JP7502425B2 - BRM TARGETING COMPOUNDS AND RELATED METHODS OF USE - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Non-provisional Patent Application No. 16/590,329, filed October 1, 2020, entitled BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE, which is a continuation-in-part of U.S. Non-provisional Application No. 16/372,345, filed April 1, 2019, entitled BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE, which is a continuation-in-part of U.S. Non-provisional Application No. 16/372,345, filed April 1, 2018, entitled BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE. No. 62/651,186, filed Jan. 28, 2019, entitled BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE, and claims priority to and the benefit of U.S. Provisional Patent Application No. 62/797,754, filed Jan. 28, 2019, entitled BRM TARGETING PROTAC COMPOUNDS AND ASSOCIATED METHODS OF USE, each of which is incorporated herein by reference in its entirety.

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

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

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

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

Switch/sucrose nonfermenting (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-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2, BRAHMA, or BRM) and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4 or BRG1). The core and regulatory subunits couple ATP hydrolysis to perturbations of histone-DNA contacts, thereby providing attachment points to transcription factors and cognate DNA elements that promote gene activity and repression.

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

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

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

The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of use thereof. In particular, the present disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that find utility as regulators of targeted ubiquitination of various polypeptides and other proteins that are degraded and/or otherwise inhibited by the bifunctional compounds described herein. The advantage of the compounds provided herein is that they may have a broad range of pharmacological activity, consistent with the degradation/inhibition of target polypeptides from virtually any protein species or family. In addition, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of disease conditions, such as cancer, e.g., SMARCA4-associated/deficient cancers, such as lung cancer or non-small cell lung cancer.

Thus, in one aspect, the disclosure provides bifunctional compounds 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 close proximity to the ubiquitin ligase, which acts to degrade (and inhibit) 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 depicted as follows:

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

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

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

In certain embodiments, the compounds described herein include a plurality of independently selected ULMs, a plurality of PTMs, a plurality of chemical linkers, or a combination thereof.

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

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

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

In an additional aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound or salt form thereof described herein and a pharma- ceutically acceptable carrier. The therapeutic composition can be used to modulate protein degradation and/or inhibition in a patient or subject, e.g., an animal, such as a human, and to treat or ameliorate a disease state or condition modulated via the degraded and/or 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 SMARCA4 mutation, cancer with SMARCA4 deficiency, or a combination thereof. In yet another aspect, the present disclosure provides a method of ubiquitinating/degrading a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound described herein, preferably comprising a VLM linked via a linker moiety, as described elsewhere herein, wherein the VLM is linked to a PTM via a linker to target the protein for degradation. Degradation of a target protein occurs when the target protein is placed in close proximity to an E3 ubiquitin ligase, thus resulting in degradation of the target protein/inhibition of the effect of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment of a disease state or condition that is regulated via the target protein by reducing the level of that protein in the patient's cells.

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

In another aspect, the present specification provides a method for identifying the degradative effect of a protein of interest in a biological system using a compound according to the present disclosure.

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

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

Diagram of the general principle of PROTAC function. (A) Exemplary PROTACs include a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that connects or joins the PTM and ULM. (B) Illustrates the functional applications of PROTACs described herein. Briefly, the ULM recognizes and binds a specific E3 ubiquitin ligase, and the PTM binds and recruits a target protein, bringing it into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and catalyzes the attachment of ubiquitin via an isopeptide bond to a lysine on the target protein, either alone or through an E2 protein (dark circle). Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteosome machinery.

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, figures and other references mentioned herein are expressly incorporated by reference in their entirety.

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)) ubiquitinates a target protein once the two proteins are brought into close proximity via a bifunctional or chimeric construct that links the E3 ubiquitin ligase protein to the target protein. Accordingly, the present disclosure provides compounds and compositions that include an E3 ubiquitin ligase binding moiety (ULM) linked to a protein target binding moiety (PTM), which results in ubiquitination of a selected target protein and associated degradation of the target protein by the proteasome (see FIG. 1). The present disclosure also provides a library of compositions and uses thereof.

In certain aspects, the disclosure provides compounds that include a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons), that can bind to a ubiquitin ligase, such as VHL. The compound also includes a moiety that can bind 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. In addition to the above, small molecule can mean that the molecule is non-peptidyl, i.e., often not considered a peptide, e.g., containing fewer than 4, 3, or 2 amino acids. In accordance with the present specification, a PTM, ULM, or PROTAC molecule can be a small molecule.

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

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

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

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

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

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

In the claims, as well as in the above 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 including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Examining Guidelines.

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

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

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

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

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

The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin conjugating enzymes, cause the attachment of ubiquitin to lysines on a target protein, which then targets the specific protein substrate for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with E2 ubiquitin conjugating enzymes, are involved in the transfer of ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is added to the first ubiquitin and a third ubiquitin is added to the second ubiquitin. Polyubiquitination marks a protein for proteasomal degradation. However, there are some ubiquitination events that are limited to monoubiquitination, where only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. A monoubiquitinated protein is not targeted for degradation by the proteasome, but may instead change its cellular location or function, for example, through binding to other proteins that have domains to which ubiquitin can be attached. Further complicating the issue, additional lysines on the ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to generate polyubiquitin that is recognized by the proteasome. As used herein, the term "alkyl," by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical having the number of carbon atoms designated, unless otherwise specified (i.e., C1-8 means 1 to 8 carbons). If no specific number of carbon atoms is present, the alkyl groups provided herein are assumed to have 1-12 carbons, 1-8 carbons, 1-6 carbons, or 1-4 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. The alkyl groups can be optionally substituted as provided herein. In some embodiments, the alkyl group is a C1-6 alkyl, and in some embodiments, the alkyl group is a C1-4 alkyl.

U.S. Patent Application No. 15/230,354, filed August 5, 2016, U.S. Patent Application No. 14/371,956, filed July 11, 2014 (published as U.S. Patent Application Publication No. 2014/0356322), 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 No. PCT/US2016/019, filed February 24, 2016 No. 328 (published as International Patent Application Publication No. WO2016/138114), and International Patent Application No. PCT/US2016/023258, filed March 18, 2016 (published as International Patent Application Publication No. WO2016/149668), and U.S. Nonprovisional Patent Application No. 15/885,671, filed January 31, 2018 (published as U.S. Patent Application Publication No. 2018/0215731), all of which are incorporated herein by reference in their entirety. Additionally, all references cited herein are incorporated herein by reference in their entirety.

The term "optionally substituted," when used in combination with a substituent defined herein, means that the substituent may, but need not, be substituted with one or more suitable functional groups or other substituents as provided herein. For example, the substituent may be selected from halo, cyano, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo(C1-6)alkyl, C1-6 alkoxy, halo(C1-6 alkoxy), C1-6 alkylthio, C1-6 alkylamino, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C1-6 alkoxy), N(C1-6 alkoxy)2, -C(O)NHC1-6 alkyl, -C(O) It may be optionally substituted with one or more of N(C1-6 alkyl)2, -C(O)NH2, -C(O)C1-6 alkyl, -C(O)2C1-6 alkyl, -NHCO(C1-6 alkyl), -N(C1-6 alkyl)CO(C1-6 alkyl), -S(O)C1-6 alkyl, -S(O)2C1-6 alkyl, oxo, phenyl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5-6 membered heteroaryl groups. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

The term "cycloalkyl" as used herein refers to a C3-12 cyclic alkyl group, including bridged and spirocyclic (e.g., adamantine). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, the cycloalkyl group is a C3-6 cycloalkyl.

The term "alkenyl," as used herein, refers to a C2-12 alkyl group in which at least two of the carbon atoms are sp2 hybridized to form a carbon-carbon double bond therebetween. The alkenyl groups provided herein can contain two or more carbon-carbon double bonds, although one is preferred. The alkyl portion of the alkenyl groups provided herein can be substituted as provided above. In some embodiments, the alkenyl group is a C2-6 alkenyl.

The term "alkynyl," as used herein, refers to a C2-12 alkyl group in which at least two of the carbon atoms are sp hybridized to form a carbon-carbon triple bond therebetween. The alkynyl groups provided herein can contain two or more carbon-carbon triple bonds, although one is preferred. The alkyl portion of the alkynyl groups provided herein can be substituted as provided above. In some embodiments, the alkynyl group is a C2-6 alkynyl.

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.

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

The term "halo(C1-x alkyl)" refers to an alkyl having 1 to x carbon atoms and substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halo groups. For example, 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(C1-C6 alkyl) include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, and 2,2,2-trifluoroethyl.

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

The term "heteroalkyl" refers to a straight or branched chain alkyl group having, for example, 2 to 14 carbons, e.g., 2 to 10 carbons, in the chain, with one or more of the carbons 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 may be a terminal group or a bridging group. As used herein, reference to a normal chain when used in the context of a bridging group refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

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

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

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 in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur, and the term also includes multiple condensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) of about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a single heterocycle (as defined above) can be fused with one or more groups selected from heterocycle (e.g., to form 1,8-decahydronapthyridinyl), carbocycle (e.g., to form decahydroquinolyl), and aryl to form a multiple condensed ring system. Thus, a heterocycle (a single saturated or partially unsaturated ring, or a multiple condensed ring system) has from about 2 to 20 carbon atoms and from 1 to 6 heteroatoms in the heterocycle. Such multiple condensed ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portions of the multiple condensed ring. The rings of a multiple condensed ring system can be connected to each other through fused bonds, spiro bonds, and bridge bonds, where permitted by valency requirements. It is understood that the individual rings of a multiple condensed ring system can 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 from about 3 to 20 atoms, including from 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 anywhere 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 a 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 includes a C2-20 heterocyclic ring. In one embodiment, the term heterocyclic includes a C2-7 heterocyclic ring. In one embodiment, the term heterocyclic includes a C2-5 heterocyclic ring. In one embodiment, the term heterocyclic includes a C2-4 heterocyclic ring. Exemplary 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, These include, but are not limited to, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidin-2-one. In one embodiment, the term "heterocycle" refers to a monocyclic, saturated or partially unsaturated 3-8 membered ring having at least one heteroatom. For example, the term includes monocyclic, saturated or partially unsaturated 4-, 5-, 6-, or 7-membered rings having at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperazine, oxirane, morpholine, and thiomorpholine. As used herein, the term "9- or 10-membered heterocycle" refers to a partially unsaturated or aromatic fused bicyclic ring system having at least one heteroatom. For example, the term 9- or 10-membered heterocycle includes bicyclic ring systems having a benzo ring fused to a 5- or 6-membered saturated, partially unsaturated, or aromatic ring containing one or more heteroatoms.

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 oxidized form, where possible.

As used herein, the term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on their mirror image partners.

As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with respect to the arrangement of the atoms or groups in space.
" indicates a mixture of E and Z stereoisomers.

As used herein, a wavy line "" that crosses a bond in a chemical structure
or a dashed line "---" indicates the point of attachment of the bond to which the wavy bond is attached in a chemical structure to the remainder of the molecule.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical techniques such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

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 invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about a chiral center. The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

When bonds in the compound formulae herein are drawn in a non-stereochemical manner (e.g., flat), the atoms to which the bonds are attached include all stereochemical possibilities. When bonds in the compound formulae herein are drawn in a prescribed stereochemical manner (e.g., bold, bold wedge, dashed line, or dashed wedge), it is understood that the atoms to which the stereochemical bonds are attached are enriched in the depicted absolute stereoisomer, unless otherwise noted. In one embodiment, the compound may be at least 51% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 80% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 90% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 95% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 97% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 98% of the absolute stereoisomer shown. In another embodiment, the compound may be at least 99% of the absolute stereoisomer shown.

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

As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the 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 where the solvent molecule is water.

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

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

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

In addition to salt forms, the present invention provides compounds that are 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. Additionally, 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.

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

Additional types of prodrugs are also included. For example, free carboxyl groups of the compounds of the invention can be derivatized as amides or alkyl esters. As another example, compounds of the invention containing free hydroxyl groups can be derivatized as prodrugs by converting the hydroxyl group to groups such as, but not limited to, phosphate esters, hemisuccinates, dimethylaminoacetates, 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 also include sulfonate and sulfate esters of hydroxy groups, as well as carbonate prodrugs.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also included, and acyl groups can be alkyl esters, optionally substituted with groups including but not limited to ether, amine, and carboxylic acid functional groups, or acyl groups are amino acid esters as described above.This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include replacing the hydrogen atom of the alcohol group with groups such as (C1-6)alkanoyloxymethyl, 1-((C1-6)alkanoyloxy)ethyl, 1-methyl-1-((C1-6)alkanoyloxy)ethyl, (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkanoyl, alpha-amino(C1-4)alkanoyl, aryl acyl, and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, each alpha-aminoacyl group being independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2, or glycosyl (the radical resulting from removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

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

Additionally, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced through metabolism in the body of a particular compound or salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

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

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

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

Compounds and Compositions In one aspect, the present disclosure provides compounds that include an E3 ubiquitin ligase binding moiety ("ULM") that is a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM). In an exemplary embodiment, the ULM is linked to a target protein binding moiety (PTM) via a chemical linker (L) according to the following structure:
(A) PTM-L-ULM
where L is a bond or chemical linker group, ULM is an E3 ubiquitin ligase binding moiety, and PTM is a target protein binding moiety. The number and/or relative positions of moieties in the compounds described herein are provided for illustrative purposes only. As will be appreciated by those skilled in the art, the compounds described herein can be synthesized with any desired number of each functional moiety and/or relative positions of each functional moiety.

In another aspect, the 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 compounds include a VLM attached, e.g., covalently, directly, or indirectly, to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the VLM and PTM are attached or linked via a chemical linker (L). The VLM binds to the VHL, the PTM recognizes the target protein, and the interaction of each moiety with their target promotes degradation of the target protein by placing the target protein in close proximity to a ubiquitin ligase protein. An exemplary bifunctional compound can be depicted as follows: PTM-VLM.

In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be depicted 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.

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

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

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

In certain embodiments, the compound may include multiple ULMs and/or multiple ULMs'. In further embodiments, the compound including at least two different ULMs, multiple ULMs, and/or multiple ULMs' further includes at least one PTM attached to the ULM or ULM' either directly or via a chemical linker, or both. In any of the embodiments described herein, the compound including at least two different ULMs may further include multiple PTMs. In still further embodiments, the PTMs are the same or optionally different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

In additional embodiments, the present disclosure provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharma- ceutically acceptable salt forms, e.g., acid salt forms and base salt forms.

式中、
破線は、少なくとも１つのＰＴＭ、別のＵＬＭもしくはＶＬＭ（ＶＬＭ’）、または少なくとも１つのＰＴＭ、ＵＬＭ’、もしくはＶＬＭ’をリンカーの他方の端部に結合させる化学リンカー部分の結合を示し、
式ＵＬＭ－ａのＸ１、Ｘ２はそれぞれ独立して、結合、Ｏ、ＮＲＹ３、ＣＲＹ３ＲＹ４、Ｃ＝Ｏ、Ｃ＝Ｓ、ＳＯ、およびＳＯ２の群から選択され、
式ＵＬＭ－ａのＲＹ３、ＲＹ４は、各々独立して、Ｈ、１つ以上のハロで任意に置換された直鎖または分岐鎖Ｃ１－６アルキル、任意に置換された（例えば、０～３個のＲＰ基で任意に置換された）Ｃ１－６アルコキシルからなる群から選択され、
式ＵＬＭ－ａのＲＰは、０、１、２、または３個の基であり、各々が独立して、Ｈ、ハロ、－ＯＨ、Ｃ１－３アルキル、Ｃ＝Ｏ、アルキル、アルコキシ、またはそれらの組み合わせの群から選択され、
式ＵＬＭ－ａのＷ３は、任意に置換されたＴ、任意に置換された－Ｔ－Ｎ（Ｒ１ａＲ１ｂ）Ｘ３、任意に置換された－Ｔ－Ｎ（Ｒ１ａＲ１ｂ）、任意に置換された－Ｔ－アリール、任意に置換された－Ｔ－ヘテロアリール、任意に置換されたＴ－ビヘテロアリール、任意に置換された－Ｔ－ヘテロシクリル、任意に置換された－Ｔ－ビヘテロシクリル、任意に置換された－ＮＲ１－Ｔ－アリール、任意に置換された－ＮＲ１－Ｔ－ヘテロアリール、または任意に置換された－ＮＲ１－Ｔ－ヘテロシクリルの群から選択され、
式ＵＬＭ－ａのＸ３は、Ｃ＝Ｏ、Ｒ１、Ｒ１ａ、Ｒ１ｂであり、
Ｒ１、Ｒ１ａ、Ｒ１ｂの各々は、独立して、Ｈ、１個以上のハロで任意に置換された直鎖もしくは分岐鎖Ｃ１－Ｃ６アルキル基、または－ＯＨ基、ＲＹ３Ｃ＝Ｏ、ＲＹ３Ｃ＝Ｓ、ＲＹ３ＳＯ、ＲＹ３ＳＯ２、Ｎ（ＲＹ３ＲＹ４）Ｃ＝Ｏ、Ｎ（ＲＹ３ＲＹ４）Ｃ＝Ｓ、Ｎ（ＲＹ３ＲＹ４）ＳＯ、およびＮ（ＲＹ３ＲＹ４）ＳＯ２からなる群から選択され、
式ＵＬＭ－ａのＴは、任意に置換されたアルキル、－（ＣＨ２）ｎ－基、任意に置換された直鎖もしくは分岐鎖－（ＣＨ２）ｎ－Ｏ－Ｃ１－Ｃ６アルキル、または任意に置換された－（ＣＨ２）ｎ－Ｏ－ヘテロシクリルの群から選択され、式中、メチレン基の各々は、ハロゲン、メチル、１個以上のハロゲンで任意に置換された直鎖もしくは分岐鎖Ｃ１－Ｃ６アルキル基、または－ＯＨ基、任意に置換されたアミノ酸側鎖、または任意に置換されたヘテロシクリルの群から選択される１個または２個の置換基で置換され、
式ＵＬＭ－ａのＷ４は、任意に置換された－ＮＲ１－Ｔ－アリールであり、式中、アリール基は、任意に置換された５～６員ヘテロアリール、または任意に置換されたアリール、任意に置換された－ＮＲ１－Ｔ－ヘテロアリール基であり得、式中、ヘテロアリールは、任意に置換されたアリール、または任意に置換されたヘテロアリール、または任意に置換された－ＮＲ１－Ｔ－ヘテロシクリルで任意に置換され、式中、－ＮＲ１は、Ｘ２に共有結合し、Ｒ１がＨまたはＣＨ３、好ましくはＨである。 Exemplary VLMs
In certain embodiments, the compounds described herein comprise 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 ULM-a group:

In the formula,
The dashed lines indicate the attachment of at least one PTM, another ULM or VLM (VLM'), or a chemical linker moiety that attaches at least one PTM, ULM', or VLM' to the other end of the linker;
Each of X1 and X2 in formula ULM-a is independently selected from the group consisting of a bond, O, NR, CRY, C=O, C=S, SO, and SO;
Each of RY3 and RY4 in formula ULM-a is independently selected from the group consisting of H, straight or branched C1-6 alkyl optionally substituted with one or more halo, and optionally substituted (e.g., optionally substituted with 0-3 RP groups) C1-6 alkoxyl;
R of formula ULM-a is 0, 1, 2, or 3 groups, each independently selected from the group of H, halo, —OH, C1-3 alkyl, C═O, alkyl, alkoxy, or combinations thereof;
W3 of formula ULM-a is selected from the group of optionally substituted T, optionally substituted -T-N(R1aR1b)X3, optionally substituted -T-N(R1aR1b), optionally substituted -T-aryl, optionally substituted -T-heteroaryl, optionally substituted T-biheteroaryl, optionally substituted -T-heterocyclyl, optionally substituted -T-biheterocyclyl, optionally substituted -NR1-T-aryl, optionally substituted -NR1-T-heteroaryl, or optionally substituted -NR1-T-heterocyclyl;
X3 in formula ULM-a is C=O, R1, R1a, or R1b;
Each of R1, R1a, and R1b is independently selected from the group consisting of H, a straight or branched C1-C6 alkyl group optionally substituted with one or more halo, or an -OH group, RY3C=O, RY3C=S, RY3SO, RY3SO2, N(RY3RY4)C=O, N(RY3RY4)C=S, N(RY3RY4)SO, and N(RY3RY4)SO2;
T of formula ULM-a is selected from the group of optionally substituted alkyl, -(CH2)n- group, optionally substituted linear or branched -(CH2)n-O-C1-C6 alkyl, or optionally substituted -(CH2)n-O-heterocyclyl, wherein each of the methylene groups is substituted with 1 or 2 substituents selected from the group of halogen, methyl, linear or branched C1-C6 alkyl group optionally substituted with one or more halogens, or -OH group, optionally substituted amino acid side chain, or optionally substituted heterocyclyl;
W4 in formula ULM-a is an optionally substituted -NR1-T-aryl, where the aryl group can be an optionally substituted 5-6 membered heteroaryl, or an optionally substituted aryl, an optionally substituted -NR1-T-heteroaryl group, where 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 covalently bonded to X2 and R1 is H or CH3, preferably H.

In certain embodiments, RP is modified to form a prodrug, including an ester or ether bond.

In any aspect or embodiment described herein, T is selected from the group of an optionally substituted alkyl, -(CH2)n- group, where each methylene group is optionally substituted with one or two substituents selected from the group of halogen, methyl, optionally substituted alkoxy, linear or branched C1-C6 alkyl groups optionally substituted with one or more halogens, C(O)NR1R1a, or NR1R1a, or R1 and R1a are joined to form an optionally substituted heterocyclyl, or -OH group, or an optionally substituted amino acid side chain, and n is 0-6, often 0, 1, 2, or 3, preferably 0 or 1.

であり、式中、Ｒ１４ａ、Ｒ１４ｂは、各々独立して、Ｈ、ハロアルキル（例えば、フルオロアルキル）、任意に置換されたアルキル、任意に置換されたアルコキシ、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたアミド、任意に置換されたアルキル－アミド、任意に置換されたアルキル－シアノ、任意に置換されたアルキル－ホスフェート、任意に置換されたヘテロアルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、アルキル－ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＮＨＣＯＲ２６、もしくはＮＨＣＨ３ＣＯＲ２６の群から選択され、Ｒ１４ａおよびＲ１４ｂのうちの他方は、Ｈであるか、またはＲ１４ａ、Ｒ１４ｂは、それらが結合している炭素原子と一緒になって、任意に置換された３～５員シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルは、エポキシドまたはアジリジンではない。 In any aspect or embodiment described herein, W4 of formula ULM-a is:

wherein R14a, R14b are each independently selected from the group of H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, alkyl-COR26, CONR27aR27b, NHCOR26, or NHCH3COR26; and the other of R14a and R14b is H, or R14a, R14b together with the carbon atom to which they are attached form an optionally substituted 3-5 membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, which is not an epoxide or aziridine.

In any of the embodiments, W5 of formula ULM-a is selected from the group of optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5-10 membered heteroaryl;
R15 of formula ULM-a is selected from the group of H, halogen, CN, C≡CH, OH, NO2, NR14aR14b, OR14a, CONR14aR14b, NRR14b, SO2NR14aR14b, NR14aSO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl.

In additional embodiments, W4 substituents for use in the present disclosure also specifically include (and are not limited to) the W4 substituents found in the particular compounds disclosed herein. Each of these W4 substituents may be used in conjunction with any number of W3 substituents, which are also disclosed herein.

In certain additional embodiments, ULM-a is optionally substituted with 0-3 RP groups in the pyrrolidine moiety. Each RP is independently H, halo, -OH, C1-3 alkyl, C=O.

In any of the embodiments described herein, W3, W4 of formula ULM-a can be independently covalently attached to a linker that is attached to one or more PTM groups;
and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM' or both to a ULM.

式中、
式ＵＬＭ－ｂのＷ３は、任意に置換されたアリール、任意に置換されたヘテロアリール、または

の群から選択され、
式ＵＬＭ－ｂのＲ９およびＲ１０は、独立して、水素、任意に置換されたアルキル、任意に置換されたシクロアルキル、任意に置換されたヒドロキシアルキル、任意に置換されたヘテロアリール、もしくはハロアルキルであるか、またはＲ９、Ｒ１０、およびそれらが結合する炭素原子が、任意に置換されたシクロアルキルを形成し、
式ＵＬＭ－ｂのＲ１１は、任意に置換されたヘテロシクリル、任意に置換されたアルコキシ、任意に置換されたヘテロアリール、任意に置換されたアリール、

の群から選択され、
式ＵＬＭ－ｂのＲ１２は、Ｈまたは任意に置換されたアルキルの群から選択され、
式ＵＬＭ－ｂのＲ１３は、Ｈ、任意に置換されたアルキル、任意に置換されたアルキルカルボニル、任意に置換された（シクロアルキル）アルキルカルボニル、任意に置換されたアラルキルカルボニル、任意に置換されたアリールカルボニル、任意に置換された（ヘテロシクリル）カルボニル、または任意に置換されたアラルキルの群から選択され、
式ＵＬＭ－ｂのＲ１４ａ、Ｒ１４ｂは、各々独立して、Ｈ、ハロアルキル（例えば、フルオロアルキル）、任意に置換されたアルキル、任意に置換されたアルコキシ、アミノメチル、アルキルアミノメチル、アルコキシメチル、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたアミド、任意に置換されたアルキル－アミド、任意に置換されたアルキル－シアノ、任意に置換されたアルキル－ホスフェート、任意に置換されたヘテロアルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、アルキル－ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＣＨ２ＮＨＣＯＲ２６、もしくは（ＣＨ２）Ｎ（ＣＨ３）ＣＯＲ２６の群から選択され、Ｒ１４ａおよびＲ１４ｂのうちの他方は、Ｈであるか、またはＲ１４ａ、Ｒ１４ｂは、それらが結合している炭素原子と一緒になって、任意に置換された３～６員シクロアルキル、ヘテロシクロアルキ、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルは、エポキシドまたはアジリジンではない。
式ＵＬＭ－ｂのＷ５は、フェニル、ナプチル、または５～１０員ヘテロアリールの群から選択され、
式ＵＬＭ－ｂのＲ１５は、Ｈ、ハロゲン、ＣＮ、Ｃ≡ＣＨ、ＯＨ、ＮＯ２、ＮＲ２７ａＲ２７ｂ、ＯＲ２７ａ、ＣＯＮＲ２７ａＲ２７ｂ、ＮＲ２７ａＣＯＲ２７ｂ、ＳＯ２ＮＲ２７ａＲ２７ｂ、ＮＲ２７ａＳＯ２Ｒ２７ｂ、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたハロアルコキシ、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたシクロアルキル、または任意に置換されたヘテロシクリルの群から選択され、
式ＵＬＭ－ｂの各Ｒ１６は、独立して、ハロ、ＣＮ、任意に置換されたアルキル、任意に置換されたアルキルアミン、任意に置換されたハロアルキル、ヒドロキシ、または任意に置換されたハロアルコキシの群から選択され、
式ＵＬＭ－ｂのｏは、０、１、２、３、または４であり、
式ＵＬＭ－ｂのＲ１８は、Ｈ、ハロ、任意に置換されたアルコキシ、シアノ、任意に置換されたアルキル、ハロアルキル、ハロアルコキシまたはリンカーの群から独立して選択され、
各Ｒ２６は、独立して、Ｈ、ＯＨ、任意に置換されたアルキル、またはＮＲ２７ａＲ２７ｂから選択され、
各Ｒ２７ａおよびＲ２７ｂは、独立して、Ｈ、任意に置換されたアルキル、任意に置換された３～５員シクロアルキルであるか、またはＲ２７ａおよびＲ２７ｂが、それらが結合している窒素原子と一緒になって、４～６員ヘテロシクリルを形成し、

式ＵＬＭ－ｂのｐは、０、１、２、３、または４であり、および式中、破線は、少なくとも１つのＰＴＭ、別のＵＬＭ（ＵＬＭ’）、または少なくとも１つのＰＴＭもしくはＵＬＭ’もしくはその両方をＵＬＭに結合する化学リンカー部分の結合部位を示す。 In certain embodiments, the ULM is VHL and is represented by the following structure:

In the formula,
W3 of formula ULM-b is optionally substituted aryl, optionally substituted heteroaryl, or

is selected from the group
R9 and R10 of formula ULM-b 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 of formula ULM-b is optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

is selected from the group
R12 of formula ULM-b is selected from the group of H or optionally substituted alkyl;
R13 of formula ULM-b is selected from the group: 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;
R14a and R14b in formula ULM-b are each independently H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, aminomethyl, alkylaminomethyl, alkoxymethyl, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amido, optionally substituted alkyl-amido, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, any wherein the other of R14a and R14b is H, or R14a, R14b together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, and wherein the spiroheterocyclyl is not an epoxide or an aziridine.
W5 of formula ULM-b is selected from the group of phenyl, naphthyl, or 5-10 membered heteroaryl;
R15 of formula ULM-b is selected from the group H, halogen, CN, C≡CH, OH, NO2, NR27aR27b, OR27a, CONR27aR27b, NR27aCOR27b, SO2NR27aR27b, NR27aSO2R27b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
Each R16 of formula ULM-b is independently selected from the group 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;
R18 of formula ULM-b is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;
each R26 is independently selected from H, OH, optionally substituted alkyl, or NR27aR27b;
each R27a and R27b is independently H, optionally substituted alkyl, optionally substituted 3- to 5-membered cycloalkyl, or R27a and R27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl;

In formula ULM-b, p is 0, 1, 2, 3, or 4, and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM' or both to a ULM.

であり、式中、Ｒ１７は、Ｈ、ハロ、任意に置換されたＣ３－６シクロアルキル、任意に置換されたＣ１－６アルキル、任意に置換されたＣ１－６アルケニル、およびＣ１－６ハロアルキルであり、Ｘａは、ＳまたはＯである。 In certain embodiments, R15 of formula ULM-b is

wherein R17 is H, halo, optionally substituted C3-6 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkenyl, and C1-6 haloalkyl; and Xa is S or O.

In certain embodiments, R17 of formula ULM-b is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl.

In certain additional embodiments, R15 of formula ULM-b is selected from the group consisting of:

In certain embodiments, R11 of formula ULM-b is selected from the group consisting of:

In any aspect or embodiment described herein, R14a, R14b of ULM-b are each independently H, optionally substituted haloalkyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, alkyl-COR26, CH2OR30, CH2NHR30, CH2NCH3R3 0, CONR27aR27b, CH2CONR27aR27b, CH2NHCOR26, or CH2NCH3COR26; the other of R14a and R14b is H, or R14a, R14b together with the carbon atom to which they are attached form an optionally substituted 3-6 membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, which spiroheterocyclyl is not an epoxide or aziridine, and said spirocycloalkyl or spiroheterocyclyl is itself optionally substituted with alkyl, haloalkyl, or -COR33, where R33 is alkyl or haloalkyl;
wherein R30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or further optionally substituted heteroarylalkyl; and R26 and R27 are as defined above.

を含み、式中、Ｒ２６、Ｒ２７、Ｒ３０、およびＲ１４ａは、上記のとおりである。 In any aspect or embodiment described herein, R15 of formula ULM-b is H, halogen, CN, C≡CH, OH, NO2, NR27aR27b, OR27a, CONR27aR27b, NR27aCOR27b, SO2NR27aR27b, NR27aSO2R27b, optionally substituted alkyl, optionally substituted haloalkyl (e.g., optionally substituted fluoroalkyl), optionally substituted haloalkoxy, optionally and optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein the optional substitutions of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are selected from CH2OR30, CH2NHR30, CH2NCH3R30, CONR27aR27b, CH2CONR27aR27b, CH2NHCOR26, CH2NCH3COR26, or

wherein R26, R27, R30, and R14a are as defined above.

を含み、式中、Ｒ２６、Ｒ２７、Ｒ３０、およびＲ１４ａは、上記のとおりである。 In any aspect or embodiment described herein, R14a, R14b of formula ULM-b are each independently selected from the group of H, optionally substituted haloalkyl, optionally substituted alkyl, CH2OR30, CH2NHR30, CH2NCH3R30, CONR27aR27b, CH2CONR27aR27b, CH2NHCOR26, or CH2NCH3COR26, and the other of R14a and R14b is H, or R14a, R14b together with the carbon atom to which they are attached are an optionally substituted 3-6 membered spirocyclo. forming an alkyl, or a spiroheterocyclyl, where the spiroheterocyclyl is not an epoxide or an aziridine, and the spirocycloalkyl or spiroheterocyclyl itself is optionally substituted with alkyl, haloalkyl, or -COR33, where R33 is alkyl or haloalkyl, and where R30 is selected from H, alkyl, alkynylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, or further optionally substituted heteroarylalkyl;
R15 of formula ULM-b is selected from H, halogen, CN, C≡CH, OH, NO2, NR27aR27b, OR27a, CONR27aR27b, NR27aCOR27b, SO2NR27aR27b, NR27aS02R27b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein the optional substitutions of the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are CH2OR30, CH2NHR30, CH2NCH3R30, CONR27aR27b, CH2CONR27aR27b, CH2NHCOR26, CH2NCH3COR26, or

wherein R26, R27, R30, and R14a are as defined above.

式中、
式ＵＬＭ－ｃ、ＵＬＭ－ｄ、およびＵＬＭ－ｅのＲ１は、Ｈ、エチル、イソプロピル、ｔｅｒｔ－ブチル、ｓｅｃ－ブチル、シクロプロピル、シクロブチル、シクロペンチル、またはシクロヘキシル、任意に置換されたアルキル、任意に置換されたシクロアルキル、任意に置換されたヒドロキシアルキル、任意に置換されたヘテロアリール、またはハロアルキルであり、
式ＵＬＭ－ｃ、ＵＬＭ－ｄ、およびＵＬＭ－ｅのＲ１４ａは、Ｈ、ハロアルキル、任意に置換されたアルキル、メチル、フルオロメチル、ヒドロキシメチル、エチル、イソプロピル、またはシクロプロピルであり、
式ＵＬＭ－ｃ、ＵＬＭ－ｄ、およびＵＬＭ－ｅのＲ１５は、Ｈ、ハロゲン、ＣＮ、Ｃ≡ＣＨ、ＯＨ、ＮＯ２、任意に置換されたヘテロアリール、任意に置換されたアリール、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたハロアルコキシ、任意に置換されたシクロアルキル、または任意に置換されたヘテロシクリルからなる群から選択され、
式ＵＬＭ－ｃ、ＵＬＭ－ｄ、およびＵＬＭ－ｅのＸは、Ｃ、ＣＨ２、またはＣ＝Ｏであり、
式ＵＬＭ－ｃ、ＵＬＭ－ｄ、およびＵＬＭ－ｅのＲ３は、存在しないか、または任意に置換された５または６員ヘテロアリールであり、
破線は、少なくとも１つのＰＴＭ、別のＵＬＭ（ＵＬＭ’）、または少なくとも１つのＰＴＭもしくはＵＬＭ’もしくは両方をＵＬＭに結合させる化学リンカー部分の結合部位を示す。 In certain embodiments, the ULM has a chemical structure selected from the group consisting of:

In the formula,
R1 in 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;
R14a of formulae ULM-c, ULM-d, and ULM-e is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R15 of formulae ULM-c, ULM-d, and ULM-e 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 in formulae ULM-c, ULM-d, and ULM-e is C, CH2, or C=O;
R3 of formulae ULM-c, ULM-d, and ULM-e is absent or an optionally substituted 5- or 6-membered heteroaryl;
The dashed lines indicate the attachment sites of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or a ULM' or both to a ULM.

式中、
式ＵＬＭ－ｆのＲ１４ａは、Ｈ、ハロアルキル、任意に置換されたアルキル、メチル、フルオロメチル、ヒドロキシメチル、エチル、イソプロピル、またはシクロプロピルであり、
式ＵＬＭ－ｆのＲ９は、Ｈであり、
式ＵＬＭ－ｆのＲ１０は、Ｈ、エチル、イソプロピル、ｔｅｒｔ－ブチル、ｓｅｃ－ブチル、シクロプロピル、シクロブチル、シクロペンチル、またはシクロヘキシルであり、
式ＵＬＭ－ｆのＲ１１は、

または任意に置換されたヘテロアリールであり、
式ＵＬＭ－ｆのｐは、０、１、２、３、または４であり、
式ＵＬＭ－ｆの各Ｒ１８は、独立して、ハロ、任意に置換されたアルコキシ、シアノ、任意に置換されたアルキル、ハロアルキル、ハロアルコキシまたはリンカーであり、
式ＵＬＭ－ｆのＲ１２は、Ｈ、Ｃ＝Ｏであり、
式ＵＬＭ－ｆのＲ１３は、Ｈ、任意に置換されたアルキル、任意に置換されたアルキルカルボニル、任意に置換された（シクロアルキル）アルキルカルボニル、任意に置換されたアラルキルカルボニル、任意に置換されたアリールカルボニル、任意に置換された（ヘテロシクリル）カルボニル、または任意に置換されたアラルキルであり、
式ＵＬＭ－ｆのＲ１５は、Ｈ、ハロゲン、Ｃｌ、ＣＮ、Ｃ≡ＣＨ、ＯＨ、ＮＯ２、任意に置換されたハロアルキル、任意に置換されたヘテロアリール、任意に置換されたアリール、

からなる群から選択され、
式中、式ＵＬＭ－ｆの破線は、少なくとも１つのＰＴＭ、別のＵＬＭ（ＵＬＭ’）、または少なくとも１つのＰＴＭもしくはＵＬＭ’もしくはその両方をＵＬＭに結合する化学リンカー部分の結合部位を示す。 In certain embodiments, the ULM comprises a group according to the following chemical structure:

In the formula,
R14a of formula ULM-f is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R9 of formula ULM-f is H;
R10 of formula ULM-f is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
R11 in the formula ULM-f is

or optionally substituted heteroaryl;
In the formula ULM-f, p is 0, 1, 2, 3, or 4;
Each R of formula ULM-f is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;
R12 of formula ULM-f is H, C=O;
R13 of formula ULM-f 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;
R15 of formula ULM-f is H, halogen, Cl, CN, C≡CH, OH, NO2, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl,

is selected from the group consisting of
wherein the dashed lines in formula ULM-f indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety that connects at least one PTM or ULM' or both to a ULM.

式中、ｎは０または１である。 In certain embodiments, the ULM is selected from the following structures:

In the formula, n is 0 or 1.

いｖ ここで、ＵＬＭ－ａ１からＵＬＭ－ａ１５、ＵＬＭ－ｂ１からＵＬＭ－ｂ１２、ＵＬＭ－ｃ１からＵＬＭ－ｃ１５、およびＵＬＭ－ｄ１からＵＬＭ－ｄ９のフェニル環は、任意でフッ素、低級アルキル、およびアルコキシ基で置換され、ここで破線は、少なくとも１つのＰＴＭ、別のＵＬＭ（ＵＬＭ’）、または少なくとも１つのＰＴＭもしくはＵＬＭ’もしくはその両方をＵＬＭ－ａに結合する化学リンカー部分の結合部位を示す。 In certain embodiments, the ULM is selected from the following structures:

wherein the phenyl rings of 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 where the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to ULM-a.

In one embodiment, the phenyl rings of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15, and ULM-d1 through ULM-d9 are functionalized as esters, which can be part of a prodrug.

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 contain an ester-linked prodrug moiety.

またはその薬学的に許容される塩を含み、
ＵＬＭ－ｇのＲ１’は、任意に置換されたＣ１－Ｃ６アルキル基、任意に置換された－（ＣＨ２）ｎＯＨ、任意に置換された－（ＣＨ２）ｎＳＨ、任意に置換された（ＣＨ２）ｎ－Ｏ－（Ｃ１－Ｃ６）アルキル基、エポキシド部分ＷＣＯＣＷ（式中、各Ｗは、独立して、ＨまたはＣ１－Ｃ３アルキル基である）を含有する任意に置換された（ＣＨ２）ｎ－ＷＣＯＣＷ－（Ｃ０－Ｃ６）アルキル基、任意に置換された－（ＣＨ２）ｎＣＯＯＨ、任意に置換された－（ＣＨ２）ｎＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２）ｎＮＨＣ（Ｏ）－Ｒ″、任意に置換された－（ＣＨ２）ｎＣ（Ｏ）－Ｎ（Ｒ″）２、任意に置換された－（ＣＨ２）ｎＯＣ（Ｏ）－Ｎ（Ｒ″）２、－（ＣＨ２Ｏ）ｎＨ、任意に置換された－（ＣＨ２）ｎＯＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２）ｎＣ（Ｏ）－Ｏ－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２Ｏ）ｎＣＯＯＨ、任意に置換された－（ＯＣＨ２）ｎＯ－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２Ｏ）ｎＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＯＣＨ２）ｎＮＨＣ（Ｏ）－Ｒ″、任意に置換された－（ＣＨ２Ｏ）ｎＣ（Ｏ）－Ｎ（Ｒ″）２、－（ＣＨ２ＣＨ２Ｏ）ｎＨ、任意に置換された－（ＣＨ２ＣＨ２Ｏ）ｎＣＯＯＨ、任意に置換された－（ＯＣＨ２ＣＨ２）ｎＯ－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２ＣＨ２Ｏ）ｎＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＯＣＨ２ＣＨ２）ｎＮＨＣ（Ｏ）－Ｒ″、任意に置換された－（ＣＨ２ＣＨ２Ｏ）ｎＣ（Ｏ）－Ｎ（Ｒ″）２、任意に置換された－ＳＯ２ＲＳ、任意に置換されたＳ（Ｏ）ＲＳ、ＮＯ２、ＣＮ、またはハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ、好ましくは、ＦまたはＣｌ）であり、
ＵＬＭ－ｇの各Ｒ″は、独立して、Ｈ、または１個もしくは２個のヒドロキシル基または最大３個のハロゲン基（好ましくは、フッ素）で任意に置換され得るＣ１－Ｃ６アルキル基であり、
ＵＬＭ－ｇのＲＳが、Ｃ１－Ｃ６アルキル基、任意に置換されたアリール、ヘテロアリール、もしくはヘテロシクリル基、または－（ＣＨ２）ｍＮ（Ｒ″）２基であり、
ＵＬＭ－ｇのＸおよびＸ’は、各々独立して、Ｃ＝Ｏ、Ｃ＝Ｓ、－Ｓ（Ｏ）、Ｓ（Ｏ）２であり、（好ましくは、ＸおよびＸ’は、両方ともＣ＝Ｏであり）、
ＵＬＭ－ｇのＲ２’は、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗアルキリ基、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗＮＲ１ＮＲ２Ｎ基、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｖＮＲ″（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、もしくは任意に置換された－ＮＲ″－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｖＮＲ″（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－ＸＲ２’－アルキリ基、任意に置換された－ＸＲ２’－アリール基、任意に置換された－ＸＲ２’－ヘテロアリール基、任意に置換された－ＸＲ２’－ヘテロシクリル基であり、
ＵＬＭ－ｇのＲ３’は、任意に置換されたアルキル、任意に置換された－（ＣＨ２）ｎ－（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－Ｃ（Ｏ）（Ｒ″）２、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、任意に置換された－ＮＲ１－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、もしくは任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロシクリル、－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－アルキル基、任意に置換された－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－アリール基、任意に置換された－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－ヘテロアリール基、任意に置換された－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－ヘテロシクリル’基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－アルキル基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－アリール基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－ヘテロアリール基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－ヘテロシクリル基、任意に置換された－ＸＲ３’－アルキル基、任意に置換された－ＸＲ３’－アリール基、任意に置換された－ＸＲ３’－ヘテロアリール基、任意に置換された－ＸＲ３’－ヘテロシクリル基であり、
ＵＬＭ－ｇのＲ１ＮおよびＲ２Ｎは、各々独立して、Ｈ、１個もしくは２個のヒドロキシル基および最大３個のハロゲン基で任意に置換されたＣ１－Ｃ６アルキル、または任意に置換された－（ＣＨ２）ｎ－アリール、－（ＣＨ２）ｎ－ヘテロアリール、もしくは－（ＣＨ２）ｎ－ヘテロシクリル基であり、
ＵＬＭ－ｇのＶは、Ｏ、ＳまたはＮＲ１であり、
ＵＬＭ－ｇの各Ｒ１’は、独立して、Ｈ、またはＣ１－Ｃ３アルキル基であり、
ＵＬＭ－ｇのＸＲ２’およびＸＲ３’は、各々独立して、任意に置換された－ＣＨ２）ｎ－、－ＣＨ２）ｎ－ＣＨ（Ｘｖ）＝ＣＨ（Ｘｖ）－（ｃｉｓまたはｔｒａｎｓ）、－ＣＨ２）ｎ－ＣＨ≡ＣＨ－、－（ＣＨ２ＣＨ２Ｏ）ｎ－、またはＣ３－Ｃ６シクロアルキル基であり、式中、Ｘｖは、Ｈ、ハロ、または任意に置換されたＣ１－Ｃ３アルキル基であり、
ＵＬＭ－ｇの各ｍは独立して、０、１、２、３、４、５、６であり、
ＵＬＭ－ｇの各ｍ’は独立して、０または１であり、
ＵＬＭ－ｇの各ｎは独立して、０、１、２、３、４、５、６であり、
ＵＬＭ－ｇの各ｎ’は独立して、０または１であり、
ＵＬＭ－ｇの各ｕは独立して、０または１であり、
ＵＬＭ－ｇの各ｖは独立して、０または１であり、
ＵＬＭ－ｇの各ｗは独立して、０または１であり、および
ＵＬＭ－ｇのＲ１’、Ｒ２’、Ｒ３’、ＸおよびＸ’のうちのいずれか１つ以上が任意で改変されて、ＰＴＭがＵＬＭ’ではない場合はリンカー基を介してＰＴＭ基に共有結合され、ＰＴＭがＵＬＭ’である場合は、ＵＬＭおよびＵＬＭ’の各々のＲ１’、Ｒ２’、Ｒ３’、ＸならびにＸ’のうちのいずれか１つ以上が任意で改変されて、直接またはリンカー基を介して互いに共有結合される。 In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, or a pharma- ceutically acceptable salt, stereoisomer, solvate or polymorph thereof, are each independently a group conforming to the following chemical structure:

or a pharma- ceutically acceptable salt thereof,
R1' of ULM-g is an optionally substituted C1-C6 alkyl group, an optionally substituted -(CH2)nOH, an optionally substituted -(CH2)nSH, an optionally substituted (CH2)n-O-(C1-C6)alkyl group, an optionally substituted (CH2)n-WCOCW-(C0-C6)alkyl group containing an epoxide moiety WCOCW (where each W is independently H or a C1-C3 alkyl group), an optionally substituted -(CH 2) nCOOH, optionally substituted -(CH2)nC(O)-(C1-C6 alkyl), optionally substituted -(CH2)nNHC(O)-R", optionally substituted -(CH2)nC(O)-N(R")2, optionally substituted -(CH2)nOC(O)-N(R")2, -(CH2O)nH, optionally substituted -(CH2)nOC(O)-(C1-C6 alkyl), optionally substituted -(CH2)nC(O)-O-(C1-C6 optionally substituted -(CH2O)nCOOH, optionally substituted -(OCH2)nO-(C1-C6 alkyl), optionally substituted -(CHO)nC(O)-(C1-C6 alkyl), optionally substituted -(OCH2)nNHC(O)-R", optionally substituted -(CHO)nC(O)-N(R")2, -(CH2CH2O)nH, optionally substituted -(CH2CH2O)nCOOH, optionally substituted -( optionally substituted —(CHCHO)C(O)—N(R″)2, optionally substituted —SORS, optionally substituted S(O)RS, NO, CN, or halogen (F, Cl, Br, I, preferably F or Cl);
Each R″ in ULM-g is independently H or a C1-C6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);
RS of ULM-g is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or a -(CH2)mN(R'')2 group;
X and X' of ULM-g are each independently C=O, C=S, -S(O), S(O)2 (preferably, X and X' are both C=O);
R2' of ULM-g is an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w alkyl group, an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w NR1NR2N group, an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w aryl, an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w-heteroaryl, an optionally substituted -(CH2)n-(C=O)vNR''(SO2)w-heterocyclyl, an optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w alkyl, an optionally substituted -NR''-(CH2)n-C(O)u(NR'')v (SO2)w-NR1NR2N, optionally substituted -NR"-(CH2)n-C(O)u(NR")v(SO2)w-NR"C(O)RN, optionally substituted -NR"-(CH2)n-(C=O)u(NR")v(SO2)w-aryl, optionally substituted -NR"-(CH2)n-(C=O)u(NR")v(SO2)w-heteroaryl or optionally substituted -NR"-(CH2)n-(C=O)vNR"(SO2)w-heterocyclyl, optionally substituted -XR2'-alkyl group, optionally substituted -XR2'-aryl group, optionally substituted -XR2'-heteroaryl group, or optionally substituted -XR2'-heterocyclyl group;
R3' of ULM-g is optionally substituted alkyl, optionally substituted -(CH2)n-(O)u(NR'')v(SO2)w-alkyl, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-NR1NR2N, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-NR''C(O)R1N, optionally substituted -(C H2)n-C(O)u(NR'')v(SO2)w-C(O)(R'')2, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-aryl, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-heteroaryl, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-heterocyclyl, optionally substituted optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-alkyl, optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-NR1NR2N, optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-NR''C(O)R1N, optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-NR''C(O)R1N optionally substituted —NR″-(CH2)n-C(O)u(NR″)v(SO2)w-aryl, optionally substituted —NR″-(CH2)n-C(O)u(NR″)v(SO2)w-heteroaryl, optionally substituted —NR1-(CH2)n-C(O)u(NR″)v(SO2)w-heterocyclyl, optionally substituted —O—(CH2)n-(C═O)u(NR″)v(SO2)w-alkyl, optionally substituted —O—( CH2)n-(C=O)u(NR'')v(SO2)w-NR1NR2N, optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w-NR''C(O)R1N, optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w-aryl, optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w- Heteroaryl, or optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w-heterocyclyl, -(CH2)n-(V)n'-(CH2)n-(V)n'-alkyl group, optionally substituted -(CH2)n-(V)n'-(CH2)n-(V)n'-aryl group, optionally substituted -(CH2)n-(V)n'-(CH2)n-( V) n'-heteroaryl groups, optionally substituted -(CH2)n-(V) n'-(CH2)n-(V) n'-heterocyclyl' groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-alkyl groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-aryl groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-heteroaryl groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-heterocyclyl groups, optionally substituted -XR3'-alkyl groups, optionally substituted -XR3'-aryl groups, optionally substituted -XR3'-heteroaryl groups, optionally substituted -XR3'-heterocyclyl groups;
R1N and R2N of ULM-g are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups and up to three halogen groups, or an optionally substituted -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl group;
V of ULM-g is O, S or NR1;
Each R1' in ULM-g is independently H or a C1-C3 alkyl group;
XR2' and XR3' of ULM-g are each independently an optionally substituted -CH2)n-, -CH2)n-CH(Xv)=CH(Xv)-(cis or trans), -CH2)n-CH≡CH-, -(CH2CHO)n-, or a C3-C6 cycloalkyl group, where Xv is H, halo, or an optionally substituted C1-C3 alkyl group;
Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6;
Each m' 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; and any one or more of R1', R2', R3', X and X' of ULM-g are optionally modified to be covalently bonded to the PTM group via a linker group if the PTM is not a ULM', and any one or more of R1', R2', R3', X and X' of each of ULM and ULM' are optionally modified to be covalently bonded to each other directly or via a linker group if the PTM is a ULM'.

式中、
ＵＬＭ－ｈの各Ｒ１’、Ｒ２’、およびＲ３’は、上記と同じであり、Ｘが、Ｃ＝Ｏ、Ｃ＝Ｓ、－Ｓ（Ｏ）基、またはＳ（Ｏ）２基、より好ましくは、Ｃ＝Ｏ基であり、
ＵＬＭ－ｈのＲ１’、Ｒ２’、およびＲ３’のうちのいずれか１つ以上が任意で改変されて、ＰＴＭがＵＬＭ’ではない場合は、ＰＴＭ基にさらに共有結合されるリンカー基を結合し、またはＰＴＭがＵＬＭ’である場合は、ＵＬＭおよびＵＬＭ’の各々のＲ１’、Ｒ２’、Ｒ３’のうちのいずれか１つ以上が任意で改変されて、直接、またはリンカー基を介して互いに共有結合される。 In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof, are each independently a group conforming to the following chemical structure:

In the formula,
each R1', R2', and R3' of ULM-h is the same as above, and X is C=O, C=S, -S(O) group, or S(O)2 group, more preferably C=O group;
Any one or more of R1', R2', and R3' of ULM-h are optionally modified to attach a linker group that is further covalently attached to the PTM group if the PTM is not a ULM', or any one or more of R1', R2', R3' of each of the ULM and ULM' are optionally modified to be covalently attached to each other directly or via a linker group if the PTM is a ULM'.

式中、
ＵＬＭ－ＩのＲ１’、Ｒ２’、およびＲ３’のうちのいずれか１つ以上が任意で改変されて、ＰＴＭがＵＬＭ’ではない場合は、ＰＴＭ基にさらに共有結合されるリンカー基を結合し、またはＰＴＭがＵＬＭ’である場合は、ＵＬＭおよびＵＬＭ’の各々のＲ１’、Ｒ２’、Ｒ３’のうちのいずれか１つ以上が任意で改変されて、直接、またはリンカー基を介して互いに共有結合される。 In any of the aspects or embodiments described herein, ULM, and, if present, ULM′, or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof, each independently conforms to the following chemical structure:

In the formula,
Any one or more of R1', R2', and R3' of ULM-I are optionally modified to attach a linker group that is further covalently attached to the PTM group if the PTM is not a ULM', or any one or more of R1', R2', R3' of each of ULM and ULM' are optionally modified to be covalently attached to each other directly or via a linker group if the PTM is a ULM'.

In further preferred aspects of the present disclosure, R1' in ULM-g to ULM-i is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl or carboxylic acid group such that the compound represents a prodrug form of the active compound. Examples of preferred R1' groups include, for example, -(CH2)nOH, (CH2)n-O-(C1-C6) alkyl groups, -(CH2)nCOOH, -(CHO)nH, optionally substituted -(CH2)nOC(O)-(C1-C6 alkyl), or optionally substituted -(CH2)nC(O)-O-(C1-C6 alkyl), where n is 0 or 1. Wherein R1' is or contains a carboxylic acid group, a hydroxyl group, or an amine group, each of which may be optionally substituted, which may be further chemically modified to provide a covalent bond to a linker group that is attached to the PTM group (including the ULM' group).

X and X' in ULM-g and ULM-h, when present, are preferably C=O, C=S, -S(O) or S(O)2 groups, more preferably C=O groups.

R2' in ULM-g to ULM-i is preferably an optionally substituted -NH-T-aryl, an optionally substituted -N(CH3)-T-aryl, an optionally substituted -NH-T-heteroaryl group, an optionally substituted -N(CH3)-T-heteroaryl, an optionally substituted -NH-T-heterocyclyl, or an optionally substituted -N(CH3)-T-heterocyclyl, preferably H; T is an optionally substituted -(CH2)n- group, each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, an amino acid side chain as described elsewhere herein, or a C1-C3 alkyl group, preferably one or two methyl groups which may be optionally substituted; and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T can also be a -(CH2O)n- group, a -(OCH2)n- group, a -(CH2CH2O)n- group, or a -(OCH2CH2)n- group, all of which are optionally substituted.

式中、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａが、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）であり、それらの基の各々が、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたフェニル基、任意に置換されたヘテロアリール、または任意に置換されたヘテロシクリル、好ましくは、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフランであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、またはオキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、ジアゾール、オキシイミダゾール、ピロール、ピロリジン、フラン、ジヒドロフラン、テトラヒドロフラン、チエン、ジヒドロチエン、テトラヒドロチエン、ピリジン、ピペリジン、ピペラジン、モルホリン、キノリン、（各々が、好ましくはＣ１－Ｃ３アルキル基で置換され、好ましくはメチルまたはハロ基、好ましくはＦまたはＣｌ）、ベンゾフラン、インドール、インドリジン、アザインドリジンからなる群から選択される任意に置換されたアリール（フェニルまたはナプチル）、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２は、各々独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、または一緒になってケト基を形成し、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎは、独立して、０、１、２、３、４、５、もしくは６（好ましくは０または１）、または任意に置換されたヘテロシクリル、好ましくはテトラヒドロフラン、テトラヒドロチエン、ピペリジン、ピペラジン、もしくはモルホリン（それらの基の各々が、置換された場合、好ましくはメチルまたはハロ（Ｆ、Ｂｒ、Ｃｌ）で置換され、それらの基の各々が、リンカー基を介してＰＴＭ基（ＵＬＭ’基を含む）に任意に結合し得る。 Preferred aryl groups for R2' of ULM-g through ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, where the phenyl or naphthyl group is linked to a PTM (including a ULM' group) with a linker group, and/or optionally a halogen (preferably F or Cl), an amine, a mono- or di-alkylamine (preferably dimethylamine), F, Cl, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which is a substituted or unsubstituted aryl group in the phenyl ring). and/or a naphthyl group substituted with at least one of a F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho, meta, and/or para positions of the phenyl ring, preferably the para position), which may be optionally substituted; an optionally substituted phenyl group (which itself is optionally linked to a PTM group including a ULM' having a linker group); and/or a naphthyl group substituted with at least one of a F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho, meta, and/or para positions of the phenyl ring, preferably the para position), which may be optionally substituted; optionally substituted isoxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methyl imidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted substituted diazole groups including methyl diazole groups, optionally substituted triazole groups including methyl substituted triazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl substituted pyridine groups, or oxapyridine groups (where the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines, or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines, optionally substituted groups according to the chemical structure

In the formula,
Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran;
RPRO in ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each of which is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPRO1 and RPRO2 of ULM-g to ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or taken together form a keto group;
Each n in ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or optionally substituted heterocyclyl, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, or morpholine (each of which groups, when substituted, is preferably substituted with methyl or halo (F, Br, Cl), each of which groups may optionally be attached to a PTM group (including a ULM' group) via a linker group.

は、

基であり、
式中、ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、上記と同じである。 In certain preferred embodiments, ULM-g to ULM-i

teeth,

It is based on
In the formula, RPRO of ULM-g to ULM-i is the same as above.

式中：
ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、ＵＬＭ－ｇ～ＵＬＭ－ｉのＲａが、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）であり、それらの基の各々が、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたヘテロシクリル、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、ピペラジンであり、それらの各々が、任意に置換され、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＹＣは、ＮまたはＣ－ＲＹＣであり、式中、ＲＹＣが、Ｈ、ＯＨ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａが、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、それらの基の各々が、リンカー基を介してＰＴＭ基（ＵＬＭ’基を含む）に任意に連結され得る。 Preferred heteroaryl groups for R2' of ULM-g through ULM-i include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran (including optionally substituted benzofuran), optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3, or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oximidazole, or a group according to the chemical structure:

In the formula:
Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra in ULM-g to ULM-i is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
YC in ULM-g through ULM-i is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl), each of which groups may be optionally linked to a PTM group (including a ULM' group) via a linker group.

好ましくは、

基であり、
式中、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、または任意に置換されたアリール、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２はそれぞれ独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、またはともにケト基を形成し、および
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎは独立して、０、１、２、３、４、５、または６（多くの場合、０または１）であり、各基のそれぞれがリンカー基を介してＰＴＭ基（ＵＬＭ’基を含む）に任意で結合され得る。 Preferred heterocyclylheterocyclyl groups for R2′ of ULM-g through ULM-i include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, each of which may be optionally substituted or is a group according to the chemical structure:

Preferably,

Based on
In the formula,
RPRO of ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclyl group;
RPRO1 and RPRO2 of ULM-g through ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; and each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), each of which may be optionally attached to a PTM group (including a ULM' group) via a linker group.

Preferred R2' substituents for ULM-g through ULM-i also specifically include (but are not limited to) the R2' substituents found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and in the drawings accompanying this specification. Each of these R2' substituents may be used in conjunction with any number of R3' substituents, also disclosed herein.

R3' in ULM-g to ULM-i is preferably an optionally substituted -NH-T-aryl, an optionally substituted -N(C1-C3 alkyl)-T-aryl, an optionally substituted -NH-T-heteroaryl group, an optionally substituted -N(C1-C3 alkyl)-T-heteroaryl, an optionally substituted -NH-T-heterocyclyl, or an optionally substituted -N(C1-C3 alkyl)-T-heterocyclyl, where T is an optionally substituted -(CH2)n- group, each of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, a C1-C3 alkyl group, or the side chain of an amino acid as otherwise described herein, preferably methyl, which may be optionally substituted, and n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T can also be a -(CH2O)n- group, a -(OCH2)n- group, a -(CH2CH2O)n- group, or a -(OCH2CH2)n- group, each of which is optionally substituted.

Preferred aryl groups for R3' in ULM-g to ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, optionally linked to the PTM group (including the ULM' group) via a linker group, and/or halogen (preferably F or Cl), amine, monoalkyl- or dialkylamine (preferably dimethylamine), amide group (preferably -(CH2)m-NRC(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 is optionally substituted with an S(O)RS group, where RS is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or a -(CH2)m(R'') group, each of which may be substituted at the ortho, meta, and/or para positions (preferably the para position) on the phenyl ring, or is an aryl (preferably phenyl), heteroaryl, or heterocyclyl. Preferably, the substituted phenyl group is an optionally substituted phenyl group (i.e., the substituted phenyl group itself is preferably F, Cl, OH, SH, COOH, CH3, CF3, OMe, OCF3, NO2, CN, or P at least one of the linker groups attached to the TM group (including the ULM′ group), the substitution occurring at the ortho, meta, and/or para positions of the phenyl ring, preferably the para position); naphthyl groups which may be optionally substituted including those described above; optionally substituted heteroaryls (preferably optionally substituted isoxazoles including methyl substituted isoxazoles, optionally substituted oxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methylimidazoles, benzyl imidazole or methoxybenzylimidazole, oximidazole or methyloximidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, pyridine groups including halo- (preferably F) or methyl-substituted pyridine groups, or oxapyridine groups (wherein the pyridine group is bonded to the phenyl group by an oxygen), or optionally substituted heterocyclyl (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydraquinoline, oxane, or thiane. Each of the aryl, heteroaryl, or heterocyclyl groups may be optionally linked to a PTM group (including a ULM' group) via a linker group.

式中：
ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）であり、それらの基の各々が、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたヘテロシクリル、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、ピペラジンであり、それらの各々が、任意に置換され、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＹＣは、ＮまたはＣ－ＲＹＣであり、式中、ＲＹＣは、Ｈ、ＯＨ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）である。該ヘテロアリール基の各々は、リンカー基を介してＰＴＭ基（ＵＬＭ’基を含む）に任意に連結され得る。 Preferred heteroaryl groups for R3' of ULM-g through ULM-i include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazo and optionally substituted aryls, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, optionally substituted thiophenes, optionally substituted thiazoles (preferably methyl and/or thiol substituted), optionally substituted isothiazoles, optionally substituted triazoles (preferably 1,2,3-triazoles substituted with methyl groups, triisopropylsilyl groups, optionally substituted —(CH2)m-O-C1-C6 alkyl groups, or optionally substituted —(CH2)m-C(O)—O-C1-C6 alkyl groups), optionally substituted pyridines (2-, 3, or 4-pyridine), or a group according to the chemical structure:

In the formula:
Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
YC in ULM-g through ULM-i is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl). Each of the heteroaryl groups may optionally be linked to a PTM group (including a ULM' group) via a linker group.

好ましくは

式中、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、またはオキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、ジアゾール、オキシイミダゾール、ピロール、ピロリジン、フラン、ジヒドロフラン、テトラヒドロフラン、チエン、ジヒドロチエン、テトラヒドロチエン、ピリジン、ピペリジン、ピペラジン、モルホリン、キノリン、（各々が、好ましくはＣ１－Ｃ３アルキル基で置換され、好ましくはメチルまたはハロ基、好ましくはＦまたはＣｌ）、ベンゾフラン、インドール、インドリジン、アザインドリジンからなる群から選択される任意に置換されたアリール（フェニルまたはナプチル）、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２は、各々独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、またはともにケト基を形成し、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎは、０、１、２、３、４、５、もしくは６（好ましくは０または１）であり、該ヘテロシクリル基の各々は、リンカー基を介してＰＴＭ基（ＵＬＭ’基を含む）に任意に連結され得る。 Preferred heterocyclyl groups for R3' of ULM-g through ULM-i include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiene, oxane, and thiane, each of which may be optionally substituted or is a group according to the chemical structure:

Preferably

In the formula,
RPRO in ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each of which is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPRO1 and RPRO2 of ULM-g to ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or 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 may optionally be linked to a PTM group (including a ULM' group) via a linker group.

Preferred R3' substituents for ULM-g through ULM-i also specifically include (but are not limited to) the R3' substituents found in the specific compounds disclosed herein, including the specific compounds disclosed in this specification and in the drawings accompanying this specification. Each of these R3' substituents may be used in conjunction with any number of R2' substituents, also disclosed herein.

ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）であり、それらの基の各々は、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたヘテロシクリル、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、ピペラジンであり、それらの各々は、任意に置換され、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＹＣは、ＮまたはＣ－ＲＹＣであり、式中、ＲＹＣは、Ｈ、ＯＨ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、またはオキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、ジアゾール、オキシイミダゾール、ピロール、ピロリジン、フラン、ジヒドロフラン、テトラヒドロフラン、チエン、ジヒドロチエン、テトラヒドロチエン、ピリジン、ピペリジン、ピペラジン、モルホリン、キノリン、（各々が、好ましくはＣ１－Ｃ３アルキル基で置換され、好ましくはメチルまたはハロ基、好ましくはＦまたはＣｌ）、ベンゾフラン、インドール、インドリジン、アザインドリジンからなる群から選択される任意に置換されたアリール（フェニルまたはナプチル）、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２は、各々独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、またはともにケト基を形成し、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎは、独立して、０、１、２、３、４、５、または６（好ましくは０または１）である。 In certain alternative preferred embodiments, R2′ of ULM-g through ULM-i is an optionally substituted —NR1-XR2′-alkyl group, an —NR1-XR2′-aryl group, an optionally substituted —NR1-XR2′-HET, an optionally substituted —NR1-XR2′-aryl-HET, or an optionally substituted —NR1-XR2′-HET-aryl;
In the formula,
R1 of ULM-g to ULM-i is H or a C1-C3 alkyl group (preferably H);
XR2' in ULM-g to ULM-i is an optionally substituted -CH2)n-, -CH2)n-CH(Xv)=CH(Xv)-(cis or trans), -(CH2)n-CH≡CH-, -(CH2CH2O)n-, or a C3-C6 cycloalkyl group;
Xv of ULM-g to ULM-i is H, halo, or a C1-C3 alkyl group optionally substituted with 1 or 2 hydroxyl groups or up to 3 halogen groups;
alkyl of ULM-g through ULM-i is an optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments the alkyl group is end-capped with a halo group, often Cl or Br);
Aryl in ULM-g to ULM-i is an optionally substituted phenyl or naphthyl group (preferably a phenyl group);
HET in ULM-g through ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each of which, when substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group according to the following chemical structure:

Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
YC in ULM-g to ULM-i is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RPRO in ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each of which is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPRO1 and RPRO2 of ULM-g to ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group;
Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).

Each of the groups may be optionally attached to a PTM group (including a ULM' group) via a linker group.

ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ０－Ｃ６アルキル）であり、それらの基の各々は、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたヘテロシクリル、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、ピペラジンであり、それらの各々は、任意に置換され、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＹＣは、ＮまたはＣ－ＲＹＣであり、式中、ＲＹＣは、Ｈ、ＯＨ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、またはオキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、ジアゾール、オキシイミダゾール、ピロール、ピロリジン、フラン、ジヒドロフラン、テトラヒドロフラン、チエン、ジヒドロチエン、テトラヒドロチエン、ピリジン、ピペリジン、ピペラジン、モルホリン、キノリン、（各々が、好ましくはＣ１－Ｃ３アルキル基で置換され、好ましくはメチルまたはハロ基、好ましくはＦまたはＣｌ）、ベンゾフラン、インドール、インドリジン、アザインドリジンからなる群から選択される任意に置換されたアリール（フェニルまたはナプチル）、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２は、各々独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、またはともにケト基を形成し、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎは、独立して、０、１、２、３、４、５、または６（好ましくは０または１）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｍ’は、０または１であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎ’は、０または１であり、
式中、該化合物の各々は、好ましくはアルキル基、アリール基またはＨｅｔ基上で、リンカーを介してＰＴＭ基（ＵＬＭ’基を含む）に任意に連結される。 In certain alternative preferred embodiments of the present disclosure, R3' of ULM-g to ULM-i is an optionally substituted -(CH2)n-(V)n'-(CH2)n-(V)n'-RS3' group, an optionally substituted -(CH2)n-N(R1')(C=O)m'-(V)n'-RS3' group, an optionally substituted -XR3'-alkyl group, an optionally substituted -XR3'-aryl group, an optionally substituted -XR3'-HET group, an optionally substituted -XR3'-aryl-HET group or an optionally substituted -XR3'-HET-aryl group;
In the formula,
RS3' is an optionally substituted alkyl group (C1-C10, preferably C1-C6 alkyl), an optionally substituted aryl group, or a HET group;
R1' is H or a C1-C3 alkyl group (preferably H);
V is O, S or NR1';
XR3' is -(CH2)n-, -(CH2CH2O)n-, -CH2)n-CH(Xv)=CH(Xv)-(cis or trans), -CH2)n-CH≡CH-, or a C3-C6 cycloalkyl group, all optionally substituted;
Xv is H, halo, or a C1-C3 alkyl group optionally substituted with 1 or 2 hydroxyl groups or up to 3 halogen groups;
alkyl is an optionally substituted C1-C10 alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is terminally terminated with a halo group, often Cl or Br);
Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group);
HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (each of which, when substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), or a group according to the following chemical structure:

Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
YC in ULM-g to ULM-i is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RPRO in ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each of which is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPRO1 and RPRO2 of ULM-g to ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group;
Each n in ULM-g to ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1);
Each m' of ULM-g to ULM-i is 0 or 1,
Each n' of ULM-g to ULM-i is 0 or 1,
wherein each of the compounds is optionally linked, preferably on an alkyl, aryl or Het group, to a PTM group (including a ULM' group) via a linker.

ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａが、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ０－Ｃ６アルキル）であり、それらの基の各々が、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたヘテロシクリル、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、ピペラジンであり、それらの各々が、任意に置換され、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＹＣは、ＮまたはＣ－ＲＹＣであり、式中、ＲＹＣが、Ｈ、ＯＨ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａが、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、またはオキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、ジアゾール、オキシイミダゾール、ピロール、ピロリジン、フラン、ジヒドロフラン、テトラヒドロフラン、チエン、ジヒドロチエン、テトラヒドロチエン、ピリジン、ピペリジン、ピペラジン、モルホリン、キノリン、（各々が、好ましくはＣ１－Ｃ３アルキル基で置換され、好ましくはメチルまたはハロ基、好ましくはＦまたはＣｌ）、ベンゾフラン、インドール、インドリジン、アザインドリジンからなる群から選択される任意に置換されたアリール（フェニルまたはナプチル）、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２はそれぞれ独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、またはともにケト基を形成し、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＨＥＴは、好ましくは、オキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、ジアゾール、オキシイミダゾール、ピロール、ピロリジン、フラン、ジヒドロフラン、テトラヒドロフラン、チエン、ジヒドロチエン、テトラヒドロチエン、ピリジン、ピぺリジン、ピペラジン、モルホリン、キノリン（各々好ましくはＣ１－Ｃ３アルキル基、好ましくはメチル、またはハロ基、好ましくはＦもしくはＣｌで置換される）、ベンゾフラン、インドール、インドリジン、アザインドリジン、または以下の化学構造に従う基であるか、

ＵＬＭ－ｇ～ＵＬＭ－ｉのＳｃは、ＣＨＲＳＳ、ＮＲＵＲＥまたはＯであり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＨＥＴは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａが、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＳＳは、Ｈ、ＣＮ、ＮＯ２、ハロ（好ましくはＦまたはＣｌ）、任意に置換されたＣ１－Ｃ６アルキル（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、任意に置換されたＯ－（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）、または任意に置換された－Ｃ（Ｏ）（Ｃ１－Ｃ６アルキル）（好ましくは１つもしくは２つのヒドロキシル基または最大で３個のハロ基で置換される）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＵＲＥは、Ｈ、Ｃ１－Ｃ６アルキル（好ましくはＨまたはＣ１－Ｃ３アルキル）、または－Ｃ（Ｏ）（Ｃ０－Ｃ６アルキル）であり、それらの基の各々が、１個もしくは２個のヒドロキシル基または最大３個のハロゲン、好ましくはフッ素基で任意に置換されるか、または任意に置換されたヘテロシクリル、例えば、ピペリジン、モルホリン、ピロリジン、テトラヒドロフラン、テトラヒドロチオフェン、ピペリジン、ピペラジンであり、それらの各々が、任意に置換され、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＹＣは、ＮまたはＣ－ＲＹＣであり、式中、ＲＹＣは、Ｈ、ＯＨ、ＣＮ、ＮＯ２、ハロ（好ましくはＣｌまたはＦ）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｃ１－Ｃ６アルキル（例えば、ＣＦ３）、任意に置換された（好ましくは１個もしくは２個のヒドロキシル基または最大３個のハロ基で置換された）Ｏ（Ｃ１－Ｃ６アルキル）、または任意に置換されたアセチレン基－Ｃ≡Ｃ－Ｒａであり、式中、Ｒａは、ＨまたはＣ１－Ｃ６アルキル基（好ましくはＣ１－Ｃ３アルキル）であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯは、Ｈ、任意に置換されたＣ１－Ｃ６アルキル、または任意に置換されたアリール、ヘテロアリール、もしくはヘテロシクリル基であり、
ＵＬＭ－ｇ～ＵＬＭ－ｉのＲＰＲＯ１およびＲＰＲＯ２はそれぞれ独立して、Ｈ、任意に置換されたＣ１－Ｃ３アルキル基であるか、またはともにケト基を形成し、
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｍ’は独立して、０または１であり、および
ＵＬＭ－ｇ～ＵＬＭ－ｉの各ｎは独立して、０、１、２、３、４、５、または６（好ましくは０または１）であり、
式中、該化合物のそれぞれは、好ましくは当該アリール基またはＨＥＴ基上で、任意でリンカー基を介してＰＴＭ基（ＵＬＭ’基を含む）に結合される。 In alternative embodiments, R3' of ULM-g through ULM-i is -(CH2)n-aryl, -(CH2CH2O)n-aryl, -(CH2)n-HET, or -(CH2CH2O)n-HET;
In the formula,
said aryl of ULM-g to ULM-i is phenyl optionally substituted with one or two substituents, where the substituents are preferably selected from -(CH2)nOH, C1-C6 alkyl which itself is optionally further substituted with CN, halo (up to three halo groups), OH, -(CH2)nO(C1-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, where the alkyl group of the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups; or The aryl group of ULM-g through ULM-i is substituted with -(CH2)nOH, -(CH2)n-O-(C1-C6)alkyl, -(CH2)n-O-(CH2)n-(C1-C6)alkyl, -(CH2)n-C(O)(C0-C6)alkyl, -(CH2)n-C(O)O(C0-C6)alkyl, -(CH2)n-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, the alkyl groups on the amine being substituted with one or two hydroxyl groups or up to optionally substituted with three halo (preferably F, Cl) groups, CN, NO2, an optionally substituted -(CH2)n-(V)m'-CH2)n-(V)m'-(C1-C6) alkyl group, a -(V)m'-(CH2CH2O)n-RPEG group, where V is O, S, or NR1', R1' is H or a C1-C3 alkyl group (preferably H), and RPEG is H or an optionally substituted C1-C6 alkyl group (including optionally substituted with a carboxyl group); The aryl group of ULM-g through ULM-i is optionally substituted with heterocyclyl, including heteroaryl, selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine (each of which, if substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), or a group according to the following chemical structure:

Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
YC in ULM-g to ULM-i is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RPRO in ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl), heteroaryl, or heterocyclyl group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, (each of which is preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
RPRO1 and RPRO2 of ULM-g to ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group;
HET in ULM-g to ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the following chemical structure:

Sc of ULM-g to ULM-i is CHRSS, NRURE or O;
RHET in ULM-g to ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RSS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups);
RURE in ULM-g to ULM-i is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C0-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocyclyl, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted;
YC in ULM-g to ULM-i is N or C-RYC, where RYC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or an optionally substituted acetylenic group -C≡C-Ra, where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
RPRO of ULM-g to ULM-i is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclyl group;
RPRO1 and RPRO2 of ULM-g to ULM-i are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group;
Each m' of ULM-g through ULM-i is independently 0 or 1, and each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1);
wherein each of the compounds is preferably attached on the aryl or HET group to a PTM group (including a ULM' group) optionally via a linker group.

式中、
ＵＬＭ－ｉのＲ１’は、ＯＨ、または患者もしくは対象においてＯＨへと代謝される基であり、
ＵＬＭ－ｉのＲ２’は、－ＮＨ－ＣＨ２－アリール－ＨＥＴ（好ましくは、メチル置換チアゾールに直接結合したフェニル）であり、
ＵＬＭ－ｉのＲ３’は、－ＣＨＲＣＲ３’－ＮＨ－Ｃ（Ｏ）－Ｒ３Ｐ１基または－ＣＨＲＣＲ３’－Ｒ３Ｐ２基であり、
ＵＬＭ－ｉのＲＣＲ３’は、Ｃ１－Ｃ４アルキル基、好ましくはメチル、イソプロピル、またはｔｅｒｔ－ブチルであり、
ＵＬＭ－ｉのＲ３Ｐ１は、Ｃ１－Ｃ３アルキル（好ましくはメチル）、任意に置換されたオキセタン基（好ましくはメチル置換）、－（ＣＨ２）ｎＯＣＨ３基（式中、ｎが、１または２（好ましくは２）である）、または

（エチルエーテル基が、好ましくはフェニル部分上でメタ置換されている）、モルホリノ基（２または３位でカルボニルに結合された）であり、
ＵＬＭ－ｉのＲ３Ｐ２は、

であり、
ＵＬＭ－ｉのアリールは、フェニルであり、
ＵＬＭ－ｉのＨＥＴは、任意に置換されたチアゾールまたはイソチアゾールであり、
ＵＬＭ－ｉのＲＨＥＴは、Ｈまたはハロ基（好ましくはＨ）である、化合物、
該化合物は、それぞれリンカー基を介してＰＴＭ基（ＵＬＭ’を含む）に任意で結合される。 In yet additional embodiments, preferred compounds include those according to the following chemical structure, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or polymorph thereof:

In the formula,
R1' of ULM-i is OH or a group that is metabolized to OH in the patient or subject;
R2' of ULM-i is -NH-CH2-aryl-HET (preferably phenyl directly bonded to a methyl substituted thiazole);
R3' of ULM-i is a -CHRCR3'-NH-C(O)-R3P1 group or a -CHRCR3'-R3P2 group;
RCR3' of ULM-i is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl;
R3P1 of ULM-i is a C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted), a -(CH2)nOCH3 group (wherein n is 1 or 2 (preferably 2)), or

(the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (attached to the carbonyl at the 2- or 3-position);
ULM-i R3P2 is

and
The aryl of ULM-i is phenyl;
HET of ULM-i is an optionally substituted thiazole or isothiazole;
Compounds in which RHET of ULM-i is H or a halo group (preferably H),
The compounds are optionally attached to the PTM groups (including ULM's) via respective linker groups.

式中、
ＵＬＭ－ｊの各Ｒ５およびＲ６は独立して、ＯＨ、ＳＨ、または任意に置換されたアルキルであるか、またはＲ５、Ｒ６およびそれらが結合する炭素原子でカルボニルを形成し、
ＵＬＭ－ｊのＲ７は、Ｈまたは任意に置換されたアルキルであり、
ＵＬＭ－ｊのＥは、結合、Ｃ＝Ｏ、またはＣ＝Ｓであり、
ＵＬＭ－ｊのＧは、結合、任意に置換されたアルキル、－ＣＯＯＨ、またはＣ＝Ｊであり、
ＵＬＭ－ｊのＪは、ＯまたはＮ－Ｒ８であり、
ＵＬＭ－ｊのＲ８は、Ｈ、ＣＮ、任意に置換されたアルキル、または任意に置換されたアルコキシであり、
ＵＬＭ－ｊのＭは、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたヘテロシクリル、または

であり、
ＵＬＭ－ｊの各Ｒ９およびＲ１０は、独立して、Ｈ、任意に置換されたアルキル、任意に置換されたシクロアルキル、任意に置換されたヒドロキシアルキル、任意に置換されたチオアルキル、ＵＬＭに結合されたジスルフィド、任意に置換されたヘテロアリール、もしくはハロアルキルであるか、またはＲ９、Ｒ１０、およびそれらが結合している炭素原子が、任意に置換されたシクロアルキルを形成し、
ＵＬＭ－ｊのＲ１１は、任意に置換されたヘテロシクリル、任意に置換されたアルコキシ、任意に置換されたヘテロアリール、任意に置換されたアリール、または

であり、
ＵＬＭ－ｊのＲ１２は、Ｈまたは任意に置換されたアルキルであり、ｑ
ＵＬＭ－ｊのＲ１３は、Ｈ、任意に置換されたアルキル、任意に置換されたアルキルカルボニル、任意に置換された（シクロアルキル）アルキルカルボニル、任意に置換されたアラルキルカルボニル、任意に置換されたアリールカルボニル、任意に置換された（ヘテロシクリル）カルボニル、または任意に置換されたアラルキル、任意に置換された（オキソアルキル）カルバメートであり、
ＵＬＭ－ｊの各Ｒ１４は、独立して、Ｈ、ハロアルキル、任意に置換されたシクロアルキル、任意に置換されたアルキル、アゼチジン、任意に置換されたアルコキシ、または任意に置換されたヘテロシクリルであり、
ＵＬＭ－ｊのＲ１５は、Ｈ、ＣＮ、任意に置換されたヘテロアリール、ハロアルキル、任意に置換されたアリール、任意に置換されたアルコキシ、または任意に置換されたヘテロシクリルであり、
ＵＬＭ－ｊの各Ｒ１６は、独立して、ハロ、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたＣＮ、または任意に置換されたハロアルコキシであり、
ＵＬＭ－ｊの各Ｒ２５は、独立して、Ｈ、もしくは任意に置換されたアルキルであるか、または両方のＲ２５基が一緒になって、オキソもしくは任意に置換されたシクロアルキル基を形成することができ、
ＵＬＭ－ｊのＲ２３は、ＨまたはＯＨであり、
ＵＬＭ－ｊのＺ１、Ｚ２、Ｚ３、およびＺ４が、独立して、ＣまたはＮであり、
ＵＬＭ－ｊのｏは、０、１、２、３もしくは４である。 In certain embodiments, a bifunctional compound comprising a ubiquitin E3 ligase binding moiety (ULM), or a pharma- ceutically acceptable salt, stereoisomer, solvate or polymorph thereof, wherein the ULM is a group according to the following chemical structure:

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

and
each R9 and R10 of ULM-j is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, a disulfide bonded to ULM, optionally substituted heteroaryl, or haloalkyl, or R9, R10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
R11 of ULM-j is optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or

and
R12 of ULM-j is H or optionally substituted alkyl, and q
R13 of ULM-j 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 R14 in ULM-j is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, azetidine, optionally substituted alkoxy, or optionally substituted heterocyclyl;
R15 of ULM-j is H, CN, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;
each R16 in ULM-j is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted CN, or optionally substituted haloalkoxy;
Each R25 of ULM-j is independently H, or an optionally substituted alkyl, or both R25 groups together can form an oxo or an optionally substituted cycloalkyl group;
R23 of ULM-j is H or OH;
Z1, Z2, Z3, and Z4 of ULM-j are independently C or N;
o of ULM-j is 0, 1, 2, 3 or 4.

In certain embodiments, G in ULM-j is C=J, J is O, R7 is H, each R14 is H, and o is 0.

である。 In certain embodiments, G of ULM-j is C=J, J is O, R7 is H, each R14 is H, R15 is an optionally substituted heteroaryl, and o is 0. In other examples, E is C=O and M is

It is.

であり、Ｍは、

である。 In certain embodiments where E of ULM-j is C=O, R11 is optionally substituted heterocyclyl or

and M is

It is.

であり、Ｒ１１が、

である、ある特定の実施形態では、各Ｒ１８は、独立して、Ｈ、ハロ、任意に置換されたアルコキシ、シアノ、任意に置換されたアルキル、ハロアルキル、またはハロアルコキシであり、ｐは、０、１、２、３、または４である。 E of ULM-j is C=O and M is

and R11 is

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

In certain embodiments, each R14 is independently substituted with at least one of H, hydroxyl, halo, amine, amide, alkoxy, alkyl, haloalkyl, or heterocycle.

ＣＮ、またはハロアルキルに従う基であり、各Ｒ１８は、独立して、Ｈ、ハロ、任意に置換されたアルコキシ、シアノ、アミノアルキル、アミドアルキル、任意に置換されたアルキル、ハロアルキル、またはハロアルコキシであり、ｐは、０、１、２、３、または４である。 In certain embodiments, R15 of ULM-j is

CN, or a group following haloalkyl, each R 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.

式中、
ＵＬＭ－ｋのＧは、Ｃ＝Ｊであり、ＪはＯであり、
ＵＬＭ－ｋのＲ７はＨであり、
ＵＬＭ－ｋの各Ｒ１４は、独立して、Ｈ、アミド、アルキル、例えば、１つ以上のＣ１－Ｃ６アルキル基またはＣ（Ｏ）ＮＲ’Ｒ”で任意に置換されたメチルであり、
Ｒ’およびＲ”は、各々独立して、Ｈ、任意に置換されたアルキル、またはシクロアルキルであり、
ＵＬＭ－ｋのｏは０であり、
ＵＬＭ－ｋのＲ１５は、ＵＬＭ－ｊについて上記に定義されるとおりであり、
ＵＬＭ－ｋのＲ１６は、ＵＬＭ－ｊについて上記に定義されるとおりであり、
ＵＬＭ－ｋのＲ１７は、Ｈ、ハロ、任意に置換されたシクロアルキル、任意に置換されたアルキル、任意に置換されたアルケニル、およびハロアルキルである。 In certain embodiments, ULM, and, if present, ULM′, are each independently a group conforming to the following chemical structure:

In the formula,
G of ULM-k is C=J, J is O,
R7 of ULM-k is H;
Each R14 in ULM-k is independently H, amido, alkyl, e.g., methyl optionally substituted with one or more C1-C6 alkyl groups or C(O)NR'R";
R′ and R″ are each independently H, optionally substituted alkyl, or cycloalkyl;
o of ULM-k is 0;
R15 of ULM-k is as defined above for ULM-j;
R16 of ULM-k is as defined above for ULM-j;
R17 of ULM-k is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.

In other examples, R17 in ULM-k is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).

式中：
ＵＬＭ－ｋのＧは、Ｃ＝Ｊであり、ＪはＯであり、
ＵＬＭ－ｋのＲ７はＨであり、
ＵＬＭ－ｋの各Ｒ１４はＨであり、
ＵＬＭ－ｋのｏは０であり、および
ＵＬＭ－ｋのＲ１５が、任意に置換された以下からなる群から選択される。

であって、式中、ＵＬＭ－ｋのＲ３０は、Ｈまたは任意に置換されたアルキルである。 In other embodiments, ULM, and, if present, ULM′, are each independently a group conforming to the following chemical structure:

In the formula:
G of ULM-k is C=J, J is O,
R7 of ULM-k is H;
Each R14 in ULM-k is H;
o in ULM-k is 0, and R15 in ULM-k is selected from the group consisting of optionally substituted:

wherein R30 of ULM-k is H or optionally substituted alkyl.

式中、
ＵＬＭ－ｋのＥは、Ｃ＝Ｏであり、
ＵＬＭ－ｋのＭは、

であり、
ＵＬＭ－ｋのＲ１１は、任意に置換された以下からなる群から選択される。

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

In the formula,
E of ULM-k is C═O,
The M in ULM-k is:

and
R11 of ULM-k is selected from the group consisting of optionally substituted:

式中、
ＵＬＭ－ｋのＥは、Ｃ＝Ｏであり、
ＵＬＭ－ｋのＲ１１は、

であり、
ＵＬＭ－ｋのＭは、

であり、
ＵＬＭ－ｋのｑは、１または２であり、
ＵＬＭ－ｋのＲ２０は、Ｈ、任意に置換されたアルキル、任意に置換されたシクロアルキル、任意に置換されたアリール、または

であり、
ＵＬＭ－ｋのＲ２１は、Ｈまたは任意に置換されたアルキルであり、
ＵＬＭ－ｋのＲ２２は、Ｈ、任意に置換されたアルキル、任意に置換されたアルコキシ、またはハロアルキルである。 In yet another embodiment, a compound of the following chemical structure:

In the formula,
E of ULM-k is C═O,
R11 of ULM-k is

and
The M in ULM-k is:

and
q of ULM-k is 1 or 2;
R20 of ULM-k is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or

and
R21 of ULM-k is H or optionally substituted alkyl;
R22 of ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.

In any embodiment described herein, R11 of ULM-j or ULM-k is selected from the group consisting of:

In certain embodiments, R11 of ULM-j or ULM-k is selected from the group consisting of:

式中、
ＵＬＭ－ｌのＸは、ＯまたはＳであり、
ＵＬＭ－ｌのＹは、Ｈ、メチルまたはエチルであり、
ＵＬＭ－ｌのＲ１７は、Ｈ、メチル、エチル、ヒドロキシメチル、またはシクロプロピルであり、
ＵＬＭ－ｌのＭは、任意に置換されたアリール、任意に置換されたヘテロアリール、または

であり、
ＵＬＭ－ｌのＲ９は、Ｈであり、
ＵＬＭ－ｌのＲ１０は、Ｈ、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたヘテロアリール、任意に置換されたアリール、任意に置換されたヒドロキシアルキル、任意に置換されたチオアルキル、またはシクロアルキルであり、
ＵＬＭ－ｌのＲ１１は、任意に置換された複素芳香族、任意に置換されたヘテロシクリル、任意に置換されたアリール、または

であり、
ＵＬＭ－ｌのＲ１２は、Ｈまたは任意に置換されたアルキルであり、
ＵＬＭ－ｌのＲ１３は、Ｈ、任意に置換されたアルキル、任意に置換されたアルキルカルボニル、任意に置換された（シクロアルキル）アルキルカルボニル、任意に置換されたアラルキルカルボニル、任意に置換されたアリールカルボニル、任意に置換された（ヘテロシクリル）カルボニル、または任意に置換されたアラルキル、任意に置換された（オキソアルキル）カルバメートである。 In certain embodiments, ULM (or ULM′, if present) is a group conforming to the following chemical structure:

In the formula,
X in ULM-1 is O or S;
Y of ULM-1 is H, methyl or ethyl;
R17 of ULM-1 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl;
M of ULM-1 is an optionally substituted aryl, an optionally substituted heteroaryl, or

and
R9 of ULM-1 is H;
R10 of ULM-1 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-1 is an optionally substituted heteroaromatic ring, an optionally substituted heterocyclyl, an optionally substituted aryl, or

and
R12 of ULM-1 is H or optionally substituted alkyl;
R13 of ULM-1 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.

式中、
ＵＬＭ－ｍのＹは、Ｈ、メチオール（ｍｅｔｈｙｏｌ）またはエチルである
ＵＬＭ－ｍのＲ９は、Ｈであり、
Ｒ１０は、イソプロピル、ｔｅｒｔ－ブチル、ｓｅｃ－ブチル、シクロペンチル、またはシクロヘキシルであり、
ＵＬＭ－ｍのＲ１１は、任意に置換されたアミド、任意に置換されたイソインドリノン、任意に置換されたイソキサゾール、任意に置換されたヘテロシクリルである。 In some embodiments, ULM, and, if present, ULM′, are each independently a group conforming to the following chemical structure:

In the formula,
Y of ULM-m is H, methyol or ethyl; R9 of ULM-m is H;
R10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;
R11 of ULM-m is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocyclyl.

式中、
ＵＬＭ－ｎのＲ１７は、メチル、エチル、またはシクロプロピルであり、
ＵＬＭ－ｎのＲ９、Ｒ１０、およびＲ１１は、上記に定義されるとおりである。他の事例では、Ｒ９は、Ｈであり、
ＵＬＭ－ｎのＲ１０は、Ｈ、アルキル、またはシクロアルキル（好ましくはイソプロピル、ｔｅｒｔ－ブチル、ｓｅｃ－ブチル、シクロペンチル、またはシクロヘキシル）である。 In another preferred embodiment of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

In the formula,
R17 of ULM-n is methyl, ethyl, or cyclopropyl;
R9, R10, and R11 of ULM-n are as defined above. In other instances, R9 is H;
R10 of ULM-n is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

またはその薬学的に許容される塩を含み、
Ｒ１は、Ｈ、任意に置換されたアルキル、または任意に置換されたシクロアルキルであり、
Ｒ３は、任意に置換された５～６員ヘテロアリールであり、
Ｗ５は、任意に置換されたフェニル、任意に置換されたナプチル、または任意に置換されたピリジニルであり、
Ｒ１４ａおよびＲ１４ｂのうちの一方は、Ｈ、任意に置換されたアルキル、任意に置換されたハロアルキル（例えば、フルオロアルキル）、任意に置換されたアルコキシ、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたヘテロルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＮＨＣＯＲ２６、もしくはＮＨＣＨ３ＣＯＲ２６であり、Ｒ１４ａおよびＲ１４ｂのうちの他方は、Ｈであるか、またはＲ１４ａ、Ｒ１４ｂは、それらが結合している炭素原子と一緒になって、任意に置換された３～６員シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルは、エポキシドまたはアジリジンではなく、
Ｒ１５は、ＣＮ、任意に置換されたフルオロアルキル、

任意に置換された

（例えば、

であり、式中、Ｒ２８ａは、ハロ、任意に置換されたアルキル、またはフルオロアルキルである）、または

であり、
各Ｒ１６は、独立して、ハロ、ＣＮ、任意に置換されたアルキル、任意に置換されたハロアルキル、ヒドロキシ、またはハロアルコキシから選択され、
各Ｒ２６は、独立して、Ｈ、任意に置換されたアルキル、またはＮＲ２７ａＲ２７ｂであり、
各Ｒ２７ａおよびＲ２７ｂは、独立して、Ｈ、任意に置換されたアルキル、任意に置換されたシクロアルキル（例えば、任意に置換された３～５員シクロアルキル）であるか、またはＲ２７ａおよびＲ２７ｂは、それらが結合している窒素原子と一緒になって、４～６員ヘテロシクリルを形成し、
各Ｒ２８は、独立して、Ｈ、ハロゲン、ＣＮ、任意に置換されたアミノアルキル、任意に置換されたアミドアルキル、任意に置換されたハロアルキル、任意に置換されたアルキル、任意に置換されたアルコキシ、任意に置換されたヘテロアルキル、任意に置換されたアルキルアミン、任意に置換されたヒドロキシアルキル、アミン、任意に置換されたアルキニル、または任意に置換されたシクロアルキルであり、
ｏは、０、１、または２であり、
ｐは、０、１、２、３、または４である。 In another preferred embodiment of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

or a pharma- ceutically acceptable salt thereof,
R1 is H, optionally substituted alkyl, or optionally substituted cycloalkyl;
R3 is an optionally substituted 5-6 membered heteroaryl;
W5 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted pyridinyl;
one of R14a and R14b 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, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26; the other of R14a and R14b is H, or R14a, R14b together with the carbon atom 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 aziridine;
R15 is CN, optionally substituted fluoroalkyl,

Arbitrarily substituted

(for example,

where R28a is halo, optionally substituted alkyl, or fluoroalkyl; or

and
each R16 is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy;
each R26 is independently H, optionally substituted alkyl, or NR27aR27b;
each R27a and R27b is independently H, optionally substituted alkyl, optionally substituted cycloalkyl (e.g., optionally substituted 3- to 5-membered cycloalkyl), or R27a and R27b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl;
each R28 is 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.

を含み、式中、
Ｘ４、Ｘ５、およびＸ６の各々が、ＣＨおよびＮから選択され、２個以下が、Ｎであり、
Ｒ１は、Ｃ１－６アルキルであり、
Ｒ３は、ＵＬＭ－ｏおよびＵＬＭ－ｐについて定義されたものと同じであり、
Ｒ１４ａおよびＲ１４ｂのうちの一方は、Ｈ、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたアルコキシ、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたアミド、任意に置換されたアルキル－アミド、任意に置換されたアルキル－シアノ、任意に置換されたアルキル－ホスフェート、任意に置換されたヘテロアルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＮＨＣＯＲ２６、もしくはＮＨＣＨ３ＣＯＲ２６であり、Ｒ１４ａおよびＲ１４ｂのうちの他方が、Ｈであるか、またはＲ１４ａおよびＲ１４ｂは、それらが結合している炭素原子と一緒になって、任意に置換された３～５員シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルは、エポキシドまたはアジリジンではなく、
各Ｒ２７ａおよびＲ２７ｂは、独立して、Ｈ Ｃ１－６アルキルまたはシクロルキル（例えば、任意に置換された３～５員シクロアルキル）であり、
ｏは、０、１、または２であり、
ｑは、１、２、３、または４であり、
Ｒ１５は、任意に置換された

またはＣＮであり、
Ｒ２８は、Ｈ、メチル、ＣＨ２Ｎ（Ｍｅ）２、ＣＨ２ＯＨ、ＣＨ２Ｏ（Ｃ１－４アルキル）、ＣＨ２ＮＨＣ（Ｏ）Ｃ１－４アルキル、ＮＨ２、

であり、
Ｒ２８Ｃは、Ｈ、メチル、フルオロ、またはクロロであり、
Ｒ１６は、Ｈ、Ｃ１－４アルキル、フルオロ、クロロ、ＣＮ、またはＣ１－４アルコキシである。 In any of the aspects or embodiments described herein, the ULM has the following formula:

wherein
Each of X4, X5, and X6 is selected from CH and N, with up to 2 being N;
R1 is C1-6 alkyl;
R3 is the same as defined for ULM-o and ULM-p;
one of R14a and R14b is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted amide, optionally substituted alkyl-amide, optionally substituted alkyl-cyano, optionally substituted alkyl-phosphate, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26; the other of R14a and R14b is H; 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 the spiroheterocyclyl is not an epoxide or aziridine;
each R27a and R27b is independently H C1-6 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;
R15 is optionally substituted

or CN,
R28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C1-4 alkyl), CH2NHC(O)C1-4 alkyl, NH2,

and
R28C is H, methyl, fluoro, or chloro;
R16 is H, C1-4 alkyl, fluoro, chloro, CN, or C1-4 alkoxy.

In any aspect or embodiment described herein, R14a and R14b are selected from H, C1-4 alkyl, C1-4 cycloalkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkyloxyalkyl, C1-4 alkyl-NR27aR27b, and CONR27aR27b.

In any aspect or embodiment described herein, at least one of R14a and R14b is H (e.g., both R14a and R14b are H).

In any aspect or embodiment described herein, at least one of R14a and R14b is an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted alkoxy, an optionally substituted hydroxylalkyl, an optionally substituted alkylamine, an optionally substituted heteroalkyl, an optionally substituted alkyl-heterocycloalkyl, an optionally substituted alkoxy-heterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26. Alternatively, in any aspect or embodiment described herein, one of R14a and R14b is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkylheterocycloalkyl, optionally substituted alkoxyheterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26, and the other of R14a and R14b is H.

を形成し、式中、Ｒ２３は、Ｈ、Ｃ１－４アルキル、－Ｃ（Ｏ）Ｃ１－４アルキルから選択される。 In any aspect or embodiment described herein, R14a and R14b, together with the carbon atom to which they are attached, represent:

where R23 is selected from H, C1-4 alkyl, -C(O)C1-4 alkyl.

またはその薬学的に許容される塩を含み、
Ｘは、ＣＨまたはＮであり、
ＵＬＭ－ｑおよびＵＬＭ－ｒのＲ１、Ｒ３、Ｒ１４ａ、Ｒ１４ｂ、およびＲ１５が、ＵＬＭ－ｏおよびＵＬＭ－ｐについて定義されたものと同じである。 In other preferred embodiments of the present disclosure, ULM, and, if present, ULM′, are each independently a group according to the following chemical structure:

or a pharma- ceutically acceptable salt thereof,
X is CH or N;
R1, R3, R14a, R14b, and R15 of ULM-q and ULM-r are the same as defined for ULM-o and ULM-p.

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

からなる群から選択され、
式中、ＶＬＭは、本明細書に記載されるリンカーを介して、任意に、任意の適切な官能基、例えば、アミン、エスター、エーテル、アルキル、またはアルコキシを介して、例えば、アリール、ヘテロアリール、フェニル、またはインドール基のフェニルを含む任意の適切な場所で、ＰＴＭに結合され得る。 In certain aspects of the present disclosure, the ULM moiety comprises:

is selected from the group consisting of
wherein the VLM may be attached to the PTM via a linker as described herein, optionally via any suitable functional group, e.g., an amine, ester, ether, alkyl, or alkoxy, at any suitable location, including, e.g., an aryl, heteroaryl, phenyl, or phenyl of an indole group.

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

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

In any aspect or embodiment described herein, the linker group L is a bond or chemical linker group represented by the formula -(AL)q-, where A is a chemical moiety and q is an integer from 1 to 100, and L is covalently attached to the PTM and ULM and provides sufficient binding of the PTM to a protein target and the ULM to E3 ubiquitin to effect target protein ubiquitination.

In any aspect or embodiment described herein, the linker group L is -(AL)q-, wherein:
(AL)q is a group linked to at least one of a ULM (e.g., VLM), a PTM moiety, or a combination thereof;
The q of the linker is an integer of 1 or more,
each AL is independently a bond, CRL1RL2, O, S, SO, SO2, NRL3, SON2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SON2NRL4, CO, CRL1=CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(=NCN)NRL4, NRL3C(=NCN), NRL3C(=CNO2)NRL4, C3-11 cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C5-13 spirocyclo optionally substituted with 0-9 RL1 and/or RL2 groups, alkyl, C3-11 heterocyclyl optionally substituted with 0-6 R and/or R groups, C5-13 spiroheterocyclyl optionally substituted with 0-8 R and/or R groups, aryl optionally substituted with 0-6 R and/or R groups, heteroaryl optionally substituted with 0-6 R and/or R groups, wherein R or R are each independently optionally linked to other groups to form a cycloalkyl and/or heterocyclyl moiety and are optionally substituted with 0-4 R groups;
RL1, RL2, RL3, RL4 and RL5 are each independently H, halo, C1-8 alkyl, OC1-8 alkyl, SC1-8 alkyl, NHC1-8 alkyl, N(C1-8 alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C3-11 heterocyclyl, OC1-8 cycloalkyl, SC1-8 cycloalkyl, NHC1-8 cycloalkyl, N(C1-8 cycloalkyl)2, N(C1-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH, SO2C1-8 alkyl, P(O)(OC1-8 alkyl)(C1-8 alkyl), P(O)(OC1-8 alkyl)2, CC-C1-8 alkyl, CCH, CH=CH(C1-8 alkyl), C(C1-8 alkyl)=CH(C1-8 alkyl), C(C1-8 alkyl), alkyl) = C(C1-8 alkyl)2, Si(OH)3, Si(C1-8 alkyl)3, Si(OH)(C1-8 alkyl)2, COC1-8 alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SON2NHC1-8 alkyl, SON2N(C1-8 alkyl)2, SONHC1-8 alkyl, SON(C1-8 alkyl)2, CONHC1-8 alkyl, CON(C1-8 alkyl)2, N(C1-8 alkyl)CONH(C1-8 alkyl), N(C1-8 alkyl)CON(C1-8 alkyl)2, NHCONH(C1-8 alkyl), NHCON(C1-8 alkyl)2, NHCONH2, N(C1-8 alkyl)SON2NH(C1-8 alkyl), N(C1-8 alkyl)SON2N(C1-8 alkyl)2, NH SO2NH(C1-8 alkyl), NHSO2N(C1-8 alkyl)2, NHSO2NH2.

In certain embodiments, q in the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

For example, in certain embodiments where the linker q is greater than 2, (AL)q is a group that is AL1 and (AL)q, and the unit AL connects the PTM to the ULM.

For example, in certain embodiments where the linker q is 2, (AL)q is a group that links to AL1 and to the ULM or PTM.

For example, in certain embodiments where the linker q is 1, the structure of the linker group L is -AL1-, where AL1 is a group that connects the ULM and PTM moieties.

In certain embodiments, the unit AL of the linker (L) comprises a group represented by a general structure selected from the group consisting of:
—NR(CH2)n-(lower alkyl)-, —NR(CH2)n-(lower alkoxyl)-, —NR(CH2)n-(lower alkoxyl)-OCH2-, —NR(CH2)n-(lower alkoxyl)-(lower alkyl)-OCH2-, —NR(CH2)n-(cycloalkyl)-(lower alkyl)-OCH2-, —NR(CH2)n-(heterocycloalkyl)-, —NR(CH2CH2O)n-(lower alkyl)-O-CH2-, —NR(CH2CH2O)n-(heterocycloalkyl)-O-CH2-, —NR(CH2CH2O)n-aryl-O-CH2-, —NR(CH2CH2O)n-(heteroaryl)-O-CH2-, —NR(CH2CH2O)n-(cyclo alkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O)n-(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O)n-(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O)n-(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O)n-cycloalkyl-O-aryl-, -NR(CH2CH2O)n-cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2)n-(cycloalkyl)-O-(heterocyclyl)-CH2, -NR(CH2CH2)n-(heterocyclyl)-(heterocyclyl)-CH2, -N(RR2)-(heterocyclyl)-CH2,
The linker's n can be 0 to 10;
R of the linker can be H, lower alkyl;
The linkers R1 and R2 may form a ring with the N-bond.

式中、
リンカーのｍ、ｎ、ｏ、ｐ、ｑ、およびｒは、独立して、０、１、２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、１６、１７、１８、１９、２０であり、
数がゼロの場合、Ｎ－Ｏ結合またはＯ－Ｏ結合は存在しない。
リンカーのＲは、Ｈ、メチルおよびエチルであり、
リンカーのＸは、ＨおよびＦであり、

ここで、リンカーのｍは、２、３、４、５であってもよく、

ここで、リンカーのｍおよびｎのそれぞれは独立して、０、１、２、３、４、５、６であってもよい。 In certain embodiments, the unit AL of the linker (L) comprises a group represented by a general structure selected from the group consisting of:
—N(R)—(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,
—O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2—,
—O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O—,
—N(R)—(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-,
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O-,
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-OCH2-,

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

wherein m in the linker may be 2, 3, 4, or 5;

wherein each of m and n in the linker may independently be 0, 1, 2, 3, 4, 5, or 6.

式中、各ｍおよびｎは独立して、０、１、２、３、４、５、または６から選択される。 In any aspect or embodiment described herein, the unit AL of the linker (L) is selected from the group consisting of:

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

式中、各ｍ、ｎ、ｏ、ｐ、ｑ、ｒ、およびｓは、独立して、０、１、２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、１６、１７、１８、１９、または２０である。 In any aspect or embodiment described herein, the unit AL of the linker (L) is selected from the group consisting of:

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

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

式中、ｍ、ｎ、ｏ、ｐ、ｑ、ｒ、ｓ、およびｔは、各々独立して、整数０、１、２、３および４から選択される。 [0043] In any aspect or embodiment described herein, the linker unit or linker (L) comprises a group represented by a structure selected from the group consisting of:
-O-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O(CH2)s-O(CH2)t-,
—O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O(CH2)s—O—,
-(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O(CH2)s-O(CH2)t-,
-CH=CH(CH2)m-O(CH2)n-O(CH2)o-O(CH2)p-O(CH2)q-O(CH2)r-O(CH2)s-O(CH2)t-,

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

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

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

式中、
ＷＬ１およびＷＬ２は、各々独立して、存在しないか、任意にＲＱで置換された０～４個のヘテロ原子を有する４～８員であり、各ＲＱは、独立して、Ｈ、ハロ、ＯＨ、ＣＮ、ＣＦ３、任意に置換された直鎖もしくは分枝鎖Ｃ１－Ｃ６アルキル、任意に置換された直鎖もしくは分枝鎖Ｃ１－Ｃ６アルコキシであるか、または２個のＲＱ基は、それらが結合している原子と一緒になって、０～４個のヘテロ原子を含有する４～８員環系を形成し、
ＹＬ１は、各々独立して、結合、（直鎖、分岐鎖、任意に置換された）かつ任意に１個以上のＣ原子がＯで置き換えられたＣ１－Ｃ６アルキル（されている）、または（直鎖、分岐鎖、任意に置換された）Ｃ１－Ｃ６アルコキシであり、
ｎは、０～１０であり、

は、ＰＴＭ部分またはＵＬＭ部分への結合点を示す。 In additional embodiments, the linker (L) includes a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety:

In the formula,
WL1 and WL2 are each independently 4-8 membered, absent or having 0-4 heteroatoms optionally substituted with RQ, each RQ is independently H, halo, OH, CN, CF3, optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, or two RQ groups taken together with the atom to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;
Each YL1 is independently a bond, a C1-C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced by O, or a C1-C6 alkoxy (linear, branched, optionally substituted);
n is 0 to 10;

indicates the point of attachment to the PTM or ULM moiety.

式中、
ＷＬ１およびＷＬ２は、各々独立して、存在しないか、アリール、ヘテロアリール、環式、ヘテロシクリル、任意に１個以上のＣ原子がＯもしくはＮで置き換えられたＣ１－６アルキル、任意に１個以上のＣ原子がＯで置き換えられたＣ１－６アルケニル、任意に１個以上のＣ原子がＯで置き換えられたＣ１－６アルキニル、二環式、ビアリール、ビヘテロアリール、またはビヘテロシクリルであり、各々が、ＲＱで任意に置換され、各ＲＱは、独立して、Ｈ、ハロ、ＯＨ、ＣＮ、ＣＦ３、ヒドロキシル、ニトロ、Ｃ≡ＣＨ、Ｃ２－６アルケニル、Ｃ２－６アルキニル、任意に置換された直鎖または分岐鎖Ｃ１－Ｃ６アルキル、任意に置換された直鎖または分岐鎖Ｃ１－Ｃ６アルコキシ、任意に置換されたＯＣ１－３アルキル（例えば、１個以上のＦで任意に置換されている）、ＯＨ、ＮＨ２、ＮＲＹ１ＲＹ２、ＣＮであるか、または２つのＲＱ基が、それらが結合している原子と一緒になって、０～４個のヘテロ原子を含有する４～８員環系を形成し、
ＹＬ１は、各々独立して、結合、ＮＲＹＬ１、Ｏ、Ｓ、ＮＲＹＬ２、ＣＲＹＬ１ＲＹＬ２、Ｃ＝Ｏ、Ｃ＝Ｓ、ＳＯ、ＳＯ２、（直鎖、分岐鎖、任意に置換された）かつ任意に１個以上のＣ原子がＯで置き換えられたＣ１－Ｃ６アルキル、または（直鎖、分岐鎖、任意に置換された）Ｃ１－Ｃ６アルコキシであり、
ＱＬは、任意に架橋され、任意に０～６個のＲＱで置換された、０～４個のヘテロ原子を有する３～６員の脂環式または芳香環であり、各ＲＱは、独立して、Ｈ、任意に１つ以上のハロもしくはＣ１－６アルコキシルで置換された、直鎖もしくは分岐鎖Ｃ１－６アルキルであるか、または２個のＲＱ基は、それらが結合している原子と一緒になって、０～２個のヘテロ原子を含有する３～８員環系を形成し、
ＲＹＬ１、ＲＹＬ２は、各々独立して、Ｈ、ＯＨ、（直鎖、分岐鎖、任意に１つ以上のハロ、Ｃ１－６アルコキシルで置換された）Ｃ１－６アルキルであるか、またはＲ１、Ｒ２は、それらが結合している原子と一緒になって、０～２個のヘテロ原子を含有する３～８員環系を形成し、
ｎは、０～１０であり、

は、ＰＴＭ部分またはＵＬＭ部分への結合点を示す。 In additional embodiments, the linker (L) includes a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety:

In the formula,
WL1 and WL2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclyl, C1-6 alkyl optionally having one or more C atoms replaced by O or N, C1-6 alkenyl optionally having one or more C atoms replaced by O, C1-6 alkynyl optionally having one or more C atoms replaced by O, bicyclic, biaryl, biheteroaryl, or biheterocyclyl, each optionally substituted with RQ, and each RQ is independently H, halo, OH, C N, CF3, hydroxyl, nitro, C≡CH, C2-6 alkenyl, C2-6 alkynyl, optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, optionally substituted OC1-3 alkyl (e.g. optionally substituted with one or more F), OH, NH2, NRY1RY2, CN, or two RQ groups together with the atom to which they are attached form a 4-8 membered ring system containing 0-4 heteroatoms;
Each YL1 is independently a bond, NRYL1, O, S, NRYL2, CRYL1RYL2, C=O, C=S, SO, SO2, C1-C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced by O, or C1-C6 alkoxy (linear, branched, optionally substituted);
QL is an optionally bridged 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, optionally substituted with 0-6 RQ, each RQ is independently H, a straight or branched C1-6 alkyl optionally substituted with one or more halo or C1-6 alkoxyl, or two RQ groups together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms;
RYL1, RYL2 are each independently H, OH, C1-6 alkyl (linear, branched, optionally substituted with one or more halo, C1-6 alkoxyl), or R1, R2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms;
n is 0 to 10;

indicates the point of attachment to the PTM or ULM moiety.

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

In any of the embodiments of the compounds described herein, the linker group may 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 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, from about 2 to 4 ethylene glycol units.

In another embodiment, the disclosure is directed to compounds comprising a PTM group as described above, which is ubiquitinated by a ubiquitin ligase and is attached to a target protein or polypeptide (e.g., SMARCA2, BRAHMA, or BRM) that is chemically attached to a ULM group, either directly or via a linker moiety L, or the PTM is alternatively a ULM' group that is also a ubiquitin ligase binding moiety, which may be the same or different as the ULM group as described above, L is a linker moiety as described above, which may or may not be present, and which chemically (covalently) attaches the ULM to the PTM, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

Ｘは、Ｏ、Ｎ、Ｓ、Ｓ（Ｏ）、およびＳＯ２からなる群から選択され、ｎは、１～５の整数であり、ＲＬ１は、水素またはアルキルであり、

は、アルキル、ハロゲン、ハロアルキル、ヒドロキシ、アルコキシ、もしくはシアノから選択される１～３個の置換基で任意に置換された、単環式もしくは二環式アリールまたはヘテロアリールであり、

は、アルキル、ハロゲン、ハロアルキル、ヒドロキシ、アルコキシ、もしくはシアノから選択される１～３個の置換基で任意に置換された、単環式もしくは二環式シクロアルキルまたはヘテロシクリルであり、フェニル環断片は、アルキル、ハロゲン、ハロアルキル、ヒドロキシ、アルコキシ、およびシアノからなる群から選択される１、２、または３個の置換基で任意に置換され得る。ある実施形態では、リンカー基Ｌは、上述のとおり最大で１０個の共有結合された構造単位を含む。 In certain embodiments, the linker group L is a group that includes one or more covalently linked structural units independently selected from the group consisting of:

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;

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

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 certain embodiments, the linker group L comprises up to 10 covalently linked structural units as described above.

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

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

In certain embodiments, the compounds described herein include a means for binding to a target protein, e.g., Brm. Thus, in certain aspects, the present disclosure provides bifunctional compounds having a means for binding to Brm and a means for binding to VHL, as well as a means for chemically linking the means for binding to Brm to the means for binding to VHL.

The compositions described below exemplify some of the series of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target SMARCA2. These binding moieties are attached to the ubiquitin ligase binding moiety, preferably through a linker, to present the target protein (to which the protein target moiety is attached) in proximity to the ubiquitin ligase for ubiquitination and degradation. Any protein (e.g., SMARCA2, BRAHMA, or BRM) that is attached to a protein target moiety or PTM group and can act on or be degraded by a ubiquitin ligase is a target protein in accordance with the present disclosure.

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

In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound or salt form thereof as described herein, and a pharma- ceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent. The therapeutic composition can be used to modulate protein degradation in a patient or subject, such as an animal, such as a human, and to treat or ameliorate a disease state or condition regulated via the degraded 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, such as at least one of SWI/SNF-associated cancer, SMARCA4 mutation-associated cancer, SMARCA4-deficient cancer, or cancer with reduced expression of SMARCA4 compared to normal SMARCA4 expression (e.g., reduced expression compared to non-mutated SMARCA4 or expression of SMARCA4 in a similarly located non-cancerous cell with wild-type SMARCA4), including lung cancer or non-small cell lung cancer. In any aspect or embodiment described herein, the cancer is at least one of a SWI/SNF-associated cancer, a SMARCA4-mutated cancer, a SMARCA4-deficient cancer, or a combination thereof, and may be lung cancer or non-small cell lung cancer.

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, such as at least one of a SWI/SNF-associated cancer, a SMARCA2-associated cancer, or a cancer having normal or overexpression of SMARCA2.

In another aspect, the disclosure relates to a method of treating a pathology or ameliorating a symptom of a disease or condition in a subject in need thereof by degrading a protein or polypeptide, where the pathology or condition is regulated via the protein or polypeptide, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound as described above, optionally in combination with a pharma- ceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent, where the composition is effective to treat or ameliorate the disease or disorder or a symptom thereof in the subject. Using the disclosed method, many conditions or symptoms can be treated, including cancer, by administering an effective amount of at least one compound described herein. The pathology or condition may be a disease caused by a microbial organism or other foreign agent, such as, for example, a virus, bacteria, fungus, protozoa, or other microorganism, or may be a pathology caused by overexpression of a protein resulting in the pathology and/or condition.

In another aspect, the present specification provides a method for identifying the degradative effect of a protein of interest in a biological system using a compound according to the present disclosure.

The term "target protein" is used herein below to describe a protein or polypeptide that is a target to which the disclosed compounds bind and are degraded by ubiquitin ligase. Such small molecule target protein binding moieties also include pharma- ceutically 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 attached to at least one ULM group (e.g., VLM) via at least one linker group L.

This protein target may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into the disclosed compounds, the activity level of the protein can be altered for therapeutic end results.

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

式中、
ＷＰＴＭ１は、任意に置換された５～６員アリールまたはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、ホスフェート、アミノ、アルキルアミノ、シアノ、またはそれらの組み合わせから選択される０、１、２、または３個の置換基で置換された５～６員アリールまたはヘテロアリール）であり、
ＷＰＴＭ２は、任意に置換された５～６員アリールまたはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、または３個の置換基で置換された５～６員アリールまたはヘテロアリール）であり、
ＷＰＴＭ３は、任意に置換された３～９員アリールもしくはヘテロアリール環（例えば、任意に置換された５～６員アリールもしくはヘテロアリール環、またはヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、もしくは３個の置換基で置換された３～９もしくは５～６員アリールもしくはヘテロアリール）、または任意に置換された４～９員シクロアルキルもしくはヘテロシクリル、例えば、任意に置換された架橋ビシクロアルキルおよび架橋ビヘテロシクリル環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、もしくは２個の置換基で置換された４～９員シクロアルキルもしくはヘテロシクリル）であり、
ＷＰＴＭ５は、存在しない（例えば、ＷＰＴＭ３が、Ｌ（リンカー）またはＵＬＭに直接連結されている）か、または任意に置換されたアルキル、任意に置換された５～６員シクロアルキル、複素環、アリール、もしくはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、または２個の置換基で置換された、５～６員シクロアルキル、複素環、アリール、またはヘテロアリール）であり、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である、二官能性化合物またはその薬学的に許容される塩、鏡像異性体、立体異性体、溶媒和物、多形、もしくはプロドラッグを提供する。 In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

In the formula,
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, phosphate, amino, alkylamino, cyano, or combinations thereof);
WPTM2 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);
WPTM3 is 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 4-9 membered cycloalkyl or heterocyclyl, such as optionally substituted bridged bicycloalkyl and bridged biheterocyclyl rings (e.g., a 4-9 membered cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);
WPTM5 is absent (e.g., WPTM3 is directly linked to L (linker) or ULM) or 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);

is a point of attachment to a linker, a ULM group, a ULM' group, a VLM group, a VLM' group, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

In any aspect or embodiment described herein, WPTM5 is piperidine.

In certain embodiments, WPTM1 includes a phosphate substitution.

In any aspect or embodiment described herein, the PTM of the PROTAC of the disclosure is represented by Formula I, wherein:
WPTM1 is an optionally substituted phenyl or pyridyl (e.g., substituted as described herein, e.g., substituted with hydroxy or phosphate substituents with or without additional optional substituents selected as described herein, e.g., phenyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, cyano, or combinations thereof);
WPTM2 is an optionally substituted 6-membered heteroaryl ring (e.g., substituted as described herein, such as pyridazine substituted with an amino group);
WPTM3 is an optionally substituted 5-6 membered heteroaryl (e.g., pyrazole, pyrrole, imidazole, oxazole, oxadiazole, or triazole);
WPTM5 is at least one of: as described in any aspect or embodiment described herein (e.g., WPTM5 can be absent or a pyridine ring); or a combination thereof.

In any aspect or embodiment described herein, including embodiments that include a PTM of formula I, WPTM3 is pyrazole or a 6-8 membered heterocyclyl (e.g., piperazine or diazabicyclooctane).

式中、
ＷＰＴＭ１、ＷＰＴＭ２、およびＷＰＴＭ５は、本明細書に記載される任意の他の態様または実施形態に記載されるとおり（例えば、ＷＰＴＭ５は、ＷＰＴＭ４がＬ（ｌｉｎｋｅｒ）またはＵＬＭに直接連結し得るため、存在してもしなくてもよい）であり、
ＷＰＴＭ４は、ＷＰＴＭ２環で縮合された、任意に置換された３～７シクロアルキルまたはヘテロシクリル（例えば、任意に置換された５～７シクロアルキルもしくはヘテロシクリル、またはヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、または３個の置換基で置換された５～７シクロアルキルまたはヘテロシクリル）であり、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である。 In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

In the formula,
WPTM1, WPTM2, and WPTM5 are as described in any other aspect or embodiment described herein (e.g., WPTM5 may be present or absent because WPTM4 may directly link to L (linker) or ULM);
WPTM4 is an optionally substituted 3-7 cycloalkyl or heterocyclyl (e.g., an optionally substituted 5-7 cycloalkyl or heterocyclyl, or a 5-7 cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a WPTM2 ring;

are points of attachment to the linker, ULM, ULM', VLM, VLM' groups.

In any aspect or embodiment described herein, the PTM of the disclosure is represented by formula II, where WPTM1, WPTM2, and WPTM5 are as described in any of the aspects or embodiments described herein, and WPTM4 is a piperazine ring. For example, in any aspect or embodiment described herein, WPTM2 and WPTM4 of formula II together comprise a dihydropyrazino[2,3-e]pyridazine as shown below:

式中、
ＷＰＴＭ１およびＷＰＴＭ２は、本明細書に記載される任意の態様または実施形態に記載されるとおりであり、
ＷＰＴＭ６およびＷＰＴＭ７は、独立して、任意に４～７シクロアルキルまたはヘテロシクリル（例えば、各々が独立して、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、または２個の置換基で置換された４～７シクロアルキルまたはヘテロシクリルである）であり、ＷＰＴＭ６およびＷＰＴＭ７の環は、スピロ連結を介して縮合または結合され、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である、二官能性化合物またはその薬学的に許容される塩、鏡像異性体、立体異性体、溶媒和物、多形、もしくはプロドラッグを提供する。 In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

In the formula,
WPTM1 and WPTM2 are as described in any aspect or embodiment described herein;
WPTM6 and WPTM7 are independently optionally 4-7 cycloalkyl or heterocyclyl (e.g., 4-7 cycloalkyl or heterocyclyl each independently substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), and the rings of WPTM6 and WPTM7 are fused or joined via a spiro linkage;

is a point of attachment to a linker, a ULM group, a ULM' group, a VLM group, a VLM' group, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by formula III, where WPTM1 and WPTM2 are each independently selected as described in any aspect or embodiment described herein (e.g., WPTM1 is a phenyl substituted with a hydroxy substituent, with or without any additional substituents described herein, and WPTM2 is a pyridazine substituted with an amino group), and WPTM6 and WPTM7 are spirocyclic ring systems, e.g., spirocyclic rings selected from the following:

式中、
ＷＰＴＭ１、ＷＰＴＭ２、およびＷＰＴＭ５は、本明細書に記載される任意の他の態様または実施形態に記載されるとおりであり、
ＲＰＴＭ１およびＲＰＴＭ２は、個々に、Ｈ、ハロ、ＨＯ、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３ハロアルキ、またはＣ１－Ｃ３アルコキシであり、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である、二官能性化合物またはその薬学的に許容される塩、鏡像異性体、立体異性体、溶媒和物、多形、もしくはプロドラッグを提供する。 In any aspect or embodiment described herein, the PTM of the present disclosure is represented by:

In the formula,
WPTM1, WPTM2, and WPTM5 are as described in any other aspect or embodiment described herein;
RPTM1 and RPTM2 are individually H, halo, HO, C1-C3 alkyl, C1-C3 haloalkoxy, or C1-C3 alkoxy;

is a point of attachment to a linker, a ULM group, a ULM' group, a VLM group, a VLM' group, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by Formula IV, wherein:
WPTM1 is a phenyl substituted with a hydroxy or phosphate substituent, with or without any additional substituents described herein;
WPTM2 is an amino-substituted pyridazine;
WPTM5 is at least one of: absent, a pyrazole ring, or a pyridine ring, or a combination thereof.

またはその薬学的に許容される塩であり、
ＷＰＴＭ３は、不在であるか、または任意に置換された５～６員ヘテロアリール、任意に置換された４～９シクロアルキルもしくはヘテロシクリル環、任意に置換された架橋ビシクロアルキル、および架橋ビヘテロシクリル環であり、
ＷＰＴＭ５は、任意に置換された５～６員ヘテロアリールまたはアリール、例えば、ピリジン、またはピリダジンである。 In any aspect or embodiment described herein, the PTM of the present disclosure is represented by:

or a pharma- ceutically acceptable salt thereof;
WPTM3 is absent or an optionally substituted 5-6 membered heteroaryl, an optionally substituted 4-9 membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl, and a bridged biheterocyclyl ring;
WPTM5 is an optionally substituted 5-6 membered heteroaryl or aryl, for example, pyridine, or pyridazine.

またはその薬学的に許容される塩を含み、
ＷＰＴＭ５は、フェニル、ピリジン、ピリミジン、またはピラジンである。 In any aspect or embodiment described herein, the PTM of the disclosure is represented by:

or a pharma- ceutically acceptable salt thereof,
WPTM5 is phenyl, pyridine, pyrimidine, or pyrazine.

またはその薬学的に許容される塩である。 In any aspect or embodiment described herein, the PTM of the present disclosure is represented by:

or a pharma- ceutically acceptable salt thereof.

またはその薬学的に許容される塩により、
式中、
ＷＰＴＭ３は、任意に置換された５～６員ヘテロアリール、任意に置換された４～９シクロアルキルもしくはヘテロシクリル環、任意に置換された架橋ビシクロアルキルおよび架橋ビヘテロシクリル環であり、
ＷＰＴＭ５は、任意に置換された５～６員ヘテロアリールまたはアリール、例えば、ピリジン、またはピリダジンであり、
Ｒｖは、独立して、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、ホスフェート、アミノ、アルキルアミノ、シアノ、またはそれらの組み合わせから選択される、０、１、２、または３個の置換基である。 In any aspect or embodiment described herein, the PTM of the disclosure is represented by:

or a pharma- ceutically acceptable salt thereof,
In the formula,
WPTM3 is an optionally substituted 5-6 membered heteroaryl, an optionally substituted 4-9 membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl and a bridged biheterocyclyl ring;
WPTM5 is an optionally substituted 5-6 membered heteroaryl or aryl, e.g., pyridine, or pyridazine;
Rv is 0, 1, 2, or 3 substituents independently selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, phosphate, amino, alkylamino, cyano, or combinations thereof.

In certain embodiments, the hydroxyl groups are modified with phosphate groups (i.e., phosphoester groups).

式中、ＷＰＴＭ１およびＷＰＴＭ２は、本明細書に記載される任意の他の態様または実施形態に記載されるとおり（例えば、ＷＰＴＭ５は、ＷＰＴＭ４がＬ（リンカー）またはＵＬＭに直接連結し得るため、存在してもしなくてもよい）であり、
ＷＰＴＭ３は、存在しないか、またはＷＰＴＭ２環で縮合された、任意に置換された５～７シクロアルキルもしくはヘテロシクリル（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、もしくは３個の置換基で置換された５～７シクロアルキルもしくはヘテロシクリル）であり、
ＷＰＴＭ４は、任意に置換された３～７員アリールもしくはヘテロアリール環（例えば、任意に置換された５～７シクロアルキルもしくはヘテロシクリル、またはヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、もしくは３個の置換基で置換された３～７もしくは５～６員アリールもしくはヘテロアリール）、または任意に置換された４～９シクロアルキルもしくはヘテロシクリル、例えば、任意に置換された架橋ビシクロアルキルおよび架橋ビヘテロシクリル環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、もしくは２個の置換基で置換された４～９シクロアルキルもしくはヘテロシクリル）であり、
ＷＰＴＭ５は、存在しない（例えば、ＷＰＴＭ３が、Ｌ（リンカー）またはＵＬＭに直接連結されている）か、または任意に置換されたアルキル、任意に置換された５～６員シクロアルキル、複素環、アリール、もしくはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、または２個の置換基で置換された、５～６員シクロアルキル、複素環、アリール、またはヘテロアリール）、例えば、任意に置換されたピラゾール環、またはピリジン環であり、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である、二官能性化合物またはその薬学的に許容される塩、鏡像異性体、立体異性体、溶媒和物、多形、もしくはプロドラッグを提供する。 In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

wherein WPTM1 and WPTM2 are as described in any other aspect or embodiment described herein (e.g., WPTM5 may or may not be present since WPTM4 may be directly linked to L (linker) or ULM);
WPTM3 is absent or is an optionally substituted 5-7 cycloalkyl or heterocyclyl (e.g., 5-7 cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a WPTM2 ring;
WPTM4 is 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 cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);
WPTM5 is absent (e.g., WPTM3 is directly linked to L (linker) or ULM) or 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), e.g., an optionally substituted pyrazole ring, or a pyridine ring;

is a point of attachment to a linker, a ULM group, a ULM' group, a VLM group, a VLM' group, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

式中、
ＷＰＴＭ１、ＷＰＴＭ２、ＷＰＴＭ３、およびＷＰＴＭ４は、本明細書に記載される任意の他の態様または実施形態に記載されるとおりであり、
ＬＰＴＭは、Ｃ１－Ｃ４アルキルまたはＣ１－Ｃ３アルコキシで任意に置換されたＣ１－Ｃ６アルキルであり、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である、二官能性化合物またはその薬学的に許容される塩、鏡像異性体、立体異性体、溶媒和物、多形、もしくはプロドラッグを提供する。 In any aspect or embodiment described herein, the PTM of the present disclosure has a chemical structure represented by:

In the formula,
WPTM1, WPTM2, WPTM3, and WPTM4 are as described in any other aspect or embodiment described herein;
LPTM is C1-C6 alkyl optionally substituted with C1-C4 alkyl or C1-C3 alkoxy;

is a point of attachment to a linker, a ULM group, a ULM' group, a VLM group, a VLM' group, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

から選択され、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である。 [0043] In any aspect or embodiment described herein, the PTM is

is selected from

are points of attachment to the linker, ULM, ULM', VLM, VLM' groups.

から選択され、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である。 [0043] In any aspect or embodiment described herein, the PTM is

is selected from

are points of attachment to the linker, ULM, ULM', VLM, VLM' groups.

から選択され、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である。 [0043] In any aspect or embodiment described herein, the PTM is

is selected from

are points of attachment to the linker, ULM, ULM', VLM, VLM' groups.

The compositions described herein exemplify some of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target proteins of interest. The references cited herein below are incorporated by reference in their entireties.

Therapeutic Compositions Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein, and a combination of an effective amount of one or more of the compounds otherwise described herein, in combination with a pharma- ceutical effective amount of a carrier, excipient, or diluent, represent a further aspect of the present disclosure.

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

Pharmaceutically acceptable base addition salts may also be used to generate pharma- ceutically acceptable salt forms of the compounds or derivatives according to the present disclosure. Chemical bases that may be used as reagents to prepare pharma- ceutically 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, base salts derived from pharma- ceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine-(meglumine), and lower alkanolammonium, as well as other pharma- ceutically acceptable organic amine base salts.

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

The compositions described herein may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers and may be administered in controlled release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins 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, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

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

Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions may be formulated by techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma-ceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring, or coloring agents may also be added, if desired.

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

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

For topical application, the pharmaceutical composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the disclosed compounds include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. In certain preferred aspects of the present disclosure, the compounds may be coated onto a stent that is surgically implanted in a patient, thereby preventing or reducing the likelihood of occlusion occurring at the stent in the patient.

Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharma- ceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

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

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

The amount of the compounds in the pharmaceutical compositions described herein that can be combined with the carrier materials to produce a single dosage form will vary depending on the host and disease being treated, as well as the particular mode of administration. Preferably, the compositions should be formulated to contain about 0.05 milligrams to about 750 milligrams or more of active ingredient, either 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.

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

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

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

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

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

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 may be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline solution or in an aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

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

Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be combined with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

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

The active compound or a pharma- ceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and/or certain preservatives, dyes and colorings, and flavors.

The active compounds or pharma- ceutically acceptable salts thereof may also be mixed with other active substances that do not impair the desired action or that complement the desired action, such as anti-cancer drugs, including pembrolizumab, among others. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anti-cancer drug, or a wound healing agent, including an antibiotic, as described elsewhere herein.

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

When administered intravenously, the preferred carrier is saline or phosphate buffered saline (PBS).

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

Liposomal suspensions may also be pharma- ceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, such as those described in U.S. Pat. No. 4,522,811, which is incorporated herein by reference in its entirety. For example, liposomal formulations may be prepared by dissolving appropriate lipids (e.g., stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol, etc.) in an inorganic solvent, which is then evaporated to leave a thin film of dried lipid on the container surface. An aqueous solution of the active compound is then placed in the container. The container is then rotated by hand to remove lipid material from the sides of the container, dispersing the lipid mass and forming the liposomal suspension.

In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, and a pharma- ceutically acceptable carrier, which can be used to modulate protein degradation in a patient or subject, e.g., an animal, such as a human, and to treat or ameliorate a disease state or condition that is modulated via the degraded protein.

As used herein, the terms "treat," "treating," and "treatment" refer to any action that benefits a patient, for which the compounds may be administered, including the treatment of any disease state or condition that is modulated via the protein to which the 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.

The present disclosure provides therapeutic compositions as described herein for causing degradation of a target protein for the treatment or amelioration of a disease, e.g., cancer. In certain additional embodiments, the disease is multiple myeloma. Thus, 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 as described herein, the compound including a ULM and a PTM, preferably linked via a linker moiety, e.g., as described elsewhere herein, where the ULM binds to the PTM, and the ULM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, such as VHL E3 ubiquitin ligase), and the PTM recognizes the target protein such that when the target protein is placed in proximity to the ubiquitin ligase, degradation of the target protein occurs, thus resulting in degradation/inhibition of the effect of the target protein and control of the protein level. The control of protein level provided by the present disclosure provides treatment of a disease state or condition that is regulated via the target protein by reducing the level of that protein in a cell, e.g., a patient cell. In certain embodiments, the method includes administering an effective amount of a compound described herein, optionally including a pharma- ceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

In additional embodiments, the present specification provides a method of treating or ameliorating a disease, disorder, or a symptom thereof in a subject or patient, e.g., an animal, e.g., 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 pharma- ceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate a disease or disorder, or a symptom thereof, in the subject.

In another aspect, the present specification provides a method for identifying the degradative effect of a protein of interest in a biological system using a compound according to the present disclosure.

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

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

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

The term "neoplasm" or "cancer" is used throughout this specification to refer to a cancerous or malignant neoplasm, i.e., a pathological process that results in the formation and growth of abnormal tissue that grows by cell proliferation, often much faster than normal, and continues to grow after stimuli that would have stopped the new growth that was initiated. Malignant neoplasms exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, recur after attempted removal, and have a high probability of causing death to the patient unless appropriately treated. As used herein, the term neoplasm is used to describe all cancerous conditions and includes pathological processes associated with malignant hematopoietic cells, ascites, and solid tumors. Examples of cancers that may be treated by the present compounds alone or in combination with at least one additional anti-cancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, hematopoietic cancer, and hematopoietic cancer. Sarcomas, including ductal sarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; colorectal 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, colorectal 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 lymphoma, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

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

The term "additional anti-cancer agent" is used to describe anti-cancer agents that may be combined with compounds according to the present disclosure to treat cancer. These agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910. Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1/2 inhibitors, JAK/STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gymatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY317615, neuradiab, vitespam, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5 -yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE -0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-21 4662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodrofluidine acetaminophen, 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, nifedipine, lutamide, 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-methyl- Lecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trase Tuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate , prednisolone, cetuximab, granulocyte-monocyte colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacytidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole , interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, paclitaxel These include lonosetron, 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.

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

Other anti-HIV agents that may be used in co-administration with the compounds according to the present disclosure include, for example, nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothiamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY, among others. 097, DMP266, baicalin (TJN-151) ADAM-II (methyl 3',3'-dichloro-4',4''-dimethoxy-5',5"-bis(methoxycarbonyl)-6,6-diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hup-1-enyl)-2-methoxybenzoate (alkenyl diarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), capravirine (AG-1549, S-1153), atevirdine (U-87201 E), aurintricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]- 4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC 633001), calanolide A (NSC 675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscarbil), HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivatives), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pipridine-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pipridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Roviride), R90385, S-2720, Suramin sodium, TBZ (thiazolbenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, tivirapine (R86183), UC-38, and UC-84.

The term "pharmaceutically acceptable salt" is used throughout the specification to describe, where appropriate, one or more salt forms of the compounds described herein that exhibit increased solubility of the compound in the gastric fluids of the patient's digestive tract and promote dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where appropriate. Suitable salts include those derived from alkali metals, e.g., potassium and sodium, alkaline earth metals, e.g., calcium, magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralizing salts of phosphates according to the present disclosure.

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

General synthetic approach The realization and optimization of the synthesis of the bifunctional molecules described herein may be undertaken in a stepwise or modular fashion. For example, the identification of compounds that bind to a target molecule may involve high-throughput or medium-throughput screening campaigns when suitable ligands are not readily available. It is not uncommon that iterative design and cycle optimization is required for initial ligands to improve suboptimal aspects identified by suitable in vitro pharmacological and/or ADMET assay data. Part of the optimization/SAR campaign is to probe ligand positions that tolerate substitution and may be suitable positions for attaching the linker chemistry referenced herein above. When crystallographic or NMR structural data are available, these can be used to focus such synthetic efforts.

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

With PTMs and ULMs (e.g., VLMs) at hand, one of skill in the art can use known synthetic methods for their combination with or without linker moieties. Linker moieties can be synthesized and functionalized with a range of compositions, lengths, and flexibility so that PTM and ULM groups can be successively attached to the distal ends of the linker. Thus, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET/PK studies. As with the PTM and ULM groups, the final bifunctional molecules can be subjected to cycles of iterative design and optimization to identify molecules with desired properties.

In some cases, protecting group strategies and/or functional group interconversions (FGI) may be required to facilitate the preparation of the desired material. Such chemical processes are known to synthetic organic chemists, and many of these chemical processes can be found in books such as, for example, "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).

Abbreviations:
ACN: Acetonitrile ADDP: 1,1'-(azodicarbonyl)dipiperidine BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride BPO: Benzoyl peroxide Cbz: Carbonylbenzyloxy DAST: Diethylaminosulfur trifluoride DBE: 1,2-dibromoethane DCM: Dichloromethane DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodipropylate DIBAL: Dithiobutylaluminum hydride DIEA or DIPEA: Diisopropylethylamine DMA: N,N-Dimethylacetamide DMF: N,N-Dimethylformamide DMP: Dess-Martin periodinane EA: Ethyl acetate EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HBTU: N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HMDS: bis(trimethylsilyl)amine HMPA: hexamethylphosphoramide LDA: lithium diisopropylamide MCPBA: meta-chloroperbenzoic acid MsCl: methanesulfonyl chloride M. W: Microwave NBS: N-bromosuccinimide NMP: N-methylpyrrolidone PCC: Pyridinium chlorochromate Pd-118 or Pd(dtpf)Cl2: 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium Pd(dba)2: Bis(dibenzylideneacetone)palladium Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium PPTS: Pyridinium p-toluenesulfonate PTSA: p-toluenesulfonic acid RuPhos-Pd-G3: XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate RuPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)
SFC: Supercritical fluid chromatography t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA: Trimethylamine TFA: Trifluoroacetic acid TLC: Thin layer chromatography TMP: 2,2,6,6-tetramethylpiperidine TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide TosCl or TsCl: p-toluenesulfonyl chloride TsOH: p-toluenesulfonic acid XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate 12354-85-7: Bis(pentamethylcyclopentadienylrhodium dichloride)

Scheme 1

As shown in Scheme 1, compounds bearing a WPTM5 moiety contain a linking group L that includes a nucleophilic group such as an amino group. When reacted with a compound that has a good leaving group LG (e.g., the perfluorosulfonyl group C4F9SO3-), a coupling product is formed. The coupling product is reacted with a monoprotected amine molecule WPTM3 under palladium catalyzed conditions to couple to the WPTM3 fragment. Following amine deprotection, the more reactive halogen atom selected from Z' and Z'' in WPTM5-WPTM3 is nucleophilically displaced with the free amino group to form WPTM5-WPTM3-WPTM2, which is then reacted with WPTM2 boronic acid to provide a PTM linking group that includes the WPTM5-WPTM3-WPTM2-WPTM1 fragment. After base catalyzed ester hydrolysis, the resulting acid is coupled with a ULM moiety bearing an amino group to combine the PTM and ULM linking moieties into one molecule.

Scheme 2

As shown in Scheme 2, a Mitsunobu reaction between a hydroxyl-containing moiety R3 and a monoprotected diol containing a linking group L gives the coupling product. Following O-deprotection, the free hydroxyl group is activated, for example as a sulfonate, and then substituted with a moiety bearing an amino group in WPTM5, WPTM5-WPTM3-WPTM2-WPTM1. After ester hydrolysis, the resulting acid is coupled with a ULM moiety bearing an amino group to combine the PTM and ULM linking moieties into one molecule.

Scheme 3

As shown in Scheme 3, a vinyl group is first introduced into the bis-halogenated derivative WPTM2. The resulting product then undergoes a palladium-catalyzed Heck coupling reaction with a halogenated moiety WPTM2 bearing a linking group L' containing an optionally protected amino group. To introduce the WPTM1 moiety, the halide moiety of WPTM2-WPTM5 is coupled with an appropriate boronic acid under Suzuki conditions, and the resulting amine is reacted with a ULM-containing aldehyde to yield the PTM-ULM coupling product.

Scheme 4

Scheme 4 illustrates exemplary coupling reactions utilized to link the PTM binding moieties WPTM5-WPTM3-WPTM2-WPTM1 with ULM-containing moieties. Such reactions may include reductive amination using sodium cyanoborohydride as a reducing agent, or condensation coupling reactions between carboxylic acids and diamines. One of skill in the art will be able to select appropriate reagents and conditions to effect the desired transformation.

Scheme 5

As shown in Scheme 5, a Mitsunobu-type reaction between the hydroxyl-containing moiety R3 and WPTM5 gives the coupling product. The halogen atom in WPTM5 is then displaced with the monoprotected diamine WPTM3 under Suzuki or Buchwald conditions. Following deprotection of the second amino group, the more reactive halogen atom attached to the WPTM2 moiety is displaced to form the WPTM5-WPTM3-WPTM2 fragment. The resulting monohalide is then reacted with an appropriate boronic acid under Suzuki conditions to give the PTM-linked moiety WPTM5-WPTM3-WPTM2-WPTM2. After ester hydrolysis, the resulting acid is then coupled with the ULM moiety bearing an amino group to combine the PTM and ULM-linked moieties into one molecule.

Scheme 6

As shown in Scheme 6, the acetal-containing ULM moiety can undergo acid-catalyzed hydrolysis under sufficiently mild conditions to form an aldehyde, which can then be reacted with the WPTM5-WPTM3-WPTM2-WPTM2 fragment bearing an amino group-containing linker L' under reductive amination conditions to form the PTM-ULM coupling product. One of skill in the art will be able to select appropriate reagents and conditions to effect the desired transformation.

Scheme 7

As shown in Scheme 7, a Mitsunobu-type reaction between a hydroxyl-containing moiety R3 and a monoprotected fluorinated diol provides a fluorine-containing intermediate. Following O-deprotection, the free hydroxyl group is activated (e.g., as a sulfonate) and then substituted with an amino-bearing moiety WPTM5-WPTM3-WPTM2-WPTM1 in WPTM5. After ester hydrolysis, the resulting acid is coupled with an amino-bearing ULM moiety to combine the PTM and ULM-linked moieties into one molecule.

Scheme 8

As shown in Scheme 8, nucleophilic displacement of the leaving group in L'-OLG with a hydroxyl-containing ester containing R3 gives a coupling product combining linkers L' and L". Subsequent base hydrolysis and coupling of the resulting acid with a ULM moiety bearing an amino group provides a ULM fragment with two consecutive linking groups L' and L". N-deprotection of the amino group of L' followed by reductive amino acid conversion with WPTM5-WPTM3-WPTM2-WPTM1-L'" aldehyde or condensation with WPTM5-WPTM3-WPTM2-WPTM1-L'" carboxylic acid gives the PTM-ULM coupling product.

Scheme 9

As shown in Scheme 9, nucleophilic displacement of the fluorine atom in the moiety WPTM5 with a hydroxyl group-containing compound bearing R3 provides the WPTM5-L-R3 halide, which is coupled to the monoprotected diamine WPTM5 under Suzuki or Buchwald conditions. Following deprotection of the second amino group, the WPTM3-WPTM5-L-R3 moiety is then reacted with the bishalogenated WPTM2 by aromatic nucleophilic displacement to provide the monohalide. Subsequent Suzuki reaction with an appropriate boronic acid provides the WPTM1-WPTM2-WPTM3-WPTM5-L-R3 ester. Base hydrolysis and coupling with an amino-bearing ULM moiety provides the PTM-ULM coupling product.

One possible approach for synthesizing the exemplary compounds of the present disclosure follows the general synthetic route detailed in the following scheme.

Those skilled in the art will appreciate that modified approaches can be utilized to attach the PTMs via different chemical linkers. For example, when WPTM5 is linked to L' via a CH2 group (X = CH2 in the above scheme), the approach depicted in the following scheme can be envisaged.

Alternatively, when WPTM5 is not present, the PTM of the exemplary compounds represented by formula I can be synthesized according to the following general scheme.

Those skilled in the art will appreciate that the general approach described herein can be modified to accommodate the particular properties of the WPTM1, WPTM2, WPTM3, WPTM4, WPTM5, WPTM6, and WPTM7 rings. For example, in some embodiments, the exemplary compound represented by formula II can be prepared as described in the following general synthetic scheme, where a skilled artisan will appreciate that additional protection/deprotection steps may be required depending on the particular chemical nature of the exemplary compound.

In one embodiment where X represents NH, exemplary compounds can be prepared according to one of the two schemes shown below, depending on whether WPTM5 is present.

Exemplary PTMs represented by general formula III can be prepared following the general approach described for compounds of formula I, in the absence of WPMT5.

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

Exemplary Synthesis of Exemplary Compound 11 Step 1

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

Step 2

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.11 g, 5.722 mmol), tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (2.14 g, 5.722 mmol), and Cs2CO3 (3.73 g, 11.444 mmol) in dry DMF (10 mL) was heated to 75 °C for 3 h. The reaction mixture was then cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water (10 mL) and brine (10 mL x 2), dried (Na2SO4), filtered, and concentrated. The crude residue (2.8 g) was used in the next reaction without further purification.

Step 3

A mixture of tert-butyl 2-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (1.5 g, 3.79 mmol), 4-bromo-6-chloropyridazin-3-amine (1.1 g, 5.69 mmol), PdCl2(dppf) (555 mg, 0.758 mmol), tBuPHBF4 (441 mg, 1.52 mmol), and Cs2CO3 (3.09 g, 9.48 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100 °C with stirring under N2 for 3 h. The solids were filtered and the filtrate was concentrated. The residue was purified by chromatography (CH2Cl2:MeOH 30:1) to give tert-butyl 2-(2-(2-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (800 mg, 53% yield).

Step 4

A suspension of tert-butyl 2-(2-(2-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (800 mg, 2.02 mmol), (2-hydroxyphenyl)boronic acid (418 mg, 3.03 mmol), cesium carbonate (1.65 g, 5.05 mmol), PdCl2(dppf) (444 mg, 0.606 mmol), and tBu3PHBF4 (352 mg, 1.212 mmol) in dioxane (10 mL) and water (1 mL) was heated to 100 °C under nitrogen for 3 h. The mixture was cooled to room temperature and the solids were filtered. The filtrate was concentrated and purified by chromatography (CH2Cl2:MeOH 40:1) to give tert-butyl 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (400 mg, 44% yield).

Step 5

To a solution of tert-butyl 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetate (400 mg, 0.88 mmol) in THF/H2O (5 mL, 2:1) was added LiOH (111 mg, 2.64 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The reaction solution was quenched with 1M HCl. The solution was dried (Na2SO4), filtered, and concentrated under reduced pressure to give crude 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetic acid (600 mg), which was used in the next step without further purification.

Step 6

To a solution of 2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetic acid (200 mg crude), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (430 mg, 1 mmol), and DIPEA (516 mg, 4 mmol) in DMF (5 mL) was added HATU (570 mg, 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (8 mL x 2), dried (Na2SO4), and filtered. The organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (6% MeOH in DCM) to give (2S,4R)-1-((S)-2-(2-(2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (22 mg).

1H NMR (400MHz, MeOD): δ 8.83 (s, 1H), 8.32 (s, 1H), 8.04 (d, J = 9.6Hz, 2H), 7.78 (d, J = 7.6Hz, 1H), 7.65 (d, J = 10.0Hz, 1H), 7.39 (d, J = 8.0Hz, 2H), 7.32-7.34 (m, 2H), 7.28 (m, 1H), 6.95 (d, J = 7.6Hz 2H), 4.69 (d, J = 9.6Hz 1H), 4.44-4.57 (m, 6H), 4.25-4.35 (m, 1H), 3.60-3.99 (m, 11H), 2.46 (s, 3H), 2.23 (m, 1H), 2.08 (m, 1H), 1.01 (s, 9H).

Exemplary compound 5 was prepared according to the following scheme using procedures similar to those described above for exemplary compound 11, as well as procedures known and appreciated by those of skill in the art.

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

Exemplary Synthesis of Exemplary Compound 9 Step 1

To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (13.5 g, 56.8 mmol) in anhydrous DMF (30 mL) was added 60% NaH (1.25 g, 31.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. Then, 4-bromo-2-fluoropyridine (5 g, 28.4 mmol) was added dropwise to the mixture and the mixture was heated to 75 °C for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EA (200 mL). The organic phase was washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column to give 14-((4-bromopyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecane-1-ol (9.0 g, 22.9 mmol, 81% yield).

Step 2

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

Step 3

A mixture of tert-butyl 17-((4-bromopyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (250 mg, 1.18 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (718 mg, 1.4 mmol), cesium carbonate (769 mg, 2.36 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), and Xantphos (138 mg, 0.24 mmol) in dioxane (5 mL) in a sealed tube was heated to 110 °C overnight under nitrogen. The mixture was extracted with EA (100 mL). The organic phase was then washed with water (10 mL), brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column to obtain tert-butyl 8-(2-((19,19-dimethyl-17-oxo-3,6,9,12,15,18-hexaoxaicosyl)oxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (550 mg, 0.86 mmol, yield 73%).

Step 4

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

Step 5

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

Step 6

To a solution of methyl 17-((4-((1R,5S)-3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoate (325 mg, 0.52 mmol) and (2-hydroxyphenyl)boronic acid (93 mg, 0.68 mmol) in dioxane (12 mL) and water (1.2 mL) was added cesium carbonate (542 mg, 1.66 mmol), PdCl2(dppf) (73.2 mg, 0.1 mmol), and t-Bu3PHBF4 (58 mg, 0.2 mmol). The solution was stirred at 100°C for 4 h under nitrogen atmosphere. The pH of the solution was adjusted to 5 with 1N HCl. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 17-((4-((1R,5S)-3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)-3,6,9,12,15-pentaoxaheptadecanoic acid (300 mg), which was used in the next step without further purification.

Step 7

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

1H NMR (400MHz, MeOD): δ 8.74 (s, 1H), 7.68-7.66 (m, 2H), 7.34-7.28 (m, 5H), 7.18-7.10 (m, 1H), 6.80-6.78 (m, 2H), 6.43-6.40 (m, 1H), 6.10 (s, 1H), 4.60-4.20 (m , 9H), 3.92-3.89 (m, 2H), 3.80-3.64 (m, 4H), 3.71-3.45 (m, 16H), 3.10-3.00 (m, 1H ), 3.00-2.90 (m, 2H), 2.37-2.34 (m, 1H), 2.35 (s, 3H), 2.18-1.99 (m, 6H), 0.92 (s, 9H).

Using similar procedures, exemplary compounds 7, 8, 10, and 35 were prepared.

Exemplary Synthesis of Exemplary Compound 6 Step 1

To a solution of 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-ol (3.49 g, 10 mmol) [prepared using a procedure similar to that described for Example A2979] in DCM (50 mL) and H2O (25 mL) was added PhI(OAc)2 (9.66 g, 30 mmol) and TEMPO (312 mg, 2 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (100 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid (3.5 g, 9.64 mmol, yield 96%).

Step 2

To a solution of 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid (3.0 g, 8.26 mmol) in MeOH (30 mL) was added SOCl2 (4.0 g, 33.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The pH of the solution was adjusted to about 8 with saturated NaHCO3. The mixture was extracted with DCM (100 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give methyl 2-(2-(2-(2-((4-bromopyridin-2-yl)oxy)ethoxy)ethoxy)ethoxy)acetate (2.9 g, 7.69 mmol, 93% yield).

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

1H NMR (400 MHz, MeOD): δ 8.82 (s, 1H), 7.76-7.74 (m, 2H), 7.42-7.34 (m, 5H), 7.22-7.18 ( m, 1H), 6.89-6.86 (m, 2H), 6.53-6.52 (m, 1H), 6.16 (s, 1H), 4.66-4.28 (m, 9H) , 4.01-4.00 (m, 2H), 3.82-3.60 (m, 12H), 3.31-3.29 (m, 1H), 3.10-3.08 (m, 2H), 2.51-2.50 (m, 1H), 2.49 (s, 3H), 2.29-2.05 (m, 6H), 2.42-2.29 (m, 2H) , 1.01 (s, 9H).

Exemplary Synthesis of Exemplary Compound 20 Step 1

To a solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (4 g, 14.2 mmol) and Et3N (8.6 g, 85.2 mmol) in DCM (50 mL) was added TsCl (8.1 g, 42.6 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc (100 mL) and water (10 mL). The organic phase was washed with brine (10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis(4-methylbenzenesulfonate) (6.0 g, 10.2 mmol, 72% yield).

Step 2

To a solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diylbis(4-methylbenzenesulfonate) (3.5 g, 5.93 mmol) in anhydrous DMF (20 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.15 g, 5.93 mmol) and Cs2CO3 (3.87 g, 11.86 mmol). The reaction mixture was stirred at 75 °C for 0.5 h. The mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and water (20 mL). The organic phase was washed with brine (20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (0.6 g, 0.98 mmol, yield 16.5%).

Step 3

To a solution of 17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl 4-methylbenzenesulfonate (0.3 g, 0.49 mmol) and (2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (268 mg, 0.49 mmol) in DMF (5 mL) was added K2CO3 (135 mg, 0.98 mmol). The mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was extracted with EA (80 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-((17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl)pi A mixture of pyrrolidine-2-carboxamide and (1-(17-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide)methyl)-5-(4-methylthiazol-5-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)-1H-pyrazol-4-yl)boronic acid (270 mg, 0.27 mmol, 56% yield) was obtained.

Step 4

(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-((17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl)pyrrolidine-2-carboxamide and (1-(17-(2-(((2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-((17-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzyl)pyrrolidine-2-carboxamide in dioxane (20 mL) and water (2 mL). To a mixture of (xoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecyl)-1H-pyrazol-4-yl)boronic acid (270 mg, 0.27 mmol) and a solution of 5-bromo-6-chloropyridazin-3-amine (85 mg, 0.41 mmol) was added cesium carbonate (220 mg, 0.68 mmol), PdCl2(dppf) (40 mg, 0.054 mmol), and t-Bu3PHBF4 (31 mg, 0.11 mmol). The solution was stirred at 100° C. for 4 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (2S,4R)-N-(2-((17-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (175 mg, 0.18 mmol, 67% yield).

Step 5

(2S,4R)-N-(2-((17-(4-(3-amino-6-chloropyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoin) in dioxane (15 mL) and water (1.5 mL). To a solution of (doline-2-yl)butanoyl)pyrrolidine-2-carboxamide (175 mg, 0.18 mmol) and (2-hydroxyphenyl)boronic acid (32 mg, 0.23 mmol) was added cesium carbonate (176 mg, 0.54 mmol), PdCl2(dppf) (53 mg, 0.072 mmol), and t-Bu3PHBF4 (42 mg, 0.144 mmol). The solution was stirred at 100° C. under nitrogen atmosphere for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (2S,4R)-N-(2-((17-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide (24 mg, 0.023 mmol, 13% yield).

1H NMR (400 MHz, MeOD): δ 8.84 (s, 1H), 8.28 (s, 1H), 8.05 (d, J = 12.4 Hz, 2H), 7.38-7.81 (m, 6H), 7.36-7.37 (m, 1H), 6.98-7.00 (m, 2H), 6.92 (d, J=7.6 Hz, 2H), 4.37-4. 59 (m, 9H), 4 . 15-4.16 (m, 2H), 3.83-3.96 (m, 6H), 3.46-3.56 (m, 16H), 2.46 (s, 3H), 2.44 ~2.45 (m, 1H), 2.21-2.22 (m, 1H), 2.09-2.10 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H) , 0.82 (d, J = 6.4 Hz, 3H).

Exemplary compounds 12, 13, and 21 were prepared using procedures similar to those described for exemplary compound 20.

Exemplary Synthesis of Exemplary Compound 14 Step 1

A 250 mL round-bottom flask was charged with a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.73 mmol, 1.00 equiv.), 4-bromo-6-chloropyridazin-3-amine (1.7 g, 8.16 mmol, 1.20 equiv.), Pd(PPh3)4 (800 mg, 0.69 mmol, 0.10 equiv.), and potassium carbonate (2.9 g, 20.98 mmol, 3.00 equiv.) in dioxane/H2O (1:1) (60 mL). The resulting solution was stirred overnight at 100 °C in an oil bath. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This yielded 1.0 g (66%) of 6-chloro-4-(1H-pyrazol-4-yl)pyridazin-3-amine as a white solid.

Step 2

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

Step 3

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

Step 4

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

Step 5

In a 50 mL round-bottom flask, add a solution of 2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate (120 mg, 0.2 mmol, 1.00 equiv.) in N,N-dimethylformamide (5 mL), (2S,4R)-4-hydroxy-1-[2-(3- Hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (130 mg, 0.2 mmol, 1.00 equiv.) [prepared as described by Qian, Y et al. in WO2017/030814], potassium carbonate (100 mg, 0.4 mmol, 2.00 equiv.) were added. The resulting solution was stirred at 70° C. for 12 hours. The resulting solution was extracted with ethyl acetate (20 mL×3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10:1). This gave 90 mg of (2S,4R)-1-[2-[3-(2-[2-[2-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethoxy]ethoxy]ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a colorless oil.

Step 6

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

The product was purified by chiral preparative HPLC using the following conditions: Column, CHIRAL ART Cellulose-SB, 2*25cm, 5um; Mobile phase, Hex--HPLC and Ethanol--HPLC (50% Ethanol--HPLC held for 24min); Detector, UV 220/254nm. This gave 17.8 mg (34%) of (2S,4R)-1-[(2S)-2-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [1H NMR (300 MHz, CD3OD): δ 8.82 (d, J = 11.1 Hz, 1H), 8.29-8.18 (m, 1H), 8.11-7.89 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.48-7.41 (m, 1H), 7.37-7.30 (m, 3H), 7.30-7.19 (m, 1H), 6.95-6.8 3 (m, 2H), 5.89 (s, 1H), 4.59-4.41 (m, 2H), 4.40-4.30 (m, 4H), 4.27-4.11 (m, 2H), 3.86 (q, J = 5.3 Hz, 2H), 3.75-3.59 (m, 6H), 3.56 (s, 3H), 2.42 (d, J = 5.0 Hz, 3H), 2.36-2.10 (m, 2H ), 2.04-2.01 (m, J = 13.1, 8.1, 4.7 Hz, 1H), 1.26 (s, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H)], and 24.4 mg (47%) of (2S,4R)-1-[(2R)-2-(3-[2-[2-(2-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1H-pyrazol-1-yl]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide [1H NMR (300 MHz, CD3OD): δ 8.82 (d, J = 6.6 Hz, 1H), 8.26 (dd, J = 3.1, 0.8 Hz, 1H), 8.10-7.96 (m, 2H), 7.86-7.75 (m, 1H), 7.45-7.30 (m, 4H), 7.25-7.22 (m, 1H), 6.96-6.84 (m, 2H), 5.88 (s, 1H), 4.70-4.42 (m, 3H), 4.41-4.33 (m, 3H), 4.28-4.17 (m , 2H), 3.87 (t, J = 5.0 Hz, 3H), 3.85-3.63 (m, 2H), 3.59-3.57 (m, 6H), 2.41 (d, J = 12.2 Hz, 3H), 2.38-2.33 (m, 1H), 2.25-2.12 (m, 1H), 2.06-2.02 (m, 1H), 1.26 (s, 1H), 0.97 (dd, J = 6.6, 1.8 Hz, 3H), 0.80 (dd, J = 6.6, 1.8 Hz, 3H)] was obtained as a white solid.

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

Exemplary Synthesis of Exemplary Compound 22 Step 1

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

Step 2

A 100 mL round bottom flask was charged with 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]ethan-1-ol (550.0 mg, 2.10 mmol, 1.00 equiv.), acetone (30 mL), Cr2O3 (100.0 mg), sulfuric acid (0.25 mL), and water (1 mL). The resulting solution was stirred at 25°C for 1 h. The resulting solution was diluted with water. The resulting solution was extracted with ethyl acetate and washed with saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This afforded 420 mg (72%) of 2-[3-[3-(benzyloxy)propyl]-1,2-oxazol-5-yl]acetic acid as a yellow oil.

Step 3

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

Step 4

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

Step 5

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

Step 6

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

Step 7

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

Step 8

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

Step 9

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

Step 10

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

Step 11

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

Step 12

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

1H-NMR: (400MHz, CD3OD) δ 8.89-8.83 (m, 1H), 8.31-8.26 (m, 1H), 8.08-8.03 (m, 2H), 7. 85-7.81 (m, 1H), 7.46-7.21 (m, 5H), 6.96-6.87 (m, 2H), 6.15 (s, 1H), 4.52- 4.44 (m, 5H), 4.41-4.31 (m, 3H), 3.91-3.8 0 (m, 2H), 3.72-3.65 (m, 1H), 3.61-3.35 (m, 6H), 2.62-2.51 (m, 2H), 2.45- 2.33 (m, 3H), 2.22-2.15 (m, 1H), 2.10-2.01 (m, 1H), 1.84-1.72 (m, 2H), 1. 30-1.24 (m, 1H), 1.03-0.97 (m, 3H), 0.91-0.75 (m, 3H).

Exemplary Synthesis of Exemplary Compound 23 and Exemplary Compound 24

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

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

Exemplary Synthesis of Exemplary Compound 27 Step 1

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

Step 2

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

Step 3

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

Step 4

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

Step 5

A 10 mL microwave tube purged and maintained under a nitrogen inert atmosphere was charged with 2-[2-[2-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)ethoxy]ethoxy]ethan-1-ol (295 mg, 0.63 mmol, 1.00 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (223 mg, 1.23 mmol, 2.00 equiv.), potassium carbonate (254 mg, 1.84 mmol, 3.00 equiv.), dioxane (4 mL), water (1 mL), and Pd(PPh3)4 (70 mg, 0.06 mmol, 0.10 equiv.). The resulting solution was stirred at 100° C. overnight. The reaction was then quenched by adding water. The resulting solution was extracted with dichloromethane/MeOH and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This gave 221 mg (61%) of 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethan-1-ol as a yellow solid.

Step 6

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

Step 7

In a 50 mL round-bottom flask, add 2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate (87 mg, 0.12 mmol, 1.00 equiv.), N,N-dimethylformamide (54 mg, 0.75 mmol, 1.00 equiv), (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylpyrrolidine-2-carboxamide (79 mg, 0.16 mmol, 2.00 equiv), and Cs2CO3 (5 g, 15.35 mmol, 127.15 equiv). The resulting solution was stirred at room temperature for 4 hours. The resulting solution was extracted with dichloromethane/MeOH and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (5:1). The collected fractions were combined and concentrated under vacuum. This gave 124 mg (99%) of (2S,4R)-1-[2-(3-[2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a yellow solid.

Step 8

A 50 mL round bottom flask was charged with (2S,4R)-1-[2-(3-[2-[2-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (131 mg, 0.13 mmol, 1.00 equiv.), methanol (5 mL), and 1 M HCl in MeOH (1.5 mL). The resulting solution was stirred at room temperature for 7 h. The resulting solution was diluted with 5 mL of H2O. The pH value of the solution was adjusted to 7 with aqueous Na2CO3 (2M). The resulting solution was extracted with dichloromethane and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The crude product was purified by preparative HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (0.05% NH3H2O) and acetonitrile (39.0% acetonitrile, max. 50.0% in 9 min); detector, UV 220nm. This gave 60 mg (48%) of (2S,4R)-1-(2-[3-[2-(2-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a yellow solid which was further purified by chiral preparative HPLC using the following conditions: Column, Chiralpak ID-2, 2*25 cm, 5 um; mobile phase, (0.1% DEA) and ethanol (30% ethanol hold for 30 min); detector, UV 254/220 nm. This gave 13.9 mg (23%) of (2S,4R)-1-[(2S)-2-[3-[2-(2-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [1H NMR (400MHz, CD3OD): δ 8.85 (m, 1H), 7.78-7.72 (m, 2H), 7.47-7.45 (m, 2H), 7.40-7.34 (m, 3H), 7.23-7.22 (m, 1H), 6.92-6.88 (m, 2H), 6.55-6.53 (m, 1H), 6.23 (s, 1H), 5.97 (s, 1H), 4.64- 4.59 (m, 2H), 4.50 (s, 3H), 4.40 (s, 2H), 4.33-4.24 (m, 4H), 3.81-3.79 (m, 2H), 3.75-3.65 (m, 8H), 3.29 (m, 1H), 3.10-3.07 (m, 2H), 2.48-2.46 (m, 3H), 2.23-2.20 (m, 1H), 2.13-2.06 (m, 6H), 3H), 1.05 (s, 1H), 0.90-0.89 (d, J = 6.8 Hz, 3H), 0.78-0.76 (d, J = 8 Hz, 3H)], and 17.9 mg (29%) of (2S,4R)-1-[(2R)-2-[3-[2-(2-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethoxy]ethoxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid [1H NMR (400MHz, CD3OD): δ 8.88 (m, 1H), 7.79-7.75 (m, 2H), 7.49-7.39 (m, 5H), 7.24 (m, 1H), 6.92-6.90 (m, 2H), 6.56-6.54 (m, 1H), 6.25-6.24 (M, 1H), 6.00 (s, 1H), 4.53-4.29 (m, 10H), 3.88-3 . 81 (m, 5H), 3.70-3.63 (m, 6H), 3.33 (m, 2H), 3.14-3.12 (m, 2H), 2.48-2.44 (m, 3H), 2.42-2.29 (m, 1H), 2.25-2.12 (m, 6H), 1.04-1.02 (d, J = 6.4 Hz, 3H), 0.88-0.86 (d, J = 6.4 Hz, 3H).

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

Exemplary Synthesis of Exemplary Compound 31 Step 1

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

Step 2

A 10 mL microwave tube purged and maintained under nitrogen inert atmosphere was charged with 2-[2-(prop-2-yn-1-yloxy)ethoxy]oxane (2.8 g, 15.20 mmol, 1.00 equiv.), ZrCp2HCl (390 mg, 0.10 equiv.), triethylamine (153 mg, 1.52 mmol, 0.10 equiv.), and pinacolborane (2.5 mL). The resulting solution was stirred overnight at 68°C in an oil bath. The reaction was then quenched by adding NH4Cl. The reaction mixture was cooled to 0°C in a water/ice bath. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated under vacuum. This yielded 3.01 g (63%) of 4,4,5,5-tetramethyl-2-[(1E)-3-[2-(oxan-2-yloxy)ethoxy]prop-1-en-1-yl]-1,3,2-dioxaborolane as a yellow liquid.

Step 3

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

Step 4

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

Step 5

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

Step 6

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

Step 7

A 50 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with 2-(3-[4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]propoxy)ethan-1-ol (650 mg, 1.55 mmol, 1.00 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (566 mg, 3.11 mmol, 2.00 equiv.), dioxane (8 mL), water (2 mL), potassium carbonate (644 mg, 4.66 mmol, 3.00 equiv.), and Pd(PPh3)4 (180 mg, 0.16 mmol, 0.10 equiv.). The resulting solution was stirred in an oil bath at 100 °C for 3 h. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with methanol/HO (85:15). The collected fractions were combined and concentrated under vacuum. This gave 400 mg (50%) of 2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethan-1-ol as a yellow oil.

Step 8

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

Step 9

A 50 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with methyl 2-(6-chloropyridin-3-yl)acetate (500 mg, 2.69 mmol, 1.00 equiv.), tert-butyl piperazine-1-carboxylate (502 mg, 2.70 mmol, 1.00 equiv.), Cs2CO3 (2.63 g, 8.07 mmol, 3.00 equiv.), toluene (10 mL), and RuPhosPd (115 mg, 0.05 equiv.). The resulting solution was stirred overnight in an oil bath at 100°C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This gave 319 mg (35%) of tert-butyl 4-[5-(2-methoxy-2-oxoethyl)pyridin-2-yl]piperazine-1-carboxylate as a yellow solid.

Step 10

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

Step 11

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

Step 12

A 50 mL round bottom flask was charged with methyl 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl)piperazin-1-yl]pyridin-3-yl]acetate (94 mg, 0.13 mmol, 1.00 equiv.), methanol (5 mL), water (2 mL), and LiOH (15 mg, 0.64 mmol, 5.00 equiv.). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with dichloromethane and the aqueous layers were combined and concentrated under vacuum. The residue was dissolved in 10 mL of methanol. The solids were filtered off. The resulting mixture was concentrated under vacuum. This gave 72 mg (78%) of 2-[6-[4-(2-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propoxy]ethyl)piperazin-1-yl]pyridin-3-yl]acetic acid as a yellow solid.

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

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

Exemplary Synthesis of Exemplary Compound 32 Step 1

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

Step 2

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

Step 3

A 50 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with a solution of ethyl 2-[2-[2-(2-[[(4-methylbenzene)sulfonyl]oxy]ethoxy)ethoxy]ethoxy]acetate (1.0 g, 2.56 mmol, 1.20 equiv.), 6-bromopyridin-2-ol (370 mg, 2.13 mmol, 1.00 equiv.), Cs2CO3 (2.1 g, 6.45 mmol, 3.00 equiv.) in N,N-dimethylformamide (20 mL). The resulting solution was stirred at 80° C. for 12 h. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This yielded 800 mg (96%) of ethyl 1-(6-bromopyridin-2-yl)-1,4,7,10-tetraoxadodecane-12-ate as a yellow solid.

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

Exemplary Synthesis of Exemplary Compound 33 Step 1

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

Step 2

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

Step 3

A 250 mL round bottom flask was charged with prop-2-yn-1-ol (10 g, 178.4 mmol, 1.0 equiv), tetrahydrofuran (100.0 mL), sodium hydride (6.4 g, 266.7 mmol, 0.9 equiv), and tert-butyl 2-bromoacetate (28 g, 143.6 mmol, 0.8 equiv). The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by adding 20 mL of aqueous ammonium chloride solution. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with ethyl acetate (30 mL x 3), and the organic layers were combined and concentrated under vacuum. This afforded 24.0 g (90%) of tert-butyl 2-(prop-2-yn-1-yloxy)acetate as a yellow solid.

Step 4

A 250 mL round bottom flask was charged with tert-butyl 2-(prop-2-yn-1-yloxy)acetate (6.6 g, 38.8 mmol, 1.0 equiv), triethylamine (400.0 mg, 3.9 mmol, 0.1 equiv), pinacolborane (20.0 mL), and ZrCp2HCl (1 g, 0.1 equiv). The resulting solution was stirred at 60°C for 12 minutes. The reaction was then quenched by adding 10 mL of ice/water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:5). This gave 5.0 g (43%) of tert-butyl 2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]acetate as a yellow oil.

Step 5

A 10 mL sealed tube was charged with 4-[1-[1-(4-bromophenyl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (300 mg, 0.6 mmol, 1.0 equiv.), tert-butyl 2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]acetate (279 mg, 0.9 mmol, 1.5 equiv.), Pd(PPh3)4 (72 mg, 0.06 mmol, 0.1 equiv.), potassium carbonate (259 mg, 1.9 mmol, 3.0 equiv.), dioxane (4.0 mL), and H2O (1.0 mL). The resulting solution was stirred at 90 °C for 5 h. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 200 mg (56%) of tert-butyl 2-[[(2E)-3-[4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]prop-2-en-1-yl]oxy]acetate as a yellow solid.

Step 6

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

Step 7

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

Step 8

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

1H NMR (300MHz, methanol-d4) δ 8.79 (s, 1H), 8.35-8.23 (m, 1H), 8.09-7.97 (m, 2H), 7.80 (d, J = 7.7 Hz, 1H), 7.43-7.37 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H ), 7.20 (s, 4H), 6.89 (t, J = 7.6 Hz, 2H), 5.64-5.52 (m, 1H), 4.66 (s, 1H), 4. 60-4.44 (m, 3H), 4.27 (d , J = 15.5 Hz, 1H), 3.92 (d, J = 4.6 Hz, 2H), 3.88-3.74 (m, 2H), 3.52 (d, J = 6.2 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.18 (d, J = 7.7 Hz, 1H), 2.07 (dd, J = 9.4, 4.2 Hz, 1H), 1.89 (dd, J = 7.3, 1.2 Hz, 6H), 1.26 (s, 1H), 1.10-0.95 (d, J = 1.6Hz, 9H), 0.95-0.90 (m, 1H).

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

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

Exemplary Synthesis of Exemplary Compound 38 and Exemplary Compound 39 Step 1

A 500 mL round bottom flask was charged with 2-(piperazin-1-yl)ethan-1-ol (26.0 g, 199.7 mmol, 1.0 equiv), dichloromethane (200.0 mL), triethylamine (40.4 g, 399.3 mmol, 2.0 equiv), and benzyl carbonochloridate (40.8 g, 239.2 mmol, 1.2 equiv). The resulting solution was stirred at 0°C for 2 h. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with dichloromethane (100 mL x 3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 22 g (42%) of benzyl 4-(2-hydroxyethyl)piperazine-1-carboxylate as a yellow oil.

Step 2

A 100 mL round bottom flask was charged with benzyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.3 g, 20.1 mmol, 1.0 equiv.) and N,N-dimethylformamide (30.0 mL). This was followed by the addition of sodium hydride (1.6 g, 66.7 mmol, 1.2 equiv.) over 5 min. To this was added 4-bromo-2-fluoropyridine (3.9 g, 22.2 mmol, 1.1 equiv.) over 20 min. The resulting solution was stirred at 0°C for 4 h. The reaction was then quenched by adding 10 mL of aqueous ammonium chloride solution. The resulting solution was extracted with ethyl acetate (50 mL x 3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10:1). This yielded 5.2 g (62%) of benzyl 4-[2-[(4-bromopyridin-2-yl)oxy]ethyl]piperazine-1-carboxylate as a yellow oil.

Step 3

A 250 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with a solution of benzyl 4-[2-[(4-bromopyridin-2-yl)oxy]ethyl]piperazine-1-carboxylate (2.1 g, 5.0 mmol, 1.0 equiv.), RuphosPd II (775.0 mg, 1.0 mmol, 0.2 equiv.), and Cs2CO3 (4.89 g, 15.0 mmol, 3.0 equiv.) in PhMe (100 mL). The resulting mixture was stirred overnight at 100 °C in an oil bath. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic layers were combined and concentrated under reduced pressure, and the residue was applied onto a silica gel column eluting with 100% ethyl acetate. This gave 670 mg (32%) of tert-butyl 8-[2-(2-[4-[(benzyloxy)carbonyl]piperazin-1-yl]ethoxy)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow solid.

Step 4

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

Step 5

A 10 mL sealed tube was charged with benzyl 4-[2-[(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethyl]piperazine-1-carboxylate hydrochloride (200.0 mg, 0.4 mmol, 1.0 equiv.), 4-bromo-6-chloropyridazin-3-amine (137.0 mg, 0.7 mmol, 1.5 equiv.), methyl sulfoxide (3.0 mL), and N,N-diisopropylethylamine (1 mL). The final reaction mixture was irradiated with microwave radiation at 130° C. for 6 h. The reaction was then quenched by adding 1 mL of water. The resulting solution was extracted with ethyl acetate (20 mL×3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10:1). This gave 100 mg (42%) of benzyl 4-[2-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)ethyl]piperazine-1-carboxylate as a brown solid.

Step 6

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

Step 7

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

Step 8

A 100 mL round bottom flask was charged with 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.9 g, 10.0 mmol, 1.00 equiv.), N,N-dimethylformamide (30 mL), ethyl 2-bromo-3-methylbutanoate (2.1 g, 10.0 mmol, 1.0 equiv.), and cesium carbonate (10.0 g, 30.7 mmol, 3.0 equiv.). The resulting solution was stirred at 90° C. for 12 h. The reaction was then quenched by adding 10 mL of water. The resulting solution was extracted with ethyl acetate (20 mL×3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:6). This yielded 3.3 g (93%) of ethyl 3-methyl-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoate as a white solid.

Step 9

A 250 mL round bottom flask was charged with ethyl 3-methyl-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoate (3.0 g, 9.3 mmol, 1.0 equiv.), tetrahydrofuran (30 mL), water (30 mL), and sodium perborate (3.5 g, 23.3 mmol, 2.5 equiv.). The resulting solution was stirred at room temperature for 12 hours. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with ethyl acetate (20 mL x 3), and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This afforded 1740 mg (88%) of ethyl 2-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanoate as a white solid.

Step 10

A 50 mL round bottom flask was charged with ethyl 2-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanoate (3.5 g, 16.5 mmol, 1.0 equiv.), methanol (10 mL), water (10 mL), and sodium hydroxide (2.7 g, 67.5 mmol, 4.0 equiv.). The resulting solution was stirred at room temperature for 12 hours. The pH value of the solution was adjusted to 2 with 2M HCl. The crude product was purified by preparative HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 5 um, 19*150 mm; mobile phase, water (0.1% FA) and acetonitrile (0.0% acetonitrile, max. 4.0% in 2 min, max. 20.0% in 8 min); detector, UV 254 nm. This gave 1.5 g (49%) of 2-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanoic acid as a white oil.

Step 11

A 100 mL round bottom flask was charged with 2-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanoic acid (500 mg, 2.7 mmol, 1.0 equiv.), N,N-dimethylformamide (20 mL), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (900 mg, 2.5 mmol, 0.9 equiv.), DIEA (1.1 g, 8.5 mmol, 3.0 equiv.), and T3P (2.6 g, 1.5 equiv.). The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by adding 5 mL of water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 800 mg (59%) of (2S,4R)-4-hydroxy-1-[2-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a yellow solid.

Step 12

A 5 mL sealed tube was charged with (2S,4R)-4-hydroxy-1-[2-(4-hydroxy-1H-pyrazol-1-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (300 mg, 0.60 mmol, 1.0 equiv.), N,N-dimethylformamide (5.0 mL), 1,2-dibromoethane (222 mg, 1.2 mmol, 2.0 equiv.), and potassium carbonate (250 mg, 1.8 mmol, 3.0 equiv.). The resulting solution was stirred at 70° C. for 12 h. The reaction was then quenched by adding 1 mL of water. The crude product was purified by preparative HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 5um, 19*150mm; mobile phase, water (10mmol/L ammonium bicarbonate) and acetonitrile (35.0% acetonitrile, max 47.0% in 8 min); detector, UV 254nm. This gave 120mg (33%) of (2S,4R)-1-[2-[4-(2-bromoethoxy)-1H-pyrazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a yellow solid.

Step 13

In a 100 mL round bottom flask, add 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[2-(piperazin-1-yl)ethoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (54.6 mg, 0.1 mmol, 1.0 equiv.), acetonitrile (10.0 mL), potassium carbonate (41 mg, 0.30 mmol, 3.0 eq.), sodium iodide (18 mg, 0.1 mmol, 1.2 eq.), (2S,4R)-1-2-[4-(2-bromoethoxy)-1H-pyrazol-1-yl]-3-methylbutanoyl-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazole-5yl)phenyl]ethyl]pyrrolidine-2-carboxamide (60 mg, 0.1 mmol, 1.0 eq.). The resulting solution was stirred at 70° C. for 12 hours. The reaction was then quenched by adding 3 mL of water. The resulting solution was extracted with ethyl acetate (30 mL×3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10/1). This gave 30 mg (29%) of (2S,4R)-1-(2-[4-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethyl]piperazin-1-yl)ethoxy]-1H-pyrazol-1-yl]-3-methylbutanoyl)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a light brown solid.

Step 14

A 25 mL round bottom flask was charged with (2S,4R)-1-[2-(4-[2-[4-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethyl)piperazin-1-yl]ethoxy]-1H-pyrazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (40 mg, 0.04 mmol, 1.0 equiv.), methanol (8 mL), and hydrogen chloride (150 mL). The resulting solution was stirred at room temperature for 6 hours. The reaction was then quenched by adding 1 mL of water. The crude product (5 mL) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 um, 19*150 mm; mobile phase, water (0.1% formic acid) and acetonitrile (13.0% acetonitrile, max 27.0% in 8 min); detector, UV 254 nm. This gave 30 mg (78%) of (2S,4R)-1-(2-[4-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethyl]piperazin-1-yl)ethoxy]-1H-pyrazol-1-yl]-3-methylbutanoyl)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid.

(2S,4R)-1-(2-[4-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethyl]piperazin-1-yl)ethoxy]-1H-pyrazol-1-yl]-3-methylbutanoyl)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide was purified by chiral preparative HPLC using the following conditions: column, Chiralpak IC, 2*25cm, 5um; mobile phase, DCM and methanol (50.0% methanol held at 11 min); detector, UV 220/254nm. This gave 5.6 mg of (2S,4R)-1-[(2R)-2-[4-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethyl]piperazin-1-yl)ethoxy]-1H-pyrazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid [1H NMR (300 MHz, methanol-d4) δ 8.89 (s, 1H), 7.85-7.72 (m, 2H), 7.56-7.36 (m, 6H), 7.31-7.16 (m, 2H), 6.97-6.85 (m, 2H), 6.58 (dd, J = 6.2, 2.2 Hz, 1H), 6.24 (d, J = 2.1 Hz, 1H), 5.05 (q, J = 6.9 Hz, 1H), 4.67 (d, J = 10.6 Hz, 1H), 4.6 0-4.47 (m, 3H), 4.46 (s, 1H), 4.39 (t, J = 5.4 Hz, 2H), 4.06 (t, J = 5.3 Hz, 2H), 3.87 (dd, J = 10.9, 4.2 Hz, 1H), 3.76 (s, 1H), 3.73-3.55 (m, 2H), 3.19-2.99 (m, 2H), 2.92-2.69 (m, 12H), 2.50 (s, 4H), 2.30-2.14 (m, 5H), 1.98 (ddd , J = 13.2, 8.7, 4.6 Hz, 1H), 1.54 (d, J = 7.0 Hz, 3H), 1.41-1.26 (m, 4H), 1.20 (t, J = 7.0 Hz, 2H), 1.08 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 4.1 Hz, 1H)], and 8.1 mg of (2S,4R)-1-[(2S)-2-[4-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)-2-propanediol, 1H], 4-hydroxy-2-(2-hydroxyphenyl)-1-(2-propanediol, 1H)]. [1H-pyrazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide was obtained as a white solid [1H NMR (300 MHz, methanol-d4) δ 8.88 (d, J = 13.8 Hz, 1H), 7.85-7.69 (m, 2H), 7.59-7.30 (m, 6H), 7.32-7.18 (m, 2H), 6.97-6.84 (m, 2H), 6.57 (dd, J = 6.1, 2.1 Hz, 1H), 6.23 (t, J = 2.7 Hz, 1H), 4.99 (q, J = 7.0 Hz, 1H), 4.78 (d, J = 8.8 Hz, 1H), 4.60 (t, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.37 (dd, J = 6.8, 4.1 Hz, 3H), 4.04 (t, J = 5.3 Hz, 2H), 3.64 (p, J = 6.7 Hz, 3H), 3.40-3.24 (m, 1H), 3.11 (dd, J = 15.8, 4.6 Hz, 2H), 2.88-2.64 (m, 12H), 2.49 (d, J = 13.8 Hz, 4H), 2.34-2.10 (m, 6H), 2.06 (s, 1H), 1.95 (td, J = 8.5, 4.2 Hz, 1H), 1.50 (d, J = 7.0 Hz, 3H), 1.33 (td, J = 7.8, 7.4, 4.4 Hz, 5H), 1.20 (t, J = 7.0 Hz, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.93 (q, J = 6.8 Hz, 1H), 0.74 (dd, J = 19.3, 6.7 Hz, 3H)].

Exemplary Synthesis of Exemplary Compound 43 and Exemplary Compound 44 Step 1

A 250 mL round bottom flask was charged with a solution of 2-bromo-4-fluoropyridine (7.8 g, 44.32 mmol, 1.05 equiv.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (9 g, 42.4 mmol, 1.00 equiv.), DIEA (25 g, 193 mmol, 4.00 equiv.) in NMP (120 mL). The resulting solution was stirred at 150 °C for 3 h. The reaction mixture was cooled. The reaction was then quenched by adding water (200 mL). The resulting solution was extracted with ethyl acetate (50 mL x 3) and the organic layers were combined. The resulting mixture was washed with water (50 mL x 1) and brine (50 mL x 1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:2). This yielded 11.7 g (75%) of tert-butyl 8-(2-bromopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow solid.

Step 2

A mixture of [(prop-2-yn-1-yloxy)methyl]benzene (10 g, 68.4 mmol, 1.00 equiv.), pinacolborane (10 mL), ZrCp2HCl (2 g), and triethylamine (850 mg, 8.40 mmol, 0.12 equiv.) was placed in a 250 mL round-bottom flask. The resulting solution was stirred in an oil bath at 65°C for 16 h. The resulting mixture was quenched with water (30 mL) and then extracted with ethyl acetate (50 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine (50 mL x 1). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This yielded 12.5 g (67%) of 2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow solid.

Step 3

A 250 mL round bottom flask purged and maintained under a nitrogen inert atmosphere was charged with tert-butyl 8-(2-bromopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.0 g, 10.9 mmol, 1.00 equiv.), 2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.48 g, 16.3 mmol, 1.50 equiv.), Pd(dppf)2Cl2 dichloromethane (890 mg, 1.09 mmol, 0.10 equiv.), and potassium carbonate (4.5 g, 32.6 mmol, 3.00 equiv.) in dioxane/H2O (80/20 mL). The resulting solution was stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This gave 4.55 g (96%) of tert-butyl 8-[2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow solid.

Step 4

A 250 mL round bottom flask purged and maintained under a nitrogen inert atmosphere was charged with a solution of tert-butyl 8-[2-[(1E)-3-(benzyloxy)prop-1-en-1-yl]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (12.9 g, 29.6 mmol, 1.00 equiv.) in methanol/HOAc (200/0.5 mL). Palladium on carbon (6 g) was added under a nitrogen atmosphere. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated under a hydrogen atmosphere using a hydrogen balloon at 50° C. for 20 hours. The solids were filtered through a celite pad and the filtrate was concentrated under reduced pressure. This yielded 10.2 g (99%) of tert-butyl 8-[2-(3-hydroxypropyl)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a yellow oil.

Step 5

A 100 mL round bottom flask was charged with tert-butyl 8-[2-(3-hydroxypropyl)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (700 mg, 2.01 mmol, 1.00 equiv.) in dichloromethane (30 mL) and Dess-Martin periodinane reagent (1.7 g, 2.00 equiv.) was added at 0-5°C. The resulting solution was stirred at room temperature for 6 h. The resulting mixture was concentrated under vacuum at 15°C. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (5:1). This gave 500 mg (72%) of tert-butyl 8-[2-(3-oxopropyl)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a white solid.

Step 6

A 50 mL round bottom flask was charged with tert-butyl 8-[2-(3-oxopropyl)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.4 g, 4.05 mmol, 1.00 equiv.), benzyl piperazine-1-carboxylate (1.07 g, 4.86 mmol, 1.20 equiv.) in dichloromethane (20 mL). This was stirred for 20 minutes and NaBH(OAc)3 (2.58 g, 12.2 mmol, 3.00 equiv.) was added at 0°C. The resulting solution was stirred at room temperature for 4 hours. The reaction was then quenched by adding water/ice (50 mL). The resulting solution was extracted with dichloromethane (50 mL x 3) and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10/1). This gave 2.19 g (98%) of tert-butyl 8-[2-(3-[4-[(benzyloxy)carbonyl]piperazin-1-yl]propyl)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a pale yellow oil.

Step 7

A 100 mL round bottom flask was charged with tert-butyl 8-[2-(3-[4-[(benzyloxy)carbonyl]piperazin-1-yl]propyl)pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.19 g, 3.98 mmol, 1.00 equiv.) in methanol (20 mL). Hydrogen chloride gas was bubbled through the resulting solution while stirring at room temperature for 1 h. The resulting mixture was concentrated under vacuum. This afforded 1.79 g (92%) of benzyl 4-[3-(4-[3,8-diazabicyclo[3.2.1]octane-8-yl]pyridin-2-yl)propyl]piperazine-1-carboxylate hydrochloride as a pale yellow solid.

Step 8

A 20 mL microwave tube purged and maintained under nitrogen inert atmosphere was charged with benzyl 4-[3-(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propyl]piperazine-1-carboxylate hydrochloride (1.79 g, 3.68 mmol, 1.00 equiv.), 4-bromo-6-chloropyridazin-3-amine (2.47 g, 11.9 mmol, 3.00 equiv.), DIEA (5.0 mL) in DMSO (10 mL). The resulting solution was stirred in an oil bath at 130 °C for 16 h. The reaction was then quenched by adding water/ice (50 mL). The resulting solution was extracted with dichloromethane (50 mL x 3) and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (5/1). This gave 1.21 g (57%) of benzyl 4-(3-[4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]propyl)piperazine-1-carboxylate as a brown solid. According to the scheme below and using the procedures described above for other examples, benzyl 4-(3-[4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]propyl)piperazine-1-carboxylate was converted to 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[3-(piperazin-1-yl)propyl]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (used in step 10).

Step 9

A 50 mL round bottom flask was charged with a solution of (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (480 mg, 1.0 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL), potassium carbonate (300 mg, 2.2 mmol, 2.2 equiv.), and 1,2-dibromoethane (300 mg, 1.6 mmol, 1.6 equiv.). The resulting solution was stirred in an oil bath at 70° C. for 2 hours. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with ethyl acetate (3×30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:0). This gave 235 mg (40%) of (2S,4R)-1-[2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a pale yellow solid.

Step 10

In a 20 mL microwave tube purged and maintained under a nitrogen inert atmosphere, 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[3-(piperazin-1-yl)propyl]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (92 mg, 0.17 mmol, 1.00 equiv.) [benzyl 4-(3-[4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diamine from step 8 according to the scheme below and using the procedures described above for other examples] was added to acetonitrile (10 mL). -diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]propyl)piperazine-1-carboxylate], (2S,4R)-1-2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylpyrrolidine-2-carboxamide (100 mg, 0.17 mmol, 1.00 equiv.), potassium carbonate (70 mg, 0.51 mmol, 3.00 equiv.), and NaI (25 mg, 0.17 mmol, 1.00 equiv.) were added to the reaction mixture. The mixture was stirred at 70° C. in an oil bath for 12 hours. The resulting solution was extracted with dichloromethane (100 mL) and the organic layers were combined. The resulting mixture was washed with brine (30 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 180 mg (crude) of (2S,4R)-1-(2-[3-[2-(4-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propyl]piperazin-1-yl)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a pale yellow solid.

According to the following scheme and using procedures similar to those described above for other examples, (2S,4R)-1-(2-[3-[2-(4-[3-[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]propyl]piperazin-1-yl)ethoxy]-1,2-o The final compound (2S,4R)-1-[(2S)-2-[3-(2-[4-[3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1] octan-8-yl]pyridin-2-yl)propyl]piperazin-1-yl]ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide and (2S,4R)-1-[(2R)-2-[3-(2-[4-[3-(4-[3-[3-amino-6- (2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propyl]piperazin-1-yl]ethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide.

Exemplary Synthesis of Exemplary Compound 40 Exemplary compound 40 was prepared according to the following scheme using procedures described for other examples above, as well as procedures that would be understood by one of skill in the art.

Exemplary Synthesis of Exemplary Compound 41 and Exemplary Compound 42 Exemplary compounds 41 and 42 were prepared according to the following scheme using the procedures described above for the other exemplary compounds.

Exemplary Synthesis of Exemplary Compound 45 Step 1

A 250 mL round-bottom flask was charged with a solution of 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethan-1-ol (1 g, 6.94 mmol, 1.00 equiv.) in dichloromethane (80 mL), triethylamine (2.8 g, 27.67 mmol, 3.00 equiv.), 4-dimethylaminopyridine (270 mg, 2.21 mmol, 0.30 equiv.), and 4-toluenesulfonyl chloride (1.9 g, 9.97 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 12 h. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:2). The collected fractions were combined and concentrated under vacuum. This yielded 1.4 g (68%) of 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate as a yellow oil.

Step 2

A 25 mL sealed tube was charged with a solution of 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate (1.4 g, 4.69 mmol, 1.00 equiv.) in N,N-dimethylformamide (10 mL), potassium carbonate (1.6 g, 11.58 mmol, 3.00 equiv.), sodium iodide (280 mg, 0.50 equiv.), and tert-butyl 2-(piperazin-1-yl)acetate (898 mg, 4.48 mmol, 1.20 equiv.). The resulting solution was stirred in an oil bath at 70° C. for 12 hours. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The resulting mixture was washed with brine and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This gave 910 mg (59%) of tert-butyl 2-(4-[2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl]piperazin-1-yl)acetate as a yellow oil.

Step 3

A 25 mL sealed tube was charged with a solution of tert-butyl 2-(4-[2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl]piperazin-1-yl)acetate (910 mg, 2.79 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL), pinacolborane (630 mg, 2.00 equiv.), ZrCp2HCl (70 mg, 0.10 equiv.), and triethylamine (1 mL, 3.00 equiv.). The resulting solution was stirred in an oil bath at 80°C for 12 h. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This gave 720 mg (57%) of tert-butyl 2-[4-[2-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethoxy)ethyl]piperazin-1-yl]acetate as a yellow oil.

Step 4

A 100 mL round bottom flask was charged with a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 9.42 mmol, 1.00 equiv.) in dimethyl sulfoxide (40 mL), N,N-diisopropylethylamine (714.0 mg, 5.52 mmol, 4.00 equiv.), 4-bromo-6-chloropyridazin-3-amine (3.0 g, 14.39 mmol, 1.50 equiv.). The resulting solution was stirred in an oil bath at 130 °C for 3 h. The reaction was then quenched by adding water (90 mL). The resulting solution was extracted with ethyl acetate (80 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine (100 mL x 1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (10/1). The collected fractions were combined and concentrated under vacuum. This gave 1.7 g (53%) of tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid.

Step 5

A 250 mL three-neck round bottom flask purged and maintained under nitrogen inert atmosphere was charged with a solution of tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.7 g, 5.00 mmol, 1.00 equiv.) in dioxane/water (50/10 mL), potassium carbonate (2.1 g, 15.19 mmol, 3.00 equiv.), (2-hydroxyphenyl)boronic acid (1.04 g, 7.54 mmol, 1.50 equiv.), tetrakis(triphenylphosphine)palladium(0) (578 mg, 0.50 mmol, 0.10 equiv.). The resulting solution was stirred at 100°C in an oil bath for 2 hours. The reaction was then quenched by the addition of water (60 mL). The resulting solution was extracted with ethyl acetate (40 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine (60 mL x 1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10/1). The collected fractions were combined and concentrated under vacuum. This gave 1.62 g (81%) of tert-butyl 3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid.

Step 6

A 250 mL round bottom flask was charged with a solution of tert-butyl 3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.62 g, 4.08 mmol, 1.00 equiv.) in dioxane (50 mL). Hydrogen chloride (gas) was introduced to the above. The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated under vacuum. This afforded 1.2 g (88%) of 2-(6-amino-5-[3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl)phenol hydrochloride as a yellow solid.

Step 7

A 100 mL round bottom flask was charged with a solution of 2-(6-amino-5-[3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl)phenol (400 mg, 1.35 mmol, 1.00 equiv.) in 1-methyl-2-pyrrolidinone (30 mL), N,N-diisopropylethylamine (693 mg, 5.36 mmol, 4.00 equiv.), 2-bromo-4-fluoropyridine (355.0 mg, 2.02 mmol, 1.50 equiv.). The resulting solution was stirred in an oil bath at 130° C. for 2 hours. The reaction was then quenched by adding water (40 mL). The resulting solution was extracted with ethyl acetate (30 mL×3) and the organic layers were combined. The resulting mixture was washed with brine (40 mL×1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (4/1). The collected fractions were combined and concentrated under vacuum. This gave 410 mg (67%) of 2-[6-amino-5-[8-(2-bromopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol as a yellow solid.

Step 8

In a 20 mL sealed tube, add a solution of tert-butyl 2-[4-[2-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethoxy)ethyl]piperazin-1-yl]acetate (628 mg, 1.38 mmol, 1.00 equiv.) in dioxane/water (5:1 mL), tetrakis(triphenylphosphinephosphine) (1R,5S)-8-(2-bromopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol (500 mg, 1.10 mmol, 0.80 equiv.) was added to a 500 mL flask. The resulting solution was stirred in an oil bath at 80° C. for 2 hours. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This yielded 540 mg (56%) of tert-butyl 2-[4-[2-(2-[[(2E)-3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)prop-2-en-1-yl]oxy]ethoxy)ethyl]piperazin-1-yl]acetate as a yellow solid.

Step 9

A 100 mL round bottom flask was charged with a solution of tert-butyl 2-[4-[2-(2-[[(2E)-3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)prop-2-en-1-yl]oxy]ethoxy)ethyl]piperazin-1-yl]acetate (200 mg, 0.29 mmol, 1.00 equiv.) in 2-propanol (30 mL) and PtO2 (10 mg, 0.10 equiv.). The resulting solution was stirred at room temperature under a hydrogen atmosphere for 12 h. The resulting solution was diluted with 50 mL of 2-propanol and then concentrated under vacuum. This yielded 190 mg (95%) of tert-butyl 2-[4-(2-[2-[3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethoxy]ethyl)piperazin-1-yl]acetate as a yellow solid.

Step 10

A 100 mL round bottom flask was charged with a solution of tert-butyl 2-[4-(2-[2-[3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethoxy]ethyl)piperazin-1-yl]acetate (190 mg, 0.27 mmol, 1.00 equiv.) in dioxane (20 mL). Hydrogen chloride (gas) was introduced to the above. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. This gave 160 mg (92%) of 2-[4-(2-[2-[3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethoxy]ethyl)piperazin-1-yl]acetic acid as a yellow solid.

Step 11

In a 100 mL round-bottom flask, add 2-[4-(2-2-[3-(4-3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-ylpyridin-2-yl)propoxy]ethoxyethyl)piperazin-1-yl]acetic acid (160 mg, 0.25 mmol, 1.00 equiv.), N,N-diisopropylethylamine (0.3 m A solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (139 mg, 0.30 mmol, 1.20 equiv.) in acetonitrile (20 mL), and T3P (188 mg, 3.00 equiv.) was charged. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The crude product (100 mL) was purified by preparative HPLC using the following conditions: Column, XBridge Prep C18 OBD column, 5um, 19*150mm; mobile phase, water (10mmol/L ammonium bicarbonate) and acetonitrile (26.0% acetonitrile, max 49.0% in 8min); detector, UV 254nm. This gave 28.5 mg (11%) of (2S,4R)-1-[(2S)-2-[2-[4-(2-[2-[3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)propoxy]ethoxy]ethyl)piperazin-1-yl]acetamide]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide as a white solid.

1H NMR (300MHz, CD3OD): δ 8.88-8.66 (m, 1H), 8.09-7.88 (m, 1H), 7.76-7.57 (m, 1H), 7.52-7.01 (m, 6H), 6.92-6.62 (m, 4H), 4.66-4.21 (m, 6H), 3.94-3.72 (m, 2H), 3.69-3.33 (m, 12H), 3.14-2.89 (m, 4H), 2.81-2.34 (m, 14H), 2.32-1.78 (m, 8H), 1.32-0.74 (m, 12H).

Exemplary Synthesis of Exemplary Compound 46 and Exemplary Compound 47 Step 1

A 50 mL round-bottom flask was charged with a solution of 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (2.0 g, 10.0 mmol, 1.0 equiv.) in N,N-dimethylformamide (20 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (4.1 g, 10.8 mmol, 1.1 equiv.), N,N-diisopropylethylamine (6.0 g, 46.4 mmol, 4.6 equiv.), and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (3.5 g, 9.5 mmol, 1.0 equiv.). The resulting solution was stirred at room temperature for 30 min. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 2.1 g (41%) of (2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a pale yellow solid.

Step 2

A 50 mL round bottom flask was charged with (2S,4R)-4-hydroxy-1-[2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.1 g, 4.1 mmol, 1.0 equiv.) and 48% aqueous hydrogen bromide (15 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum to yield 1.9 g of crude product.

Step 3

A 50 mL round-bottom flask was charged with a solution of (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.9 g, 3.8 mmol, 1.0 equiv.) in CH3CN (20 mL), potassium carbonate (3.5 g, 25.3 mmol, 6.6 equiv.), sodium iodide (800.0 mg, 5.3 mmol, 1.4 equiv.), and 1,2-dibromoethane (1 g, 5.3 mmol, 1.4 equiv.). The resulting solution was stirred overnight at 60 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 1.1 g (48%) of (2S,4R)-1-[2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid.

Step 4

In a 50 mL round bottom flask, add a solution of (2S,4R)-1-[2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (200 mg, 0.3 mmol, 1.0 equiv.) in CH3CN (20 mL), potassium carbonate (400 mg, 2.9 mmol, 8.8 equiv.), sodium iodide (80 mg, 0.53 mmol, 1.6 equiv.), and 6-[2-(methoxymethoxy)phenyl]-4-(8-2-[2-(piperazin-1-yl)ethoxy]pyridin-4-yl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (190 mg, 0.4 mmol, 1.1 equiv.) [prepared as described above for other examples]. The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (5:1). This gave 180 mg (51%) of (2S,4R)-1-[2-(3-[2-[4-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a pale yellow solid.

Step 5

A 50 mL round-bottom flask was charged with a solution of (2S,4R)-1-[2-(3-[2-[4-(2-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]ethyl)piperazin-1-yl]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (180 mg, 0.17 mmol, 1.0 equiv.) in methanol (5 mL) and hydrogen chloride (0.068 mL of a 4 M solution in dioxane, 0.27 mmol, 1.6 equiv.). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by chiral preparative HPLC using the following conditions: Column; Mobile phase, Column: CHIRALPAK ID-03, 2.0 cm I.D*25 cm L (5 um); Mobile phase A: MTBE (0.2% IPA)--HPLC, Mobile phase B: Methanol--HPLC, Flow rate: 18 mL/min, Gradient: 50B to 50B in 18 min, 254/220 nm. This gave 46.7 mg of (2S,4R)-1-[(2S)-2-[3-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]ethyl]piperazin-1-yl)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid [1H NMR (300 MHz, DMSO-d6) δ 14.10 (s, 1H), 8.99-8.83 (m, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.92-7.83 (m, 2H), 7.75-7.12 (m, 6H), 6.81 (td, J = 8.4, 2.2 Hz, 2H), 6.49 (dd, J = 6.1, 2.0 Hz, 1H), 6.15-5.93 (m, 4H), 5.06 (d, J = 3.6H z, 1H), 4.98-4.79 (m, 1H), 4.38 (t, J = 7.7 Hz, 3H), 4.19 (dt, J = 21.0, 5.6 Hz, 5H), 3.98 (m, 1H), 3.71 (d, J = 8.6 Hz, 2H), 3.57-3.34 (m, 2H), 3.33-3.15 (m, 2H), 2.97 (d, J = 11.6 Hz, 4H), 2.57-2.40 (d, J = 8.0 Hz, 11H), 2.3 1-2.07 (m, 1H), 2.06-1.97 (m, 2H), 1.91-1.66 (m, 3H), 1.42 (d, J = 7.0 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H), 0.92-0.67 (m, 6H)], and 54.4 mg of (2S,4R)-1-[(2R)-2-[3-[2-(4-[2-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazinyl] ... [1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid [1H NMR (300 MHz, DMSO-d6) δ 14.11 (s, 1H), 8.95 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 7.88-7.75 (d, J = 5.9 Hz, 2H), 7.49-7.28 (m, 6H), 7.18 (ddd, J = 8.3, 7.0, 1.6 Hz, 1H), 6.88-6.75 (m, 2H), 6.49 (dd, J = 6.2, 2.0 Hz, 1H), 6.16-6.02 (m, 2H), 5.93 (s, 2H), 5.05 (d, J = 3.7 Hz, 1H), 5.00-4.81 (m, 1H), 4.46 (s, 2H), 4.39-4.13 (m , 6H), 3.72-3.55 (m, 2H), 3.45-3.35 (m, 1H), 3.21 (d, J = 11.7 Hz, 2H), 2.98 (d, J = 11.6 Hz, 2H), 2.59 (q, J = 6.5 Hz, 4H), 2.42 (s, 6H), 2.17 (dd, J = 20.0, 8.3 Hz, 3H), 1.94 (s, 4H), 1.75 (t, J = 9.6 Hz, 1H), 1.37 (dd, J = 20.9, 7.0 Hz, 3H), 1.17 (d, J = 14.9 Hz, 1H), 1.05-0.87 (m, 3H), 0.77 (dd, J = 10.6, 6.7 Hz, 3H)].

Exemplary Synthesis of Exemplary Compound 48 Step 1

A 100 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with methyl 2-(6-chloropyridin-3-yl)acetate (1.86 g, 10.0 mmol, 1.00 equiv), toluene (50 mL), Cs2CO3 (10.0 g, 30.0 mmol, 3.00 equiv), 1-benzylpiperazine (2.11 g, 12.0 mmol, 1.2 equiv), and RuPhosPd (0.39 g, 0.05 equiv). The resulting solution was stirred in an oil bath at 100 °C for 10 h. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (100 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (v:v = 1/3). This yielded 1.1 g (32%) of methyl 2-[6-(4-benzylpiperazin-1-yl)pyridin-3-yl]acetate as a yellow solid.

Step 2

A 100 mL three-necked round bottom flask purged and maintained under nitrogen inert atmosphere was charged with tetrahydrofuran (30 mL), lithium aluminum hydride (0.34 g, 3.00 equiv.). Following this, a solution of methyl 2-[6-(4-benzylpiperazin-1-yl)pyridin-3-yl]acetate (1.0 g, 3.01 mmol, 1.00 equiv.) in tetrahydrofuran (5 mL) was added dropwise with stirring at 0°C for 5 minutes. The resulting solution was stirred at 25°C for 10 hours. The reaction was then quenched by adding water (3 mL), aqueous sodium hydroxide (5%), water (3 mL) with stirring at 0°C. The solid was collected by filtration. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (v:v=1:10). This yielded 750 mg (81%) of 2-[6-(4-benzylpiperazin-1-yl)pyridin-3-yl]ethan-1-ol as a pale yellow solid.

Step 3

A 50 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with 2-[6-(4-benzylpiperazin-1-yl)pyridin-3-yl]ethan-1-ol (750 g, 2.5 mmol, 1.00 equiv.), N,N-dimethylformamide (20 mL), sodium hydride (60%) (200 mg, 8.4 mmol, 2.00 equiv.) at 0°C. The resulting solution was stirred at 0°C for 0.5 h. Following this, 3-bromoprop-1-yne (390 mg, 3.3 mmol, 1.30 equiv.) was added dropwise with stirring at 0°C. The resulting solution was allowed to react with stirring at 25°C for an additional 12 h. The reaction was then quenched by adding water (20 mL) at 0°C. The resulting solution was extracted with ethyl acetate (20 mL x 2) and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (v:v=1:3). This gave 602 mg (71%) of 1-benzyl-4-[5-[2-(prop-2-yn-1-yloxy)ethyl]pyridin-2-yl]piperazine as a yellow oil.

Step 4

In a 25 mL sealed tube purged and maintained under nitrogen inert atmosphere, 1-benzyl-4-[5-[2-(prop-2-yn-1-yloxy)ethyl]pyridin-2-yl]piperazine (1.0 g, 3.00 mmol, 1.00 equiv.), tetrahydrofuran (15 mL), pinacolborane (2 mL), ZrCp2HCl (0.077 g, 0.10 equiv.), triethylamine (0.030 g, 0.10 equiv.) were placed. The resulting solution was stirred in an oil bath at 70°C for 12 hours. The reaction was then quenched by adding water (5 mL). The resulting solution was extracted with ethyl acetate (10 mL x 2) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This gave 1.05 g (75%) of 1-benzyl-4-[5-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazine as an orange oil.

Step 5

A 100 mL round bottom flask was charged with 1-benzyl-4-[5-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazine (928 mg, 2.00 mmol, 1.00 equiv.), dichloromethane (25 mL). This was followed by the dropwise addition of 1-chloroethyl chloroformate (568.0 mg, 3.97 mmol, 2.00 equiv.) with stirring at 0°C. The resulting solution was stirred at 25°C for 1 hour. The resulting mixture was concentrated under vacuum. Ethyl alcohol (5 mL) was added. The resulting solution was allowed to react with stirring for an additional 2 hours while the temperature was maintained at 80°C in an oil bath. The resulting mixture was concentrated under vacuum. This gave 0.71 g (95%) of 1-[5-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazine as a yellow oil.

Step 6

A 100 mL three-neck round bottom flask purged and maintained under nitrogen inert atmosphere was charged with N-(2-aminoethyl)-N-(2-chloroethyl)-5-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-amine (410 mg, 1.00 mmol, 1.00 equiv.) in dichloromethane and N,N-diisopropylethylamine (645 mg, 4.99 mmol, 5.00 equiv.), and tert-butyl 2-bromoacetate (585 mg, 3.00 mmol, 3.00 equiv.). The resulting solution was stirred at 25°C for 12 hours. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This yielded 0.32 g (66%) of tert-butyl 2-[4-[5-(2-[[(2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazin-1-yl]acetate as a yellow oil.

Step 7

In a 25 mL sealed tube purged and maintained under a nitrogen inert atmosphere, 2-6-amino-5-[8-(2-bromopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-ylphenol (158 mg, 0.35 mmol, 1.00 equiv.) in dioxane/water (v:v=4:1) was added to prepare tert-butyl 2-[4-[5-(2-[[(2 E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazin-1-yl]acetate (205 mg, 0.42 mmol, 1.20 equiv.), potassium carbonate (145 mg, 1.05 mmol, 3.00 equiv.), and Pd(dppf)Cl2 (12 mg, 0.02 mmol, 0.05 equiv.) were added. The resulting solution was stirred at 80° C. in an oil bath for 3 hours. The reaction mixture was cooled to 25° C. Then, the reaction was quenched by adding water (5 mL). The resulting solution was extracted with ethyl acetate (20 mL×2) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (v:v=10:1). This yielded 0.16 g (63%) of tert-butyl 2-[4-[5-(2-[[(2E)-3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazin-1-yl]acetate as a pale yellow solid.

Using the procedures described above for the other examples, as well as procedures that would be understood by one of skill in the art, tert-butyl 2-[4-[5-(2-[[(2E)-3-(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)prop-2-en-1-yl]oxy]ethyl)pyridin-2-yl]piperazin-1-yl]acetate was converted to the final compound (2S ,4R)-1-((2S)-2-(2-(4-(5-(2-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)propoxy)ethyl)pyridin-2-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

Exemplary Synthesis of Exemplary Compound 49 Step 1

A 100 mL round bottom flask was charged with benzyl 3-hydroxyazetidine-1-carboxylate (3.11 g, 15.01 mmol, 1.00 equiv.), dichloromethane (30 mL), tert-butyl 2-bromoacetate (4.37 g, 22.40 mmol, 1.50 equiv.), sodium hydroxide (37% in water) (30 mL), and TBAC (4.17 g, 1.00 equiv.) at 0°C. The resulting solution was stirred at 25°C for 3 hours. The resulting solution was extracted with dichloromethane (2 x 30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/5). This gave 3.6 g (75%) of benzyl 3-[2-(tert-butoxy)-2-oxoethoxy]azetidine-1-carboxylate as a colorless oil.

Step 2

A 250 mL round bottom flask was charged with benzyl 3-[2-(tert-butoxy)-2-oxoethoxy]azetidine-1-carboxylate (3.22 g, 10.02 mmol, 1.00 equiv), ethanol (100 mL), and palladium on carbon (0.322 g). The resulting solution was stirred at 25°C under an H2 atmosphere for 12 h. The solids were collected by filtration. The resulting mixture was concentrated under vacuum. This gave 1.75 g (93%) of tert-butyl 2-(azetidin-3-yloxy)acetate as a colorless oil.

Step 3

A 50 mL round bottom flask was charged with tert-butyl 2-(azetidin-3-yloxy)acetate (374 mg, 2.00 mmol, 1.00 equiv), N,N-dimethylformamide (15 mL), potassium carbonate (828 mg, 5.99 mmol, 3.00 equiv), and 1,2-dibromoethane (1.86 g, 9.90 mmol, 5.00 equiv). The resulting solution was stirred at 25°C for 12 hours. The reaction was then quenched by adding water (10 mL). The resulting solution was extracted with ethyl acetate (2 x 20 mL) and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/3). This gave 80 mg (14%) of tert-butyl 2-[[1-(2-bromoethyl)azetidin-3-yl]oxy]acetate as a colorless oil.

Using procedures described above for other examples, as well as procedures that would be apparent to one of skill in the art, tert-butyl 2-[[1-(2-bromoethyl)azetidin-3-yl]oxy]acetate was converted to the final compound (2S,4R)-1-((2S)-2-(2-((1-(2-(4-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)propyl)piperazin-1-yl)ethyl)azetidin-3-yl)oxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

Exemplary Synthesis of Exemplary Compound 51 Exemplary compound 51 was prepared according to the following scheme using procedures from the examples described above (e.g., exemplary compound 37) and procedures understood by one of skill in the art.

Exemplary Synthesis of Exemplary Compound 52 Exemplary compound 52 was prepared according to the following scheme.

Exemplary Synthesis of Exemplary Compound 53 Exemplary compound 53 was prepared according to the following scheme.

Exemplary Synthesis of Exemplary Compound 54 and Exemplary Compound 55 Step 1

A 100 mL round bottom flask was charged with 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (2.1 g, 10.5 mmol, 1.00 equiv.), ethanol (20.0 g, 434 mmol, 41.2 equiv.), and sulfuric acid (2.0 g, 20.4 mmol, 1.9 equiv.). The resulting solution was stirred in an oil bath at 70° C. for 12 hours. The resulting mixture was concentrated under vacuum. This afforded 1.9 g (79%) of ethyl 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoate as a white solid.

Step 2

A 50 mL round bottom flask was charged with ethyl 2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoate (1.9 g, 8.4 mmol, 1.0 equiv.) and sulfuryl chloride (20 mL). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This gave 1.5 g (69%) of ethyl 2-(4-chloro-3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoate as a yellow oil.

Step 3

A 50 mL round bottom flask was charged with a solution of ethyl 2-(4-chloro-3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoate (1.5 g, 5.7 mmol, 1.0 equiv.) in methanol/H2O (5/5 mL) and lithium hydroxide (300 mg, 12.5 mmol, 2.2 equiv.). The resulting solution was stirred overnight at 50 °C in an oil bath. The pH value of the solution was adjusted to 6 with 1 M HCl. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined and concentrated under vacuum. The crude product was purified by preparative HPLC with the following conditions: Column; Mobile phase, Column: XBridge Prep C18 OBD Column, 5um, 19*150mm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN, Flow rate: 20mL/min, Gradient: 34%B to 48%B in 8min, 220nm. This gave 300mg (22.4%) of 2-(4-chloro-3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid as a white solid.

Step 4

A 50 mL round-bottom flask was charged with a solution of 2-(4-chloro-3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoic acid (260 mg, 1.1 mmol, 1.0 equiv.) in N,N-dimethylformamide (20 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360 mg, 1.0 mmol, 0.9 equiv.), N,N-diisopropylethylamine (350 mg, 2.7 mmol, 2.4 equiv.), and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (350 mg, 1.1 mmol, 1.0 equiv.). The resulting solution was stirred at room temperature for 30 min. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 275 mg (45%) of (2S,4R)-1-[2-(4-chloro-3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a white solid.

Step 5

A 50 mL round bottom flask was charged with (2S,4R)-1-[2-(4-chloro-3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (275 mg, 0.5 mmol, 1.0 equiv.) and a 4 M solution of hydrogen chloride in dioxane (25 mL). The resulting solution was stirred in an oil bath at 60 °C for 96 h. The resulting mixture was concentrated under vacuum. This gave 259 mg (97%) of (2S,4R)-1-[2-(4-chloro-3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide as a yellow solid.

According to the following scheme and using the procedures described for the preceding examples above, (2S,4R)-1-[2-(4-chloro-3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide was synthesized into the final compound (2S,4R)-1-((2S)-2-(3-(2-(4-(2-((4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)ethyl)piperazin-1-yl)ethoxy)-4-chloroisoxazol- and (2S,4R)-1-((2R)-2-(3-(2-(4-(2-((4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)ethyl)piperazin-1-yl)ethoxy)-4-chloroisoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

Exemplary Synthesis of Exemplary Compound 56 Step 1

A 250 mL round bottom flask was charged with a solution of 3-(benzyloxy)cyclobutan-1-one (6.0 g, 34.05 mmol, 1.0 equiv) in ethanol (100 mL). This was followed by the addition of sodium borohydride (1.25 g, 33.94 mmol, 1.00 equiv) in portions at 0° C. The resulting solution was stirred at 0° C. for 3 hours. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (50 mL×2) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This afforded 6.0 g (99%) of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol as a pale yellow oil.

Step 2

A 500 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with a solution of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol (8.0 g, 44.89 mmol, 1.10 equiv.) in N,N-dimethylformamide (100 mL). Sodium hydride (60%) (2.15 g, 89.58 mmol, 1.20 equiv.) was then added in portions at 0°C. To this was added 4-bromo-2-fluoropyridine (70.0 g, 39.78 mmol, 1.00 equiv.). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding water/ice. The resulting solution was extracted with ethyl acetate (80 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine (80 mL x 2). The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This gave 7.0 g (53%) of 4-bromo-2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridine as a pale yellow oil.

Step 3

A 500 mL round bottom flask purged and maintained under a nitrogen inert atmosphere was charged with a solution of 4-bromo-2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridine (8.4 g, 25.13 mmol, 1.30 equiv.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.11 g, 19.36 mmol, 1.00 equiv.), sodium tert-butoxide (3.2 g, 33.2 mmol, 1.5 equiv.), Xantphos (2.32 g, 4.01 mmol, 0.20 equiv.), and Pd2(dba)3CH2Cl2 (430.0 mg, 0.40 mmol, 0.02 equiv.) in toluene (200 mL). The resulting solution was stirred at 100 °C overnight. The reaction was then quenched by adding water (100 mL). The resulting solution was extracted with ethyl acetate (80 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine (100 mL x 2). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/hexane (1:1). This gave 8.0 g (89%) of tert-butyl 8-[2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a pale yellow oil.

Step 4

To a solution of tert-butyl 8-[2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (7.0 g, 15.03 mmol, 1.00 equiv.) in 150 mL of ethanol, palladium hydroxide (7.0 g, 49.85 mmol, 3.32 equiv.) and acetic acid (2 mL) were added in a 250 mL round-bottom flask under nitrogen atmosphere. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated under hydrogen atmosphere using a hydrogen balloon at 50° C. for 3 days, then filtered through a celite pad and concentrated under reduced pressure. This yielded 5.4 g (96%) of tert-butyl 8-[2-[(1s,3s)-3-hydroxycyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a pale yellow oil.

Step 5

A 100 mL round bottom flask was charged with a solution of tert-butyl 8-[2-[(1s,3s)-3-hydroxycyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.0 g, 13.32 mmol, 1.00 equiv.) in a mixture of ethyl acetate and methanol (10:1) (50 mL). Hydrogen chloride (gas) was passed through the solution. The resulting mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. This gave 4.0 g (96%) of (1s,3s)-3-[(4-[3,8-diazabicyclo[3.2.1]octane-8-yl]pyridin-2-yl)oxy]cyclobutan-1-ol hydrochloride as an off-white solid.

Step 6

A 20 mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen was charged with a solution of (1s,3s)-3-[(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]cyclobutan-1-ol hydrochloride (1.0 g, 3.21 mmol, 1.00 equiv.) in dimethylsulfoxide (10 mL). N,N-diisopropylethylamine (5 mL) and 4-bromo-6-chloropyridazin-3-amine (3.01 g, 14.44 mmol, 4.00 equiv.) were then added. The resulting solution was stirred at 130° C. for 16 hours. The reaction was then quenched by adding water (50 mL). The resulting solution was extracted with ethyl acetate (3×30 mL) and the organic layers were combined. The resulting mixture was washed with brine (3×50 mL). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 490 mg (38%) of (1s,3s)-3-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)cyclobutan-1-ol as a yellow oil.

Step 7

A 20 mL pressure tank reactor purged and maintained under a nitrogen inert atmosphere was charged with a solution of (1s,3s)-3-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)cyclobutan-1-ol (800 mg, 1.99 mmol, 1.00 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (544 mg, 2.99 mmol, 1.50 equiv.), potassium carbonate (824 mg, 6.0 mmol, 3.00 equiv.), and Pd(PPh3)4 (230 mg, 0.20 mmol, 0.10 equiv.) in a mixed solvent (15 mL) of dioxane and water (4:1). The resulting solution was stirred at 90° C. for 2 h. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (50 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine (50 mL x 2). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 820 mg (82%) of (1s,3s)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutan-1-ol as a yellow solid.

Step 8

A 50 mL three-neck round bottom flask purged and maintained under an inert atmosphere was charged with a solution of triphenylphosphine (351 mg, 1.34 mmol, 2.00 equiv.) in tetrahydrofuran (distilled) (30 mL). This was followed by the dropwise addition of diisopropyl azodicarboxylate (270 mg, 1.34 mmol, 2.00 equiv.) with stirring at 0° C., resulting in the appearance of a white precipitate. To this was added (1s,3s)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutan-1-ol (338 mg, 0.67 mmol, 1.00 equiv.) and 6-bromopyridin-3-ol (232 mg, 1.33 mmol, 1.50 equiv.) at 0° C. The resulting solution was stirred at 50° C. overnight. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10:1). This gave 389 mg (88%) of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-bromopyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine as a yellow solid.

Step 9

In a 20 mL pressure tank reactor purged and maintained under a nitrogen inert atmosphere, 155 mg of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-bromopyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine in a mixture of dioxane and water (3:1) (8 mL) was added. A solution of 3-(2,4-dioxaborolan-2-yl, 0.23 mmol, 1.00 equiv.), tert-butyldimethyl{[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy}silane (140 mg, 0.47 mmol, 2.00 equiv.), potassium carbonate (95 mg, 0.69 mmol, 0.15 equiv.), Pd(PPh3)4Cl2CH2Cl2 (28 mg, 0.03 mmol, 2.00 equiv.) was charged. The resulting solution was stirred at 80° C. for 1 h. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate (30 mL×3) and the organic layers were combined. The resulting mixture was washed with brine (30 mL×2). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 130 mg (74%) of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-[3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]pyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine as a pale yellow oil.

Step 10

A 25 mL round bottom flask was charged with a solution of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-[3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]pyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (120 mg, 0.16 mmol, 1.00 equiv.) in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (1 M in tetrahydrofuran) (3.2 mL, 2.00 equiv.). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). The crude product was further purified by flash preparative HPLC (CombiFlash®-1) using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% ACN increasing to 40% ACN within 30 min; detector, UV 220 nm. This gave 70 mg (69%) of 3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-ol as a pale yellow solid.

Step 11

A 50 mL three-neck round bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with a solution of tributylphosphine (149 mg, 0.74 mmol, 10.00 equiv.) in tetrahydrofuran (20 mL). This was followed by the dropwise addition of a solution of tetramethylazodicarboxamide (126 mg, 0.73 mmol, 10.00 equiv.) in tetrahydrofuran (5 mL) at -5°C with stirring. To this mixture was added (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (42 mg, 0.09 mmol, 1.20 equiv.) and (2E)-3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-ol (47 mg, 0.07 mmol, 1.00 equiv.). The resulting solution was stirred at 50° C. overnight. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate (30 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine (50 mL). The organic phase was evaporated under reduced pressure and applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 32 mg (39%) of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-[3-methyl-2-(3-[[(2E)-3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-yl]oxy]-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide as a pale yellow solid.

Step 12

A 25 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with a solution of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-(3-methyl-2-[3-[(3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-yl)oxy]-1,2-oxazol-5-yl]butanoyl)pyrrolidine-2-carboxamide (23 mg, 0.02 mmol, 1.00 equiv.) in methanol (3 mL) and 37% hydrochloric acid (1.5 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. with a water/ice bath. The pH value of the solution was adjusted to 7 with NH4HCO3. The resulting solution was extracted with dichloromethane (30 mL×3) and the organic layers were combined. The resulting mixture was washed with brine (50 mL×3). The mixture was dried over anhydrous sodium sulfate. The crude product was purified by preparative HPLC with the following conditions: column, XBridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, water (10 mmol/L NH4HCO3) and ACN (41.0% ACN, max. 62.0% in 8 min); detector, UV 254 nm. This gave 8.1 mg (37%) of (2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-1-(3-methyl-2-[3-[(3-[5-[(1r,3r)-3-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-yl)oxy]-1,2-oxazol-5-yl]butanoyl)pyrrolidine-2-carboxamide as a pale yellow solid.

Exemplary Synthesis of Exemplary Compound 57 Exemplary compound 57 was prepared according to the following scheme using the procedures described above for the production of other exemplary compounds.

Exemplary Synthesis of Exemplary Compound 47 Step 1

To a solution of 2-piperazin-1-ylethanol (60 g, 460 mmol, 1 eq.), sodium bicarbonate (116 g, 1.38 mol, 3 eq.) in dioxane (300 mL) and water (300 mL), benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (137 g, 553 mmol, 1.2 eq.) was added at 0°C. The reaction mixture was then stirred at 20°C for 2 hours. The reaction mixture was diluted with water (300 mL) and then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate:methanol = 500:1 to 100:1). The compound benzyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (74 g, 279 mmol, 60% yield) was obtained as a pale yellow oil.

Step 2

To a solution of sodium hydride (6.26 g, 156 mmol, 1.3 equiv.) in dimethylformamide (240 mL), benzyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (35 g, 132 mmol, 1.1 equiv.) was added at 0°C for 0.5 h. Then, 4-bromo-2-fluoro-pyridine (21.18 g, 120 mmol, 1 equiv.) was added into the reaction and stirred at 25°C for 1 h. The reaction mixture was quenched by adding saturated ammonium chloride solution (500 mL) and then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (dichloromethane:methanol = 1:0 to 200:1). The compound benzyl 4-[2-[(4-bromo-2-pyridyl)oxy]ethyl]piperazine-1-carboxylate (39.2 g, 92 mmol, 76% yield) was obtained as a pale yellow solid.

Step 3

A vial was charged with benzyl 4-[2-[(4-bromo-2-pyridyl)oxy]ethyl]piperazine-1-carboxylate (18.15 g, 43 mmol, 1 eq.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (11 g, 51 mmol, 1.2 eq.), [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (1.68 g, 2.16 mmol, 0.05 eq.), cesium carbonate (28.14 g, 86.36 mmol, 2 eq.) and added to toluene (350 mL). The mixture was purged with nitrogen for 5 minutes and then heated to 110° C. for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1 to 0:1). Tert-butyl 8-[2-[2-(4-benzyloxycarbonylpiperazin-1-yl)ethoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (18.37 g, 31.30 mmol, 72% yield) was obtained as a pale yellow solid.

Step 4

To a mixture of tert-butyl 8-[2-[2-(4-benzyloxycarbonylpiperazin-1-yl)ethoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (18.3 g, 33.17 mmol, 1 eq.) in methanol (150 mL) was added hydrochloric acid/methanol (4 M, 360 mL, 43.41 eq.). The reaction mixture was then stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the compound without purification. Compound benzyl 4-[2-[[4-(3,8-diazabicyclo[3.2.1]octane-8-yl)-2-pyridyl]oxy]ethyl]piperazine-1-carboxylate (19 g, crude) was obtained as a yellow solid.

Step 5

To a mixture of benzyl 4-[2-[[4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-pyridyl]oxy]ethyl]piperazine-1-carboxylate (19 g, 42.08 mmol, 1 eq.), 4-bromo-6-chloro-pyridazin-3-amine (10.52 g, 50.49 mmol, 1.2 eq.) in dimethyl sulfoxide (190 mL), diisopropylethylamine (54.38 g, 420.76 mmol, 10 eq.) was added. The reaction mixture was then stirred at 130° C. for 5 hours. The reaction mixture was quenched by adding water (600 mL), then diluted with ethyl acetate (150 mL) and extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (150 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1:1 to dichloromethane:methanol = 50:1). The compound benzyl 4-[2-[[4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]ethyl]piperazine-1-carboxylate (12.6 g, 21 mmol, 50% yield) was obtained as a pale yellow solid.

Step 6

To a mixture of benzyl 4-[2-[[4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]ethyl]piperazine-1-carboxylate (10.6 g, 18.30 mmol, 1 eq.), (2-hydroxyphenyl)boronic acid (5.05 g, 36.61 mmol, 2 eq.) in dioxane (160 mL) and water (25 mL), tetrakis[triphenylphosphine]palladium(0) (2.12 g, 1.83 mmol, 0.1 eq.) and potassium carbonate (5.06 g, 36.61 mmol, 2 eq.) were added. The reaction mixture was then stirred at 110°C for 2 hours. The reaction mixture was diluted with water (200 mL) and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (basic conditions: column: Phenomenex Gemini C18 250*50 mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 50%-80%, 20 min 60% min) to give the desired compound. Compound benzyl 4-[2-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]ethyl]piperazine-1-carboxylate (7 g, 10.22 mmol, 55% yield) was obtained as a yellow solid.

Step 7

To a solution of benzyl 4-[2-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]ethyl]piperazine-1-carboxylate (7 g, 10.99 mmol, 1 equiv.) in tetrahydrofuran (100 mL) was added palladium hydroxide on activated carbon catalyst (0.7 g, 0.49 mmol, 0.04 equiv.) under nitrogen. The reaction mixture was then stirred under hydrogen (50 Psi) at 60° C. for 48 hours. 150 mL of ethyl alcohol was then added to the reaction mixture. The reaction mixture was filtered and concentrated under reduced pressure to give 2-[6-amino-5-[8-[2-(2-piperazin-1-ylethoxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol (5 g, 9.68 mmol, 88% yield).

Step 8

To a solution of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (3.5 g, 17.57 mmol, 1 eq.) in N,N-dimethylformamide (40 mL), 2-bromo-1,1-diethoxy-ethane (5.19 g, 26.35 mmol, 1.5 eq.) and potassium carbonate (4.86 g, 35.14 mmol, 2 eq.) were added. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was quenched by adding 50 mL of water, then diluted with 100 mL of water and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with saline (100 mL x 2), 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 = 100:1 to 50:1). The desired compound, methyl 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoate (4.38 g, 12.50 mmol, 71% yield), was obtained as a colorless oil.

Step 9

To a solution of methyl 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoate (4.38 g, 12.5 mmol, 1 equiv.) in methanol (30 mL) and water (15 mL) was added lithium hydroxide monohydrate (2.10 g, 50 mmol, 4 equiv.). The reaction mixture was stirred at 40°C for 2 h. The pH was adjusted to 4-5 with 1 M hydrogen chloride and the reaction mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoic acid (4 g, crude) as a colorless oil.

Step 10

To a solution of 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoic acid (3.84 g, 11.99 mmol, 1 equiv.) in N,N-dimethylformamide (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.47 g, 14.38 mmol, 1.2 equiv.). The reaction mixture was stirred at 20°C for 0.5 h. To the mixture was then added a solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (4.41 g, 11.99 mmol, 1 eq.) and triethylamine (3.64 g, 35.96 mmol, 5 mL, 3 eq.) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 20° C. for 0.15 h. The reaction mixture was quenched by adding water (30 mL), then diluted with water (80 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine (80 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane:methanol=100:1 to 50:1). The desired compound (2S,4R)-1-[2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (7 g, 10.96 mmol, 91% yield) was obtained as a white solid.

Step 11

(2S,4R)-1-[2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (7 g, 11.39 mmol, 1 eq.) was separated by SFC. Conditions were: Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); Mobile phase: [0.1% NH3H2O IPA]; B%: 35%-35%, 2.4 min: 550 min. (2S,4R)-1-[(2S)-2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (3.2 g, 5.08 mmol, 89% yield) and (2S,4R)-1-[(2R)-2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.67 g, 4.17 mmol, 73% yield) were obtained as white solids.

Step 12

To a solution of (2S,4R)-1-[(2R)-2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2 g, 3.25 mmol, 1 eq.) in tetrahydrofuran (40 mL) was added sulfuric acid (1 M, 40 mL, 12.3 eq.). The solution was heated to 50°C for 7 h. The solution was cooled to 20°C and quenched with saturated sodium bicarbonate solution to pH = 8. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated in vacuo. The crude product was used directly in the next step. (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)isoxazol-5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.7 g, 2.52 mmol, 77% yield) was obtained as a white solid.

Step 13

To a solution of (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(2-oxoethoxy)isoxazol-5-yl]butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (930 mg, 1.38 mmol, 1 equiv.) and 2-[6-amino-5-[8-[2-(2-piperazin-1-ylethoxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol (691 mg, 1.38 mmol, 1 equiv.) in methanol (15 mL) and dichloromethane (5 mL), acetic acid (82 mg, 1.38 mmol, 1 equiv.) was added. The solution was stirred at 30°C for 0.5 h. Sodium cyanoborohydride (129 mg, 2.06 mmol, 1.5 equiv) was then added to the solution and stirred for 7 h at 30° C. The solvent was removed in vacuo and the crude product was purified by preparative HPLC (Column: Phenomenex Synergi Max-RP 250*50 mm*10 um; Mobile phase: [Water (10 mM NH4HCO3)-ACN]; B%: 45ACN%-75ACN%, 28 min, 78% min). (2S,4R)-1-[(2R)-2-[3-[2-[4-[2-[[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]ethyl]piperazin-1-yl]ethoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (840 mg, 0.8 mmol, 58% yield, 98% purity) was obtained as a white solid.

Exemplary Synthesis of Exemplary Compounds 59 and 60

Prepared as depicted in the following scheme using the procedures described above for the other examples.

Exemplary Synthesis of Exemplary Compound 61

Step 1

In a 500 mL round bottom flask, to a solution of 1-(6-bromopyridin-3-yl)ethan-1-one (10 g, 49.99 mmol, 1 equiv.) in EtOH (200 mL) was added sodium borohydride (4 g, 105.73 mmol, 2.11 equiv.) in water (80 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:1) to give 1-(6-bromopyridin-3-yl)ethan-1-ol (9.2 g, 91%) as a yellow oil.

Step 2

In a 100 mL round bottom flask, methanesulfonyl chloride (1.3 g, 11.35 mmol, 1.15 equiv.) was added to a solution of 1-(6-bromopyridin-3-yl)ethan-1-ol (2 g, 9.90 mmol, 1 equiv.) and triethylamine (3 g, 0.03 mmol) in dichloromethane (30 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (20 mL x 1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This gave 1-(6-bromopyridin-3-yl)ethyl methanesulfonate (1.6 g, 23%) as a yellow solid.

Step 3

In a 25 mL sealed tube, 1-(6-bromopyridin-3-yl)ethyl methanesulfonate (1.4 g, 1.2 eq.), 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (350 mg, 1 eq.), and potassium carbonate (490 mg, 3.0 eq.) were added to N,N-dimethylformamide (15 mL) at room temperature. The resulting mixture was stirred at 60° C. for 2 hours under nitrogen atmosphere. The aqueous layer was extracted with dichloromethane (50 mL×3). The residue was washed with brine (20 mL×1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with dichloromethane/methyl alcohol (10:1) to obtain 4-[1-[1-(6-bromopyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (90 mg, 16%) as a yellow solid.

Using the procedures described for other examples above, 4-[1-[1-(6-bromopyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine was converted to the final compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 62 Step 1

To a mixture of 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (300 mg, 1.01 mmol, 1 eq.), 1-bromo-2-(2-bromoethoxy)ethane (702 mg, 3.03 mmol, 3 eq.) in dimethylformamide (3 mL), potassium carbonate (418 mg, 3.03 mmol, 3 eq.) was added. The reaction mixture was then stirred at 70°C for 2 h. Water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1). 4-[1-[2-(2-bromoethoxy)ethyl]pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (100 mg, 0.22 mmol, 22% yield) was obtained as a yellow oil.

Step 2

To a solution of 4-[1-[2-(2-bromoethoxy)ethyl]pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (100 mg, 0.22 mmol, 1 eq.) and tert-butyl piperazine-1-carboxylate (83 mg, 0.44 mmol, 2 eq.) in acetonitrile (2 mL), N,N-diisopropylethylamine (86.49 mg, 0.66 mmol, 3 eq.) was added. The reaction mixture was then stirred at 100°C for 12 h. Water (5 mL) was added and the reaction mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1). The compound tert-butyl 4-[2-[2-[4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]pyrazol-1-yl]ethoxy]ethyl]piperazine-1-carboxylate (93 mg, 0.15 mmol, 71% yield) was obtained as a yellow solid.

Using the procedures described for other examples above, tert-butyl 4-[2-[2-[4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]pyrazol-1-yl]ethoxy]ethyl]piperazine-1-carboxylate was converted to the final compound according to the following scheme.

Exemplary compounds 165 and 124 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compound 64

Step 1

To a solution of pyridin-4-ol (3.20 g, 33.66 mmol, 1.5 eq.) and 3-benzyloxycyclobutanol (4 g, 22.44 mmol, 1 eq.) in tetrahydrofuran (200 mL), triphenylphosphine (7.06 g, 26.93 mmol, 1.2 eq.) and diisopropyl azodicarboxylate (5.45 g, 26.93 mmol, 1.2 eq.) were added in one portion under nitrogen at 10 °C. The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (50 mL) was poured into the mixture and stirred for 1 min. The aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 20:1, 5:1). The residue was purified by flash C18 column chromatography [acetonitrile:water (0.5% ammonium hydroxide) = 5% to 50%]. The compound 4-(3-benzyloxycyclobutoxy)pyridine (3.2 g, 12.53 mmol, yield 55%) was obtained as a white solid.

Step 2

To a solution of 4-(3-benzyloxycyclobutoxy)pyridine (4.2 g, 16.45 mmol, 1 equiv.) in toluene (65 mL) was added benzyl bromide (2.81 g, 16.45 mmol, 1 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove toluene. The crude product was triturated with petroleum ether (80 mL). The compound 1-benzyl-4-(3-benzyloxycyclobutoxy)pyridine-1-ium bromide (6.5 g, 15.25 mmol, 92% yield) was obtained as a white solid.

Step 3

To a solution of 1-benzyl-4-(3-benzyloxycyclobutoxy)pyridin-1-ium bromide (6.5 g, 15.25 mmol, 1 equiv.) in ethanol (120 mL) was added sodium borohydride (3.46 g, 91.47 mmol, 6 equiv.) at 0°C. The mixture was stirred at 15°C for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol. The residue was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Compound 1-benzyl-4-(3-benzyloxycyclobutoxy)-3,6-dihydro-2H-pyridine (4.5 g, 12.88 mmol, 84% yield) was obtained as a colorless oil.

Step 4

To a solution of 1-benzyl-4-(3-benzyloxycyclobutoxy)-3,6-dihydro-2H-pyridine (4.5 g, 12.88 mmol, 1 equiv.) in tetrahydrofuran (95 mL) and ethanol (70 mL), palladium-activated carbon catalyst (0.5 g, 10% purity) was added under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 Psi) at 25°C for 24 h and then at 35°C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol:ammonium hydroxide=20:1:0, 10:1:0.1). Compound 3-[(1-benzyl-4-piperidyl)oxy]cyclobutanol (2.8 g, 10.71 mmol, 83% yield) was obtained as a colorless oil.

Step 5

To a solution of 3-[(1-benzyl-4-piperidyl)oxy]cyclobutanol (1.1 g, 4.21 mmol, 1 equiv.) in methanol (10 mL), palladium hydroxide (591 mg) and di-tert-butyl dicarbonate ester (1.84 g, 8.42 mmol, 2 equiv.) were added under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 psi) at 25°C for 12 h. The reaction mixture was filtered and the filter was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=20:1-2:1). The compound tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (820 mg, 3.02 mmol, 71% yield) was obtained as a colorless oil.

Step 6

A mixture of tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (1 g, 3.69 mmol, 1 eq.), 4-bromo-2-fluoro-pyridine (778 mg, 4.42 mmol, 1.2 eq.), and cesium carbonate (2.40 g, 7.37 mmol, 2 eq.) in acetonitrile (10 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 90° C. under nitrogen atmosphere for 12 h. The reaction mixture was filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-10:1). The compound tert-butyl 4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (1.36 g, 3.18 mmol, 86% yield) was obtained as a colorless oil.

Step 7

To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 g, 47.11 mmol, 1 eq.) in dichloromethane (140 mL), CbzCl (9.64 g, 56.53 mmol, 8.04 mL, 1.2 eq.) and triethylamine (8.58 g, 84.79 mmol, 11.80 mL, 1.8 eq.) were added. The mixture was stirred at 20 °C for 20 h. TLC (dichloromethane:methanol = 10:1) showed that reactant 1 was not completely consumed, so CbzCl (1.61 g, 9.42 mmol, 1.34 mL, 0.2 eq.) was added again. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was washed twice with water (80 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0 to 4:1). Compound 8-benzyl 3-(tert-butyl) 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.48 g, 33.14 mmol, 70% yield) was obtained as a colorless oil.

Step 8

To a solution of 8-benzyl 3-(tert-butyl) 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (6.20 g, 17.90 mmol, 1 equiv.) in dichloromethane (80 mL), trifluoroacetic acid (12.32 g, 108.05 mmol, 8.00 mL, 6.04 equiv.) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was adjusted to pH = 8 with saturated aqueous sodium bicarbonate and extracted with chloroform and isopropanol (80 mL x 3, 5:1). The combined layers were dried over anhydrous sodium sulfate and concentrated to give benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.7 g, 17.68 mmol, 98% yield, 92% purity) as a yellow oil.

Step 9

A mixture of benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (784 mg, 3.18 mmol, 1 equiv.), tert-butyl 4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (1.36 g, 3.18 mmol, 1 equiv.), [2-(2-aminophenyl)phenyl]-chloropalladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (148 mg, 0.19 mmol, 0.06 equiv.), and cesium carbonate (2.07 g, 6.37 mmol, 2 equiv.) in toluene (27 mL) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 110 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0 to 1:1). Compound 8-[2-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.35 g, 2.28 mmol, 71% yield) was obtained as a colorless oil.

Step 10

To a solution of benzyl 8-[2-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.35 g, 2.28 mmol, 1 equiv.) in a mixture of tetrahydrofuran (27 mL) and ethanol (27 mL), palladium hydroxide on activated carbon catalyst (320 mg, 10% purity) was added under nitrogen. The suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred under hydrogen (50 psi) at 60 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The compound tert-butyl 4-[3-[[4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (932 mg, 2.03 mmol, 89% yield) was obtained as a brown solid.

Step 11

A mixture of tert-butyl 4-[3-[[4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (932 mg, 2.03 mmol, 1 eq.), 4-bromo-6-chloro-pyridazin-3-amine (508 mg, 2.44 mmol, 1.2 eq.), N,N-diisopropylethylamine (2.63 g, 20.32 mmol, 3.54 mL, 10 eq.) in dimethylsulfoxide (30 mL) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 130 °C for 3 h. The reaction mixture was diluted with water (30 mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The residue was purified by semi-preparative reverse phase HPLC (column: [Phenomenex Gemini C18 250*50 10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 45%-70%, 24 min; 53% min). The compound tert-butyl 4-[3-[[4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (772 mg, 1.32 mmol, 64% yield) was obtained as a yellow oil.

Step 12

A mixture of tert-butyl 4-[3-[[4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]oxy]cyclobutoxy]piperidine-1-carboxylate (772 mg, 1.32 mmol, 1 eq.), (2-hydroxyphenyl)boronic acid (218 mg, 1.58 mmol, 1.2 eq.), tetrakis[triphenylphosphine]palladium(0) (152 mg, 0.13 mmol, 0.1 eq.), potassium carbonate (364 mg, 2.63 mmol, 2 eq.) in a mixture of dioxane (12 mL) and water (2 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 90 °C for 10 h under nitrogen atmosphere. The reaction mixture was concentrated to give the crude product. The residue was purified by semi-preparative reverse phase HPLC (column: [Kromasil 250*50mm*10um; mobile phase: [water (0.1% trifluoroacetic acid)-ACN]; B%: 20ACN% to 50ACN%, 20min). The compound tert-butyl-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]piperidine-1-carboxylate (500mg, 0.71mmol, 54% yield, 91% purity) was obtained as a yellow solid.

Step 13

To a solution of tert-butyl 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]piperidine-1-carboxylate (500 mg, 0.78 mmol, 1 equiv.) in dichloromethane (5 mL) was added hydrochloric acid/dioxane (4 M, 5 mL, 25.75 equiv.). The mixture was stirred at 20°C for 2 h. The mixture was concentrated to give the crude product. The compound 2-[6-amino-5-[8-[2-[3-(4-piperidyloxy)cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol (500 mg, crude, trihydrochloride salt) was obtained as a yellow solid.

Step 14

2-[6-amino-5-[8-[2-[3-(4-piperidyloxy)cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol trihydrochloride (400 mg, 612 umol, 1 equiv.) and (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-[3-(2-oxo) To a solution of N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (331 mg, 0.61 mmol, 1 eq.) was added sodium acetate (201 mg, 2.45 mmol, 4 eq.), followed by acetic acid until pH=6, followed by cyanoborohydride (192 mg, 3.06 mmol, 5 eq.). The mixture was stirred at 20° C. for 10 h. The reaction mixture was diluted with water (20 mL) and extracted three times with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by semi-preparative reverse phase HPLC (Column: Phenomenex Synergi C18 150*25*10um; Mobile phase: [Water (0.225% FA)-ACN] B%: 18%-48%, 9 min). (2S,4R)-1-[(2R)-2-[3-[2-[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]ethoxy]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide bistrifluoroacetate (321 mg, 0.28 mmol, 45% yield) was obtained as an off-white solid.

Exemplary compounds 63 and 146 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compounds 67 and 68

Step 1

To a stirred solution of NaOH (10 g, 0.250 mol, 2.7 equiv) in water (500 mL), benzyl alcohol (10 g, 92.47 mmol, 1 equiv), 1,4-dibromobutane (39.93 g, 184.9 mmol, 2.00 equiv), and Bu4NHSO4 (0.78 g, 2.297 mmol, 0.02 equiv) were added at room temperature. The resulting mixture was stirred at 70°C for 2 h and then diluted with hexane (100 mL). The resulting mixture was washed with 3 x 50 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (10:1). This gave [(4-bromobutoxy)methyl]benzene (10 g, 44%) as a colorless oil.

Step 2

To a solution of 2-(2-hydroxyethoxy)ethan-1-ol (14.18 g, 133.7 mmol, 5 eq.) in DMF (100 mL) was added sodium hydride (60% in oil, 2.15 g, 2.5 eq.) under nitrogen atmosphere at 0° C. After 15 min, [(4-bromobutoxy)methyl]benzene (6.5 g, 26.7 mmol, 1 eq.) was added to the reaction mixture. The resulting mixture was stirred at 25° C. for 3 h and then quenched by adding water (250 mL). The resulting mixture was extracted with EA (3×200 mL). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (60%). This gave 2-[2-[4-(benzyloxy)butoxy]ethoxy]ethan-1-ol (4 g, 72%) as a colorless oil.

Step 3

To a stirred solution of 2-[2-[4-(benzyloxy)butoxy]ethoxy]ethan-1-ol (2.4 g, 8.94 mmol, 1 eq.) and DMAP (218 mg, 1.79 mmol, 0.2 eq.) in DCM solution (50 mL), TsCl (5.1 g, 26.83 mmol, 3 eq.) and TEA (2.7 g, 26.83 mmol, 3 eq.) were added at room temperature. The resulting mixture was stirred at 40° C. overnight. The reaction mixture was diluted with DCM (100 mL) and washed with 2×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:1). This gave 2-[2-[4-(benzyloxy)butoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate (2.4 g, 64%) as a pale yellow solid.

Step 4

To a solution of 2-[2-[4-(benzyloxy)butoxy]ethoxy]ethyl 4-methylbenzene-1-sulfonate (3.5 g, 8.28 mmol, 1 eq.) in 100 mL of EtOH, 10% Pd/C (3.5 g) and CH3COOH (0.95 mL, 15.88 mmol, 2.01 eq.) were added under nitrogen atmosphere. The flask was evacuated and flushed with hydrogen. The resulting mixture was hydrogenated overnight at 40° C. under hydrogen atmosphere using a hydrogen balloon, then filtered through a celite pad and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 30 min. This gave 4-(2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethoxy)butan-1-ol (2.2 g, 80%) as a colorless oil.

Step 5

To a stirred solution of methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (1.5 g, 7.53 mmol, 1 equiv.) and 4-(2-[2-[(4-methylbenzenesulfonyl)oxy]ethoxy]ethoxy)butan-1-ol (3.0 g, 9.04 mmol, 1.2 equiv.) in acetone (50 mL), Cs2CO3 (4.9 g, 15.04 mmol, 2.00 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 4 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (10:1). This yielded methyl 2-(3-[2-[2-(4-hydroxybutoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoate (800 mg, 30%).

Step 6

To a stirred solution of methyl 2-(3-[2-[2-(4-hydroxybutoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)-3-methylbutanoate (550 mg, 1.53 mmol, 1 equiv.) in DCM (20 mL) was added Dess-Martin periodinane (1298 mg, 3.06 mmol, 2 equiv.) at 0 °C. The resulting mixture was stirred at 30 °C for 2 h and then quenched by adding saturated sodium thiosulfate solution. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic phases were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2/MeOH 10:1) to give methyl 3-methyl-2-(3-[2-[2-(4-oxobutoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)butanoate (440 mg, 80%) as a pale yellow solid.

Using procedures similar to those described for a range of other examples (e.g., exemplary compound 91), as well as those that would be apparent to one of skill in the art, methyl 3-methyl-2-(3-[2-[2-(4-oxobutoxy)ethoxy]ethoxy]-1,2-oxazol-5-yl)butanoate was converted to the final compound according to the following scheme.

Exemplary compounds 65, 66, 71, 73, and 74 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compounds 69 and 70

Step 1

A 250 mL round bottom flask was charged with a solution of 3-(benzyloxy)cyclobutan-1-one (6.0 g, 34.05 mmol, 1.0 equiv) in ethanol (100 mL). This was followed by the addition of sodium borohydride (1.25 g, 33.94 mmol, 1.00 equiv) in portions at 0° C. The resulting solution was stirred at 0° C. for 3 hours. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (50 mL×2) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This afforded 6.0 g (99%) of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol as a pale yellow oil.

Step 2

A solution of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol (8.0 g, 44.89 mmol, 1.10 equiv.) in N,N-dimethylformamide (100 mL) was placed in a 500 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen. Sodium hydride (60%) (2.15 g, 89.58 mmol, 1.20 equiv.) was then added in portions at 0°C. To this was added 4-bromo-2-fluoropyridine (70.0 g, 39.78 mmol, 1.00 equiv.). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by adding water/ice. The resulting solution was extracted with ethyl acetate (80 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine (80 mL x 2). The resulting mixture was concentrated under reduced pressure. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:1). This yielded 7.0 g (53%) of 4-bromo-2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridine as a pale yellow oil.

Step 3

A 500 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of 4-bromo-2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridine (8.4 g, 25.13 mmol, 1.30 equiv.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.11 g, 19.36 mmol, 1.00 equiv.), sodium tert-butoxide (3.2 g, 33.2 mmol, 1.5 equiv.), Xantphos (2.32 g, 4.01 mmol, 0.20 equiv.), Pd2(dba)3CH2Cl2 (430.0 mg, 0.40 mmol, 0.02 equiv.) in toluene (200 mL). The resulting solution was stirred at 100 °C overnight. The reaction was then quenched by adding water (100 mL). The resulting solution was extracted with ethyl acetate (80 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine (100 mL x 2). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/hexane (1:1). This gave 8.0 g (89%) of tert-butyl 8-[2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a pale yellow oil.

Step 4

To a solution of tert-butyl 8-[2-[(1s,3s)-3-(benzyloxy)cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (7.0 g, 15.03 mmol, 1.00 equiv.) in 150 mL of ethanol was added palladium hydroxide catalyst (7.0 g, 49.85 mmol, 3.32 equiv.) and acetic acid (2 mL) in a 250 mL round-bottom flask under nitrogen atmosphere. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated under hydrogen atmosphere at 50° C. for 3 days using a hydrogen balloon, then filtered through a celite pad and concentrated under reduced pressure. This yielded 5.4 g (96%) of tert-butyl 8-[2-[(1s,3s)-3-hydroxycyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate as a pale yellow oil.

Step 5

A 100 mL round bottom flask was charged with a solution of tert-butyl 8-[2-[(1s,3s)-3-hydroxycyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.0 g, 13.32 mmol, 1.00 equiv.) in a mixture of ethyl acetate and methanol (10:1) (50 mL). Hydrogen chloride (g) was passed through. The resulting mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. This gave 4.0 g (96%) of (1s,3s)-3-[(4-[3,8-diazabicyclo[3.2.1]octane-8-yl]pyridin-2-yl)oxy]cyclobutan-1-ol hydrochloride as an off-white solid.

Step 6

A 20 mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen was charged with a solution of (1s,3s)-3-[(4-[3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]cyclobutan-1-ol hydrochloride (1.0 g, 3.21 mmol, 1.00 equiv.) in dimethylsulfoxide (10 mL). N,N-diisopropylethylamine (5 mL) and 4-bromo-6-chloropyridazin-3-amine (3.01 g, 14.44 mmol, 4.00 equiv.) were then added. The resulting solution was stirred at 130° C. for 16 hours. The reaction was then quenched by adding water (50 mL). The resulting solution was extracted with ethyl acetate (3×30 mL) and the organic layers were combined. The resulting mixture was washed with brine (3×50 mL). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 490 mg (38%) of (1s,3s)-3-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)cyclobutan-1-ol as a yellow oil.

Step 7

A 20-mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen was charged with a solution of (1s,3s)-3-([4-[3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl]oxy)cyclobutan-1-ol (800.0 mg, 1.99 mmol, 1.00 equiv.) in a mixture of dioxane and water (4:1) (15 mL), [2-(methoxymethoxy)phenyl]boronic acid (543.5 mg, 2.99 mmol, 1.50 equiv.), potassium carbonate (823.9 mg, 6.0 mmol, 3.00 equiv.), and Pd(PPh3)4 (230.0 mg, 0.20 mmol, 0.10 equiv.). The resulting solution was stirred at 90 °C for 2 h. The reaction was then quenched by adding water (30 mL). The resulting solution was extracted with ethyl acetate (50 mL x 2) and the organic layers were combined. The resulting mixture was washed with brine (50 mL x 2). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 820.0 mg (82%) of (1s,3s)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutan-1-ol as a yellow solid.

Step 8

To a stirred solution of 6-bromopyridin-3-ol (12.70 g, 72.9 mmol, 1.00 equiv.) and imidazole (7.45 g, 109.5 mmol, 1.50 equiv.) in DMF (100 mL), TBSCl (16.50 g, 109.47 mmol, 1.50 equiv.) was added portionwise under nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction was quenched with water (100 mL) at room temperature and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 2-bromo-5-[(tert-butyldimethylsilyl)oxy]pyridine (19 g, 90%) as a colorless oil.

Step 9

To a stirred mixture of 2-bromo-5-[(tert-butyldimethylsilyl)oxy]pyridine (4.00 g, 13.88 mmol, 1.00 equiv.) and NaI (10.40 g, 69.38 mmol, 5.00 equiv.) in 1,4-dioxane (20 mL), CuI (0.26 g, 1.365 mmol, 0.10 equiv.) and methyl[2-(methylamino)ethyl]amine (0.12 g, 1.361 mmol, 0.10 equiv.) were added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110° C. for 5 h under a nitrogen atmosphere. The reaction mixture was filtered and the filter cake was rinsed with 1,4-dioxane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/EtOAc (5:1) to give 5-[(tert-butyldimethylsilyl)oxy]-2-iodopyridine (4.2 g, 90%) as an off-white solid.

Step 10

To a stirred solution of 5-[(tert-butyldimethylsilyl)oxy]-2-iodopyridine (4.20 g, 12.53 mmol, 1.00 equiv.) in THF (20 mL) was added TBAF (1 mol/L, 27 mL, 27 mmol, 2.00 equiv.) dropwise under hydrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/EtOAc (2:1) to give 6-iodopyridin-3-ol (2.3 g, 83%) as a pale yellow solid.

Step 11

To a solution of PPh3 (523 mg, 2.00 mmol, 2.00 equiv.) in THF (10 mL), DIAD (403 mg, 2.00 mmol, 2.00 equiv.), (1s,3s)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutan-1-ol (504 mg, 1.00 mmol, 1 equiv.), and 6-iodopyridin-3-ol (265 mg, 1.20 mmol, 1.20 equiv.) were added at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 5 min, heated to 50°C, and stirred at 50°C for 2 h under nitrogen atmosphere. The reaction was quenched by adding water (20 mL) at room temperature, and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-iodopyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (382 mg, 54%) as a pale yellow solid.

Step 12

To a solution of (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (780 mg, 1.56 mmol, 1.00 equiv.) in acetone (40 mL), Cs2CO3 (1019 mg, 3.13 mmol, 2.00 equiv.), and 3-bromoprop-1-yne (558 mg, 4.69 mmol, 3.00 equiv.) were added at room temperature. The resulting mixture was stirred at 50°C for 3 h under a nitrogen atmosphere. The mixture was filtered and the filter cake was rinsed with THF (50 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[3-methyl-2-[3-(prop-2-yn-1-yloxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (520 mg, 62%) as an off-white solid.

Step 13

To a stirred mixture of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-iodopyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (224 mg, 0.317 mmol, 1.00 equiv.) and CuI (6.0 mg, 0.032 mmol, 0.10 equiv.) in DMF (5 mL) was added TEA (96 mg, 0.950 mmol, 3.00 equiv.) and Pd(PPh3)2Cl2 (22.2 mg, 0.032 mmol, 0.10 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for 5 minutes and then added to a solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[3-methyl-2-[3-(prop-2-yn-1yloxy)-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (170 mg, 0.317 mmol, 1.00 equiv) in DMF (2 mL). The reaction mixture was stirred at 65° C. for 2 hours under nitrogen atmosphere. The reaction was quenched by adding water (30 mL). The resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with dichloromethane/methanol (9:1) to give (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-(3-methyl-2-[3-[(3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-yn-1-yl)oxy]-1,2-oxazol-5-yl]butanoyl)pyrrolidine-2-carboxamide (175 mg, 49%) as a pale yellow solid.

The two diastereomers of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-(3-methyl-2-[3-[(3-[5-[(1r,3r)-3-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]cyclobutoxy]pyridin-2-yl]prop-2-yn-1-yl)oxy]-1,2-oxazol-5-yl]butanoyl)pyrrolidine-2-carboxamide (620 mg) were separated by chiral HPLC under the following conditions: Column: CHIRALPAK IG, 2.0 cm I. D*25 cm (5 um); Mobile phase A: MeOH (8 mmol/L NH3.MeOH), Mobile phase B: DCM, Flow rate: 20 mL/min, Gradient: 30% B to 30% B in 17 min; 220/254 nm; RT1: 8.495 min; RT2: 12.854 min. This yielded 137 mg (22%) of isomer 1, tentatively identified as (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[3-[(3-[5-[(1r,3r)-3-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]cyclobutoxy]pyridin-2-yl]prop-2-yn-1-yl)oxy]-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (pale yellow solid), and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-[3-[(3-[5-[(1r,3r)-3-[(4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridin-2-yl)oxy]cyclobutoxy]pyridin-2-yl]prop-2-yn-1-yl)oxy]-1,2-oxazol-5-yl]butanoyl]pyrrolidine-2-carboxamide (off-white solid) was obtained in an amount of 199 mg (32%).

Exemplary compounds 226, 227, 231, 232, 236, and 237 were synthesized using similar procedures.

Exemplary Synthesis of Exemplary Compound 76

Step 1

To a solution of (1S)-1-(4-bromophenyl)ethanamine (5 g, 24.99 mmol, 1.0 equiv.) in dichloromethane (100 mL) was added triethylamine (2.53 g, 24.99 mmol, 1.0 equiv.) at 0°C. The mixture was then stirred at 0°C for 30 minutes. Di-tert-butyl dicarbonate ester (5.45 g, 24.99 mmol, 1.0 equiv.) was then added and the mixture was stirred at 0°C for 30 minutes followed by 20°C for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), diluted with water (50 mL), extracted with dichloromethane (100 mL x 2), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was stirred with petroleum ether:ethyl acetate (50 mL, v/v = 5/1) and then filtered. Tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (6.4 g, 20.68 mmol, yield 82%) was obtained as a white solid.

Step 2

To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (3 g, 9.99 mmol, 1.0 eq.) and 2-methyl-1H-imidazole (902 mg, 10.99 mmol, 1.1 eq.) in dimethyl sulfoxide (15 mL), L-proline (1.38 g, 11.99 mmol, 1.2 eq.), cesium carbonate (9.77 g, 29.98 mmol, 3.0 eq.), and copper iodide (2.28 g, 11.99 mmol, 1.2 eq.) were added under nitrogen. The mixture was then stirred at 130° C. for 12 hours. The mixture was diluted with water (200 mL), filtered, and then extracted with ethyl acetate (200 mL×3), washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by reverse-phase flash chromatography (formic acid). tert-Butyl N-[(1S)-1-[4-(2-methylimidazol-1-yl)phenyl]ethyl]carbamate (250 mg, 0.83 mmol, 8% yield) was obtained as a yellow oil.

Using the procedures described above for exemplary compounds 47 and 64, tert-butyl N-[(1S)-1-[4-(2-methylimidazol-1-yl)phenyl]ethyl]carbamate was converted to the final compound as detailed in the scheme below.

Exemplary compound 75 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 116

Step 1

To a solution of 1-(6-bromo-3-pyridyl)ethanone (11.88 g, 59.41 mmol, 1.2 eq.) and tetraethoxytitanium (22.58 g, 99.01 mmol, 2 eq.) in tetrahydrofuran (50 mL) was added (R)-2-methylpropane-2-sulfinamide (6 g, 49.50 mmol, 1 eq.) under nitrogen. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was quenched by adding water (30 mL) and then further diluted with water (100 mL), filtered, and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to produce the desired compound (R,E)-N-(1-(6-bromopyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (16 g, 43.27 mmol, 87% yield) as a pale yellow solid.

Step 2

To a solution of (R,E)-N-(1-(6-bromopyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (16 g, 52.77 mmol, 1 eq.) in tetrahydrofuran (160 mL) was added L-selectride (1 M, 158 mL, 3 eq.) at 0°C. The reaction mixture was warmed and stirred at 20°C for 3 h. The reaction mixture was quenched by adding water (100 mL), then further diluted with water (100 mL), filtered, and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by recrystallization from petroleum ether:ethyl acetate = 1:1 (10 mL). The residue was then purified by semi-preparative reverse phase HPLC (FA conditions: column: Phenomenex Synergi Max-RP 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-55%, 30 min). N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]-2-methyl-propane-2-sulfinamide (4.7 g, 12.89 mmol, 24% yield) was obtained as a white solid.

Step 3

To a solution of N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]-2-methyl-propane-2-sulfinamide (2.6 g, 8.52 mmol, 1 equiv.) in dichloromethane (20 mL) was added hydrochloric acid/methanol (4 M, 21.3 mL, 10 equiv.). The reaction mixture was stirred at 20°C for 0.15 h. The reaction mixture was concentrated under reduced pressure to give (1S)-1-(6-bromo-3-pyridyl)ethanamine (1.9 g, crude, hydrochloride salt) as a white solid.

Step 4

To a solution of (1S)-1-(6-bromo-3-pyridyl)ethanamine hydrochloride (1.9 g, 8.00 mmol, 1 eq.) in dichloromethane (20 mL), triethylamine (2.43 g, 24.00 mmol, 3.34 mL, 3 eq.) was added at 0 °C for 0.5 h, followed by di-tert-butyl dicarbonate (2.62 g, 12.00 mmol, 2.76 mL, 1.5 eq.) at 0 °C for 0.5 h. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by adding water (20 mL), then further diluted with 60 mL of water and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 50:1 to 3:1). tert-Butyl N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]carbamate (2.2 g, 7.06 mmol, 88% yield) was obtained as a white solid.

Step 5

To a solution of 5-bromo-4-methyl-thiazole (800 mg, 4.49 mmol, 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.37 g, 5.39 mmol, 1.2 eq.) in dioxane (10 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (164 mg, 0.22 mmol, 0.05 eq.) and potassium acetate (882 mg, 8.99 mmol, 2 eq.). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (1 g, crude) as a brown oil, which was used without purification.

Step 6

To a solution of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (617 mg, 2.74 mmol, 1.5 eq.) and tert-butyl N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]carbamate (550 mg, 1.83 mmol, 1 eq.) in dioxane (12 mL) and water (2 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (134 mg, 0.18 mmol, 0.1 eq.) and potassium carbonate (505 mg, 3.65 mmol, 2 eq.) were added. The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by adding water (10 mL), then diluted with water (30 mL), filtered and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative TLC (petroleum ether:ethyl acetate=1:1). The desired compound tert-butyl N-[(1S)-1-[6-(4-methylthiazol-5-yl)-3-pyridyl]ethyl]carbamate (200 mg, 0.62 mmol, 34% yield) was obtained as a pale yellow solid.

tert-Butyl N-[(1S)-1-[6-(4-methylthiazol-5-yl)-3-pyridyl]ethyl]carbamate was converted to the final compound as described above for exemplary compound 76.

Exemplary compound 160 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 117

Step 1

To a solution of tert-butyl N-[(1S)-1-(6-bromo-3-pyridyl)ethyl]carbamate (1 g, 3.32 mmol, 1 eq.) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M, 2.9 mL, 2.2 eq.) at -78 °C. The mixture was stirred at -78 °C for 0.5 h, then N,N-dimethylformamide (728 mg, 9.96 mmol, 0.8 mL, 3 eq.) was added to the mixture at -78 °C and the mixture was stirred at -78 °C for 0.5 h. The mixture was warmed to 15 °C for 1 h. The reaction mixture was quenched by adding saturated ammonium chloride (10 mL), then diluted with water (20 mL), filtered, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 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 1:1). The desired compound tert-butyl N-[(1S)-1-(6-formyl-3-pyridyl)ethyl]carbamate (550 mg, 2.20 mmol, 66% yield) was obtained as a pale yellow solid.

Step 2

To a solution of tert-butyl N-[(1S)-1-(6-formyl-3-pyridyl)ethyl]carbamate (550 mg, 2.20 mmol, 1 eq.) and 1-(1-isocyanoethylsulfonyl)-4-methyl-benzene (506 mg, 2.42 mmol, 1.1 eq.) in methanol (10 mL), potassium carbonate (607 mg, 4.39 mmol, 2 eq.) was added. The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was quenched by adding water (20 mL), then diluted with water (10 mL), filtered, and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1). The desired compound tert-butyl N-[(1S)-1-[6-(4-methyloxazol-5-yl)-3-pyridyl]ethyl]carbamate (570 mg, 1.65 mmol, 75% yield, 87% purity) was obtained as a white solid.

tert-Butyl N-[(1S)-1-[6-(4-methyloxazol-5-yl)-3-pyridyl]ethyl]carbamate was converted to the final compound as described for exemplary compound 76.

Exemplary compounds 161, 229, and 230 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compound 81

Step 1

A 250 mL round bottom flask was charged with 1-(4-hydroxyphenyl)ethan-1-one (6.0 g, 44.08 mmol, 1 equiv.), tert-butyl(chloro)dimethylsilane (10 g, 66.1 mmol, 1.5 equiv.), and K2CO3 (12 g, 88.14 mmol, 2 equiv.) in DMF (100 mL). The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by adding water (100 mL). The resulting mixture was extracted with dichloromethane (100 mL x 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:10). This gave 5.2 g (47%) of 1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethan-1-one as an off-white solid.

Step 2

A 250 mL round bottom flask was charged with 1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethan-1-one (5 g, 20.0 mmol, 1 equiv.) in MeOH (100 mL), to which sodium borohydride (1.5 g, 39.94 mmol, 2 equiv.) was added portionwise at room temperature. The resulting solution was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/1). This gave 3.8 g (76%) of 1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethan-1-ol as a yellow oil.

Step 3

A 250 mL round bottom flask was charged with 1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethan-1-ol (3.8 g, 15.05 mmol, 1 eq.) and TEA (6.1 g, 60.21 mmol, 4 eq.) in dichloromethane (100 mL), to which methanesulfonyl chloride (2.1 g, 18.07 mmol, 1.20 eq.) was added slowly at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. This gave 3.6 g of crude 1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethyl methanesulfonate as a yellow solid.

Step 4

A 250 mL round bottom flask was charged with 1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethyl methanesulfonate (5.0 g, 15.13 mmol, 1 eq.), 2-(cyclopenta-1,4-dien-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.5 g, 18.17 mmol, 1.20 eq.), and K2CO3 (6.3 g, 45.38 mmol, 3 eq.) in DMF (150 mL) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight. The reaction was then quenched by adding water (150 mL). The resulting mixture was extracted with dichloromethane (150 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:5). This gave 600 mg (9%) of 1-(1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a yellow solid.

Using procedures similar to those described for other examples, 1-(1-[4-[(tert-butyldimethylsilyl)oxy]phenyl]ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was converted to the final compound according to the following scheme:

Exemplary compound 156 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 162

Step 1

A 250 mL round bottom flask was charged with a solution of 1-(6-fluoropyridin-3-yl)ethan-1-one (4.17 g, 29.97 mmol, 1 equiv.) in EtOH (60 mL). The solution was cooled to 0° C. in a water/ice bath and a solution of sodium borohydride (2.27 g, 61.65 mmol, 2.06 equiv.) in H2O (10 mL) was added dropwise. The resulting solution was stirred at room temperature for 0.5 h. The reaction mixture was carefully quenched with water (400 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 3.87 g (91%) of 1-(6-fluoropyridin-3-yl)ethan-1-ol as a pale yellow oil.

Step 2

A 500 mL three-neck round bottom flask purged and maintained under nitrogen inert atmosphere was charged with 1-(6-fluoropyridin-3-yl)ethan-1-ol (4.06 g, 28.76 mmol, 1 equiv.) in dichloromethane (200 mL). The solution was cooled to 0 °C in a water/ice bath and PPh3 (11.28 g, 43.01 mmol, 1.50 equiv.) and NBS (7.66 g, 43.04 mmol, 1.50 equiv.) were added sequentially at 0 °C. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:9). This gave 5.83 g (99%) of 5-(1-bromoethyl)-2-fluoropyridine as a pale yellow liquid.

Step 3

A 100 mL round-bottom flask was charged with a solution of 5-(1-bromoethyl)-2-fluoropyridine (3.06 g, 15.00 mmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.20 g, 16.49 mmol, 1.10 equiv.), and K2CO3 (4.15 g, 30.03 mmol, 2.00 equiv.) in DMF (50 mL). The resulting mixture was stirred in an oil bath at 60 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (400 mL). The mixture was extracted with ethyl acetate (100 mL × 4) and the combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 3.43 g (72%) of 2-fluoro-5-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl]pyridine as a pale yellow solid.

Step 4

In a 100 mL round bottom flask purged and maintained under a nitrogen inert atmosphere, 2-fluoro-5-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl]pyridine (2.54 g, 8.01 mmol, 1 equiv., 4-bromo-6-chloropyridazin-3-amine (2.00 g, 9.60 mmol, 1.20 equiv.), Na2CO3 (2.12 g, 20.00 mmol, 2.50 equiv.), and Pd(dppf)Cl2.CH2Cl2 (327 mg, 0.40 mmol) in dioxane (50 mL) and H2O (8 mL) were added. mol, 0.05 equiv.) was charged. The resulting mixture was stirred in an oil bath at 90° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The mixture was extracted with ethyl acetate (300 mL×2), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (20:1). This gave 1.88 g (74%) of 6-chloro-4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]pyridazin-3-amine as a brown solid.

Step 5

In a 30 mL sealed tube purged and maintained with nitrogen inert atmosphere, 6-chloro-4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]pyridazin-3-amine (765 mg, 2.40 mmol, 1 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (524 mg, 2.88 mmol, 1.20 equiv.), K2CO3 (829 mg, 6.00 mmol, 2.50 equiv.), and Pd(dppf)Cl2. CH2Cl2 (196 mg, 0.24 mmol, 0.10 equiv.) in dioxane (18 mL) and H2O (3 mL) were placed. The resulting mixture was stirred in an oil bath at 100 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (20:1). This yielded 860 mg (85%) of 4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine as a brown solid.

Step 6

A 50 mL round bottom flask purged and maintained under a nitrogen inert atmosphere was charged with ethane-1,2-diol (1.48 g, 23.84 mmol, 10.03 equiv.) in DMF (15 mL). The solution was cooled to 0°C in a water/ice bath, to which NaH (0.76 g, 19.00 mmol, 7.99 equiv., 60%) was added portionwise at 0°C. The resulting mixture was stirred at room temperature for 1.5 h, after which a solution of 4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (1.00 g, 2.38 mmol, 1 equiv.) in DMF (5 mL) was added dropwise at 0°C. The reaction mixture was stirred for an additional 3 h while the temperature was maintained at 55°C in an oil bath. The reaction mixture was cooled to room temperature and then quenched by adding water (200 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (15:1). This gave 361 mg (33%) of 2-([5-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]pyridin-2-yl]oxy)ethan-1-ol as a pale yellow solid.

Step 7

A 50 mL round bottom flask purged and maintained with a nitrogen inert atmosphere was charged with a solution of tetramethylazodicarboxamide (861 mg, 5.00 mmol, 10.00 equiv.) and tributylphosphine (1.01 g, 4.99 mmol, 9.98 equiv.) in THF (15 mL) at 0°C. To the mixture was added a mixture of 2-([5-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]pyridin-2-yl]oxy)ethan-1-ol (231.3 mg, 0.50 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (249 mg, 0.50 mmol, 1.00 equiv.). The resulting solution was stirred at 0° C. for 10 min and then at 50° C. in an oil bath for an additional 2 h. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The resulting mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10/1). The resulting product was further purified by preparative HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 19 x 150 mm, 5 um; Mobile phase, water (containing 10 mmol/L NH4HCO3) and acetonitrile, 35% ACN, up to 53% in 8 min. This gave 68 mg (14%) of (2S,4R)-1-(2-(3-(2-(5-(1-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide as an off-white solid.

Using procedures similar to those described in other examples above, (2S,4R)-1-(2-(3-(2-(5-(1-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was converted to the final compound.

Exemplary compound 157 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 100 Step 1

To a stirred mixture of ethanol (350 mL, 7.60 mmol, 0.04 equiv.) and water (60 mL, 3.33 mmol, 0.02 equiv.) at room temperature, anhydrous sodium acetate (18 g, 264.71 mmol, 1.47 equiv.) was added portionwise under nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (500 mL). The aqueous layer was extracted with ethyl acetate (300 mL×2). The residue was washed with brine (100 mL×2), dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5) to give 1-(4-bromophenyl)-2-hydroxyethan-1-one (32 g, 83%) as a white solid.

Step 2

In a 1 L round bottom flask, 1-(4-bromophenyl)-2-hydroxyethan-1-one (32 g, 148.8 mmol, 1 equiv.), methylene chloride (500 mL), imidazole (30 g, 440.7 mmol, 2.96 equiv.), 4-dimethylaminopyridine (1.8 g, 14.73 mmol, 0.10 equiv.), and tert-butyldimethylsilyl chloride (26.8 g, 177.8 mmol, 1.19 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with methylene chloride (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:20) to give 1-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethan-1-one (29 g, 59%) as a pale yellow solid.

Step 3

In a 1 L three-neck round bottom flask, 1-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethan-1-one (27 g, 81.99 mmol, 1 eq.), tetrahydrofuran (500 mL), and (S)-2-methylpropane-2-sulfinamide (19.5 g, 160.9 mmol, 1.96 eq.) were added at room temperature. To the stirred solution, Ti(i-PrO)4 (70 g, 246.5 mmol, 3.01 eq.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:15) to give (S)-N-[(1Z)-1-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethylidene]-2-methylpropane-2-sulfinamide (16 g, 45%) as a yellow oil.

Step 4

In a 500 mL three-neck round bottom flask, (S)-N-[(1Z)-1-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethylidene]-2-methylpropane-2-sulfinamide (15 g, 34.68 mmol, 1 eq.) and tetrahydrofuran (150 mL) were added at room temperature. To the stirred solution, BH3.THF (52 mL, 52 mmol, 1.5 eq.) was added dropwise at −70° C. under nitrogen atmosphere. The resulting mixture was stirred at −70° C. for 1 h under nitrogen atmosphere. The reaction was quenched with methanol at room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (100 mL×2). The filtrate was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:2) to give (S)-N-[(1R)-1-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethyl]-2-methylpropane-2-sulfinamide (5.6 g, 37%) as a yellow solid.

Step 5

A 100 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with (S)-N-[(1R)-1-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethyl]-2-methylpropane-2-sulfinamide (2.6 g, 5.98 mmol, 1.00 equiv.), dioxane (30 mL), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (2 g, 8.88 mmol, 1.48 equiv.), potassium carbonate (2.5 g, 18.09 mmol, 3.02 equiv.), water (5 mL), and Pd(dppf)Cl2.CH2Cl2 (440 mg, 0.51 mmol, 0.09 equiv.). The resulting solution was stirred at 90 °C for 2 h. The solids were filtered off. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (35 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:5). This gave 2.5 g (92%) of (S)-N-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-2-methylpropane-2-sulfinamide as an orange oil.

Step 6

A 250 mL round bottom flask was charged with (S)-N-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-2-methylpropane-2-sulfinamide (2.6 g, 5.74 mmol, 1.00 equiv.) in dioxane (100 mL, 4 M) and hydrogen chloride. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. This gave 1.5 g (96%) of (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride as a yellow oil.

Step 7

A 250 mL round bottom flask was charged with ethyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (1 g, 4.69 mmol, 1 equiv.), Cs2CO3 (4.5 g, 13.81 mmol, 3.0 equiv.), and 1,2-dibromoethane (2.60 g, 13.84 mmol) in acetone (100 mL). The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by water (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (3:10). This afforded 600 mg (40%) of ethyl 2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate as a pale yellow oil.

Using procedures described for other examples and apparent to one skilled in the art, (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol and ethyl 2-[3-(2-bromoethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate were converted to (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide according to the following scheme.

For example, (2S,4R)-1-(2-(3-(2-bromoethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was converted to the final compound using a procedure similar to that described in exemplary compound 47.

Exemplary compound 158 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 115

Step 1

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 min and then heated to 80 °C for 1 h. The reaction mixture was cooled to 20 °C and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude product was purified by 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, crude) was obtained as a colorless oil.

Step 2

A flask was charged with tert-butyl N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (1.90 g, 5.47 mmol, 1.1 eq.), 2-bromo-1-methyl-imidazole (800 mg, 4.97 mmol, 1 eq.), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (181 mg, 0.24 mmol, 0.05 eq.), sodium carbonate (1.05 g, 9.94 mmol, 2 eq.), dioxane (18 mL), and water (3 mL). The mixture was purged with nitrogen for 5 minutes and heated to 110 °C for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1). Tert-butyl N-[(1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethyl]carbamate (850 mg, 2.82 mmol, 56% yield) was obtained as a grey solid.

Step 3

To a solution of tert-butyl N-[(1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethyl]carbamate (850 mg, 2.82 mmol, 1 equiv.) in dioxane (2 mL) was added hydrogen chloride solution (4 M in dioxane, 10 mL, 14.18 equiv.). The solution was stirred at 20°C for 1 h. The solvent was removed in vacuo. (1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethanamine (670 mg, crude, hydrochloride salt) was obtained as a grey solid.

Step 4

To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (651 mg, 2.82 mmol, 1 equiv.) in N,N-dimethylformamide (2 mL) was added 1-hydroxybenzotriazole (456 mg, 3.38 mmol, 1.2 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (648 mg, 3.38 mmol, 1.2 equiv.). The solution was stirred at 20° C. for 0.5 h, then a solution of (1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethanamine (670 mg, 2.82 mmol, 1 eq, hydrochloride salt) and N,N-diisopropylethylamine (1.09 g, 8.46 mmol, 1.47 mL, 3 eq) in N,N-dimethylformamide (3 mL) was added to the solution and stirred for 11.5 h. The solvent was removed in vacuo. The crude residue was purified by semi-preparative reverse phase HPLC (column: Phenomenex Gemini C18 250*50 10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 20%-50%, 20 min; 60% min). Tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (800 mg, 1.93 mmol, 68% yield) was obtained as a colorless oil.

Step 5

To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (350 mg, 0.84 mmol, 1 equiv.) in dichloromethane (3 mL), hydrochloric acid/dioxane (4 M in dioxane, 3 mL, 14.21 equiv.) was added. The reaction mixture was then stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (400 mg, crude, hydrochloride salt) as a pale yellow solid.

For example, (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(1-methylimidazol-2-yl)phenyl]ethyl]pyrrolidine-2-carboxamide was converted to the final compound using the procedure described in exemplary compound 47.

Compound 159 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 162

Step 1

A 250 mL round bottom flask was charged with a solution of 1-(6-fluoropyridin-3-yl)ethan-1-one (4.17 g, 29.97 mmol, 1 equiv.) in EtOH (60 mL). The solution was cooled to 0° C. in a water/ice bath and a solution of sodium borohydride (2.27 g, 61.65 mmol, 2.06 equiv.) in H2O (10 mL) was added dropwise. The resulting solution was stirred at room temperature for 0.5 h. The reaction mixture was carefully quenched with water (400 mL) and extracted with ethyl acetate (200 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This gave 3.87 g (91%) of 1-(6-fluoropyridin-3-yl)ethan-1-ol as a pale yellow oil.

Step 2

A 500 mL three-neck round bottom flask purged and maintained under nitrogen inert atmosphere was charged with 1-(6-fluoropyridin-3-yl)ethan-1-ol (4.06 g, 28.76 mmol, 1 equiv.) in dichloromethane (200 mL). The solution was cooled to 0 °C in a water/ice bath and PPh3 (11.28 g, 43.01 mmol, 1.50 equiv.) and NBS (7.66 g, 43.04 mmol, 1.50 equiv.) were added sequentially at 0 °C. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:9). This gave 5.83 g (99%) of 5-(1-bromoethyl)-2-fluoropyridine as a pale yellow liquid.

Step 3

A 100 mL round-bottom flask was charged with a solution of 5-(1-bromoethyl)-2-fluoropyridine (3.06 g, 15.00 mmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.20 g, 16.49 mmol, 1.10 equiv.), and K2CO3 (4.15 g, 30.03 mmol, 2.00 equiv.) in DMF (50 mL). The resulting mixture was stirred in an oil bath at 60 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (400 mL). The mixture was extracted with ethyl acetate (100 mL × 4) and the combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 3.43 g (72%) of 2-fluoro-5-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl]pyridine as a pale yellow solid.

Step 4

In a 100 mL round bottom flask purged and maintained under a nitrogen inert atmosphere, 2-fluoro-5-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl]pyridine (2.54 g, 8.01 mmol, 1 equiv., 4-bromo-6-chloropyridazin-3-amine (2.00 g, 9.60 mmol, 1.20 equiv.), Na2CO3 (2.12 g, 20.00 mmol, 2.50 equiv.), and Pd(dppf)Cl2.CH2Cl2 (327 mg, 0.40 mmol) in dioxane (50 mL) and H2O (8 mL) were added. mol, 0.05 equiv.) was charged. The resulting mixture was stirred in an oil bath at 90° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The mixture was extracted with ethyl acetate (300 mL×2), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (20:1). This gave 1.88 g (74%) of 6-chloro-4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]pyridazin-3-amine as a brown solid.

Step 5

In a 30 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 6-chloro-4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]pyridazin-3-amine (765 mg, 2.40 mmol, 1 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (524 mg, 2.88 mmol, 1.20 equiv.), K2CO3 (829 mg, 6.00 mmol, 2.50 equiv.), and Pd(dppf)Cl2.CH2Cl2 (196 mg, 0.24 mmol, 0.10 equiv.) in dioxane (18 mL) and H2O (3 mL) were placed. The resulting mixture was stirred in an oil bath at 100 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (20:1). This yielded 860 mg (85%) of 4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine as a brown solid.

Step 6

A 50 mL round bottom flask purged and maintained under a nitrogen inert atmosphere was charged with ethane-1,2-diol (1.48 g, 23.84 mmol, 10.03 equiv.) in DMF (15 mL). The solution was cooled to 0°C in a water/ice bath, to which NaH (0.76 g, 19.00 mmol, 7.99 equiv., 60%) was added portionwise at 0°C. The resulting mixture was stirred at room temperature for 1.5 h, after which a solution of 4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (1.00 g, 2.38 mmol, 1 equiv.) in DMF (5 mL) was added dropwise at 0°C. The reaction mixture was stirred for an additional 3 h while the temperature was maintained at 55°C in an oil bath. The reaction mixture was cooled to room temperature and then quenched by adding water (200 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (15:1). This gave 361 mg (33%) of 2-([5-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]pyridin-2-yl]oxy)ethan-1-ol as a pale yellow solid.

Step 7

A 50 mL round bottom flask purged and maintained with a nitrogen inert atmosphere was charged with a solution of tetramethylazodicarboxamide (861 mg, 5.00 mmol, 10.00 equiv.) and tributylphosphine (1.01 g, 4.99 mmol, 9.98 equiv.) in THF (15 mL) at 0°C. To the mixture was added a mixture of 2-([5-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]pyridin-2-yl]oxy)ethan-1-ol (231.3 mg, 0.50 mmol, 1 equiv.) and (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (249 mg, 0.50 mmol, 1.00 equiv.). The resulting solution was stirred at 0° C. for 10 min and then at 50° C. in an oil bath for an additional 2 h. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The resulting mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10/1). The resulting product was further purified by preparative HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 19 x 150 mm, 5 um; Mobile phase, water (containing 10 mmol/L NH4HCO3) and acetonitrile, 35% ACN, up to 53% in 8 min. This gave 68 mg (14%) of (2S,4R)-1-(2-(3-(2-(5-(1-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide as an off-white solid.

Using procedures similar to those described in other examples above, (2S,4R)-1-(2-(3-(2-(5-(1-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was converted to the final compound.

Exemplary compound 157 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 82

Step 1

A 100 mL round bottom flask was charged with methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (498 mg, 2.50 mmol, 1 equiv.), 2-(2-bromoethoxy)oxane (627.3 mg, 3.00 mmol, 1.20 equiv.), Cs2CO3 (1.63 g, 5.00 mmol, 2.00 equiv.), and NaI (37.5 mg, 0.25 mmol, 0.10 equiv.) in acetone (20 mL). The resulting mixture was stirred in an oil bath at 50 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:9). This gave 570 mg (70%) of methyl 3-methyl-2-[3-[2-(oxan-2-yloxy)ethoxy]-1,2-oxazol-5-yl]butanoate as a pale yellow oil.

Step 2

A 100 mL round bottom flask was charged with methyl 3-methyl-2-[3-[2-(oxan-2-yloxy)ethoxy]-1,2-oxazol-5-yl]butanoate (520 mg, 1.59 mmol, 1 equiv.) in dioxane (6 mL), to which HCl solution (4 M in dioxane, 6 mL) was added at room temperature. The resulting solution was stirred at room temperature for 3 h. The pH value of the solution was adjusted to 8 with saturated NaHCO3. The resulting mixture was extracted with dichloromethane (100 mL x 4), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/1). This gave 332 mg (86%) of methyl 2-[3-(2-hydroxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate as a pale yellow oil.

Step 3

A 50 mL round bottom flask purged and maintained under a nitrogen inert atmosphere was charged with methyl 2-[3-(2-hydroxyethoxy)-1,2-oxazol-5-yl]-3-methylbutanoate (375 mg, 1.54 mmol, 1.20 equiv.) in DMF (6 mL). The solution was cooled to 0°C in a water/ice bath and NaH (128.4 mg, 3.21 mmol, 2.50 equiv., 60%) was added. The resulting mixture was stirred at room temperature for 1 h and a solution of 4-[1-[1-(6-fluoropyridin-3-yl)ethyl]-1H-pyrazol-4-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (540 mg, 1.28 mmol, 1 equiv.) in DMF (4 mL) was added dropwise at 0°C. The resulting mixture was stirred for an additional hour while the temperature was maintained at 35°C in an oil bath. The reaction mixture was then quenched by adding saturated NH4Cl solution (30 mL) and the pH value of the resulting mixture was adjusted to about 8 with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (30/1). This gave 540 mg (65%) of methyl 2-[3-[2-([5-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]pyridin-2-yl]oxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoate as a light brown solid.

Using procedures similar to those described in other examples above, methyl 2-[3-[2-([5-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]pyridin-2-yl]oxy)ethoxy]-1,2-oxazol-5-yl]-3-methylbutanoate was converted to the final compound.

Exemplary compound 163 was prepared using a similar procedure.

Exemplary Syntheses of Exemplary Compound 93 and Exemplary Compound 164

Step 1

To a solution of 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1.8 g, 7.46 mmol, 1 eq.) in DMF (20 mL) was added sodium hydride (60% in oil, 358 mg, 14.9 mmol, 2 eq.) at 0 °C. The mixture was stirred for 15 min. Then 2-(2-bromoethoxy)oxane (2.3 g, 11.00 mmol, 1.47 eq.) was added and the mixture was warmed to 50 °C and stirred for 16 h. The reaction mixture was quenched by water (100 mL), extracted with DCM (100 mL x 3), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:7). This yielded 1.0 g (36%) tert-butyl 2-[2-(oxan-2-yloxy)ethoxy]-7-azaspiro[3.5]nonane-7-carboxylate as a colorless oil.

Step 2

A 100 mL round bottom flask was charged with a solution of tert-butyl 2-[2-(oxan-2-yloxy)ethoxy]-7-azaspiro[3.5]nonane-7-carboxylate (1.0 g, 2.71 mmol, 1 equiv.) in dioxane (15 mL) to which was added hydrogen chloride in 1,4-dioxane solution (4.0 M, 15 mL). The resulting solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure. This gave 800 mg (53%) of 2-[7-azaspiro[3.5]nonan-2-yloxy]ethan-1-ol as a yellow oil.

Step 3

A 100 mL round bottom flask was charged with 2-[7-azaspiro[3.5]nonan-2-yloxy]ethan-1-ol (600 mg, 3.24 mmol, 1 eq.), Et3N (983 mg, 9.72 mmol, 3 eq.) in DCM (30.0 mL), to which CbzCl (663 mg, 3.89 mmol, 1.2 eq.) was added at room temperature. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was then diluted with 50 mL of water and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This afforded 210 mg (20%) of benzyl 2-(2-hydroxyethoxy)-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil.

Step 4

A 50 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with benzyl 2-(2-hydroxyethoxy)-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 1.25 mmol, 1 eq.), Et3N (380 mg, 3.76 mmol, 3 eq.) in DCM (20 mL) to which MsCl (287 mg, 2.50 mmol, 2.00 eq.) was added at 0°C. The resulting mixture was stirred in a water/ice bath at 0°C for 1 h. The reaction mixture was quenched by adding water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. This gave 420 mg (85%) of benzyl 2-[2-(methanesulfonyloxy)ethoxy]-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil.

Step 5

A 100 mL round bottom flask was charged with a solution of benzyl 2-[2-(methanesulfonyloxy)ethoxy]-7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 0.75 mmol, 1 equiv.), 6-[2-(methoxymethoxy)phenyl]-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]pyridazin-3-amine (291 mg, 0.75 mmol, 1 equiv.), K2CO3 (313 mg, 2.26 mmol, 3 equiv.), NaI (113 mg, 0.75 mmol, 1 equiv.) in MeCN (15 mL). The resulting mixture was stirred in an oil bath at 75 °C for 16 h. The solids were filtered and the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This gave 130 mg (25%) of benzyl 2-[2-(9-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-7-azaspiro[3.5]nonane-7-carboxylate as a yellow oil.

Step 6

A 100 mL round bottom flask was charged with a solution of benzyl 2-[2-(9-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy]-7-azaspiro[3.5]nonane-7-carboxylate (230 mg, 0.33 mmol, 1 equiv.) in THF (5 mL), to which lithium triethylborohydride (1.0 M in THF, 1.65 mmol, 5.0 equiv.) was added at 0°C. The resulting mixture was stirred at room temperature for 16 h, then quenched by water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This gave 140 mg (76%) of 4-[4-(2-[7-azaspiro[3.5]nonan-2-yloxy]ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine as a yellow oil.

Using the procedures described for other examples above, 4-[4-(2-[7-azaspiro[3.5]nonan-2-yloxy]ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine was converted to the final compound according to the following scheme.

Exemplary compound 164 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 113

Step 1

To a solution of but-2-yn-1,4-diol (10 g, 116.16 mmol, 1 eq.), 2,3-dihydro-2H-pyran (9.77 g, 116.16 mmol, 10.6 mL, 1 eq.) in dichloromethane (200 mL), pyridinium p-toluenesulfonate (2.92 g, 11.62 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 40 °C for 1 h. Water (200 mL) was added to the mixture, and the resulting mixture was extracted with dichloromethane (150 mL x 2). The combined organic phase was washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 1: 1). 4-Tetrahydropyran-2-yloxybut-2-yn-1-ol (10.2 g, 59.93 mmol, 51% yield) was obtained as a pale yellow oil.

Step 2

To a solution of 4-tetrahydropyran-2-yloxybut-2-yn-1-ol (5 g, 29.38 mmol, 1 eq.), triphenylphosphine (7.70 g, 29.38 mmol, 1 eq.) in dichloromethane (100 mL), carbon tetrabromide (10.72 g, 32.31 mmol, 1.1 eq.) was added at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 100:1). 2-(4-bromobut-2-ynoxy)tetrahydropyran (4 g, 17.16 mmol, 58% yield) was obtained as a pale yellow oil.

Step 3

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3 g, 15.46 mmol, 1 eq.), 2-(4-bromobut-2-ynoxy)tetrahydropyran (3.96 g, 17.01 mmol, 1.1 eq.) in acetonitrile (30 mL), potassium carbonate (2.56 g, 18.55 mmol, 1.2 eq.) was added. The reaction mixture was stirred at 70 °C for 12 h. Water (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 200: 1 to 3: 1). 1-(4-tetrahydropyran-2-yloxybut-2-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (4.5 g, 13.00 mmol, 84% yield) was obtained as a pale yellow oil.

Step 4

To a solution of 1-(4-tetrahydropyran-2-yloxybut-2-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2 g, 5.78 mmol, 1 eq.), 4-bromo-6-chloro-pyridazin-3-amine (1.20 g, 5.78 mmol, 1 eq.) in dioxane (60 mL) and water (20 mL), sodium carbonate (1.53 g, 14.44 mmol, 2.5 eq.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (422 mg, 0.58 mmol, 0.1 eq.) were added under nitrogen. The reaction mixture was stirred at 110 °C for 3 h. Water (200 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (100 mL x 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 (dichloromethane:methanol=1:0 to 50:1). 6-chloro-4-[1-(4-tetrahydropyran-2-yloxybut-2-ynyl)pyrazol-4-yl]pyridazin-3-amine (1.3 g, 3.40 mmol, 58% yield) was obtained as a yellow solid.

Step 5

To a solution of 6-chloro-4-[1-(4-tetrahydropyran-2-yloxybut-2-ynyl)pyrazol-4-yl]pyridazin-3-amine (1.6 g, 4.60 mmol, 1 eq.) in methanol (15 mL) was added hydrochloric acid solution (4 M in methanol, 15 mL, 13.04 eq.). The reaction mixture was stirred at 20°C for 1 h. Saturated sodium bicarbonate (50 mL) was added to the mixture to adjust the pH to about 6, and then the resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. 4-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]but-2-yn-1-ol (1.0 g, 3.79 mmol, 82% yield) was obtained as a pale yellow solid.

Step 6

To a solution of 4-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]but-2-yn-1-ol (1.0 g, 3.79 mmol, 1 eq.), triphenylphosphine (1.19 g, 4.55 mmol, 1.2 eq.) in tetrahydrofuran (20 mL), carbon tetrabromide (1.51 g, 4.55 mmol, 1.2 eq.) was added. The reaction mixture was stirred at 20°C for 1 h. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol = 1:0 to 50:1). 4-[1-(4-bromobut-2-ynyl)pyrazol-4-yl]-6-chloro-pyridazin-3-amine (1.0 g, 1.87 mmol, 49% yield) was obtained as a pale yellow solid.

Step 7

To a solution of 4-[1-(4-bromobut-2-ynyl)pyrazol-4-yl]-6-chloro-pyridazin-3-amine (1 g, 1.87 mmol, 1 eq.) and tert-butyl piperazine-1-carboxylate (696 mg, 3.74 mmol, 2 eq.) in acetonitrile (10 mL), N,N-diisopropylethylamine (724 mg, 5.60 mmol, 1.0 mL, 3 eq.) was added. The mixture was stirred at 80 °C for 12 h. Water (30 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol = 1:0 to 20:1). Tert-butyl 4-[4-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]but-2-ynyl]piperazine-1-carboxylate (600 mg, 1.34 mmol, 71% yield) was obtained as a brown solid.

Step 8

To a solution of tert-butyl 4-[4-[4-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-1-yl]but-2-ynyl]piperazine-1-carboxylate (500 mg, 1.16 mmol, 1 eq.), (2-hydroxyphenyl)boronic acid (192 mg, 1.39 mmol, 1.2 eq.) in dioxane (10 mL) and water (2 mL), potassium carbonate (400 mg, 2.89 mmol, 2.5 eq.) and tetrakis[triphenylphosphine]palladium(0) (134 mg, 0.12 mmol, 0.1 eq.) were added under nitrogen. The reaction mixture was stirred at 110 °C for 10 h. Water (100 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1). Tert-butyl 4-[4-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]but-2-ynyl]piperazine-1-carboxylate (340 mg, 0.65 mmol, 56% yield) was obtained as a pale yellow solid.

Using the procedures described for other examples above, tert-butyl 4-[4-[4-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-1-yl]but-2-ynyl]piperazine-1-carboxylate was converted to the final compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 83

Step 1

A 250 mL round bottom flask was charged with methyl 4-(1-hydroxyethyl)benzoate (2.5 g, 13.87 mmol, 1 equiv.), triphenylphosphine dibromide (5.9 g, 13.87 mmol, 1 equiv.) in DCM (100 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (v:v=1:12). This gave 2.3 g (68%) of methyl 4-(1-bromoethyl)benzoate as a colorless oil.

Step 2

A 30 mL vial was charged with methyl 4-(1-bromoethyl)benzoate (1.2 g, 4.94 mmol, 1 equiv.), 6-[2-(methoxymethoxy)phenyl]-4-(1H-pyrazol-4-yl)pyridazin-3-amine (1.2 g, 3.95 mmol, 0.80 equiv.), K2CO3 (2.0 g, 14.81 mmol, 3.00 equiv.), NaI (739.9 mg, 4.94 mmol, 1.00 equiv.) in DMF (15 mL). The resulting mixture was stirred in an oil bath at 60 °C for 3 h. The reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This gave 600 mg (26%) of methyl 4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]benzoate as a yellow oil.

Step 3

A 100 mL round bottom flask was charged with a solution of methyl 4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]benzoate (600 mg, 1.31 mmol, 1 equiv.) in THF (20 mL), to which LiAlH4 (495.6 mg, 13.06 mmol, 10.00 equiv.) was added at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was then quenched by adding Na2SO4.10H2O (4.8 g, 15.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. The solids in the reaction mixture were filtered and the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This gave 310 mg (55%) of [4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]methanol as a yellow oil.

Step 4

A 100 mL round bottom flask was charged with a solution of [4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]methanol (310 mg, 0.72 mmol, 1 equiv.) in DCM (10.0 mL, 117 mmol, 218 equiv.) to which manganese dioxide (1.2 g, 14.37 mmol, 20 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The solids were filtered and the filtrate was concentrated under reduced pressure. This afforded 286 mg (93%) of 4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]benzaldehyde as a yellow solid.

Step 5

A 100 mL round bottom flask was charged with 4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]benzaldehyde (300.0 mg, 0.70 mmol, 1 eq.), benzyl piperazine-1-carboxylate (185 mg, 0.84 mmol, 1.2 eq.), HOAc (0.1 mL, 1.75 mmol, 2.50 eq.) in DCM (10 mL). The resulting mixture was stirred for 0.5 h and then NaBH(OAc)3 (444.1 mg, 2.10 mmol, 3 eq.) was added. The resulting mixture was stirred for an additional 16 h at room temperature. The reaction mixture was then quenched by water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (20 mL x 2) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (v:v=10:1). This gave 260 mg (59%) of benzyl 4-([4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]methyl)piperazine-1-carboxylate as a yellow oil.

Step 6

A 100 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with a solution of benzyl 4-([4-[1-(4-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1H-pyrazol-1-yl)ethyl]phenyl]methyl)piperazine-1-carboxylate (260.0 mg, 0.41 mmol, 1 equiv.) in THF (8 mL) to which lithium triethylborohydride (2.1 mL, 2.05 mmol, 5.00 equiv.) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched by water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium, and concentrated. This gave 200 mg (98%) of 6-[2-(methoxymethoxy)phenyl]-4-[1-(1-[4-[(piperazin-1-yl)methyl]phenyl]ethyl)-1H-pyrazol-4-yl]pyridazin-3-amine as a yellow oil.

Using the procedures described above for other examples, 6-[2-(methoxymethoxy)phenyl]-4-[1-(1-[4-[(piperazin-1-yl)methyl]phenyl]ethyl)-1H-pyrazol-4-yl]pyridazin-3-amine was converted to the title compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 167

Step 1

To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (5 g, 16.7 mmol, 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.08 g, 20.0 mmol, 1.2 eq.) in dioxane (100 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (975 mg, 1.33 mmol, 0.08 eq.) and potassium acetate (3.27 g, 33.31 mmol, 2 eq.) were added. The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1). The compound tert-butyl N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (8.2 g, 16.44 mmol, 99% yield) was obtained as a yellow oil.

Step 2

A mixture of ethyl 5-bromothiazole-4-carboxylate (3.49 g, 14.77 mmol, 0.9 eq.), tert-butyl N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (5.70 g, 16.41 mmol, 1 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (120 mg, 0.16 mmol, 0.01 eq.), potassium carbonate (4.54 g, 32.83 mmol, 2 eq.) in a mixture of dioxane (130 mL) and water (22 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 80 °C under nitrogen atmosphere for 10 h. The reaction mixture was concentrated, water (50 mL) was added, and then extracted twice with ethyl acetate (60 mL). The combined organic layers were washed twice with a saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0 to 1:1). The compound ethyl 5-[4-[(1S)-1-(tert-butoxycarbonylamino)ethyl]phenyl]thiazole-4-carboxylate (5.07 g, 13.48 mmol, yield 82%) was obtained as a yellow solid.

Step 3

A solution of ethyl 5-[4-[(1S)-1-(tert-butoxycarbonylamino)ethyl]phenyl]thiazole-4-carboxylate (4 g, 10.63 mmol, 1 equiv.) in tetrahydrofuran (60 mL) was cooled to −78°C under nitrogen atmosphere. Then, diisobutylaluminum hydride THF solution (1 M, 11.69 mL, 1.1 equiv.) was added dropwise at −78°C. The reaction mixture was stirred at −78°C for 0.5 h. The reaction was quenched by adding methanol (2 mL) followed by water (50 mL). The mixture was extracted with ethyl acetate (40 mL x 2). The organic layer was dried over sodium sulfate and then concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (10-50% ethyl acetate in petroleum ether). The compound tert-butyl N-[(1S)-1-[4-(4-formylthiazol-5-yl)phenyl]ethyl]carbamate (3.2 g, 9.63 mmol, 91% yield) was obtained as a white solid.

Step 4

To a solution of dimethylamine hydrochloride (368 mg, 4.51 mmol, 0.41 mL, 3 eq.) in dichloromethane (30 mL), triethylamine (609 mg, 6.02 mmol, 0.84 mL, 4 eq.), a solution of tert-butyl N-[(1S)-1-[4-(4-formylthiazol-5-yl)phenyl]ethyl]carbamate (500 mg, 1.50 mmol, 1 eq.) in dichloromethane (10 mL), and sodium triacetoxyborohydride (1.28 g, 6.02 mmol, 4 eq.) were added and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by adding water (50 mL) and extracted twice with dichloromethane (40 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, and concentrated to give the product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1). The compound tert-butyl N-[(1S)-1-[4-[4-[(dimethylamino)methyl]thiazol-5-yl]phenyl]ethyl]carbamate (364 mg, 1.01 mmol, yield 67%) was obtained as a yellow oil.

Using the procedure described for exemplary compound 76, tert-butyl N-[(1S)-1-[4-[4-[(dimethylamino)methyl]thiazol-5-yl]phenyl]ethyl]carbamate was converted to the final product.

Exemplary Synthesis of Exemplary Compound 168

Step 1

To a mixture of ethyl 5-[4-[(1S)-1-(tert-butoxycarbonylamino)ethyl]phenyl]thiazole-4-carboxylate (900 mg, 2.39 mmol, 1 eq.) and calcium chloride (796 mg, 7.17 mmol, 3 eq.) in water (40 mL) and tetrahydrofuran (20 mL), sodium borohydride (181 mg, 4.78 mmol, 2 eq.) was added under nitrogen at 0°C. The mixture was warmed to 5°C and stirred for 2 h. Hydrochloric acid (5 M, 4.50 mL) and acetone (4.95 mL) were added at 0°C and the reaction mixture was stirred at 5°C for an additional 0.5 h. The pH was adjusted to 5 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (20 mL x 4). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by semi-preparative reverse phase HPLC (basic conditions, column: Waters Xbridge 150*50 10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 25%-55%, 11.5 min). The compound tert-butyl N-[(1S)-1-[4-[4-(hydroxymethyl)thiazol-5-yl]phenyl]ethyl]carbamate (400mg, 1.20mmol, 50% yield) was obtained as a white solid.

Using the procedure described for exemplary compound 76, tert-butyl N-[(1S)-1-[4-[4-(hydroxymethyl)thiazol-5-yl]phenyl]ethyl]carbamate was converted to the final product.

Exemplary compounds 211 and 219 are also prepared using procedures similar to those described above.

Exemplary Synthesis of Exemplary Compound 169

Step 1

Prepared using the procedure described for exemplary compound 168.

Step 2

To a solution of (5-bromothiazol-4-yl)methanol (980 mg, 5.05 mmol, 1 eq.) in THF (30 mL) was added sodium hydride (404 mg, 10.10 mmol, 2 eq.) under nitrogen at 0°C. The mixture was stirred at 0°C for 30 minutes, then iodomethane (3.58 g, 25.25 mmol, 1.57 mL, 5 eq.) was added at 0°C. The mixture was stirred under nitrogen at 15°C for 2 hours. The mixture was cooled to 0°C and slowly quenched with a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain 5-bromo-4-(methoxymethyl)thiazole (910 mg, 4.37 mmol, yield 86%) as a yellow solid.

Step 3

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 min and then heated to 80 °C for 1 h. The reaction mixture was cooled to 20 °C and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (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, crude) was obtained as a colorless oil.

Step 4

To a mixture of 5-bromo-4-(methoxymethyl)thiazole (900 mg, 4.33 mmol, 1 equiv.) and tert-butyl N-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (2.25 g, 6.49 mmol, 1.5 equiv.) in dioxane (30 mL) and water (5 mL), potassium carbonate (1.20 g, 8.65 mmol, 2 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (316 mg, 0.43 mmol, 0.1 equiv.) were added in one portion at 15°C under nitrogen. The mixture was stirred at 90°C for 3 h. The mixture was cooled to 15°C, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain tert-butyl N-[(1S)-1-[4-[4-(methoxymethyl)thiazol-5-yl]phenyl]ethyl]carbamate (1.87 g, crude) as a yellow solid.

Using the procedure described for exemplary compound 76, tert-butyl N-[(1S)-1-[4-[4-(methoxymethyl)thiazol-5-yl]phenyl]ethyl]carbamate tert-butyl N-[(1S)-1-[4-[4-(hydroxymethyl)thiazol-5-yl]phenyl]ethyl]carbamate was converted to the final product.

Exemplary compounds 184 and 185 were also prepared using procedures similar to those described above.

Exemplary Synthesis of Exemplary Compounds 170 and 134

Step 1

To a solution of methyl 2-[3-(3-hydroxypropyl)isoxazol-5-yl]-3-methyl-butanoate (460 mg, 1.91 mmol, 1 equiv.) in dichloromethane (5 mL) was added Dess-Martin periodinane (970 mg, 2.29 mmol, 1.2 equiv.). The reaction mixture was stirred at 20 °C for 1 h. Ethyl acetate (50 mL) was added to the mixture, the mixture was filtered, and the filtrate was concentrated in vacuum. The organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 50: 1). Methyl 3-methyl-2-[3-(3-oxopropyl)isoxazol-5-yl]butanoate (300 mg, 1.25 mmol, 65% yield) was obtained as a colorless oil.

Using the procedures described above for other examples, methyl 3-methyl-2-[3-(3-oxopropyl)isoxazol-5-yl]butanoate was converted to the final compound according to the following scheme.

Exemplary compounds 190 and 191 were prepared using procedures similar to those described above.

Exemplary Synthesis of Exemplary Compound 112

Step 1

To a solution of but-3-yn-1-ol (5 g, 71.34 mmol, 1 equiv.) in dichloromethane (150 mL), pyridinium p-toluenesulfonate (1.9 g, 7.56 mmol, 0.1 equiv.) and 3,4-dihydro-2H-pyran (9.48 g, 112.70 mmol, 10.3 mL, 1.58 equiv.) were added at 15°C, and the mixture was stirred at 15°C for 18 h. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-10:1). 2-but-3-ynoxytetrahydropyran (10.6 g, 68.74 mmol, 96% yield) was obtained as a colorless oil.

Step 2

To a solution of 2-but-3-ynoxytetrahydropyran (2 g, 12.97 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M, 5.7 mL, 1.1 eq.) at −78°C, and the mixture was stirred at −78°C for 1 h. Then, paraformaldehyde (2.10 g, 23.35 mmol, 1.8 eq.) was added to the mixture and stirred at −78°C for 30 min and at 20°C for 15 h. The mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with ethyl acetate (2×40 mL). The combined organic phase was dried over sodium sulfate and then concentrated to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1 to 0:1). 5-Tetrahydropyran-2-yloxypent-2-yn-1-ol (1.4 g, 7.60 mmol, 58% yield) was obtained as a colorless oil.

Step 3

To a mixture of 5-tetrahydropyran-2-yloxypent-2-yn-1-ol (1.4 g, 7.60 mmol, 1 eq.) and p-toluenesulfonyl chloride (2.90 g, 15.20 mmol, 2 eq.) in tetrahydrofuran (15 mL), potassium hydroxide (2.13 g, 38.00 mmol, 5 eq.) was added. The reaction mixture was then stirred at 20°C for 2 h. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50: 1 to 10: 1). Compound 5-tetrahydropyran-2-yloxypent-2-ynyl 4-methylbenzenesulfonate (2.5 g, 7.39 mmol, 97% yield) was obtained as a colorless oil.

Step 4

To a solution of 5-tetrahydropyran-2-yloxypent-2-ynyl 4-methylbenzenesulfonate (2.5 g, 7.39 mmol, 1 eq.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.72 g, 8.86 mmol, 1.2 eq.) in acetonitrile (20 mL), potassium carbonate (2.04 g, 14.77 mmol, 2 eq.) was added. The reaction mixture was then stirred at 80° C. for 12 h. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1). The compound 1-(5-tetrahydropyran-2-yloxypent-2-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2 g, 5.55 mmol, 75% yield) was obtained as a pale yellow oil.

Using the procedures described above for other examples, 1-(5-tetrahydropyran-2-yloxypent-2-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole was converted to the final compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 131

Using procedures described for other examples above and that would be apparent to one of skill in the art, (2S,4R)—N-((R)-2-(dimethylamino)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-oxoethyl)-4-hydroxypyrrolidine-2-carboxamide was prepared according to the following scheme.

Using the procedures described for other examples above, (2S,4R)-N-((R)-2-(dimethylamino)-1-(4-(4-methylthiazol-5-yl)phenyl)-2-oxoethyl)-4-hydroxypyrrolidine-2-carboxamide was converted to the final compound.

Exemplary compound 171 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 172

Step 1

To a solution of tert-butyl N-[(1S)-1-[4-(4-formylthiazol-5-yl)phenyl]ethyl]carbamate (2 g, 6.02 mmol, 1 eq.) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.16 g, 6.02 mmol, 1 eq.) in methanol (20 mL) was added potassium carbonate (1.66 g, 12.03 mmol, 2 eq.) at 0 °C. The reaction mixture was stirred at 15 °C for 16 h. Then 1-diazo-1-dimethoxyphosphoryl-propan-2-one (116 mg, 0.60 mmol, 0.1 eq.) was added and the reaction mixture was stirred at 15 °C for an additional 1 h. Ethyl acetate (50 mL) and water (40 mL) were added and the mixture was separated. The organic layer was dried over sodium sulfate and then concentrated under vacuum to give a residue that was purified by silica gel column chromatography (10-30% ethyl acetate in petroleum ether) to give tert-butyl N-[(1S)-1-[4-(4-ethynylthiazol-5-yl)phenyl]ethyl]carbamate (1.8 g, 5.48 mmol, 91% yield) as a white solid.

Step 2

To a solution of tert-butyl N-[(1S)-1-[4-(4-ethynylthiazol-5-yl)phenyl]ethyl]carbamate (400 mg, 1.22 mmol, 1 equiv.), dimethylamine (1.37 g, 12.18 mmol, 1.54 mL, 10 equiv.), and triformol (362 mg, 4.02 mmol, 3.3 equiv.) in dioxane (8 mL) was added copper iodide (232 mg, 1.22 mmol, 1 equiv.) at 0°C. The reaction mixture was degassed and filled with nitrogen three times, then stirred at 30°C for 4 h. The reaction solution was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (0-8% methanol in dichloromethane) to give tert-butyl N-[(1S)-1-[4-[4-[3-(dimethylamino)prop-1-ynyl]thiazol-5-yl]phenyl]ethyl]carbamate (274 mg, 0.71 mmol, 58% yield) as a pale yellow gum.

Using the procedure described for exemplary compound 76, tert-butyl N-[(1S)-1-[4-[4-[3-(dimethylamino)prop-1-ynyl]thiazol-5-yl]phenyl]ethyl]carbamate was converted to the final compound.

Exemplary Synthesis of Exemplary Compound 132

Step 1

To a mixture of 2,2-diethoxyethanol (22.87 g, 170 mmol, 1.5 equiv.) and 4-bromo-2-fluoro-pyridine (20 g, 113.65 mmol, 1 equiv.) in acetonitrile (200 mL), cesium carbonate (74.06 g, 227 mmol, 2 equiv.) was added in one portion under nitrogen at 15°C. The mixture was stirred at 90°C for 3 h. The mixture was cooled to 20°C, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether) to give 4-bromo-2-(2,2-diethoxyethoxy)pyridine (22.8 g, 74.7 mmol, 66% yield) as a yellow oil.

Step 2

To a mixture of 4-bromo-2-(2,2-diethoxyethoxy)pyridine (10 g, 34.46 mmol, 1 eq.) and benzyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (8.49 g, 34.46 mmol, 1 eq.) in toluene (200 mL), cesium carbonate (22.46 g, 68.93 mmol, 2 eq.) and [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (1.61 g, 2.07 mmol, 0.06 eq.) were added in one portion under nitrogen at 15 °C. The mixture was stirred at 110 °C for 12 h. The mixture was cooled to 20 °C, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1, 3/1) to obtain benzyl 8-[2-(2,2-diethoxyethoxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (12.1 g, 26.6 mmol, 77% yield) as a yellow oil.

Step 3

To a solution of benzyl 8-[2-(2,2-diethoxyethoxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (13.1 g, 28.76 mmol, 1 equiv.) in tetrahydrofuran (300 mL) and ethanol (300 mL) was added 10% palladium hydroxide on carbon (4.04 g, 2.88 mmol, 0.1 equiv.) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 60 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. Crude 8-[2-(2,2-diethoxyethoxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane (8.27 g, 25.73 mmol, 89.47% yield) was obtained as a brown oil.

Using procedures described for other examples above, as well as standard procedures that would be apparent to one of skill in the art, 8-[2-(2,2-diethoxyethoxy)-4-pyridyl]-3,8-diazabicyclo[3.2.1]octane was converted to the final compound according to the following scheme.

Using procedures similar to those described for exemplary compound 132, the following exemplary compounds were prepared: 135, 136, 139, 141, 133, 140, 142, and 210.

Exemplary Synthesis of Exemplary Compounds 173 and 102

Step 1

A 250 mL three-neck round bottom flask purged and maintained under nitrogen inert atmosphere was charged with 1,4-dibromobenzene (12.0 g, 50.8 mmol, 1.0 equiv) in THF (150.0 mL) at -78 °C. Then, n-butyllithium solution (1 M in hexanes, 60.9 mL, 60.9 mmol, 1.2 equiv) was added at -78 °C. The resulting mixture was stirred at -78 °C for 30 minutes, and then 2,2-difluoroethyl acetate (12.6 g, 101.5 mmol, 2.0 equiv) was added slowly at -78 °C. The cooling bath was removed and the resulting mixture was stirred at room temperature for an additional hour. The reaction was then quenched by adding 50 mL of water. The resulting mixture was extracted with ethyl acetate (250 mL x 3), and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:10). This gave 7.6 g (64%) of 1-(4-bromophenyl)-2,2-difluoroethan-1-one as a pale yellow semi-solid.

Step 2

In a 30 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, 1-(4-bromophenyl)-2,2-difluoroethan-1-one (3.5 g, 14.9 mmol, 1.0 equiv.), (S)-2-methylpropane-2-sulfinamide (3.6 g, 29.8 mmol, 2.0 equiv.), and tetrakis(propan-2-yloxy)titanium (12.7 g, 44.7 mmol, 3.0 equiv.) in THF (10 mL) were placed under nitrogen atmosphere. The resulting mixture was stirred at 80 °C in an oil bath under nitrogen atmosphere for 14 h. The mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:5). This yielded 2.8 g (56%) of (S)-N-[(1Z)-1-(4-bromophenyl)-2,2-difluoroethylidene]-2-methylpropane-2-sulfinamide as a yellow oil.

Step 3

A solution of (S)-N-[(1Z)-1-(4-bromophenyl)-2,2-difluoroethylidene]-2-methylpropane-2-sulfinamide (2.8 g, 8.3 mmol, 1 equiv.) and BH3-THF (40.0 mL, 40.0 mmol, 1.0 M, 4.8 equiv.) in THF (40.0 mL) was placed in a 250 mL three-neck round bottom flask purged and maintained under nitrogen inert atmosphere at 0°C. The resulting mixture was stirred at 0°C for 1 h, then warmed to room temperature and stirred at room temperature for an additional 6 h. The reaction was quenched by the addition of 100 mL of water. The resulting mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with dichloromethane/petroleum ether (1:1). This yielded 1.3 g (45%) of (S)-N-[(1R)-1-(4-bromophenyl)-2,2-difluoroethyl]-2-methylpropane-2-sulfinamide as a white solid.

Step 4

A 30 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with (S)-N-[(1R)-1-(4-bromophenyl)-2,2-difluoroethyl]-2-methylpropane-2-sulfinamide (1.3 g, 3.8 mmol, 1.0 equiv.), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (1.25 g, 5.5 mmol, 1.5 equiv.), K2CO3 (1.5 g, 11.3 mmol, 3.0 equiv.), and Pd(dppf)Cl2. CH2Cl2 (62.0 mg, 0.08 mmol, 0.02 equiv.) in dioxane (15.0 mL) and water (3.0 mL) under nitrogen atmosphere. The resulting suspension was stirred at 90 °C for 12 h in an oil bath under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This gave 750.0 mg (56%) of (S)-N-[(1R)-2,2-difluoro-1-[4-(4-methyl-1,3-thiazol-5-yl)-phenyl]ethyl]-2-methylpropane-2-sulfinamide as a pale yellow solid.

Using procedures similar to those described for other examples in this application, (S)-N-[(1R)-2,2-difluoro-1-[4-(4-methyl-1,3-thiazol-5-yl)-phenyl]ethyl]-2-methylpropane-2-sulfinamide was converted to the final compound according to the following scheme:

Exemplary compounds 267 and 268 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compound 174

Step 1

To a solution of tert-butyl N-[(1S)-1-[4-[4-(hydroxymethyl)thiazol-5-yl]phenyl]ethyl]carbamate (400 mg, 1.20 mmol, 1 equiv.), isoindoline-1,3-dione (352 mg, 2.39 mmol, 2 equiv.), and triphenylphosphine (471 mg, 1.79 mmol, 1.5 equiv.) in tetrahydrofuran (8 mL) was added N,N-diisopropyl azodicarboxylate (290 mg, 1.44 mmol, 0.27 mL, 1.2 equiv.) at 0°C. The mixture was stirred at 15°C for 16 h. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to produce tert-butyl N-[(1S)-1-[4-[4-[(1,3-dioxoisoindolin-2-yl)methyl]thiazol-5-yl]phenyl]ethyl]carbamate (560 mg) as a white solid.

Step 2

A mixture of tert-butyl N-[(1S)-1-[4-[4-[(1,3-dioxoisoindolin-2-yl)methyl]thiazol-5-yl]phenyl]ethyl]carbamate (600 mg, 1.29 mmol, 1 eq.) and hydrazine hydrate (661 mg, 12.94 mmol, 0.64 mL, 98% purity, 10 eq.) in ethanol (24 mL) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 70°C for 3 h. The reaction mixture was filtered and the filter cake was washed with ethanol (30 mL). The filtrate was concentrated to give the crude product. Compound tert-butyl N-[(1S)-1-[4-[4-(aminomethyl)thiazol-5-yl]phenyl]ethyl]carbamate (530 mg, crude) was obtained as a white solid.

Step 3

To a solution of tert-butyl N-[(1S)-1-[4-[4-(aminomethyl)thiazol-5-yl]phenyl]ethyl]carbamate (618 mg, 1.85 mmol, 1 eq.) and triethylamine (563 mg, 5.56 mmol, 0.77 mL, 3 eq.) in dichloromethane (30 mL), acetic anhydride (227 mg, 2.22 mmol, 0.21 mL, 1.2 eq.) was added at 0°C. The mixture was stirred at 15°C for 3 h. The reaction mixture was diluted with water (30 mL) and then the organic layer was concentrated to give the crude product. The crude product was purified by preparative TLC (dichloromethane:methanol=10:1). The compound tert-butyl N-[(1S)-1-[4-[4-(acetamidomethyl)thiazol-5-yl]phenyl]ethyl]carbamate (400 mg, 1.07 mmol, yield 58%) was obtained as a white solid.

Using the procedure described for exemplary compound 76, tert-butyl N-[(1S)-1-[4-[4-(acetamidomethyl)thiazol-5-yl]phenyl]ethyl]carbamate was converted to the final compound.

Exemplary Synthesis of Exemplary Compound 175 Step 1

To a solution of tert-butyl N-[(1S)-1-[4-(4-ethynylthiazol-5-yl)phenyl]ethyl]carbamate (1.73 g, 5.27 mmol, 1 eq.) in tetrahydrofuran (50 mL) was added n-butyllithium (2.5 M, 4.42 mL, 2.1 eq.) under nitrogen at −78°C. The reaction mixture was stirred at −50°C for 2 h. Triformol (474 mg, 5.27 mmol, 1 eq.) was then added and the reaction mixture was warmed to 10°C for 22 h. The reaction mixture was stirred at 10°C for an additional 20 h. Water (40 mL) was added and the mixture was extracted with ethyl acetate (40 mL). The organic layer was dried over sodium sulfate and then concentrated under vacuum. The residue was purified by silica gel column chromatography (10-80% ethyl acetate in petroleum ether) to give tert-butyl N-[(1S)-1-[4-[4-(3-hydroxyprop-1-ynyl)thiazol-5-yl]phenyl]ethyl]carbamate (480 mg, 1.34 mmol, 25% yield) as a white solid. 950 mg of starting material was recovered.

Using the procedure described for exemplary compound 174, tert-butyl N-[(1S)-1-[4-[4-(3-hydroxyprop-1-ynyl)thiazol-5-yl]phenyl]ethyl]carbamate was converted to tert-butyl (S)-(1-(4-(4-(3-acetamidoprop-1-yn-1-yl)thiazol-5-yl)phenyl)ethyl)carbamate.

Using a procedure similar to that described for exemplary compound 76, tert-butyl (S)-(1-(4-(4-(3-acetamidoprop-1-yn-1-yl)thiazol-5-yl)phenyl)ethyl)carbamate was converted to the final compound.

Exemplary Synthesis of Exemplary Compound 178

Prepared according to the following scheme using the procedures described above.

Exemplary compound 176 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 180

Prepared according to the following scheme using the procedures described above.

Exemplary compound 179 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 183

Step 1

To a solution of 2,2-diethoxyethanol (2.06 g, 15.38 mmol, 1.5 eq.) in THF (50 mL) was added sodium hydride (615 mg, 15.38 mmol, 60% purity, 1.5 eq.) at 0°C and the mixture was stirred at 0°C for 30 minutes. To this was then added a solution of tert-butyl 2-bromoacetate (2 g, 10.25 mmol, 1.52 mL, 1 eq.) in THF (50 mL) at 0°C and the reaction mixture was stirred under nitrogen at 15°C for 2 hours. The mixture was cooled to 0°C and quenched by a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1 to 20/1) to obtain tert-butyl 2-(2,2-diethoxyethoxy)acetate (883 mg, 3.56 mmol, 34% yield) as a yellow oil.

Step 2

To tert-butyl 2-(2,2-diethoxyethoxy)acetate (0.7 g, 2.82 mmol, 1 equiv.) in a mixture of THF (3 mL), methanol (3 mL), and water (6 mL) was added lithium hydroxide monohydrate (1.18 g, 28.19 mmol, 10 equiv.) in one portion at 15°C under nitrogen. The mixture was stirred for 2 h. The pH was adjusted to 6 with 1 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (35 mL x 4). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product 2-(2,2-diethoxyethoxy)acetic acid (460 mg, crude) was obtained as a yellow oil.

Step 3

To a mixture of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (0.2 g, 0.45 mmol, 1 eq.) and 2-(2,2-diethoxyethoxy)acetic acid (87 mg, 0.45 mmol, 1 eq.) in N,N-dimethylformamide (10 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (222 mg, 0.59 mmol, 1.3 eq.) and triethylamine (137 mg, 1.35 mmol, 0.19 mL, 3 eq.) were added in one portion under nitrogen at 15°C. The mixture was stirred at 15°C for 1 h. The mixture was poured into ice water (w/w=1/1, 20 mL) and stirred for 5 min. The aqueous layer was extracted with ethyl acetate (20 mL×4). The combined organic phase was washed with brine (15 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by semi-preparative reverse phase HPLC (formic acid condition; column: Phenomenex Synergi C18 150*25*10um mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 9 min). The product (2S,4R)-1-[(2S)-2-[[2-(2,2-diethoxyethoxy)acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (230 mg, 0.37 mmol, 82% yield) was obtained as a yellow oil.

According to the scheme below and using the procedures described above for other examples, (2S,4R)-1-[(2S)-2-[[2-(2,2-diethoxyethoxy)acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide was converted to the final compound.

Exemplary Synthesis of Exemplary Compound 86

Step 1

At 0 °C, to a solution of PPh3 (4.68 g, 17.836 mmol, 3.0 equiv.) in THF (100 mL) was added DIAD (3.61 g, 17.836 mmol, 3.0 equiv.), and (1s,3s)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutan-1-ol (3.0 g, 5.945 mmol, 1 equiv.) under nitrogen atmosphere. To the above mixture was added 6-bromopyridin-3-ol (2.07 g, 11.891 mmol, 2.0 equiv.) dropwise over 5 min at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 5 minutes, then heated to 50°C and stirred at 50°C for 2 hours. The reaction was quenched with water (25 mL) and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (10:1) to give 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-bromopyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (2.3 g, 59%) as a pale yellow solid.

Step 2

The following reaction was carried out in four parallel equal batches and combined for workup and purification. In each batch, 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-[(6-bromopyridin-3-yl)oxy]cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (571 mg, 0.864 mmol, 1.00 equiv.) and tert-butyl ether in 1,4-dioxane (15 mL) and water (5 mL). To a solution of dimethyl[[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]oxy]silane (387 mg, 1.297 mmol, 1.50 equiv.) was added K2CO3 (1.07 g, 0.008 mmol, 3.0 equiv.) and Pd(dppf)Cl2-CH2Cl2 (105 mg, 0.130 mmol, 0.15 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. Each reaction was quenched by adding water (50 mL) at room temperature and the resulting mixtures were combined and extracted with EtOAc (90 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (10:1) to give 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-([6-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]pyridin-3-yl]oxy)cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (total 2.1 g, 76%) as a pale yellow solid.

Step 3

To a stirred solution of 6-[2-(methoxymethoxy)phenyl]-4-(8-[2-[(1r,3r)-3-([6-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]pyridin-3-yl]oxy)cyclobutoxy]pyridin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-amine (2.10 g, 2.79 mmol, 1.00 equiv.) in THF (20 mL), TBAF (1 mol/L, 8.3 mL, 8.3 mmol, 3.0 equiv.) was added dropwise at 0° C. under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding water (25 mL). The resulting mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This gave 3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-ol (1.1 g, 62%) as a pale yellow solid.

Step 4

To a solution of tributylphosphine (634 mg, 3.14 mmol, 10.00 equiv.) and tetramethylazodicarboxamide (588 mg, 3.14 mmol, 10.00 equiv.) in THF, (2S,4R)-4-hydroxy-1-[2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (172 mg, 0.345 mmol, 1.10 equiv.) and (2E)-3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-ol (70 mg, 0.11 mmol, 1 equiv.) were added under nitrogen atmosphere at −10° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction was quenched by adding water (50 mL) at room temperature and the resulting mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to give (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[3-methyl-2-(3-[[(2E)-3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-yl]oxy]-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide (120 mg, 34%) as a pale yellow solid.

Using standard procedures described above for other examples, (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[3-methyl-2-(3-[[(2E)-3-[5-[(1r,3r)-3-[[4-(3-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl]oxy]cyclobutoxy]pyridin-2-yl]prop-2-en-1-yl]oxy]-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide was converted to the final compound.

Exemplary compounds 186, 206, and 207 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compound 189

Step 1

To a solution of tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (2 g, 7.37 mmol, 1 eq.) in N,N-dimethylformamide (40 mL) was added sodium hydride (353 mg, 8.84 mmol, 60% purity, 1.2 eq.) at 0°C. The mixture was stirred at 25°C for 1 h. Then, 2-benzyloxyethyl 4-methylbenzenesulfonate (3.39 g, 11.06 mmol, 1.5 eq.) in N,N-dimethylformamide (2 mL) was added. The mixture was stirred at 60°C for 15 h. The reaction mixture was quenched by adding water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 50ACN%-80ACN%, 26 min, 20% min). The compound tert-butyl 4-[3-(2-benzyloxyethoxy)cyclobutoxy]piperidine-1-carboxylate (2.1 g, 5.18 mmol, 70% yield) was obtained as a colorless oil.

Step 2

To a solution of tert-butyl 4-[3-(2-benzyloxyethoxy)cyclobutoxy]piperidine-1-carboxylate (2.1 g, 5.18 mmol, 1 equiv.) in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 5% palladium on activated carbon catalyst (500 mg) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 Psi) at 25°C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The compound tert-butyl 4-[3-(2-hydroxyethoxy)cyclobutoxy]piperidine-1-carboxylate (1.6 g, 5.07 mmol, 97% yield) was obtained as a colorless oil.

Using the procedures described above for other examples, tert-butyl 4-[3-(2-hydroxyethoxy)cyclobutoxy]piperidine-1-carboxylate was converted to the final compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 194

Step 1

To a solution of 1,4-dimethyl-1H-pyrazole (2.5 g, 26.0 mmol, 1 eq.) in tetrahydrofuran (50 mL), n-butyllithium in hexane solution (2.5 M in hexane, 78.0 mmol, 31 mL, 3 eq.) was added dropwise at 0°C under nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h and then cooled to -78°C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.52 g, 78.017 mmol, 3 eq.) was added and the reaction mixture was stirred at -78°C for 0.5 h and then slowly warmed to 0°C. The reaction was quenched with brine and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This yielded 2.6 g (45%) of 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid.

Step 2

A 250 mL round-bottom flask was charged with tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (1.0 g, 3.331 mmol, 1 equiv.), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.48 g, 6.664 mmol, 2.00 equiv.), K2CO3 (1.38 g, 9.963 mmol, 2.99 equiv.), and Pd(dppf)Cl2 (244.0 mg, 0.333 mmol, 0.10 equiv.) in dioxane (16 mL) and H2O (2 mL). The resulting mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This yielded 1.63 g (99%) of benzyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate as a pale yellow solid.

Benzyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate was converted to the final compound using the procedures described above for other examples.

Exemplary compound 193 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 144

Step 1

To a solution of 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoic acid (1 g, 5.40 mmol, 1 equiv.) in methanol (10 mL) was added thionyl chloride (2.57 g, 21 mmol, 1.57 mL, 4 equiv.) at 0 °C. The reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (1 g, 5.02 mmol, 92% yield) was obtained as a yellow oil.

Step 2

To a solution of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (800 mg, 4.02 mmol, 1 eq.) in acetonitrile (5 mL), potassium carbonate (1.11 g, 8.03 mmol, 2 eq.) and perfluorobutylsulfonyl fluoride (1.46 g, 4.82 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (80 mL x 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 20/1). Methyl 3-methyl-2-[3-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)isoxazol-5-yl]butanoate (530 mg, 1.10 mmol, 27% yield) was obtained as a colorless oil.

Step 3

A solution of methyl 3-methyl-2-[3-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)isoxazol-5-yl]butanoate (400 mg, 0.83 mmol, 1 eq.) and tert-butyl piperazine-1-carboxylate (154 mg, 0.83 mmol, 1 eq.) in dimethylformamide (5 mL) was stirred at 130 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1). Tert-butyl 4-[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]piperazine-1-carboxylate (130 mg, 0.35 mmol, 42% yield) was obtained as a colorless oil.

Step 4

To a solution of tert-butyl 4-[5-(1-methoxycarbonyl-2-methyl-propyl)isoxazol-3-yl]piperazine-1-carboxylate (130 mg, 0.35 mmol, 1 equiv.) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL) was added lithium hydroxide (44 mg, 1.06 mmol, 3 equiv.). The reaction mixture was stirred at 15°C for 1 h. Water (3 mL) was added. The pH was adjusted to 6 with hydrochloric acid (1M in water) and extracted with ethyl acetate (10 mL x 5). The combined organic layers were washed with brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 2-[3-(4-tert-butoxycarbonylpiperazin-1-yl)isoxazol-5-yl]-3-methyl-butanoic acid (100 mg, 0.28 mmol, 79% yield) was obtained as a white solid.

Step 5

To a solution of 2-[3-(4-tert-butoxycarbonylpiperazin-1-yl)isoxazol-5-yl]-3-methyl-butanoic acid (100 mg, 0.28 mmol, 1 equiv.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129 mg, 0.33 mmol, 1.2 equiv.) in dimethylformamide (5 mL), (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (104 mg, 0.28 mmol, 1 equiv.) and diisopropylethylamine (109 mg, 0.84 mmol, 3 equiv.) were added. 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 x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1). tert-Butyl 4-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]piperazine-1-carboxylate (180 mg, 0.26 mmol, 92% yield) was obtained as a colorless oil.

Step 6

tert-Butyl 4-[5-[1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]piperazine-1-carboxylate (200 mg, 0.29 mmol, 1 equiv.) was separated by chiral supercritical fluid chromatography. Instrument: CASWH-Prep-SFC-C, SFC Column: DAICEL Chiralpak AS (250 mm*30 mm, 10 um); Mobile phase: Ethanol in CO2 (0.1% NH3.H2O), 25%-25%; Flow rate: 55 g/min, Wavelength: 220 nm. Obtained tert-butyl 4-[5-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]piperazine-1-carboxylate (80 mg, 0.11 mmol, 76% yield, 95% purity) as a white solid. tert-Butyl 4-[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]piperazine-1-carboxylate (70 mg, 0.1 mmol, 68% yield, 98% purity) was obtained as a white solid.

Step 7

To a solution of tert-butyl 4-[5-[(1R)-1-[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]-2-methyl-propyl]isoxazol-3-yl]piperazine-1-carboxylate (70 mg, 0.1 mmol, 1 equiv.) in dichloromethane (2 mL) was added hydrochloric acid (4 M in dioxane, 3 mL). The reaction mixture was stirred at 15°C for 1 h. The reaction mixture was concentrated under reduced pressure. (2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-piperazin-1-ylisoxazol-5-yl)butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (55 mg, 0.09 mmol, 91% yield) was obtained as a white solid.

Step 8

(2S,4R)-4-hydroxy-1-[(2R)-3-methyl-2-(3-piperazin-1-ylisoxazol-5-yl)butanoyl]-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (100 mg, 0.16 mmol, 1 equiv., hydrochloride salt), 1,2-dibromoethane (31 mg, 0.1 To a mixture of 2-[6-amino-5-[8-[2-[3-(4-piperidyloxy)cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol dihydrochloride (102 mg, 0.16 mmol, 1 eq.), N,N-diisopropylethylamine (128 mg, 0.99 mmol, 6 eq.) was added. The mixture was stirred at 100° C. under microwave for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Phenomenex Synergi C18 150*25*10 um; Mobile phase: [Water (0.225% FA)-ACN]; B%: 5%-35%, 10 min). The compound (2S,4R)-1-[(2R)-2-[3-[4-[2-[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]ethyl]piperazin-1-yl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide formate (24.6 mg, 0.02 mmol, 12% yield) was obtained as an off-white solid.

Prepared using a similar procedure as exemplary compound 195.

Exemplary Synthesis of Exemplary Compounds 197 and 352

Prepared using procedures similar to those described for exemplary compounds 112 and 116.

Exemplary Synthesis of Exemplary Compound 114

Step 1

To a solution of ethyl 2-fluoro-3-oxo-butanoate (33.6 g, 226.82 mmol, 28.47 mL, 1 eq.) and ethylene glycol (70.39 g, 1.13 mol, 63.42 mL, 5 eq.) in toluene (500 mL), boron trifluoride ethyl etherate (3.36 g, 23.67 mmol, 2.92 mL, 0.1 eq.) was added. The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (300 mL) and extracted twice with ethyl acetate (300 mL). The combined organic phase was washed twice with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 10: 1). The compound ethyl 2-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)acetate (29.3 g, 152.5 mmol, yield 67%) was obtained as a colorless oil.

Step 2

To a solution of ethyl 2-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)acetate (29.3 g, 152.46 mmol, 1 eq.) and hydroxylamine hydrochloride (21.19 g, 304.92 mmol, 2 eq.) in pyridine (164 mL), sodium methoxide (28%) in methanol (61 mL) was added dropwise over 1 h at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered, and the filtrate was diluted with tetrahydrofuran (500 mL) and further filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to give the product. Compound 2-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)ethanehydroxamic acid (10.4 g, 58.1 mmol, 38% yield) was obtained as an orange oil.

Step 3

A solution of 2-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)ethanehydroxamic acid (10.35 g, 57.77 mmol, 1 eq.) in sulfuric acid (18 M, 50 mL, 15.58 eq.) was stirred at 70 °C for 2 h. The reaction mixture was poured into ice water (250 mL) and then extracted twice with ethyl acetate (250 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was used directly in the next step without purification. Compound 4-fluoro-5-methyl-isoxazol-3-ol (4.60 g, 39.29 mmol) was obtained as a yellow solid.

Step 4

To a solution of 4-fluoro-5-methyl-isoxazol-3-ol (5.7 g, 48.69 mmol, 1 eq.) in dichloromethane (228 mL), p-toluenesulfonic acid monohydrate (926 mg, 4.87 mmol, 0.1 eq.) and 3,4-dihydro-2H-pyran (20.48 g, 243.43 mmol, 22.26 mL, 5 eq.) were added. The mixture was stirred at 20 °C for 10 h. The reaction mixture was poured into water (100 mL) and the pH was adjusted to 7 with saturated sodium bicarbonate solution (60 mL). The mixture was then extracted twice with dichloromethane (200 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 8:1). The compound 4-fluoro-5-methyl-3-tetrahydropyran-2-yloxy-isoxazole (7.94 g, 39.5 mmol, yield 81%) was obtained as a yellow solid.

Step 5

To a solution of 4-fluoro-5-methyl-3-tetrahydropyran-2-yloxy-isoxazole (8.07 g, 40.13 mmol, 1 eq.) in tetrahydrofuran (115 mL), potassium bis(trimethylsilyl)amide (1 M, 60.20 mL, 1.5 eq.) was added dropwise under nitrogen at −78° C. and the reaction mixture was stirred at −78° C. for 0.5 h. Carbon dioxide (15 psi) was then bubbled through the reaction mixture at −78° C. for 1 h and the mixture was stirred at 20° C. for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (150 mL) and extracted twice with ethyl acetate (100 mL). The aqueous layer was adjusted to pH=3 at 0° C. with aqueous hydrochloric acid (1 M) and then extracted with chloroform and isopropanol (v/v=5:1, 150 mL, 3 times). The combined layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. Compound 2-(4-fluoro-3-tetrahydropyran-2-yloxy-isoxazol-5-yl)acetic acid (8.07 g, 32.91 mmol) was obtained as a yellow solid.

Step 6

To a solution of 2-(4-fluoro-3-tetrahydropyran-2-yloxy-isoxazol-5-yl)acetic acid (7.87 g, 32.10 mmol, 1 eq.) in a mixture of methanol (70 mL) and ethyl acetate (70 mL), trimethylsilyl diazomethane ether solution (2 M, 24.07 mL, 1.5 eq.) was added dropwise at -10 °C, and the mixture was stirred at -10 °C for 1 h. The reaction mixture was adjusted to pH = 7 with acetic acid, and ethyl acetate (150 mL) was added. The organic layer was washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1). The compound methyl 2-(4-fluoro-3-tetrahydropyran-2-yloxy-isoxazol-5-yl)acetate (4.51 g, 17.40 mmol, yield 54%) was obtained as a colorless oil.

Step 7

To a solution of methyl 2-(4-fluoro-3-tetrahydropyran-2-yloxy-isoxazol-5-yl)acetate (4.42 g, 17.05 mmol, 1 equiv.) in dimethylformamide (66 mL) was added potassium tert-butoxide (2.87 g, 25.58 mmol, 1.5 equiv.) at 0°C, followed by 2-iodopropane (3.48 g, 20.46 mmol, 2.05 mL, 1.2 equiv.). The mixture was stirred at 20°C for 12 h. The reaction mixture was diluted with water (60 mL) and extracted three times with ethyl acetate (80 mL). The combined layers were washed twice with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether). The compound methyl 2-(4-fluoro-3-tetrahydropyran-2-yloxy-isoxazol-5-yl)-3-methyl-butanoate (5.25 g) was obtained as a yellow oil.

Step 8

To a solution of methyl 2-(4-fluoro-3-tetrahydropyran-2-yloxy-isoxazol-5-yl)-3-methyl-butanoate (5.48 g, 18.19 mmol, 1 eq.) in a mixture of dichloromethane (20 mL) and tetrahydrofuran (5 mL) and water (5 mL), hydrochloric acid/dioxane (4 M, 30.00 mL, 6.60 eq.) was added. The mixture was stirred at 20 °C for 20 h. The reaction mixture was poured into saturated sodium carbonate solution (300 mL) and then extracted three times with methyl tert-butyl ether (100 mL). The pH of the aqueous layer was adjusted by adding hydrochloric acid solution (3 M) until pH = 2. The aqueous layer was extracted three times with chloroform (150 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. The residue was purified by semi-preparative reverse phase (column: Kromasil 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 21ACN% to 51ACN%, 29 min, 79% min). The compound methyl 2-(4-fluoro-3-hydroxy-isoxazol-5-yl)-3-methyl-butanoate (1.27g, 5.86mmol, 32% yield) was obtained as a white solid.

Step 9

Methyl 2-(4-fluoro-3-hydroxy-isoxazol-5-yl)-3-methyl-butanoate (0.5 g, 2.30 mmol, 1 eq.), 2-bromo-1,1-diethoxy-ethane (907 mg, 4.60 mmol, 0.69 mL, 2 eq.) and potassium carbonate (636 mg, 4.60 mmol, 2 eq.) were taken in a microwave tube in dimethylsulfoxide (8 mL). The sealed tube was heated under microwave irradiation at 80 °C for 2 h. After LCMS showed starting material still remained, the sealed tube was heated under microwave irradiation at 80 °C for an additional 2 h. The mixture was filtered and concentrated in vacuo. The residue was purified by semi-preparative reverse phase (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 9 min). Compound methyl 2-[3-(2,2-diethoxyethoxy)-4-fluoro-isoxazol-5-yl]-3-methyl-butanoate (266 mg, 0.80 mmol, 35% yield) was obtained as a yellow oil, and 46 mg of methyl 2-(4-fluoro-3-hydroxy-isoxazol-5-yl)-3-methyl-butanoate was recovered.

Using a procedure similar to that described above for exemplary compound 76, methyl 2-[3-(2,2-diethoxyethoxy)-4-fluoro-isoxazol-5-yl]-3-methyl-butanoate was converted to the final compound.

Exemplary compounds 198, 208, 209, 269, and 270 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compound 200

Step 1

To a solution of (2R)-2-amino-2-(4-bromophenyl)ethanol (1.74 g, 6.89 mmol, 1 eq., hydrochloride salt) in tetrahydrofuran (25 mL) was added triethylamine (2.79 g, 27.56 mmol, 3.84 mL, 4 eq.) and tert-butoxycarbonyl tert-butyl carbonate (1.80 g, 8.27 mmol, 1.90 mL, 1.2 eq.). The mixture was stirred at 30°C for 12 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with aqueous brine solution (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with petroleum ether/ethyl acetate (22 mL, v:v=10:1). The compound tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxy-ethyl]carbamate (2 g, 6.33 mmol, 91% yield) was obtained as a white solid.

Step 2

A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxy-ethyl]carbamate (2.0 g, 6.33 mmol, 1 eq.), 4-methylthiazole (1.25 g, 12.65 mmol, 1.15 mL, 2 eq.), potassium acetate (1.24 g, 12.65 mmol, 2 eq.), and palladium acetate (142 mg, 0.63 mmol, 0.1 eq.) in dimethylacetamide (40 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100°C under nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to remove dimethylacetamide. The residue was extracted with ethyl acetate (40 mL x 2) and washed with saturated brine (40 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to 1/2). The compound tert-butyl N-[(1R)-2-hydroxy-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate (1.45 g, 3.98 mmol, 63% yield) was obtained as a yellow oil.

Using a procedure similar to that described for exemplary compound 180 above, tert-butyl N-[(1R)-2-hydroxy-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamate was converted to the final compound.

Exemplary compounds 199, 158, and 100 were prepared using similar procedures.

Exemplary Synthesis of Exemplary Compound 202

Step 1

To a solution of 1-(4-bromo-2-hydroxy-phenyl)ethanone (10 g, 46.50 mmol, 1.0 equiv.) in dimethylformamide (50 mL) was added potassium carbonate (9.64 g, 69.75 mmol, 1.5 equiv.). Then, iodomethane (13.20 g, 93.00 mmol, 2.0 equiv.) was added into the mixture at 0°C. The mixture was then stirred at 20°C for 12 hours. The mixture was diluted with water (200 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and then concentrated. 1-(4-bromo-2-methoxy-phenyl)ethanone (10.5 g, 45.84 mmol, 98% yield) was obtained as a yellow solid.

Step 2

To a solution of 1-(4-bromo-2-methoxy-phenyl)ethanone (10 g, 43.65 mmol, 1.18 eq.) in tetrahydrofuran (50 mL), titanium tetraethoxide (16.94 g, 74.26 mmol, 2.0 eq.) was added. Then, 2-methylpropane-2-sulfinamide (4.5 g, 37.13 mmol, 1.0 eq.) was added to the mixture, and the mixture was purged with N2 three times. The mixture was then stirred at 70°C for 12 hours. The mixture was quenched with water (100 mL), diluted with water (200 mL), filtered, then extracted with ethyl acetate (200 mL x 3), washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1). ((R,E)-N-(1-(4-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide (9 g, 27.09 mmol, 73% yield) was obtained as a yellow oil.

Step 3

To a solution of ((R,E)-N-(1-(4-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfinamide (9 g, 27.09 mmol, 1.0 equiv.) in tetrahydrofuran (90 mL) was added L-selectride (1 M, 81.26 mL, 3.0 equiv.) at 0° C. The mixture was then stirred at 20° C. for 2 h. The mixture was quenched with water (100 mL), diluted with water (20 mL), and diluted with ethyl acetate (300 mL). The mixture was extracted with 100 mL of hexane (3×100 mL), washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1 to 1:1). N-[(1S)-1-(4-bromo-2-methoxy-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (5.5 g, 16.45 mmol, 60% yield) was obtained as a yellow oil.

Step 4

To a solution of N-[(1S)-1-(4-bromo-2-methoxy-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (4.7 g, 14.06 mmol, 1.0 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.36 g, 21.09 mmol, 1.5 eq.) in dioxane (12 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (1.03 g, 1.41 mmol, 0.1 eq.) and potassium acetate (2.76 g, 28.12 mmol, 2.0 eq.) were added. The mixture was then purged with N2 three times. The mixture was then stirred at 90 °C for 5 h. The mixture was diluted with water (20 mL), filtered, then extracted with ethyl acetate (50 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1). N-[(1S)-1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (4.5 g, 11.80 mmol, yield 84%) was obtained as a yellow oil.

N-[(1S)-1-[2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide was converted to (S)-1-(2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine according to the following scheme:

S)-1-(2-Methoxy-4-(4-methylthiazol-5-yl)phenyl)ethan-1-amine was converted to the final compound using procedures similar to those described for other examples above (e.g., exemplary compound 64).

Exemplary compound 201 was prepared using procedures similar to those described above.

Exemplary Synthesis of Exemplary Compound 203

Step 1

To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)ethyl]carbamate (2 g, 6.66 mmol, 1 eq.) in N,N-dimethylformamide (20 mL), palladium tetrakistriphenylphosphine (770 mg, 0.67 mmol, 0.1 eq.) and zinc cyanide (782 mg, 6.66 mmol, 0.4 mL, 1 eq.) were added. The reaction solution was stirred at 80° C. for 14 hours. The solution was quenched with water (80 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (20 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1 to 3:1) to give the product. tert-Butyl N-[(1S)-1-(4-cyanophenyl)ethyl]carbamate (1.6 g, 6.50 mmol, 97.50% yield) was obtained as a colorless gum.

Using the procedure described above, tert-butyl N-[(1S)-1-(4-cyanophenyl)ethyl]carbamate was converted to the final compound.

Exemplary compound 204 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 91

Step 1

A 100 mL round bottom flask was charged with tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (3.5 g, 13.7 mmol, 1.0 equiv.) and TEA (4.1 g, 0.1 mmol, 3.0 equiv.) in DCM (8 mL), to which CbzCl (2.8 g, 0.1 mmol, 1.2 equiv.) was slowly added. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched by adding 20 mL of water and extracted with DCM (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:0). This yielded 4.0 g (75%) of 4-benzyl 9-tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate as a white oil.

Step 2

A 100 mL round bottom flask was charged with 4-benzyl 9-tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (4.0 g, 10.2 mmol, 1.0 equiv.) in dioxane (15 mL) and then hydrogen chloride in 1,4-dioxane solution (4.0 M, 4 mL) was added. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. This gave 2.9 g (87%) of benzyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate hydrochloride as a solid.

Step 3

A 30 mL sealed tube was charged with benzyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate hydrochloride (2.9 g, 8.9 mmol, 1.0 equiv.), 4-bromo-6-chloropyridazin-3-amine (2.1 g, 0.1 mmol), and DIEA (3.9 g, 0.1 mmol) in DMSO (8 mL). The resulting mixture was stirred in an oil bath at 130 °C for 12 h. The reaction mixture was then quenched by adding 20 mL of water/ice. The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:0). This yielded 3.1 g (84%) of benzyl 9-(3-amino-6-chloropyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate as a yellow solid.

Step 4

A 30 mL sealed tube was charged with benzyl 9-(3-amino-6-chloropyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (3.1 g, 7.4 mmol, 1.0 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (2.7 g, 0.1 mmol, 2.0 equiv.), Pd(PPh3)4 (859.4 mg, 0.7 mmol, 0.1 equiv.), and K2CO3 (3.1 g, 0.1 mmol, 3.0 equiv.) in dioxane (5 mL) and H2O (1 mL). The resulting mixture was stirred in an oil bath at 100 °C for 12 h and then extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10:1). This yielded 3.2 g (83%) of benzyl 9-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate as a yellow solid.

Step 5

In a 100 mL round bottom flask, to a solution of benzyl 9-[3-amino-6-[2-(methoxymethoxy)phenyl]pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (3.2 g, 6.2 mmol, 1.0 equiv.) in methanol (10 mL) was added Pd(OH)2/C (10%, 500 mg) under nitrogen atmosphere. The flask was then evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature under a hydrogen atmosphere using a hydrogen balloon, then filtered through a celite pad and concentrated under reduced pressure. This gave 1.8 g (76%) of 6-[2-(methoxymethoxy)phenyl]-4-[1-oxa-4,9-diazaspiro[5.5]undecane-9-yl]pyridazin-3-amine as a yellow solid.

Step 6

A 250 mL round bottom flask was charged with a solution of but-2-yn-1,4-diol (2.58 g, 30.00 mmol, 1.00 equiv.), silver oxide (10.35 g, 45.00 mmol, 1.50 equiv.), and potassium iodide (498 mg, 3.00 mmol, 0.10 equiv.) in dichloromethane (80 mL). 4-Methylbenzenesulfonyl chloride (5.70 g, 30.00 mmol, 1.00 equiv.) was then added. The reaction mixture was stirred overnight at room temperature. The insoluble solids were filtered and the filtrate was concentrated. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:2). This gave 6.13 g (85%) of 4-hydroxybut-2-yn-1-yl 4-methylbenzenesulfonate as a yellow oil.

Step 7

A 250 mL round bottom flask was charged with a solution of 4-hydroxybut-2-yn-1-yl 4-methylbenzenesulfonate (6.13 g, 25.54 mmol, 1.10 equiv.), benzyl piperazine-1-carboxylate (5.11 g, 23.22 mmol, 1.00 equiv.), and potassium carbonate (12.82 g, 92.88 mmol, 4.00 equiv.) in DMF (40 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then quenched with water (400 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were dried over sodium sulfate and concentrated. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This gave 2.01 g (30%) of benzyl 4-(4-hydroxybut-2-yn-1-yl)piperazine-1-carboxylate as a yellow oil.

Step 8

A 250 mL round bottom flask was charged with a solution of benzyl 4-(4-hydroxybut-2-yn-1-yl)piperazine-1-carboxylate (2.01 g, 6.98 mmol, 1.00 equiv.) and potassium hydroxide (3.91 g, 69.80 mmol, 10.00 equiv.) in diethyl ether (100 mL). 4-Methylbenzenesulfonyl chloride (1.99 g, 10.47 mmol, 1.50 equiv.) was then added. The reaction mixture was stirred overnight at room temperature. The insoluble solids were filtered off. The filtrate was washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. This afforded 1.80 g (59%) of benzyl 4-(4-(tosyloxy)but-2-yn-1-yl)piperazine-1-carboxylate as a yellow oil.

Step 9

A 250 mL round bottom flask was charged with a solution of benzyl 4-(4-(tosyloxy)but-2-yn-1-yl)piperazine-1-carboxylate (1.80 g, 4.07 mmol, 2.50 equiv.), 6-(2-(methoxymethoxy)phenyl)-4-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridazin-3-amine (627 mg, 1.63 mmol, 1.00 equiv.), sodium iodide (366 mg, 2.44 mmol, 1.50 equiv.), potassium carbonate (900 mg, 6.52 mmol, 4.0 equiv.) in acetonitrile (70 mL). The resulting mixture was stirred at 70 °C overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were concentrated and the residue was applied onto a silica gel column eluted with methanol/dichloromethane (1:10). This gave 180 mg (17%) of benzyl 4-(4-(9-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)but-2-yn-1-yl)piperazine-1-carboxylate as a brown solid.

Step 10

To a solution of benzyl 4-(4-(9-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)but-2-yn-1-yl)piperazine-1-carboxylate (1.60 g, 2.44 mmol, 1.00 equiv.) in methanol (40 mL) in a 100 mL round bottom flask, platinum dioxide (221.8 mg, 0.98 mmol, 0.40 equiv.) was added under nitrogen atmosphere. The flask was evacuated and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature using a hydrogen balloon for 4 h. The mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with methanol/dichloromethane (1:10). This yielded 444.0 mg (28%) of benzyl 4-(4-(9-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butyl)piperazine-1-carboxylate as a brown solid.

Step 11

A 100 mL round bottom flask was charged with a solution of benzyl 4-(4-(9-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)butyl)piperazine-1-carboxylate (444 mg, 0.67 mmol, 1.00 equiv.) in THF (8 mL), to which was added a solution of lithium triethylborohydride in THF (1.0 M, 8 mL). The resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched by saturated NH4Cl solution (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. This gave 292 mg (83%) of 6-(2-(methoxymethoxy)phenyl)-4-(4-(4-(piperazin-1-yl)butyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridazin-3-amine as a brown oil.

Using procedures similar to those described above for other examples, 6-(2-(methoxymethoxy)phenyl)-4-(4-(4-(piperazin-1-yl)butyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridazin-3-amine was converted to the final compound according to the following scheme.

Exemplary compound 205 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 188

Prepared according to the following scheme using procedures similar to those described above for exemplary compound 91.

Exemplary compound 187 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 192

Using procedures described for other examples, as well as procedures that would be apparent to one of skill in the art, benzyl 4-(2-((1r,3r)-3-(2-(9-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy)cyclobutoxy)ethyl)piperazine-1-carboxylate was prepared according to the following scheme.

Using a procedure similar to that described for exemplary compound 91, benzyl 4-(2-((1r,3r)-3-(2-(9-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethoxy)cyclobutoxy)ethyl)piperazine-1-carboxylate was converted to the final compound.

Exemplary Synthesis of Exemplary Compounds 212 and 213

Prepared using procedures similar to those described in steps 1 and 2 of exemplary compound 117, followed by the steps described for exemplary compound 180.

Exemplary Synthesis of Exemplary Compounds 214 and 215

Using standard procedures that would be apparent to one skilled in the art, tert-butyl (2S,4R)-4-hydroxy-2-((2-methoxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate was prepared according to the following scheme.

tert-Butyl (2S,4R)-4-hydroxy-2-((2-methoxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate was converted to the final compound using standard procedures as described for other examples above.

Exemplary Synthesis of Exemplary Compound 238

Step 1

To a solution of methyl 3-hydroxycyclobutanecarboxylate (14.2 g, 109.11 mmol, 1.00 equiv.) in DMF (150 mL), sodium hydride (5.24 g, 130.93 mmol, 60% purity, 1.20 equiv.) was added and the mixture was stirred at 0° C. for 0.5 h. Then, benzyl bromide (20.53 g, 120.02 mmol, 14.26 mL, 1.1 equiv.) was added and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by saturated ammonium chloride solution (200 mL) at 25° C., then diluted with water (100 mL) and extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with brine (150 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate/petroleum ether gradient). The compound methyl 3-benzyloxycyclobutanecarboxylate (8.9 g, 40.41 mmol, 37% yield) was obtained as a pale yellow oil.

Step 2

To a solution of lithium aluminum hydride (1.53 g, 40.41 mmol, 1.00 equiv.) in tetrahydrofuran (80 mL) was added methyl 3-benzyloxycyclobutanecarboxylate (8.90 g, 40.41 mmol, 1.00 equiv.) at 0° C., and the mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with water (1 mL), sodium hydroxide solution (15%, 2 mL), and water (3 mL) at 25° C., then diluted with ethyl acetate (80 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate/petroleum ether). Compound (3-benzyloxycyclobutyl)methanol (7.4 g, 38.5 mmol, 95% yield) was obtained as a colorless oil.

Step 3

To a solution of (3-benzyloxycyclobutyl)methanol (7.4 g, 38.49 mmol, 1.00 equiv.) and 3,4-dihydro-2H-pyran (16.19 g, 192.5 mmol, 17.6 mL, 5.00 equiv.) in dichloromethane (125 mL), pyridinium p-toluenesulfonate (967 mg, 3.85 mmol, 0.10 equiv.) was added and the mixture was stirred at 25 °C for 12 h. Water (200 mL) was added to the mixture and the resulting mixture was extracted with dichloromethane (100 mL x 2). The combined organic layers were then washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1: 0 to 20: 1). The compound 2-[(3-benzyloxycyclobutyl)methoxy]tetrahydropyran (10.20 g, 36.9 mmol, 95% yield) was obtained as a colorless oil.

Step 4

To a solution of 2-[(3-benzyloxycyclobutyl)methoxy]tetrahydropyran (10.20 g, 36.9 mmol, 1.00 equiv.) in methanol (100 mL) was added 10% palladium on carbon (2 g, 36.91 mmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25°C for 16 h. The reaction was filtered and concentrated under reduced pressure to give a residue. Compound 3-(tetrahydropyran-2-yloxymethyl)cyclobutanol (6.28 g, 33.7 mmol, 91% yield) was obtained as a colorless oil.

Step 5

To a solution of pyridin-4-ol (4 g, 42.06 mmol, 1 eq.), 3-(tetrahydropyran-2-yloxymethyl)cyclobutanol (8.62 g, 46.27 mmol, 1.1 eq.), and triphenylphosphine (33.10 g, 126.18 mmol, 3 eq.) in toluene (40 mL), diisopropyl azodicarboxylate (25.52 g, 126.18 mmol, 24.5 mL, 3 eq.) in toluene (20 mL) was added dropwise under nitrogen at 0°C. The reaction mixture was stirred at 100°C for 12 hours. The mixture was concentrated in vacuum to remove most of the toluene. Water (150 mL) and ethyl acetate (100 mL) were added to the mixture, hydrochloric acid solution (2 M) was added to the mixture to adjust the pH to about 3, and the resulting mixture was extracted with ethyl acetate (100 mL x 2). Saturated sodium bicarbonate was added to the aqueous phase to adjust the pH to about 8, and the resulting mixture was extracted with ethyl acetate (150 mL x 5). The combined organic phase was washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by preparative HPLC (column: Kromasil Eternity XT 250*80 mm*10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-30%, 31 min). ((1r,3r)-3-(pyridin-4-yloxy)cyclobutyl)methanol (4.2 g, 23.0 mmol, 54% yield) was obtained as a pale yellow oil.

Step 6

To a solution of ((1r,3r)-3-(pyridin-4-yloxy)cyclobutyl)methanol (4.2 g, 23.44 mmol, 1 equiv.) in toluene (40 mL), benzyl bromide (4.41 g, 25.78 mmol, 3.1 mL, 1.1 equiv.) was added. The reaction mixture was stirred at 80°C for 4 h. The mixture was concentrated in vacuo. The residue was triturated with petroleum ether and ethyl acetate (40 mL, V/V=1/1). 1-benzyl-4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)pyridin-1-ium (8 g, 22.8 mmol, 97% yield) was obtained as a white solid.

Step 7

To a solution of 1-benzyl-4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)pyridin-1-ium (8 g, 22.84 mmol, 1 equiv.) in ethanol (100 mL) was added sodium borohydride (1.73 g, 45.68 mmol, 2 equiv.) at 0°C. The reaction mixture was stirred at 20°C for 4 h. Water (100 mL) was added to the mixture to quench the reaction. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 50:1 to 0:1). ((1r,3r)-3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)cyclobutyl)methanol (5.2 g, 19.02 mmol, 83% yield) was obtained as a pale yellow oil.

Step 8

To a solution of [3-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]cyclobutyl]methanol (5.2 g, 19.02 mmol, 1 eq.) and di-tert-butyl dicarbonate (8.30 g, 38.04 mmol, 8.7 mL, 2 eq.) in methanol (100 mL), 10% palladium on activated carbon catalyst (0.7 g) and palladium hydroxide 20% on carbon (0.7 g) were added under nitrogen. The reaction mixture was stirred at 40° C. for 16 h under hydrogenation (50 psi). The mixture was filtered through a celite pad and the filtrate was concentrated to give the crude product. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 0:1). tert-Butyl 4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)piperidine-1-carboxylate (4.5 g, 15.77 mmol, 83% yield) was obtained as a colorless oil.

Step 9

To a solution of tert-butyl 4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)piperidine-1-carboxylate (2.5 g, 8.76 mmol, 1 eq.) in dichloromethane (25 mL) was added Dess-Martin periodinane (4.46 g, 10.51 mmol, 1.2 eq.) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The mixture was filtered and saturated sodium bicarbonate (50 mL) was added to the mixture. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1). tert-Butyl 4-((1r,3r)-3-formylcyclobutoxy)piperidine-1-carboxylate (2.0 g, 7.06 mmol, 80% yield) was obtained as a colorless oil.

Step 10

To a solution of tert-butyl 4-((1r,3r)-3-formylcyclobutoxy)piperidine-1-carboxylate (2.0 g, 7.06 mmol, 1 equiv.) in methanol (20 mL) was added potassium carbonate (1.95 g, 14.12 mmol, 2 equiv.) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.42 g, 7.41 mmol, 1.05 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. Water (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 20:1). tert-Butyl 4-((1r,3r)-3-ethynylcyclobutoxy)piperidine-1-carboxylate (1.3 g, 4.65 mmol, 66% yield) was obtained as a colorless oil.

Step 11

To a solution of tert-butyl 4-((1r,3r)-3-ethynylcyclobutoxy)piperidine-1-carboxylate (1.7 g, 6.09 mmol, 1 eq.) in tetrahydrofuran (17 mL) was added n-butyllithium (2.5 M, 3.6 mL, 1.5 eq.) at −78°C. The mixture was stirred at −78°C for 0.5 h. Then, isobutyl chloroformate (1.66 g, 12.17 mmol, 1.6 mL, 2 eq.) was added to the mixture, and the reaction mixture was stirred at −78°C for 0.5 h and at 20°C for 1 h. Saturated ammonium chloride (80 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1). tert-Butyl 4-((1r,3r)-3-(3-isobutoxy-3-oxoprop-1-yn-1-yl)cyclobutoxy)piperidine-1-carboxylate (2 g, 5.27 mmol, 86% yield) was obtained as a pale yellow oil.

Step 12

To a solution of tert-butyl 4-[3-(3-isobutoxy-3-oxo-prop-1-ynyl)cyclobutoxy]piperidine-1-carboxylate (2 g, 5.27 mmol, 1 eq.) in dichloromethane (20 mL) was added a solution of diisobutylaluminum hydride in DCM (1 M, 6.3 mL, 1.2 eq.) at −78 °C. The reaction mixture was stirred at −78 °C for 1 h. Saturated sodium bicarbonate (10 mL) was added to the mixture, and ethyl acetate (100 mL) was added to the mixture. The mixture was filtered through a celite pad and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (70 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1). tert-Butyl 4-((1r,3r)-3-(3-oxoprop-1-yn-1-yl)cyclobutoxy)piperidine-1-carboxylate (1.2 g, 3.90 mmol, 74% yield) was obtained as a colorless oil.

Step 13

To a solution of tert-butyl 4-[3-(3-oxoprop-1-ynyl)cyclobutoxy]piperidine-1-carboxylate (1.2 g, 3.90 mmol, 1 equiv.) in ethanol (10 mL) was added sodium borohydride (177 mg, 4.68 mmol, 1.2 equiv.) in three portions at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. Water (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1). tert-Butyl 4-((1r,3r)-3-(3-hydroxyprop-1-yn-1-yl)cyclobutoxy)piperidine-1-carboxylate (1.06 g, 3.43 mmol, 87% yield) was obtained as a colorless oil.

Step 14

To a solution of tert-butyl 4-((1r,3r)-3-(3-hydroxyprop-1-yn-1-yl)cyclobutoxy)piperidine-1-carboxylate (1.06 g, 3.43 mmol, 1 equiv.) in dichloromethane (10 mL) was added triphenylphosphine (1.08 g, 4.11 mmol, 1.2 equiv.) and carbon tetrabromide (1.36 g, 4.11 mmol, 1.2 equiv.) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 20:1). tert-butyl 4-[3-(3-bromoprop-1-ynyl)cyclobutoxy)piperidine-1-carboxylate (1 g, 2.69 mmol, 78% yield) was obtained as a pale yellow oil.

Using the procedures described for other examples above, tert-butyl 4-((1r,3r)-3-(3-hydroxyprop-1-yn-1-yl)cyclobutoxy)piperidine-1-carboxylate was converted to the final compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 216

Step 1

A mixture of 2-bromo-4-fluoro-pyridine (310 mg, 1.76 mmol, 1.2 eq.), 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (500 mg, 1.46 mmol, 1 eq.), and diisopropylethylamine (2.27 g, 17.57 mmol, 3 mL, 12 eq.) in dimethylsulfoxide (30 mL) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 130 °C for 5 h. The reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product. The residue was purified by semi-preparative reverse phase chromatography (column: Phenomenex Synergi C18 150*30mm*4um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10 min). 4-[8-(2-bromo-4-pyridyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (562 mg, 1.13 mmol, 77% yield) was obtained as a yellow solid.

Step 2

4-[8-(2-bromo-4-pyridyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-amine (568 mg, 1.14 mmol, 1 equiv.), tert-butyl 4-((1r,3r)-3-ethynylcyclobutoxy)piperidine-1-carboxylate (479 mg, 1.71 mmol) in dimethylformamide (35 mL) A mixture of 1,2-dichlorophenyl ether (1.5 equiv.), bis(triphenylphosphine)palladium(II) dichloride (80 mg, 0.1 mmol, 0.1 equiv.), copper iodide (22 mg, 0.1 mmol, 0.1 equiv.), and N-isopropylpropan-2-amine (8.13 g, 80.38 mmol, 11.36 mL, 70.39 equiv.) was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen atmosphere at 75° C. for 12 h. The reaction mixture was diluted with water (30 mL) and extracted three times with ethyl acetate (60 mL). The combined organic layers were washed twice with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The residue was purified by semi-preparative reverse phase chromatography (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 25 min). tert-Butyl 4-((1r,3r)-3-((4-(3-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)ethynyl)cyclobutoxy)piperidine-1-carboxylate (581 mg, 0.8 mmol, 73% yield) was obtained as a yellow solid.

tert-Butyl 4-((1r,3r)-3-((4-(3-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)ethynyl)cyclobutoxy)piperidine-1-carboxylate was converted to the final compound as described for other examples above.

Exemplary Synthesis of Exemplary Compounds 217 and 218

Step 1

To a solution of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (500 mg, 2.51 mmol, 1 eq.) and 3-bromopropan-1-ol (523 mg, 3.77 mmol, 0.34 mL, 1.5 eq.) in N,N-dimethylformamide (5 mL), potassium carbonate (693 mg, 5.02 mmol, 2 eq.) was added at 20°C, and the mixture was stirred at 80°C for 4 h. The reaction mixture was quenched by water (20 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1 to 4:1). Methyl 2-[3-(3-hydroxypropoxy)isoxazol-5-yl]-3-methyl-butanoate (370 mg, 1.44 mmol, 57% yield) was obtained as a colorless oil.

Step 2

To a solution of methyl 2-[3-(3-hydroxypropoxy)isoxazol-5-yl]-3-methyl-butanoate (370 mg, 1.44 mmol, 1 equiv.) in dichloromethane (5 mL), triethylamine (291 mg, 2.88 mmol, 0.40 mL, 2 equiv.) and p-toluenesulfonyl chloride (411 mg, 2.16 mmol, 1.5 equiv.) were added successively at 20°C and stirred at 20°C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=3/1). Methyl 3-methyl-2-[3-[3-(p-tolylsulfonyloxy)propoxy]isoxazol-5-yl]butanoate (438 mg, 1.06 mmol, 74% yield) was obtained as a colorless oil.

Step 3

To a solution of methyl 3-methyl-2-[3-[3-(p-tolylsulfonyloxy)propoxy]isoxazol-5-yl]butanoate (250 mg, 0.61 mmol, 1 eq.) and 2-[6-amino-5-[8-[2-[3-(4-piperidyloxy)cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol (386 mg, 0.61 mmol, 1 eq., 2-trifluoroacetate salt) in dimethyl sulfoxide (3 mL), N,N-diisopropylethylamine (314 mg, 2.43 mmol, 0.42 mL, 4 eq.) and potassium iodide (10 mg, 0.06 mmol, 0.1 eq.) were added at 20°C and the mixture was stirred at 80°C for 12 h. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1). Methyl 2-[3-[3-[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]propoxy]isoxazol-5-yl]-3-methyl-butanoate (90 mg, 0.11 mmol, 17% yield) was obtained as a yellow oil.

Using the procedures described for other examples above, methyl 2-[3-[3-[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]propoxy]isoxazol-5-yl]-3-methyl-butanoate was converted to the final compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 223

Step 1

To a solution of methyl 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoate (500 mg, 1.59 mmol, 1 eq.) in N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (423 mg, 3.17 mmol, 2 eq.). The reaction mixture was stirred at 70°C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (20 mL x 2). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 65%-95%, 9 min) to give methyl 2-[4-chloro-3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoate (337 mg, 0.965 mmol, 61% yield) as a colorless oil.

Step 2

To a solution of methyl 2-[4-chloro-3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoate (377 mg, 1.08 mmol, 1 eq.) in methanol (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (181 mg, 4.31 mmol, 4 eq.). The reaction mixture was stirred at 20°C for 2 hours. The mixture was cooled to 0°C, the pH was adjusted to 6 with 1M hydrogen chloride, and then the solution was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25 10um; mobile phase: [water (0.225% FA)-ACN]; B%: 54%-74%, 7.8 min) to give the product. 2-[4-chloro-3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoic acid (229 mg, 0.68 mmol, 63% yield) was obtained as a white solid.

2-[4-chloro-3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoic acid was converted to the final compound using the procedures described for other examples above.

Exemplary compound 222 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 225

Step 1

To a solution of 5-bromo-2-methyl-benzonitrile (5 g, 25.50 mmol, 1 equiv.) in carbon tetrachloride (50 mL), N-bromosuccinimide (4.77 g, 26.78 mmol, 1.05 equiv.) and 2,2-azobis(2-methylpropionitrile) (419 mg, 2.55 mmol, 0.1 equiv.) were added under nitrogen. The reaction mixture was stirred at 80 °C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1). 5-bromo-2-(bromomethyl)benzonitrile (4.5 g, 16.37 mmol, 64% yield) was obtained as a pale yellow solid.

Step 2

To a solution of 5-bromo-2-(bromomethyl)benzonitrile (4.4 g, 16.00 mmol, 1 eq.) and tert-butyl N-tert-butoxycarbonylcarbamate (4.17 g, 19.20 mmol, 1.2 eq.) in acetonitrile (50 mL), potassium carbonate (4.42 g, 32.01 mmol, 2 eq.) was added. The reaction mixture was stirred at 50 °C for 12 h. LCMS showed that most of the 5-bromo-2-(bromomethyl)benzonitrile was consumed. Water (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1). tert-Butyl N-[(4-bromo-2-cyano-phenyl)methyl]-N-tert-butoxycarbonyl-carbamate (6.4 g, 15.56 mmol, 97% yield) was obtained as a colorless oil.

Step 3

To a solution of tert-butyl N-[(4-bromo-2-cyano-phenyl)methyl]-N-tert-butoxycarbonyl-carbamate (2 g, 4.86 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.36 g, 5.35 mmol, 1.1 eq.) in dioxane (20 mL), potassium acetate (1.19 g, 12.16 mmol, 2.5 eq.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (356 mg, 0.49 mmol, 0.1 eq.) were added under nitrogen. The reaction mixture was stirred at 90 °C for 12 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give tert-butyl N-tert-butoxycarbonyl-N-[[2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (2.2 g, crude) as a black oil.

Step 4

To a solution of tert-butyl N-tert-butoxycarbonyl-N-[[2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (2.2 g, 4.80 mmol, 1 eq.), 5-bromo-4-methyl-thiazole (940 mg, 5.28 mmol, 1.1 eq.) in dioxane (20 mL) and water (4 mL), potassium carbonate (1.66 g, 12.00 mmol, 2.5 eq.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (351 mg, 0.48 mmol, 0.1 eq.) were added under nitrogen. The reaction mixture was stirred at 100 °C for 12 h. Water (100 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 1:1). tert-Butyl N-tert-butoxycarbonyl-N-[[2-cyano-4-(4-methylthiazol-5-yl)phenyl]methyl]carbamate (1.7 g, 3.96 mmol, 82% yield) was obtained as a pale yellow solid.

tert-Butyl N-tert-butoxycarbonyl-N-[[2-cyano-4-(4-methylthiazol-5-yl)phenyl]methyl]carbamate was converted to the final compound as described above for other examples.

Exemplary compound 224 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 126

Step 1

To a mixture of benzyl 3-oxoazetidine-1-carboxylate (25 g, 122 mmol, 1 eq.) and 2-methylpropane-2-sulfinamide (14.8 g, 122 mmol, 1 eq.) in THF (250 mL), titanium(IV) isopropylate (38.9 g, 171 mmol, 35.4 mL, 1.4 eq.) was added in one portion under nitrogen at 15 °C. The mixture was stirred at 60 °C for 2 h. The mixture was poured into ethyl acetate and ice water (1000 mL), stirred for 20 min, and filtered. The aqueous phase was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1 to 8/1) to give benzyl 3-tert-butylsulfinyliminoazetidine-1-carboxylate (39 g, crude) as a yellow solid.

Step 2

To a solution of 1-bromo-4-iodo-benzene (35.78 g, 126 mmol, 1 equiv.) in THF (350 mL), n-butyllithium (2.5 M, 50.6 mL, 1 equiv.) was added dropwise under nitrogen at −70° C., and the mixture was stirred at this temperature for 30 min. Then, a solution of benzyl 3-tert-butylsulfinyl iminoazetidine-1-carboxylate (39 g, 126.46 mmol, 1 equiv.) in THF (70 mL) was added dropwise under nitrogen. The reaction mixture was stirred at −70° C. for 1 h. The mixture was quenched with ice water (200 mL). The aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic phase was washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1). The crude product was then purified by semi-preparative reverse phase HPLC (column: Phenomenex luna c18 250mm*100mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40ACN% to 70ACN%, 45min) to give benzyl 3-(4-bromophenyl)-3-(tert-butylsulfinylamino)azetidine-1-carboxylate (4.62g, 9.93mmol, 7% yield) as a yellow oil. Additionally, 4.16g of slightly impure product (86% purity) was recovered as a yellow oil.

Step 3

To a mixture of benzyl 3-(4-bromophenyl)-3-(tert-butylsulfinylamino)azetidine-1-carboxylate (4.62 g, 9.93 mmol, 1 eq.), potassium acetate (1.95 g, 19.85 mmol, 2 eq.), and 4-methylthiazole (1.97 g, 19.85 mmol, 1.8 mL, 2 eq.) in dimethylacetamide (60 mL), palladium(II) acetate (223 mg, 0.99 mmol, 0.1 eq.) was added in one portion at 20°C under nitrogen. The mixture was stirred at 100°C for 16 hours. The mixture was cooled to 20°C, poured into ice water (w/w=1/1, 100 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50 mL x 4). 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 semi-preparative reverse phase HPLC (formic acid conditions; column: Phenomenex Synergi Max-RP 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 45ACN% to 75ACN%, 29 min) to give benzyl 3-(tert-butylsulfinylamino)-3-[4-(4-methylthiazol-5-yl)phenyl]azetidine-1-carboxylate (2.3 g, 4.76 mmol, 48% yield) as a yellow solid.

Step 4

A solution of benzyl 3-(tert-butylsulfinylamino)-3-[4-(4-methylthiazol-5-yl)phenyl]azetidine-1-carboxylate (3.4 g, 7.03 mmol, 1 eq.) and hydrochloric acid/methanol (4 M, 30 mL, 17.07 eq.) in dichloromethane (5 mL) was stirred at 25°C for 2 h. The compound benzyl 3-amino-3-[4-(4-methylthiazol-5-yl)phenyl]azetidine-1-carboxylate hydrochloride (3 g, crude) was obtained as a white solid.

Step 5

To a mixture of benzyl 3-amino-3-[4-(4-methylthiazol-5-yl)phenyl]azetidine-1-carboxylate hydrochloride (3 g, 7.21 mmol, 1 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.11 g, 10.82 mmol, 1.5 eq.), and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (1.67 g, 7.21 mmol, 1 eq.) in N,N-dimethylformamide (40 mL), triethylamine (2.19 g, 21.64 mmol, 3.0 mL, 3 eq.) was added in one portion under nitrogen at 15°C. The mixture was stirred at 15°C for 1 h. The mixture was poured into ice water (w/w=1/1, 100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (60 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 semi-preparative reverse phase HPLC (column: Phenomenex Synergi Max-RP 250*80 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 30 min). The compound tert-butyl (2S,4R)-2-[[1-benzyloxycarbonyl-3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (3.32 g, 5.60 mmol, 77% yield) was obtained as a white solid.

Step 6

To a mixture of tert-butyl (2S,4R)-2-[[1-benzyloxycarbonyl-3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (1.1 g, 1.86 mmol, 1 equiv.) and triethylamine (666 mg, 6.59 mmol, 0.9 mL, 3.55 equiv.) in dichloromethane (100 mL), palladium(ii) chloride (329.10 mg, 1.86 mmol, 1 equiv.) was added in one portion under nitrogen at 0° C. Triethylsilane (2.81 g, 24.13 mmol, 3.8 mL, 13 equiv.) was added and the reaction mixture was stirred at 20° C. for 2 h. To the reaction, trifluoroacetic acid (4.23 g, 37.14 mmol, 2.75 mL, 20.01 equiv.) was added and the mixture was stirred at 20° C. for an additional hour. The mixture was filtered and concentrated under reduced pressure at 40° C. The residue was purified by semi-preparative reverse phase HPLC (formic acid conditions; column: Kromasil 250*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 26 ACN% to 56 ACN%, 28 min). tert-Butyl (2S,4R)-4-hydroxy-2-[[3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate (336 mg, 0.73 mmol, 39% yield) was obtained as a white solid.

Step 7

A mixture of tert-butyl (2S,4R)-4-hydroxy-2-[[3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate (390 mg, 0.85 mmol, 1 eq.) and formaldehyde (138 mg, 1.70 mmol, 0.1 mL, 37% purity, 2 eq.) in dichloromethane (15 mL) was stirred at 20°C for 30 min. Acetic acid (51 mg, 0.85 mmol, 1 eq.) and sodium triacetoxyborohydride (901 mg, 4.25 mmol, 5 eq.) were added and the mixture was stirred at 20°C for 5 h. The mixture was concentrated under reduced pressure at 40°C. The residue was purified by semi-preparative reverse phase HPLC (formic acid condition; column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 0%-30%, 10 min). tert-Butyl (2S,4R)-4-hydroxy-2-[[1-methyl-3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate (300 mg, 0.63 mmol, 74% yield) was obtained as a yellow oil.

Using procedures similar to those described in other examples above, tert-butyl (2S,4R)-4-hydroxy-2-[[1-methyl-3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate was converted to the final compound.

Exemplary compound 228 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compounds 233 and 234

Prepared according to the following scheme using procedures similar to those described for exemplary compounds 76 and 70.

Exemplary Synthesis of Exemplary Compound 127

Step 1

To a mixture of tert-butyl (2S,4R)-4-hydroxy-2-[[3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]pyrrolidine-1-carboxylate (300 mg, 0.65 mmol, 1 eq.) and triethylamine (198 mg, 1.96 mmol, 3 eq.) in dichloromethane (60 mL), acetic anhydride (100.18 mg, 0.98 mmol, 91.9 uL, 1.5 eq.) was added in one portion under nitrogen at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure at 45°C. The residue was purified by semi-preparative reverse phase HPLC (basic conditions, column: Waters Xbridge 150*25 5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 10%-40%, 10 min). The crude product tert-butyl (2S,4R)-2-[[1-acetyl-3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (232 mg, 0.46 mmol, 71% yield) was obtained as a yellow oil.

Using the procedures described for the examples above, tert-butyl (2S,4R)-2-[[1-acetyl-3-[4-(4-methylthiazol-5-yl)phenyl]azetidin-3-yl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate was converted to the final product.

Exemplary compound 235 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 240

Using a procedure similar to that described for exemplary compound 202, tert-butyl (S)-(1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate was prepared according to the following scheme.

Using procedures similar to those described in other examples, (tert-butyl (S)-(1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate was converted to the final compound.

Exemplary compound 239 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compounds 243 and 244

Step 1

To a solution of ethyl trifluoroacetate (21.31 g, 150 mmol, 20.7 mL, 1.5 eq.) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (1 M, 120 mL, 1.2 eq.) at −78 °C. The mixture was stirred at −78 °C for 1 h. Then, 1-(6-bromo-3-pyridyl)ethanone (20 g, 100 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added dropwise to the mixture at −78 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched by adding saturated ammonium chloride (200 mL) and water (500 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was triturated with petroleum ether and ethyl acetate (255 mL, petroleum ether:ethyl acetate=50:1) and filtered to give a pale yellow solid. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1 to 0:1). 1-(6-bromo-3-pyridyl)-4,4,4-trifluoro-butane-1,3-dione (28 g, 94.6 mmol, 94% yield) was obtained as a yellow solid.

Step 2

To a solution of 1-(6-bromo-3-pyridyl)-4,4,4-trifluoro-butane-1,3-dione (15 g, 50.67 mmol, 1 eq.) in acetonitrile (150 mL), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane; ditetrafluoroborate (44.87 g, 126.7 mmol, 2.5 eq.) was added. The reaction mixture was stirred at 90 °C for 3 h. Then, water (1.83 g, 101.3 mmol, 1.8 mL, 2 eq.) was added to the mixture and the reaction mixture was stirred at 90 °C for 15 min. Then, triethylamine (25.64 g, 253.3 mmol, 35.2 mL, 5 eq.) was added to the mixture at 20 °C and the reaction mixture was stirred at 20 °C for 16 h. Water (300 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 1:0 to 10:1). 1-(6-bromo-3-pyridyl)-2,2-difluoro-ethanone (7.9 g, crude) was obtained as a brown oil.

Step 3

To a solution of 1-(6-bromo-3-pyridyl)-2,2-difluoro-ethanone (7.9 g, 33.47 mmol, 1 equiv.) in ethanol (80 mL) was added sodium borohydride (1.27 g, 33.47 mmol, 1 equiv.) in three portions at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Water (200 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 1: 1). 1-(6-bromo-3-pyridyl)-2,2-difluoro-ethanol (5.3 g, 21.20 mmol, 63% yield) was obtained as a pale yellow oil.

Step 4

To a solution of 1-(6-bromo-3-pyridyl)-2,2-difluoro-ethanol (3.3 g, 13.86 mmol, 1 eq.) and isoindoline-1,3-dione (2.45 g, 16.64 mmol, 1.2 eq.) in tetrahydrofuran (30 mL) was added triphenylphosphine (4.36 g, 16.64 mmol, 1.2 eq.) followed by dropwise diisopropyl azodicarboxylate (3.36 g, 16.64 mmol, 3.2 mL, 1.2 eq.) in tetrahydrofuran (5 mL) under nitrogen at 0°C. The reaction mixture was stirred at 20°C for 12 h. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0 to 5:1). 2-[1-(6-bromo-3-pyridyl)-2,2-difluoro-ethyl]isoindoline-1,3-dione (2.8 g, 6.89 mmol, 49% yield) was obtained as a pale yellow solid.

Step 5

To a solution of 2-[1-(6-bromo-3-pyridyl)-2,2-difluoro-ethyl]isoindoline-1,3-dione (2 g, 5.45 mmol, 1 eq.) in ethanol (20 mL) was added hydrazine hydrate (1.36 g, 27.24 mmol, 1.3 mL, 5 eq.). The reaction mixture was stirred at 80 °C for 2 h. Ethanol (30 mL) was added to the mixture, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was used directly in the next step. 1-(6-bromo-3-pyridyl)-2,2-difluoro-ethanamine (1.2 g, crude) was obtained as a pale yellow solid.

Step 6

To a solution of 1-(6-bromo-3-pyridyl)-2,2-difluoro-ethanamine (1.2 g, 5.06 mmol, 1 eq.) and sodium bicarbonate (850 mg, 10.12 mmol, 2 eq.) in tetrahydrofuran (5 mL) and water (5 mL), di-tert-butyl dicarbonate (2.21 g, 10.12 mmol, 2.3 mL, 2 eq.) was added. The reaction mixture was stirred at 20 °C for 2 h. Water (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3:1). The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 40%-65%, 22 min). tert-Butyl N-[1-(6-bromo-3-pyridyl)-2,2-difluoro-ethyl]carbamate (1.4g, 4.15mmol, 82% yield) was obtained as a pale yellow solid.

Step 7

To a solution of tert-butyl N-[1-(6-bromo-3-pyridyl)-2,2-difluoro-ethyl]carbamate (2 g, 5.93 mmol, 1 eq.), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (3.34 g, 14.83 mmol, 2.5 eq.) in dioxane (50 mL) and water (10 mL), potassium carbonate (2.05 g, 14.83 mmol, 2.5 eq.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (434 mg, 0.59 mmol, 0.1 eq.) were added under nitrogen. The reaction mixture was stirred at 100 °C for 12 h. Water (150 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1-1:1). The residue was then further purified by preparative HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min). tert-Butyl N-[2,2-difluoro-1-[6-(4-methylthiazol-5-yl)-3-pyridyl]ethyl]carbamate (480 mg, 1.33 mmol, 22% yield) was obtained as a pale yellow solid.

Step 8

tert-Butyl N-[2,2-difluoro-1-[6-(4-methylthiazol-5-yl)-3-pyridyl]ethyl]carbamate (480 mg, 1.35 mmol, 1 equiv.) was purified by preparative SFC (SFC column: DAICEL CHIRALPAK AY 250×50 mm, I.D., 10 um; mobile phase: ethyl alcohol 30%-30% in CO2; flow rate: 60 g/min; wavelength: 220 nm). Isomer 1 (tentatively designated as tert-butyl N-[(1S)-2,2-difluoro-1-[6-(4-methylthiazol-5-yl)-3-pyridyl]ethyl]carbamate; 200 mg, 0.56 mmol, 82% yield) was obtained as a pale yellow solid. Isomer 2 (tentatively designated as tert-butyl N-[(1R)-2,2-difluoro-1-[6-(4-methylthiazol-5-yl)-3-pyridyl]ethyl]carbamate; 210 mg, 0.59 mmol, 87% yield) was obtained as a pale yellow solid.

Step 9

To a solution of 2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoic acid (400 mg, 1.33 mmol, 1 eq.) and methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (241 mg, 1.33 mmol, 1 eq., hydrochloride salt) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (686 mg, 5.31 mmol, 0.9 mL, 4 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (605 mg, 1.59 mmol, 1.2 eq.) were added at 0°C. The reaction mixture was stirred at 20°C for 1 h. Water (50 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 36%-66%, 10 min). Methyl (2S,4R)-1-[2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate (450 mg, 1.05 mmol, 78% yield) was obtained as a colorless oil.

Step 10

The mixture was purified by preparative SFC (SFC column: DAICEL CHIRALPAK IC 250x30mm, I.D., 10um; mobile phase: methanol in CO2 (0.1% NH4OH) 30%-30%; flow rate: 50g/min; wavelength: 220nm). Methyl (2S,4R)-1-[(2S)-2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate (180mg, 0.36mmol, 69% yield) was obtained as a colorless oil. Methyl (2S,4R)-1-[(2R)-2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate (220 mg, 0.51 mmol, 96% yield) was obtained as a colorless oil.

Using procedures similar to those described above for other examples, methyl (2S,4R)-1-[(2R)-2-[3-(2,2-diethoxyethoxy)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-pyrrolidine-2-carboxylate was converted to the final compound according to the following scheme.

Exemplary compound 243 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 246

Step 1

A 50 mL round bottom flask was charged with (2R)-2-(4-bromophenyl)-2-[[(tert-butoxy)carbonyl]amino]acetic acid (1 g, 3.029 mmol, 1 eq.) in DMF (15 mL), to which diisopropylethylamine (1.57 g, 12.115 mmol, 4 eq.), N-methylcyclobutanamine hydrochloride (368 mg, 3.03 mmol, 1 eq.), and BOP (1.61 g, 3.63 mmol, 1.2 eq.) were added in sequence. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by adding water (10 mL). The resulting mixture was extracted with ethyl acetate (4 x 30 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/1). This yielded 1.1 g (91%) of tert-butyl N-[(R)-(4-bromophenyl)[cyclobutyl(methyl)carbamoyl]methyl]carbamate as a yellow solid.

Step 2

A 100 mL round-bottom flask was charged with tert-butyl N-[(R)-(4-bromophenyl)[cyclobutyl(methyl)carbamoyl]methyl]carbamate (1 g, 2.52 mmol, 1 eq.), K2CO3 (1.04 g, 7.55 mmol, 3 eq.), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (850 mg, 3.78 mmol, 1.5 eq.), and Pd(dppf)Cl2 (184 mg, 0.25 mmol, 0.1 eq.) in dioxane (10 mL) and H2O (2 mL) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C in an oil bath under nitrogen atmosphere for 3 h. The mixture was concentrated and the residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/1). This yielded 480 mg (46%) of tert-butyl N-[(R)-[cyclobutyl(methyl)carbamoyl][4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamate as a yellow solid.

Using procedures similar to those described above for other examples, tert-butyl N-[(R)-[cyclobutyl(methyl)carbamoyl][4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamate was converted to the final compound.

Exemplary compound 245 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 248

Step 1

A 250 mL round-bottom flask was charged with a solution of 4-(trifluoromethyl)benzaldehyde (3.0 g, 17.2 mmol, 1.0 equiv.), (S)-2-methylpropane-2-sulfinamide (4.2 g, 0.035 mmol, 2.0 equiv.), and titanium isopropoxide (14.9 g, 0.052 mmol, 3.0 equiv.) in THF (50 mL). The resulting solution was stirred at 80 °C in an oil bath for 16 h. The reaction was then quenched by adding 200 mL of water, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:1). This yielded 3.1 g (65%) of (S)-2-methyl-N-[[4-(trifluoromethyl)phenyl]methylidene]propane-2-sulfinamide as a yellow oil.

Step 2

To a solution of (S)-2-methyl-N-[[4-(trifluoromethyl)phenyl]methylidene]propane-2-sulfinamide (3.1 g, 11.2 mmol, 1.0 equiv.) in DCM (20 mL) was added dropwise over a period of 20 min at −48° C. under nitrogen atmosphere with methylmagnesium chloride solution (3.0 M in ether, 5 mL). The resulting mixture was then stirred at room temperature for 2 h. The reaction mixture was then quenched by adding 50 mL of saturated NH4Cl solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1). This gave 1.83 g (56%) of (S)-2-methyl-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide as a white solid.

Step 3

A 100 mL round-bottom flask was charged with (S)-2-methyl-N-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide (1.8 g, 6.2 mmol, 1.0 equiv.) in methanol (10 mL). Aqueous hydrogen chloride (37%, 5 mL) was then added. The resulting solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. This afforded 970 mg (82%) of (1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine as a white solid.

(1S)-1-[4-(trifluoromethyl)phenyl]ethan-1-amine was converted to the final compound using procedures similar to those described above for other examples.

Example compound 247 was prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 404

As shown in the scheme above, tert-butyl 4-((1R,3R)-3-((4-bromopyridin-2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate was deprotected under acidic conditions and the resulting free cyclic amine was reacted with an activated isoxazole derivative to form methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate as the coupling product. Palladium-catalyzed reaction of the pyridyl bromide fragment in the product with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, followed by cleavage of the tert-butyloxycarbonyl (Boc) protecting group, yielded the free amine, which underwent nucleophilic coupling reaction with 4-bromo-6-chloropyridazin-3-amine under heating in DMSO in the presence of an amine. Suzuki coupling reaction of pyridazine bromide with (2-hydroxyphenyl)boronic acid completed the assembly of the PTM binding moiety. Ester hydrolysis followed by condensation with (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide gave the desired final products as a mixture of diastereomers, which were separated by supercritical fluid chromatography (SFC).

Exemplary Synthesis of Exemplary Compound 411

As shown in the scheme above, Mitsunobu reaction between methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate and (1R,3R)-3-(benzyloxy)cyclobutanol, followed by benzyloxy group cleavage, provided methyl 2-(3-((1S,3S)-3-hydroxycyclobutoxy)isoxazol-5-yl)-3-methylbutanoate. Activation of the hydroxy group with trifluoromethanesulfonic anhydride, followed by triflate displacement with a cyclic amine containing WPTM5-WPTM3-WPTM2-WPTM1 fragment, afforded the coupling product containing linking group L. Ester hydrolysis, followed by condensation with (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide afforded the desired final product.

Exemplary Synthesis of Exemplary Compound 428

As shown in the scheme above, 4-bromo-6-chloropyridazin-3-amine was converted to the 4-vinyl derivative, which underwent a Heck coupling reaction with tert-butyl 4-((1R,3R)-3-((4-bromopyridin-2-yl)oxy)cyclobutoxy)piperidine-1-carboxylate to generate the coupling product. The 6-chloropyridazine moiety in the product was then reacted with (2-hydroxyphenyl)boronic acid under Suzuki conditions to assemble the WPTM5-WPTM3 fragment. Subsequent Boc deprotection followed by reductive amination with (2S,4R)-4-hydroxy-1-((R)-3-methyl-2-(3-(2-oxoethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide provided the desired final product.

Exemplary Synthesis of Exemplary Compound 445

As shown in the scheme above, the hydroxyl group in tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate was activated with tosyl chloride and the resulting tosylate was nucleophilically substituted with methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate. The Boc group in the product was cleaved and the free cyclic amine was reacted with 3-(hydroxymethyl)cyclobutanone and sodium triacetoxyborohydride to form methyl 2-(3-(2-(1-(3-(hydroxymethyl)cyclobutyl)piperidin-4-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoate. Dess-Martin oxidation of the hydroxyl group followed by reductive amination of the resulting aldehyde with a spiro-amine afforded the coupled product combining the PTM binding moiety and the linking group L. Ester hydrolysis followed by condensation with (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide gave the desired final product.

Exemplary Syntheses of Exemplary Compounds 449-456

As shown in the scheme above, the assembly of the first coupling fragment started with tert-butyl 4-acetylpiperidine-1-carboxylate, which was reduced to the alcohol and converted to the tosylate. The tosyl group was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and the product was coupled with 4-bromo-6-chloropyridazin-3-amine under Suzuki conditions to give a racemic mixture of tert-butyl 4-(1-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate, which was separated by using chiral supercritical fluid chromatography (SFC). Subsequent Boc deprotection provided the desired first coupling fragment in enantiomerically pure form.

Formation of the second coupling fragment began with 3-methylenecyclobutanecarbonitrile, which was hydrolyzed to the carboxylic acid and protected as the benzyl ester. Hydrolytic cleavage of the endo double bond followed by oxidation provided a diastereomeric mixture of alcohols, which were separated by using supercritical fluid chromatography (SFC). The individual alcohols were oxidized with Dess-Martin periodinane to give the desired isomeric aldehydes.

Reductive amination of the first and second coupling fragments with sodium borohydride followed by base hydrolysis gave (1R,3S)-3-((4-((S)-1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-1-yl)ethyl)piperidin-1-yl)methyl)cyclobutanecarboxylic acid, which was condensed with (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(3-(2-(piperidin-4-yl)ethoxy)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the desired product. This method can be conveniently used to synthesize all enantiomerically pure isomers of the desired product by introducing reagents and intermediates with the appropriate stereochemistry.

Exemplary Synthesis of Exemplary Compound 458

As shown in the scheme above, tert-butyl 4-formylpiperidine-1-carboxylate underwent reductive amination with (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(3-(piperazin-1-yl)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide and sodium cyanoborate to generate (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(3-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide after Boc deprotection. Subsequent reductive amination of the resulting compound with (1R,3R)-3-((4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)cyclobutanecarbaldehyde under similar conditions provided the desired final product.

Exemplary Synthesis of Exemplary Compound 474

As shown in the scheme above, Mitsunobu reaction between 4-hydroxypyridine and tert-butyl 4-hydroxypiperidine-1-carboxylate provided tert-butyl 4-(pyridin-4-yloxy)piperidine-1-carboxylate, which was converted to a salt by alkylating the pyridine nitrogen with benzyl bromide. The pyridine ring was then reduced by a two-step procedure to form a double piperidine derivative, which was reacted with methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate under heteroaromatic nucleophilic substitution conditions to form the coupling product. Ester hydrolysis followed by condensation of the resulting acid with (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide provided the diastereomeric final products, which were separated by supercritical fluid chromatography (SFC).

Exemplary syntheses of exemplary compounds 494, 495

As shown in the scheme above, the synthesis of the PTM binding moiety began with 3-((4-methoxybenzyl)oxy)propan-1-ol, which was treated with sodium hydride to open the (S)-2-methyloxirane. Bromination of the resulting alcohol followed by bromide displacement with the enolate derived from methyl 2-(3-methylisoxazol-5-yl)acetate provided (3R)-methyl 4-(3-hydroxypropoxy)-3-methyl-2-(3-methylisoxazol-5-yl)butanoate. Mitsunobu reaction of the product with 4-bromopyridin-2-ol followed by palladium catalyzed coupling of the pyridyl bromide moiety with mono-Boc protected 3,8-diazabicyclo[3.2.1]octane gave tert-butyl 8-(2-(3-((2R)-4-methoxy-2-methyl-3-(3-methylisoxazol-5-yl)-4-oxobutoxy)propoxy)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. Subsequent Boc group cleavage provided the free amine, which underwent nucleophilic coupling reaction with 4-bromo-6-chloropyridazin-3-amine by heating in aprotic polar solvent (DMSO) in the presence of amine (DIEA). Suzuki coupling reaction of the pyridazine bromide with (2-hydroxyphenyl)boronic acid completed the assembly of the PTM binding moiety. Ester hydrolysis followed by condensation with (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide gave the desired final products as a mixture of diastereomers, which were separated by supercritical fluid chromatography (SFC).

Exemplary syntheses of exemplary compounds 496, 497

As shown in the above scheme, the desired product was obtained by reductive amination of (2S,4R)-1-((R)-2-(3-(4-formylpiperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide with 2-(6-amino-5-(1-((R)-4-((1r,3R)-3-(piperidin-4-yloxy)cyclobutyl)but-3-yn-2-yl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol in the presence of sodium cyanoborohydride. This method can be conveniently used to synthesize all enantiomerically pure isomers of the desired product by introducing the coupling counterpart with the appropriate stereochemistry.

Exemplary Synthesis of Exemplary Compound 499

As shown in the scheme above, tert-butyl 4-(5-(1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate as a diastereomeric mixture was separated into individual isomers. Each of these isomers was then reacted with (1R,3R)-3-((4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-yl)oxy)cyclobutanecarbaldehyde to provide the desired final product in enantiomerically pure form. This method can be conveniently used to synthesize all enantiomerically pure isomers of a desired product by introducing coupling counterparts with the appropriate stereochemistry.

Exemplary Synthesis of Exemplary Compound 143 Step 1

To a solution of methyl 2-(3-methylisoxazol-5-yl)-3-methylbutanoate (265 g, 1.33 mol) [prepared as described for exemplary compound 144] in MeCN (1.6 L), K2CO3 (367.71 g, 2.66 mol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (482.25 g, 1.60 mol, 280.38 mL) were added. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeCN. The residue was diluted with water (1.5 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (458 g, 886.42 mmol) as a brown oil.

Step 2

To a mixture of methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (160 g, 332.44 mmol) and 4-(dimethoxymethyl)piperidine (79.40 g, 498.66 mmol) in DMF (1.6 L) was added DIEA (128.90 g, 997.32 mmol, 173.72 mL) in one portion at 25° C. under nitrogen. The mixture was stirred at 80° C. for 12 h. The mixture was cooled to 25° C. and poured into ice water (w:w=1:1) (3 L) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (1 L×5). The combined organic phase was washed with brine (300 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The mixture was dissolved in EtOAc (70 mL) and filtered to remove insoluble material. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 80:1 to 0:1) to obtain methyl 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoate (34 g, 100 mmol) as an orange syrup.

Step 3

To a mixture of methyl 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoate (350 mg, 1.03 mmol, 1 equiv.) in tetrahydrofuran (1 mL) and methanol (1 mL), lithium hydroxide (2 M, 1 mL, 1.95 equiv.) was added in one portion under nitrogen. The mixture was stirred at 25°C for 1 h. The pH was adjusted to 5-6 with trifluoroacetic acid and concentrated under reduced pressure at 45°C. The mixture was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 9 min) to give 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoic acid (190 mg) as a yellow oil.

Step 4

To a mixture of 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoic acid (190 mg, 0.58 mmol, 1 eq.), N,N-diisopropylethylamine (225 mg, 1.75 mmol, 0.3 mL, 3 eq.), and (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (257 mg, 0.70 mmol, 1.2 eq., hydrochloride salt) in N,N-dimethylformamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (288 mg, 0.76 mmol, 1.3 eq.) in one portion at 0°C under nitrogen. The mixture was stirred at 25°C for 1 hour. The mixture was poured into ice water (w/w=1/1) (30 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol=10/1) to give (2S,4R)-1-[2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (208 mg) as a yellow oil.

Step 5

(2S,4R)-1-[2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-thyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (200 mg, 0.31 mmol, 1 eq.) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O IPA]; B%: 45%-45%, 3.0 min; 65 min). The mixture was concentrated under reduced pressure at 45°C.

(2S,4R)-1-[(2S)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (90 mg) (retention time: 1.884 min in chiral SFC) was obtained as a yellow oil.

(2S,4R)-1-[(2S)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (90 mg, 0.13 mmol, 42% yield, 94% purity) (retention time: 2.230 min in chiral SFC) was obtained as a yellow oil.

Step 6

To a solution of (2S,4R)-1-[(2R)-2-[3-[4-dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (80 mg, 0.13 mmol, 1 equiv.) in tetrahydrofuran (2 mL), sulfuric acid solution (1 M, 2 mL, 16.00 equiv.) was added. The reaction mixture was stirred at 50 °C for 5 h. The mixture was added to saturated sodium bicarbonate (10 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and used directly in the next step. Crude (2S,4R)-1-[(2R)-2-[3-(4-formyl-1-piperidyl)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (68 mg) was obtained as a pale yellow solid and used directly in the next step.

Step 7

To a solution of 2-[6-amino-5-[8-[2-[3-(4-piperidyloxy)cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol dihydrochloride (2.08 g, 3.37 mmol, 1 eq.) in methanol (40 mL), sodium acetate (829 mg, 10.11 mmol, 3 eq.) was added, and the mixture was then cooled to 100° C. To the mixture was added (2S,4R)-1-[(2R)-2-[3-(4-formyl-1-piperidyl)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2 g, 3.37 mmol, 1 eq.) and acetic acid (23 mg, 0.33 mmol, 0.1 eq.). The mixture was stirred at 25° C. for 0.5 h, and then to the mixture was added sodium cyanoborohydride (1.06 g, 16.84 mmol, 5 eq.). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 22 min). (2S,4R)-1-[(2R)-2-[3-[4-[[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]methyl]-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide formate (1196 mg, 1.02 mmol) was obtained as a white solid.

Exemplary Synthesis of Exemplary Compound 143 Step 1

To a solution of methyl 2-(3-methylisoxazol-5-yl)-3-methylbutanoate (265 g, 1.33 mol) [prepared as described for exemplary compound 144] in MeCN (1.6 L), K2CO3 (367.71 g, 2.66 mol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (482.25 g, 1.60 mol, 280.38 mL) were added. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeCN. The residue was diluted with water (1.5 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (458 g, 886.42 mmol) as a brown oil.

Step 2

To a mixture of methyl 3-methyl-2-(3-(((perfluorobutyl)sulfonyl)oxy)isoxazol-5-yl)butanoate (160 g, 332.44 mmol) and 4-(dimethoxymethyl)piperidine (79.40 g, 498.66 mmol) in DMF (1.6 L) was added DIEA (128.90 g, 997.32 mmol, 173.72 mL) in one portion at 25° C. under nitrogen. The mixture was stirred at 80° C. for 12 h. The mixture was cooled to 25° C. and poured into ice water (w:w=1:1) (3 L) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (1 L×5). The combined organic phase was washed with brine (300 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The mixture was dissolved in EtOAc (70 mL) and filtered to remove insoluble material. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 80:1 to 0:1) to obtain methyl 2-(3-(4-(dimethoxymethyl)piperidin-1-yl)isoxazol-5-yl)-3-methylbutanoate (34 g, 100 mmol) as an orange syrup.

Step 3

To a solution of methyl 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoate (10 g, 29.38 mmol, 1 equiv.) in MeOH (30 mL), aqueous LiOH solution (6 M, 30.00 mL, 6.13 equiv.) and THF (30 mL) were added. The mixture was stirred at 25 °C for 1 h. The pH of the reaction mixture was adjusted by 1 M HCl (200 mL), diluted with water (200 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Crude 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoic acid (9.5 g, 29.11 mmol) was obtained as a yellow oil.

Step 4

To a solution of (2S,4R)-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (10.71 g, 29.11 mmol, 1 eq.), DIPEA (11.29 g, 87.32 mmol, 15.21 mL, 3 eq.), and 2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoic acid (9.5 g, 29.11 mmol, 1 eq.) in DMF (100 mL), HATU (16.60 g, 43.66 mmol, 1.5 eq.) was added under nitrogen at 0°C. The mixture was warmed to 25°C and stirred for 1 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water (0.225% FA)-MeCN]; B%: 30%-60%, 15 min). (2S,4R)-1-[2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (18 g, 27.57 mmol) was obtained as a white solid.

Step 5

(2S,4R)-1-[2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (5 g, 7.81 mmol, 1 eq.) was purified by preparative SFC (column: DAICEL CHIRALPAK AD-H 250 mm x 30 mm, I.D., 5 um; mobile phase: isopropanol (0.1% NH3H2O) 40%-40% in CO2; flow rate: 70 g/min; wavelength: 220 nm) and (column: DAICEL CHIRALPAK AD 250 mm x 30 mm, I.D., 10 um; mobile phase: isopropanol (0.1% NH3H2O) 40%-40% in CO2; flow rate: 70 g/min; wavelength: 220 nm) and separated twice.

The compound (2S,4R)-1-[(2S)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.5 g, 3.91 mmol) was obtained as a white solid.

The compound (2S,4R)-1-[(2R)-2-[3-[4-(dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.4 g, 3.68 mmol) was obtained as a white solid.

Step 6

To a solution of (2S,4R)-1-[(2R)-2-[3-[4-dimethoxymethyl)-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.2 g, 1.88 mmol, 1 equiv.) in THF (15 mL) was added H2SO4 (1 M, 13.85 mL, 7.38 equiv.). The mixture was stirred at 50°C for 2 h. The reaction mixture was quenched by adding saturated NaHCO3 (30 mL), then diluted with water (30 mL) and extracted with brine (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. Crude (2S,4R)-1-[(2R)-2-[3-(4-formyl-1-piperidyl)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (1.05 g, 1.77 mmol) was obtained as a white solid.

Step 7

To a solution of 2-[6-amino-5-[8-[2-[3-(4-piperidyloxy)cyclobutoxy]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol dihydrochloride (2.08 g, 3.37 mmol, 1 eq.) in methanol (40 mL), sodium acetate (829 mg, 10.11 mmol, 3 eq.) was added, and the mixture was then cooled to 100° C. To the mixture was added (2S,4R)-1-[(2R)-2-[3-(4-formyl-1-piperidyl)isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2 g, 3.37 mmol, 1 eq.) and acetic acid (23 mg, 0.33 mmol, 0.1 eq.). The mixture was stirred at 25° C. for 0.5 h, and then to the mixture was added sodium cyanoborohydride (1.06 g, 16.84 mmol, 5 eq.). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 22 min). (2S,4R)-1-[(2R)-2-[3-[4-[[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]methyl]-1-piperidyl]isoxazol-5-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide formate (1196 mg, 1.02 mmol) was obtained as a white solid.

Exemplary Synthesis of Exemplary Compound 594 Prepared according to the following scheme using procedures similar to those described for other examples above.

Exemplary compound 596 can be prepared using a similar procedure.

Exemplary Synthesis of Exemplary Compound 602 Prepared according to the following scheme using procedures similar to those described for exemplary compound 143.

Exemplary Synthesis of Exemplary Compound 607 Prepared using procedures described for Exemplary Compound 143 and Exemplary Compound 178.

Exemplary Synthesis of Exemplary Compound 610: Prepared according to the following scheme using procedures similar to those described for Exemplary Compound 143 and Exemplary Compound 188, as well as other examples above.

Exemplary Synthesis of Exemplary Compound 616 Prepared according to the following scheme using procedures similar to those described for the above examples.

Exemplary Synthesis of Exemplary Compound 618: Prepared according to the following scheme using procedures described for Exemplary Compound 610 and Exemplary Compound 143, as well as other examples above.

Exemplary Synthesis of Exemplary Compound 626 Step 1

A 250 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with tert-butyl 4-[(1r,3r)-3-hydroxycyclobutoxy]piperidine-1-carboxylate (5 g, 18.43 mmol, 1.0 equiv), DMF (100 mL) and NaH (2.22 g, 55.42 mmol, 3.0 equiv, 60% in oil) was added at 0°C. This was allowed to react at room temperature for 15 minutes. This was followed by the addition of 4-bromo-2-fluoropyridine (3.57 g, 20.27 mmol, 1.1 equiv). The resulting solution was stirred at room temperature for 4 hours. The reaction was then quenched by adding 100 mL of water/ice. The resulting solution was extracted with (100 mL x 3) ethyl acetate and the organic layers were combined. The resulting mixture was washed with (100 mL x 1) brine. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/2). The collected fractions were combined and concentrated under vacuum. This gave 6.3 g (80%) of tert-butyl 4-[(1r,3r)-3-[(4-bromopyridin-2-yl)oxy]cyclobutoxy]piperidine-1-carboxylate as a yellow oil.

Step 2

A 250 mL round bottom flask purged and maintained under nitrogen inert atmosphere was charged with 4-bromo-6-chloropyridazin-3-amine (5 g, 24.0 mmol, 1.0 equiv), n-propanol (100 mL), TEA (7.28 g, 72.0 mmol, 3 equiv), potassium trifluorovinylborate (2.39 g, 25.0 mmol, 1.05 equiv), and Pd(dppf)Cl2.CH2Cl2 (1.96 g, 2.39 mmol, 0.10 equiv). The resulting solution was stirred in an oil bath at 100 °C for 4 h. The solids were filtered off. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1/1). The collected fractions were combined and concentrated under vacuum. This gave 2.3 g (62%) of 6-chloro-4-ethenylpyridazin-3-amine as a yellow solid.

Step 3

In a 20 mL sealed tube purged and maintained under a nitrogen inert atmosphere was placed 6-chloro-4-ethenylpyridazin-3-amine (910 mg, 5.84 mmol, 1.0 equiv.), DMF (14 mL), TEA (1775 mg, 17.5 mmol, 3.0 equiv.), tert-butyl 4-[(1r,3r)-3-[(4-bromopyridin-2-yl)oxy]cyclobutoxy]piperidine-1-carboxylate (2.50 g, 5.849 mmol, 1.0 equiv.), tri-o-tolylphosphine (1780 mg, 5.85 mmol, 1.0 equiv.), Pd(OAc)2 (131 mg, 0.585 mmol, 0.10 equiv.). The resulting solution was stirred in an oil bath at 130 °C for 16 h. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with ethyl acetate (20 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine (20 mL x 3). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (10/1). The collected fractions were combined and concentrated under vacuum. This gave 625 mg (21%) of tert-butyl 4-[(1r,3r)-3-([4-[(E)-2-(3-amino-6-chloropyridazin-4-yl)ethenyl]pyridin-2-yl]oxy)cyclobutoxy]piperidine-1-carboxylate as a brown solid.

tert-Butyl 4-[(1r,3r)-3-([4-[(E)-2-(3-amino-6-chloropyridazin-4-yl)ethenyl]pyridin-2-yl]oxy)cyclobutoxy]piperidine-1-carboxylate was converted to the final compound using the procedures described for exemplary compound 143 and other examples above.

Exemplary Synthesis of Exemplary Compound 630 Step 1

To a solution of methyl 4-aminothiazole-5-carboxylate (0.4 g, 2.53 mmol, 1 eq.) and triethylamine (512 mg, 5.06 mmol, 0.7 mL, 2 eq.) in dichloromethane (30 mL), di-tert-butyl dicarbonate (1.10 g, 5.06 mmol, 1.2 mL, 2 eq.) and 4-dimethylaminopyridine (62 mg, 0.50 mmol, 0.2 eq.) were added in one portion under nitrogen at 25°C. The mixture was stirred at 25°C for 16 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 to 8/1) to give methyl 4-[bis(tert-butoxycarbonyl)amino]thiazole-5-carboxylate (850 mg) as a yellow oil.

Step 2

To a solution of methyl 4-[bis(tert-butoxycarbonyl)amino]thiazole-5-carboxylate (850 mg, 2.37 mmol, 1 equiv.) in ethanol (20 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide in water (1 M, 30 mL) at 25 °C, and the mixture was stirred at 70 °C for 3 h. The reaction mixture was cooled to 25 °C, the pH was adjusted to 4-5 with 2 M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Compound 4-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (620 mg, crude) was obtained as a white solid.

Step 3

To a mixture of 4-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (600 mg, 2.46 mmol, 1 eq.) and potassium phosphate (521 mg, 2.46 mmol, 1 eq.) in acetonitrile (30 mL), tetrabutylammonium tribromide (2.37 g, 4.91 mmol, 2 eq.) was added in one portion under nitrogen at 30 °C. The mixture was stirred at 50 °C for 16 h. The mixture was cooled to 20 °C and poured into a mixture of saturated aqueous sodium thiosulfate (20 mL) and saturated aqueous sodium carbonate (20 mL). The aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with saline (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1 to 8/1) to obtain tert-butyl N-(5-bromothiazol-4-yl)carbamate (460 mg) as a yellow solid.

Step 4

To a mixture of tert-butyl N-[(1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (572 mg, 1.65 mmol, 1 eq.), potassium carbonate (455 mg, 3.30 mmol, 2 eq.), and tert-butyl N-(5-bromothiazol-4-yl)carbamate (460 mg, 1.65 mmol, 1 eq.) in water (3 mL) and dioxane (18 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium] (96 mg, 0.13 mmol, 0.08 eq.) was added in one portion at 20°C under nitrogen. The mixture was stirred at 90°C for 2 h. The mixture was cooled to 20°C, poured into ice water (w/w=1/1, 20 mL), and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 30/1 to 5/1) to give tert-butyl N-[5-[4-[(1S)-1-(tert-butoxycarbonylamino)ethyl]phenyl]thiazol-4-yl]carbamate (620 mg, crude) as a yellow solid.

Step 5

A solution of tert-butyl N-[5-[4-[(1S)-1-(tert-butoxycarbonylamino)ethyl]phenyl]thiazol-4-yl]carbamate (620 mg, 1.48 mmol, 1 equiv) in hydrochloric acid/methanol (4 M, 10 mL) was stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure at 45°C. The crude product 5-[4-[(1S)-1-aminoethyl]phenyl]thiazol-4-amine hydrochloride (406 mg, crude) was obtained as a yellow solid.

Using procedures described for other examples above, 5-[4-[(1S)-1-aminoethyl]phenyl]thiazol-4-amine was converted to the title compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 638 Prepared according to the following scheme using procedures similar to those described for other examples above (particularly Exemplary Compound 238 and Exemplary Compound 607).

Exemplary Synthesis of Exemplary Compound 640: Prepared according to the following scheme using procedures described for Exemplary Compound 203 and Exemplary Compound 143, as well as other examples above.

Exemplary Synthesis of Exemplary Compound 642 Prepared according to the following scheme using procedures described for exemplary compound 143 and other examples above.

Exemplary Synthesis of Exemplary Compound 664 The intermediate 2-(6-amino-5-(1-(1-(1-(((1s,3s)-3-(piperidin-4-yloxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol was prepared according to the following scheme using procedures similar to those described for other examples above.

2-(6-amino-5-(1-(1-(1-(((1s,3s)-3-(piperidin-4-yloxy)cyclobutyl)methyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol was converted to the title compound as described for illustrative Example 143 and other examples above.

Exemplary Synthesis of Exemplary Compound 665 The intermediate 2-(6-amino-5-(1-(1-(1-((1s,3s)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol was prepared according to the following scheme.

2-(6-amino-5-(1-(1-(1-((1s,3s)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)pyridazin-3-yl)phenol was converted to the title compound as described for illustrative Example 143 and other examples above.

Exemplary Synthesis of Exemplary Compound 678 The intermediate (2S,4R)-N-((S)-1-(4-ethynylphenyl)ethyl)-1-((R)-2-(3-(4-formylpiperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide was prepared according to the following scheme.

(2S,4R)-N-((S)-1-(4-ethynylphenyl)ethyl)-1-((R)-2-(3-(4-formylpiperidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide was converted to the title compound using the procedure described for exemplary compound 143 above.

Exemplary Synthesis of Exemplary Compound 692 Step 1

A mixture of 3-benzyloxycyclobutanol (100 g, 561.08 mmol, 1 eq.) and benzyl 4-oxopiperidine-1-carboxylate (143.97 g, 617.19 mmol, 123.1 mL, 1.1 eq.) in acetonitrile (2000 mL) was degassed and purged with nitrogen three times. To the mixture was then added chloro(dimethyl)silane (53.09 g, 561.08 mmol, 1 eq.) at 0° C. The mixture was stirred at 25° C. under nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water (2 L). The organic layer was extracted with ethyl acetate (1 L×2). The combined organic layers were washed with brine (500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=30/1 to 20:1) to give the product. Benzyl 4-(3-benzyloxycyclobutoxy)piperidine-1-carboxylate (89 g, 225.04 mmol) was obtained as a colorless oil.

Step 2

To a solution of benzyl 4-(3-benzyloxycyclobutoxy)piperidine-1-carboxylate (65 g, 164.35 mmol, 1 equiv.) in ethanol (300 mL) and tetrahydrofuran (300 mL), palladium on activated carbon catalyst (6 g, 1.44 mmol, 10% purity), palladium hydroxide on activated carbon catalyst (6 g, 8.54 mmol, 20% purity), and di-tert-butyl dicarbonate (53.80 g, 246.53 mmol, 56.6 mL, 1.5 equiv.) were added under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 Psi) at 40 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1, 0/1). The crude product, tert-butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (30.8 g, 113.5 mmol), was obtained as a white solid.

Step 3

tert-Butyl 4-(3-hydroxycyclobutoxy)piperidine-1-carboxylate (5 g, 18.43 mmol, 1 eq.), 4-bromopyridin-2-ol (3.85 g, 22.11 mmol, 1.2 eq.), triphenylphosphine (7.25 g, 27.64 mmol, 1.5 eq.), and diisopropyl azodicarboxylate (5.59 g, 27.64 mmol, 5.4 mL, 1.5 eq.) in toluene (40 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under nitrogen atmosphere at 110° C. for 12 hours. The reaction mixture was cooled to 20° C., then filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=50/1 to 10/1) to give the product. tert-Butyl 4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (7 g, 16.38 mmol) was obtained as a pale yellow oil.

Step 4

A solution of tert-butyl 4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carboxylate (4 g, 9.36 mmol, 1 eq.) in hydrochloride/methanol (4 M, 25 mL, 10.68 eq.) was stirred at 25°C for 10 min. The reaction solution was concentrated under vacuum to give the crude product, which was used directly in the next step without further purification. 4-Bromo-2[3-(4-piperidyloxy)cyclobutoxy]pyridine hydrochloride (3.2 g, 8.80 mmol) was obtained as a pale yellow oil.

Step 5

To a solution of 4-bromo-2-[3-(4-piperidyloxy)cyclobutoxy]pyridine (3.2 g, 8.80 mmol, 1 eq., hydrochloride salt) in N,N-dimethylformamide (40 mL) was added triethylamine (5.34 g, 52.79 mmol, 7.4 mL, 6 eq.) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (2.42 g, 10.56 mmol, 1.2 eq.). After addition, the mixture was stirred at 20°C for 2 minutes. To the mixture was then added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.01 g, 10.56 mmol, 1.2 eq.) at 0°C, and the mixture was stirred under nitrogen at 20°C for 1 hour. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna c18 250 mm * 100 mm * 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 20 min). The compound tert-butyl 4-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carbonyl]piperidine-1-carboxylate (4.5 g, 8.36 mmol) was obtained as a white solid.

Step 6

To a solution of tert-butyl 4-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]piperidine-1-carbonyl]piperidine-1-carboxylate (3.5 g, 6.50 mmol, 1 eq.) in tetrahydrofuran (70 mL), zirconium chloride (IV) (3.03 g, 13.0 mmol, 1.1 mL, 2 eq.) was added at -20 ° C. and the mixture was stirred at -20 ° C. for 1 h. Then, methylmagnesium bromide (3 M, 13 mL, 6 eq.) was added slowly to the mixture at -10 ° C. The mixture was stirred at 30 ° C. for 12 h. The reaction mixture was diluted by saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-50%, 20min). The compound tert-butyl 4-[1-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]-1-piperidyl]-1-methyl-ethyl]piperidine-1-carboxylate (1g, 1.81mmol, 27% yield) was obtained as a pale yellow oil.

Using procedures similar to those described for exemplary compound 143, exemplary compound 616, and other examples, tert-butyl 4-[1-[4-[3-[(4-bromo-2-pyridyl)oxy]cyclobutoxy]-1-piperidyl]-1-methyl-ethyl]piperidine-1-carboxylate was converted to the title compound according to the following scheme.

Exemplary Synthesis of Exemplary Compound 698: Prepared according to the following scheme using procedures similar to those described for Exemplary Compound 638 and Exemplary Compound 640.

Exemplary Synthesis of Exemplary Compound 707 Prepared according to the following scheme using procedures described for other examples above.

The present specification further provides a method for controlling protein levels using cells. The method is based on the use of compounds described herein that are known to interact with specific target proteins, whereby the in vivo degradation of the target protein leads to the control of the amount of protein in a biological system, preferably for a specific therapeutic benefit.

The following examples are used to complement the explanation of this disclosure, but are in no way to be construed as limiting this disclosure.

Specific Embodiments of the Disclosure The disclosure includes the following specific embodiments, which may include all of the features recited in the embodiments that follow, as specified. Where appropriate, the embodiments may further include, inclusively or in the alternative, the features recited in the embodiments that follow (e.g., the eighth embodiment may include the features recited in the first embodiment, as recited, and/or may include any of the features of the second through seventh embodiments).

式中、
ＷＰＴＭ１は、任意に置換された５～６員アリールまたはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、または３個の置換基で置換された５～６員アリールまたはヘテロアリール）であり、
ＷＰＴＭ２が、任意に置換された５～６員アリールまたはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、または３個の置換基で置換された５～６員アリールまたはヘテロアリール）であり、
ＷＰＴＭ３は、存在しないか、または任意に置換された５～６員アリールもしくはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、もしくは３個の置換基で置換された５～６員アリールもしくはヘテロアリール）、または任意に置換された４～９シクロアルキルもしくはヘテロシクリル、任意に置換された架橋ビシクロアルキルおよび架橋ビヘテロシクリル（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、もしくは２個の置換基で置換された４～９シクロアルキルもしくはヘテロシクリル）であり、
ＷＰＴＭ４は、ＷＰＴＭ２環で縮合された任意に置換された５～７シクロアルキルまたはヘテロシクリル（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、２、または３個の置換基で置換された５～７シクロアルキルまたはヘテロシクリル）であり、
ＷＰＴＭ５は、存在しないか、または任意に置換された５～６員アリールもしくはヘテロアリール環（例えば、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、または２個の置換基で置換された５～６員アリールまたはヘテロアリール）であり、
ＷＰＴＭ６およびＷＰＴＭ７は、独立して、任意に４～７シクロアルキルまたはヘテロシクリル（例えば、各々が独立して、ヒドロキシ、ハロゲン、アルコキシ、アルキル、ハロアルキル、アミノ、アルキルアミノ、およびシアノから選択される０、１、または２個の置換基で置換された４～７シクロアルキルまたはヘテロシクリルである）であり、ＷＰＴＭ６およびＷＰＴＭ７の環は、スピロ連結を介して縮合または結合され、

は、リンカー、ＵＬＭ基、ＵＬＭ’基、ＶＬＭ基、ＶＬＭ’基への結合点である、二官能性化合物またはその薬学的に許容される塩、鏡像異性体、立体異性体、溶媒和物、多形、もしくはプロドラッグを提供する。 In certain embodiments, the description provides the following exemplary SMARCA2 (i.e., BRAHMA or BRM) PROTAC molecules (compounds 1-765 of Table 1A, Table IB, Table 1C, Table ID, Table 2A, Table 2B, Table 2C, and Table 2D), including salts, prodrugs, polymorphs, analogs, derivatives, and deuterated forms thereof. In certain embodiments, the description provides a bifunctional compound having the following chemical structure: PTM-L-ULM, where ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to von Hippel-Lindau E3 ubiquitin ligase, L is a bond or chemical linkage moiety linking the ULM and the PTM, and PTM is a small molecule comprising a SMARCA2 protein targeting moiety having a chemical structure represented by Formula I, II, III, IVa, or IVb;

In the formula,
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);
WPTM2 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);
WPTM3 is absent or an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), or an optionally substituted 4-9 cycloalkyl or heterocyclyl, optionally substituted bridged bicycloalkyl, and bridged biheterocyclyl (e.g., a 4-9 cycloalkyl or heterocyclyl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);
WPTM4 is an optionally substituted 5-7 cycloalkyl or heterocyclyl (e.g., 5-7 cycloalkyl or heterocyclyl substituted with 0, 1, 2, or 3 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano) fused to a WPTM2 ring;
WPTM5 is absent or an optionally substituted 5-6 membered aryl or heteroaryl ring (e.g., a 5-6 membered aryl or heteroaryl substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano);
WPTM6 and WPTM7 are independently optionally 4-7 cycloalkyl or heterocyclyl (e.g., 4-7 cycloalkyl or heterocyclyl each independently substituted with 0, 1, or 2 substituents selected from hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, and cyano), and the rings of WPTM6 and WPTM7 are fused or joined via a spiro linkage;

is a point of attachment to a linker, a ULM group, a ULM' group, a VLM group, a VLM' group, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof.

またはその薬学的に許容される塩を含み、
ＷＰＴＭ１は、任意に置換されたフェニルまたはピリジル（例えば、本明細書に記載されるように選択された追加の任意の置換基を有するかまたは有しないヒドロキシ置換基で置換されたフェニルなど、本明細書に記載されるように置換された）であり、
ＷＰＴＭ２は、任意に置換された６員ヘテロアリール環（例えば、アミノ基で置換されたピリダジンなど、本明細書に記載されるように置換された）であり、
ＷＰＴＭ３は、任意に置換された５～６員ヘテロアリール（例えば、ピラゾール、ピロール、イミダゾール、オキサゾール、オキサジアゾール、もしくはトリアゾール）、または任意に置換された４～９シクロアルキルもしくはヘテロシクリル環、任意に置換された架橋ビシクロアルキル、および架橋ビヘテロシクリル環が存在しない。 In any of the aspects of the embodiments described herein, the PTM is represented by formula I:

or a pharma- ceutically acceptable salt thereof,
WPTM1 is an optionally substituted phenyl or pyridyl (e.g., substituted as described herein, such as phenyl substituted with a hydroxy substituent, with or without additional optional substituents selected as described herein);
WPTM2 is an optionally substituted 6-membered heteroaryl ring (e.g., substituted as described herein, such as pyridazine substituted with an amino group);
WPTM3 is free of optionally substituted 5-6 membered heteroaryl (e.g., pyrazole, pyrrole, imidazole, oxazole, oxadiazole, or triazole), or optionally substituted 4-9 cycloalkyl or heterocyclyl rings, optionally substituted bridged bicycloalkyl, and bridged biheterocyclyl rings.

またはその薬学的に許容される塩を含み、
ＷＰＴＭ３は、不在であるか、または任意に置換された５～６員ヘテロアリール、任意に置換された４～９シクロアルキルもしくはヘテロシクリル環、任意に置換された架橋ビシクロアルキル、および架橋ビヘテロシクリル環であり、
ＷＰＴＭ５は、任意に置換された５～６員ヘテロアリールである。 In any of the aspects or embodiments described herein, the PTM may be represented by the formula:

or a pharma- ceutically acceptable salt thereof,
WPTM3 is absent or an optionally substituted 5-6 membered heteroaryl, an optionally substituted 4-9 membered cycloalkyl or heterocyclyl ring, an optionally substituted bridged bicycloalkyl, and a bridged biheterocyclyl ring;
WPTM5 is an optionally substituted 5-6 membered heteroaryl.

またはその薬学的に許容される塩を含み、
ＷＰＴＭ５は、フェニルまたはピリジニルである。 In any of the aspects or embodiments described herein, the PTM may be represented by the formula:

or a pharma- ceutically acceptable salt thereof,
WPTM5 is phenyl or pyridinyl.

またはその薬学的に許容される塩である。 In any of the aspects or embodiments described herein, the PTM may be represented by the formula:

or a pharma- ceutically acceptable salt thereof.

またはその薬学的に許容される塩を含み、
ＷＰＴＭ１は、追加の任意の置換基を有するかまたは有しないヒドロキシ置換基で置換されたフェニルであり、
ＷＰＴＭ２は、アミノ基で置換されたピリダジンであり、
ＷＰＴＭ６およびＷＰＴＭ７は、スピロ環状環系（例えば、

In any of the aspects or embodiments described herein, the PTM is represented by formula III:

or a pharma- ceutically acceptable salt thereof,
WPTM1 is a phenyl substituted with a hydroxy substituent, with or without additional optional substituents;
WPTM2 is an amino-substituted pyridazine;
WPTM6 and WPTM7 are spirocyclic ring systems, e.g.

またはその薬学的に許容される塩を含み、
ＷＰＴＭ１は、本明細書に記載される追加の任意の置換基を有するかまたは有しないヒドロキシ置換基で置換されたフェニルであり、
ＷＰＴＭ２は、アミノ基で置換されたピリダジンであり、
ＷＰＴＭ５は、存在しないか、またはピラゾール環もしくはピリジン環である。 In any of the aspects or embodiments described herein, the PTM is represented by formula IVa or IVb,

or a pharma- ceutically acceptable salt thereof,
WPTM1 is phenyl substituted with a hydroxy substituent, with or without any additional substituents described herein;
WPTM2 is an amino-substituted pyridazine;
WPTM5 is absent or is a pyrazole ring or a pyridine ring.

In any of the aspects or embodiments described herein, the PTM is selected from the group consisting of:

式中、
Ｗ３は、任意に置換されたアリール、任意に置換されたヘテロアリール、または

の群から選択され、
Ｒ９およびＲ１０は独立して、水素、任意に置換されたアルキル、任意に置換されたシクロアルキル、任意に置換されたヒドロキシアルキル、任意に置換されたヘテロアリール、またはハロアルキルであるか、またはＲ９、Ｒ１０、およびそれらが結合する炭素原子が、任意に置換されたシクロアルキルを形成し、
Ｒ１１は、任意に置換されたヘテロシクリル、任意に置換されたアルコキシ、任意に置換されたヘテロアリール、任意に置換されたアリール、

の群から選択され、
Ｒ１２は、Ｈまたは任意に置換されたアルキルの群から選択され、
Ｒ１３は、Ｈ、任意に置換されたアルキル、任意に置換されたアルキルカルボニル、任意に置換された（シクロアルキル）アルキルカルボニル、任意に置換されたアラルキルカルボニル、任意に置換されたアリールカルボニル、任意に置換された（ヘテロシクリル）カルボニル、または任意に置換されたアラルキルの群から選択され、
Ｒ１４ａ、Ｒ１４ｂは、各々独立して、Ｈ、ハロアルキル（例えば、フルオロアルキル）、任意に置換されたアルキル、任意に置換されたアルコキシ、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたヘテロルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＮＨＣＯＲ２６、またはＮＨＣＨ３ＣＯＲ２６の群から選択され、Ｒ１４ａおよびＲ１４ｂのうちの他方が、Ｈであり、またはＲ１４ａ、Ｒ１４ｂが、それらが結合している炭素原子と一緒になって、任意に置換された３～５員シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルが、エポキシドまたはアジリジンではなく、
Ｗ５は、任意に置換されたフェニル、任意に置換されたナプチル、または任意に置換された５～１０員ヘテロアリールであり、
Ｒ１５は、Ｈ、ハロゲン、ＣＮ、ＯＨ、ＮＯ２、ＮＲ２７ａＲ２７ｂ、ＯＲ２７ａ、ＣＯＮＲ２７ａＲ２７ｂ、ＮＲ２７ａＣＯＲ２７ｂ、ＳＯ２ＮＲ２７ａＲ２７ｂ、ＮＲ２７ａＳＯ２Ｒ２７ｂ、任意に置換されたアルキル、任意に置換されたハロアルキル（例えば、任意に置換されたフルオロアルキル）、任意に置換されたハロアルコキシ、任意に置換されたアリール、任意に置換されたヘテロアリール、任意に置換されたシクロアルキル、または任意に置換されたヘテロシクリルの群から選択され、
各Ｒ１６は、独立して、ハロ、ＣＮ、任意に置換されたアルキル、任意に置換されたハロアルキル、ヒドロキシ、または任意に置換されたハロアルコキシの群から選択され、
ｏは、０、１、２、３、または４であり、
Ｒ１８は、Ｈ、ハロ、任意に置換されたアルコキシ、シアノ、任意に置換されたアルキル、ハロアルキル、ハロアルコキシまたはリンカーの群から独立して選択され、
各Ｒ２６は、独立して、Ｈ、任意に置換されたアルキル、またはＮＲ２７ａＲ２７ｂから選択され、
各Ｒ２７ａおよびＲ２７ｂは、独立して、Ｈ、任意に置換されたアルキル、任意に置換されたシクロアルキル（例えば、任意に置換された３～５員シクロアルキル）であるか、またはＲ２７ａおよびＲ２７ｂは、それらが結合している窒素原子と一緒になって、４～６員ヘテロシクリルを形成し、
ｐは、０、１、２、３、または４であり、および式中、破線は、少なくとも１つのＰＴＭ、別のＵＬＭ（ＵＬＭ’）、または少なくとも１つのＰＴＭもしくはＵＬＭ’もしくはその両方をＵＬＭに結合する化学リンカー部分の結合部位を示す。 In any aspect or embodiment described herein, the ULM is a chemical structure represented by:

In the formula,
W3 is optionally substituted aryl, optionally substituted heteroaryl, or

is selected from the group
R and R are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R, R 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,

is selected from the group
R12 is selected from the group of H or optionally substituted alkyl;
R13 is selected from the group: 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;
R14a, R14b are each independently selected from the group of H, haloalkyl (e.g., fluoroalkyl), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26; the other of R14a and R14b is H; or R14a, R14b together with the carbon atom to which they are attached form an optionally substituted 3-5 membered cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocyclyl, wherein the spiroheterocyclyl is not an epoxide or aziridine;
W5 is an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted 5-10 membered heteroaryl;
R15 is selected from the group of H, halogen, CN, OH, NO2, NR27aR27b, OR27a, CONR27aR27b, NR27aCOR27b, SO2NR27aR27b, NR27aSO2R27b, 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;
Each R16 is independently selected from the group of halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
o is 0, 1, 2, 3, or 4;
R18 is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy, or a linker;
Each R26 is independently selected from H, optionally substituted alkyl, or NR27aR27b;
each R27a and R27b is independently H, optionally substituted alkyl, optionally substituted cycloalkyl (e.g., optionally substituted 3- to 5-membered cycloalkyl), 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, and wherein the dashed lines indicate the site of attachment of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM' or both to a ULM.

式中、
Ｒ１は、Ｈ、任意に置換されたアルキル、任意に置換されたシクロアルキル、任意に置換されたヒドロキシアルキル、任意に置換されたヘテロアリール、またはハロアルキルであり、
Ｒ１４ａは、Ｈ、ハロアルキル、任意に置換されたアルキル、メチル、フルオロメチル、ヒドロキシメチル、エチル、イソプロピル、またはシクロプロピルであり、
Ｒ１５は、Ｈ、ハロゲン、ＣＮ、ＯＨ、ＮＯ２、任意に置換されたヘテロアリール、任意に置換されたアリール、任意に置換されたアルキル（例えば、任意に置換されたハロアルキル）、任意に置換されたハロアルキル、任意に置換されたハロアルコキシ、任意に置換されたシクロアルキル、または任意に置換されたヘテロシクリルからなる群から選択され、
Ｘは、Ｃ、ＣＨ２、またはＣ＝Ｏであり、
Ｒ３は、存在しないか、または任意に置換された５もしくは６員ヘテロアリールであり、
破線は、少なくとも１つのＰＴＭ、別のＵＬＭ（ＵＬＭ’）、または少なくとも１つのＰＴＭもしくはＵＬＭ’もしくはその両方をＵＬＭに結合する化学リンカー部分の結合部位を示す。 In any aspect or embodiment described herein, the ULM has a chemical structure selected from the group consisting of:

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, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
R15 is selected from the group consisting of H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl (e.g., optionally substituted haloalkyl), optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted heterocyclyl;
X is C, CH2, or C=O;
R3 is absent or is an optionally substituted 5- or 6-membered heteroaryl;
The dashed lines indicate the attachment sites of at least one PTM, another ULM (ULM'), or a chemical linker moiety linking at least one PTM or ULM', or both, to a ULM.

またはその薬学的に許容される塩を含み、
ＵＬＭ－ｇのＲ１’は、任意に置換されたＣ１－Ｃ６アルキル基、任意に置換された－（ＣＨ２）ｎＯＨ、任意に置換された－（ＣＨ２）ｎＳＨ、任意に置換された（ＣＨ２）ｎ－Ｏ－（Ｃ１－Ｃ６）アルキル基、エポキシド部分ＷＣＯＣＷ（式中、各Ｗは、独立して、ＨまたはＣ１－Ｃ３アルキル基である）を含有する任意に置換された（ＣＨ２）ｎ－ＷＣＯＣＷ－（Ｃ０－Ｃ６）アルキル基、任意に置換された－（ＣＨ２）ｎＣＯＯＨ、任意に置換された－（ＣＨ２）ｎＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２）ｎＮＨＣ（Ｏ）－Ｒ″、任意に置換された－（ＣＨ２）ｎＣ（Ｏ）－Ｎ（Ｒ″）２、任意に置換された－（ＣＨ２）ｎＯＣ（Ｏ）－Ｎ（Ｒ″）２、－（ＣＨ２Ｏ）ｎＨ、任意に置換された－（ＣＨ２）ｎＯＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２）ｎＣ（Ｏ）－Ｏ－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２Ｏ）ｎＣＯＯＨ、任意に置換された－（ＯＣＨ２）ｎＯ－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２Ｏ）ｎＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＯＣＨ２）ｎＮＨＣ（Ｏ）－Ｒ″、任意に置換された－（ＣＨ２Ｏ）ｎＣ（Ｏ）－Ｎ（Ｒ″）２、－（ＣＨ２ＣＨ２Ｏ）ｎＨ、任意に置換された－（ＣＨ２ＣＨ２Ｏ）ｎＣＯＯＨ、任意に置換された－（ＯＣＨ２ＣＨ２）ｎＯ－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＣＨ２ＣＨ２Ｏ）ｎＣ（Ｏ）－（Ｃ１－Ｃ６アルキル）、任意に置換された－（ＯＣＨ２ＣＨ２）ｎＮＨＣ（Ｏ）－Ｒ″、任意に置換された－（ＣＨ２ＣＨ２Ｏ）ｎＣ（Ｏ）－Ｎ（Ｒ″）２、任意に置換された－ＳＯ２ＲＳ、任意に置換されたＳ（Ｏ）ＲＳ、ＮＯ２、ＣＮ、またはハロゲン（Ｆ、Ｃｌ、Ｂｒ、Ｉ、好ましくは、ＦまたはＣｌ）であり、
ＵＬＭ－ｇの各Ｒ″は、独立して、Ｈ、または１個もしくは２個のヒドロキシル基または最大３個のハロゲン基（好ましくは、フッ素）で任意に置換され得るＣ１－Ｃ６アルキル基であり、
ＵＬＭ－ｇのＲＳは、Ｃ１－Ｃ６アルキル基、任意に置換されたアリール、ヘテロアリール、もしくはヘテロシクリル基、または－（ＣＨ２）ｍＮ（Ｒ″）２基であり、
ＵＬＭ－ｇのＸおよびＸ’は、各々独立して、Ｃ＝Ｏ、Ｃ＝Ｓ、－Ｓ（Ｏ）、Ｓ（Ｏ）２であり（好ましくは、ＸおよびＸ’は、両方ともＣ＝Ｏであり）、
ＵＬＭ－ｇのＲ２’は、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗアルキリ基、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗＮＲ１ＮＲ２Ｎ基、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、任意に置換された－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｖＮＲ″（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、もしくは任意に置換された－ＮＲ″－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｖＮＲ″（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－ＸＲ２’－アルキリ基、任意に置換された－ＸＲ２’－アリール基、任意に置換された－ＸＲ２’－ヘテロアリール基、任意に置換された－ＸＲ２’－ヘテロシクリル基であり、
ＵＬＭ－ｇのＲ３’は、任意に置換されたアルキル、任意に置換された－（ＣＨ２）ｎ－（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－Ｃ（Ｏ）（Ｒ″）２、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、任意に置換された－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－ＮＲ″－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、任意に置換された－ＮＲ１－（ＣＨ２）ｎ－Ｃ（Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロシクリル、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アルキル、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ１ＮＲ２Ｎ、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ＮＲ″Ｃ（Ｏ）Ｒ１Ｎ、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－アリール、任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロアリール、もしくは任意に置換された－Ｏ－（ＣＨ２）ｎ－（Ｃ＝Ｏ）ｕ（ＮＲ″）ｖ（ＳＯ２）ｗ－ヘテロシクリル、－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－アルキル基、任意に置換された－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－アリール基、任意に置換された－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－ヘテロアリール基、任意に置換された－（ＣＨ２）ｎ－（Ｖ）ｎ’－（ＣＨ２）ｎ－（Ｖ）ｎ’－ヘテロシクリル’基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－アルキル基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－アリール基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－ヘテロアリール基、任意に置換された－（ＣＨ２）ｎ－Ｎ（Ｒ１’）（Ｃ＝Ｏ）ｍ’－（Ｖ）ｎ’－ヘテロシクリル基、任意に置換された－ＸＲ３’－アルキル基、任意に置換された－ＸＲ３’－アリール基、任意に置換された－ＸＲ３’－ヘテロアリール基、任意に置換された－ＸＲ３’－ヘテロシクリル基であり、
ＵＬＭ－ｇのＲ１ＮおよびＲ２Ｎは、各々独立して、Ｈ、１個もしくは２個のヒドロキシル基および最大３個のハロゲン基で任意に置換されたＣ１－Ｃ６アルキル、または任意に置換された－（ＣＨ２）ｎ－アリール、－（ＣＨ２）ｎ－ヘテロアリール、もしくは－（ＣＨ２）ｎ－ヘテロシクリル基であり、
ＵＬＭ－ｇのＶは、Ｏ、ＳまたはＮＲ１であり、
ＵＬＭ－ｇの各Ｒ１’は、独立して、Ｈ、またはＣ１－Ｃ３アルキル基であり、
ＵＬＭ－ｇのＸＲ２’およびＸＲ３’は、各々独立して、任意に置換された－ＣＨ２）ｎ－、－ＣＨ２）ｎ－ＣＨ（Ｘｖ）＝ＣＨ（Ｘｖ）－（ｃｉｓまたはｔｒａｎｓ）、－ＣＨ２）ｎ－ＣＨ≡ＣＨ－、－（ＣＨ２ＣＨ２Ｏ）ｎ－、またはＣ３－Ｃ６シクロアルキル基であり、式中、Ｘｖは、Ｈ、ハロ、または任意に置換されたＣ１－Ｃ３アルキル基であり、
ＵＬＭ－ｇの各ｍは独立して、０、１、２、３、４、５、６であり、
ＵＬＭ－ｇの各ｍ’は独立して、０または１であり、
ＵＬＭ－ｇの各ｎは独立して、０、１、２、３、４、５、６であり、
ＵＬＭ－ｇの各ｎ’は独立して、０または１であり、
ＵＬＭ－ｇの各ｕは独立して、０または１であり、
ＵＬＭ－ｇの各ｖは独立して、０または１であり、
ＵＬＭ－ｇの各ｗは独立して、０または１であり、および
ＰＴＭがＵＬＭ’でない場合、ＵＬＭ－ｇのＲ１’、Ｒ２’、Ｒ３’、Ｘ、およびＸ’のうちのいずれか１つ以上が任意に修飾されて、リンカー基を介してＰＴＭ基に共有結合するか、またはＰＴＭがＵＬＭ’である場合、ＵＬＭおよびＵＬＭ’の各々のＲ１’、Ｒ２’、Ｒ３’、Ｘ、およびＸ’のうちのいずれか１つ以上は任意に修飾されて、直接もしくはそのリンカー基を介して互いに共有結合する。 In any of the aspects or embodiments described herein, the ULM may be a group according to the following chemical structure:

or a pharma- ceutically acceptable salt thereof,
R1' of ULM-g is an optionally substituted C1-C6 alkyl group, an optionally substituted -(CH2)nOH, an optionally substituted -(CH2)nSH, an optionally substituted (CH2)n-O-(C1-C6)alkyl group, an optionally substituted (CH2)n-WCOCW-(C0-C6)alkyl group containing an epoxide moiety WCOCW (where each W is independently H or a C1-C3 alkyl group), an optionally substituted -(CH 2) nCOOH, optionally substituted -(CH2)nC(O)-(C1-C6 alkyl), optionally substituted -(CH2)nNHC(O)-R", optionally substituted -(CH2)nC(O)-N(R")2, optionally substituted -(CH2)nOC(O)-N(R")2, -(CH2O)nH, optionally substituted -(CH2)nOC(O)-(C1-C6 alkyl), optionally substituted -(CH2)nC(O)-O-(C1-C6 optionally substituted -(CH2O)nCOOH, optionally substituted -(OCH2)nO-(C1-C6 alkyl), optionally substituted -(CHO)nC(O)-(C1-C6 alkyl), optionally substituted -(OCH2)nNHC(O)-R", optionally substituted -(CHO)nC(O)-N(R")2, -(CH2CH2O)nH, optionally substituted -(CH2CH2O)nCOOH, optionally substituted -( optionally substituted —(CHCHO)C(O)—N(R″)2, optionally substituted —SORS, optionally substituted S(O)RS, NO, CN, or halogen (F, Cl, Br, I, preferably F or Cl);
Each R″ in ULM-g is independently H or a C1-C6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);
RS of ULM-g is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclyl group, or a -(CH2)mN(R'')2 group;
X and X' of ULM-g are each independently C=O, C=S, -S(O), S(O)2 (preferably, X and X' are both C=O);
R2' of ULM-g is an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w alkyl group, an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w NR1NR2N group, an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w aryl, an optionally substituted -(CH2)n-(C=O)u(NR'')v(SO2)w-heteroaryl, an optionally substituted -(CH2)n-(C=O)vNR''(SO2)w-heterocyclyl, an optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w alkyl, an optionally substituted -NR''-(CH2)n-C(O)u(NR'')v (SO2)w-NR1NR2N, optionally substituted -NR"-(CH2)n-C(O)u(NR")v(SO2)w-NR"C(O)RN, optionally substituted -NR"-(CH2)n-(C=O)u(NR")v(SO2)w-aryl, optionally substituted -NR"-(CH2)n-(C=O)u(NR")v(SO2)w-heteroaryl or optionally substituted -NR"-(CH2)n-(C=O)vNR"(SO2)w-heterocyclyl, optionally substituted -XR2'-alkyl group, optionally substituted -XR2'-aryl group, optionally substituted -XR2'-heteroaryl group, or optionally substituted -XR2'-heterocyclyl group;
R3' of ULM-g is optionally substituted alkyl, optionally substituted -(CH2)n-(O)u(NR'')v(SO2)w-alkyl, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-NR1NR2N, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-NR''C(O)R1N, optionally substituted -(C H2)n-C(O)u(NR'')v(SO2)w-C(O)(R'')2, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-aryl, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-heteroaryl, optionally substituted -(CH2)n-C(O)u(NR'')v(SO2)w-heterocyclyl, optionally substituted optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-alkyl, optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-NR1NR2N, optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-NR''C(O)R1N, optionally substituted -NR''-(CH2)n-C(O)u(NR'')v(SO2)w-NR''C(O)R1N optionally substituted —NR″-(CH2)n-C(O)u(NR″)v(SO2)w-aryl, optionally substituted —NR″-(CH2)n-C(O)u(NR″)v(SO2)w-heteroaryl, optionally substituted —NR1-(CH2)n-C(O)u(NR″)v(SO2)w-heterocyclyl, optionally substituted —O—(CH2)n-(C═O)u(NR″)v(SO2)w-alkyl, optionally substituted —O—( CH2)n-(C=O)u(NR'')v(SO2)w-NR1NR2N, optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w-NR''C(O)R1N, optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w-aryl, optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w- Heteroaryl, or optionally substituted -O-(CH2)n-(C=O)u(NR'')v(SO2)w-heterocyclyl, -(CH2)n-(V)n'-(CH2)n-(V)n'-alkyl group, optionally substituted -(CH2)n-(V)n'-(CH2)n-(V)n'-aryl group, optionally substituted -(CH2)n-(V)n'-(CH2)n-( V) n'-heteroaryl groups, optionally substituted -(CH2)n-(V) n'-(CH2)n-(V) n'-heterocyclyl' groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-alkyl groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-aryl groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-heteroaryl groups, optionally substituted -(CH2)n-N(R1')(C=O)m'-(V) n'-heterocyclyl groups, optionally substituted -XR3'-alkyl groups, optionally substituted -XR3'-aryl groups, optionally substituted -XR3'-heteroaryl groups, optionally substituted -XR3'-heterocyclyl groups;
R1N and R2N of ULM-g are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups and up to three halogen groups, or an optionally substituted -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl group;
V of ULM-g is O, S or NR1;
Each R1' in ULM-g is independently H or a C1-C3 alkyl group;
XR2' and XR3' of ULM-g are each independently an optionally substituted -CH2)n-, -CH2)n-CH(Xv)=CH(Xv)-(cis or trans), -CH2)n-CH≡CH-, -(CH2CHO)n-, or a C3-C6 cycloalkyl group, where Xv is H, halo, or an optionally substituted C1-C3 alkyl group;
Each m in ULM-g is independently 0, 1, 2, 3, 4, 5, or 6;
Each m' 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; and when the PTM is not a ULM', any one or more of R1', R2', R3', X, and X' of ULM-g are optionally modified to be covalently bonded to the PTM group via a linker group, or when the PTM is a ULM', any one or more of R1', R2', R3', X, and X' of each of the ULM and ULM' are optionally modified to be covalently bonded to each other directly or via their linker groups.

またはその薬学的に許容される塩を含み、
Ｒ１は、Ｈ、任意に置換されたアルキル、または任意に置換されたシクロアルキルであり、
Ｒ３は、任意に置換された５～６員ヘテロアリールであり、
Ｗ５は、任意に置換されたフェニル、任意に置換されたナプチル、または任意に置換されたピリジニルであり、
Ｒ１４ａおよびＲ１４ｂのうちの一方は、Ｈ、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたアルコキシ、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたヘテロルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＮＨＣＯＲ２６、もしくはＮＨＣＨ３ＣＯＲ２６であり、Ｒ１４ａおよびＲ１４ｂのうちの他方は、Ｈであり、またはＲ１４ａ、Ｒ１４ｂは、それらが結合している炭素原子と一緒になって、任意に置換された３～５員シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルが、エポキシドまたはアジリジンではなく、
Ｒ１５は、ＣＮ、任意に置換されたフルオロアルキル、

任意に置換された

（例えば、

式中、Ｒ２８ａは、ハロ、任意に置換されたアルキル、またはフルオロアルキルである）、または

であり、
各Ｒ１６は、独立して、ハロ、ＣＮ、任意に置換されたアルキル、任意に置換されたハロアルキル、ヒドロキシ、またはハロアルコキシから選択され、
各Ｒ２６は、独立して、Ｈ、任意に置換されたアルキル、またはＮＲ２７ａＲ２７ｂであり、
各Ｒ２７ａおよびＲ２７ｂは、独立して、Ｈ、任意に置換されたアルキル、任意に置換されたシクロアルキル（例えば、任意に置換された３～５員シクロアルキル）であるか、またはＲ２７ａおよびＲ２７ｂは、それらが結合している窒素原子と一緒になって、４～６員ヘテロシクリルを形成し、
Ｒ２８は、Ｈ、任意に置換されたアルキル、任意に置換されたアルコキシ、任意に置換されたヘテロアルキル、任意に置換されたアルキルアミン、任意に置換されたヒドロキシアルキル、アミン、任意に置換されたアルキニル、または任意に置換されたシクロアルキルであり、
ｏは、０、１、または２である。 In any of the aspects or embodiments described herein, the ULM has the following formula:

or a pharma- ceutically acceptable salt thereof,
R1 is H, optionally substituted alkyl, or optionally substituted cycloalkyl;
R3 is an optionally substituted 5-6 membered heteroaryl;
W5 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted pyridinyl;
one of R14a and R14b is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26; the other of R14a and R14b is H; or R14a, 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 the spiroheterocyclyl is not an epoxide or aziridine;
R15 is CN, optionally substituted fluoroalkyl,

Arbitrarily substituted

(for example,

wherein R28a is halo, optionally substituted alkyl, or fluoroalkyl; or

and
each R16 is independently selected from halo, CN, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or haloalkoxy;
each R26 is independently H, optionally substituted alkyl, or NR27aR27b;
each R27a and R27b is independently H, optionally substituted alkyl, optionally substituted cycloalkyl (e.g., optionally substituted 3- to 5-membered cycloalkyl), or R27a and R27b 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 alkylamine, optionally substituted hydroxyalkyl, amine, optionally substituted alkynyl, or optionally substituted cycloalkyl;
o is 0, 1, or 2.

を含み、式中、
Ｘ４、Ｘ５、およびＸ６の各々が、ＣＨおよびＮから選択され、２個以下が、Ｎであり、
Ｒ１は、Ｃ１－６アルキルであり、
Ｒ１４ａおよびＲ１４ｂのうちの一方が、Ｈ、任意に置換されたアルキル、任意に置換されたハロアルキル、任意に置換されたアルコキシ、任意に置換されたヒドロキシルアルキル、任意に置換されたアルキルアミン、任意に置換されたヘテロルキル、任意に置換されたアルキル－ヘテロシクロアルキル、任意に置換されたアルコキシ－ヘテロシクロアルキル、ＣＯＲ２６、ＣＯＮＲ２７ａＲ２７ｂ、ＮＨＣＯＲ２６、もしくはＮＨＣＨ３ＣＯＲ２６であり、Ｒ１４ａおよびＲ１４ｂのうちの他方が、Ｈであり、またはＲ１４ａおよびＲ１４ｂが、それらが結合している炭素原子と一緒になって、任意に置換された３～５員シクロアルキル、ヘテロシクロアルキル、スピロシクロアルキル、もしくはスピロヘテロシクリルを形成し、スピロヘテロシクリルが、エポキシドまたはアジリジンではなく、
各Ｒ２７ａおよびＲ２７ｂは、独立して、ＨまたはＣ１－６アルキルもしくはシクロアルキル（例えば、３～５員シクロアルキル）であり、
ｑが、１、２、３、または４であり、
Ｒ１５は、

またはＣＮであり、
Ｒ２８は、Ｈ、メチル、ＣＨ２Ｎ（Ｍｅ）２、ＣＨ２ＯＨ、ＣＨ２Ｏ（Ｃ１－４アルキル）、ＣＨ２ＮＨＣ（Ｏ）Ｃ１－４アルキル、ＮＨ２、

または

であり、
Ｒ２８Ｃは、Ｈ、メチル、フルオロ、またはクロロであり、
Ｒ１６は、Ｈ、Ｃ１－４アルキル、フルオロ、クロロ、ＣＮ、またはＣ１－４アルコキシである。 In any of the aspects or embodiments described herein, the ULM has the following formula:

wherein
Each of X4, X5, and X6 is selected from CH and N, with up to 2 being N;
R1 is C1-6 alkyl;
one of R14a and R14b is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkyl-heterocycloalkyl, optionally substituted alkoxy-heterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26; the other of R14a and R14b is H; 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 the spiroheterocyclyl is not an epoxide or aziridine;
each R27a and R27b is independently H or C1-6 alkyl or cycloalkyl (e.g., 3- to 5-membered cycloalkyl);
q is 1, 2, 3, or 4;
R15 is,

or CN,
R28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C1-4 alkyl), CH2NHC(O)C1-4 alkyl, NH2,

or

and
R28C is H, methyl, fluoro, or chloro;
R16 is H, C1-4 alkyl, fluoro, chloro, CN, or C1-4 alkoxy.

In any aspect or embodiment described herein, R14a and R14b are selected from H, C1-4 alkyl, C1-4 cycloalkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkyloxyalkyl, C1-4 alkyl-NR27aR27b, and CONR27aR27b.

In any aspect or embodiment described herein, at least one of R14a and R14b is H (e.g., both R14a and R14b are H).

In any aspect or embodiment described herein, at least one of R14a and R14b is an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted alkoxy, an optionally substituted hydroxylalkyl, an optionally substituted alkylamine, an optionally substituted heteroalkyl, an optionally substituted alkyl-heterocycloalkyl, an optionally substituted alkoxy-heterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26. Alternatively, in any aspect or embodiment described herein, one of R14a and R14b is optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hydroxylalkyl, optionally substituted alkylamine, optionally substituted heteroalkyl, optionally substituted alkylheterocycloalkyl, optionally substituted alkoxyheterocycloalkyl, COR26, CONR27aR27b, NHCOR26, or NHCH3COR26, and the other of R14a and R14b is H.

を形成し、式中、Ｒ２３は、Ｈ、Ｃ１－４アルキル、－Ｃ（Ｏ）Ｃ１－４アルキルから選択される。本明細書に記載される態様または実施形態のいずれにおいても、ＵＬＭは、以下の式、

またはその薬学的に許容される塩のものであり、式中、ＵＬＭ－ｑおよびＵＬＭ－ｒのＲ１、Ｒ３、Ｒ１４ａ、Ｒ１４ｂ、およびＲ１５は、本明細書に記載されるとおりであり、Ｘは、ＣＨまたはＮである。 In any aspect or embodiment described herein, R14a and R14b, together with the carbon atom to which they are attached, represent:

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

or a pharma- ceutically acceptable salt thereof, wherein R1, R3, R14a, R14b, and R15 of ULM-q and ULM-r are as described herein; and X is CH or N.

In any of the aspects or embodiments described herein, R1 is C1-6 alkyl.

In any of the aspects or embodiments described herein, one of R14a and R14b is H, C1-6 alkyl, C1-6 haloalkyl, optionally substituted C1-4 alkylamine, C1-6 alkoxy, (CH2)qC1-6 alkoxy, (CH2)qC1-6 alkoxy-C3-C7 heterocycloalkyl, (CH2)qOH, (CH2)qNR27aR27b, (CH2)qNHCOC1-6 alkyl, C3-6 cycloalkyl, or NR27aR27b, each R26 is independently H, C1-6 alkyl, or NR27aR27b, each R27a and R27b is independently H or C1-6 alkyl, and q is 1, 2, 3, or 4.

In any of the aspects or embodiments described herein, one of R14a and R14b is H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, optionally substituted C1-4 alkylamine, (CH2)qC1-6 alkoxy, (CH2)qC1-6 alkoxy-C3-C7 heterocycloalkyl, (CH2)qOH, (CH2)qNR27aR27b, (CH2)qNHCOC1-6 alkyl, C3-6 cycloalkyl, or NR27aR27b, each R26 is independently H, C1-4 alkyl, or NR27aR27b, each R27a and R27b is independently H or C1-4 alkyl, and q is 1 or 2.

であり、
Ｒ２９は、Ｈ、Ｃ１－６アルキル、ＮＲ２７ａＲ２７ｂまたはｑＮＨＣＯＣ１－６アルキルであり、
式中、ｑは、１または２である。 In any of the aspects or embodiments described herein, R28 is C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, (CH2)qOC1-6 alkyl, (CH2)qOH, (CH2)qNR27aR27b, (CH2)qNHCOC1-6 alkyl, or

and
R29 is H, C1-6 alkyl, NR27aR27b or qNHCOC1-6 alkyl;
In the formula, q is 1 or 2.

In any of the aspects or embodiments described herein, R3 is isoxazolyl, 4-chloroisoxazolyl, 4-fluoroisoxazolyl, or pyrazolyl. In any of the aspects or embodiments described herein, X is CH.

またはその薬学的に許容される塩を有し、
式中、
Ｒ１、Ｒ１４ａ、およびＲ１４ｂは、本明細書に記載されるとおりであり、
Ｘは、ＣＨまたはＮであり、
Ｒ３０は、Ｈ、Ｆ、またはＣｌであり、
Ｒ１６は、Ｈ、Ｃ１－４アルキル、フルオロ、クロロ、ＣＮ、またはＣ１－４アルコキシであり、
Ｒ２８は、Ｈ、メチル、ＣＨ２Ｎ（Ｍｅ）２、ＣＨ２ＯＨ、ＣＨ２Ｏ（Ｃ１－４アルキル）、ＣＨ２ＮＨＣ（Ｏ）Ｃ１－４アルキル、ＮＨ２、

である。 In any aspect or embodiment described herein, the ULM has the following formula:

or a pharma- ceutically acceptable salt thereof;
In the formula,
R1, R14a, and R14b are as described herein;
X is CH or N;
R30 is H, F, or Cl;
R16 is H, C1-4 alkyl, fluoro, chloro, CN, or C1-4 alkoxy;
R28 is H, methyl, CH2N(Me)2, CH2OH, CH2O(C1-4 alkyl), CH2NHC(O)C1-4 alkyl, NH2,

It is.

またはその薬学的に許容される塩によるものであり、式中、Ｒ１、Ｒ１４ａ、およびＲ１４ｂは、本明細書に記載されるとおりであり、Ｒ３０は、Ｈ、Ｆ、またはＣｌである。 In any of the aspects or embodiments described herein, the ULM has the following formula:

or a pharma- ceutically acceptable salt thereof, wherein R1, R14a, and R14b are as described herein, and R30 is H, F, or Cl.

In any aspect or embodiment described herein, the ULM is a ULM provided in Table 1A, Table 1B, Table 1C, Table 1D, Table 2A, Table 2B, Table 2C, or Table 2D.

In any of the aspects or embodiments described herein, the compound includes a linker (L) as described herein.

In any of the aspects or embodiments described herein, the linker (L) is a polyethyleneoxy group optionally substituted with aryl or phenyl containing 1 to 10 ethylene glycol units.

In any of the aspects or embodiments described herein, the compound is selected from the compounds of Tables 1A, 1B, 1C, 1D, 2A, 2B, 2C, and 2D (e.g., selected from compounds 1-765).

In any of the aspects or embodiments described herein, the compound has a Dmax of 80% or greater.

In an additional aspect, the description provides a composition comprising an effective amount of a bifunctional compound described herein and a pharma- ceutically acceptable carrier.

In any of the aspects or embodiments described herein, the compositions described herein further comprise at least one additional bioactive agent or another bifunctional compound described in any of claims 1-32.

In any of the aspects or embodiments described herein, the additional bioactive agent is an anticancer agent.

In any of the aspects or embodiments described herein, the compositions described herein include a pharma- ceutically acceptable carrier and an effective amount of at least one compound described herein to treat a disease or disorder in a subject, and the methods include administering the composition to a subject in need thereof, wherein the compound is effective to treat or ameliorate at least one symptom of the disease or disorder.

In any aspect or embodiment described herein, the disease or disorder is associated with accumulation and aggregation of SMARCA1, BRAHMA, or BRM. In any aspect or embodiment described herein, the disease or disorder is cancer. In any aspect or embodiment described herein, the cancer is a SWI/SNF-associated cancer, or a cancer with a SMARCA4 mutation (e.g., lung cancer or non-small cell lung cancer). In any aspect or embodiment described herein, the cancer is a SMARCA4-deficient cancer, or a cancer with reduced expression of SMARCA4 compared to normal SMARCA4 expression (e.g., compared to non-mutated SMARCA4 or SMARCA4 expression in similarly located non-cancer cells with wild-type SMARCA4), e.g., lung cancer or non-small cell lung cancer.

Assay and Degradation Data Western Blot Screening of BRM Degradation in SW1573 Cells To assess BRM degradation (Dmax and DC50), cells were seeded at 8000 cells/well in 96-well black/clear bottom plates in 180 μL of DMEM growth medium (containing 1% pen-strep, 1% HEPES, and 10% FBS) per well. Plates were incubated overnight to allow attachment. The following morning cells were treated by adding 20 μL of 10x target compound concentration (1% DMSO) to the appropriate wells and returned to the incubator overnight (18-20 hours). Final DMSO concentration was 0.1%.

For lysis, adherent cells were washed once with 100 μL DPBS. Cells were lysed in 40 μL 1X RIPA + HALT protease inhibitors on ice for 10 min and frozen at -80°C until use. Thawed lysates were washed by filtration through a 1.2 μm filter plate or alternatively spun at 2300 g for 30 min at 4°C.

To blot, for each western sample, 30 μL of lysate was added to 10 μL of 4x LDS sample buffer, then denatured in a thermal cycler at 95°C for 5 minutes and placed on ice. Samples were loaded onto a 4-15% Tris/Glycine gel and run at 250 constant volts for 25 minutes in 1x Tris/Glycine buffer with 4 μL of ladder and 12 μL of each sample loaded for each blot. Proteins were transferred from the gel to NC using a BioRad Turbo dry transfer unit using the Turbo/midi default program. All blots were rinsed with ddH2O and blocked in 5% BSA in TBST (0.1%) on a rocker for 1 hour at room temperature. Blots were exposed to primary antibodies in 5% BSA in TBST (0.1%) on a rocker (1:1000 for BRM (Cell Signaling Tech. Cat. No. 11966) and 1:2000 for alpha-tubulin (Cell Signaling Tech. Cat. No. 3873), control proteins, overnight at 4°C. Blots were washed 3 times for 5 min with TBST (0.1%) on a rocker at room temperature. Secondary antibodies were added and blots were incubated with 1:18,000 anti-rabbit-HRP and/or anti-mouse-HRP in 5% BSA in TBST (0.1%) for 1 hr on a rocker at room temperature. Blots were washed 3 times for 5 min in TBST (0.1%) on a rocker at room temperature. Signals were analyzed using a Femto Maximum The blot was developed with Sensitivity substrate for 4 minutes and read on a ChemiDoc™.

Intracellular Western Screening of BRM Degradation in SW1573 Cells To assess BRM degradation (Dmax and DC50), cells were seeded at 8000 cells/well in 96-well black/clear bottom plates in 180 μL of DMEM growth medium (containing 1% pen-strep, 1% HEPES, and 10% FBS) per well. Plates were incubated overnight to allow attachment. The following morning cells were treated by adding 20 μL of 10x compound (1% DMSO) to the appropriate wells and returned to the incubator overnight (18-20 hours). Final DMSO concentration was 0.1%.

For treatment, plates were removed from the incubator, medium was removed, and 200 μL of cold (4°C) DPBS was immediately added to all wells. DPBS was then removed, 50 μL of 4% paraformaldehyde (PFA) in DPBS (4°C) was added to all wells, and plates were incubated at room temperature for 20 minutes. PFA was then removed, 200 μL of TBS-T with 0.5% Triton X-100 was added to all wells, and plates were incubated at room temperature for 30 minutes. TBS-T with 0.5% Triton X-100 was then removed, 50 μL of Li-Cor blocking solution was added, and plates were incubated at room temperature for at least 1 hour. The blocking solution was removed and 50 μL of Li-Cor blocking solution was added containing a primary antibody cocktail with control proteins (1:1000 for BRM (Cell Signaling Tech. Cat. No. 11966) and 1:2000 for alpha-tubulin (Sigma Cat. No. T6074)). The plate was then placed in a cold room until the next day.

The next day, plates were washed 3 times with TBS-T, 200 μL per well. 50 μL of secondary antibody cocktail in LI-COR blocking solution (anti-rabbit_800 nm and anti-mouse_680 nm) was added to all wells (diluted 1:5000). Plates were incubated at room temperature for at least 1 hour, protected from light. Plates were washed 2 times with TBS-T, 200 μL per well.

To read each plate, the TBS-T was removed and each plate was inverted and tapped onto a paper towel. Plates were read on a LI-COR Odyssey with default intensity settings of 5.0 for both channels. LI-COR images were analyzed using the intracellular Western feature in Image Studio Lite.

The following compounds exhibited targeted protein degradation when tested under the conditions described above.

Novel bifunctional molecules containing SMARCA2, BRAHMA, or BRM protein recruitment moieties and E3 ligase recruitment moieties are described through PROTAC technology. The bifunctional molecules of the present disclosure actively degrade SMARCA2, resulting in robust cell growth inhibition and apoptosis induction. PROTAC-mediated protein degradation offers a promising strategy in targeting pathological proteins that are "undruggable" by conventional approaches.

The contents of all references, patents, pending patent applications and published patents cited throughout this application are expressly incorporated herein by reference. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the present disclosure described herein. Such equivalents are intended to be encompassed by the following claims. It should be understood that the detailed examples and embodiments described herein are provided as examples only for illustrative purposes and are not to be considered as limiting the present disclosure in any way. Various modifications or alterations in that respect will be suggested to those skilled in the art and are within the spirit and scope of the present application and are contemplated within the scope of the appended claims. For example, the relative amounts of the components may be altered to optimize the desired effect, additional components may be added, and/or similar components may be substituted for one or more of the components described. Additional beneficial features and functions associated with the systems, methods, and processes of the present disclosure will be apparent from the appended claims. Moreover, those skilled in the art will recognize or be able to ascertain many equivalents to the specific embodiments of the present disclosure described herein using no more than routine experimentation. Such equivalents are intended to be encompassed by the following claims.

Claims (12)

Chemical Structure:
PTM-L-ULM
or a pharma- ceutically acceptable salt thereof,
In the formula,
The ULM is
and
In the formula,
R ¹ is C _1-3 alkyl;
R ^14a is C _1-3 alkyl;
R ^14b is H or C _1-3 alkyl;
^R15 is
and
R ²⁸ is C _1-3 alkyl;
^R3 is isoxazolyl;
o is 0, 1 or 2;
R ¹⁶ is H, C _1-4 alkyl, fluoro, chloro, CN, or C _1-4 alkoxy;
Each of X ⁴ , X ⁵ , and X ⁶ is CH;
indicates the binding site of the L to the ULM;
The L is
-( ^AL ) _q-
is a chemical linking moiety linking the ULM and the PTM, represented by
In the formula,
q is 1, 2, 3, 4 or 5;
each A ^L is independently CH ₂ , O, cyclobutyl, piperidinyl, or piperazinyl;
The PTM is
and
In the formula,
W _PTM1 is phenyl optionally substituted with hydroxy;
W _PTM2 is pyridazinyl substituted with amino;
W _PTM3 is pyrazolyl or 3,8-diazabicyclo[3.2.1]octanyl;
W _PTM4 is piperidinyl;
L _PTM is C ₁ -C ₃ alkylene;
is the point of attachment to said L , or a pharma- ceutically acceptable salt thereof. 2. The compound of claim 1 , wherein the PTM is selected from the following:
The compound according to claim 1, wherein o is 0. The compound of claim 1, wherein R ^14a is C _1-3 alkyl and R ^14b is H. The ULM is
and
In the formula,
R ₃₀ is H;
The compound of claim 1 , wherein R ₂₈ is methyl. 2. The compound of claim 1, selected from: A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. The pharmaceutical composition of claim 7, further comprising an anticancer agent. A pharmaceutical composition for use in treating cancer, comprising a compound according to any one of claims 1 to 6 or a pharma- ceutical acceptable salt thereof. The pharmaceutical composition for use according to claim 9, wherein the cancer is a SWI/SNF-associated cancer or a cancer with a SMARCA4 mutation. The pharmaceutical composition for use according to claim 9, wherein the cancer is a SMARCA4-deficient cancer or a cancer in which SMARCA4 expression is reduced compared to normal SMARCA4 expression. The pharmaceutical composition for use according to claim 9, wherein the cancer is lung cancer or non-small cell lung cancer.