(CH2) n OC(O)-N(R″)2, -(CHO) n H, optionally substituted -(CH2) n OC(O)-(C 1-6 alkyl), optionally substituted -(CH) n C(O)-O-(C 1-6 alkyl), optionally substituted -(CHO) n COOH, optionally substituted -(OCH2) n O-(C 1-6 alkyl), optionally substituted -(CHO) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2) n NHC(O)-R″, optionally substituted —(CHO) n C(O)-N(R″)2, -(CH2CH2O) n H, optionally substituted -(CH2CH2O) n COOH, optionally substituted -(OCH2CH2) n O-(C 1-6 alkyl), optionally substituted -(CH2CH2O) n C(O)-(C 1-6 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 (preferably F or Cl), Each R″ of ULM-g is independently H or C which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine). 1-6 is an alkyl group, ULM-g R S is C 1-6 an alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or —(CH) m N(R″)2 group, X and X' of ULM-g are each independently C=O, C=S, -S(O), or S(O)2 (preferably, both X and X' are C=O); ULM-g R 2’ is an optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w Alkyl groups, optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w NR 1N R 2N group, optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR″) v (SO2) w -heteroaryl, optionally substituted -(CH) n -(C=O) v NR″(SO2) w -heterocyclyl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -alkyl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w-NR 1N R 2N , optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -NR″C(O)R 1N , optionally substituted -NR"-(CH) n -(C=O) u (NR″) v (SO2) w -aryl, optionally substituted -NR"-(CH) n -(C=O) u (NR″) v (SO2) w -heteroaryl or optionally substituted -NR"-(CH) n -(C=O) v NR″(SO2) w -heterocyclyl, optionally substituted -X R2’ -alkyl group; optionally substituted -X R2’ -aryl group; optionally substituted -X R2’ -heteroaryl group; optionally substituted -X R2’ -heterocyclyl group, ULM-g R 3’ is an optionally substituted alkyl, optionally substituted -(CH2) n -(O) u (NR″) v (SO2) w -alkyl, optionally substituted -(CH) 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 -(CH) n -C(O) u (NR″) v (SO2) w -heterocyclyl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -alkyl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -NR 1N R 2N , optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -NR″C(O)R 1N , optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -aryl, optionally substituted -NR"-(CH) n -C(O) u (NR″) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR″) v (SO2) w -heterocyclyl, optionally substituted -O-(CH)-(C=O) u (NR″) v(SO2) w -alkyl, optionally substituted -O-(CH)-(C=O) u (NR″) v (SO2) w -NR 1N R 2N , optionally substituted —O—(CH)—(C═O) u (NR″) v (SO2) w -NR″C(O)R 1N , optionally substituted —O—(CH)—(C═O) u (NR″) v (SO2) w -aryl, optionally substituted -O-(CH) n -(C=O) u (NR″) v (SO2) w -heteroaryl or optionally substituted -O-(CH) n -(C=O) u (NR″) v (SO2) w -heterocyclyl;-(CH2) n -(V) n’ -(CH2) n -(V) n’ -alkyl group, optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -aryl group, optionally substituted -(CH) n -(V) n’ -(CH2) n -(V) n’ -heteroaryl group, optionally substituted -(CH) n -(V) n’ -(CH2) n -(V) n’ -heterocyclyl ’ group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -alkyl group, optionally substituted -(CH2) n-N(R 1’ )(C=O) m’ -(V) n’ -aryl group, optionally substituted -(CH) n -N(R 1’ )(C=O) m’ -(V) n’ -heteroaryl group, optionally substituted -(CH) n -N(R 1’ )(C=O) m’ -(V) n’ -heterocyclyl group, optionally substituted -X R3’ -alkyl group; optionally substituted -X R3’ -aryl group; optionally substituted -X R3’ -heteroaryl group; optionally substituted -X R3’ -heterocyclyl group, ULM-g R 1N and R 2N are each independently a C optionally substituted with H, one or two hydroxyl groups, and up to three halogen groups; 1-6 alkyl, or optionally substituted -(CH2) n -aryl, -(CH2) n -heteroaryl or -(CH2) n -heterocyclyl group, V of ULM-g is O, S, or NR1; Each R of ULM-g 1’ are independently H or C 1-3 is an alkyl group, ULM-g X R2’ and X R3’ are each independently an optionally substituted —(CH) n -, -(CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, -(CHCHO) n -, or a C3-C6 cycloalkyl group, where X vis H, halo, or an optionally substituted C1-C3 alkyl group; each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each m' in ULM-g is independently 0 or 1; each n in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6; Each n' in ULM-g is independently 0 or 1; Each u in ULM-g is independently 0 or 1; Each v in ULM-g is independently 0 or 1; Each w of ULM-g is independently 0 or 1; ULM-g R 1’ , R 2’ , R 3’ , any one or more of X and X' is optionally modified to covalently attach to a PTM group), or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0133] In any of the aspects or embodiments described herein, ULM is a group according to the following chemical structure: [ka] (In the formula, ULM-h R 1’ , R 2’ and R 3’ are the same as above, and X is a C=O, C=S, —S(O) group or an S(O) group, more preferably a C=O group; ULM-h R 1’ , R 2’ and R 3’ any one or more of which are optionally modified to be attached to a linker group that is further covalently attached to the PTM group, or A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0134] In any of the aspects or embodiments described herein, ULM has the chemical structure: [ka] (In the formula, ULM-I R 1’ , R 2’ and R 3’ any one or more of which are optionally modified to be attached to a linker group that is further covalently attached to the PTM group, or A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

[0135] In a further preferred embodiment of the present disclosure, R of ULM-g to ULM-i 1’ is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxyl group such that the compound represents a prodrug form of the active compound. Exemplary preferred R 1’ Examples of the group include -(CH2) n OH, (CH2) n -O-(C1-C6) alkyl group, -(CH2) n COOH, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), or optionally substituted —(CH2) n C(O)—O—(C1-C6 alkyl), where n is 0 or 1. R 1’ is or contains a carboxylic acid group, a hydroxyl group, or an amine group, the hydroxyl group, carboxylic acid group, or amine (each of which may be optionally substituted) may be further chemically modified to provide a covalent linkage to a linker group to which a PTM group is attached.

[0136] In some embodiments, X and X′ of ULM-g and ULM-h, when present, are preferably C═O, C═S, —S(O) or —S(O) groups, more preferably C═O groups.

[0137] In some embodiments, R of ULM-g through ULM-i 2’ is preferably an optionally substituted -NH-T-aryl, an optionally substituted -N(CH)-T-aryl, an optionally substituted -NH-T-heteroaryl group, an optionally substituted -N(CH)-T-heteroaryl, an optionally substituted -NH-T-heterocyclyl, or an optionally substituted -N(CH)-T-heterocyclyl, preferably H, and T is an optionally substituted -(CH) n - group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, which substituents are preferably halogen, an amino acid side chain as described elsewhere herein, or an optionally substituted C 1-3 Alkyl groups are selected from, preferably one or two methyl groups, and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1. Alternatively, T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n - groups, all of which are optionally substituted.

[0138] ULM-g~ULM-i R 2’ Preferred aryl groups include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, where the phenyl or naphthyl group is connected to the PTM with a linker group and / or is selected from the group consisting of halogen (preferably F or Cl), amine, mono- or di-alkylamine (preferably dimethylamine), F, Cl, OH, COOH, C 1-6alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably para), optionally substituted phenyl groups (the phenyl group itself is optionally connected to the PTM group by a linker group), and / or naphthyl groups optionally substituted with at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN groups (at the ortho, meta, and / or para positions of the phenyl ring, preferably para), which may be optionally substituted; optionally substituted heteroaryl, preferably optionally substituted isoxazoles including methyl substituted isoxazoles, optionally substituted oxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, methyl substituted pyrrolidones, optionally substituted pyrrole including pyrrolidine, optionally substituted imidazole including methylimidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oxaimidazole or methyloximidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl-substituted pyridine or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted quinoline, optionally substituted groups according to a chemical structure selected from: [ka] (In the formula, ULM-g~ULM-i Sc is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens), or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl) ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C 1-6 alkyl) (each of these groups is optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine)), or an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran); ULM-g~ULM-i R PROis H, optionally substituted C 1-6 alkyl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1-3 an optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl group selected from the group consisting of alkyl groups, preferably methyl, or halogen (preferably fluorine or chlorine), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and RPRO2 are each independently H, optionally substituted C 1-3 are alkyl groups or together form a keto group, Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or an optionally substituted heterocyclyl, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, or morpholine (each of these groups, if substituted, is preferably substituted with methyl or halo (F, Br, Cl), and each of these groups can optionally be attached to a PTM group via a linker group).

[0139] In certain embodiments, ULM-g to ULM-i [ka] teeth, [ka] R of ULM-g to ULM-i is a group PRO and n are the same as above.

[0140] In some embodiments, R of ULM-g through ULM-i 2’ Heteroaryl groups for include optionally substituted quinoline (which may be attached to the pharmacophore or any carbon atom within the quinoline ring may be substituted), 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 oxoimidazole.

[0141] In some embodiments, R of ULM-g through ULM-i 2’ The heteroaryl group for is a group selected from: [ka] (In the formula, ULM-g~ULM-i S c is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens (e.g., CF)), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (Wherein, R of ULM-g to ULM-i a is H or C 1-6Alkyl groups (preferably C 1-3 alkyl) ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens); ULM-g~ULM-i R URE is H, C1-C6 alkyl (preferably H or C 1-3 alkyl) or -C(O)(C 1-6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine), or optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3alkyl), each of which can be optionally connected to a PTM group via a linker group).

[0142] In some embodiments, R of ULM-g through ULM-i 2’ HeterocyclylHeterocyclyl groups for include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, each of which groups can be optionally substituted.

[0143] In some embodiments, R of ULM-g through ULM-i 2’ is a group selected from: [ka] (In the formula, ULM-g~ULM-i R PRO is H, optionally substituted C 1-6 alkyl or an optionally substituted aryl, heteroaryl or heterocyclyl group; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), and each of these groups can optionally be connected to a PTM group via a linker group).

[0144] In some embodiments, R of ULM-g through ULM-i 2’ Substituents also include the R groups found in the identified compounds disclosed herein, including the specific compounds disclosed in this specification and the accompanying drawings. 2’ Substituents are specifically included (but not limited to the specific compounds of this disclosure). These R 2’ Each of the substituents may be any number of R 3’It may be used with a substituent.

[0145] In some embodiments, R of ULM-g through ULM-i 3’ is an optionally substituted -NH-T-aryl, an optionally substituted -N(C1-C3 alkyl)-T-aryl, an optionally substituted -NH-T-heteroaryl group, an optionally substituted -N(C 1-3 -T-heteroaryl, optionally substituted -NH-T-heterocyclyl, or optionally substituted -N(C-C alkyl)-T-heterocyclyl, where T is an optionally substituted -(CH) n - group, each one of the methylene groups may be optionally substituted with one or two substituents, which may be selected from halogen, a C1-C3 alkyl group (e.g., methyl), or the side chain of an amino acid as otherwise described herein, preferably methyl, each of which may be optionally substituted, and n is 0 to 6, often n is 0, 1, 2, or 3, preferably n is 0 or 1. Alternatively, T may be -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, or -(OCH2CH2) n - groups, each of which can be optionally substituted.

[0146] In some embodiments, R of ULM-g through ULM-i 3’ Aryl groups for include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, where the phenyl or naphthyl group is optionally connected to a PTM group via a linker group, and / or is selected from the group consisting of halogen (preferably F or Cl), amine, mono- or dialkylamine (preferably dimethylamine), amide group (preferably -(CH) m-NR1C(O)R2 group, where m, R1 and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN, or S(O)2R S Group(R S is C 1-6 an alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or —(CH) mand (R") groups), each of which may be substituted at the ortho, meta and / or para positions of the phenyl ring, preferably the para position of the phenyl ring, or is aryl (preferably phenyl), heteroaryl, or heterocyclyl. Preferably, the substituent phenyl group is an optionally substituted phenyl group (i.e., the substituent phenyl group itself is preferably substituted with at least one of F, Cl, OH, SH, COOH, CH, CF, OMe, OCF, NO, CN, or a linker group attached to a PTM group, the substitution occurring at the ortho, meta and / or para positions of the phenyl ring, preferably the para position of the phenyl ring), an optionally substituted naphthyl group, including those described above, an optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, ... optionally substituted thiazoles, including substituted thiazoles; optionally substituted pyrroles, including methyl-substituted pyrroles; methylimidazole, benzylimidazole, or methoxybenzylimidazole; optionally substituted imidazoles, including oxoimidazole or methyloxoimidazole; optionally substituted diazole groups, including methyldiazole groups; optionally substituted triazole groups, including methyl-substituted triazole groups; pyridine groups, including halo- (preferably F)- or methyl-substituted pyridine groups, or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen); or optionally substituted heterocyclyl (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane). Each of the aryl, heteroaryl, or heterocyclyl groups may optionally be connected to a PTM group via a linker group.

[0147] In some embodiments, R of ULM-g through ULM-i 3’is an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2-, 3-, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted -(CH) m -O-C1-C6 alkyl group or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl group), or an optionally substituted pyridine (2-, 3-, or 4-pyridine).

[0148] In some embodiments, R of ULM-g through ULM-i 3’ is a group selected from: [ka] (In the formula, ULM-g~ULM-i S c is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens); ULM-g~ULM-i R URE is H, C 1-6 Alkyl (preferably H or C 1-3 alkyl) or -C(O)(C 1-6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 Each of the heteroaryl groups can be optionally connected to a PTM group via a linker group.

[0149] In some embodiments, R of ULM-g through ULM-i 3’ is tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, and thiane, each of which groups can be optionally substituted.

[0150] In some embodiments, R of ULM-g through ULM-i 3’ is a group selected from: [ka] (In the formula, ULM-g~ULM-i R PRO is H, optionally substituted C 1-6 alkyl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1-3an optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl group selected from the group consisting of alkyl groups, preferably methyl, or halo groups, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group; Each n in ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of the heterocyclyl groups can optionally be connected to a PTM group via a linker group.

[0151] In some embodiments, R of ULM-g through ULM-i 3’ Substituents also include the R groups found in the identified compounds disclosed herein, including the specific compounds disclosed in this specification and the accompanying drawings. 3’ These R 3’ Each of the substituents may be any number of R 2’ It may be used with a substituent.

[0152] In certain alternative embodiments, R of ULM-g through ULM-i 2’ is an optionally substituted -NR1-X R2’ -Alkyl group, -NR1-X R2’ -aryl group; optionally substituted -NR1-X R2’ -HET, optionally substituted -NR1-X R2’ -aryl-HET or optionally substituted -NR1-X R2’ -HET-aryl, wherein R1 of ULM-g~ULM-i is H or C 1-3 an alkyl group (preferably H), ULM-g~ULM-i X R2’is an optionally substituted -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group; ULM-g~ULM-i X v is H, halo, or C optionally substituted with one or two hydroxyl groups or up to three halogens 1-3 is an alkyl group, The alkyl of ULM-g to ULM-i is optionally substituted C 1-0 Alkyl (preferably C 1-6 alkyl) groups (in certain preferred embodiments, the alkyl groups are end-capped with a halogen, often chlorine or bromine); Aryl of ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET of ULM-g to ULM-i is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each, when substituted, preferably C 1-3 substituted with an alkyl group, preferably methyl, or a halogen, preferably fluorine or chlorine; or [ka] is selected from ULM-g~ULM-i S c is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HETis H, CN, NO, halogen (preferably chlorine or fluorine), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl) ULM-g~ULM-i R SS is H, CN, NO, halogen (preferably fluorine or chlorine), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens), optionally substituted O—(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens); ULM-g~ULM-i R URE is H, C 1-6 Alkyl (preferably H or C 1-3 alkyl) or -C(O)(C 1-6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine), or optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YCis H, OH, CN, NO, halogen (preferably chlorine or fluorine), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C 1-6 alkyl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1-3 an optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl group selected from the group consisting of alkyl groups, preferably methyl, or halogen (preferably fluorine or chlorine), benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C 1-3 are alkyl groups or together form a keto group, Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of these groups is optionally connected to a PTM group via a linker group.

[0153] In some embodiments, R of ULM-g through ULM-i 3’is an optionally substituted -(CH2) n -(V) n’ -(CH2) n -(V) n’ -R S3’ group, optionally substituted -(CH2) n -N(R 1’ )(C=O) m’ -(V) n’ -R S3’ ' group, optionally substituted -X R3’ -alkyl group, optionally substituted -X R3’ -aryl group; optionally substituted -X R3’ -HET group, optionally substituted -X R3’ -aryl-HET group or optionally substituted -X R3’- HET-aryl group, wherein R S3’ is an optionally substituted alkyl group (e.g., C 1-10 Alkyl (preferably C 1-6 alkyl), an optionally substituted aryl group, or a HET group; R 1’ is H or C 1-3 an alkyl group (preferably H), V is O, S, or NR 1’ and X R3’ is -(CH2) n -, -(CH2CH2O) n -, -(CH2) n -CH(X v )=CH(X v )-(cis or trans), -(CH2) n -CH≡CH-, or C 3-6 cycloalkyl groups, all of which may be optionally substituted; X v is H, halo, or C optionally substituted with one or two hydroxyl groups or up to three halogens 1-3 is an alkyl group, Alkyl is an optionally substituted C 1-10Alkyl (preferably C 1-6 alkyl) groups (in certain preferred embodiments, the alkyl groups are end-capped with a halogen, often chlorine or bromine); aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thienes, dihydrothienes, tetrahydrothienes, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each of which, when substituted, is preferably C 1-3 substituted with an alkyl group (preferably methyl) or a halogen (preferably fluorine or chlorine), or a group selected from the following: [ka] ULM-g~ULM-i S c is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halogen (preferably fluorine or chlorine), optionally substituted C1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens); ULM-g~ULM-i R URE is H, C 1-6 Alkyl (preferably H or C 1-3 alkyl) or -C(O)(C 0-6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine), or is an optionally substituted heterocyclyl (e.g., optionally substituted piperidinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydrothiophenyl, optionally substituted piperidinyl, optionally substituted piperazinyl); ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably chlorine or fluorine), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens), or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl) ULM-g~ULM-i RPRO is H, optionally substituted C 1-6 alkyl, optionally substituted aryl (phenyl or naphthyl), optionally substituted heteroaryl, or optionally substituted heterocyclyl, wherein the optionally substituted heteroaryl or optionally substituted heterocyclyl is selected from optionally substituted oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, diazolyl, oxoimidazolyl, pyrrolyl, pyrrolidinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, dihydrothienyl, tetrahydrothienyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, benzofuranyl, indolyl, indolizinyl, or azaindolizinyl, and the optional substituents are selected from C 1-3 alkyl groups (e.g., methyl), halogen (e.g., F or Cl); ULM-g~ULM-i R PRO1 and R PRO2 are each independently H, optionally substituted C 1-3 are alkyl groups or together form a keto group, each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each m' in ULM-g to ULM-i is 0 or 1, Each n' in ULM-g to ULM-i is 0 or 1, The alkyl, aryl, or HET group is optionally connected to the PTM group via a linker.

[0154] In an alternative embodiment, R of ULM-g through ULM-i 3 ' is -(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET, or -(CH2CH2O) n -HET, wherein The aryl of ULM-g to ULM-i is preferably —(CH)n OH, C1-C6 alkyl (CN, up to three halogens, may be further substituted with OH), -(CH2) n O(C1-C6) alkyl, amine, mono- or di-(C 1-6 phenyl optionally substituted with one or two substituents selected from alkyl)amines (wherein the alkyl group on the amine is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine and chlorine); Aryl of ULM-g to ULM-i is -(CH2) n OH, -(CH2) n -O-(C 1-6 ) alkyl, -(CH2) n -O-(CH2) n -(C 1-6 ) alkyl, -(CH2) n -C(O)(C 0-6 ) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C 0-6 ) alkyl, amine, mono- or di-(C 1-6 alkyl)amines (where the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine and chlorine)), CN, NO, optionally substituted -(CH) n -(V) m’ -CH2) n -(V) m’ -(C 1-6 ) alkyl, -(V) m’ -(CH2CH2O) n -R PEG wherein V is O, S, or NR 1’ and R 1’ is H or a C1-C3 alkyl group (preferably H), and R PEG is H or optionally substituted C 1-6 an alkyl group (including optionally substituted with a carboxyl group); or Aryl of ULM-g to ULM-i is oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (when substituted, each is preferably C 1-3 optionally substituted with an alkyl group (preferably methyl) or halogen (preferably fluorine or chlorine), or heterocyclyl, including heteroaryl, selected from the group consisting of groups selected from: [ka] ULM-g~ULM-i S c is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halogen (preferably fluorine or chlorine), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1-6alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens); ULM-g~ULM-i R URE is H, C 1-6 Alkyl (preferably H or C 1-3 alkyl) or -C(O)(C 0-6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halogen (preferably chlorine or fluorine), optionally substituted C 1-6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl), ULM-g~ULM-i R PRO is H, optionally substituted C 1-6alkyl, or oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably C 1-3 an optionally substituted aryl (phenyl or naphthyl), heteroaryl or heterocyclyl group selected from the group consisting of alkyl groups, preferably methyl, or halogen, preferably fluorine or chlorine, benzofuran, indole, indolizine, azaindolizine; ULM-g~ULM-i R PRO1 and RPRO2 are each independently H, optionally substituted C 1-3 are alkyl groups or together form a keto group, The HET of ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oxoimidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, or quinoline (each preferably C 1-3 substituted with an alkyl group (preferably methyl) or a halogen (preferably fluorine or chlorine), benzofuran, indole, indolizine, azaindolizine, or a group according to the following chemical structure: [ka] ULM-g~ULM-i S c is CHR SS , N.R. URE , or O, ULM-g~ULM-i R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C 1-6Alkyl (preferably substituted with one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens) or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl), ULM-g~ULM-i R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted —C(O)(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); ULM-g~ULM-i R URE is H, C 1-6 Alkyl (preferably H or C 1-3 alkyl) or -C(O)(C 0-6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine), or optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; ULM-g~ULM-i Y C is N or CR YC where R YC is H, OH, CN, NO, halogen (preferably chlorine or fluorine), optionally substituted C 1-6alkyl (preferably substituted with one or two hydroxyl groups or up to three halogens (e.g., CF), optionally substituted O(C 1-6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halogens), or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1-6 Alkyl groups (preferably C 1-3 alkyl) ULM-g~ULM-i R PRO is H, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; ULM-g~ULM-i R PRO1 and RPRO2 are each independently H, optionally substituted C 1-3 are alkyl groups or together form a keto group, Each m' in ULM-g to ULM-i is independently 0 or 1; each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each of the compounds is optionally connected, preferably on the aryl or HET group, to a PTM group via a linker group.

[0155] In yet additional embodiments, preferred compounds are compounds according to the following chemical structure: [ka] (In the formula, ULM-i R 1’ is OH or a group that is metabolized to OH in the patient or subject, ULM-i R 2’ is -NH-CH-aryl-HET (preferably a phenyl directly linked to a methyl substituted thiazole); ULM-i R 3’ is -CHR CR3’ -NH-C(O)-R 3P1 group or -CHR CR3’ -R 3P2 It is the basis, ULM-i R CR3’ is C 1-4 an alkyl group, preferably methyl, isopropyl or tert-butyl; ULM-i R 3P1 is C 1-3 Alkyl (preferably methyl), optionally substituted oxetane group (preferably methyl substituted), -(CH2) n OCH3 group, where n is 1 or 2 (preferably 2), or [ka] group (the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (linked to the carbonyl at the 2- or 3-position), ULM-i R 3P2 teeth, [ka] It is the basis, The aryl of ULM-i is phenyl, HET of ULM-i is an optionally substituted thiazole or isothiazole; ULM-i R HET is H or a halo group (preferably H), or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, each of which is optionally connected to a PTM group via a linker group.

[0156] In certain embodiments, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group according to the following chemical structure: [ka] ULM-j (In the formula, each R and R of ULM-j is independently OH, SH, or optionally substituted alkyl, or R, R and the carbon atom to which they are attached combine to form a carbonyl; R7 of ULM-j is H or optionally substituted alkyl; E of ULM-j is a bond, C=O, or C=S, G of ULM-j is a bond, optionally substituted alkyl, —COOH or C═J; J of ULM-j is O or N-R8, R8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy; M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or [ka] and 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 to a ULM, optionally substituted heteroaryl, or haloalkyl, or R, R 10 and the carbon atom to which they are attached, join to form an optionally substituted cycloalkyl; ULM-j R 11 is an optionally substituted heterocyclyl, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, or [ka] and ULM-j R 12is H or optionally substituted alkyl, ULM-j R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, Each R of ULM-j 14 are independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, azetidine, optionally substituted alkoxy, or optionally substituted heterocyclyl; ULM-j R 15 is H, CN, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; Each R of ULM-j 16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted CN, or optionally substituted haloalkoxy; Each R of ULM-j 25 are independently H or optionally substituted alkyl, or both R 25 The groups may be taken together to form an oxo or an optionally substituted cycloalkyl group; ULM-j R 23 is H or OH, Z1, Z2, Z3, and Z4 of ULM-j are independently C or N; ULM-j, wherein o is 0, 1, 2, 3, or 4), or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0157] In certain embodiments, when G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and o is 0.

[0158] In certain embodiments, when G of ULM-j is C=J, J is O, R7 is H, and each R 14 is H and R 15 is an optionally substituted heteroaryl and o is 0. In other cases, E is C=O and M is [ka] is.

[0159] In certain embodiments, when E of ULM-j is C═O, R 11 is optionally substituted heterocyclyl or [ka] and M is [ka] is.

[0160] In certain embodiments, when E of ULM-j is C═O, M is [ka] and R 11 teeth, [ka] and each R 18 is independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0161] In certain embodiments, each R 14is independently substituted with at least one of H, hydroxyl, halo, amine, amido, alkoxy, alkyl, haloalkyl, or heterocycle.

[0162] In certain embodiments, R of ULM-j 15 teeth, [ka] CN, or haloalkyl, and each R 18 is independently H, halo, optionally substituted alkoxy, cyano, aminoalkyl, amidoalkyl, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0163] In certain embodiments, ULM is a group according to the following chemical structure: [ka] (In the formula, G of ULM-k is C=J, J is O, R7 of ULM-k is H, Each R of ULM-k 14 are independently H, amide, alkyl, e.g., methyl (one or more C 1-6 or C(O)NR'R" optionally substituted with alkyl groups; R' and R" are each independently H, optionally substituted alkyl, or cycloalkyl; ULM-k's o is 0, ULM-k R 15 is as defined above for ULM-j, ULM-k R 16 is as defined above for ULM-j, ULM-k R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl).

[0164] In other cases, the R of ULM-k 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

[0165] In other embodiments, ULM is a group according to the following chemical structure: [ka] (In the formula, G of ULM-k is C=J, J is O, R7 of ULM-k is H, Each R of ULM-k 14 is H, ULM-k's o is 0, ULM-k R 15 is selected from the group consisting of optionally substituted: [ka] (Wherein, R of ULM-k 30 is H or optionally substituted alkyl).

[0166] In other embodiments, ULM is a group according to the following chemical structure: [ka] (In the formula, E of ULM-k is C=O, The M in ULM-k is [ka] and ULM-k R 11 is selected from the group consisting of optionally substituted: [ka]

[0167] In yet another embodiment, a compound of the following chemical structure: [ka] (In the formula, E of ULM-k is C=O, ULM-k R 11 teeth, [ka] and The M in ULM-k is [ka] and q of ULM-k is 1 or 2, ULM-k R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or [ka] and ULM-k R 21 is H or optionally substituted alkyl, ULM-k R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl).

[0168] In any embodiment described herein, R of ULM-j or ULM-k 11 is selected from the group consisting of: [ka] [ka]

[0169] In certain embodiments, R of ULM-j or ULM-k 11 is selected from the group consisting of: [ka] [ka]

[0170] In certain embodiments, ULM is a group according to the following chemical structure: [ka] (In the formula, X in ULM-1 is O or S; Y of ULM-l is H, methyl or ethyl; ULM-l R 17 is H, methyl, ethyl, hydroxymethyl or cyclopropyl, M of ULM-l is optionally substituted aryl, optionally substituted heteroaryl, or [ka] and R9 of ULM-l is H, ULM-l R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl; R11 of ULM-l is an optionally substituted heteroaromatic ring, an optionally substituted heterocyclyl, an optionally substituted aryl, or [ka] and ULM-l R 12 is H or optionally substituted alkyl, ULM-l R 13is 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).

[0171] In some embodiments, ULM is a group according to the following chemical structure: [ka] (In the formula, Y of ULM-m is H, methiol or ethyl; R9 of ULM-m is H, R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; ULM-m R 11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, an optionally substituted heterocyclyl).

[0172] In other preferred embodiments of the present disclosure, ULM is a group according to the following chemical structure: [ka] (In the formula, ULM-n R 17 is methyl, ethyl, or cyclopropyl; ULM-n R9, R 10 , and R 11 is as defined above). In other cases, R9 is H; ULM-n R 10is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0173] In other preferred embodiments of the present disclosure, ULM is a group according to the following chemical structure: [ka] or a pharmaceutically acceptable salt thereof, R1 is H, optionally substituted alkyl or optionally substituted cycloalkyl; R3 is an optionally substituted 5-6 membered heteroaryl; W 5 is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted pyridinyl; R 14a and R 14b one of which is H, optionally substituted alkyl, optionally substituted haloalkyl (e.g., fluoroalkyl), optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 and R 14a and R 14b The other is H or R 14a , R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or an aziridine; R 15is CN, optionally substituted fluoroalkyl, [ka] and Each R 16 is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy; Each R 26 are independently H, optionally substituted alkyl, or NR 27a R 27b and Each R 27a and R 27b are independently H, optionally substituted alkyl, optionally substituted cycloalkyl (e.g., optionally substituted 3- to 5-membered cycloalkyl), or R 27a and R 27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; Each R 28 are independently H, halogen, CN, optionally substituted aminoalkyl, optionally substituted amidoalkyl, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted alkylamine, optionally substituted hydroxyalkyl, amine, optionally substituted alkynyl, or optionally substituted cycloalkyl; o is 0, 1 or 2; p is 0, 1, 2, 3, or 4).

[0174] In any of the aspects or embodiments described herein, ULM is represented by the following formula: [ka] (In the formula, X 4 , X 5 , and X6 are selected from CH and N, where N is 2 or less; R 1 is C 1-6 is alkyl, R 3 is the same as the definition for ULM-o and ULM-p, R 14a and R 14b one of which is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphoric acid, 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 is H or R 14a and R 14b together with the carbon atoms to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or aziridine; Each R 27a and R 27b are independently H, C 1-6 alkyl or cycloalkyl (e.g., optionally substituted 3- to 5-membered cycloalkyl); o is 0, 1, or 2; q is 1, 2, 3 or 4; R 15 is optionally replaced [ka] or CN, R 28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C 1-4 alkyl), CH2NHC(O)C 1-4 Alkyl, NH2, [ka] and R 28C is H, methyl, fluoro, or chloro; R 16 is H, C 1-4 Alkyl, fluoro, chloro, CN, or C 1-4 (alkoxy).

[0175] In any aspect or embodiment described herein, R 14a and R 14b is H, C 1-4 Alkyl, C 1-4 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkyloxyalkyl, C 1-4 Alkyl-NR 27a R 27b and CONR 27a R 27b is selected from.

[0176] In any aspect or embodiment described herein, R 14a and R 14b At least one of is H (e.g., R 14a and R 14b are both H).

[0177] In any aspect or embodiment described herein, R 14a and R 14bat least one of optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR 26 ,CONR 27a R 27b , NHCOR 26 , or NHCH3COR 26 Alternatively, in any aspect or embodiment described herein, R 14a and R 14b one of which is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted 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 is H.

[0178] In any aspect or embodiment described herein, R 14a and R 14b together with the carbon atoms to which they are attached, [ka] where R 23 is H, C 1-4 Alkyl, -C(O)C 1-4 alkyl.

[0179] In other preferred embodiments of the present disclosure, ULM is a group according to the following chemical structure: [ka] or a pharmaceutically acceptable salt thereof, X is CH or N; R1, R3, and R of ULM-q and ULM-r 14a , R 14b , and R 15 is the same as the definition for ULM-o and ULM-p).

[0180] In any of the aspects or embodiments described herein, the ULM described herein may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Additionally, in any of the aspects or embodiments described herein, the ULM described herein may be coupled to a PTM via a bond or by a chemical linker.

[0181] In certain embodiments of the disclosure, the ULM moiety is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (wherein the VLM can be connected to the PTM via a linker described herein at any suitable position, e.g., an aryl, heteroaryl, phenyl, or phenyl of an indole group, optionally via any suitable functional group, e.g., an amine, ester, ether, alkyl, or alkoxy).

[0182] In any of the aspects or embodiments described herein, the ULM is a ULM provided in Table 1.

[0183] Exemplary Linkers In any of the aspects or embodiments described herein, the compound comprises a linker (L) described herein.

[0184] In certain embodiments, the compounds described herein include a means for chemically coupling a PTM to a ULM, e.g., one or more PTMs are chemically linked or coupled to one or more ULMs (e.g., at least one of the VLMs) via a chemical linker (L). In certain embodiments, the linker group L is a linker group consisting of one or more covalently connected structural units (e.g., -A L 1… (A L ) q -or-(A L ) q -), wherein A L 1 is a group that is coupled to a PTM, and (A L ) q is the group coupled to the ULM.

[0185] In any aspect or embodiment described herein, the connection or coupling of the linker (L) to the ULM (e.g., VLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, any subsequent heteroatom, if present, is separated by at least one single carbon atom (e.g., —CH—), e.g., by an acetal or aminal group. By way of further example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

[0186] In any aspect or embodiment described herein, the linker group L may be a bond or a group of the formula -(A L )q -, where A is a chemical moiety and q is an integer between 1 and 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, , 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80), where L covalently binds to both the PTM and ULM, providing binding of the PTM to the protein target and ULM to the E3 ubiquitin ligase, resulting in ubiquitination of the target protein.

[0187] In any aspect or embodiment described herein, the linker group L may be a bond or a group of the formula -(A L ) q -, where A is a chemical moiety, q is an integer between 6 and 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25), and L is covalently attached to both the PTM and the ULM, providing for attachment of the PTM to a protein target and attachment of the ULM to an E3 ubiquitin ligase in sufficient proximity to effect ubiquitination of the target protein.

[0188] In any aspect or embodiment described herein, the linker group L is -(A L ) q - in which (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; q of the linker is an integer of 1 or greater, Each A L is a bond, CR L1 RL2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 0 to 9 R L1 and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 8 R L1 and / or R L2 C optionally substituted with a group 5-13 Spiroheterocyclyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 and independently selected from the group consisting of heteroaryl optionally substituted with a group, wherein R L1 or R L2 each independently, optionally linked to other groups, L5 forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R L1 , R L2 , R L3 , RL4 and R L5 are independently H, halo, and C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 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 1-8alkyl)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 SO2 NH2.

[0189] In any aspect or embodiment described herein, each A L is CR L1 R L2 , O, N.R. L3 ,CONR L3 , CO, CR L1 =CR L2 , C≡C, 1 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heteocyclyl, 1 to 6 R L1 and / or R L2 aryl optionally substituted with a group, and 1 to 6 R L1 and / or R L2 and independently selected from the group consisting of heteroaryl optionally substituted with a group, wherein R L1 or R L2 each independently, optionally linked to other groups, L5 forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R L1 , R L2 , R L3 , and R L5 are each independently a halogen, C 1-8 Alkyl, OC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, CCH, COC 1-8 alkyl, CO2H, CN, CF3, CHF2, CH2F, or NO2.

[0190] In certain embodiments, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0191] In certain embodiments, for example, when the linker q is greater than 2, (A L ) q is A L 1 and (A L ) q is a group to the unit A L couples a PTM to a ULM.

[0192] In certain embodiments, for example, when the q of the linker is 2, (A L ) q is A L 1 and a ULM or PTM.

[0193] In certain embodiments, for example, when the q of the linker is 1, the structure of the linker group L is -A L 1- and A L 1 is a group connecting the ULM moiety and the PTM moiety.

[0194] In certain embodiments, the unit A of the linker (L) L includes groups represented by a general structure selected from the group consisting of: -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(lower alkoxyl)-OCH2-, -NR(CH2) n-(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(heterocycloalkyl)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(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)-CH 2、 -NR(CH2CH2) n -(heterocyclyl)-(heterocyclyl)-CH, -N(R1R2)-(heterocyclyl)-CH, where n of the linker can be 0 to 10; R of the linker can be H, lower alkyl, The linkers R1 and R2 can form a ring together with the N to which they are connected).

[0195] In any aspect or embodiment described herein, L is selected from the group consisting of: [ka] [ka] (In the formula, each of m, n, o, p, q, and t is independently selected from the integers 0, 1, 2, 3, and 4 (preferably 0, 1, or 2); u, w, and v are each independently selected from the integers 0 and 1; X L is -C(CH2)-, -C(CH3)H-, -CH2-, -O-, C=O, or -NH-CH2-, R L is H, OH, F, Cl, or methyl; W L2 is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g., hydroxy, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from haloalkyl, or amino; [ka] is selected from W L3 is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g., hydroxy, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from haloalkyl, or amino; [ka] is selected from W L5 is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g., hydroxy, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, C1-3 a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from haloalkyl, or amino; [ka] is selected from W L6 is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g., hydroxy, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from haloalkyl, or amino; [ka] is selected from W L7 is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g., hydroxy, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from haloalkyl, or amino; [ka] is selected from W L8 is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene (e.g., hydroxy, halogen, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 a 6- to 12-membered or 8- to 12-membered spirocycloalkylene or spiroheterocyclylene substituted with 0, 1, or 2 substituents selected from haloalkyl, or amino; [ka] (selected from).

[0196] In any aspect or embodiment described herein, W L2 teeth, [ka] is selected from.

[0197] In any aspect or embodiment described herein, W L3 teeth, [ka] is.

[0198] In any aspect or embodiment described herein, [ka]

[0199] In any aspect or embodiment described herein, W L5 teeth, [ka] is selected from.

[0200] In any aspect or embodiment described herein, W L6 teeth, [ka] is selected from.

[0201] In any aspect or embodiment described herein, W L7 teeth, [ka] is selected from.

[0202] In any aspect or embodiment described herein, W L8 teeth, [ka] is selected from.

[0203] In any aspect or embodiment described herein, W L7 teeth, [ka] and / or W L8 teeth, [ka] is selected from.

[0204] In any aspect or embodiment described herein, each m, n, o, p, q, and t of the chemical linking moiety (L) is independently selected from the integers 0, 1, or 2.

[0205] In any aspect or embodiment described herein, L is selected from the group consisting of: [ka] [ka] [ka]

[0206] In additional embodiments, the linker (L) includes, but is not limited to, a structure selected from the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety: [ka] (In the formula, W L1 and WL2 are independently absent, R Q wherein each R is a 4-8 membered ring containing 0-4 heteroatoms optionally substituted with Q are independently H, halogen, OH, CN, CF3, optionally substituted straight or branched chain C 1-6 Alkyl, optionally substituted straight or branched chain C 1-6 Alkoxy or two 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 are each independently a bond, C 1-6 Alkyl (linear, branched, optionally substituted) and optionally one or more C atoms substituted by O; or C 1-6 alkoxy (straight chain, branched chain, optionally substituted); n is an integer from 0 to 10, [ka] indicates the point of attachment to the PTM or ULM).

[0207] In additional embodiments, the linker (L) includes, but is not limited to, a structure selected from the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety: [ka] (In the formula, W L1 and W L2 are each independently absent, aryl, heteroaryl, ring, heterocyclyl, C 1-6 Alkyl and optionally one or more C atoms replaced by O or N, C 1-6 Alkenyl and optionally one or more C atoms replaced by O, C 1-6Alkynyl and optionally one or more C atoms replaced by O, bicyclic, biaryl, biheteroaryl, or biheterocyclyl, each of which is R Q and each R Q are independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched chain C 1-6 Alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more -F), OH, NH, NR Y1 R Y2 , CN or two 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 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms replaced by O; C1-C6 alkoxy (linear, branched, optionally substituted), Q L is a 3-6 membered alicyclic or aromatic ring containing 0-4 heteroatoms, which are optionally bridged and are Q and each R Q are independently selected from H, straight or branched chain C optionally substituted with one or more halo groups; 1-6 Alkyl or C 1-6 Alkoxyl or two R Q the groups, together with the atoms to which they are attached, form a 3- to 8-membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 are independently H, OH, C1-6 Alkyl (straight chain, branched chain, optionally substituted with one or more halo, C 1-6 alkoxyl) or R 1 , R 2 together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms; n is an integer from 0 to 10, [ka] indicates the point of attachment to the PTM or ULM).

[0208] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl group, a phenyl group, a benzyl group, an alkyl group, an alkylene group, or a heterocyclyl group. In certain embodiments, the linker can be asymmetric or symmetric.

[0209] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0210] In another embodiment, the present disclosure is directed to a compound or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof comprising a PTM group as described above, wherein the PTM group binds to a target protein or polypeptide (e.g., SMARCA2, BRAHMA, or BRM) that is ubiquitinated by a ubiquitin ligase, and is chemically linked to a ULM group either directly or through a linker moiety, L, which is a linker moiety as described above, which may or may not be present, that chemically (covalently) links the ULM to the PTM.

[0211] In certain embodiments, the linker group L is a group comprising one or more covalently connected structural units independently selected from the following: [ka] X is selected from the group consisting of O, N, S, S(O), and SO2, n is an integer from 1 to 5, and R L1 is hydrogen or alkyl, [ka] is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; [ka] is a monocyclic or bicyclic cycloalkyl or heterocyclyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano, and the phenyl ring fragment may be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano. In one embodiment, the linker group L comprises up to 10 covalently connected structural units as described above.

[0212] In any aspect or embodiment described herein, the ULM and PTM groups are covalently linked to the linker group via any group that is appropriate and stable for the linker chemistry. In any aspect or embodiment described herein, the linkers are independently covalently linked to the ULM and PTM groups via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which may be inserted anywhere on the ULM and PTM groups to provide for maximal binding of the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain embodiments, when the PTM group is a ULM group, the target protein to be degraded may be the ubiquitin ligase itself.) In any aspect or embodiment described herein, the linker may be linked to an optionally substituted alkyl, alkylene, alkenyl or alkynyl group, aryl group, or heterocyclyl group on the ULM and / or PTM group.

[0213] Exemplary PTMs In any aspect or embodiment of the present disclosure, the PTM group is a moiety that binds to a target protein, such as switch / sucrose non-fermenting (SWI / SNF)-related matrix-binding actin-dependent chromatin regulator 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 the SMARCA2 or BRM protein (binds to the target protein SMARCA2, BRAHMA, or BRM).

[0214] In certain embodiments, the compounds described herein include a means for binding to a target protein, such as Brm. Thus, in certain aspects, the present disclosure provides bifunctional compounds having a means for binding to Brm, a means for binding to VHL, and a means for chemically coupling the means for binding to Brm to the means for binding to VHL.

[0215] The compositions described below exemplify some of the components of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target SMARCA2. These binding moieties are linked, preferably via a linker, to a ubiquitin ligase binding moiety to present the target protein (bound to the protein target moiety) in proximity to a ubiquitin ligase for ubiquitination and degradation. Any protein (e.g., SMARCA2, BRAHMA, or BRM) that can be bound to a protein target moiety or PTM group and act on or be degraded by a ubiquitin ligase is a target protein according to the present disclosure.

[0216] The present disclosure may be used to treat many disease states and / or conditions, including any disease state and / or condition in which protein regulation is aberrant (e.g., SMARCA4 deficiency / mutation) and in which the patient would benefit from the degradation and / or inhibition of proteins such as SMARCA2, BRAHMA, or BRM.

[0217] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition regulates protein degradation in a patient or subject, for example, an animal such as a human, and can be used to treat or improve a disease state or condition regulated through the degraded protein. In certain embodiments, the therapeutic composition described herein can be used to cause the degradation of a protein of interest for the treatment or improvement of a disease, for example, at least one of cancers, including lung cancer or non-small cell lung cancer, SWI / SNF-associated cancer, SMARCA4 mutation-associated cancer, SMARCA4-deficient cancer, or cancer in which SMARCA4 expression is reduced compared to normal SMARCA4 expression (e.g., reduced expression compared to expression of unmutated SMARCA4 or wild-type SMARCA4 at a similar location). In any aspect or embodiment described herein, the disease is at least one of SWI / SNF-associated cancer, cancer with SMARCA4 mutation, cancer with SMARCA4 deficiency, or a combination thereof, and may be lung cancer or non-small cell lung cancer.

[0218] In certain additional embodiments, the therapeutic compositions described herein may be used to effect degradation of a protein of interest for the treatment or amelioration of a disease, e.g., a cancer, such as at least one of a SWI / SNF-associated cancer, a SMARCA2-associated cancer, or a cancer with normal or overexpression of SMARCA2.

[0219] In an alternative aspect, the present disclosure relates to a method for treating a pathology or ameliorating the symptoms of a disease or condition in a subject in need thereof by degrading a protein or polypeptide that regulates the pathology or condition, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle, and optionally an additional bioactive agent, wherein the composition is effective to treat or ameliorate the disease or disorder or symptoms thereof in the subject. The method according to the present disclosure can be used to treat many pathologies or conditions, including cancer, by administering an effective amount of at least one compound described herein. The pathology or condition may be caused by a microbial or other exogenous agent, such as a virus, bacteria, fungus, protozoan, or other microorganism, or may be a pathology caused by overexpression of a protein that results in the pathology and / or condition.

[0220] In another aspect, the present description provides methods for determining the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0221] The term "target protein" is used to describe a protein or polypeptide that is targeted for conjugation with a compound according to the present disclosure and subsequent degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target 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.

[0222] Protein targets can be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into compounds according to the present disclosure can alter the activity level of the protein for therapeutic end results.

[0223] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein, such as SMARCA2 or BRM, or other protein or polypeptide of interest, and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. The compositions described below are illustrative of some of the components of small molecule target proteins.

[0224] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by: [ka] (In the formula, W PTM1 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano, or a combination thereof); W PTM2 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM3is an optionally substituted 3-9 membered aryl or heteroaryl ring (e.g., an optionally substituted 5-6 membered aryl or heteroaryl ring, or a 3-9 or 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), or an optionally substituted 4-10 membered cycloalkyl or heterocyclyl, such as optionally substituted bridged bicycloalkyl and bridged biheterocyclyl rings (e.g., a 4-10 membered cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM5 is absent (in which case, W PTM3 is directly connected to L (linker) or ULM), or an optionally substituted alkyl, an optionally substituted 5-6 membered cycloalkyl, heterocycle, aryl or heteroaryl ring (e.g., a 5-6 membered cycloalkyl, heterocycle, aryl or heteroaryl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); [ka] is the point of attachment to the linker, ULM group, or VLM group). In any aspect or embodiment described herein, W PTM5 is piperidine.

[0225] In certain embodiments, W PTM1 contains a phosphate substitution.

[0226] In any aspect or embodiment described herein, the PTM of the disclosure is represented by Formula I and is at least one of the following: W PTM1is an optionally substituted phenyl or pyridyl (e.g., phenyl substituted with a hydroxy or phosphate substituent, substituted as described herein and with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof, with or without additional optional substituents selected as described herein); W PTM2 is an optionally substituted 6-membered heteroaryl ring (e.g., substituted as described herein, e.g., pyridazine substituted with a pyridazineamino group); W PTM3 is an optionally substituted 5-6 membered heteroaryl (e.g., pyrazole, pyrrole, imidazole, oxazole, oxadiazole, or triazole): W PTM5 is as described in any aspect or embodiment described herein (e.g., W PTM5 may be absent or a pyridine ring); or A combination of these.

[0227] In any aspect or embodiment described herein, e.g., an embodiment comprising a PTM of Formula I, W PTM3 is pyrazole or a 6- to 8-membered heterocyclyl (e.g., piperazine or diazabicyclooctane).

[0228] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by: [ka] (In the formula, W PTM1 , W PTM2 , and W PTM5 is as described in any aspect or embodiment described herein (e.g., W PTM5may or may not be present, in which case WPTM4 may be directly connected to L (linker) or ULM), W PTM4 is W PTM2 an optionally substituted 3-7 carbon cycloalkyl or heterocyclyl (e.g., an optionally substituted 5-7 carbon cycloalkyl or heterocyclyl or a 5-7 carbon cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a ring; [ka] is the point of attachment to the linker, ULM group, or VLM group).

[0229] In any aspect or embodiment described herein, the PTM of the disclosure is represented by Formula II, wherein W PTM1 , W PTM2 and W PTM5 is as described in any 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 form the dihydropyrazino[2,3-e]pyridazine shown below: [ka]

[0230] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by: [ka] (In the formula, W PTM1 and W PTM2 is as described in any aspect or embodiment described herein; W PTM6 and W PTM7 are independently an optional 4-7 cycloalkyl or heterocyclyl (e.g., 4-7 cycloalkyl or heterocyclyl each substituted with 0, 1, or 2 substituents independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM6 and W PTM7 are fused or linked via a spiro connection; [ka] is the point of attachment to the linker, ULM group, or VLM group).

[0231] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by Formula III, wherein W PTM1 and W PTM2 are each independently selected as described in any aspect or embodiment described herein (e.g., W PTM1 is phenyl substituted with a hydroxy substituent, with or without additional optional substituents selected as described herein; W PTM2 is a pyridazine substituted with an amino group), W PTM6 and W PTM7 is a spirocyclic ring system, for example a spirocyclic ring selected from: [ka]

[0232] In any aspect or embodiment described herein, the PTM of the disclosure is represented by: [ka] (In the formula, W PTM1 is as described in any other aspect or embodiment described herein, e.g., WPTM1 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM2 is as described in any other aspect or embodiment described herein, e.g., W PTM2 is an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM5 is as described in any other aspect or embodiment described herein, e.g., W PTM5 is absent or optionally substituted alkyl, an optionally substituted 5- to 6-membered cycloalkyl, heterocycle, aryl, or heteroaryl ring (e.g., a 5- to 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), provided that the heteroatom is not directly attached to a carbon atom of a carbon-carbon double bond or a carbon-carbon triple bond; L PTM is selected from the group consisting of alkyne or alkene optionally substituted with 1 to 2 substituents independently selected from methyl, fluoro, or haloalkyl; C1-C2 alkyl optionally substituted with 1 to 2 substituents selected from methyl, fluoro, or haloalkyl; or cyclopropyl optionally substituted with 1 to 2 substituents selected from methyl, fluoro, or haloalkyl; R PTM1 and R PTM2are independently H, halogen, OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; [ka] is the point of attachment to the linker, ULM group, or VLM group).

[0233] In any aspect or embodiment described herein, R PTM1 and R PTM2 are independently H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0234] In any aspect or embodiment described herein, W PTM5 is an optionally substituted alkyl, an optionally substituted 5-6 membered cycloalkyl, heterocycle, aryl, or heteroaryl ring (e.g., a 5-6 membered cycloalkyl, heterocycle, aryl, or heteroaryl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), with the proviso that the heteroatom is not directly attached to a carbon atom of a carbon-carbon double bond or a carbon-carbon triple bond.

[0235] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by Formula IV and is at least one of the following: W PTM1 is phenyl substituted with a hydroxy or phosphate substituent, with or without additional optional substituents selected as described herein; W PTM2 is a pyridazine substituted with an amino group; W PTM5 is absent, a pyrazole ring, or a pyridine ring; or A combination of these.

[0236] In any aspect or embodiment described herein, the PTM of the disclosure is represented by: [ka] or a pharmaceutically acceptable salt thereof, W PTM3 is absent or optionally substituted 5-6 membered heteroaryl, optionally substituted 4-9 membered cycloalkyl or heterocyclyl rings, optionally substituted bridged bicycloalkyl and bridged biheterocyclyl rings; W PTM5 is an optionally substituted 5-6 membered heteroaryl or aryl, for example, pyridine, or pyridazine.

[0237] In any aspect or embodiment described herein, the PTM of the disclosure is represented by: [ka] or a pharmaceutically acceptable salt thereof (wherein W PTM5 is phenyl, pyridine, pyrimidine or pyrazine).

[0238] In any aspect or embodiment described herein, the PTM of the disclosure is represented by: [ka] or a pharmaceutically acceptable salt thereof.

[0239] In any aspect or embodiment described herein, the PTM of the disclosure is represented by: [ka] or a pharmaceutically acceptable salt thereof, W PTM3is an optionally substituted 5- to 6-membered heteroaryl, an optionally substituted 4- to 9-membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl and bridged biheterocyclyl ring, and W PTM5 is an optionally substituted 5-6 membered heteroaryl or aryl, e.g., pyridine, or pyridazine, and R is 0, 1, 2, or 3 substituents independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano, or combinations thereof.

[0240] In certain embodiments, the hydroxyl group is modified with a phosphate group (ie, a phosphoester group).

[0241] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by:

[0242] [ka] (In the formula, W PTM1 and W PTM2 is as described in any aspect or embodiment described herein (e.g., W PTM5 may or may not be present, in which case WPTM4 may be directly connected to L (linker) or ULM), W PTM3 is absent, or W PTM2 an optionally substituted 5-7 carbon cycloalkyl or heterocyclyl (e.g., a 5-7 carbon cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a ring; W PTM4is an optionally substituted 3-7 membered aryl or heteroaryl ring (e.g., an optionally substituted 5-7 cycloalkyl or heterocyclyl, or a 3-7 or 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), or an optionally substituted 4-9 cycloalkyl or heterocyclyl, such as optionally substituted bridged bicycloalkyl and bridged biheterocyclyl rings (e.g., a 4-9 or 5-7 cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano); W PTM5 is absent (in which case, W PTM4 is directly connected to L (linker) or ULM), or an optionally substituted alkyl, an optionally substituted 5-6 membered cycloalkyl, heterocycle, aryl or heteroaryl ring (e.g., a 5-6 membered cycloalkyl, heterocycle, aryl or heteroaryl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), such as an optionally substituted pyrazole or pyridine ring; [ka] is the point of attachment to the linker, ULM group, or VLM group).

[0243] In any aspect or embodiment described herein, the PTM of the disclosure has a chemical structure represented by: [ka] (In the formula, W PTM1is a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano, or combinations thereof; W PTM2 is a 5-6 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof; W PTM3 is absent, a 3-9 membered aryl or heteroaryl ring optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or a combination thereof; a 3-9 membered cycloalkyl or heterocyclyl optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or a combination thereof; or a bridged bicycloalkyl or bridged biheterocyclyl optionally substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or a combination thereof; W PTM4 is a 3- to 7-membered cycloalkyl or heterocyclyl optionally substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, phosphate, alkylamino, cyano, or combinations thereof; L PTM is O or C1-C6 alkyl optionally substituted with ═O, C1-C4 alkyl or C1-C3 alkoxy; [ka] is the point of attachment to the linker, ULM group, or VLM group).

[0244] In any aspect or embodiment described herein, the PTM is selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, [ka] is the point of attachment to the chemical linking moiety).

[0245] In any aspect or embodiment described herein, the PTM is selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, [ka] is the point of attachment to the chemical linking moiety (e.g., the chemical linker group is attached to a carbon or heteroatom of the designated ring).

[0246] In any aspect or embodiment described herein, the PTM is selected from: [ka] [ka] (In the formula, [ka] is the point of attachment to the linker, ULM group, and / or VLM group).

[0247] The compositions described herein are illustrative of some of the components of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. The references cited below are incorporated herein by reference in their entirety.

[0248] therapeutic composition Disclosed herein are pharmaceutical compositions comprising an effective amount of at least one bifunctional compound combination described herein in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, and represent a further aspect of the present disclosure. In some embodiments, the pharmaceutical compositions disclosed herein further comprise an additional pharmaceutically active compound as described elsewhere herein.

[0249] The compositions of the present disclosure include, where applicable, pharmaceutically acceptable salts of the compounds described herein, particularly acid or base addition salts. The pharmaceutically acceptable acid addition salts of the basic compounds can be prepared and formed from non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as, among others, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts).

[0250] Bases that can be used to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and pharmaceutically acceptable lower alkanolammonium and other base salts of organic amines.

[0251] The compounds described herein may be administered in single or divided doses by oral, parenteral, or topical routes in accordance with the present disclosure. Administration of the active compounds may range from continuous administration (intravenous infusion) to multiple oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository routes, among others. Enteric-coated oral tablets may also be used to improve the bioavailability of the compounds from oral administration. The most effective dosage form may depend on the pharmacokinetics of the particular agent selected and the severity of the patient's disease. Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intranasal, intratracheal, or intrapulmonary administration may also be used. Accordingly, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. Compounds according to the present disclosure may be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Sustained or controlled release forms are preferably administered orally, but may also be in suppository and transdermal or other topical form. Intramuscular injection in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0252] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in controlled-release formulations.The pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0253] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0254] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions. Acceptable vehicles and solvents include 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 monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable formulations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0255] 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 liquids.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When oral aqueous suspensions are required, active ingredients can be combined with emulsifiers and suspending agents.In addition, if desired, some sweeteners, flavorings or colorings can be added.

[0256] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These suppositories are solid at room temperature but liquid at rectal temperature, so that they melt in the rectum and release the drug. They can be prepared by mixing the drug with a suitable non-irritating excipient. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0257] The amount of compound in the pharmaceutical compositions described herein that may be combined with carrier materials to produce a single dosage form can vary depending on the host and disease being treated and the particular mode of administration. Preferably, the compositions should be formulated to contain about 0.05 milligrams to about 750 milligrams or more of the active ingredient, alone or in combination with at least one other compound according to the present disclosure, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams.

[0258] It is also understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the particular compound employed, the patient's age, body 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 particular disease or condition being treated.

[0259] Patients or subjects in need of therapy using the compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure (including a pharmaceutically acceptable salt, solvate or polymorph thereof), optionally in a pharmaceutically acceptable carrier or diluent, either alone or in combination with other known therapeutic agents as otherwise specified herein.

[0260] The compounds can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, or subcutaneously.

[0261] 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 serious toxic effects to the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein are in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, and more usually 0.5 to about 25 mg per kilogram of recipient / patient body weight per day.

[0262] The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, those containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. In many cases, an oral dosage of about 25 to 250 mg is convenient.

[0263] 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 by administration as a bolus of the active ingredient. Oral administration is also suitable for achieving effective plasma concentrations of the active agent.

[0264] The concentration of the active compound in the drug composition depends 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 also be noted that the dosage value will vary depending on the severity of the condition to be alleviated. For any particular subject, the specific dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and it should be further understood that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or implementation of the claimed compositions. The active ingredient may be administered at once or may be divided into several small doses to be administered at various time intervals.

[0265] Oral compositions generally contain an inert diluent or an edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. To administer an oral therapeutic agent, the active compound or its prodrug derivative may be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition.

[0266] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. If the unit dosage form is a capsule, in addition to the above-mentioned types of materials, it may contain a liquid carrier such as fatty oil. In addition, the unit dosage form may contain various other materials that modify the physical form of the dosage form, such as sugar coating, shellac, or enteric coating.

[0267] 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 may also contain certain preservatives, dyes and colorings and flavors.

[0268] The active compound or a pharmaceutically acceptable salt thereof can also be mixed with other active materials that do not impair the desired action, or with materials that complement the desired action, such as anticancer agents, including pembrolizumab, among others. In certain preferred embodiments of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anticancer agent or a wound healing agent, including an antibiotic, as described elsewhere herein.

[0269] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical administration may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, and phosphates, and agents for adjusting isotonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0270] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0271] In one embodiment, the active compound is prepared with a carrier that protects the compound from rapid excretion 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 clear to those skilled in the art.

[0272] Liposomal suspensions can also be pharmaceutically acceptable carriers.Liposomal suspensions can be prepared according to methods known to those skilled in the art, for example, according to the method described in U.S. Patent No. 4,522,811 (its entirety is incorporated herein by reference).For example, liposomal preparations can be prepared as follows: suitable lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, aracadyl phosphatidylcholine, and cholesterol) are dissolved in an inorganic solvent, which is then evaporated, leaving a thin film of dry lipid on the surface of the container.Then, an aqueous solution of active compound is placed in the container.Then, the container is rotated by hand to remove lipid material from the side of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0273] Treatment method In an additional aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition 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.

[0274] The terms "treat," "treating," and "treatment," as used herein, refer to any act of providing a benefit to a patient to which the present compounds may be administered, including treatment of any disease state or condition that is modulated via the protein to which the present compounds bind. Disease states or conditions, including cancers such as lung cancer, including non-small cell lung cancer, that may be treated using compounds according to the present disclosure are described herein above.

[0275] The present disclosure provides therapeutic compositions described herein for effecting degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In certain additional embodiments, the disease is multiple myeloma. Accordingly, in another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound described herein comprising a ULM and a PTM, preferably linked by a linker moiety, e.g., as described elsewhere herein, wherein the ULM is coupled to the PTM, the ULM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase such as VHL E3 ubiquitin ligase), and the PTM recognizes the target protein, such that, when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, resulting in degradation / inhibition of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides for treating a disease state or condition regulated via a target protein by reducing the level of that protein in a cell, e.g., a patient's cell. In certain embodiments, the methods include administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0276] In additional embodiments, the description provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, comprising administering to a subject in need thereof an effective amount, e.g., a therapeutically effective amount, of a composition comprising a compound described herein or a salt form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

[0277] In another aspect, the present description provides methods for determining the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0278] In another embodiment, the present disclosure is directed to a method of treating a human patient for a disease state or condition that is regulated through a protein, and where degradation of the protein would provide a therapeutic benefit to the patient, the method comprising administering to a patient in need thereof an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be caused by a microbial or other foreign agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that results in the disease state and / or condition.

[0279] The term "disease state or condition" is used to describe any disease state or condition in which dysregulation of a protein (i.e., increased expression of a protein in a patient) occurs and degradation of one or more proteins in the patient can provide beneficial treatment or symptomatic relief to a patient in need thereof. In certain cases, the disease state or condition can be cured.

[0280] Exemplary disease states or conditions that can be treated using the bifunctional compounds of the present disclosure include asthma, autoimmune diseases such as multiple sclerosis, cancer, ciliopathy, 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, and Turner syndrome. In certain embodiments, the compounds disclosed herein are used to treat cancer.

[0281] The terms "neoplasia" or "cancer" are used throughout this specification to refer to the formation and growth of cancerous or malignant neoplasms, i.e., pathological processes that result in abnormal tissue that often grows by more rapid than normal cell proliferation and continues to grow after the stimulus that initiated the new growth has ceased. Malignant neoplasms partially or completely lack structural organization and functional coordination with normal tissue, many of which invade surrounding tissues, metastasize to several sites, tend to recur despite attempted resection, and can lead to the death of the patient unless properly treated. As used herein, the term neoplasia is used to describe all cancerous conditions and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that may be treated with the compounds either alone or in combination with at least one additional anti-cancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, vascular Sarcomas, including sarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that may be treated using compounds according to the present disclosure include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B ALL, precursor B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0282] The term "bioactive agent" is used to describe an agent, other than a compound according to the present disclosure, that is used in combination with the present compounds as an agent having biological activity that assists in achieving the intended treatment, inhibition and / or prevention / prophylaxis for which the present compounds are used. Preferred bioactive agents for use herein include those that have pharmacological activity similar to that resulting from the use or administration of the present compounds, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, antibacterial agents, anti-fungal agents, etc.

[0283] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that may be combined with a compound according to the present disclosure to treat cancer. These agents include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 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 kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, doxorubicin liposomal, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, butter Ranib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662 , tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, Daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine,Raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD12 1974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony stimulator Stimulatory factors, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,Alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, daunorubicin liposomal, Edwina-asparaginase, strontium-89, casopitant, netupin These include antagonist, NK-1 receptor antagonist, 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.

[0284] The term "pharmaceutically acceptable salt" is used throughout this specification to describe one or more salt forms of the compounds described herein that are provided to enhance the solubility of the compound in the gastric fluids of a patient's gastrointestinal tract, where applicable, to facilitate dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium, magnesium, and ammonium salts, among many other acids and bases well known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0285] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (such as an ester, amide, other prodrug group, etc.) that, upon administration to a patient, directly or indirectly provides the compound or an active metabolite of the compound. [Example]

[0286] Abbreviation: ACN: acetonitrile

[0287] ADDP: 1,1'-(azodicarbonyl)dipiperidine

[0288] BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride

[0289] BPO: Benzoyl peroxide

[0290] Cbz: carbonylbenzyloxy

[0291] DAST: Diethylaminosulfur trifluoride

[0292] DBE: 1,2-dibromoethane

[0293] DCM: dichloromethane

[0294] DEAD: Diethyl azodicarboxylate

[0295] DIAD: Diisopropyl azodicarboxylate

[0296] DIBAL: dithiobutylaluminum hydride

[0297] DIEA or DIPEA: Diisopropylethylamine

[0298] DMA: N,N-dimethylacetamide

[0299] DMF: N,N-dimethylformamide

[0300] DMP: Dess-Martin periodinane

[0301] EA: Ethyl acetate

[0302] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0303] HBTU: N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate

[0304] HMDS: Bis(trimethylsilyl)amine

[0305] HMPA: hexamethylphosphoramide

[0306] LDA: lithium diisopropylamide

[0307] MCPBA: metachloroperoxybenzoic acid

[0308] MsCl: methanesulfonyl chloride

[0309] MW: Microwave

[0310] NBS: N-bromosuccinimide

[0311] NMP: N-methylpyrrolidone

[0312] PCC: Pyridinium chlorochromate

[0313] Pd-118 or Pd(dtpf)Cl2: 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium

[0314] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium

[0315] Pd(dba)2: Bis(dibenzylideneacetone)palladium

[0316] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium

[0317] PPTS: Pyridinium p-toluenesulfonate

[0318] PTSA: p-toluenesulfonic acid

[0319] RuPhos-Pd-G3:XPhos-Pd-G3:[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0320] RuPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0321] SFC: Supercritical Fluid Chromatography

[0322] t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0323] TEA: Trimethylamine

[0324] TFA: Trifluoroacetic acid

[0325] TLC: Thin Layer Chromatography

[0326] TMP: 2,2,6,6-tetramethylpiperidine

[0327] TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide

[0328] TosCl or TsCl: p-toluenesulfonyl chloride

[0329] TsOH: p-toluenesulfonic acid

[0330] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0331] XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl

[0332] XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0333] 12354-85-7: Bis(pentamethylcyclopentadienyl rhodium dichloride)

[0334] General synthetic approach The PTMs represented by Formulas I-VII can be synthesized according to the general synthetic routes detailed in the following schemes.

[0335] For PTMs represented by Formula I, a possible general synthetic approach is outlined in the following scheme: [ka]

[0336] Those skilled in the art will recognize that PTM3 But, W PTM3 W via N atoms in PTM2 and W PTM5 When the heterocycloalkyl is connected to N It will be appreciated that the Ar approach can be applied; otherwise, alternative transition metal catalyzed coupling approaches (e.g., Suzuki coupling) may be more appropriate (e.g., W PTM3 is aryl or heteroaryl).

[0337] Furthermore, those skilled in the art will recognize that W PTM5 (or W PTM5AWhen S is an aryl or heteroaryl, the Buchwald coupling described in the scheme above or S N You will recognize that the Ar or Suzuki coupling approach is applicable in most cases. Otherwise, W PTM5 (or W PTM5A When ) is a heterocycloalkyl, the exact approach will depend on the nature of the functional groups present in said heterocycloalkyl. Examples of possible approaches (reductive amination, nucleophilic substitution reactions) are provided in the following schemes. [ka]

[0338] PTM is represented by the general formula V, and W PTM1 and W PTM2 When S is more specifically defined, the compound can be synthesized as described in the following scheme. N It will be appreciated that alternative catalysts, temperatures, solvents, and other experimental conditions compatible with the Ar reaction and the transition metal-mediated coupling reaction may also be used. [ka]

[0339] Those skilled in the art will also recognize that modified approaches are available that allow for attachment of PTMs via different chemical linkers. For example, W PTM5 is connected to L through a CH2 group (X=CH2 in the above scheme). ’ In the case of a connection to a network, the approach described in the following scheme can be envisaged: [ka]

[0340] Or W PTM5 is absent, the PTM of the exemplary bifunctional decomposition compound represented by Formula I is such that the reactive NH is W PTM3If present in W, it can be synthesized according to the following general scheme: PTM3 The linker bond to W PTM5 This can be achieved using the approach described above for [ka]

[0341] Those skilled in the art will recognize that PTM1 , W PTM2 , W PTM3 , W PTM4 , W PTM5 , W PTM6 and W PTM7 It will be appreciated that the synthetic approaches described herein can be modified to suit the particular properties of each ring of Formula II. For example, in some embodiments, an exemplary PTM represented by Formula II can be prepared as described in the following general synthetic scheme, although one of skill in the art will recognize that additional protection / deprotection steps may be required depending on the particular chemical nature of the compound: [ka]

[0342] In some embodiments, when X represents NH, the bifunctional compound is W PTM5 It can be prepared according to one of the two schemes shown below, depending on whether W is present, in which case PTM5 Or L is W PTM4 connected to the N atom of: [ka]

[0343] PTMs represented by general formula IVa can be prepared according to the following general scheme: [ka]

[0344] Those skilled in the art will recognize that PTM5 When is aryl or heteroaryl, W shown in the above scheme PTM5 Those skilled in the art will recognize that the approach to generating connected alkynes is applicable in most cases. PTM5 It will be appreciated that when is a cycloalkyl or heterocycloalkyl, alternative approaches to the generation of the alkyne can be utilized, for example, an approach based on the Ohira-Bestmann reagent as shown in the following scheme: [ka]

[0345] Additionally, PTMs represented by general formulae IVb1 and IVb2 can be prepared according to the following general scheme, as one possible approach: [ka]

[0346] Those skilled in the art will recognize that in many cases the applicable synthetic approach may depend on the exact nature of the components included in the PTM moiety and the nature of the connectivity between them. For example, W PTM3 When contains a reactive NH functionality, many synthetic approaches can be envisioned relating to the preparation of PTMs described by general formula VII, some non-limiting examples of which are depicted in the following scheme: [ka]

[0347] Those skilled in the art will recognize that the bifunctional compounds of the present disclosure can be prepared using a variety of possible sequences of steps. In some embodiments, the bifunctional compounds of the present disclosure are assembled by joining two fragments via a final connection at the center of a linker using the synthetic method shown in the following scheme, for example, preferred general method A. [ka]

[0348] In some embodiments, the PTM-L referred to in Method A 1A The -heterocycloalkyl motif can be formed by the addition of L as shown in General Methods B and C. 1A can be assembled by introducing connections to [ka]

[0349] Those skilled in the art will recognize that certain protecting groups can be used interchangeably in the context of general methods A, B, and C. For example, a Cbz protecting group may be used in place of Boc, in which case alternative cleavage methods (e.g., TMSI / ACN or Pd / C, H) may be utilized.

[0350] Furthermore, those skilled in the art will recognize that the heterocycloalkyl in General Methods A, B, and C is also, by extension, meant to include heterocycloalkyls of different ring sizes than those explicitly indicated, and that the character of heterocycloalkyl is also, by extension, meant to include heteroaryls containing reactive NH functionality. For example, in some embodiments, the heteroaryl can be an optionally substituted imidazole or an optionally substituted pyrazole. The heteroaryl can be subjected to the reductive amination or nucleophilic substitution reaction conditions described in Methods A, B, and C. Those skilled in the art will also recognize that the heteroaryl may require a different protecting group (e.g., SEM) than those shown in the schemes above.

[0351] In some embodiments, a final connection can be introduced between the two portions of the ULM motif as shown in the scheme of General Method D below. [ka]

[0352] The implementation and optimization of the synthesis of the bifunctional molecules described herein may be approached in a stepwise or modular manner.

[0353] In a very similar manner, ligands for E3 ligases, i.e., ULM / VLM, can be identified and optimized.

[0354] Those skilled in the art can use known synthesis methods for combinations of PTMs and ULMs (e.g., VLMs) with or without linker moieties, using available PTMs and ULMs. Linker moieties can be synthesized with a variety of compositions, lengths, and flexibility and can be functionalized to allow sequential attachment of PTM and ULM groups to the distal ends of the linker. In this manner, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. As with PTM and ULM groups, the final bifunctional molecules can undergo repeated cycles of design and optimization to identify molecules with desired properties.

[0355] In some cases, protecting group strategies and / or functional group transformations (FGI) may be required to facilitate the preparation of the desired materials. Such chemical processes are well known to synthetic organic chemists, many of which can be found in texts such as "Greene's Protective Groups in Organic Synthesis" by Peter G.M.Wuts and Theodora W. Greene (Wiley) and "Organic Synthesis: The Disconnection Approach" by Stuart Warren and Paul Wyatt (Wiley).

[0356] Exemplary Synthesis of Compound 1 Prepared according to the following schemes using procedures commonly known to those skilled in the art. [ka]

[0357] Exemplary Synthesis of Compound 2 Step 1 [ka] A flask was charged with tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (1.4 g, 4.66 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.42 g, 5.60 mmol, 1.2 equiv.), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (170 mg, 0.23 mmol, 0.05 equiv.), potassium acetate (915 mg, 9.33 mmol, 2 equiv.), and dioxane (30 mL). The mixture was purged with nitrogen for 10 minutes and then heated to 80 °C for 1 hour. The reaction mixture was cooled to 20 °C and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate=10:1). tert-Butyl N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (1.9 g) was obtained as a colorless oil.

[0358] Step 2 [ka] To a mixture of 5-bromo-1-methyl-pyrazole (800 mg, 4.97 mmol, 1 equiv.), potassium carbonate (1.37 g, 9.94 mmol, 2 equiv.), and tert-butyl N-(5-bromothiazol-4-yl)carbamate (2.07 g, 5.96 mmol, 1.2 equiv.) in water (5 mL) and dioxane (30 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (290 mg, 0.40 mmol, 0.08 equiv.) was added in one portion at 20°C under nitrogen. The mixture was stirred at 90°C for 12 hours. The mixture was cooled to 20°C, poured into ice water (w / w=1 / 1, 50 mL), and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1 to 5 / 1) to give tert-butyl N-[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethyl]carbamate (1.6 g) as a yellow solid.

[0359] tert-Butyl N-[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethyl]carbamate was converted to the title compound according to the following scheme using procedures commonly known to those skilled in the art. [ka] [ka]

[0360] Exemplary Synthesis of Compound 4 Step 1 [ka] A mixture of 1-(4-bromo-3-fluoro-phenyl)ethanone (1 g, 4.61 mmol, 1 equiv.), zinc cyanide (1.08 g, 9.22 mmol, 2 equiv.), and tetrakis[triphenylphosphine]palladium(0) (532 mg, 0.46 mmol, 0.1 equiv.) in N,N-dimethylformamide (10 mL) was stirred at 80 °C under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL × 2) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1). Compound 4-acetyl-2-fluoro-benzonitrile (530 mg, 3.25 mmol) was obtained as a pale yellow solid.

[0361] Step 2 [ka] To a solution of 4-acetyl-2-fluoro-benzonitrile (0.26 g, 1.59 mmol, 1 equivalent) in ethanol (10 mL) was added sodium borohydride (121 mg, 3.19 mmol, 2 equivalents) at 0 ° C. The mixture was warmed to 25 ° C. and stirred for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (0.1 mL) at 25 ° C. and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 1). The compound 2-fluoro-4-(1-hydroxyethyl)benzonitrile (190 mg, 1.15 mmol) was obtained as a colorless oil.

[0362] Step 3 [ka] To a mixture of tert-butyl N-tert-butoxycarbonylcarbamate (325 mg, 1.50 mmol, 1.3 equiv.), 2-fluoro-4-(1-hydroxyethyl)benzonitrile (190 mg, 1.15 mmol, 1 equiv.), and triphenylphosphine (453 mg, 1.73 mmol, 1.5 equiv.) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (349 mg, 1.73 mmol, 1.5 equiv.) at 0° C. The mixture was warmed to 25° C. and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=40 / 1). The compound N-tert-butoxycarbonyl-N-[1-(4-cyano-3-fluoro-phenyl)ethyl]carbamate tert-butyl (70 mg, 0.19 mmol) was obtained as a colorless oil.

[0363] Step 4 [ka] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[1-(4-cyano-3-fluoro-phenyl)ethyl]carbamate (70 mg, 0.19 mmol, 1 equivalent) in dichloromethane (5 mL), hydrochloric acid / methanol (4 M, 1 mL, 20.82 equivalents) was added at 25 °C, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The compound 4-(1-aminoethyl)-2-fluoro-benzonitrile (38.5 mg, crude, hydrochloride salt) was obtained as a white solid and used directly in the next step.

[0364] 4-(1-aminoethyl)-2-fluorobenzonitrile was converted to the title compound as shown in the scheme below using procedures commonly known to those skilled in the art. [ka]

[0365] Compounds 3 and 5 were prepared using procedures similar to compound 4.

[0366] Exemplary Synthesis of Compounds 6, 7, 8, and 9 [ka] To a mixture of tert-butyl 4-[1-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]ethyl]piperidine-1-carboxylate (3 g, 7.37 mmol, 1 equiv.), (2-hydroxyphenyl)boronic acid (1.53 g, 11.06 mmol, 1.5 equiv.), and potassium carbonate (3.06 g, 22.12 mmol, 3 equiv.) in dioxane (50 mL) and water (9 mL) was added tetrakis[triphenylphosphine]palladium(0) (852 mg, 0.73 mmol, 0.1 equiv.). The mixture was degassed and purged with nitrogen three times. The reaction mixture was stirred at 90° C. for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*80mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-50%, 20 min). The compound tert-butyl 4-[1-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (2.7 g, 5.81 mmol, 79% yield) was obtained as a yellow solid.

[0367] tert-Butyl 4-[1-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate was converted to the title compound as shown in the following scheme using procedures commonly known to those skilled in the art. [ka] [ka]

[0368] Exemplary compounds 8 and 9 were prepared using similar procedures.

[0369] Exemplary Synthesis of Compound 10 Compound 10 was prepared according to the following scheme using procedures commonly known to those skilled in the art. [ka]

[0370] Exemplary Synthesis of Compound 11 Compound 11 was prepared according to the following scheme using procedures commonly known to those skilled in the art. [ka]

[0371] Exemplary Synthesis of Compound 12 Compound 12 was prepared according to the following scheme using procedures commonly known to those skilled in the art. [ka] [ka]

[0372] Exemplary Synthesis of Compound 13 Step 1 [ka] To a solution of ethylmagnesium bromide solution (3 M, 55.7 mL, 6 equiv.) in tetrahydrofuran (120 mL) was added dropwise a solution of tert-butyl 4-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carbonyl]piperidine-1-carboxylate (15 g, 27.86 mmol, 1 equiv.) in tetrahydrofuran (60 mL) under nitrogen at −70° C. The temperature was maintained below −70° C., and a solution of titanium(IV) isopropoxide (15.83 g, 55.71 mmol, 16.4 mL, 2 equiv.) in tetrahydrofuran (60 mL) was added. The resulting mixture was heated to 70° C. for 1 h. The mixture was cooled to 10° C. and quenched with saturated ammonium chloride solution (200 mL). The aqueous phase was extracted with ethyl acetate (100 mL×4). The combined organic phase was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1). The resulting material was further purified by preparative HPLC (column: Phenomenex Luna C18 150*40 mm*15 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 28% to 58%, 11 min) to afford tert-butyl 4-[1-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]piperidine-1-carboxylate (810 mg, 1.47 mmol, 5% yield) as a yellow solid.

[0373] Step 2 [ka] tert-Butyl 4-[1-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]piperidine-1-carboxylate (810 mg, 1.63 mmol, 1 equiv.) in hydrogen chloride / methanol (4 M, 10 mL, 24.47 equiv.) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure at 45 °C. The residue was diluted with water (20 mL), the pH was adjusted to 8–9 with solid sodium bicarbonate, and the mixture was stirred for 15 min. The aqueous phase was extracted with ethyl acetate (50 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Crude 4-bromo-2-[3-[[1-[1-(4-piperidyl)cyclopropyl]-4-piperidyl]oxy]cyclobutoxy]pyridine (780 mg) was obtained as a yellow oil and used directly without purification.

[0374] Step 3 [ka] A mixture of 4-bromo-2-[3-[[1-[1-(4-piperidyl)cyclopropyl]-4-piperidyl]oxy]cyclobutoxy]pyridine (780 mg, 1.73 mmol, 1 equiv.), N,N-diisopropylethylamine (1.12 g, 8.66 mmol, 1.5 mL, 5 equiv.), and methyl 3-methyl-2-[3-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)isoxazol-5-yl]butanoate (1.67 g, 3.46 mmol, 2 equiv.) in dimethyl sulfoxide (5 mL) was stirred at 100° C. for 1 hour. The mixture was cooled to 25° C., diluted with ethyl acetate (100 mL), washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%~60%, 22 min) to give methyl 2-[3-[4-[1-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoate (510 mg, 0.80 mmol) as a yellow solid.

[0375] Step 4 [ka] To a mixture of methyl 2-[3-[4-[1-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methylbutanoate (510 mg, 0.80 mmol, 1 equiv.), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (257 mg, 1.21 mmol, 1.5 equiv.), and cesium carbonate (789 mg, 2.42 mmol, 3.0 equiv.) in dioxane (10 mL) was added (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate [RuPhos Pd G3] (67 mg, 0.08 mmol, 0.1 equiv) was added in one portion at 25°C under nitrogen. The mixture was heated to 90°C and stirred for 6 hours. The mixture was cooled to 25°C and concentrated under reduced pressure at 45°C. The residue was poured into ice-water (w / w = 1 / 1) (30 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 2) to give tert-butyl 8-[2-[3-[[1-[1-[1-[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]-4-piperidyl]cyclopropyl]-4-piperidyl]oxy]cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (260 mg, 0.34 mmol) as a yellow oil.

[0376] Step 5 [ka] To a mixture of tert-butyl 8-[2-[3-[[1-[1-[1-[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]-4-piperidyl]cyclopropyl]-4-piperidyl]oxy]cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (260 mg, 0.34 mmol, 1.0 equiv.) in dichloromethane (10 mL), trifluoroacetic acid (4.62 g, 40.52 mmol, 3 mL, 118.90 equiv.) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure at 45 °C. The residue was poured into ice water (w / w = 1 / 1) (30 mL), and the pH was adjusted to 8-9 with solid sodium bicarbonate. The mixture was stirred for 15 min. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude methyl 2-[3-[4-[1-[4-[3-[[4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methylbutanoate (210 mg, 0.31 mmol) as a yellow oil, which was used without further purification.

[0377] Step 6 [ka] Methyl 2-[3-[4-[1-[4-[3-[[4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methylbutanoate (150 mg, 0.22 mmol, 1.0 equiv.), 4-bromo-6-chloro-pyridazin-3-amine (235 mg, 1.13 mmol, 5.0 equiv.), and N,N-diisopropylethylamine (146 mg, 1.13 mmol, 5.0 equiv.) were placed in a microwave tube containing dimethyl sulfoxide (6 mL). The sealed tube was heated at 120 °C for 6 h under microwave irradiation. The mixture was cooled to 25° C., diluted with ethyl acetate (60 mL), washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give methyl 2-[3-[4-[1-[4-[3-[[4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methylbutanoate (120 mg, 0.15 mmol) as a yellow oil.

[0378] Step 7 [ka] Methyl 2-[3-[4-[1-[4-[3-[[4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoate (150 mg, 0.18 mmol, 1.0 equiv) in dioxane (6 mL), A mixture of (2-hydroxyphenyl)boronic acid (52 mg, 0.37 mmol, 2.0 equiv.), methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane (13 mg, 0.02 mmol, 0.1 equiv.) and aqueous potassium phosphate (1.5 M, 0.4 mL, 3 equiv.) was degassed and then heated to 90°C under nitrogen for 6 h. The mixture was cooled to 25°C, diluted with ethyl acetate (60 mL), washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give methyl 2-[3-[4-[1-[4-[3-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoate (110 mg, 0.12 mmol) as a yellow oil.

[0379] Methyl 2-[3-[4-[1-[4-[3-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]cyclobutoxy]-1-piperidyl]cyclopropyl]-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoate was converted to the title compound according to the following scheme using the procedures described above and procedures commonly known to those skilled in the art. [ka]

[0380] Exemplary Synthesis of Compound 14 Compound 14 was prepared according to the following scheme using procedures similar to those described for compound 13 and procedures commonly known to those skilled in the art. [ka]

[0381] Compounds 15, 16, 17, and 26 were prepared using similar procedures.

[0382] Exemplary Synthesis of Compound 19 Compound 19 was prepared according to the following scheme using procedures commonly known to those skilled in the art. [ka]

[0383] Exemplary Synthesis of Compound 20 [ka] To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (2.1 g, 9.99 mmol, 1 equiv.) in tetrahydrofuran (25 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 20 mL, 2 equiv.) dropwise at −65° C. and then stirred at this temperature for 1 hour. A solution of ethyl chloroformate (2.17 g, 19.97 mmol, 1.9 mL, 2 equiv.) in tetrahydrofuran (5 mL) was then added at −65° C., and the mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) at 0° C. and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 3 / 1). 1-(tert-butyl)4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (2.48 g, 8.78 mmol, 88% yield) was obtained as a colorless oil.

[0384] The title compound was prepared according to the following scheme using procedures commonly known to those skilled in the art. [ka]

[0385] Exemplary Synthesis of Compound 22 [ka] To a mixture of zirconium(iv) chloride (3.61 g, 15.47 mmol, 1.2 equiv.) in tetrahydrofuran (120 mL) was added a solution of tert-butyl 8-(1-benzyloxycarbonylpiperidine-4-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.9 g, 12.89 mmol, 1 equiv.) in tetrahydrofuran (60 mL) dropwise over 0.5 h at −60° C. under nitrogen. Methylmagnesium bromide solution (3 M, 25.8 mL, 6 equiv.) was then added to the mixture at −60° C., and the mixture was stirred for 0.5 h. The resulting mixture was then warmed to 25° C. and stirred for 6 h. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 30 ACN% to 60 ACN%, 30 min). The compound 8-[1-(1-benzyloxycarbonyl-4-piperidyl)-1-methyl-ethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester (2.5 g, 5.30 mmol, 41% yield) was obtained as a colorless oil.

[0386] Compound 22 was prepared according to the following scheme using the procedures described above and procedures commonly known to those skilled in the art. [ka]

[0387] Exemplary Synthesis of Compound 23 [ka] To a solution of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (500 mg, 2.30 mmol, 1 equiv.) in dichloromethane (10 mL) was added Dess-Martin periodinane (1.17 g, 2.76 mmol, 1.2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was cooled to 0 °C and quenched with saturated sodium thiosulfate solution (50 mL) and saturated sodium bicarbonate solution. The mixture was stirred for 15 minutes and extracted with dichloromethane (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). The compound tert-butyl (2S)-2-formylmorpholine-4-carboxylate (400 mg, 1.86 mmol) was obtained as a colorless oil.

[0388] (2S)-tert-butyl 2-formylmorpholine-4-carboxylate was converted to the title compound using the procedure described above and according to the following scheme. [ka]

[0389] Exemplary synthesis of compound 24 [ka] A mixture of methyl 3-hydroxycyclobutanecarboxylate (1 g, 7.68 mmol, 1 equiv.) and benzyl 4-oxopiperidine-1-carboxylate (1.97 g, 8.45 mmol, 1.6 mL, 1.1 equiv.) in acetonitrile (10 mL) was degassed and purged with nitrogen three times. To this was then added chloro(dimethyl)silane (727 mg, 7.68 mmol, 1 equiv.) at 0° C. The mixture was stirred under a nitrogen atmosphere at 25° C. for 12 hours. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%~70%, 10 min). The compound 4-(3-methoxycarbonylcyclobutoxy)piperidine-1-carboxylate benzyl (500 mg, 1.44 mmol, 18% yield) was obtained as a colorless oil.

[0390] Benzyl 4-(3-methoxycarbonylcyclobutoxy)piperidine-1-carboxylate was converted to tert-butyl 4-((1r,3r)-3-formylcyclobutoxy)piperidine-1-carboxylate as shown in the following scheme. [ka]

[0391] Compound 24 was prepared according to the following scheme using the procedures described or referenced above and general procedures known to those skilled in the art. [ka]

[0392] Exemplary Synthesis of Compound 25 Compound 25 was prepared according to the following scheme using the procedure described above. [ka]

[0393] Exemplary Synthesis of Compound 27 Compound 27 was prepared according to the following scheme using procedures described above and procedures commonly known to those skilled in the art. [ka]

[0394] Exemplary Synthesis of Compound 28 Compound 28 was prepared according to the following scheme using the procedure described above. [ka]

[0395] Compound 55 was prepared using a similar procedure.

[0396] Exemplary Synthesis of Compound 29 Step 1 [ka] To a stirred solution of NaBH (76.13 mg, 2.01 mmol, 1.1 equiv) in EtOH (5 mL) was added a solution of benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 1.83 mmol, 1.0 equiv) in EtOH (5 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH Cl (2 mL) and concentrated under reduced pressure to remove EtOH. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give crude benzyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (488 mg, 1.77 mmol) as a gray oil, which was used directly in the next step without further purification.

[0397] Step 2 [ka] To a solution of benzyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (388 mg, 1.41 mmol, 1.0 equiv) in DMF (5 mL) was added NaH (68 mg, 60% dispersion in mineral oil, 1.69 mmol, 1.2 equiv) at 0 °C. The mixture was stirred at 0 °C under N for 10 min. Then, 4-bromo-2-fluoro-pyridine (247.99 mg, 1.41 mmol, 1.0 equiv) was added. The mixture was warmed to 20 °C and stirred at 20 °C under N for 3 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® SilicaFlash Column, eluting with 0–15% ethyl acetate / petroleum ether @ 55 mL / min) to give benzyl 2-[(4-bromo-2-pyridyl)oxy]-7-azaspiro[3.5]nonane-7-carboxylate (584 mg, 1.35 mmol) as a yellow oil.

[0398] Benzyl 2-[(4-bromo-2-pyridyl)oxy]-7-azaspiro[3.5]nonane-7-carboxylate was converted to 2-(5-(8-(2-((7-azaspiro[3.5]nonan-2-yl)oxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-aminopyridazin-3-yl)phenol using a procedure similar to that described for exemplary compound 13, as shown in the following scheme. [ka]

[0399] Step 8 [ka] To a solution of 2-[6-amino-5-[8-[2-(7-azaspiro[3.5]nonan-2-yloxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol trifluoroacetate (285 mg, 454.07 μmol, 1.0 equiv.) and tert-butyl 4-formylpiperidine-1-carboxylate (96.84 mg, 454.07 μmol, 1.0 equiv.) in methanol (3.0 mL) and acetic acid (0.3 mL), 2-methylpyridineborane (242.84 mg, 2.27 mmol, 5.0 equiv.) was added. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. Water (15 mL) and saturated aqueous NaHCO3 (10 mL) were added to the residue, and the solution was extracted with EtOAc (25 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (10% methanol / dichloromethane) to give tert-butyl 4-[[2-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]-7-azaspiro[3.5]nonan-7-yl]methyl]piperidine-1-carboxylate (163 mg, 0.23 mmol) as a yellow solid.

[0400] tert-Butyl 4-[[2-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]-7-azaspiro[3.5]nonan-7-yl]methyl]piperidine-1-carboxylate was converted to the title compound as shown in the following scheme. [ka]

[0401] Exemplary Synthesis of Compound 30 Step 1 [ka] To a solution of 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methylbutanoic acid (3.8 g, 11.64 mmol, 1 equiv.), (2S,4R)-tert-butyl 4-hydroxypyrrolidine-2-carboxylate (3.27 g, 17.46 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.64 g, 17.46 mmol, 1.5 equiv.) was added. The N,N-reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*80mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-55%, 20 min). The compound (2S,4R)-1-[(2S)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate tert-butyl ester (910 mg, 1.84 mmol) was obtained as a yellow oil. The compound (2R)-1-[(2R)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate tert-butyl (820 mg, 1.65 mmol) was obtained as a yellow solid.

[0402] Step 2 [ka] To a solution of tert-butyl (2S,4R)-1-[(2R)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate (100 mg, 0.20 mmol, 1 equiv.) in acetonitrile (2.5 mL) and water (2.5 mL), trifluoroacetic acid (385 mg, 3.38 mmol, 16.73 equiv.) was added. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The compound (2S,4R)-1-[(2R)-2-[3-(4-formyl-1-piperidyl)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate tert-butyl (90 mg, 0.20 mmol) was obtained as a white solid.

[0403] (2S,4R)-1-[(2R)-2-[3-(4-formyl-1-piperidyl)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate tert-butyl was converted to the title compound as described in the scheme below. [ka]

[0404] Synthesis of compound 31 Compound 31 was prepared according to the following scheme using the procedures described above and procedures commonly known to those skilled in the art. [ka]

[0405] Exemplary Synthesis of Compound 34 Step 1 [ka] A mixture of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (0.5 g, 2.51 mmol, 1 equiv.), 3-bromoprop-1-yne (1.12 g, 7.53 mmol, 0.8 mL, 3 equiv.), and cesium carbonate (1.64 g, 5.02 mmol, 2 equiv.) in acetone (15 mL) was stirred at 50 °C under nitrogen for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1). The compound methyl 3-methyl-2-(3-prop-2-ynoxyisoxazol-5-yl)butanoate (460 mg, 1.94 mmol) was obtained as a pale yellow oil.

[0406] Step 2 [ka] To a solution of 2-bromopyrimidin-5-ol (3 g, 17.14 mmol, 1 equiv.) in dichloromethane (70 mL) was added imidazole (1.75 g, 25.72 mmol, 1.5 equiv.) and tert-butylchlorodimethylsilane (3.88 g, 25.72 mmol, 3.2 mL, 1.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The compound (2-bromopyrimidin-5-yl)oxy-tert-butyl-dimethyl-silane (4.7 g, 16.25 mmol) was obtained as a colorless oil.

[0407] Step 3 [ka] A mixture of (2-bromopyrimidin-5-yl)oxy-tert-butyl-dimethyl-silane (2.7 g, 9.33 mmol, 1 equiv.), sodium iodide (7.0 g, 46.67 mmol, 5 equiv.), cuprous iodide (178 mg, 0.93 mmol, 0.1 equiv.), and N,N'-dimethylethane-1,2-diamine (82 mg, 0.93 mmol, 0.1 mL, 0.1 equiv.) in dioxane (40 mL) was stirred at 110 °C under nitrogen for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1). The compound tert-butyl-(2-iodopyrimidin-5-yl)oxy-dimethyl-silane (1.7 g, 5.06 mmol) was obtained as a white solid.

[0408] Step 4 [ka] A mixture of methyl 3-methyl-2-(3-prop-2-ynoxyisoxazol-5-yl)butanoate (200 mg, 0.84 mmol, 1 equiv.), tert-butyl-(2-iodopyrimidin-5-yl)oxydimethylsilane (340 mg, 1.01 mmol, 1.2 equiv.), bis(triphenylphosphine)palladium(II) dichloride (59 mg, 0.08 mmol, 0.1 equiv.), cuprous iodide (16 mg, 0.08 mmol, 0.1 equiv.), and triethylamine (256 mg, 2.53 mmol, 0.4 mL, 3 equiv.) in N,N-dimethylformamide (6 mL) was stirred at 65° C. under nitrogen for 16 h (glove box). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (0.225% FA)-ACN]; B%: 68%~95%, 11 min). The compound 2-[3-[3-(5-hydroxypyrimidin-2-yl)prop-2-ynoxy]isoxazol-5-yl]-3-methyl-butanoate (240 mg, 0.72 mmol) was obtained as a brown oil.

[0409] (1s,3s)-3-((4-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)pyridin-2-yl)oxy)cyclobutan-1-ol was prepared according to the following scheme using the procedures described above for exemplary compounds 13 and 6 as well as procedures generally known to one skilled in the art. [ka]

[0410] (1s,3s)-3-((4-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)piperazin-1-yl)pyridin-2-yl)oxy)cyclobutan-1-ol was converted to the title compound according to the following scheme using procedures commonly known to those skilled in the art. [ka]

[0411] Exemplary Synthesis of Compound 35 Compound 35 was prepared according to the following scheme using the procedures described above and general procedures known to those skilled in the art. [ka]

[0412] Compounds 73, 92, 106, 113, 141, 142, and 143 were prepared using similar procedures.

[0413] Exemplary Synthesis of Compound 36 Step 1 [ka] To a solution of methoxymethyl(triphenyl)phosphonium chloride (15.76 g, 45.97 mmol, 2.2 equiv.) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (1 M, 41.8 mL, 2 equiv.) under nitrogen at −10° C. The mixture was stirred at −10° C. for 1 hour. Then, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 20.89 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was added at −10° C. The mixture was warmed to 25° C. and stirred for 15 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (30 mL) at 25° C., then diluted with 20 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 5:1) to obtain the compound tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (4.5 g, 16.83 mmol) as a colorless oil.

[0414] Step 2 [ka] To a solution of trifluoroacetic acid (539 mg, 4.73 mmol, 1.26 equiv.) in acetonitrile (36 mL) and water (9 mL), tert-butyl 2-(methoxymethylene)-7-azaspiro[3.5]nonane-7-carboxylate (1 g, 3.74 mmol, 1 equiv.) was added. The resulting mixture was stirred at 25 °C for 1 hour. The mixture was added to saturated sodium bicarbonate (100 mL), and the mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10:1). The compound tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 2.76 mmol) was obtained as a colorless oil.

[0415] Step 3 [ka] To a solution of tert-butyl 2-formyl-7-azaspiro[3.5]nonane-7-carboxylate (700 mg, 2.76 mmol, 1 equiv.) in methanol (7 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (637 mg, 3.32 mmol, 1.2 equiv.) and potassium carbonate (764 mg, 5.53 mmol, 2 equiv.) at 0 °C. The mixture was stirred at 25 °C for 12 h. 50 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100:1 to 20:1). The compound tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 2.01 mmol) was obtained as a colorless oil.

[0416] Step 4 [ka] To a solution of tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate (500 mg, 2.01 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M, 1.6 mL, 2 equiv.) at −70° C. The mixture was stirred at −70° C. for 0.5 hours. Then, acetaldehyde (265 mg, 6.02 mmol, 3 equiv.) was added to the mixture. The reaction mixture was stirred at −70° C. for 1 hour. 50 mL of water was added to the mixture, and then the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50:1 to 5:1). The compound tert-butyl 2-(3-hydroxybut-1-ynyl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 1.36 mmol) was obtained as a yellow oil.

[0417] Step 5 [ka] To a solution of tert-butyl 2-(3-hydroxybut-1-ynyl)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 1.36 mmol, 1 equiv.) in dichloromethane (5 mL) was added triphenylphosphine (429 mg, 1.64 mmol, 1.2 equiv.) and tetrabromomethane (543 mg, 1.64 mmol, 1.2 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1). The compound tert-butyl 2-(3-bromobut-1-ynyl)-7-azaspiro[3.5]nonane-7-carboxylate (233 mg, 0.65 mmol) was obtained as a white solid.

[0418] Step 6 [ka] A mixture of tert-butyl 2-(3-bromobut-1-ynyl)-7-azaspiro[3.5]nonane-7-carboxylate (223 mg, 0.62 mmol, 1 equiv.), 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (186 mg, 0.62 mmol, 1 equiv.), and potassium carbonate (259 mg, 1.88 mmol, 3 equiv.) in acetonitrile (3 mL) and 1-methyl-2-pyrrolidinone (1 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under nitrogen at 80° C. for 12 hours. 50 mL of water was added to the mixture, and then the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%~70%, 10 min). The compound tert-butyl 2-[3-[4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]pyrazol-1-yl]but-1-ynyl]-7-azaspiro[3.5]nonane-7-carboxylate (130 mg, 0.23 mmol) was obtained as a yellow oil.

[0419] tert-Butyl 2-[3-[4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]pyrazol-1-yl]but-1-ynyl]-7-azaspiro[3.5]nonane-7-carboxylate was converted to the title compound as shown in the following scheme. [ka]

[0420] Exemplary Synthesis of Compound 38 [ka] To a solution of methyl 2-(bromomethyl)benzoate (3.7 g, 16.15 mmol, 1 equiv.) and methyl 2-amino-3-methyl-butanoate (3.25 g, 19.38 mmol, 1.2 equiv., hydrochloride salt) in acetonitrile (70 mL) was added N,N-diisopropylethylamine (10.44 g, 80.76 mmol, 14.1 mL, 5 equiv.). The reaction mixture was stirred at 50 °C for 2 hours and then at 90 °C for 3 hours. Water (100 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1). Methyl 3-methyl-2-(1-oxoisoindolin-2-yl)butanoate (3.4 g, 13.75 mmol) was obtained as a pale yellow oil.

[0421] Methyl 3-methyl-2-(1-oxoisoindolin-2-yl)butanoate was converted to (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylic acid as described in the following scheme using procedures commonly known to those skilled in the art. [ka]

[0422] A mixture of (3S)-3-(4-bromophenyl)-3-(tert-butoxycarbonylamino)propanoic acid (1 g, 2.91 mmol, 1 equiv.), 4-methylthiazole (2.88 g, 29.05 mmol, 2.6 mL, 10 equiv.), palladium(II) acetate (65 mg, 0.29 mmol, 0.1 equiv.), potassium carbonate (602 mg, 4.36 mmol, 1.5 equiv.), tricyclohexylphosphonium tetrafluoroborate (106 mg, 0.29 mmol, 0.1 equiv.), and 2,2-dimethylpropanoic acid (89 mg, 0.87 mmol, 0.1 mL, 0.3 equiv.) in N,N-dimethylformamide (10 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. under a nitrogen atmosphere for 16 h. 50 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 10% to 50%, 22 min). The compound (3S)-3-(tert-butoxycarbonylamino)-3-[4-(4-methylthiazol-5-yl)phenyl]propanoic acid (400 mg, 1.10 mmol) was obtained as a yellow solid.

[0423] The title compound was obtained from 2-(6-amino-5-(8-(2-((1r,3r)-3-(piperidin-4-yloxy)cyclobutoxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol [prepared as described in US20190300521] according to the following scheme: [ka]

[0424] Exemplary Synthesis of Compound 39 Compound 39 was prepared according to the following scheme using procedures similar to those described for compounds 2 and 29. [ka]

[0425] Exemplary Synthesis of Compound 40 Step 1 [ka] To a solution of (1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethanamine (1.6 g, 6.73 mmol, 1 equiv., hydrochloride salt) and triethylamine (3.41 g, 33.65 mmol, 4.7 mL, 5 equiv.) in dichloromethane (25 mL) was added N-(benzyloxycarbonyloxy)succinimide (2.52 g, 10.10 mmol, 1.5 equiv.) at 0° C. The reaction solution was stirred at 20° C. for 12 hours. The reaction solution was concentrated in vacuo to remove the solvent, diluted with water (30 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10:1 to 2:1) to give benzyl N-[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethyl]carbamate (2.1 g, 6.26 mmol) as a white solid.

[0426] Step 2 [ka] To a solution of N-[(1S)-1-[4-(2-methylpyrazol-3-yl)phenyl]ethyl]benzylcarbamate (220 mg, 0.66 mmol, 1 equiv.) in N,N-dimethylformamide (4 mL) was added Selectfluor® fluorination reagent (302 mg, 0.85 mmol, 1.3 equiv.). The reaction solution was stirred at 50° C. for 12 hours. The reaction solution was cooled to 20° C., diluted with water (30 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL×4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1). Benzyl N-[(1S)-1-[4-(4-fluoro-2-methyl-pyrazol-3-yl)phenyl]ethyl]carbamate (260 mg, 0.74 mmol) was obtained as a colorless gum.

[0427] Step 3 [ka] To a solution of N-[(1S)-1-[4-(4-fluoro-2-methyl-pyrazol-3-yl)phenyl]ethyl]benzylcarbamate (260 mg, 0.74 mmol, 1 equiv.) in acetonitrile (5 mL), trimethyliodosilane (294 mg, 1.47 mmol, 0.2 mL, 2 equiv.) was added at 0 °C, and the reaction solution was stirred at 20 °C for 1 h. The reaction solution was quenched with methanol (8 mL) and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 1% to 31%, 10 min). (1S)-1-[4-(4-fluoro-2-methyl-pyrazol-3-yl)phenyl]ethanamine trifluoroacetate (168 mg, 0.50 mmol) was obtained as a pale yellow solid.

[0428] Step 4 [ka] To a solution of 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methylbutanoic acid (3.8 g, 11.64 mmol, 1 equiv.), tert-butyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (3.27 g, 17.46 mmol, 1.5 equiv.) in N,N-dimethylformamide (10 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.64 g, 17.46 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (4.51 g, 34.93 mmol, 6.1 mL, 3 equiv.) were added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*80 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30% to 60%, 25 min). The compound (2S,4R)-1-[(2S)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate tert-butyl ester (910 mg, 1.84 mmol) was obtained as a yellow oil. The compound (2S,4R)-1-[(2R)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate tert-butyl (820 mg, 1.65 mmol) was obtained as a yellow solid.

[0429] The title compound was prepared according to the following scheme using procedures similar to those described for compounds 2 and 4. [ka]

[0430] Exemplary Synthesis of Compound 41 Prepared according to the following schemes using procedures described for other examples above and procedures generally known to those skilled in the art. [ka]

[0431] Compounds 53, 54, 146, and 147 were prepared using similar procedures. Exemplary Synthesis of Compound 42 Step 1 [ka]

[0432] A mixture of 4-iodo-1H-pyrazole (10 g, 51.55 mmol, 1 equiv.), cuprous iodide (982 mg, 5.16 mmol, 0.1 equiv.), tetrakis[triphenylphosphine]palladium(0) (2.98 g, 2.58 mmol, 0.05 equiv.), and triethylamine (15.65 g, 154.66 mmol, 21.5 mL, 3 equiv.) in N,N-dimethylformamide (100 mL) was degassed three times with nitrogen. Ethynyl(trimethyl)silane (10.13 g, 103.11 mmol, 14.3 mL, 2 equiv.) was then added to the solution at 25 °C. The solution was degassed three times with nitrogen and stirred at 25 °C for 16 h. The mixture was diluted with ethyl acetate (100 mL), filtered through a pad of silica gel (100-200 mesh), and washed with ethyl acetate (300 mL). The resulting solution was washed with saturated aqueous ammonium chloride solution (200 mL × 2) and brine (200 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to give the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50 mm*10 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 35% to 60%, 20 min). Trimethyl-[2-(1H-pyrazol-4-yl)ethynyl]silane (1.66 g, 10.10 mmol) was obtained as a pale yellow solid.

[0433] Step 2 [ka] To a solution of trimethyl-[2-(1H-pyrazol-4-yl)ethynyl]silane (1.66 g, 10.10 mmol, 1 equiv.) and tert-butyl 4-[1-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (3.88 g, 10.10 mmol, 1 equiv.) in acetonitrile (32 mL) was added cesium carbonate (6.58 g, 20.21 mmol, 2 equiv.). The reaction mixture was stirred at 80° C. for 12 hours. The mixture was cooled to 25° C. and diluted with water (60 mL). The resulting solution was extracted with ethyl acetate (60 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%~70%, 20 min) to give tert-butyl 4-[1-(4-ethynylpyrazol-1-yl)ethyl]piperidine-1-carboxylate (2.1 g, 6.92 mmol) as a pale yellow solid.

[0434] tert-Butyl 4-[1-(4-ethynylpyrazol-1-yl)ethyl]piperidine-1-carboxylate was converted to the title compound according to the following scheme using procedures described above and procedures commonly known to those skilled in the art. [ka]

[0435] Similar procedures were used to prepare the following examples: Compounds 78 (including the procedure for the final step described for Compound 14), 90, and 91.

[0436] Exemplary synthesis of compound 43 Prepared according to the following schemes using the procedures described in the examples above and procedures generally known to those skilled in the art. [ka]

[0437] Exemplary synthesis of compound 44 Prepared according to the following scheme using the procedures of the examples described above. [ka]

[0438] Exemplary Synthesis of Compounds 45 and 81 [ka] A solution of tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (610 mg, 2.25 mmol, 1.0 equiv.) and CDI (383 mg, 2.36 mmol, 1.05 equiv.) in anhydrous THF (12 mL) was stirred at 20 °C for 2 h under N. Then, benzyl piperazine-1-carboxylate (495 mg, 2.25 mmol, 1.0 equiv.) was added, followed by TEA (455 mg, 4.50 mmol, 2.0 equiv.). The mixture was stirred at 75 °C for 16 h under N. Water (20 mL) was added to the mixture, which was then extracted with ethyl acetate (30 mL × 3). The combined extracts were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by Biotage® Combiflash (column: 12 g Biotage® Silica Flash column; elution: gradient of 0 to 26% ethyl acetate in petroleum ether) to give O1-benzyl O4-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]cyclobutyl]piperazine-1,4-carboxylate (530 mg, 0.95 mmol) as a colorless gum.

[0439] O1-Benzyl O4-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]cyclobutyl]piperazine-1,4-carboxylate was converted to the title compound according to the following scheme using the procedures described above and general procedures known to one skilled in the art. [ka]

[0440] Using similar procedures and those described above for compound 2, compounds 114 and 115 were prepared.

[0441] Exemplary synthesis of compound 47 Using the procedures described above and procedures commonly known to those skilled in the art, the following schemes were prepared. [ka]

[0442] Exemplary synthesis of compound 49 Prepared according to the following schemes using procedures described for other examples above and general procedures commonly known to those skilled in the art. [ka]

[0443] Compound 50 was prepared using an analogous procedure.

[0444] Compounds 59 and 60 were prepared using a similar procedure and tert-butyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate as the starting material.

[0445] Exemplary Synthesis of Compound 56 Step 1 [ka] To a mixture of methyl 3-hydroxycyclobutanecarboxylate (2.0 g, 15.37 mmol, 1.0 equiv.) and 1H-imidazole (3.14 g, 46.10 mmol, 3.0 equiv.) in dichloromethane (30 mL) was added tert-butyldimethylsilyl chloride (3.47 g, 23.05 mmol, 1.5 equiv.) under nitrogen at 15 °C. The mixture was stirred at 15 °C for 16 h. The mixture was washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 50 / 1) to give methyl 3-[tert-butyl(dimethyl)silyl]oxycyclobutanecarboxylate (3.2 g, 13.09 mmol) as a colorless oil.

[0446] Step 2 [ka] To a mixture of methyl 3-[tert-butyl(dimethyl)silyl]oxycyclobutanecarboxylate (3.2 g, 13.09 mmol, 1 equiv.) in dichloromethane (120 mL) under nitrogen was added diisobutylaluminum hydride (1 M, 17.0 mL, 1.3 equiv.) at −60° C. The mixture was stirred at −60° C. for 1 hour. The reaction mixture was quenched by the addition of methanol (3 mL) at −70° C. and then diluted with dichloromethane (100 mL) and saturated potassium sodium tartrate solution (200 mL). The mixture was stirred for 6 hours and then extracted with dichloromethane (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give 3-[tert-butyl(dimethyl)silyl]oxycyclobutanecarbaldehyde (2.5 g, 11.66 mmol) as a colorless oil.

[0447] Step 3 [ka] To a mixture of 3-[tert-butyl(dimethyl)silyl]oxycyclobutanecarbaldehyde (2.50 g, 11.66 mmol, 1.0 equiv.) and trimethoxymethane (15.09 g, 142.23 mmol, 12.2 equiv.) in methanol (6 mL) was added pyridinium p-toluenesulfonate (293 mg, 1.17 mmol, 0.1 equiv.) in one portion at 15° C. under nitrogen. The mixture was stirred at 15° C. for 16 hours. The mixture was poured into saturated sodium bicarbonate solution (10 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give tert-butyl-[3-(dimethoxymethyl)cyclobutoxy]-dimethyl-silane (2.2 g, 8.45 mmol) as a colorless oil.

[0448] Step 4 [ka] To a mixture of tert-butyl-[3-(dimethoxymethyl)cyclobutoxy]-dimethyl-silane (2.2 g, 8.45 mmol, 1.0 equiv.) in tetrahydrofuran (60 mL) was added tetrabutylammonium fluoride (1 M, 12.7 mL, 1.5 equiv.) in one portion at 15° C. under nitrogen. The mixture was stirred at 15° C. for 2 hours. The mixture was concentrated under reduced pressure at 45° C. The residue was diluted with ethyl acetate (50 mL), washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 3-(dimethoxymethyl)cyclobutanol (1.01 g, 6.91 mmol) as a yellow oil.

[0449] Step 5 [ka] To a mixture of 3-(dimethoxymethyl)cyclobutanol (1.01 g, 6.91 mmol, 1.0 equiv.), 4-dimethylaminopyridine (84 mg, 0.69 mmol, 0.1 equiv.), and p-toluenesulfonyl chloride (2.63 g, 13.82 mmol, 2.0 equiv.) in dichloromethane (20 mL), triethylamine (2.1 g, 20.73 mmol, 2.9 mL, 3.0 equiv.) was added in one portion at 15 °C under nitrogen. The mixture was stirred at 15 °C for 6 hours. The mixture was concentrated under reduced pressure at 45 °C. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1, 10 / 1) to give 3-(dimethoxymethyl)cyclobutyl 4-methylbenzenesulfonate (1.3 g, 4.33 mmol) as a yellow oil.

[0450] [3-(dimethoxymethyl)cyclobutyl]4-methylbenzenesulfonate was converted to the title compound according to the following scheme using procedures commonly known to those skilled in the art. [ka]

[0451] Exemplary Synthesis of Compound 57 [ka] To a solution of benzyl piperazine-1-carboxylate (1 g, 4.54 mmol, 0.9 mL, 1 equiv.) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (968 mg, 4.54 mmol, 1 equiv.) in dimethyl sulfoxide (5 mL) was added N,N-diisopropylethylamine (1.17 g, 9.08 mmol, 1.6 mL, 2 equiv.). The mixture was stirred at 110 °C for 1 h. 30 mL of water was added to the mixture, and then the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1 to 3 / 1). Benzyl 4-[(1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl)methyl]piperazine-1-carboxylate (1.2 g, 2.77 mmol) was obtained as a yellow oil.

[0452] Benzyl 4-[(1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl)methyl]piperazine-1-carboxylate was converted to the title compound according to the following scheme using the procedures described for other examples above. [ka]

[0453] Exemplary Synthesis of Compound 58 Prepared according to the following schemes using procedures described for other examples above and procedures generally known to those skilled in the art. [ka]

[0454] Exemplary Synthesis of Compound 61 Prepared according to the following schemes using procedures described for other examples above and general procedures known to those skilled in the art. [ka]

[0455] Compound 71 was prepared using an analogous procedure.

[0456] Exemplary Synthesis of Compound 62 Prepared according to the following schemes using procedures described for other examples above and general procedures known to those skilled in the art. [ka]

[0457] Exemplary Synthesis of Compound 63 Prepared according to the following schemes using procedures described for other examples above and general procedures known to those skilled in the art. [ka]

[0458] Exemplary Synthesis of Compounds 64 and 65 [ka] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.0 g, 19.87 mmol, 1.0 equiv.) in tetrahydrofuran (100 mL) was added CDI (3.2 g, 19.87 mmol, 1.0 equiv.), and the mixture was stirred at 20 °C under N for 2 h. Then, benzyl piperazine-1-carboxylate (4.4 g, 19.87 mmol, 1.0 equiv.) was added, followed by TEA (4.02 g, 39.75 mmol, 2.0 equiv.). The mixture was stirred at 75 °C under N for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by Biotage® Combiflash (column: 120 g Biotage® Silica Flash column; elution: gradient of 0 to 42% methyl tert-butyl ether in petroleum ether) to give O1-benzyl O4-(1-tert-butoxycarbonyl-4-piperidyl)piperazine-1,4-dicarboxylate (3.85 g, 7.62 mmol) as a white solid.

[0459] O1-Benzyl O4-(1-tert-butoxycarbonyl-4-piperidyl)piperazine-1,4-dicarboxylate was converted to the title compound as described in the scheme below. [ka]

[0460] Exemplary Synthesis of Compound 68 Step 1 [ka] To a solution of 3-(benzyloxymethyl)cyclobutanone (3 g, 15.77 mmol, 1 eq.) in tetrahydrofuran (60 mL), L-selectride (1 M, 18.9 mL, 1.2 eq.) was slowly added at -70°C. The mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL) at 25°C, and then extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1). The compound 3-(benzyloxymethyl)cyclobutanol (2.8 g, 14.56 mmol) was obtained as a colorless oil.

[0461] Step 2 [ka] To a solution of 3-(benzyloxymethyl)cyclobutanol (1.4 g, 7.28 mmol, 1 equiv.), methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (1.74 g, 8.74 mmol, 1.2 equiv.), and triphenylphosphine (4.20 g, 16.02 mmol, 2.2 equiv.) in tetrahydrofuran (60 mL), diisopropyl azodicarboxylate (2.94 g, 14.56 mmol, 2.8 mL, 2 equiv.) was slowly added at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 60%-90%, 30 min). The compound methyl 2-[3-[3-(benzyloxymethyl)cyclobutoxy]isoxazol-5-yl]-3-methyl-butanoate (2.3 g, 6.16 mmol) was obtained as a brown oil.

[0462] Step 3 [ka] To a solution of methyl 2-[3-[3-(benzyloxymethyl)cyclobutoxy]isoxazol-5-yl]-3-methylbutanoate (2.2 g, 5.89 mmol, 1 equiv.) in dichloromethane (50 mL) was added a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.01 g, 8.84 mmol, 1.5 equiv.) in water (10 mL) at 15 °C. The mixture was stirred at 15 °C for 40 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 um); mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 20 min). The compound methyl 2-[3-[3-(hydroxymethyl)cyclobutoxy]isoxazol-5-yl]-3-methyl-butanoate (1.1 g, 3.88 mmol) was obtained as a brown oil.

[0463] Step 4 [ka] To a solution of (1S)-1-(4-bromophenyl)ethanamine (24.9 g, 124.5 mmol, 1 equiv.) in tetrahydrofuran (350 mL) was added triethylamine (37.8 g, 373.4 mmol, 3 equiv.) followed by di-tert-butyl dicarbonate (28.5 g, 130.7 mmol, 30 mL, 1.05 equiv.) dropwise under nitrogen at 0° C. The mixture was then stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (400 mL) was added, and the mixture was stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether (250 mL). The compound N-[(1S)-1-(4-bromophenyl)ethyl]carbamate tert-butyl (34.5 g, 114.93 mmol, 92% yield) was obtained as a white solid.

[0464] Step 5 [ka] To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (14.5 g, 48.30 mmol, 1 equiv.) and 4-methylthiazole (7.18 g, 72.45 mmol, 1.5 equiv.) in dimethylacetamide (15 mL) was added palladium(II) acetate (542 mg, 2.42 mmol, 0.05 equiv.) and potassium acetate (9.48 g, 96.61 mmol, 2 equiv.). The mixture was stirred at 90 °C for 12 h. Water (300 mL) was added, and the mixture was stirred for 1 min. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase C18 column chromatography [ACN / HO (0.5% FA) 5% to 50%]. tert-Butyl N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate (9.8 g, 29.85 mmol, 61% yield) was obtained as a gray solid.

[0465] Step 6 [ka] To a solution of tert-butyl N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate (1.5 g, 4.71 mmol, 1 equiv.) in dichloromethane (20 mL) was added hydrochloric acid / dioxane (4 M, 20 mL, 17 equiv.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove dichloromethane. The crude product was triturated with petroleum ether (100 mL). Crude (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (1.1 g) was obtained as a yellow solid.

[0466] Step 7 [ka] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (998 mg, 4.32 mmol, 1.1 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.79 g, 4.71 mmol, 1.2 equiv.) in dimethylformamide (10 mL) was added (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (1 g, 3.92 mmol, 1 equiv.) and diisopropylethylamine (1.52 g, 11.77 mmol, 2.05 mL, 3 equiv.). The reaction mixture was stirred at 15 °C for 0.5 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate, 100:1 to 30:1). tert-Butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (1.2 g, 2.78 mmol, 70% yield) was obtained as a white solid.

[0467] Step 8 [ka] To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (1 g, 2.32 mmol, 1 equiv.) in dichloromethane (10 mL) was added hydrochloric acid (2.5 M in dioxane, 5 mL, 5.4 equiv.). The reaction mixture was stirred at 15° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (800 mg, 2.17 mmol, 93% yield) was obtained as a colorless oil.

[0468] Methyl 2-[3-[3-(hydroxymethyl)cyclobutoxy]isoxazol-5-yl]-3-methyl-butanoate was converted to (2S,4R)-4-hydroxy-1-((R)-2-(3-((1r,3R)-3-(hydroxymethyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide using procedures described in other examples above and procedures commonly known to one skilled in the art according to the following scheme. [ka]

[0469] (2S,4R)-4-Hydroxy-1-((R)-2-(3-((1r,3R)-3-(hydroxymethyl)cyclobutoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was converted to the title compound according to the following scheme. [ka]

[0470] Compound 67 was prepared using an analogous procedure.

[0471] Exemplary Synthesis of Compound 69 Step 1 [ka] To a solution of 4-bromo-6-chloro-pyridazin-3-amine (5 g, 23.99 mmol, 1 equiv.) and potassium vinyltrifluoroborate (3.37 g, 25.19 mmol, 1.05 equiv.) in n-propyl alcohol (50 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.96 g, 2.40 mmol, 0.1 equiv.) and triethylamine (7.28 g, 71.96 mmol, 10 mL, 3 equiv.). The mixture was then degassed and purged with nitrogen three times. The mixture was stirred at 100 °C under a nitrogen atmosphere for 4 hours. The reaction mixture was diluted with 200 mL of water and extracted with 100 mL of ethyl acetate (10 mL × 3). The combined organic layers were washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 1 / 1). The compound 6-chloro-4-vinyl-pyridazin-3-amine (1.9 g, 12.17 mmol, yield 51%, purity 99%) was obtained as a yellow solid.

[0472] Step 2 [ka] To a solution of 4-iodo-1H-pyrazole (1 g, 5.16 mmol, 1 equiv.) and tert-butyl 4-[1-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (2.37 g, 6.19 mmol, 1.2 equiv.) in acetonitrile (20 mL) was added cesium carbonate (3.36 g, 10.31 mmol, 2 equiv.). The mixture was stirred at 80 °C for 10 h. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with 30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 * 70 mm, 15 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 50 ACN% to 80 ACN%, 30 min). The compound tert-butyl 4-[1-(4-iodopyrazol-1-yl)ethyl]piperidine-1-carboxylate (1.8 g, 4.40 mmol) was obtained as a colorless oil.

[0473] Step 3 [ka] To a solution of 2-(6-amino-5-vinyl-pyridazin-3-yl)phenol (500 mg, 2.34 mmol, 1 equiv.) and tert-butyl 4-[1-(4-iodopyrazol-1-yl)ethyl]piperidine-1-carboxylate (950.30 mg, 2.34 mmol, 1 equiv.) in toluene (15 mL), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (198 mg, 0.23 mmol, 0.1 equiv.) and cesium carbonate (1.15 g, 3.52 mmol, 1.5 equiv.) were added. The mixture was stirred at 110 °C under nitrogen for 5 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). The compound tert-butyl 4-[1-[4-[(E)-2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]vinyl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate (176 mg, 0.36 mmol) was obtained as a yellow solid.

[0474] tert-Butyl 4-[1-[4-[(E)-2-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]vinyl]pyrazol-1-yl]ethyl]piperidine-1-carboxylate was converted to the title compound as described in the scheme below. [ka]

[0475] Exemplary Synthesis of Compound 70 Prepared according to the following schemes using the procedures described or referenced above and general procedures known to those skilled in the art. [ka]

[0476] Exemplary synthesis of compound 74 Step 1 [ka] To a solution of 4-iodo-1H-pyrazole (10 g, 51.55 mmol, 1 equiv.) in tetrahydrofuran (100 mL) was added sodium hydride (3.09 g, 77.33 mmol, 60% in mineral oil, 1.5 equiv.) at 0°C, and the mixture was stirred at 0°C for 2 hours. 2-(trimethylsilyl)ethoxymethyl chloride (8.60 g, 51.55 mmol, 9.1 mL, 1 equiv.) was added to the mixture at 0°C. The reaction solution was stirred at 20°C for 12 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (100 mL × 2). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10:1) to give the product. 2-[(4-iodopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (14.47 g, 44.63 mmol, 87% yield) was obtained as a yellow oil.

[0477] Step 2 [ka] To a solution of 2-[(4-iodopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (9.5 g, 29.30 mmol, 1 equiv.) in dichloromethane (100 mL), isopropylmagnesium chloride (2 M, 22.0 mL, 1.5 equiv.) was added dropwise at 0°C, and the solution was stirred at 0°C for 1 hour. Then, a solution of benzyl 4-acetylpipe...

Claims

1. A compound having the following chemical structure: PTM-L-ULM or a pharmaceutically acceptable salt thereof (In the formula, (a) L is -(A Ｌ ) ｑ - where: (A Ｌ ) ｑ is a group connecting the ULM and the PTM, q is an integer from 1 to 100, Each A Ｌ is CR Ｌ１ R Ｌ２ , O, SO ２ , N.R. Ｌ３ , C.O.R. Ｌ３ , CO, CR Ｌ１ =CR Ｌ２ , C≡C, 1 to 6 R Ｌ１ and / or R Ｌ２ C optionally substituted with a group ３－１１ cycloalkyl, 1 to 6 R Ｌ１ and / or R Ｌ２ C optionally substituted with a group ３－１１ heterocyclyl, 1 to 6 R Ｌ１ and / or R Ｌ２ aryl optionally substituted with a group, and 1 to 6 R Ｌ１ and / or R Ｌ２ heteroaryl optionally substituted with a group; R Ｌ１ and R Ｌ２ each independently optionally linked to other groups, and Ｌ５ forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R Ｌ１ , R Ｌ２ , R Ｌ３ , and R Ｌ５ are each independently a halogen, C １－８ Alkyl, OC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, OC ３－８ Cycloalkyl, NHC ３－８ Cycloalkyl, N(C 3-8 cycloalkyl) 2 , N(C ３－８ cycloalkyl)(C １－８ alkyl), OH, NH 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 , COC １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , CHF ２ , C.H. ２ F. NO. ２ , CONHC １－８ alkyl, or CON(C １－８ alkyl) ２ and (b) the ULM is 【Chemistry 341】 and During the ceremony, W ３ is an optionally substituted aryl, an optionally substituted heteroaryl, or 【Chemistry 342】 and R9 and R10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; or R9, R10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R11 is optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl; 【Transformation 343】 and R12 is H or optionally substituted alkyl; R13 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; One of R14a and R14b is H, amino, haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamino, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphoric acid, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, alkyl-COR26, CONR27aR27b, NHCOR26, or NHCH ３ COR26, and the other of R14a and R14b is H; or or R14a and R14b together with the carbon atom to which they are attached form an optionally substituted 3- to 5-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl or spiroheterocyclyl, wherein said spiroheterocyclyl is not epoxy or aziridinyl; W ５ is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted 5-10 membered heteroaryl; R15 is H, halogen, CN, C≡CH, OH, NO ２ , NR27aR27b, OR27a, CONR27aR27b, NR27aCOR27b, SO ２ NR27aR27b, NR27aSO ２ R27b is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; each R16 is independently halo, CN, optionally substituted alkyl, optionally substituted alkylamino, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, 3, or 4; each R18 is independently H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; each R26 is independently H, OH, optionally substituted alkyl, or NR27aR27b; each R27a and R27b is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, or or R27a and R27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; p is 0, 1, 2, 3, or 4; 【Chemistry 299】 is the point of attachment to L; (c) the PTM is 【Chemical 300-1】 【Chemical 300-2】 【Chemical 300-3】 【Chemical 300-4】 【Chemical 300-5】 【Chemical 300-6】 【Transformation 344】 where: 【Chemical 301】 is the point of attachment to said L).

2. The PTM is 【Chemistry 345】 【Chemical 302-2】 where: 【Chemical 303】 is the point of attachment to said L.

3. The compound is 【Transformation 346】 or a pharmaceutically acceptable salt thereof (In the formula, X is CH or N; R30 is H, F, or Cl; R1 is C １－６ 2. The compound of claim 1, wherein:

4. The compound of claim 3, wherein one of R14a and R14b is H, methyl, or C1 fluoroalkyl, and the other is H.

5. R15 is cyano, halogen, 【Transformation 347】 4. The compound of claim 3, wherein:

6. Each R １６ However, individually, H, C １－４ Alkyl, fluoro, chloro, NH ２ , C.N., and C. １－４ is an alkoxy, R28A is H or methyl; R28B is H, methyl, or halogen; R28 is H, methyl, CH ２ N (Me) ２ , C.H. ２ OH, CH ２ O (C １－４ alkyl), CH ２ NHC(O)C １－４ Alkyl, NH ２ , 【Chemical 306】 2. The compound of claim 1 selected from:

7. The ULM is 【Transformation 348】 (In the formula, R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R14a is H, haloalkyl, optionally substituted alkyl, isopropyl, or cyclopropyl; R15 is H, halogen, CN, C≡CH, OH, NO ２、 optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted heterocyclyl; X is CH ２ or C═O, R3 is absent or optionally substituted 5- or 6-membered heteroaryl; 【Chemical 308】 is the point of attachment to said L.

8. The ULM has the following formula: 【Chemistry 349】 (In the formula, R1 is H, optionally substituted alkyl, or optionally substituted cycloalkyl; R3 is an optionally substituted 5-6 membered heteroaryl; W ５ is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted pyridinyl; one of R14a and R14b is H, optionally substituted alkyl, haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamino, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, optionally substituted heteroalkyl, or optionally substituted alkyl-heterocycloalkyl, and the other of R14a and R14b 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 said spiroheterocyclyl is not epoxy or aziridinyl; R15 is CN, C≡CH, fluoroalkyl, [Chemical 350] or optionally replaced 【Chemistry 351】 and each R16 is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy; each R27a and R27b is independently H, optionally substituted alkyl, optionally substituted 3-5 membered cycloalkyl, or or R ２７ａ and R ２７ｂ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl; R28 is H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted alkylamino, optionally substituted hydroxyalkyl, amino, optionally substituted alkynyl, or optionally substituted cycloalkyl; o is 0, 1 or 2; 【Chemistry 352】 is the point of attachment to L.

9. The ULM is 【Chemical 312】 (In the formula, o is 0, 1, or 2; X ４ , X ５ , and X ６ are selected from CH and N, where N is 2 or less; R １ is C １－６ is alkyl, R １４ａ and R １４ｂ one of is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamino, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, or optionally substituted heteroalkyl, or optionally substituted alkyl-heterocycloalkyl; and R １４ａ and R １４ｂ the other is H, Each R27a and R27b is independently H or C １－６ alkyl or 3- to 5-membered cycloalkyl; R １５ teeth, 【Chemistry 313】 or CN, R ２８ is H, methyl, CH ２ N (Me) ２ , C.H. ２ OH, CH ２ O (C １－４ alkyl), CH ２ NHC(O)C １－４ Alkyl, NH ２ , 【Chemical 314】 and R ２８Ｃ is H, methyl, fluoro, or chloro; R １６ is H, C １－４ Alkyl, fluoro, chloro, CN, or C １－４ 2. The compound of claim 1, wherein:

10. R １４ａ and R １４ｂ One of them is H, C １－４ Alkyl, C １－４ Cycloalkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkyloxyalkyl, C １－４ Alkyl-NR27aR27b and CONR ２７ａ R ２７ｂ and R １４ａ and R １４ｂ the other is H, and 【Chemical Industry 315】 is the point of attachment to said L.

11. The ULM is 【Chemistry 353】 (In the formula, X is CH or N; One of R 14a and R 14b is H, C １－６ Alkyl, C １－６ haloalkyl, optionally substituted C １－４ Alkylamino, C １－６ Alkoxy, (CH ２ ) ｑ C １－６ alkoxy, (CH 2 ) q C 1-6 alkoxy-C 3-7 heterocycloalkyl, (CH ２ ) ｑ OH, (CH ２ ) ｑ NR ２７ａ R ２７ｂ , C ３－６ cycloalkyl, or NR27aR27b, where R １４ａ and R １４ｂ The other is H, q is 1, 2, 3 or 4; 【Chemical 317】 is the point of attachment to said L.

12. R １ The compound of claim 11 , wherein is methyl.

13. One of R14a and R14b is H, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, optionally substituted C １－４ Alkylamino, (CH ２ ) ｑ OH, (CH ２ ) ｑ NR27aR27b,C ３－６ 2. The compound of claim 1, wherein R is cycloalkyl, or NR27aR27b, and the other of R14a and R14b is H.

14. Each R27a and R27b is independently H or C １－４ The compound of claim 1 , wherein the aryl group is alkyl.

15. 2. The compound of claim 1, wherein q is 1 or 2.

16. R28 is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, (CH ２ ) ｑ O.C. １－６ Alkyl, (CH ２ ) ｑ OH, (CH ２ ) ｑ NR27aR27b, (CH ２ ) ｑ NHCOC １－６ alkyl, or 【Chemistry 354】 and R29 is H, C １－６ alkyl, NR27aR27b or (CH 2 ) ｑ NHCOC １－６ is alkyl, The compound of claim 5 , wherein q is 1 or 2.

17. R ３ The compound of claim 7, wherein is isoxazolyl, 4-chloroisoxazolyl, 4-fluoroisoxazolyl, or pyrazolyl.

18. 4. The compound of claim 3, wherein X is CH.

19. The ULM is 【Chemical 355】 (In the formula, X is CH or N; R30 is H, F or Cl; R1 is C １－６ is alkyl, one of R14a and R14b is H, methyl, or C1 fluoroalkyl, and the other is H; R15 is cyano, halogen, 【Transformation 356】 and Each R １６ is H, C １－４ Alkyl, fluoro, chloro, NH ２ , CN, or C １－４ is an alkoxy, R28A is H or methyl; R28B is H, methyl, or halogen; R28 is H, methyl, CH ２ N (Me) ２ , C.H. ２ OH, CH ２ O (C １－４ alkyl), CH ２ NHC(O)C １－４ Alkyl, NH ２ , 【Chemistry 357】 and 【Chemistry 322】 is the point of attachment to said L.

20. The ULM is 【Chemistry 323-1】 【Chemistry 323-2】 【Chemical 358】 2. The compound of claim 1, wherein:

21. The ULM is 【Chemistry 359】 2. The compound of claim 1, wherein:

22. L is 【Chemical 325-1】 【Chemical 360】 where: each m, n, o, and p in L is independently 0, 1, 2, 3, or 4; each u, w, and v in L is independently 0 and 1; X Ｌ is -C(CH ２ ) -, -C(CH ３ ) H-, -CH ２ -, -O-, C=O, or -NH-CH ２ - and R Ｌ is H, OH, F, Cl, or methyl; W Ｌ２ is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene; W Ｌ３ is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene; W Ｌ５ is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene; W Ｌ６ is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene; W Ｌ７ is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene; W Ｌ８ The compound of claim 1, wherein is an optionally substituted 6- to 12-membered spirocycloalkylene or spiroheterocyclylene.

23. 22. The compound of claim 21, wherein each of m, n, o, p, q, and t is independently 0, 1, or 2.

24. W Ｌ２ but, 【Chemistry 326】 is selected from W Ｌ３ but, 【Chemistry 327】 and W Ｌ５ but, 【Chemical 328】 is selected from W Ｌ６ but, 【Chemistry 329】 is selected from W Ｌ７ but, 【Chemistry 330】 is selected from W Ｌ８ but, 【Chemistry 331】 or W Ｌ７ but, 【Chemistry 332】 and / or W Ｌ８ but, 【Chemical 333】 23. The compound of claim 22, selected from:

25. L is 【Chemistry 334-1】 【Chemistry 334-2】 【Chemical 361】 2. The compound of claim 1, wherein: 【Request Item 26】 【Chemistry 362-1】 【Chemistry 362-2】 【Chemistry 362-3】 【Chemistry 362-4】 【Chemistry 362-5】 【Chemistry 362-6】 【Chemistry 362-7】 【Chemistry 362-8】 【Chemistry 362-9】 【Chemistry 362-10】 【Chemistry 362-11】 【Chemistry 362-12】 【Chemistry 362-13】 【Chemistry 362-14】 【Chemistry 362-15】 【Chemistry 362-16】 【Chemistry 362-17】 【Chemistry 362-18】 【Chemistry 362-19】 【Chemistry 362-20】 【Chemistry 362-21】 【Chemistry 362-22】 【Chemistry 362-23】 【Chemistry 362-24】 【Chemistry 362-25】 【Chemistry 362-26】 【Chemistry 362-27】 【Chemistry 362-28】 or a pharmaceutically acceptable salt thereof.

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

28. 28. The pharmaceutical composition of claim 27, further comprising an anti-cancer agent.

29. A pharmaceutical composition for use in the treatment of cancer, comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

30. 30. The composition of claim 29, wherein the cancer is lung cancer or non-small cell lung cancer.

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