SMYD3 protacs for the treatment of HPV-negative squamous cell carcinoma

Abstract

In one aspect, the disclosure relates to proteolysis targeting chimeras (PROTACs) targeting SMYD3, methods of making the same, pharmaceutical compositions comprising same, and methods of treating squamous cell carcinomas (SCC) and other cancers using the same. In some aspects, the cancers are human papillomavirus (HPV) negative. In another aspect, disclosed are new SMYD3 inhibitors. Also disclosed are methods of killing cancer cells.

Description

ATTORNEY DOCKET NO. E-202-2024-1 -PC-01SMYD3 PROTACS FOR THE TREATMENT OF HPV-NEGATIVE SQUAMOUS CELL CARCINOMACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 63 / 687,489, filed August 27, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] SMYD3 is a lysine methyltransferase that is significantly overexpressed in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) tumors compared to normal buccal squamous epithelium. SMYD3 depletion decreases the proliferation, colony formation, cell cycling, and invasive potential of HPV-negative HNSCC cells and significantly decreases tumor growth in vivo in HPV-negative HNSCC tumor xenografts. SMYD3 has been found to drive cell cycle and epithelial-mesenchymal transition pathways in HPV- negative HNSCC. Additionally, SMYD3 depletion using anti-sense oligonucleotides enhances interferon response signatures and activates CD8+ T-cells and neutrophils in the tumor microenvironment (TME) of MOC1 tumors. SMYD3 represses tumor-intrinsic interferon response in HPV-negative HNSCC.

[0003] Currently, there are a number of commercially available SMYD3 inhibitors, including BAY- 6035 and EPZ031686; however, none of these are efficacious and specific enough to target and inhibit SMYD3 at < 5 pM in vitro. Additionally, SMYD3 may have both enzymatic and non- enzymatically mediated oncogenic functions that cannot be hindered only with enzymatic inhibition.

[0004] Despite advances in SMYD3 research, there is still a scarcity of compounds that are potent, efficacious, and selective inhibitors of SMYD3 and also effective in the treatment of HNSCC and other cancers associated with SMYD3 overexpression. These needs and other needs are satisfied by the present disclosure.SUMMARY

[0005] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to proteolysis targeting chimeras (PROTACs) targeting SMYD3, methods of making the same, pharmaceutical compositions comprising same, and methods of treating squamous cell carcinomas (SCC) and other cancersATTORNEY DOCKET NO. E-202-2024-1 -PC-01 using the same. In some aspects, the cancers are human papillomavirus (HPV) negative. In another aspect, disclosed are new SMYD3 inhibitors. Also disclosed are methods of killing cancer cells.

[0006] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0008] FIGs. 11-1 J show SMYD3 inhibitors BAY-6035 and EPZ031686 tested at various concentrations against HPV-negative HN-6 head and neck squamous cell carcinoma cell line.

[0009] FIGs. 2A-2H show SMYD3 inhibitors BAY-6035 and EPZ031686 tested at various concentrations against HPV-negative HN-SCC-151 head and neck squamous cell carcinoma cell line.

[0010] FIGs. 3A-3N show a disclosed PROTAC tested at various concentrations against HPV- negative HN-6 and HN-SCC-151 cells as well as against a normalized buccal mucosa squamous cell line (BEAS2B).

[0011] FIGs. 4A-4N show a disclosed PROTAC tested at various concentrations against HPV- negative HN-6 and HN-SCC-151 cells as well as against a normalized buccal mucosa squamous cell line (BEAS2B).

[0012] FIGs. 5A-5I show a disclosed PROTAC tested at various concentrations against HPV- negative HN-6 and HN-SCC-151 cells as well as against a normalized buccal mucosa squamousATTORNEY DOCKET NO. E-202-2024-1 -PC-01 cell line (BEAS2B).

[0013] FIGs. 6A-6K show a disclosed PROTAC tested at various concentrations against HPV- negative HN-6 and HN-SCC-151 cells as well as against a normalized buccal mucosa squamous cell line (BEAS2B).

[0014] FIGs. 7A-7B show IAP-08 mediated SMYD3 degradation is rescued through proteasomal inhibition.

[0015] FIG. 8 shows quantified colony formation assay results with novel SMYD3 SD inhibitors and with the Epizyme inhibitor EPZ031686. HN13 and HN-SCC-151 cells were seeded in 6-well plates and next day, treatment was initiated with SMYD3 SD inhibitors at concentrations of 0, 2.5 pM, 5 pM and 10 pM for 48h. At 48h, cells were fixed and stained with crystal violet, and colonies were counted using Image J. Results shown represent average number of colonies obtained from three biological replicates. Standard errors shown. Student t-test, *p=0.01-0.05, **p=0.005-0.01 , ***p=0.001-0.005, ****p<0.001.

[0016] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.DETAILED DESCRIPTION

[0017] In one aspect, disclosed herein are compounds having Formula I or pharmaceutically acceptable salts thereof:T-L-WFormula I; wherein T is a targeting group having Formula II:V-X-ZFormula II; wherein V is bonded to X and wherein V is a substituted or unsubstituted C3-C8 aryl or heteroaryl group;ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 wherein X is a C3-C8 heterocycloalkyl, bridged heterocycloalkyl group, spiro heterocycloalkyl group, or a C3-C8 aryl or heteroaryl group; wherein Z is bonded to L and is a substituted or unsubstituted C4-C9 cycloalkyl or heterocycloalkyl group: wherein L is a linker moiety having Formula III:Formula III; wherein Y is a substituted or unsubstituted C2-C5 polyalkylene glycol, C1-C20 substituted or unsubstituted alkyl group, substituted or unsubstituted C5-C9 aryl group, substituted or unsubstituted C5-C9 heteroaryl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted fused cycloalkyl group, substituted or unsubstituted or unsubstituted alkyl aryl group, or any combination thereof; and wherein W is an E3 ligase binding moiety.

[0018] In another aspect, W can be selected from the following moieties:ATTORNEY DOCKET NO. E-202-2024-1 -PC-01wherein Ri, if present, is selected from hydrogen and C1-C4 alkyl; wherein R2, if present, is selected from hydrogen and C1-C4 alkyl; and wherein R3, if present, is selected from hydrogen and C1-C4 alkyl.

[0019] In still another aspect, Y can be a substituted or unsubstituted cycloalkyl or fused cycloalkyl group including, but not limited to,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0020] In an alternative aspect, Y can be a substituted or unsubstituted C5-C9 aryl group or C5-

[0021] In some aspects, the C2-C5 polyalkylene glycol can be polyethylene glycol. In another aspect, Y can beand m can be from 1 to 20, or m can be from 1 to 8, or m can be 1 , 2, 3, 4, 5, 6, 7, or 8. In another aspect, Y can beand n can be from 1 to 20, or n can be from 1 to 8, or n can be 1 , 2, 3, 4, 5, 6, 7, or 8.

[0022] In yet another aspect, V can be selected fromwherein R4, if present, is a hydroxyl group or a substituted or unsubstituted C3-C8 heteroaryl or heteroalkyl group, and wherein a double bond indicated by * has E or Z stereochemistry. In oneATTORNEY DOCKET NO. E-202-2024-1 -PC-01 aspect, R4can be selected fromr any combination thereof.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0025] In one aspect, T is EPZ031686 or a derivative thereof, wherein the derivatization allows the active moiety of EPZ031686 to effectively target SMYD3:ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0026] In still another aspect, the compound has Formula IV;Formula IV; wherein o and p are each an integer between 1 and 5.

[0027] In an aspect, o can be 1 and p can be 3, but other values are also contemplated and should be considered disclosed. Further in this aspect, other variables including V, Y, and W are defined as discussed previously.

[0028] In another aspect, the compound can be selected fromATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0029] Also disclosed herein are compounds having SMYD3 inhibitory activity. In an aspect, the compounds and / or pharmaceutically acceptable salts have Formula V, wherein V, o, and p are as defined previously, and wherein Q is a substituted or unsubstituted C3-C12 aryl or alkyl group:ATTORNEY DOCKET NO. E-202-2024-1 -PC-01Formula V

[0030] In one aspect, Q can be selected from:any combination thereof.In any of these aspects, the compound or pharmaceutically acceptable salt can have the formula:ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0031] In one aspect, the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CFA assay at a concentration of 1 pM or less, or at a concentration of 0.5 pM or less, or at a concentration of 0.1 pM or less. In a further aspect, methods for performing a CFA assay are described in the Examples.

[0032] In another aspect, the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CCK8 assay at a concentration of 2.5 pM or less, or at a concentration of 0.5 pM or less, or at a concentration of 0.1 pM or less. In a still further aspect, methods for performing a CCK8 assay are described in the Examples.

[0033] In still another aspect, the compound degrades SMYD3 with an efficiency of greater than 50% at a concentration of 2.5 pM or less, or at a concentration of 1 pM or less, or at a concentration of 0.5 pM or less.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0034] Also disclosed herein are pharmaceutical compositions including the disclosed compounds and salts. In some aspects, the pharmaceutical compositions include at least one carrier or excipient. In still another aspect, the composition can include a topical dosage form, a parenteral dosage form, or an oral dosage form.

[0035] Furthermore, disclosed herein is a method for killing cancer cells, the method including contacting the cancer cells with a disclosed compound, salt, or pharmaceutical composition. In another aspect, the cells include breast cancer cells or squamous cell carcinoma (SCC) cells. In some aspects, the SCC is HPV negative. In yet another aspect, the SCC can be head and neck SCC, SCC of the lung, SCC of the esophagus, SCC of the bladder, or any combination thereof. In any of these aspects, the cancer cells can overexpress SMYD3. In a further aspect, in the disclosed method, the compound specifically binds to and causes degradation of SMYD3.

[0036] Also disclosed herein is a method for treating or preventing cancer in a subject, the method including at least the step of administering a therapeutically effective amount of a disclosed compound, salt, or pharmaceutical composition to the subject. Also disclosed herein is a method for reducing or preventing the growth of a tumor in a subject, the method including at least the step of administering a therapeutically effective amount of a disclosed compound, salt, or pharmaceutical composition to the subject.

[0037] In any of these aspects, the compound or pharmaceutical composition can be administered orally, topically, or intravenously. In another aspect, the tumor can be a breast tumor or squamous cell carcinoma (SCC). In some aspects, the SCC is HPV negative. In yet another aspect, the SCC can be head and neck SCC, SCC of the lung, SCC of the esophagus, SCC of the bladder, or any combination thereof. In any of these aspects, the tumor can overexpress SMYD3. In a further aspect, in the disclosed method, the compound specifically binds to and causes degradation of SMYD3.

[0038] In one aspect, the subject is a mammal such as, for example, a human, non-human primate, cat, dog, rat, mouse, guinea pig, rabbit, hamster, horse, cattle, swine, sheep, or goat.

[0039] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspectsATTORNEY DOCKET NO. E-202-2024-1 -PC-01 described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0040] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0041] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0042] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0043] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0044] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0045] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one ofATTORNEY DOCKET NO. E-202-2024-1 -PC-01 ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0046] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Definitions

[0047] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0048] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a warhead,” “a targeting group,” or “a linker,” include, but are not limited to, combinations of two or more such warheads, targeting groups, or linkers, and the like.

[0049] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0050] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. 'about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0051] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or subranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0052] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0053] As used herein, the term “effective amount” refers to an amount that is sufficient to achieve the desired modification of a physical property of the composition or material. For example, an “effective amount” of a PROTAC refers to an amount that is sufficient to achieve the desired improvement in the property modulated by the formulation component, e.g. achieving the desired level of degradation of SMYD3. The specific level in terms of wt% in a composition required as an effective amount will depend upon a variety of factors including the type and stage of cancer being treated, subject body weight, and any concurrent treatments being administered.

[0054] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0055] As used herein, a “PROTAC” is a proteolysis targeting chimera, or a small molecule having two active domains and a linker, wherein the PROTAC is capable of causing the ubiquitination and / or degradation or inactivation of unwanted proteins. In a further aspect, as a mechanism of action, a PROTAC activates intracellular proteolysis. In one aspect, one of the active domains engages an E3 ubiquitin ligase and the other binds the target protein (e.g., SMYD3).Chemical Definitions

[0056] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0057] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure isATTORNEY DOCKET NO. E-202-2024-1 -PC-01 not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( / .e., further substituted or unsubstituted).

[0058] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0059] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain ( / .e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0060] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0061] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, theATTORNEY DOCKET NO. E-202-2024-1 -PC-01 term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyal kyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0062] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0063] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0064] The term “alkanediyl” as used herein, refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, — CH2— (methylene), — CH2CH2— , — CH2C(CH3)2CH2— , and — CH2CH2CH2— are non-limiting examples of alkanediyl groups.

[0065] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA1— OA2or — OA1— (OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0066] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0067] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0068] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can beATTORNEY DOCKET NO. E-202-2024-1 -PC-01 unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0069] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0070] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized TT electrons above and below the plane of the molecule, where the TT clouds contain (4n+2) TT electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0071] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0072] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0073] The terms “amine” or “amino” as used herein are represented by the formula — NAW, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0074] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) and — N (-alkyl)2, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0075] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0076] The term “ester” as used herein is represented by the formula — OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A1O(O)C-A2-C(O)O)a— or — (A1O(O)C-A2-OC(O))a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0077] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A1O-A2O)a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0078] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0079] The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0080] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0081] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methyl pyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1 ,2- b]pyridazinyl, imidazo[1 ,2-a]pyrazinyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0082] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1 ,2,3-oxadiazole, 1 ,2,5-oxadiazole and 1 ,3,4-oxadiazole,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 thiadiazole, including, 1 ,2,3-thiadiazole, 1,2,5-thiadiazole, and 1 ,3,4-thiadiazole, triazole, including, 1 ,2,3-triazole, 1,3,4-triazole, tetrazole, including 1 ,2,3,4-tetrazole and 1 ,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1 ,2,4-triazine and 1 ,3,5-triazine, tetrazine, including 1 ,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0083] The term “bicyclic heterocycle’’ or “bicyclic heterocyclyl’’ as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1 , 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1 ,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, 2,3-dihydro- 1 ,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1 H-pyrazolo[4,3-c]pyridin-3-yl; 1 H-pyrrolo[3,2- b]pyridin-3-yl; and 1 H-pyrazolo[3,2-b]pyridin-3-yl.

[0084] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0085] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula — OH.

[0086] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0087] The term “azide” or “azido” as used herein is represented by the formula — N3.

[0088] The term “nitro” as used herein is represented by the formula — NO2.

[0089] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0090] The term “silyl” as used herein is represented by the formula — SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0091] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A1, — S(O)2A1, — OS(O)2A1, or — OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0092] The term “thiol” as used herein is represented by the formula — SH.

[0093] “R1,” “R2,” “R3,”... “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant ( / .e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0094] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( / .e., further substituted or unsubstituted).

[0095] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0096] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)o-40R°; -O(CH2)0-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)0-4SRO; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; - N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O_4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)0-4N(RO)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)Ro; -C(S)R°; - (CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)Ro; -OC(O)(CH2)0-4SR-, SC(S)SR°; -(CH2)O-4SC(0)R°; -(CH2)O-4C(0)NR°2; -C(S)NRO2; -C(S)SR°; -(CH2)O-4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)0-4SSRO; - (CH2)O-4S(0)2R°; -(CH2)O_4S(0)2OR°; -(CH2)0-4OS(O)2RO; -S(O)2NRO2; -(CH2)O-4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2;P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(C1-4 straight or branched alkylene)O- N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o-ATTORNEY DOCKET NO. E-202-2024-1 -PC-011 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0097] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -CN, -N3, -(CH2)0_ SH, -(CH2)O-2NH2, -straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, - CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0098] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, O6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0099] Suitable substituents on the aliphatic group of R* include halogen, -R* -(haloR*), -OH, - OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partiallyATTORNEY DOCKET NO. E-202-2024-1 -PC-01 unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0100] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NRt2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, - S(O)2Rt, -S(O)2NR+2, -C(S)NR+2I-C(NH)NR+2, or -N(R+)S(O)2R+; wherein each Rt is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rt, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0101] Suitable substituents on the aliphatic group of Rt are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR", -NR*2, or - NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0102] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, trifl ate, mesylate, tosylate, and brosylate.

[0103] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-lnterscience, 1999).

[0104] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited to alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0105] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified ( / .e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0106] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0107] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0108] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0109] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0110] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).ATTORNEY DOCKET NO. E-202-2024-1 -PC-01The prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable 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 referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-lngold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0111] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36CI, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof canATTORNEY DOCKET NO. E-202-2024-1 -PC-01 generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0112] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0113] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0114] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.keto form enol form amide form imidic acid formLikewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[0115] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particularATTORNEY DOCKET NO. E-202-2024-1 -PC-01 modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0116] In some aspects, a structure of a compound can be represented by a formula:which is understood to be equivalent to a formula:wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, R"<aRn<bRn(c), Rn<dand Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn<a> is halogen, then R',(b)is not necessarily halogen in that instance.

[0117] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0118] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0119] In various aspects, it is contemplated herein that the disclosed compounds further comprise their biosteric equivalents. The term “bioisosteric equivalent” refers to compounds or groups that possess near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical and biological properties. Examples of such equivalents are: (i) fluorine vs. hydrogen, (ii) oxo vs. thia, (iii) hydroxyl vs. amide, (iv) carbonyl vs. oxime, (v) carboxylate vs. tetrazole. Examples of such bioisosteric replacements can be found in the literature and examples of such are: (i) Burger A, Relation of chemical structure and biological activity; in Medicinal Chemistry Third ed., Burger A, ed.; Wiley-lnterscience; New York, 1970, 64-80; (ii) Burger, A.; “Isosterism and bioisosterism in drug design”; Prog. Drug Res. 1991 , 37, 287-371 ; (iii) Burger A, “Isosterism and bioanalogy in drug design”, Med. Chem. Res. 1994, 4, 89-92; (iv) Clark R D, Ferguson A M, Cramer R D, “Bioisosterism and molecular diversity”, Perspect. Drug Discovery Des. 1998, 9 / 10 / 11 , 213-224; (v) Koyanagi T, Haga T, “Bioisosterism in agrochemicals”, ACS Symp. Ser. 1995, 584, 15-24; (vi) Kubinyi H, “Molecular similarities. Part 1. Chemical structure and biological activity”, Pharm. UnsererZeit 1998, 27, 92-106; (vii) Lipinski C A.; “Bioisosterism in drug design”; Annu. Rep. Med. Chem. 1986, 21 , 283-91 ; (viii) Patani G A, LaVoie E J, “Bioisosterism: A rational approach in drug design”, Chem. Rev. (Washington, D.C.) 1996, 96, 3147-3176; (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic ligands”, Curr. Med. Chem. 1998, 5, 493-512 (x) Thornber C W, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev. 1979, 8, 563-80.

[0120] In further aspects, bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered substantially identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Preferred bioisosteres of esters, amides or carboxylic acids are compounds containing two sites for hydrogen bond acceptance. In one embodiment, the ester, amide or carboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted 1 H-imidazolyl, an optionally substituted oxazolyl, 1 H-tetrazolyl, [1 ,2,4]triazolyl, or an optionally substituted [1 ,2,4]oxadiazolyl.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0121] In various aspects, it is contemplated herein that the disclosed compounds further comprise their isotopically-labelled or isotopically-substituted variants, i.e., compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,180,170,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopically-labelled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.

[0122] In various aspects, the disclosed compounds can possess at least one center of asymmetry, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The stereoisomers can be present in the mixtures in any arbitrary proportions. In some aspects, provided this is possible, the disclosed compounds can be present in the form of the tautomers.

[0123] Thus, methods which are known per se can be used, for example, to separate the disclosed compounds which possess one or more chiral centers and occur as racemates into their optical isomers, i.e., enantiomers or diastereomers. The separation can be effected by means of column separation on chiral phases or by means of recrystallization from an optically active solvent or using an optically active acid or base or by means of derivatizing with an optically active reagent, such as an optically active alcohol, and subsequently cleaving off the residue.

[0124] In various aspects, the disclosed compounds can be in the form of a co-crystal. The term “co-crystal” means a physical association of two or more molecules which owe their stabilityATTORNEY DOCKET NO. E-202-2024-1 -PC-01 through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889- 1896, 2004. Preferred co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0125] The term “pharmaceutically acceptable co-crystal” means one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0126] In a further aspect, the disclosed compounds can be isolated as solvates and, in particular, as hydrates of a disclosed compound, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates.

[0127] The disclosed compounds can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed compound with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosed compound with a suitable inorganic or organic base.

[0128] Acidic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting moieties comprising one or more nitrogen groups with a suitable acid. In various aspects, acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. In a further aspect, salts further include, but are not limited, to the following: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinate, 2- naphthalenesulfonate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Also, basic nitrogencontaining groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

[0129] Basic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In further aspects, bases which may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.Pharmaceutical Definitions

[0130] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0131] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta- blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or prodrugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0132] As used herein, “attached” can refer to covalent or non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, TT-TT interactions, cation-TT interactions, anion-TT interactions, polar TT-interactions, and hydrophobic effects.

[0133] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.

[0134] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarilyATTORNEY DOCKET NO. E-202-2024-1 -PC-01 have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as breast cancer or an HPV-free squamous cell carcinoma. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of breast cancer or HPV-free squamous cell carcinoma in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0135] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0136] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0137] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0138] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

[0139] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0140] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount ofATTORNEY DOCKET NO. E-202-2024-1 -PC-01 a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0141] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0142] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0143] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0144] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, 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 pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginateATTORNEY DOCKET NO. E-202-2024-1 -PC-01 and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0145] The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, nontoxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0146] The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6- membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0147] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0148] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0149] The term “contacting” as used herein refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.

[0150] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-lngold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E / Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

[0151] It is understood, that unless otherwise specified, temperatures referred to herein areATTORNEY DOCKET NO. E-202-2024-1 -PC-01 based on atmospheric pressure (i.e. one atmosphere).

[0152] Described herein are PROTACs that have therapeutic or clinical utility. Also described herein are methods of synthesizing the PROTACs Also described herein are methods of administering the PROTACs to a subject in need thereof. In some aspects, the subject can have cancer, such as an HPV-free squamous cell carcinoma. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.

[0153] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.

[0154] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, parenterally, transmucosally, transdermally, intramuscularly, intravenously, intraperitoneally, intraventricularly, or intracranially.

[0155] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternalATTORNEY DOCKET NO. E-202-2024-1 -PC-01 injection and infusion.

[0156] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.

[0157] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic use, salts of the disclosed compounds are those wherein the counter ion is pharmaceutically acceptable. However, salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure. Pharmaceutically acceptable acid and base addition salts are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the disclosed compounds are able to form.

[0158] In various aspects, a disclosed compound comprising an acidic group or moiety, e.g., a carboxylic acid group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.

[0159] Bases which can be used to prepare the pharmaceutically acceptable base-addition saltsATTORNEY DOCKET NO. E-202-2024-1 -PC-01 of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines. In a further aspect, derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. In various aspects, such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N,N'- dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, A / -methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, hydrabamine salts, and salts with amino acids such as, for example, histidine, arginine, lysine and the like. The foregoing salt forms can be converted by treatment with acid back into the free acid form.

[0160] In various aspects, a disclosed compound comprising a protonatable group or moiety, e.g., an amino group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with a basic reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0161] Acids that can be used to prepare the pharmaceutically acceptable acid-addition salts ofATTORNEY DOCKET NO. E-202-2024-1 -PC-01 the base compounds are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids. Exemplary, but non-limiting, inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like. Exemplary, but non-limiting, organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like. In a further aspect, the acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0162] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0163] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and doesATTORNEY DOCKET NO. E-202-2024-1 -PC-01 not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

[0164] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0165] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0166] The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound.

[0167] Because of the ease in administration, oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. However, other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like. Accordingly, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0168] The disclosed pharmaceutical compositions in an oral dosage form can comprise one or more pharmaceutical excipient and / or additive. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for exampleATTORNEY DOCKET NO. E-202-2024-1 -PC-01 stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also optionally hydrated); glycerol esters and polyglycerol esters of saturated fatty acids C12H24O2 to CI8H36O2and their mixtures, it being possible for the glycerol hydroxy groups to be totally or also only partly esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentacrythritol, sorbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroformals, tetra hydrofurfuryl alcohol, polyglycol ethers with C1-C12-alcohols, dimethylacetamide, lactamides, lactates, ethylcarbonates, silicones (in particular medium-viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

[0169] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used to produce the oral dosage form. Those that may for example be considered are: polymerizates as well as copolymerizates of acrylic acid and / or methacrylic acid and / or their esters; copolymerizates of acrylic and methacrylic acid esters with a lower ammonium group content (for example EudragitR RS), copolymerizates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example EudragitR RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate, carboxy methyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, -phthalate succinate as well as methyl cellulose phthalic acid half ester; zein; ethyl cellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerizate; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0170] Plasticizing agents that may be considered as coating substances in the disclosed oralATTORNEY DOCKET NO. E-202-2024-1 -PC-01 dosage forms are: citric and tartaric acid esters (acetyl-tri ethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropylphthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate.

[0171] Moreover, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0172] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In a further aspect, a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0173] In various aspects, an oral dosage form, such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0174] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calciumATTORNEY DOCKET NO. E-202-2024-1 -PC-01 phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0175] A tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0176] In various aspects, a solid oral dosage form, such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach. In various aspects, enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid- methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form” Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)). In a further aspect, the enteric coating may comprise hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.

[0177] In various aspects, an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier. Examples of water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl cellulose, or stearic acid.

[0178] In various aspects, an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle. For example, a liquidATTORNEY DOCKET NO. E-202-2024-1 -PC-01 dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.

[0179] Pharmaceutical compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0180] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe. The pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0181] Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In some aspects, a disclosed parenteral formulation can comprise about 0.01-0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline.

[0182] In various aspects, a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include but not limited to water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer’s, and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like. In a further aspect, a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient.

[0183] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase “topical application” means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane. By selecting the appropriate carrier and optionally other ingredients that can be included in the composition, as is detailed herein below, the compositions of the present invention may be formulated into any form typically employed for topical application. A topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0184] In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may beATTORNEY DOCKET NO. E-202-2024-1 -PC-01 administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment

[0185] Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives. The specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience). As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.

[0186] Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.

[0187] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and / or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0188] Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.

[0189] Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred organic macromolecules, i.e. , gelling agents, are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol™. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

[0190] Sprays generally provide the active agent in an aqueous and / or alcoholic solution which can be misted onto the skin for delivery. Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated active agent at the site of administration.

[0191] Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique. Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcoholATTORNEY DOCKET NO. E-202-2024-1 -PC-01 content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.

[0192] Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir. Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch prior to its use. Skin patches may further comprise a removable cover, which serves for protecting it upon storage.

[0193] Examples of patch configuration which can be utilized with the present invention include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive. In such a transdermal patch design, the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. In the multilayer drug-in-adhesive patch a membrane is disposed between two distinct drug-in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0194] Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition. Representative examples of suitable carriers according to the present invention therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Other suitable carriers according to the present invention include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

[0195] Topical compositions of the present disclosure can, if desired, be presented in a pack orATTORNEY DOCKET NO. E-202-2024-1 -PC-01 dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising the topical composition of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0196] Another patch system configuration which can be used by the present invention is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi- permeable membrane and adhesive. The adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration which can be utilized by the present invention is a matrix system design which is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

[0197] The exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present disclosure.

[0198] Depending on the mode of administration, the pharmaceutical composition will compriseATTORNEY DOCKET NO. E-202-2024-1 -PC-01 from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0199] In the treatment conditions which require reduction of SMYD3 activity an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0200] Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day. In various aspects, such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

[0201] A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowlyATTORNEY DOCKET NO. E-202-2024-1 -PC-01 by osmotic pressure, or by any other known means of controlled release.

[0202] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response.

[0203] The present disclosure is further directed to a method for the manufacture of a medicament for modulating SMYD3 activity (e.g., treatment of one or more cancers associated with SMYD3 overexpression) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present disclosure further relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0204] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.

[0205] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

[0206] As already mentioned, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.

[0207] As already mentioned, the present disclosure also relates to a pharmaceutical composition comprising a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for a disclosed compound or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament. The present disclosure also relates toATTORNEY DOCKET NO. E-202-2024-1 -PC-01 a combination of disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and an SMYD3 inhibitor. The present disclosure also relates to such a combination for use as a medicine. The present disclosure also relates to a product comprising (a) disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and (b) an additional anti-SMYD3 therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the modulatory effect of the disclosed compound and the additional therapeutic agent. The different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.

[0208] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

[0209] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.EXAMPLES

[0210] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.Example 1 : Synthesis and Characterization of CompoundsGeneral synthetic Scheme for synthesis of compound 7ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0211] 2,2,2-Trichloroethyl ((! / ?, 3r,5S)-8-(((1-(3-((tert- butoxycarbonyl)amino)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)carbamate (3): To a stirred solution of benzyl 4-((((7 / ?,3r,5S)-3-(((2,2,2- trichloroethoxy)carbonyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidine-1- carboxylate (1.2 g, 2.01 mmol) in DCM (5 mL), and acetonitrile (20 mL), were added sequentially tert-butyl (3-bromopropyl)carbamate (957.4 mg, 4.021 mmol), EtsN (0.84 mL, 6.031 mmol) and DMAP (24.56 mg, 0.2 mmol) at 0 °C. The resulting mixture was stirred at room temperature forATTORNEY DOCKET NO. E-202-2024-1 -PC-01 overnight. After the completion of the reaction (the progress of the reaction was monitored by LCMS) the solution was concentrated and purified by flash chromatography on silica gel (5% MeOH in DCM) to give of title compound 0.95 g (76%) as a white solid.1H NMR (400 MHz, CDCI3) 6 5.38 (s, 1 H) , 5.27 (d, J = 6.4 Hz, 1 H), 4.70 (s, 2H), 4.22 (dq, J = 5.6, 3.0 Hz, 2H), 3.93 (q, J = 6.7 Hz, 1 H), 3.15 (q, J = 6.3 Hz, 2H), 2.89 (dd, J = 6.5, 4.3 Hz, 4H), 2.37 (t, J = 6.8 Hz, 2H), 2.30 - 2.08 (m, 4H), 2.02 - 1.85 (m, 9H), 1.63 (p, J = 6.7 Hz, 2H), 1.41 (s, 9H);13C NMR (101 MHz, cdcl3) 6 156.1 , 153.8, 95.5, 78.8, 77.4, 77.2, 77.0, 76.7, 74.4, 59.4, 56.9, 55.6, 53.3, 43.4, 39.8, 37.5, 32.1 , 32.0, 28.9, 28.4, 26.5; LC-MS (ESI): (m / z) = 619 [M+H]

[0212] tert-Butyl(3-(4-((((7R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octan-8- yl)sulfonyl)methyl)piperidin-1-yl)propyl)carbamate (4): To a stirred solution of 2,2,2- trichloroethyl ((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)carbamate (850 mg, 1.48 mmol) in glacial acetic acid (15 ml_), was added zinc (970 mg, 10 eq, 14.8 mmol) at room temperature, and the resulting heterogenous solution was stirred at room temperature for the 2 hrs. After completion of the reaction (as indicated by LCMS), the glacial acetic acid was removed under vacuum and the crude residue was neutralized with saturated NaHCO3solution (10 mL). The resulting solution was extracted with DCM (50 mL x 5), and the combined organics were dried over anhydrous Na2SO4 and filtered. The solution was concentrated under vacuum to get crude product (4), which was used without further purification. LC-MS (ESI): (m / z) = 445 [M+H],

[0213] tert-Buty I -(3-(4-(((( 1 R,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)carbamate (6): To a stirred solution of (7R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-amine (700 mg, 1.76 mmol) in DMF (10 mL), were added 6-chloro-2- oxoindoline-5-carboxylic acid (559 mg, 2.64 mmol), EDCI (675 mg, 3.52 mmol), HOBt (539 mg, 3.52 mmol) and Et3N (982 pL, 7.04 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h. After completion of the reaction (as indicated by LCMS), the volatiles wereATTORNEY DOCKET NO. E-202-2024-1 -PC-01 removed under vacuum and the crude material was purified by reverse phase chromatography without workup using a gradient of 10-55% acetonitrile in water with the addition of 0.05% trifluoroacetic acid (TFA) to give title compound 550 mg (55%) as white solid.1H NMR (400 MHz, CD3OD-d4) 6 11.42 (s, 1H), 9.01 (d, J = 4.6 Hz, 1 H), 8.02 (s, 1 H), 7.75 (t, J = 5.8 Hz, 1H), 7.63 (s, 1 H), 4.91 (s, 2H), 4.76 (d, J = 6.1 Hz, 1 H), 4.43-4.04 (m, 4H), 3.90 (d, J = 6.1 Hz, 2H), 3.76 (q, J = 7.0 Hz, 6H), 2.89 (dt, J = 29.8, 10.8 Hz, 6H), 2.73 (d, J = 14.6 Hz, 4H), 2.55 (q, J = 7.7 Hz, 2H), 2.30 (t, J = 12.4 Hz, 2H), 2.18 (s, 9H);13C NMR (101 MHz, DMSO-d6) 6 176.8, 166.9, 156.2, 146.0, 130.1 , 129.5, 125.3, 125.1 , 110.1 , 78.3, 56.6, 55.4, 54.5, 51.9, 48.2, 42.0, 37.6, 36.6, 35.7, 30.1, 29.0, 28.7, 28.3, 24.7; LC-MS (ESI): (m / z) = 637 [M+H],

[0214] N-((1 / ?,5S)-8-(((1-(3-Aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (7): The compound tertbutyl (3-(4-((((1 ?,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8-azabicyclo[3.2.1]octan-8- yl)sulfonyl)methyl)piperidin-1-yl)propyl)carbamate (500 mg, 0.78 mmol) was dissolved in 20% TFA in DCM (10 ml_) and stirred for 1h at room temperature, After the completion of the reaction (as indicated by LCMS), the solution was concentrated and dried to give the title product, which was used for next step without further purification (7). LC-MS (ESI): (m / z) = 537 [M+H],

[0215] N-((7 / ?,3r,5S)-8-(((1-(3-(2-Azidoacetamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (8): The compound N- ((7R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide 7 (100 mg, 1 eq, 0.186 mmol) was dissolved in DMF (2 mL), were added 2,5-dioxopyrrolidin-1-yl 2-azidoacetate (73.6 mg, 2 eq, 0.372 mmol) and DIPEAATTORNEY DOCKET NO. E-202-2024-1 -PC-01(60.0 mg, 80.9 pL, 2.5 eq, 0.465 mmol) at 0 °C. After completion of the reaction (as indicated by LCMS), the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give title compound 65 mg (56%) as white solid.1H NMR (400 MHz, DMSO-d6) 5 10.61 (s, 1 H), 9.27 (s, 1 H), 8.26 (t, J = 5.7 Hz, 1 H), 8.20 (d, = 4.7 Hz, 1 H), 7.21 (s, 1 H), 6.82 (s, 1 H), 4.11 (d, J = 5.6 Hz, 2H), 3.96 (d, J = 10.0 Hz, 1H), 3.82 (s, 2H), 3.46 (d, J = 23.9 Hz, 9H), 3.12 (dt, J = 18.5, 6.1 Hz, 5H), 3.00 - 2.90 (m, 5H), 2.57 (s, 1 H), 2.21 - 1.71 (m, 17H), 1.49 (q, J = 13.2 Hz, 2H);13C NMR (101 MHz, DMSO) 5 176.8, 173.2, 168.0, 166.9, 146.0, 130.1 , 129.5, 125.3, 125.1 , 110.1 , 56.6, 55.4, 54.4, 51.9, 51.3, 42.0, 36.6, 36.4, 35.7, 30.1 , 29.0, 28.3, 25.7, 24.2; LC-MS (ESI): (m / z) = 621 [M+H],General Procedure 1A

[0216] To a stirred solution of the tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1- oxopropan-2-yl)(methyl)carbamate hydrochloric salt (1.0 eq) in DMF (2 mL), were sequentially added bis(2,5-dioxopyrrolidin-1-yl) decanedioate (2 eq) and DIPEA (2 eq) were added at 0 °C. The resulting mixture was stirred at room temperature for 1h. After completion of the reaction (asATTORNEY DOCKET NO. E-202-2024-1 -PC-01 indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to give corresponding product.

[0217] 2,5-Dioxopyrrolidin-1 -yl-8-(((3S,5S)-1 -((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-((( / ?)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-8-oxooctanoate (9a): General procedure 1A was followed on 150 mg (0.25 mmol) scale of the ((S)-1-(((S)-2-((2S,4S)-4-amino- 2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2- oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate hydrochloric salt. The crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford 120 mg (66%) of title compound.1H NMR (400 MHz, DMSO-de) 58.37 (d, J = 8.6 Hz, 1 H), 8.10 (d, = 7.6 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 1 H), 7.17 - 7.03 (m, 3H), 4.96 - 4.86 (m, 1 H), 4.35 - 4.18 (m, 3H), 4.03 (dd, J = 9.9, 6.8 Hz, 1 H), 3.29 (dd, J = 9.8, 7.6 Hz, 1 H), 2.71 (d, J = 8.3 Hz, 5H), 2.63 (t, J = 7.2 Hz, 2H), 2.35 (dt, J = 12.7, 7.6 Hz, 1 H), 2.03 (t, J = 7.4 Hz, 2H), 1.90 - 1 .54 (m, 8H), 1.48 (p, J = 7.3 Hz, 2H), 1 .39 (d, J = 11.2 Hz, 11 H), 1.30 - 0.83 (m, 8H);13C NMR (101 MHz, DMSO-d6) 6 172.3, 171.3, 170.7, 170.2, 169.4, 137.8, 137.4, 129.0, 128.8, 127.1 , 126.1 , 79.4, 58.9, 55.3, 52.7, 48.1 , 47.1 , 35.8, 34.9, 30.6, 30.5, 30.3, 29.2, 29.1 , 28.6, 28.5, 28.5, 28.2, 26.3, 26.2, 26.0, 25.9, 25.3, 24.6, 20.7; LC-MS (ESI): (m / z) = 837 [M+H],

[0218] 2,5-dioxopyrrolidin-1-yl 16-(((3S,5S)-1 -((S)-2-((S)-2-((tertbutoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-((( / ?)-1, 2,3,4-ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 tetrahydronaphthalen-1 -yl)carbamoyl)pyrrolidin-3-yl)amino)-16-0X0-4,7,10, 13- tetraoxahexadecanoate (9b): General procedure 1A was followed on 100 mg (0.17 mmol) scale of the ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford 110 mg (67%) of title compound.1H NMR (500 MHz, CDCh) 6 8.18 (s, 1 H), 7.50 (d, J = 8.3 Hz, 1 H), 7.06 (t, J = 6.8 Hz, 2H), 7.00 (dd, J = 12.7,7.3 Hz, 2H), 5.01 (q, J = 6.0 Hz, 1 H), 4.75 - 4.44 (m, 2H), 4.42 - 4.19 (m, 5H), 3.99 (dd, J = 10.9,5.3 Hz, 1 H), 3.85 - 3.64 (m, 4H), 3.57 (d, J = 6.2 Hz, 13H), 2.81 (t, J = 6.3 Hz, 2H), 2.77 - 2.63 (m, 9H), 2.46 (q, J = 6.2 Hz, 2H), 2.27 (d, = 13.8 Hz, 1 H), 2.15 (ddd, J = 14.4, 8.9, 6.5 Hz, 1 H), 1.93 (td, J = 10.4, 5.3 Hz, 1 H), 1.75 (h, J = 6.5 Hz, 3H), 1.66 - 1.42 (m, 5H), 1.38 (s, 9H), 1.20 (d, J = 7.1 Hz, 3H), 1.01 (t, J = 11.6 Hz, 3H), 0.94 - 0.74 (m, 2H);13C NMR (126 MHz, CDCh) 6 172.7, 171.7, 170.9, 169.1 , 166.8, 137.3, 136.0, 129.2, 128.3, 127.4, 126.1 , 70.6, 70.6, 70.5, 70.4, 70.4, 70.3, 66.9, 65.7, 60.1 , 55.4, 55.3, 49.5, 48.0, 36.9, 32.1 , 31.6, 29.9, 29.2, 29.1 , 28.5, 28.3, 25.9, 25.7, 25.6, 20.0; LC-MS (ESI): (m / z) = 957 [M+H],

[0219] 2,5-dioxopyrrolidin-1-yl-8-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)amino)-8-oxooctanoate (9c): General procedure 1A was followed on 100 mg (0.316 mmol) scale of the 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3- dione. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford 79 mg (44%) of title compound as pale yellow solid.1H NMR (500 MHz, CDCh) 5 8.60 (s, 1H), 7.43 (dd, J = 8.5, 7.2 Hz, 1 H), 7.02 (d, J = 7.1 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 6.33 (q, J = 5.9 Hz, 2H), 4.86 (dd, J = 11 .9, 5.4 Hz, 1 H), 3.39 (q, J = 4.7 Hz, 4H), 2.92 - 2.63 (m, 7H), 2.58 - 2.46 (m, 3H), 2.12 - 2.00 (m, 3H), 1.59 (dp, J = 40.3, 7.3 Hz, 4H), 1.42 - 1.20 (m, 5H);13C NMR (126 MHz, CDCh) 6 174.0, 171.6, 169.6, 169.5, 168.9, 168.7, 167.6, 146.8, 136.3,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01132.5, 116.8, 111.9, 110.2, 48.9, 42.1 , 39.0, 36.0, 31.4, 30.9, 28.3, 28.0, 25.6, 25.1 , 24.3, 22.7;LC-MS (ESI): (m / z) = 570 [M+H]

[0220] 2,5-dioxopyrrolidin-1-yl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)-4-oxo-7,10,13,16-tetraoxa-3-azanonadecan-19-oate (9d): General procedure 1A was followed on 200 mg (0.316 mmol) scale of the 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1 , 3-dione. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford 130 mg (59%) of title compound as pale yellow solid.1H NMR (500 MHz, CDCI3) 68.99 (s, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.08 (d, J = 5.7 Hz, 1 H), 6.98 (dd, J = 17.7, 7.9 Hz, 2H), 6.40 (d, J = 5.9 Hz, 1 H), 4.89 - 4.81 (m, 1 H), 3.74 (t, J = 6.3 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H), 3.58 - 3.48 (m, 13H), 3.38 (q, J = 2.9 Hz, 4H), 2.84 - 2.65 (m, 10H), 2.39 (t, J = 5.7 Hz, 2H);13C NMR (126 MHz, CDCI3) 5 172.6, 171.8, 169.3, 169.3, 168.9, 167.6, 166.8, 146.8, 136.2, 132.4, 116.9, 111.6, 110.1 , 70.6, 70.5, 70.4, 70.3, 70.1 , 70.1 , 67.0, 65.7, 53.5, 48.9, 42.0, 38.8, 36.7, 32.1 , 31.4, 25.6, 22.7; LC-MS (ESI): (m / z) = 690 [M+H]ATTORNEY DOCKET NO. E-202-2024-1 -PC-01General Procedure 1 B

[0221] To a stirred solution of tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-((( / ?)-1,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1- oxopropan-2-yl)(methyl)carbamate (1 eq, 0.13 mmol) in DMF (2 ml_), were added sequentially dicarboxylic acid (1.5 eq, 0.19 mmol), HATU (1.5 eq, 0.19 mmol) DIPEA ( 3.0 eq, 0.39 mmol) at 0 °C. The resulting mixture was stirred at rt for 4h. After completion of the reaction (as indicated by LCMS) crude material was purified by reverse phase chromatography without workup using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA to get the corresponding product.

[0222] (1 S,3r)-3-(((3S,5S)-1 -((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-((( / ?)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamoyl)cyclobutane-1 -carboxylic acid (9e): General procedure 1B was followed on 75 mg (0.13 mmol) scale of the tert-butyl ((S)- 1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)- 1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford of title compound 91 mg (67%).1H NMR (400 MHz, DMSO-d6) 5 8.39 (d, J = 8.7 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 1 H), 7.29 (d, J = 7.4 Hz, 1 H), 7.17 - 7.03 (m, 3H), 4.91 (q, = 8.0 Hz, 1 H), 4.28 (h, = 8.1 Hz, 3H), 4.02 (dd, J = 9.9, 6.6 Hz, 1 H), 3.31 (dd, J = 9.8, 7.3 Hz, 1 H), 2.96 (qd, J = 9.2, 3.3 Hz, 2H), 2.71 (d, J = 9.5 Hz, 5H), 2.41 - 2.17 (m, 5H), 1.96 - 1.49 (m, 10H), 1.39 (d, J = 10.3 Hz, 9H), 1.26 - 0.82 (m, 8H);13C NMR (101 MHz, DMSO-d6) 5 176.8, 174.1 , 171.4, 170.2, 137.8, 137.4, 129.0, 128.8, 127.1 , 126.1 , 79.4, 58.9, 55.3, 52.8, 48.3, 47.1 , 36.0, 34.9, 34.8, 30.5, 30.3, 29.2, 29.1 , 28.5, 27.7, 27.6, 26.3, 26.2, 26.0, 20.7; LC-MS (ESI): (m / z) = 710 [M+H]ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0223] 4-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2- cyclohexylacetyl)-5-((( / ?)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3- yl)carbamoyl)benzoic acid (9f): General procedure 1 B was followed on 75 mg scale of the tertbutyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA to afford 45 mg (48%) of title compound as white solid.1H NMR (400 MHz, DMSO-d6) 5 9.06 (d, J = 7.9 Hz, 1 H), 8.54 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.16 - 6.99 (m, 3H), 5.00 - 4.90 (m, 1 H), 4.55 (q, J = 6.8 Hz, 1 H), 4.34 (dt, J = 14.5, 7.6 Hz, 2H), 4.05 (dd, J = 10.1 , 6.2 Hz, 1 H), 3.58 (dd, J = 10.2, 6.2 Hz, 1 H), 2.72 (d, J = 8.4 Hz, 5H), 1.88 (ddq, J = 22.6, 12.1 , 6.7 Hz, 4H), 1.78 - 1.46 (m, 5H), 1.38 (s, 9H), 1.20 (d, J = 7.5 Hz, 3H), 1.01 (dq, J = 41.2, 10.5 Hz, 2H);13C NMR (101 MHz, DMSO-d6) 5 171.8, 170.4, 167.2, 165.5, 138.2, 137.7, 137.4, 133.7, 129.8, 129.0, 128.8, 127.8, 127.1 , 126.1 , 79.4, 59.0, 55.4, 53.1 , 49.1, 47.3, 34.6, 30.5, 30.2, 29.2, 29.1 , 28.5, 26.3, 26.2, 26.0, 20.7; LC-MS (ESI): (m / z) = 732 [M+H]

[0224] 5-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2- cyclohexylacetyl)-5-((( / ?)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 yl)carbamoyl)nicotinic acid (9g): General procedure 1 B was followed on 75 mg scale of the tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to afford 60 mg (64%) of title compound as white solid.1H NMR (400 MHz, DMSO-d6) 6 9.22 (d, J = 7.7 Hz, 2H), 8.69 (s, 1 H), 8.50 (d, J = 8.7 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.10 (dt, J = 23.0, 7.5 Hz, 4H), 4.95 (q, J = 7.3 Hz, 1 H), 4.55 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.8 Hz, 2H), 4.11 (dd, J = 10.1 , 6.6 Hz, 1H), 3.57 (dd, = 10.0, 7.1 Hz, 1 H), 2.72 (d, J = 10.4 Hz, 6H), 2.01 - 1.47 (m, 13H), 1.39 (d, J = 11.7 Hz, 11 H), 1.24 - 0.80 (m, 11 H);13C NMR (101 MHz, DMSO) 5 171.5, 170.3, 166.2, 164.0, 152.8, 152.3, 137.7, 137.4, 136.0, 129.0, 128.9, 127.1 , 126.1 , 79.4, 58.9, 55.4, 52.7, 49.0, 47.2, 34.6, 30.5, 30.2, 29.2, 29.1 , 28.5, 26.3, 26.2, 26.0, 20.7; LC-MS (ESI): (m / z) = 733 [M+H]

[0225] 6-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2- cyclohexylacetyl)-5-((( / ?)-1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3- yl)carbamoyl)pyrimidine-4-carboxylic acid (9h). General procedure 1 B was followed on 50 mg (0.086%) scale of the tert-butyl ((S)-1 -(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1- oxopropan-2-yl)(methyl)carbamate hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10- 75% acetonitrile in water with the addition of 0.05% TFA to afford 41 mg (65%) of title compound as white solid.1H NMR (400 MHz, DMSO-d6) 6 9.70 (d, J = 8.4 Hz, 1 H), 9.47 (d, J = 1 .3 Hz, 1 H), 8.46 (d, J = 8.7 Hz, 1 H), 8.40 (d, J = 1.3 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.16 - 7.00 (m, 3H), 4.94 (td, J = 8.3, 4.6 Hz, 1 H), 4.64 (p, J = 6.5 Hz, 1 H), 4.43 - 4.26 (m, 2H), 4.03 (dd, J = 10.4, 6.1 Hz, 1 H), 3.68 (dd, J = 10.3, 5.0 Hz, 1 H), 2.71 (d, J= 8.8 Hz, 5H), 1.97 (dt, J = 13.0, 5.3 Hz, 1 H), 1.89 - 1.45 (m, 4H), 1.39 (d, J = 12.1 Hz, 10H), 1.19 (d, J = 7.2 Hz, 4H), 1.11 - 0.83 (m, 6H);13CATTORNEY DOCKET NO. E-202-2024-1 -PC-01NMR (101 MHz, DMSO-d6) 6 171.6, 170.4, 165.2, 162.4, 159.0, 158.9, 158.2, 137.8, 137.4, 129.0, 128.8, 127.1 , 126.0, 118.0, 79.4, 59.1 , 55.3, 53.3, 49.1, 47.2, 34.5, 30.5, 30.2, 29.2, 29.1 , 28.5, 26.2, 26.0, 20.7; LC-MS (ESI): (m / z) = 734 [M+H]

[0226] (1 / ?,2 / ?,3S,4r)-4-(((3S,5S)-1 -((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-(((R)-1,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamoyl)bicyclo[1.1.1]pentane-2- carboxylic acid (9i): General procedure 1 B was followed on 45 mg (0.077 mmol) scale of the tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate hydrochloric salt. After completion of the reaction, the crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford 30 mg (64%) of title compound as white solid.1H NMR (400 MHz, DMSO-d6) 6 12.45 (s, 1 H), 8.46 (d, J = 8.6 Hz, 1 H), 8.27 (d, J = 8.1 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.10 (dt, J = 23.3, 7.5 Hz, 3H), 4.91 (t, J = 7.0 Hz, 1 H), 4.28 (t, J = 7.8 Hz, 3H), 4.06 - 3.88 (m, 1 H), 3.44 - 3.33 (m, 1 H), 2.71 (d, J = 5.8 Hz, 5H), 2.33 (dt, J = 13.9, 7.4 Hz, 1 H), 2.08 (s, 6H), 1.94 - 1.51 (m, 9H), 1.39 (d, J = 12.4 Hz, 9H), 1.28 - 0.80 (m, 8H);13C NMR (101 MHz, DMSO) 5 171.6, 171.2, 170.3, 168.7, 137.7, 137.4, 129.0, 128.9, 127.1, 126.1 , 79.4, 62.6, 62.0, 58.9, 53.0, 51.9, 48.1, 47.2, 37.0, 34.6, 30.5, 30.2, 29.2, 29.0, 28.5, 26.3, 26.0, 20.7; LC-MS (ESI): (m / z) = 722 [M+H]ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0227] tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-((2S,4S)-4-(pent-4-ynamido)-2-(((R)- 1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)ethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate (9j): General procedure 1 B was followed on 50 mg (0.086 mmol) scale of the tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1 ,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2- yl)(methyl)carbamate hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-85% acetonitrile in water with the addition of 0.05% TFA to afford 45 mg (79%) of title compound as white solid.1H NMR (400 MHz, DMSO-d6) 5 8.36 (d, J = 8.6 Hz, 1 H), 8.21 (d, J = 7.5 Hz, 1 H), 7.30 (d, J = 7.4 Hz, 1 H), 7.17 - 6.93 (m, 3H), 4.92 (td, J = 8.3, 4.2 Hz, 1 H), 4.26 (tq, J = 15.3, 7.9 Hz, 3H), 4.06 (dd, J = 9.8, 6.9 Hz, 1 H), 3.28 (t, J = 8.9 Hz, 1H), 2.80 - 2.62 (m, 7H), 2.35 (ddd, J = 9.5, 5.6, 2.8 Hz, 3H), 2.24 (t, J = 7.2 Hz, 2H), 1.91 - 1.51 (m, 9H), 1 .39 (d, J = 10.9 Hz, 11 H), 1 .28 - 0.82 (m, 9H);13C NMR (101 MHz, DMSO-d6) 5 171.2, 170.6, 170.2, 137.8, 137.4, 129.0, 128.8, 127.1 , 126.1 , 84.0, 79.4, 79.4, 71.8, 71.7, 58.9, 55.3, 52.5, 48.2, 47.1, 34.9, 34.7, 30.5, 30.3, 29.2, 29.1 , 28.5, 26.3, 26.2, 26.0, 20.7, 14.5; LC-MS (ESI): (m / z) = 664 [M+H]

[0228] 4-((4-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2- cyclohexylacetyl)-5-((( / ?)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3- yl)carbamoyl)phenyl)buta-1,3-diyn-1-yl)benzoic acid (9k): General procedure 1 B was followed on 75 mg (0.13 mmol) scale of the tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-((( / ?)- 1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1- oxopropan-2-yl)(methyl)carbamate hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10- 85% acetonitrile in water with the addition of 0.05% TFA to afford 40 mg (36%) of title compound as white solid.1HNMR (400 MHz, DMSO-d6) 5 9.05 (d, J = 7.8 Hz, 1 H), 8.55 (d, J = 8.6 Hz, 1 H),ATTORNEY DOCKET NO. E-202-2024-1 -PC-017.99 - 7.93 (m, 2H), 7.92 - 7.86 (m, 2H), 7.73 (ddd, J = 8.3, 3.4, 1.8 Hz, 4H), 7.33 (d, J = 7.6 Hz, 1 H), 7.11 (dt, J= 23.1, 7.2 Hz, 3H), 4.95 (d, J= 5.7 Hz, 1H), 4.55 (q, J= 6.7 Hz, 1H), 4.34 (dt, J = 16.7, 7.8 Hz, 2H), 4.03 (t, J= 8.0 Hz, 1H), 3.58 (t, J= 8.1 Hz, 1H), 2.72 (d, J= 5.8 Hz, 5H), 1.96 - 1.78 (m, 4H), 1.78- 1.48 (m, 4H), 1.37 (s, 9H), 1.19 (d, J= 7.4 Hz, 3H), 1.13-0.83 (m, 4H); LC-MS (ESI): (m / z) = 855 [M+H]

[0229] 4-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)carbamoyl)phenyl)buta-1,3-diyn-1-yl)benzoic acid (9I): General procedure 1B was followed on 150 mg (0.47 mmol) scale of the terf-butyl 4-((2-aminoethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1, 3-dione hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA to afford 108 mg (38%) of title compound as white solid.1H NMR (500 MHz, DMSO-d6) 513.11 (s, 1H), 11.03 (s, 1H), 8.76 (t, J = 5.4 Hz, 1H), 7.91 (d, J= 8.0 Hz, 2H), 7.81 (d, J= 8.0 Hz, 2H), 7.72-7.61 (m, 4H), 7.51 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.96 (d, J= 7.0 Hz, 1H), 6.78 (t, J=6.2 Hz, 1H), 4.99 (dd, J= 12.8, 5.4 Hz, 1H), 3.43 (dq, J = 27.8, 6.8 Hz, 4H), 2.82 (ddd, J= 17.9, 13.9, 5.4 Hz, 1H), 2.56 -2.45 (m, 2H), 2.02-1.91 (m, 1H);13C NMR (126 MHz, DMSO-d6) 6173.3, 170.6, 169.2, 167.8, 167.0, 166.3, 146.8, 136.7, 135.8, 133.2, 133.2, 133.0, 132.7, 132.2, 130.1, 128.1, 125.0, 123.3, 117.7, 111.1, 109.8, 82.8, 82.2, 76.0, 75.3, 49.0, 41.7, 39.3, 31.5, 22.6; LC-MS (ESI): (m / z) = 589 [M+H]ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0230] 4-((( S -1 -((2S,4R)-4-hydroxy-2-(((S)-1 -(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamoyl)benzoic acid (9m): General procedure 1 B was followed on 150 mg (0.337 mmol) scale of the (2S,4 / ?)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloric salt. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to afford 130 mg (67%) of title compound.1H NMR (400 MHz, DMSO-d6) 5 9.04 (s, 1 H), 8.40 (d, J = 7.8 Hz, 1 H), 8.14 (d, J = 9.0 Hz, 1 H), 8.04 - 7.96 (m, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.37 (d, = 8.3 Hz, 2H), 4.92 (p, J = 7.0 Hz, 1 H), 4.75 (d, J = 9.1 Hz, 1 H), 4.45 (t, J = 8.1 Hz, 1 H), 4.29 (t, J = 3.6 Hz, 1 H), 3.66 (d, J = 3.4 Hz, 2H), 2.44 (s, 3H), 2.07 - 1 .97 (m, 1 H), 1.79 (ddd, J =12.9, 8.6, 4.6 Hz, 1 H), 1.36 (d, J = 7.0 Hz, 3H), 1.02 (s, 9H);13C NMR (101 MHz, DMSO-d6) 6 171.0, 169.7, 167.2, 166.3, 159.4, 159.0, 158.6, 158.2, 152.3, 147.6, 145.3, 138.4, 133.5, 131.9,129.9, 129.6, 129.3, 128.3, 126.8, 69.3, 59.2, 58.0, 56.9, 48.2, 38.2, 36.1 , 27.0, 26.9, 22.9, 16.1 ; LC-MS (ESI): (m / z) = 593 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01General Procedure 2A

[0231] A stirred solution of N-((7R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (1.0 eq, 0.037 mmol) in DMF (1 ml_), were sequentially added NHS ester of corresponding compound (1.1 eq, 0.040 mmol) and DI PEA (2.0 eq, 0.74 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup the resulting product was used for next step without characterization. The resulting above product (0.037 mml) was dissolved 20% TFA in DCM (2 ml_) and the resulting solution was stirred at room temperature for 1 h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to give corresponding product.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0232] N1-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N8-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)octanediamide (EPZ031686-IAP-01):General procedure 2A was followed on 20 mg (0.037 mmol) scale of the N-((7R,3r,5S)-8-(((1-(3- aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2- oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TEA to afford 21 mg (44%) of title compound as white solid.1H NMR (400 MHz, CD3OD-d6) 3 8.47 (d, J = 8.4 Hz, 1 H), 7.40 - 7.34 (m, 1 H), 7.30 (s, 1 H), 7.11 (dtd, J = 16.9, 7.9, 5.9 Hz, 3H), 6.94 (s, 1 H), 5.06 (t, J = 7.2 Hz, 1H), 4.52 - 4.38 (m, 3H), 4.31 - 4.09 (m, 5H), 3.87 (q, J = 6.9 Hz, 1 H), 3.65 - 3.50 (m, 4H), 3.26 (d, J = 6.5 Hz, 1 H), 3.05 (dd, J = 45.3, 14.7 Hz, 7H), 2.87 - 2.73 (m, 2H), 2.66 (s, 4H), 2.50 (dt, J = 14.7, 7.8 Hz, 1 H), 2.40 - 2.11 (m, 10H), 2.10 - 1.57 (m, 14H), 1.47 (d, J = 7.0 Hz, 3H), 1.41 - 1.05 (m, 10H); LC-MS (ESI): (m / z) = 1159 [M+H]

[0233] N1-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N16-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-4,7,10,13- tetraoxahexadecanediamide (EPZ031686-IAP-02): General procedure 2A was followed on 25 mg (0.046 mmol) scale of the N-((7R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-ATTORNEY DOCKET NO. E-202-2024-1 -PC-018-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 18 mg (33%) of title compound as white solid.1H NMR (400 MHz, MeOD-d4) 5 5.05 (t, J = 7.1 Hz, 1 H), 4.56 - 4.38 (m, 3H), 4.24 (t, J = 8.4 Hz, 3H), 4.13 (d, J = 6.6 Hz, 1 H), 3.89 (q, J = 7.0 Hz, 1 H), 3.74 (td, J = 6.1 , 3.4 Hz, 4H), 3.62 (d, J = 6.0 Hz, 13H), 3.55 - 3.48 (m, 3H), 3.32 (d, J = 7.9 Hz, 2H), 3.12 (dd, J = 16.1 , 7.0 Hz, 3H), 3.00 (t, J = 12.7 Hz, 2H), 2.78 (dd, J = 11.0, 6.2 Hz, 1 H), 2.66 (d, J = 0.9 Hz, 3H), 2.47 (t, J = 6.0 Hz, 4H), 2.28 (t, J = 12.1 Hz, 4H), 2.16 (d, J = 7.9 Hz, 1 H), 2.09 - 1.63 (m, 12H), 1.47 (d, J = 7.0 Hz, 3H), 1.38 - 1.01 (m, 5H);13C NMR (101 MHz, MeOD-d4) 5178.1 , 174.0, 172.1 , 171.7, 170.7, 168.7, 168.5, 145.8, 137.1 , 136.2, 130.2, 129.5, 128.5, 128.4, 126.8, 125.7, 124.8, 124.7, 110.4, 70.1 , 70.1 , 70.0, 69.9, 69.9, 66.8, 66.7, 59.2, 56.8, 56.2, 55.6, 53.9, 52.7, 52.1 , 48.4, 42.3, 39.8, 36.3, 36.1 , 35.3, 34.1 , 30.4, 30.2, 29.9, 29.1 , 28.9, 28.8, 28.5,28.1, 25.8, 25.6, 24.1 , 20.2, 14.8; HRMS (ESI) calcd for C64H95CINioOi3SNa+(MNa+) 1301.6387, found 1301.6388.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01General Procedure 2B

[0234] A stirred solution of N-((7R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (1.0 eq, 0.037 mmol) in DMF (1 mL), were sequentially added corresponding IAP carboxylic acid (1.1 eq, 0.040 mmol), HATU (1 .5 eq, 0.055 mmol) and DI PEA (3.0 eq, 0.111 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h to 4h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup the resulting product was used for next step without characterization. The resulting above product (0.037 mmol) was dissolved 20% TFA in DCM (2 mL) and the resulting solution was stirred at room temperature for 1 h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to give corresponding product.

[0235] (1S,3R)-N1-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N3-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-(((R)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)cyclobutane-1,3-dicarboxamide (EPZ031686-IAP-03): General procedure 2B was followed on 17 mg (0.031 mmol) scale of the N-((7R,3 / ',5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 8 mg (23%) of title compound.1H NMR (400 MHz, MeOD-d4) 6 7.73 (s, 1 H), 7.37 (d, 3 = 7.2 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1 H), 7.11 (dq, J = 16.8, 9.3 Hz, 3H), 6.98 - 6.91 (m, 1 H), 6.53 (s, OH), 5.04 (s, 1 H), 4.58 - 4.31 (m, 3H), 4.31 - 4.06 (m, 5H), 3.89 (t, 3 = 7.3 Hz, 1 H), 3.58 (t, 3 = 13.2 Hz, 4H), 3.30 (tt, 3 = 4.4, 1.8 Hz, 6H), 3.22 - 2.97 (m, 7H), 2.79 (d, 3 = 11 .4 Hz, 2H), 2.57 - 2.39 (m, 6H), 2.34 - 1 .62 (m, 25H), 1.47 (dd, 3 = 6.9, 2.4 Hz, 3H), 1.37 - 0.99 (m, 5H);13C NMR (101 MHz, MeOD-d4) 5 1777.0,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01175.9, 171.9, 170.7, 168.7, 145.6, 137.1 , 136.1, 130.2, 129.5, 128.5, 128.4, 126.8, 125.6, 124.6, 110.4, 59.3, 56.8, 56.2, 55.6, 54.3, 53.0, 52.1 , 48.6, 42.3, 39.8, 36.3, 36.2, 35.9, 35.7, 34.1 , 30.4, 30.1, 29.8, 29.0, 28.8, 28.8, 28.5, 28.1 , 27.4, 27.3, 25.8, 25.6, 24.2, 20.2; HRMS (ESI) calcd forC58H82CINIO09S+(MH+) 1129.5675, found 1129.5667.

[0236] N1-(3-(4-((((l / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N4-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)terephthalamide (EPZ031686-IAP- 04): General procedure 2B was followed on 15 mg (0.023 mmol) scale of the N-( 1R,3r,5S)-8- (((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2- oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 11 mg (42%) of title compound.1H NMR (400 MHz, MeOD-d4) 6 8.60 (d, J = 8.5 Hz, 1 H), 7.97 (q, J = 8.3 Hz, 4H), 7.40 (d, J = 7.3 Hz, 1 H), 7.29 (s, 1 H), 7.11 (dt, J = 18.2, 7.0 Hz, 3H), 6.94 (s, 1 H), 5.09 (d, J = 7.3 Hz, 1 H), 4.76 (s, 1 H), 4.57 - 4.45 (m, 2H), 4.23 (s, 2H), 4.13 (dd, J = 10.5, 5.2 Hz, 2H), 3.96 - 3.79 (m, 2H), 3.62 (d, J = 12.2 Hz, 2H), 3.51 (d, J = 9.8 Hz, 4H), 3.21 - 3.09 (m, 3H), 3.03 (t, J = 12.8 Hz, 2H), 2.88 - 2.71 (m, 1 H), 2.66 (s, 3H), 2.65 - 2.54 (m, 1H), 2.38 - 1.53 (m, 21 H), 1.48 (d, J = 7.0 Hz, 3H), 1.29 - 0.96 (m, 7H);13C NMR (101 MHz, MeOD-d4) 6 172.4, 170.9, 168.7, 168.4, 166.7, 137.1 , 136.7, 136.6, 136.1 , 128.5, 128.4, 127.3, 127.2, 126.8, 125.6, 124.6, 59.4, 56.8, 56.1, 55.5, 54.5, 53.8, 52.2, 49.5, 42.3, 40.0, 36.5, 36.2, 33.9, 30.4, 30.1 , 29.8, 28.9, 28.8, 28.6, 28.1 , 25.8, 25.7, 25.6, 24.2, 20.2, 14.8; LC-MS (ESI): (m / z) = 1151 [M+H]ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0237] N3-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N5-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyridine-3,5-dicarboxamide(EPZ031686-IAP-05): General procedure 2B was followed on 20 mg (0.031 mmol) scale of the N-((1R,3 / ',5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 13 mg (37%) of title compound as a white solid.1H NMR (400 MHz, MeOD-d4) 6 9.18 (d, J = 22.0 Hz, 2H), 8.71 (s, 1 H), 8.59 (d, J = 8.6 Hz, 1 H), 7.46 - 7.36 (m, 1 H), 7.30 (s, OH), 7.11 (dt, J = 18.1, 7.1 Hz, 3H), 6.94 (d, J = 4.4 Hz, 1 H), 5.19 - 5.03 (m, 1 H), 4.79 - 4.72 (m, 1H), 4.60 - 4.47 (m, 2H), 4.30 - 4.09 (m, 4H), 3.94 - 3.71 (m, 2H), 3.62 (d, J = 11.9 Hz, 2H), 3.53 (d, J = 5.0 Hz, 3H), 3.19 (t, J = 7.9 Hz, 2H), 3.13 (d, J = 5.8 Hz, 1 H), 3.01 (t, J = 12.5 Hz, 1 H), 2.79 (td, J = 14.8, 8.4 Hz, 2H), 2.66 (s, 4H), 2.34 - 1.56 (m, 18H), 1.48 (d, J = 7.0 Hz, 3H), 1.33 - 0.99 (m, 6H);13C NMR (101 MHz, MeOD-d4) 5 172.2,170.8, 168.7, 168.5, 166.3, 164.7, 150.2, 150.1, 137.1 , 136.2, 134.6, 130.2, 129.5, 128.5, 128.4,126.8, 125.6, 124.6, 110.4, 59.4, 56.8, 56.1, 55.5, 54.5, 53.4, 52.2, 49.5, 42.3, 40.0, 36.5, 36.3, 33.9, 30.4, 30.1 , 29.8, 29.0, 28.8, 28.8, 28.5, 28.2, 25.8, 25.7, 25.6, 24.1 , 20.2, 14.8; HRMS (ESI) calcd for C59H79CINiiO9S+(MH+) 1152.5471 , found 1152.5482.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0238] N4-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N6-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1, 2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)pyrimidine-4,6-dicarboxamide (EPZ031686-IAP-07): General procedure 2B was followed on 15 mg (0.028 mmol) scale of the N-((1 / ?,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 10 mg (54 %) of title compound as a white solid.1H NMR (400 MHz, DMSO-d6) 5 10.59 (s, 1H), 9.71 (d, J = 8.3 Hz, 1 H), 9.44 (d, J = 2.5 Hz, 1 H), 9.38 (s, 1 H), 8.50 (d, = 8.6 Hz, 1 H), 8.44 (d, J - 2.2 Hz, 1 H), 8.17 (d, J - 4.7 Hz, 1 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.21 (s, 1 H), 7.08 (dd, J = 20.6, 7.3 Hz, 4H), 6.81 (d, J = 2.4 Hz, 1 H), 4.95 (s, 1 H), 4.67 (s, 1 H), 4.45 - 4.28 (m, 2H), 4.07 (d, J = 18.7 Hz, 4H), 3.94 (s, 1 H), 3.70 (d, J = 10.4 Hz, 1H), 3.34 (d, J = 27.1 Hz, 16H), 3.01 (dd, J= 14.0, 6.4 Hz, 4H), 2.92 - 2.83 (m, 3H), 2.70 (s, 2H), 2.48 (s, 2H), 2.33 (d, J = 6.5 Hz, 3H), 2.13 - 1.44 (m, 28H), 1.36 (d, J = 12.0 Hz, 2H), 1.17 - 0.87 (m, 12H);13C NMR (101 MHz, DMSO-d6) 6 176.8, 174.5,171.7, 170.5, 166.9, 162.4, 162.3, 159.4, 159.1, 158.0, 146.0, 137.8, 137.4, 130.2, 129.6, 129.0,128.8, 127.1 , 126.0, 125.3, 125.1 , 115.6, 110.1 , 59.4, 59.1 , 57.7, 57.0, 55.3, 54.7, 53.5, 49.1 , 47.3, 42.0, 36.7, 35.7, 34.5, 32.5, 31.8, 30.1 , 29.1, 28.3, 26.3, 26.0, 20.7, 19.4; HRMS (ESI) calcd for C58H78CINI2O9S+(MH+) 1153.5424, found 1153.5442.

[0239] 6-chloro-N-((7R,3r,5S)-8-(((1-(3-(4-((4-(((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-3-yl)carbamoyl)phenyl)buta-1,3-diyn-1-ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 yl)benzamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide (EPZ031686-IAP-08). General procedure 2B was followed on 15 mg (0.028 mmol) scale of the N-(( 1R, 3r, 5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 8 mg (22%) of title compound as a white solid.1H NMR (400 MHz, DMSO-d6) 5 10.59 (s, 1 H), 9.06 (d, J = 7.8 Hz, 1 H), 8.66 - 8.54 (m, 2H), 8.18 (d, J = 4.7 Hz, 1 H), 7.96 - 7.80 (m, 5H), 7.76 - 7.66 (m, 4H), 7.37 - 7.30 (m, 1 H), 7.20 (d, J = 1.2 Hz, 1 H), 7.15 - 7.04 (m, 3H), 6.81 (s, 1 H), 5.00 - 4.90 (m, 1 H), 4.55 (h, J = 6.5 Hz, 1 H), 4.43 - 4.33 (m, 2H), 4.11 - 4.00 (m, 3H), 3.94 (d, J = 5.8 Hz, 1 H), 3.59 (dd, = 10.1 , 6.0 Hz, 1 H), 3.49 (s, 2H), 3.26 (d, J = 8.7 Hz, 4H), 2.97 (dd, = 13.0, 6.3 Hz, 3H), 2.82 (d, J = 11.2 Hz, 2H), 2.76 - 2.64 (m, 2H), 2.29 (t, J= 7.1 Hz, 2H), 2.16 (s, 3H), 2.08 (dd, J = 25.0, 6.9 Hz, 2H), 1.95 - 1.46 (m, 21 H);13C NMR (101 MHz, DMSO-d6) 6 176.8, 174.7, 171.8, 170.5, 166.9, 165.5, 165.1 , 145.9, 137.7, 137.4, 136.1 , 135.3, 133.0, 132.9, 130.2, 129.6, 129.0, 128.9, 128.0, 128.0, 127.1 , 126.1 , 125.3, 125.1 , 123.6, 123.1 , 110.1 , 82.5, 82.3, 75.5, 75.3, 59.5, 59.0, 57.7, 56.4, 55.3, 54.7, 53.5, 53.2, 49.1 , 47.3, 42.0, 38.5, 36.7, 35.7, 34.6, 32.4, 31.9, 30.2, 29.2, 28.4, 28.3, 26.8, 26.3, 26.2, 26.0, 20.7, 19.5; HRMS (ESI) calcd for CyoHs^lNwOgS" (MH+) 1275.5832, found 1275.5841.

[0240] (1R,2S,3S,4S)-N2-(3-(4-((((7R,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N4-((3S,5S)-1-((S)-2- cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)-1,2,3,4- tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)bicyclo[1.1.1]pentane-2,4- dicarboxamide (EPZ031686-IAP-09): General procedure 2B was followed on 15 mg (0.028 mmol) scale of the N-((1R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of theATTORNEY DOCKET NO. E-202-2024-1 -PC-01 reaction, crude material was purified by reverse phase chromatography without workup using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to afford 12 mg (37%) of title compound as a white solid.1H NMR (400 MHz, DMSO-d6) 510.60 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.28 (d, J= 8.1 Hz, 1H), 8.19 (d, J = 4.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 6.1 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.22 (s, 1H), 7.17-7.04 (m, 3H), 6.83 (d, J= 1.7 Hz, 1H), 4.94 (s, 1H), 4.34 (dt, J = 19.7, 7.8 Hz, 3H), 4.10 (s, 2H), 3.95 (d, J = 6.9 Hz, 2H), 3.50 (s, 2H), 3.43 (t, J= 8.2 Hz, 1H), 3.11 -2.92 (m, 6H), 2.85-2.65 (m, 4H), 2.43-2.31 (m, 1H), 2.26-2.00 (m, 12H), 1.98 - 1.46 (m, 16H), 1.36 - 0.89 (m, 14H);13C NMR (101 MHz, DMSO-d6) 5176.8, 174.8, 171.7, 170.5, 169.1, 169.0, 166.9, 145.9, 137.6, 137.4, 130.2, 129.6, 129.0, 127.1, 126.1, 125.3, 125.1, 110.1, 59.5, 58.9, 57.7, 56.2, 55.3, 54.7, 53.4, 53.1, 51.6, 48.1, 47.2, 42.0, 38.5, 38.4, 37.5, 36.7, 35.7, 34.7, 32.4, 31.8, 30.1, 29.2, 29.1, 28.5, 28.3, 26.9, 26.4, 26.3, 26.0, 20.6, 19.5; HRMS (ESI) calcd for C59H82CINIO09S+(MH+) 1141.5675, found 1141.5693.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0241] A stirred solution of N-((1R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (1.0 eq, 0.028 mmol) in DMF (1 mL), were sequentially added NHS ester of corresponding compound (1.1 eq, 0.031mmol) and DI PEA (2.0 eq, 0.56 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to get pure product.

[0242] N1-(3-(4-((((1 / ?,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N8-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)octanediamide(EPZ031686-CRBN-01): General procedure 2C was followed on 15 mg (0.028 mmol) scale of the N- ((1 / ?,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)- 6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to afford 13 mg (47%) of title compound as a yellow solid.1H NMR (400 MHz, MeOD-d4) 6 7.56 (dd, J = 8.6, 7.1 Hz, 1 H), 7.30 (d, J = 1.1 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 7.06 (dd, 3 = 7.1 , 0.6 Hz, 1 H), 6.94 (s, 1 H), 5.06 (dd, 3 = 12.6, 5.5 Hz, 1 H), 4.22 (s, 2H), 4.12 (t, 3 = 6.8 Hz, 1 H), 3.55 (q, 3 = 10.4 Hz, 3H), 3.50 - 3.38 (m, 4H), 3.26 (t, 3 = 6.5 Hz, 2H), 3.16 - 2.95 (m, 5H);13C NMR (101 MHz, MeOD-d4) 6 175.4, 173.3, 170.3, 169.2, 168.5, 167.9, 146.8, 135.9, 132.5, 129.5, 124.5, 116.7, 110.7, 110.3, 56.7, 55.6, 54.2, 52.2, 48.8, 42.3, 41.4, 38.3, 36.3, 35.5, 35.4, 30.8, 30.1 , 28.9, 28.6, 28.4, 28.1, 25.3, 25.2, 24.2, 22.4; HRMS (ESI) calcd for C48H63CIN9O10S+(MH+) 992.4107, found 992.4108.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0243] N1-(3-(4-((((7K,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N16-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4,7,10,13- tetraoxahexadecanediamide (EPZ031686-CRBN-02). General procedure 2C was followed on 18 mg (0.033 mmol) scale of the N-((7 / ?,3r;5S)-8-(((1-(3-aminopropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to afford 14 mg (38%) of title compound.1H NMR (400 MHz, MeOD-d4) 5 7.57 (ddd, J = 8.9, 7.1 , 1.8 Hz, 1 H), 7.30 (d, J = 1.7 Hz, 1 H), 7.14 (dd, J = 8.6, 1.7 Hz, 1 H), 7.06 (dd, J = 7.0, 1.7 Hz, 1H), 6.94 (d, J =1.7 Hz, 1 H), 5.06 (ddd, 12.4, 5.5, 1.7 Hz, 1 H), 4.22 (s, 3H), 4.11 (dt, J = 6.8, 4.0 Hz, 1 H), 3.83 - 3.66 (m, 5H), 3.58 (t, J = 2.2 Hz, 18H), 3.51 - 3.41 (m, 5H), 3.17 - 3.06 (m, 4H), 2.98 (t, J =12.7 Hz, 2H), 2.92 - 2.65 (m, 5H), 2.50 - 2.40 (m, 5H), 2.33 - 2.19 (m, 6H), 2.19 - 1.86 (m, 8H), 1.66 (q, J = 13.5 Hz, 2H);13C NMR (101 MHz, MeOD-d4) 5 178.1, 174.1 , 173.2, 173.2, 170.2, 169.2, 168.4, 167.8, 146.7, 145.8, 135.9, 132.5, 130.2, 129.5, 124.8, 124.7, 116.8, 110.8, 110.4, 110.0, 70.1 , 70.0, 70.0, 69.9, 66.8, 66.7, 56.8, 55.6, 53.7, 52.1, 48.8, 42.3, 41.4, 38.4, 36.3, 36.2, 36.0, 35.2, 30.8, 30.2, 28.9, 28.1, 24.1 , 22.4; HRMS (ESI) calcd for C52H7ICIN90I4S+(MH+) 1112.4530, found 1112.4547.

[0244] N1-(3-(4-((((1 / ?,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N8-((S)-1-((2S,4 / ?)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)octanediamide (EPZ031686-VHL-01): General procedure 2C was followed on 18 mg (0.033 mmol) scale of the N-((1R,3 / ',5S)-8-(((1-(3-aminopropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to afford 16 mgATTORNEY DOCKET NO. E-202-2024-1 -PC-01(43%) of title compound as a white solid.1H NMR (400 MHz, MeOD-d4) 6 8.88 (d, J = 2.4 Hz, 1 H), 8.51 (d, J = 7.5 Hz, 1 H), 8.28 (d, J = 5.2 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H), 7.46 - 7.36 (m, 4H), 7.30 (s, 1 H), 6.94 (s, 1 H), 5.00 (t, J = 6.9 Hz, 1 H), 4.66 - 4.52 (m, 2H), 4.43 (s, 1 H), 4.24 (s, 2H), 3.87 (d, J = 11.1 Hz, 1 H), 3.75 (dd, J = 11.0, 4.0 Hz, 1 H), 3.55 (d, J = 12.5 Hz, 4H), 3.27 (d, J = 6.6 Hz, 2H), 3.18 - 2.94 (m, 5H), 2.47 (d, J = 1.1 Hz, 4H), 2.34 - 2.13 (m, 6H), 2.11 - 1.87 (m, 7H), 1.71 - 1.55 (m, 7H), 1.50 (d, J = 7.0 Hz, 3H), 1.38 - 1.31 (m, 5H), 1.04 (d, J = 1.1 Hz, 9H); LC-MS (ESI): (m / z) = 1120 [M+H]

[0245] N1-(3-(4-(((('f / ?,5r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N16-((S)-1-((2S,4 / ?)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)-4,7,10,13-tetraoxahexadecanediamide (EPZ031686-VHL-02):General procedure 2C was followed on 20 mg (0.037 mmol) scale of the N-((7R,3r,5S)-8-(((1-(3- aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2- oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to afford 18 mg (39%) of title compound.1H NMR (400 MHz, MeOD-d4) 5 8.94 (s, 1 H), 7.51 - 7.36 (m, 4H), 7.30 (d, J = 1 .3 Hz, 1 H), 6.94 (d, J = 1 .4 Hz, 1 H), 5.00 (q, J = 7.0 Hz, 1 H), 4.64 (d, J= 1.3 Hz, 1 H), 4.62 - 4.52 (m, 1 H), 4.43 (s, 1 H), 4.24 (s, 2H), 4.18 - 4.07 (m, 1 H), 3.86 (d, J = 11.0 Hz, 1H), 3.79 - 3.69 (m, 5H), 3.62 (dq, J = 3.6, 1.8 Hz, 14H), 3.34 (d, J= 6.4 Hz, 2H), 3.19 - 3.08 (m, 3H), 3.00 (t, J = 12.8 Hz, 2H), 2.67 - 2.55 (m, 1 H), 2.55 - 2.43 (m, 6H), 2.36 - 1.87 (m, 13H), 1.68 (q, J = 13.6 Hz, 2H), 1.50 (dd, J = 7.0, 1.4 Hz, 3H), 1.08 - 1.01 (m, 9H);13C NMR (101 MHz, MeOD-d4) 5 178.0, 174.1 , 172.2, 171.8, 170.7, 168.5, 151.7, 145.8, 144.3, 130.2,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01130.0, 129.5, 129.1 , 126.2, 124.8, 124.7, 110.4, 70.2, 70.1 , 70.1 , 70.1 , 70.0, 69.9, 69.5, 66.9,66.8, 59.2, 57.6, 56.9, 56.6, 55.6, 53.8, 52.1 , 48.7, 42.3, 37.4, 36.3, 36.1 , 35.9, 35.3, 35.2, 30.2,28.9, 28.1 , 25.7, 24.1, 21.0, 14.3; HRMS (ESI) calcd for CeoHsyCINgO^ (MH+) 1240.5553, found 1240.5575.General Procedure 2D

[0246] A stirred solution of N-((1R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (1.0 eq, 0.028mmol) in DMF (1 ml_), were sequentially added corresponding IAP carboxylic acid (1.1 eq, 0.031 mmol), HATU (1 .5 eq, 0.042 mmol) and DI PEA (3.0 eq, 0.84 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h to 4h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to get pure product.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0247] 6-chloro-N-((7R,3r,5S)-8-(((1-(3-(4-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethyl)carbamoyl)phenyl)buta-1,3-diyn-1- yl)benzamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2- oxoindoline-5-carboxamide (EPZ031686-CRBN-03): General procedure 2D was followed on 15 mg (0.028mmol) scale of the N-((7 / ?,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to afford 15 mg (49%) of title compound as yellow solid.1H NMR (500 MHz, DMSO-d6) 6 11.04 (s, 1 H), 10.57 (s, 1 H), 9.16 (s, 1 H), 8.75 (dt, J = 30.3, 5.7 Hz, 2H), 8.16 (d, J = 4.6 Hz, 1 H), 7.83 (dd, J = 11.0, 8.2 Hz, 4H), 7.67 (dd, = 11.1 , 8.1 Hz, 4H), 7.51 (t, J = 7.8 Hz, 1 H), 7.20 - 7.14 (m, 2H), 6.96 (d, J = 7.0 Hz, 1 H), 6.78 (d, J = 5.5 Hz, 2H), 4.99 (dd, J = 12.8, 5.5 Hz, 1 H), 4.06 (s, 2H), 3.90 (q, J = 6.2 Hz, 1 H), 3.41 (d, J = 7.0 Hz, 3H), 3.26 (dq, J = 15.9, 6.6 Hz, 2H), 3.12 - 2.75 (m, 6H), 2.55 - 2.46 (m, 2H), 2.16 - 1.92 (m, 8H), 1.87 (d, J = 16.4 Hz, 7H), 1.46 (t, J = 13.1 Hz, 2H);13C NMR (126 MHz, DMSO-de) 6 176.8, 173.2, 170.5, 169.2, 167.8, 167.0, 166.3, 166.1 , 158.5, 158.3, 146.9, 146.0, 136.7, 135.8, 135.7, 132.9, 132.7, 130.2, 129.6, 128.1 , 125.3, 125.2, 123.5, 123.4, 118.7, 117.7, 116.3, 111.1 , 110.2, 109.9, 82.5, 82.4, 75.5, 75.4, 56.7, 55.4, 54.6, 51.9, 49.0, 42.0, 41.8, 37.1, 36.7, 35.8, 31.5, 30.2, 29.0, 28.4, 24.4, 22.7; LC-MS (ESI): (m / z) = 1108 [M+H]

[0248] (1S,3R)-N1-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N3-((S)-1-((2S,4R)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)cyclobutane-1,3-dicarboxamide (EPZ031686-VHL-03): GeneralATTORNEY DOCKET NO. E-202-2024-1 -PC-01 procedure 2D was followed on 15 mg (0.028mmol) scale of the N-((7R,3r,5S)-8-(((1-(3- aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2- oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to afford 11 mg (37%) of title compound as a white solid.1H N MR (400 MHz, MeOD- d4) 5 8.53 (d, J = 7.4 Hz, 1 H), 8.28 (d, J = 5.2 Hz, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.52 - 7.36 (m, 4H), 7.30 (d, J = 1.6 Hz, 1 H), 6.94 (d, J = 1.4 Hz, 1H), 4.99 (q, J = 6.9 Hz, 1 H), 4.64 (dd, J= 7.4, 2.3 Hz, 1 H), 4.56 (t, J = 8.3 Hz, 1 H), 4.44 (s, 1 H), 4.24 (s, 2H), 4.13 (s, 1 H), 3.88 (d, J = 11.1 Hz, 1 H), 3.83 - 3.72 (m, 1H), 3.59 (d, J = 12.7 Hz, 2H), 3.54 (s, 2H), 3.27 (d, J = 7.1 Hz, 3H), 3.18 - 2.95 (m, 6H), 2.58 - 1.87 (m, 21 H), 1.66 (dt, J = 24.3, 10.6 Hz, 2H), 1.50 (dd, J= 7.1, 1.4 Hz, 3H), 1.03 (d, J = 1.5 Hz, 9H);13C NMR (101 MHz, MeOD-d4) 6 177.3, 176.0, 171.8, 170.8, 145.8, 144.3, 130.2, 129.1 , 126.2, 126.0, 124.7, 110.4, 69.6, 59.2, 57.7, 56.9, 56.6, 55.6, 54.3, 52.1 , 48.7, 42.3, 37.4, 36.3, 36.0, 35.7, 35.5, 35.2, 30.2, 28.8, 28.1 , 27.6, 27.0, 25.6, 24.2, 21.0, 14.4; LC-MS (ESI): (m / z) = 1090 [M+H]

[0249] N1-(3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)-N4-((S)-1-((2S,4 / ?)-4- hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2-yl)terephthalamide (EPZ031686-VHL-04). General procedure 2D was followed on 15 mg (0.033mmol) scale of the N-((7 / ?,3r;5S)-8-(((1-(3-aminopropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to afford 8 mg (20%) of title compound as a white solid.1H NMR (400 MHz, MeOD-d4) 5 8.98 (s, 1H), 8.59 (d, J = 7.5 Hz, 1 H), 8.28 (d, J = 5.3 Hz, 1 H), 8.02 (d, J = 9.0 Hz, 1 H), 7.98 - 7.89 (m, 5H), 7.53 - 7.35 (m, 5H), 7.30 (s, 1 H), 6.94 (d, J = 2.0 Hz, 1 H), 5.11 - 4.97 (m, 1 H), 4.95 - 4.88 (m, 2H), 4.60 (t, J = 8.5 Hz, 1H), 4.47 (s, 1 H), 4.24 (s, 2H), 4.13 (s, 1 H), 3.95 (d, J = 11.1 Hz, 1 H), 3.81 (d, J =ATTORNEY DOCKET NO. E-202-2024-1 -PC-0110.8 Hz, 1 H), 3.64 (d, J = 12.1 Hz, 2H), 3.52 (d, J = 8.0 Hz, 4H), 3.23 - 3.13 (m, 3H), 3.05 (t, J =12.8 Hz, 2H), 2.48 (s, 3H), 2.35 - 1.90 (m, 19H), 1.67 (dt, J = 21.5, 10.5 Hz, 3H), 1.51 (dd, J = 7.1 , 2.0 Hz, 3H), 1.20 - 1 .05 (m, 9H);13C NMR (101 MHz, MeOD-d4) 6 171 .7, 170.7, 168.5, 167.6, 145.8, 144.3, 137.0, 136.5, 130.2, 129.5, 129.1 , 127.4, 127.2, 126.2, 126.1 , 124.6, 110.3, 69.6, 59.3, 58.2, 56.9, 55.5, 54.5, 52.2, 48.7, 42.3, 37.4, 36.4, 36.3, 35.8, 30.2, 28.9, 28.2, 25.7, 24.2, 21.0, 14.3; HRMS (ESI) calcd for CseHyiCINgC^ (MH+) 1112.4505, found 1112.4497.

[0250] 6-chloro-N-((7R,3r,5S)-8-(((1-(3-(2-(4-(5-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)amino)-5-oxopentyl)-1 H-1 ,2,3-triazol-1 -yl)acetamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dioxoindoline-5-carboxamide (EPZ031686-VHL-05): To a stirred solution of N-((7R,3r,5S)-8-(((1-(3-(2- azidoacetamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2- oxoindoline-5-carboxamide (10 mg, 1 eq, 16 pmol) in DMSO (1 ml_), were added (2S,4R)-1-((S)- 2-(hept-6-ynamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (8.9 mg, 1 eq, 16 pmol) Cui (0.31 mg, 0.1 eq, 1.6 pmol) and Et3N (1.6 mg, 2.2 pL, 1 eq, 16 pmol) at room temperature. The resulting solution was stirred at room temperature for 5h. After completion of the reaction, the crude material was purified by reverse phase chromatography using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to afford 10 mg (52%) of title compound as off white solid.1H NMR (400 MHz, DMSO) 6 11 .31 (s, 1 H), 9.33 (d, J = 52.0 Hz, 1 H), 8.97 (s, 1 H), 8.44 (t, J = 5.9 Hz, 1 H), 7.83 - 7.73 (m, 2H), 7.48 (s, 1 H), 7.42 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 6.97 (s, 1H), 5.01 (s, 2H), 4.90 (t, J = 7.2 Hz, 1 H), 4.50 (d, J = 9.2 Hz, 1 H), 4.40 (t, J = 7.9 Hz, 1 H), 4.26 (s, 1 H), 4.11 (s, 3H), 3.97 (s, 2H), 3.58 (s, 2H), 3.44 (d, J = 11.8 Hz, 2H), 3.27 (d, J = 7.4 Hz, 1 H), 3.12 (dd, JATTORNEY DOCKET NO. E-202-2024-1 -PC-01= 21.2, 6.1 Hz, 4H), 3.01 - 2.90 (m, 4H), 2.59 (d, J = 7.2 Hz, 3H), 2.44 (s, 3H), 2.28 (t, J = 10.9 Hz, 1H), 2.18 - 1.71 (m, 11H), 1.50 (dd, J = 24.5, 11.2 Hz, 6H), 1.36 (d, J = 7.0 Hz, 3H), 0.92 (s, 9H);13C NMR (101 MHz, DMSO) 5 183.2, 172.4, 171.1, 170.0, 166.3, 165.7, 159.9, 151.9, 148.2, 147.0, 145.1 , 140.0, 131.7, 131.6, 130.1, 129.3, 126.8, 125.3, 123.7, 116.7, 113.4, 69.2, 59.0, 56.8, 56.7, 55.4, 54.3, 52.0, 51.9, 48.1, 42.1 , 38.2, 36.6, 35.6, 35.0, 30.1, 29.0, 29.0, 28.3, 26.9, 25.4, 25.2, 24.2, 22.9, 16.4; LC-MS (ESI): (m / z) = 1187 [M+H]

[0251] 6-chloro-N-((7 / ?,3r,5S)-8-(((1-(3-(2-(4-(3-(((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2- (methylamino)propanamido)acetyl)-5-((( / ?)-1,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-3-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1- yl)acetamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2,3- dioxoindoline-5-carboxamide (EPZ031686-IAP-006a), and 6-chloro-N-((7 / ?,3r,5S)-8-(((1-(3- (2-(4-(3-(((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-5-((( / ?)- 1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-3-oxopropyl)-1H-ATTORNEY DOCKET NO. E-202-2024-1 -PC-011,2,3-triazol-1-yl)acetamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-oxoindoline-5-carboxamide (EPZ031686-IAP-06b): To stirred solution of N-((7 / ?,3 / ',5S)-8-(((1-(3-(2-azidoacetamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (20 mg, 1 q, 32 pmol)in DMSO (1 mL), were sequentially added tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-oxo-2-((2S,4S) 4- (pent-4-ynamido)-2-(((F?)-1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1- yl)ethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (26 mg, 1.2 eq, 39 pmol), and Copper(l) iodide (0.61 mg, 0.1 eq, 3.2 pmol) and Et3N (3.3 mg, 4.5 pL, 1 eq, 32 pmol) at room temperature. The resulting mixture was stirred at room temperature for overnight. After completion of the reaction (as indicated by LCMS), the crude material was purified by reverse phase chromatography using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA, the resulting product was used for next step without characterization. The resulting product was dissolved in 20% TFA in DCM (1 mL) and stirred at room temperature for 1 h. After completion of the reaction (as indicated by LCMS), the crude material was purified by reverse phase chromatography using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to give the title compound as an inseparable mixture with combined 11 mg (29%).1H NMR (400 MHz, CD3OD) 6 8.39 (dd, J = 21.1, 6.6 Hz, 4H), 7.81 (s, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.37 (d, J = 7.1 Hz, 2H), 7.17 - 7.02 (m, 8H), 6.95 (dd, J = 4.2, 1.5 Hz, 1 H), 5.04 (d, J = 6.9 Hz, 3H), 4.52 - 4.37 (m, 7H), 4.23 (s, 7H), 4.13 (s, 2H), 3.88 (q, J = 6.9 Hz, 3H), 3.62 - 3.46 (m, 8H), 3.35 (d, J = 6.7 Hz, 5H), 3.12 (s, 7H), 3.01 (q, J = 9.8 Hz, 10H), 2.78 (dd, J = 11.2, 6.5 Hz, 5H), 2.66 (d, J = 1.6 Hz, 8H), 2.55 (dt, J = 36.5, 7.3 Hz, 7H), 2.35 - 1.56 (m, 39H), 1.55 - 1.44 (m, 8H), 1.38 - 1.00 (m, 14H); LC-MS (ESI): (m / z) = 1198 [M+H] and LC-MS (ESI): (m / z) = 1184 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0252] 6-chloro-N-((7 / ?,3r,5S)-8-(((1-(3-(4-((4-(((3S,5S)-1-((S)-2-cyclohexyl-2-((S)-2- (methylamino)propanamido)acetyl)-5-((( / ?)-1,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-3-yl)carbamoyl)phenyl)buta-1,3-diyn-1- yl)benzamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2,3- dioxoindoline-5-carboxamide (EPZ031686-IAP-10): To a stirred solution of the tert-butyl ((S)- 1-(((S)-2-((2S,4S)-4-(4-((4-((3-(4-((((7 / ?,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)propyl)carbamoyl)phenyl)buta-1 ,3- diyn-1-yl)benzamido)-2-((( ?)-1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1- cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (25 mg, 1 eq, 18 pmol), in DMF (0.5 mL), were added Cupric acetate, monohydrate (0. 36 mg, 0.1 eq, 1.8 pmol), and K2CO3 (0.18 mg, 0.1 eq, 1.8 pmol) at room temperature. After completion of the reaction (as indicated by LCMS), the crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% trifluoracetic acid, after lyophilization of the solvent, product was used dissolved in 20% TFA in DCM (1 mL) and stirred at room temperature for 1h. After completion of the reaction (as indicated by LCMS), the volatiles were removed under pressure and crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% trifluoracetic acid to give title product 15 mg (65%) as pale yellow solid.1H NMR (500 MHz, DMSO-de) 0 11.29 (s, 1 H), 9.29 (d, J = 58.2 Hz, 1 H), 9.00 (d, J = 7.8 Hz, 1 H), 8.91 - 8.68 (m, 5H), 8.52 (d, J = 8.6 Hz, 1H), 8.30 (d, J = 4.7 Hz, 1 H), 7.84 (t, J = 8.0 Hz, 4H), 7.68 (t, J = 7.2 Hz, 4H), 7.43 (s, 1 H), 7.26 (d, J = 7.6 Hz, 1 H), 7.12 - 7.06 (m, 1H), 7.04 (t, J = 7.2 Hz, 2H), 6.93 (s, 1H), 4.95 - 4.87 (m, 1 H), 4.51 (p, J = 6.9 Hz, 1 H), 4.33 (dt, J = 16.0, 7.9 Hz, 2H), 4.05 (d, J = 13.6 Hz, 3H), 3.92 (q, J = 6.4 Hz, 1 H), 3.80 (d, J = 6.6 Hz, 1 H), 3.60 - 3.19 (m, 15H), 3.15 - 2.87 (m, 6H), 2.75 - 2.62 (m, 2H), 2.12 - 1.96 (m, 8H), 1.94 - 1.39 (m, 20H), 1.26 (d, J = 6.9 Hz, 4H), 1.17 - 0.88 (m, 6H).13C NMR (126 MHz, DMSO-de) 6 183.2, 171.7, 169.9, 169.1 , 166.0, 165.7, 165.2, 160.0, 152.0, 140.0, 137.7, 137.5, 135.7, 135.3, 133.1 , 132.9, 131.8, 129.1, 128.8, 128.2, 128.0, 127.2, 126.1 , 125.3, 123.6,123.4, 118.9, 116.7, 116.5, 113.4, 82.5, 75.5, 75.4, 59.0, 56.6, 56.3, 55.9, 55.4, 54.6, 53.3, 51.9, 49.1, 47.3, 42.1 , 37.1 , 36.6, 34.5, 31.2, 30.2, 30.2, 29.2, 29.0, 28.9, 28.6, 28.3, 26.2, 26.2, 26.0,24.4, 20.7, 16.2; LC-MS (ESI): (m / z) = 1289 [M+H]ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0253] 6-chloro-N-((7 / ?,3r,5S)-8-(((1-(3-(4-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethyl)carbamoyl)phenyl)buta-1 ,3-diyn-1- yl)benzamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2,3- dioxoindoline-5-carboxamide (EPZ031686-CRBN-04): To a stirred solution of the oxindole 6- chloro-N-((7 / ?,3r,5S)-8-(((1-(3-(4-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4- yl)amino)ethyl)carbamoyl)phenyl)buta-1 ,3-diyn-1-yl)benzamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxoindoline-5-carboxamide (8 mg, 1 eq, 7 pmol), in DMF (0.5 ml_), were added Cupric acetate, monohydrate (0.1 mg, 0.08 pL, 0.1 eq, 0.7 pmol), and K2CO3 (0.1 mg, 0.1 eq, 0.7 pmol) at room temperature. After completion of the reaction (as indicated by LCMS), the crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 5.5 mg (70%) as pale yellow solid. LC-MS (ESI): (m / z) = 1122 [M+H],

[0254] 6-chloro-2,3-dioxo-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide (EPZ031686-SD1): The oxindole EPZ031686 (40 mg, 1 Eq, 68 pmol) was dissolved in DMF (1 mL), was added CU(OAC)2*H2O (10 mol%) , K2CO3 (10 mol%) at room temperature and filled with oxygen gas using an oxygen balloon. The reaction mixture was stirred at 50 °C under oxygen atmosphere for 1h. After completion of the reaction (as indicated by LCMS), the reaction mixture was allowed toATTORNEY DOCKET NO. E-202-2024-1 -PC-01 cool to room temperature and the crude material was purified by reverse phase chromatography without workup using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to give the title compound 35 mg (85%) as pale yellow solid. LC-MS (ESI): (m / z) = 605 [M+H],

[0255] (Z)-6-chloro-3-((3,5-dimethyl-1 H-pyrrol-2-yl)methylene)-2-oxo-N-((1 R,3r,5S)-8-(((1- (4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide (EPZ031686-SD2): The oxindole EPZ031686 (20 mg, 1 eq, 34 pmol) and 3,5- dimethyl-1 H-pyrrole-2-carbaldehyde (5.0 mg, 1.2 eq, 41 pmol) was dissolved in ethanol (2 ml_), was added piperidine (2.9 mg, 3.3 pL, 1 eq, 34 pmol) at room temperature. The reaction mixture was stirred at 70 °C 2h. After completion of the reaction (as indicated by LCMS), the reaction mixture was allowed to room temperature and the crude material was purified by reverse phase chromatography without workup using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 35 mg (85%) as pale yellow solid; HRMS (ESI) calcd for C33H40N5O4SCIF3+[M-H]+ 694.2442 found 694.2449.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0256] (Z)-6-chloro-3-(hydroxyimino)-2-oxo-N-((1 R,3r,5S)-8-(((1 -(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide (EPZ031686-SD3): A solution of EPZ031686-SD1 (12 mg, 1 eq, 20 pmol) in water (1 ml_), was added hydroxylamine hydrochloride (2.1 mg, 1.5eEq, 30 pmol) at room temperature and was heated to 75 °C for 30 min, then sodium acetate (4.9 mg, 3.0 eq, 59 pmol) was added in and the solution was continued to reflux for another 30 min. The mixture was cooled down to room temperature and purified by reverse phase chromatography without workup using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 8 mg (70 %) as off white solid; LC-MS (ESI): (m / z) = 620 [M+H],

[0257] 6-chloro-2,3-dioxo-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide (EPZ031686-SD1 or SD1): The EPZ031686 (40 mg, 0.068 mmol) was dissolved in DMF (1 ml_), was added Cu(OAc)2«H2O (1 .2 mg, 0.0068 mmol) , K2CO2(9.3 mg, 0.068) at room temperature and filled with oxygen gas using an oxygen balloon. The reaction mixture was stirred at 50 °C under oxygen atmosphere for 1 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was allowed to room temperature and the crude material was purified by reverse phase chromatography without workup using a gradient of 10-55% acetonitrile in water with the addition of 0.05% TFA to give the title compound 35 mg (85%, 0.057 mmol) as pale yellow solid.1H NMR (500 MHz, DMSO) 5 11.35 (d, J = 4.1 Hz, 1 H), 9.45 (s, 1 H), 8.37 (d, J = 4.8 Hz, 1 H), 7.50 (s, 1 H), 7.00 (d, J = 1.4 Hz, 1 H), 4.14 (p, J = 3.1 Hz, 2H), 3.99 (d, J = 6.0 Hz, 1 H), 3.51 (d, J = 12.2 Hz, 2H), 3.10 (dd, J = 13.7, 6.7 Hz, 3H), 2.99 (d, = 11.2 Hz, 2H), 2.43 - 2.30 (m, 3H), 2.16 - 2.04 (m, 7H), 1.99 - 1.83 (m, 8H), 1.52 (q, J = 12.4 Hz, 2H);13C NMR (126 MHz, DMSO) 5 183.2,165.7, 160.0, 152.0, 140.0, 131.8, 128.7, 126.6, 125.3, 116.7, 113.4, 56.5, 55.4, 55.0, 51.9, 48.2,30.7, 30.4, 30.2, 30.1 , 30.0, 29.0, 28.3, 25.6, 17.0, 17.0; LC-MS (ESI): (m / z) = 605 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0258] (Z)-6-chloro-3-(hydroxyimino)-2-oxo-N-((1 R,3r,5S)-8-(((1 -(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide (EPZ031686-SD3 or SD3): A solution of EPZ031686-SD1 (12 mg, 0.02 mmol) in water (1 mL), was added hydroxylamine hydrochloride (2.1 mg, 0.03 mmol) at room temperature and was heated to 75 °C for 30 min, then sodium acetate (4.9 mg, 0.059 mmol) was added in and the solution was continued to reflux for another 30 min. The mixture was cooled down to room temperature, and purified by reverse phase chromatography without workup using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 8 mg (70 %, 0.014 mmol) as off white solid;1H NMR (500 MHz, CD3OD_SPE) 5 8.39 (d, J = 5.3 Hz, 1 H), 8.07 (s, 1 H), 6.99 (s, 1 H), 4.24 (s, 3H), 4.18 - 4.10 (m, 2H), 3.61 (s, 3H), 3.22 - 3.12 (m, 6H), 3.08 (d, J = 27.7 Hz, 3H), 2.30 (ddt, J = 14.5, 6.6, 4.1 Hz, 6H), 2.15 (t, = 7.1 Hz, 3H), 2.03 (ddd, J = 18.8, 12.1 , 4.0 Hz, 8H);13C NMR (126 MHz, CD3OD_SPE) 5 168.0, 165.8, 161.8, 144.2, 143.0, 134.2, 130.4, 127.9, 127.3, 125.7, 118.0, 115.7, 114.8, 111.3, 56.9, 55.6, 52.3, 42.4, 36.2, 30.3, 30.0, 28.8, 28.2, 17.0; LC-MS (ESI): (m / z) = 620 [M+H],

[0259] (Z)-6-chloro-3-(methoxyimino)-2-oxo-N-((1 R,3r,5S)-8-(((1-(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide ((EPZ031686-SD4 or SD4): A solution of EPZ031686-SD1 (16 mg, 0.026 mmol) in methanol (1 mL), was added O-methylhydroxylamine hydrochloride (4.4 mg, 0.053 mmol) and K2HPO4 (13.8 mg, 0.079 mmol) at R. After stirred for 2 h at ambient temperature, the solvent was removed in vacuo and purified by reverse phase chromatography without workup using a gradientATTORNEY DOCKET NO. E-202-2024-1 -PC-01 of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 7 mg (41 %, 0.0106 mmol) as off white solid. LC-MS (ESI): (m / z) = 634 [M+H],General Procedure 2E for SD2, SD5, SD12, SD13, SD14, SD15, SD16:

[0260] The EPZ031686 (20mg, 0.034 mol) and carbaldehyde (5 mg, 0.041 mmol) was dissolved in ethanol (2 ml_), was added piperidine (3.3 pL, 0.034 mmol) at room temperature. The reaction mixture was stirred at 70 °C 2h. After completion of the reaction (as indicated by LCMS), the reaction mixture was allowed to cool to RT and the crude material was purified by reverse phase chromatography without workup to give pure product.

[0261] (Z)-6-chloro-3-((3,5-dimethyl-1 H-pyrrol-2-yl)methylene)-2-oxo-N-((1R,3r,5S)-8-(((1- (4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide (EPZ031686-SD2 or SD2): General procedure 2E was followed on 20 mg (0.034mmol) scale of the EPZ031686. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 35 mg (85%, 0.0289 mmol) as pale yellow solid; HRMS (ESI) calcd for C33H40N5O4SCIF3+[M-H] + 694.2442 found 694.2449.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0262] (Z)-6-chloro-3-((4-methyl-1H-imidazol-5-yl)methylene)-2-oxo-N-((1R,3r,5S)-8-(((1- (4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide (EPZ031686-SD5 or SD5): General procedure 2E was followed on 30 mg (0.051 mmol) scale of the EPZ031686. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to give the title compound 28 mg (81 %, 0.041 mmol) as pale yellow solid;1H NMR (500 MHz, CD3OD_SPE) 6 8.85 (s, 1 H), 8.82 (s, 1 H), 7.94 (s, 1 H), 7.77 (s, 1 H), 7.62 (s, 1 H), 7.41 (s, 1 H), 6.90 (s, 1 H), 6.78 (s, 1 H), 4.24 (s, 4H), 4.18 - 4.09 (m, 2H), 3.68 - 3.59 (m, 3H), 3.21 - 3.11 (m, 7H), 3.04 (t, J = 12.9 Hz, 4H), 2.57 (s, 3H), 2.42 (s, 2H), 2.36 - 2.18 (m, 12H), 2.13 - 1.95 (m, 12H), 1.80 - 1.63 (m, 4H);13C NMR (126 MHz, CD3OD_SPE) 5 169.7, 168.2, 142.1 , 135.4, 133.5, 131.8, 130.6, 127.9, 125.7, 125.2, 124.8, 122.5, 120.7, 119.9, 111.1 , 56.8, 55.6, 55.6, 55.4, 52.2, 42.5, 42.4, 36.4, 36.2, 30.6, 30.3, 30.1 , 29.8, 28.7, 28.2, 16.9, 8.8, 8.4, 8.3. LC-MS (ESI): (m / z) = 683 [M+H],

[0263] 6-chloro-2-oxo-3-(pyridin-4-ylmethylene)-N-((1 R,3r,5S)-8-(((1 -(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide (EPZ031686-SD12 or SD12): General procedure 2E was followed on 30 mg (0.051 mmol) scale of the EPZ031686. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to give the title compound 22 mg (64%, 0.032 mmol) as pale yellow solid;1H NMR (500 MHz, CD3OD_SPE) 68.67 (s, 3H), 8.59 (s, 4H), 7.84 (d, J = 5.0 Hz, 3H), 7.72 (s, 1 H), 7.65 (d, J = 4.9 Hz, 2H), 7.39 (s, 1 H), 6.99 (s, 1 H), 4.21 (d, J = 25.2 Hz, 4H), 4.03 (t, J = 6.9 Hz, 1 H), 3.39 (d, J = 12.2 Hz, 3H), 3.16 - 3.08 (m, 4H), 2.94 (q, J = 7.3 Hz, 3H), 2.76 (s, 3H), 2.34 - 2.12 (m, 7H), 2.10 - 1.87 (m, 11 H), 1.64 (p, J = 14.6 Hz, 4H);13C NMR (126 MHz, CD3OD_SPE) 6 169.0, 168.3, 167.9, 149.6, 148.9, 148.8, 145.3, 143.6, 133.7, 133.6, 129.8, 129.4, 129.2, 128.1 , 125.9, 123.4, 123.1 , 123.0, 120.8, 119.3, 111.6, 110.6, 57.0, 55.6, 55.5, 52.2, 44.3, 42.5, 42.4, 36.4, 36.1 , 30.8, 30.6, 30.3, 29.2, 28.2, 28.2, 22.4, 21.7, 17.6; LC-MS (ESI): (m / z) = 680 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0264] 6-chloro-2-oxo-3-(pyrimidin-5-ylmethylene)-N-((1R,3r,5S)-8-(((1 -(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide (EPZ031686-SD13 or SD13): General procedure 2E was followed on 35 mg (0.059mmol) scale of the EPZ031686. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to give the title compound 29 mg (72%, 0.042 mmol) as pale yellow solid.1H NMR (500 MHz, CD3OD_SPE) 5 9.48 (s, 2H), 9.24 - 9.02 (m, 3H), 7.73 (s, 1 H), 7.69 (d, J = 5.6 Hz, 1 H), 7.38 (s, 1H), 6.98 (s, 1 H), 6.90 (s, 1 H), 4.28 - 4.11 (m, 5H), 4.04 (d, J = 7.0 Hz, 1 H), 3.10 (dt, J = 26.3, 5.7 Hz, 13H), 2.65 (t, J = 7.9 Hz, 4H), 2.41 - 2.14 (m, 11 H), 2.09 - 1.99 (m, 13H), 1.88 - 1.74 (m, 8H), 1.69 (dd, J = 7.0, 4.4 Hz, 2H), 1.51 (q, J = 12.5 Hz, 4H);13C NMR (126 MHz, DMSO) 5 168.3, 167.4, 166.9, 166.3, 159.0, 158.9, 158.8, 158.6, 158.4, 158.4, 157.2,145.5, 143.1 , 133.2, 131.6, 131.0, 130.5, 129.9, 129.7, 129.4, 129.3, 128.5, 127.0, 123.2, 123.1 ,121.6, 119.4, 119.0, 116.6, 111.8, 110.7, 57.3, 55.3, 52.7, 49.1 , 42.2, 42.1 , 36.8, 36.5, 31.1 , 30.9,30.6, 30.4, 28.5, 28.4, 22.6, 22.1; LC-MS (ESI): (m / z) = 681 [M+H],

[0265] 6-chloro-2-oxo-3-(pyridin-3-ylmethylene)-N-((1 R,3r,5S)-8-(((1 -(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide (EPZ031686-SD14 or SD14). General procedure 2E was followed on 20 mg (0.034mmol) scale of the EPZ031686. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to give the title compound 8 mg (52%, 0.0176 mmol) as pale yellow solid.1H NMR (500 MHz, CD3OD_SPE) 5 8.12 (dt, J = 7.8, 2.0 Hz, 1 H), 7.80 - 7.73 (m, 2H), 7.43 (s, 1H), 6.98 (s, 1 H), 4.23 (s, 2H), 4.20 - 4.12 (m, 3H), 4.07 - 4.01 (m, 1 H), 3.16 - 3.02 (m, 10H), 2.62 (t, J = 7.9 Hz, 4H), 2.36 - 2.16 (m, 13H), 1.99 (ddd, J = 30.3, 21.4, 13.7 Hz, 18H), 1.86 -ATTORNEY DOCKET NO. E-202-2024-1 -PC-011.73 (m, 4H), 1.69 (q, J= 5.9 Hz, 1 H), 1.59 - 1.45 (m, 4H);13C NMR (126 MHz, CD3OD_SPE) 5169.1 , 167.9, 149.8, 149.0, 145.0, 139.0, 137.0, 133.6, 133.1 , 129.2, 128.5, 123.4, 122.5, 120.3, 119.6, 111.5, 57.6, 56.4, 55.5, 55.5, 52.6, 44.3, 42.5, 42.4, 36.4, 36.1 , 30.9, 30.7, 30.4, 28.2, 28.1 , 22.4, 21.7, 18.4; LC-MS (ESI): (m / z) = 680 [M+H],

[0266] 6-chloro-3-(4-cyano-5-fluoro-2-methoxybenzylidene)-2-oxo-N-((1R,3r,5S)-8-(((1- (4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline- 5-carboxamide (EPZ031686-SD15 or SD15). General procedure 2E was followed on 40 mg (0.068 mmol) scale of the EPZ031686. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-70% acetonitrile in water with the addition of 0.05% TFA to give the title compound 35 mg (69%, 0.046 mmol) as pale yellow solid.1H NMR (500 MHz, CD3OD_SPE) 5 7.91 (s, OH), 7.70 - 7.61 (m, 2H), 7.50 (d, J = 5.0 Hz, 1 H), 7.38 (d, J = 5.2 Hz, OH), 7.32 (s, 1H), 6.98 (s, 1 H), 6.91 (s, OH), 4.21 (d, J = 21.0 Hz, 4H), 4.09 - 4.04 (m, 1 H), 3.95 (s, 1 H), 3.91 (s, 3H), 3.04 (dd, J = 12.7, 5.8 Hz, 3H), 2.97 (d, J = 11.6 Hz, 3H), 2.49 - 2.42 (m, 3H), 2.30 - 1.91 (m, 17H), 1.80 - 1.70 (m, 3H), 1.50 - 1.39 (m, 3H);13C NMR (126 MHz, CD3OD_SPE) 6 169.1 , 167.9, 145.0, 133.3, 130.6, 129.2, 128.9, 123.1, 119.5,117.1 , 116.9, 115.0, 113.2, 111.5, 102.1 , 57.8, 56.8, 56.0, 55.5, 52.9, 42.5, 36.1 , 31.9, 31.0, 30.9,28.1, 18.8; . LC-MS (ESI): (m / z) = 752 [M+H],

[0267] (E)-6-chloro-3-(cyclopropylmethylene)-2-oxo-N-((1R,3r,5S)-8-(((1 -(4,4,4- trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5- carboxamide (EPZ031686-SD16 or SD16): General procedure 2E was followed on 30 mg (0.051 mmol) scale of the EPZ031686. After the completion of the reaction, crude material wasATTORNEY DOCKET NO. E-202-2024-1 -PC-01 purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 18 mg (55%, 0.028 mmol) as pale yellow solid.1H NMR (500 MHz, CD3OD_SPE) 58.32 (d, J = 5.3 Hz, 1 H), 7.76 (s, 1 H), 7.43 (s, OH), 6.94 (s, 1H), 6.87 (s, OH), 6.38 (d, J = 11.4 Hz, 1 H), 4.23 (s, 3H), 4.20 - 4.05 (m, 2H), 3.62 (d, J = 12.3 Hz, 3H), 3.25 - 2.93 (m, 8H), 2.39 - 2.11 (m, 14H), 2.10 - 1.93 (m, 10H), 1.74 - 1.51 (m, 3H), 1.28 (dd, J = 7.6, 2.8 Hz, 2H), 1.19 (dq, J = 7.0, 4.3 Hz, 1 H), 0.97 - 0.89 (m, 2H), 0.86 - 0.80 (m, 1 H);13C NMR (126 MHz, CD3OD_SPE) 6 169.8, 169.5, 168.7, 168.5, 151.3, 149.8, 143.0, 141.0, 130.4, 130.1 , 129.7, 129.4, 129.3, 127.9, 125.7, 124.4, 123.7, 122.8, 122.6, 121.7, 118.8, 110.7, 110.2, 56.8, 55.6, 55.6, 55.4, 52.3, 42.4, 42.3, 36.3, 36.3, 30.3, 30.1 , 30.1 , 28.8, 28.1 , 28.1 , 16.9, 16.9, 13.1 , 12.2, 9.9, 9.6; LC-MS (ESI): (m / z) = 643 [M+H],General Procedure 2F for SD17, SD18, SD19, SD20, and SD21

[0268] A stirred solution of N-((7R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (30, 0.056 mmol) in DMF (2 mL), were sequentially added corresponding carboxylic acid (7.5 mg, 0.061 mmol), HATU (31.9 mg, 0.085 mmol) and DIPEA (0.029 mL, 0.168 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h to 4h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to get pure product.

[0269] 6-chloro-2-oxo-N-((1 R,3r,5S)-8-(((1-(3-(picolinamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide (EPZ031686-SD17 or SD17): General procedure 2F was followed on 30 mg (0.056 mmol) scale of the EPZ031686-SD. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 21 mg (59%, 0.33 mmol) as white solid.1H NMR (500 MHz,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01CD3OD_SPE) 5 8.63 (d, J = 4.8 Hz, 1 H), 8.10 (d, J = 7.8 Hz, 1 H), 7.97 (td, J = 7.8, 1.7 Hz, 1 H), 7.56 (dd, J = 7.6, 4.8 Hz, 1H), 7.30 (s, 1 H), 6.94 (s, 1 H), 4.23 (s, 2H), 4.12 (t, J = 7.0 Hz, 1 H), 3.62 (d, J = 12.3 Hz, 2H), 3.54 (d, J = 7.4 Hz, 4H), 3.21 - 3.12 (m, 4H), 3.03 (t, J = 12.5 Hz, 2H), 2.28 (dq, J = 12.8, 4.0 Hz, 5H), 2.14 (t, J = 7.1 Hz, 2H), 2.11 - 1.96 (m, 8H), 1.66 (q, J = 13.5 Hz, 2H);13C NMR (126 MHz, CD3OD_SPE) 5 178.1, 178.0, 168.5, 166.3, 150.8, 148.5, 145.8, 137.5, 130.2, 129.5, 128.5, 126.6, 124.9, 124.8, 124.7, 124.6, 124.6, 121.9, 120.7, 110.4, 56.9, 55.6, 54.5, 52.2, 42.3, 36.3, 35.9, 35.1, 30.2, 28.9, 28.2, 24.3. LC-MS (ESI): (m / z) = 643 [M+H],

[0270] 6-chloro-N-((1R,3r,5S)-8-(((1-(3-(nicotinamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxoindoline-5-carboxamide (EPZ031686-SD18 or SD18). General procedure 2F was followed on 30 mg (0.056 mmol) scale of the EPZ031686-SD. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 16 mg (45%, 0.025 mmol) as white solid. LC-MS (ESI): (m / z) = 643 [M+H],

[0271] N-((1R,3r,5S)-8-(((1-(3-([1,1'-biphenyl]-4-carboxamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (EPZ031686-SD19 or SD19): General procedure 2F was followed on 25 mg (0.046 mmol) scale of the EPZ031686-SD. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-60% acetonitrile in water with the addition of 0.05% TFA to give the title compound 21 mg (63%, 0.29 mmol) as white solid.1H NMR (500 MHz, CD3OD_SPE) 5 8.28 (d, J = 5.3 Hz, 1H), 7.96 - 7.90 (m, 2H), 7.77 - 7.71 (m, 2H), 7.69 - 7.63 (m, 2H), 7.50 - 7.42 (m, 2H), 7.42 - 7.35 (m, 1 H), 7.29 (d, J = 1.2 Hz, 1 H), 6.94 (s, 1 H), 4.24 (s, 2H), 4.13 (q, J = 6.4 Hz, 1 H), 3.64 (d, J = 12.8 Hz, 2H), 3.53 (d, J = 4.2 Hz, 4H), 3.22 - 3.13 (m,ATTORNEY DOCKET NO. E-202-2024-1 -PC-014H), 3.09 - 3.00 (m, 2H), 2.34 - 2.25 (m, 6H), 2.15 (q, J = 7.0 Hz, 2H), 2.11 - 1.91 (m, 7H), 1.69 (q, J = 13.5 Hz, 2H);13C NMR (126 MHz, CD3OD_SPE) 5 178.0, 169.3, 168.5, 145.7, 144.7, 139.7, 132.2, 130.2, 129.5, 128.7, 127.8, 127.6, 126.7, 124.9, 124.6, 110.4, 56.9, 55.6, 54.4, 52.2, 42.3, 36.3, 35.1 , 30.2, 28.9, 28.2, 24.4; LC-MS (ESI): (m / z) = 718 [M+H],

[0272] 6-chloro-N-((1R,3r,5S)-8-(((1-(3-(4-chlorobenzamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-oxoindoline-5-carboxamide(EPZ031686-SD20 or SD20): General procedure 2F was followed on 25 mg (0.046 mmol) scale of the EPZ031686-SD. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TEA to give the title compound 20 mg (64%, 0.029 mmol) as white solid;1H NMR (500 MHz, DMSO) 6 7.84 - 7.78 (m, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.16 (s, 1 H), 6.78 (s, 1 H), 4.08 - 4.03 (m, 2H), 3.90 (t, J = 6.9 Hz, 1H), 3.43 (d, J = 11.5 Hz, 3H), 3.26 (q, J = 6.0 Hz, 3H), 3.12 - 2.96 (m, 5H), 2.96 - 2.85 (m, 2H), 2.18 - 1.97 (m, 7H), 1.94 - 1.75 (m, 8H), 1.47 (t, J = 13.2 Hz, 2H);13C NMR (126 MHz, DMSO) 6 176.9, 176.9, 176.8, 176.7, 176.7, 167.0, 166.9, 165.9, 165.9, 158.7, 158.4, 146.1 , 146.1 , 146.0, 146.0, 145.9, 145.9, 136.6, 133.5, 133.4, 130.1 , 130.1 , 130.1, 129.6, 129.6, 128.8, 125.4, 125.3, 125.3, 125.2, 125.1 , 125.1 , 125.0, 110.2, 110.1 , 67.5, 56.6, 55.4, 54.5,54.5, 51.8, 51.8, 48.1 , 42.0, 41.9, 37.0, 36.9, 36.7, 36.6, 35.7, 30.2, 30.2, 29.0, 29.0, 28.3, 27.2,25.6, 24.5, 24.4; LC-MS (ESI): (m / z) = 676 [M+H],

[0273] 6-chloro-2-oxo-N-((1 R,3r,5S)-8-(((1-(3-(pyrimidine-5-carboxamido)propyl)piperidin- 4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)indoline-5-carboxamide (EPZ031686-SD21 or SD21): General procedure 2F was followed on 25 mg (0.046 mmol) scale of the EPZ031686-SD. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-50% acetonitrile in water with the addition of 0.05% TFA to give the title compound 18 mg (60%, 0.027 mmol) as white solid;1H NMR (500 MHz,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01CD3OD_SPE) 5 9.28 (s, 1H), 9.17 (s, 2H), 7.29 (d, J = 1.3 Hz, 1 H), 6.94 (s, 1 H), 4.23 (s, 2H), 4.12 (t, J = 7.0 Hz, 1 H), 3.64 (d, J = 12.3 Hz, 2H), 3.53 (d, J = 6.7 Hz, 4H), 3.23 - 3.18 (m, 2H), 3.14 (d, J = 5.9 Hz, 2H), 3.08 - 2.99 (m, 2H), 2.33 - 2.23 (m, 6H), 2.15 (t, J = 7.0 Hz, 2H), 2.12 - 1.97 (m, 7H), 1.69 (q, J = 13.4 Hz, 2H);13C NMR (126 MHz, CD3OD_SPE) 5 178.1 , 168.5, 165.0,161.3, 161.0, 159.8, 155.8, 145.8, 130.2, 129.5, 127.9, 124.8, 124.7, 110.4, 56.9, 55.6, 54.5, 52.2,42.3, 36.5, 36.3, 30.2, 28.8, 28.2, 24.1 ; LC-MS (ESI): (m / z) = 644 [M+H],General Procedure 2G for SD6-8

[0274] A stirred solution of (1 R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-amine (40 mg, 0.1 mmol) in DMF (2.5 mL), were sequentially added corresponding carboxylic acid (30 mg, 0.15 mmol), HOBt (30 mg, 0.2 mmol), EDC (38 mg, 0.2 mmol) and TEA (41 pL, 0.3 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h to 4h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was purified by reverse phase chromatography without workup to get pure product.

[0275] 2-cyclopropyl-N-((1 R,3r,5S)-8-(((1 -(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)benzo[d]oxazole-5-carboxamide(EPZ031686-SD6 or SD6). General procedure 2G was followed on 40 mg (0.1 mmol) scale of the (1 R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan- 3-amine. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA to give the title compound 48 mg (79%, 0.079 mmol) as white solid.1H NMR (500 MHz, DMSO) 5 8.54 (d, J = 5.0 Hz, 1H), 7.94 (dd, J = 7.4, 2.1 Hz, 1 H), 7.58 (dtd, J = 16.3, 7.4, 1.7 Hz, 2H), 7.32 (s, 1 H), 4.15 (q, J = 4.2 Hz, 2H), 4.05 (tdt, J = 6.9, 4.8, 2.4 Hz, 1 H), 3.04 (d, J = 6.0 Hz, 2H), 2.81 (d, J = 11.1 Hz, 2H), 2.35 - 2.20 (m, 4H), 2.13 - 2.00 (m, 6H), 1.99 - 1.76 (m, 7H), 1.63 (p, J = 7.3 Hz, 2H), 1.30 (qd, J = 12.0, 3.7 Hz, 2H);13C NMR (126 MHz, DMSO) 5 167.6, 160.0,ATTORNEY DOCKET NO. E-202-2024-1 -PC-01158.9, 132.8, 131.5, 131.4, 130.5, 129.4, 128.5, 127.2, 125.5, 104.2, 57.6, 56.7, 55.3, 53.2, 42.4,36.2, 32.4, 31.8, 31.0, 30.8, 28.7, 19.5; LC-MS (ESI): (m / z) = 583 [M+H],

[0276] 5-cyclopropyl-N-((1 R,3r,5S)-8-(((1 -(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (EPZ031686-SD7 orSD7): General procedure 2G was followed on 35 mg (0.088 mmol) scale of the (1R,3r,5S)- 8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA to give the title compound 30 mg (64%, 0.056 mmol) as white solid. LC-MS (ESI): (m / z) = 533 [M+H],

[0277] 5-(2-chlorophenyl)-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide (EPZ031686- SD8 or SD8): General procedure 2G was followed on 40 mg (0.1 mmol) scale of the (1 R,3r,5S)- 8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-amine. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA to give the title compound 43 mg (71%, 0.071 mmol) as white solid.1H NMR (500 MHz, DMSO) 5 8.54 (d, J - 5.0 Hz, 1 H), 7.94 (dd, J = 7.4, 2.1 Hz, 1 H), 7.71 (dd, J = 7.8, 1.6 Hz, 1 H), 7.58 (dtd, J = 16.3, 7.4,1.7 Hz, 2H), 7.32 (s, 1H), 4.15 (q, = 4.2 Hz, 2H), 4.05 (tdt, J = 6.9, 4.9, 2.3 Hz, 1 H), 3.04 (d, J = 6.0 Hz, 2H), 2.81 (d, J = 11.0 Hz, 2H), 2.25 (dddd, J = 27.9, 16.1 , 13.3, 7.7 Hz, 4H), 2.08 (dddd, J = 25.9, 17.1 , 9.4, 3.3 Hz, 6H), 1.98 - 1.75 (m, 7H), 1.63 (p, J = 7.3 Hz, 2H), 1.30 (qd, J = 11.9,3.7 Hz, 2H);13C NMR (126 MHz, DMSO) 5 167.6, 160.0, 158.9, 132.8, 131.5, 131.4, 130.5, 128.5, 125.5, 104.2, 57.6, 56.7, 55.3, 53.2, 42.4, 32.4, 31.8, 31.0, 28.7, 19.5; LC-MS (ESI): (m / z) = 603 [M+H],Synthesis of EPZ031686-SD9, Scheme 1 :ATTORNEY DOCKET NO. E-202-2024-1 -PC-0110278] benzyl 4-((((1R,4R,5S)-5-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptan-2- yl)sulfonyl)methyl)piperidine-1-carboxylate: To stirred solution of tert-butyl (6- aminospiro[3.3]heptan-2-yl)carbamate (250.0 mg, 1.105 mmol) in DCM (5 mL), were added Et3N (0.6 mL, 4.4 mmol), and benzyl 4-((chlorosulfonyl)methyl)piperidine-1-carboxylate (403 mg, 1.2 mmol) in DCM (2 ml) at 0 °C. The resulting mixture was stirred at RT for overnight. After the completion of the reaction, it was quenched with water (10 mL), and extracted with DCM (100 mL x 2). The solvent was removed under vacuum and the crude material was purified by silica gel flash chromatography using a gradient of 0-5% MeOH in DCM to give the title compound 500 mg (86%, 0.94 mmol) as white solid ; LC-MS (ESI): (m / z) = 522 [M+H-Boc],

[0279] tert-butyl ((1 R,4R,5S)-2-(((1 -(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-2- azabicyclo[2.2.1]heptan-5-yl)carbamate: To a stirred solution of the of benzyl 4-((((1 R,4R,5S)- 5-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)sulfonyl)methyl)piperidine-1- carboxylate (500 mg, 0.98 mmol) in AcOH (10 ml_), was added Pd / C (50 mg, 10%w / w) at RT. The resulting solution was stirred at RT for 4 h under hydrogen pressure (hydrogen balloon was used for hydrogen pressure). After complete consumption of starting material, the reaction mixture was filtered to remove the solids and filtrate was concentrated to get the crude product which was pure enough and used for the next step without purification. To a stirred solution of the tert-butyl (6-- U S -ATTORNEY DOCKET NO. E-202-2024-1 -PC-01((piperidin-4-ylmethyl)sulfonamido)spiro[3.3]heptan-2-yl)carbamate (380 mg, 0.98 mmol) in DMF (5 mL), were added 1 ,1 ,1 ,5,5,5-hexafluoropentane (521 mg, 2.89 mmol), Et3N (0.4 pL, 2.89 mmol) and DMAP (11 mg, 0.096 mmol) at RT. The resulting solution was stirred at RT for overnight. After the completion of the reaction, it was quenched with water (20 mL), and extracted with EA (100 mLx 2). The solvent was removed under vacuum and the crude material was purified by silica gel flash chromatography using a gradient of 0-5% MeOH in DCM to give the title compound 350 mg (72%, 0.70 mmol) as white solid.1H NMR (500 MHz, CDCh) 3 4.86 (d, J = 8.8 Hz, 1 H), 4.61 (d, J = 8.2 Hz, 1 H), 3.94 (q, J = 7.8 Hz, 1 H), 3.72 (h, J = 8.3 Hz, 1 H), 2.82 - 2.75 (m, 4H), 2.42 (dq, J = 18.2, 8.9 Hz, 2H), 2.26 (dt, J = 19.0, 6.8 Hz, 4H), 2.05 (ddd, J = 11.1 , 8.2, 5.6 Hz, 2H), 1.93 - 1.74 (m, 9H), 1.68 - 1.58 (m, 2H), 1.35 (s, 10H);13C NMR (126 MHz, CDCh) 6 154.9, 128.4 (q), 79.4, 59.4, 57.0, 53.2, 44.0, 43.7, 43.5, 42.9, 42.6, 41.5, 32.1 , 31.8 (q), 28.4, 19.5, 19.5; LC-MS (ESI): (m / z) = 498 [M+H],

[0280] 6-chloro-2-oxo-N-(6-(((1-(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonamido)spiro[3.3]heptan-2-yl)indoline-5-carboxamide (EPZ031686-SD9 orSD9): tert-Butyl (6-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonamido)spiro[3.3]heptan-2- yl)carbamate (105 mg, 0.2 mmol) was dissolved into 20% TFA in DCM (5 mL) and stirred at RT for 1 h. After completion of the reaction, solvent was removed under vacuum and dried then used for next reaction without further purification. A stirred solution of amine (86.6 mg, 0.2 mmol) in DMF (5 mL), were sequentially added 6-chloro-2-oxoindoline-5-carboxylic acid (63 mg, 0.3 mmol), HOBt (61 mg, 0.4 mmol), EDC (76 mg, 0.4 mmol) and Et3N (81 pL, 0.6 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h to 4h. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10- 65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 85 mg (58%, 0.116) as white solid.1H NMR (500 MHz, CD3OD_SPE) 6 7.37 (s, 1 H), 7.02 (s, 1 H), 4.42 (p, J = 8.1 Hz, 1 H), 3.87 (p, J = 8.2 Hz, 1 H), 3.73 (d, J = 12.3 Hz, 2H), 3.32 - 3.25 (m, 2H), 3.17 - 3.07 (m, 4H), 2.72 - 2.59 (m, 2H), 2.50 - 2.29 (m, 7H), 2.25 - 2.07 (m, 6H), 1.76 (q, J = 13.6 Hz, 2H);13C NMR (126 MHz, CD3OD_SPE) 6 178.1 , 178.0, 167.7, 145.7, 130.3, 130.3, 129.4, 127.9, 125.7, 124.7, 124.7, 124.6, 124.6, 110.5, 57.0, 55.4, 52.3, 43.5, 43.1 , 42.7, 41.4, 41.0, 40.9, 30.8, 29.8, 28.8, 17.0, 16.9, 16.9, 16.9; LC-MS (ESI): (m / z) = 591 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01Synthesis of EPZ031686-SD10, Scheme 2

[0281] tert-butyl 4-((4-((((1R,3r,5S)-3-(((2,2,2-trichloroethoxy)carbonyl)amino)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)methyl)piperidine-1- carboxylate: To a stirred solution of the 2,2,2-trichloroethyl ((1 R,3r,5S)-8-((piperidin-4- ylmethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (500 mg, 1.08 mmol) in) in DMF (5 mL), were added was added tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (601 mg, 2.16 mmol), Et3N (328 mg, 3.24 mmol) and DMAP (13.2 mg, 0.108 mol) at RT. The resulting solution was stirred at RT for overnight. After the completion of the reaction, it was quenched with water (50 mL), and extracted with EA (200 mL x 2). The solvent was removed under vacuum crude material was purified by silica gel flash chromatography using a gradient of 0-5% MeOH in DCM to give the title compound 292 mg (41%, 0.44 mmol) as white solid. LC-MS (ESI): (m / z) = 659[M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0282] tert-butyl 4-((4-((((1 R,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)methyl)piperidine-1 - carboxylate: To a stirred solution of tert-butyl 4-((4-((((1R,3r,5S)-3-amino-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (150 mg, 0.227 mmol)in acetic acid (10 mL), was added zinc (148 mg, 2.27 mmol) at 0 °C. The resulting solution was stirred at RT for 2h. After completion of the reaction, the solids were filtered up and the solution was concentrated under vacuum. Resulting crude residue was quenched with saturated NaHCO3solution(10 mL) and extracted with DCM (100 mL x 4). The solvent was removed under vacuum and the resulting crude product was used for next step without further purification. A stirred solution of resulting amine in DMF (5 mL), were sequentially added 6-chloro- 2-oxoindoline-5-carboxylic acid (72 mg, 0.68 mmol), HOBt (69 mg, 0.45 mmol), EDC (85 mg, 0.4 mmol) and TEA (0.92p, 0.6 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h to 4h. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 85 mg (58%, 0.131 mmol) as white solid. LC-MS (ESI): (m / z) = 678 [M+H],

[0283] N-((1R,3r,5S)-8-(((1-((1-acetylpiperidin-4-yl)methyl)piperidin-4-yl)methyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-2-oxoindoline-5-carboxamide (EPZ031686-SD10 orSD10): tert-butyl 4-((4-((((1 R,3r,5S)-3-(6-chloro-2-oxoindoline-5-carboxamido)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (50.00 mg, 0.073 mmol) was dissolved into 20% TFA in DCM (2 mL) and stirred at RT for 1h. After completion of the reaction, solvent was removed under vacuum and dried then used for next reaction without further purification. To a stirred solution of resulting amin (42.6 mg, 0.073 mmol) in DMF (2 mL), were added 2,5-dioxopyrrolidin-1-yl acetate (23.1 mg, 0.146 mmol) and DIPEAATTORNEY DOCKET NO. E-202-2024-1 -PC-01(10.8 mg, 0.146 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2h to 4h. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 26 mg (48%, 0.035 mmol) as white solid.1H NMR (500 MHz, CD3OD_SPE) 5 7.30 (s, 1 H), 6.94 (d, = 1.3 Hz, 1H), 4.48 (ddt, J = 13.1 , 4.4, 2.3 Hz, 1 H), 4.20 (d, J = 4.5 Hz, 2H), 4.17 - 4.08 (m, 1 H), 3.89 (ddt, J = 13.6, 4.6, 2.3 Hz, 1 H), 3.09 (td, J = 13.0, 2.6 Hz, 1 H), 3.03 (d, J = 5.9 Hz, 2H), 2.90 (d, J = 11.5 Hz, 2H), 2.62 (td, J = 12.8, 2.7 Hz, 1 H), 2.27 (ddd, J = 14.8, 7.1 , 4.3 Hz, 2H), 2.19 (d, J = 6.6 Hz, 2H), 2.14 (t, J = 7.0 Hz, 1H), 2.08 - 1.89 (m, 11 H), 1.87 - 1.74 (m, 3H), 1.49 - 1.37 (m, 2H), 1.19 - 0.99 (m, 2H);13C NMR (126 MHz, CD3OD_SPE) 5 178.1 , 170.0, 168.5, 145.8, 130.2, 129.6, 124.8, 124.7, 110.4, 64.4, 58.1 , 55.5, 53.7, 53.6, 46.3, 42.4, 41.5, 36.3, 33.2, 32.2, 31.3, 31.1 , 30.4, 28.1, 19.9; LC-MS (ESI): (m / z) = 620 [M+H],Synthesis of EPZ031686-SD11, Scheme 3

[0284] benzyl 4-((((1R,4R,5S)-5-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptan-2- yl)sulfonyl)methyl)piperidine-1-carboxylate: To stirred solution of compound tert-butyl ((1 R,4R,5S)-2-azabicyclo[2.2.1]heptan-5-yl)carbamate (0.5 g, 2 mmol) in DCM (5 mL), were added benzyl 4-((chlorosulfonyl)methyl)piperidine-1 -carboxylate (0.9 g, 3 mmol), and added Et3N (1 mL, 7 mmol) in DCM (2 mL) at 0 °C. The resulting mixture was stirred at RT for overnight. AfterATTORNEY DOCKET NO. E-202-2024-1 -PC-01 the completion of the reaction, it was quenched with water (10 mL), and extracted with DCM (100 mL x 2). The solvent was removed under vacuum and the crude material was purified by silica gel flash chromatography using a gradient of 0-5% MeOH in DCM to give the title compound 0.65g (50%, 1 mmol) as white solid. LC-MS (ESI): (m / z) = 408 [M+H, -Boe],

[0285] tert-butyl ((1 R,4R,5S)-2-(((1 -(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-2- azabicyclo[2.2.1]heptan-5-yl)carbamate: To a stirred solution of the of benzyl 4-((((1 R,4R,5S)- 5-((tert-butoxycarbonyl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)sulfonyl)methyl)piperidine-1- carboxylate (400.0 mg, 0.78 mmol) in AcOH (10 mL), was added Pd / C (40 mg, 10%w / w) at RT. The resulting solution was stirred at RT for 3 h under hydrogen pressure (hydrogen balloon was used for hydrogen pressure). After complete consumption of starting material, the reaction mixture was filtered to remove the solids and filtrate was concentrated to get the crude product which was pure enough and used for the next step without purification. Resulting amine (318 mg, 0.78 mmol) in DMF (5 mL), were added 4-bromo-1 , 1 ,1 -trifluorobutane (300.7 mg, 1.574 mmol), Et3N (0.32 mL, 2.34 mmol) and DMAP (9.61 mg, 0.078 mmol) at RT. The resulting solution was stirred at RT for overnight. After the completion of the reaction, it was quenched with water (20 mL), and extracted with EA (100 mL x 2). The solvent was removed under vacuum crude material was purified by silica gel flash chromatography using a gradient of 0-5% MeOH in DCM to give the title compound 320 mg (84%, 0.65 mmol) as white solid. LC-MS (ESI): (m / z) = 484 [M+H],

[0286] 6-chloro-2-oxo-N-((1 R,4R,5S)-2-(((1 -(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-2-azabicyclo[2.2.1]heptan-5-yl)indoline-5-carboxamide (EPZ031686-SD11 or SD11): tert-butyl ((1 R,4R,5S)-2-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)- 2-azabicyclo[2.2.1]heptan-5-yl)carbamate (155 mg, 0.32 mmol) was dissolved into 20% TFA in DCM (5 mL) and stirred at RT for 1h. After completion of the reaction, solvent was removed under vacuum and dried then used for next reaction without further purification. A stirred solution ofATTORNEY DOCKET NO. E-202-2024-1 -PC-01 amine (122 mg, 0.32 mmol) in DMF (5 mL), were sequentially added 6-chloro-2-oxoindoline-5- carboxylic acid (101 mg, 0.48 mmol), HOBt (98 mg, 0.64 mmol), EDC (122 mg, 0.64 mmol) and TEA (0.131 mL, 0.93 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h. After the completion of the reaction, crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 95 mg (53%, 0.169 mmol) as white solid.1H NMR (500 MHz, CD3OD_SPE) 6 7.30 (s, 1 H), 6.94 (s, 1 H), 4.19 (s, 2H), 4.08 (dd, J = 8.4, 4.0 Hz, 2H), 3.62 (d, J = 12.3 Hz, 4H), 3.51 (d, J = 10.6 Hz, 1 H), 3.36 (dd, J = 9.2, 3.8 Hz, 2H), 3.20 - 3.15 (m, 4H), 3.12 (d, J = 9.1 Hz, 2H), 3.08 - 3.00 (m, 8H), 2.77 - 2.71 (m, 2H), 2.40 - 2.18 (m, 11 H), 2.09 - 1.93 (m, 5H), 1.79 (d, J = 10.6 Hz, 2H), 1.74 - 1.58 (m, 9H); LC-MS (ESI): (m / z) = 577 [M+H],

[0287] N-((1R,3r,5S)-8-(((1-(3-([1,1'-biphenyl]-4-carboxamido)propyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-chloro-3-((3,5-dimethyl-1H-pyrrol-2- yl)methylene)-2-oxoindoline-5-carboxamide: The EPZ031686-SD19 (35mg, 0.048 mol) and carbaldehyde (9 mg, 0.073 mmol) was dissolved in ethanol (2 mL), was added piperidine ( 7.2 pL, 0.073 mmol) at RT. The reaction mixture was stirred at 70 °C 2h. After completion of the reaction (as indicated by LCMS), the reaction mixture was allowed to cool RT and the crude material was purified by reverse phase chromatography without workup to give title product (20 mg. 0.024 mmol) as pale yellow solid.1H NMR (500 MHz, CD3OD_SPE) 5 7.95 - 7.89 (m, 1 H), 7.75 - 7.69 (m, 1 H), 7.67 - 7.62 (m, 1 H), 7.57 - 7.52 (m, OH), 7.48 - 7.34 (m, 2H), 6.88 - 6.82 (m, OH), 5.97 (d, J = 2.8 Hz, OH), 4.25 (s, 1 H), 4.17 (s, 1 H), 3.63 (d, J = 12.3 Hz, 1 H), 3.51 (t, J = 6.5 Hz, 1 H), 3.21 - 3.12 (m, 2H), 3.04 (t, J= 12.7 Hz, 1 H), 2.36 - 2.18 (m, 7H), 2.05 (dd, J = 17.5, 11.3 Hz, 4H), 1.71 (t, J = 13.5 Hz, 1 H).;13C NMR (126 MHz, CD3OD_SPE) 6 170.0, 169.3, 169.1 , 144.6, 139.7, 139.3, 137.8, 134.2, 132.2, 128.7, 127.8, 127.6, 127.2, 127.0, 126.7, 125.4, 124.1 , 117.2, 112.8, 109.9, 56.9, 55.6, 54.4, 52.2, 42.3, 36.4, 36.3, 30.2, 28.9, 28.2, 24.3, 12.3, 10.2.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0288] tert-butyl ((1 R,3r,5S)-8-(((1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)carbamate: To a stirred solution of the tert-butyl ((1 R,3r,5S)-8-((piperidin-4-ylmethyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)carbamate (75.00 mg, 0.19 mmol) in DMF (5 ml_), were added 4- (4-(2-bromoacetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 , 3-dione (107.6 mg, 0.232 mmol), and K2CO3 (53.49 mg, 0.387.1 mol) at RT. The resulting solution was stirred at RT for overnight. After completion of the reaction, added water (25 mL) to the reaction mixture and extracted with ethyl acetate (3 x 50 mL). The solvent was removed under vacuum crude and the material was purified by silica gel flash chromatography using a gradient of 0-5% MeOH in DCMATTORNEY DOCKET NO. E-202-2024-1 -PC-01 to give the title compound 95 mg (64%, 0.123 mmol) as white solid. LC-MS (ESI): (m / z) = 770 [M+H].

[0289] 6-chloro-N-((1R,5S)-8-(((1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)- 2-oxoindoline-5-carboxamide(EPZ031686-CRBN-05): tert-butyl ((1R,3r,5S)-8-(((1-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (50 mg, 0.064 mmol) was dissolved into 20% TFA in DCM (5 ml_) and stirred at RT for 1h. After completion of the reaction, solvent was removed under vacuum and dried then used for next reaction without further purification. A solution of the above amine (43.5 mg, 0.064 mmol) in DMF (3 ml_), were sequentially added 6- chloro-2-oxoindoline-5-carboxylic acid (20 mg, 0.48 mmol), HOBt (20 mg, 0.13 mmol), EDC (25 mg, 0.13 mmol) and TEA (0.036 ml_, 0.259 mmol) at 0 °C. The resulting mixture was stirred at RT for 3h. After the completion of the reaction, the crude material was purified by reverse phase chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 28 mg (51 mg, 0.032 mmol) as pale yellow solid. LC-MS (ESI): (m / z) = 863 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0290] N-((1R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(2-chlorophenyl)isoxazole-3-carboxamide. To a stirred solution of tert-butyl (3-(4-((((1 R,5S)-3-amino-8-azabicyclo[3.2.1]octan-8- yl)sulfonyl)methyl)piperidin-1-yl)propyl)carbamate (200 mg, 0.449 mmol), in DMF (5.000 mL), added 5-(2-chlorophenyl)isoxazole-3-carboxylic acid (150.9 mg, 0.675 mol), HOBt (137.8 mg, 0.899 mmol), EDC (172.5 mg, 0.899 mmol) and EtaN (182 mg, 1 .79 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3h. After the completion of the reaction, crude material was purified by reverse phase column chromatography using a gradient of 10-65% acetonitrile in water with the addition of 0.05% TFA to give the title compound 215 mg (73%, 0.33 mmol). LC- MS (ESI): (m / z) = 650 [M+H],

[0291] N-((1R,3r,5S)-8-(((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-(2-chlorophenyl)isoxazole-3-carboxamide: N-((1R,3r,5S)-8- (((1-(3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(2- chlorophenyl)isoxazole-3-carboxamide (50.00 mg, 0.077 mmol) was dissolved into 20% TFA in DCM (5 mL) and stirred at RT for 1h. After completion of the reaction, solvent was removed under vacuum , the crude material was purified by reverse phase chromatography using a gradient of 10-45% acetonitrile in water with the addition of 0.05% TFA to give the title compound 40 mg (94%, 0.073 mmol). LC-MS (ESI): (m / z) = 550 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0292] 5-(2-chlorophenyl)-N-((1R,3r,5S)-8-(((1-(3-(4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)piperazine-1 -carbonyl)phenyl)buta-1 ,3-diyn-1- yl)benzamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide(EPZ031686-CRBN-06): The compound N-((1R,3r,5S)-8-(((1-(3- aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(2- chlorophenyl)isoxazole-3-carboxamide (40 mg, 0.073 mmol) was dissolved in DMF (2 ml_), added 4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4-yl)piperazine-1-carbonyl)phenyl)buta- 1 ,3-diyn-1-yl)benzoic acid (53 mg, 0.087 mmol), HATU (41 mg, 0.109 mmol) and DIPEA (32 pL, 0.181 mmol) sequentially at RT. The resulting mixture was stirred at rt for 4h. After completion of the reaction (as indicated by LCMS) crude material was purified by reverse phase chromatography without workup using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TEA to get the corresponding product. LC-MS (ESI): (m / z) = 1145 [M+H],ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0293] 5-(2-chlorophenyl)-N-((1R,3r,5S)-8-(((1-(3-(4-((4-(((3S,5S)-1-((S)-2-cyclohexyl-2-((S)- 2-(methylamino)propanamido)acetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1- yl)carbamoyl)pyrrolidin-3-yl)carbamoyl)phenyl)buta-1,3-diyn-1- yl)benzamido)propyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide (EPZ031686-IAP-12): To a stirred solution of N-((1 R,3r,5S)-8-(((1- (3-aminopropyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(2- chlorophenyl)isoxazole-3-carboxamide (30 mg, 0.054 mmol) in DMF (2 ml_), were added sequentially 4-((4-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)- 2-cyclohexylacetyl)-5-(((R)-1 ,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 yl)carbamoyl)phenyl)buta-1 ,3-diyn-1-yl)benzoic acid (51 mg, 0.06 mmol), HATU (31 mg, 0.081 mmol) and DI PEA ( 23 pL, 0.136 mmol) at 0 °C. The resulting mixture was stirred at RT for 4h. After completion of the reaction (as indicated by LCMS) crude material was purified by reverse phase chromatography without workup using a gradient of 10-75% acetonitrile in water with the addition of 0.05% TFA, the resulting product was used for next step without characterization. The resulting above product was dissolved 20% TFA in DCM (2 mL) and stirred at RT for 1h. After completion of the reaction (as indicated by LCMS) the volatiles were removed under vacuum and the crude material was reverse phase chromatography without workup using a gradient of 10- 75% acetonitrile in water with the addition of 0.05% TFA to get the title compound 25 mg (33%, 0.18 mmol) as white solid.1H NMR (500 MHz, DMSO) 5 9.01 (d, J = 7.8 Hz, 1 H), 8.59 (t, J = 5.5 Hz, 1 H), 8.52 (d, J = 8.7 Hz, 1 H), 8.47 (d, J = 5.0 Hz, 1 H), 8.19 - 8.11 (m, 1 H), 7.84 (dt, J = 15.6, 7.4 Hz, 5H), 7.70 - 7.61 (m, 5H), 7.57 - 7.46 (m, 2H), 7.28 (d, J = 7.6 Hz, 1 H), 7.24 (s, 1 H), 7.09 - 7.00 (m, 3H), 4.91 (q, J = 8.2 Hz, 1 H), 4.50 (q, J = 6.9 Hz, 1 H), 4.33 (dt, J = 14.5, 8.0 Hz, 2H), 4.08 (s, 2H), 4.04 - 3.91 (m, 2H), 3.54 (dd, J = 10.0, 6.2 Hz, 1 H), 3.25 - 3.17 (m, 3H), 2.97 (d, J = 5.8 Hz, 2H), 2.84 (d, J = 11.0 Hz, 2H), 2.68 (d, J = 14.4 Hz, 2H), 2.31 (d, J = 7.3 Hz, 2H), 2.22 (s, 2H), 2.06 - 1.85 (m, 9H), 1.83 - 1.73 (m, 3H), 1.70 - 1.44 (m, 6H), 1.25 (d, J = 12.1 Hz, 2H), 1.17 - 0.84 (m, 6H). LC-MS (ESI): (m / z) = 1287 [M+H],Example 2: Experimental MethodsColony formation assay (CFA)

[0294] HN-6, HN-SCC-151 and BEAS2B (normalized squamous cell line) cells were seeded into 6-well plates (1000 cells / well) and treated with increasing concentrations of SMYD3 PROTAC compounds or SMYD3 inhibitors. The cells were left for total of 10 days. Following the treatment, plates were washed with PBS, fixed with 1 % paraformaldehyde solution and stained with crystal violet [Crystal violet 0.5% (wt / vol), 25% methanol and 1%Formaldehyde], Next, wells were thoroughly washed with water and air-dried, followed by imaging. The number of colonies formed in each well were performed using Image-J.Cell Proliferation and Cytotoxicity Assay

[0295] Two thousand cells were plated onto a 24-well plate and allowed to grow for 24hrs prior to the addition of PROTAC compound or inhibitors. After 24hr cells were treated with increasing concentrations of PROTAC or inhibitor. Measurements were taken at 3, 6 and 9 days of incubation with the PROTAC or inhibitors using Cell Counting Kit-8 (CCK8) to assess the viability of the cells.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0296] For CCK8 assays, media was removed by aspiration, CCK8 (270 pL media + 30 pL CCK8) was added to each well and incubated at 37 °C for 2 hrs, and absorbance was read at 450 nm.Western Blotting

[0297] Western blotting was performed to assess the degrading efficiency of the different PROTAC compounds. Following treatment with PROTAC for 24 hrs, whole-cell extracts were prepared by lysing the cells on ice using RIPA lysis buffer (Sigma-Aldrich, cat. R0278) with the addition of Turbonuclease (Sigma-Aldrich, cat. T4330). Lysates were cleared (12,5003g, 15 minutes, 4 °C), and protein concentration was assessed. Lysates prepared with equal amounts of protein were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS- PAGE) in 4-20% gradient gels (Bio-Rad) and transferred onto nitrocellulose membranes. Blots were incubated O / N with desired primary antibodies, followed by incubation with secondary antibody next day. Blots were imaged using LCOR imager.Example 3: Results

[0298] Exemplary PROTACs were synthesized and subjected to the testing described in Example 2. Results including degradation efficiency and CCK8 / CFA testing are presented in Table 1 below. Warhead, targeting group, and small molecule control structures are presented in Table 2 below.ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01

[0299] The in vitro efficacy of the SD1-SD21 inhibitors was investigated in two HPV-negative head and neck squamous cell carcinoma cell lines (HN13, HN-SCC-151) with endogenous expression of SMYD3. Colony formation assays were conducted for this purpose. Specifically, HN-6 and HN-SCC-151 cells were seeded into 6-well plates (2000 cells / well) and treated with increasing concentrations of each of the SD SMYD3 inhibitors. The cells were treated for a total of 10 days. Following treatment, the plates were washed with PBS, fixed with 1% paraformaldehyde solution and stained with crystal violet [crystal violet 0.5% (wt / vol), 25% methanol and 1 % formaldehyde]. Next, the wells were thoroughly washed with water and airdried. The number of colonies in each well were quantified using Image-J. For purposes of brevity, FIG. 8 shows the in vitro efficacy of the 9 most efficacious SD SMYD3 inhibitors. Compared to EPZ031686, which showed no efficacy at concentrations as high as 10 pM, all 9 SD SMYD3 inhibitors induced a significant decrease by more than 50% at concentrations ranging from 1-10 pM.

[0300] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of theATTORNEY DOCKET NO. E-202-2024-1 -PC-01 principles of the disclosure. Many variations and modifications may be made to the abovedescribed embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

1. ATTORNEY DOCKET NO. E-202-2024-1 -PC-01CLAIMSWhat is claimed is:

1. A compound having Formula I or a pharmaceutically acceptable salt thereof:T-L-WFormula I; wherein T comprises a targeting group having Formula II:V-X-ZFormula II; wherein V is bonded to X and wherein V comprises a substituted or unsubstituted C3-C8 aryl or heteroaryl group; wherein X comprises a C3-C8 heterocycloalkyl, bridged heterocycloalkyl group, spiro heterocycloalkyl group, or a C3-C8 aryl or heteroaryl group; wherein Z is bonded to L and comprises a substituted or unsubstituted C4-C9 cycloalkyl or heterocycloalkyl group: wherein L comprises a linker moiety having Formula III:Formula III; wherein Y comprises a substituted or unsubstituted C2-C5 polyalkylene glycol, C1-C20 substituted or unsubstituted alkyl group, substituted or unsubstituted C5-C9 aryl group, substituted or unsubstituted C5-C9 heteroaryl group, substituted or unsubstituted C3-C6 cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted fused cycloalkyl group, substituted or unsubstituted or unsubstituted alkyl aryl group, or any combination thereof; and wherein W comprises an E3 ligase binding moiety.ATTORNEY DOCKET NO. E-202-2024-1 -PC-012. The compound or salt of claim 1 , wherein W is selected fromwherein Ri, if present, is selected from hydrogen and C1-C4 alkyl; wherein R2, if present, is selected from hydrogen and C1-C4 alkyl; and wherein R3, if present, is selected from hydrogen and C1-C4 alkyl.ATTORNEY DOCKET NO. E-202-2024-1 -PC-013. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y is a substituted or unsubstituted cycloalkyl or fused cycloalkyl group.

4. The compound or pharmaceutically acceptable salt of claim 3, wherein Y is selected from5. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y is a substituted or unsubstituted C5-C9 aryl group or C5-C9 heteroaryl group.

6. The compound of pharmaceutically acceptable salt of claim 5, wherein Y is selected from7. The compound or pharmaceutically acceptable salt of claim 1 wherein the C2-C5 polyalkylene glycol is polyethylene glycol.

8. The compound or pharmaceutically acceptable salt of claim 7, wherein Y iswherein m is from 1 to 20.

9. The compound or pharmaceutically acceptable salt of claim 8, wherein m is from 1 to 8.

10. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y isand wherein n is from 1 to 20.

11. The compound or pharmaceutically acceptable salt of claim 10, wherein n is 4.

12. The compound or pharmaceutically acceptable salt of any one of claim 1 , wherein V is selected fromATTORNEY DOCKET NO. E-202-2024-1 -PC-01wherein R4, if present, is hydroxyl group or a substituted or unsubstituted C3-C8 heteroaryl or heteroalkyl group, and wherein a double bond indicated by * has E or Z stereochemistry.

13. The compound or pharmaceutically acceptable salt of claim 12, wherein R4is selectedcombination thereof.

14. The compound or pharmaceutically acceptable salt of claim 1 , wherein X is selected from15. The compound or pharmaceutically acceptable salt of claim 1, wherein Z is selected fromATTORNEY DOCKET NO. E-202-2024-1 -PC-01or any combination thereof.

16. The compound or pharmaceutically acceptable salt of claim 1, wherein T is EPZ031686 or a derivative thereof:EPZ031686.

17. The compound or pharmaceutically acceptable salt of claim 16, wherein T is a derivative ofATTORNEY DOCKET NO. E-202-2024-1 -PC-0118. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound hasFormula IVFormula IV; wherein o and p are each an integer from 1 to 5.

19. The compound or pharmaceutically acceptable salt of claim 18, wherein o is 1.

20. The compound or pharmaceutically acceptable salt of claim 18, wherein p is 3.

21. The compound or pharmaceutically acceptable salt of claim 18, wherein V is selected fromATTORNEY DOCKET NO. E-202-2024-1 -PC-01combination thereof; wherein R4, if present, is a substituted or unsubstituted C3-C8 heteroaryl or heteroalkyl group; and wherein a double bond indicated by * has E or Z stereochemistry.

22. The compound or pharmaceutically acceptable salt of claim 21 , wherein R4is selectedcombination thereof.

23. The compound or pharmaceutically acceptable salt of claim 18, wherein Y is selected fromcombination thereof.

24. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound isATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-01ATTORNEY DOCKET NO. E-202-2024-1 -PC-0125. A compound or pharmaceutically acceptable salt having Formula VFormula V;ATTORNEY DOCKET NO. E-202-2024-1 -PC-01 wherein o and p are each an integer from 1 to 5; wherein V comprises a substituted or unsubstituted C3-C8 aryl or heteroaryl group; and wherein Q comprises a substituted or unsubstituted C3-C12 aryl or alkyl group.

26. The compound or pharmaceutically acceptable salt of claim 25, wherein o is 1.

27. The compound or pharmaceutically acceptable salt of claim 25, wherein p is 3.

28. The compound or pharmaceutically acceptable salt of claim 25, wherein V is selected fromcombination thereof; wherein R4, if present, is a substituted or unsubstituted C3-C8 heteroaryl or heteroalkyl group; and wherein a double bond indicated by * has E or Z stereochemistry.

29. The compound or pharmaceutically acceptable salt of claim 28, wherein R4 is selectedany combination thereof.

30. The compound or pharmaceutically acceptable salt of claim 25, wherein Q is selected fromany combination thereof.ATTORNEY DOCKET NO. E-202-2024-1 -PC-0131. The compound or pharmaceutically acceptable salt of claim 25, wherein the compound isATTORNEY DOCKET NO. E-202-2024-1 -PC-0132. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CFA assay at a concentration of 1 pM or less.

33. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CFA assay at a concentration of 0.5 pM or less.

34. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CFA assay at a concentration of 0.1 pM or less.

35. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CCK8 assay at a concentration of 2.5 pM or less.

36. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CFA assay at a concentration of 0.5 pM or less.

37. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound or pharmaceutically acceptable salt kills greater than 50% of cancer cells in a CFA assay at a concentration of 0.1 pM or less.

38. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound degrades SMYD3 with an efficiency of greater than 50% at a concentration of 2.5 pM or less.ATTORNEY DOCKET NO. E-202-2024-1 -PC-0139. The compound or pharmaceutically acceptable salt of any one of claims 1-310, wherein the compound degrades SMYD3 with an efficiency of greater than 50% at a concentration of 1 M or less.

40. The compound or pharmaceutically acceptable salt of any one of claims 1-31 , wherein the compound degrades SMYD3 with an efficiency of greater than 50% at a concentration of 0.5 pM or less.

41. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1-31 .

42. The pharmaceutical composition of claim 41, further comprising at least one carrier or excipient.

43. The pharmaceutical composition of claim 41, wherein the composition comprises a topical dosage form, a parenteral dosage form, or an oral dosage form.

44. A method for killing cancer cells, the method comprising contacting the cancer cells with the compound or pharmaceutically acceptable salt of any one of claims 1-31.

45. The method of claim 44, wherein the cancer cells comprise breast cancer cells or squamous cell carcinoma (SCC) cells.

46. The method of claim 45, wherein the SCC is HPV negative.

47. The method of claim 45, wherein the SCC is head and neck SCC, SCC of the lung, SCC of the esophagus, SCC of the bladder, or any combination thereof.

48. The method of any one of claims 44, wherein the cancer cells overexpress SMYD3.

49. The method of any one of claims 44, wherein the compound specifically binds to and causes degradation of SMYD3.

50. A method for treating or preventing cancer in a subject, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1-310 to the subject.

51. A method for reducing or preventing the growth of a tumor in a subject, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1-31 to the subject.

52. The method of claim 50, wherein the compound is administered orally, topically, or intravenously.ATTORNEY DOCKET NO. E-202-2024-1 -PC-0153. The method of any one of claims 50, wherein the cancer comprises breast cancer or a squamous cell carcinoma (SCC).

54. The method of claim 53, wherein the SCC is HPV negative.

55. The method of claim 53, wherein the SCC is head and neck SCC, SCC of the lung, SCC of the esophagus, SCC of the bladder, or any combination thereof.

56. The method of any one of claims 50, wherein the cancer overexpresses SMYD3.

57. The method of any one of claims 50, wherein the compound specifically binds to and causes degradation of SMYD3.

58. The method of any one of claims 50, wherein the subject is a mammal.

59. The method of claim 28, wherein the mammal is a human, non-human primate, cat, dog, rat, mouse, guinea pig, rabbit, hamster, horse, cattle, swine, sheep, or goat.

60. The method of claim 59, wherein the mammal is a human.

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