WO2025034789A1 - Arylbenzoisoxazole compounds as ip6k and ipmk degraders and methods of use thereof - Google Patents

Abstract

Arylbenzoisoxazole compounds of Formula I, where R¹ and R² are defined herein, are useful for degrading isoforms of IP6K and IPMK, and for treating diseases and disorders such as non- alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cancer, and viral infections. Methods of using compounds of Formula I for prevention or treatment of such diseases and disorders, pharmaceutical compositions comprising the compounds, and methods of preparing the compounds are also disclosed.

Description

ARYLBENZOISOXAZOLE COMPOUNDS AS IP6K AND IPMK DEGRADERS AND METHODS OF USE THEREOF TECHNICAL FIELD [0001] The present disclosure relates to arylbenzoisoxazole containing compounds for treating diseases and disorders mediated by IP6K and IPMK degraders. The disclosure also relates to compositions comprising the compounds and methods of using the same to treat obesity and obesity-related diseases, including various forms of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), cancer, and viral infections. GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant No. A21-1479-004 awarded by National Institutes of Health National Cancer Institute. The government has certain rights in the invention. BACKGROUND [0003] The incidence of worldwide obesity has more than doubled since 1980.^1-3 In obesity, excess fat accumulation causes adipocyte dysfunction, releases inflammatory cytokines, promotes insulin resistance, and reduces the fat-storing ability of adipocytes. Thus, obesity significantly increases the risk of co-morbidities such as type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular disease, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), reproductive dysfunction, respiratory abnormalities, psychiatric and neurodegenerative diseases, and certain types of cancer.^4-5 Consequently, obesity greatly contributes to economic and social burdens.⁶ A combination of lifestyle modification and pharmacology has been shown to have beneficial effects in combating obesity.^{2, 7-8} Even a 5-10% loss in body weight/fat has been shown to decrease liver- and cardio-metabolic diseases in human patients.^9-10 Yet, limited success has been achieved in reducing body weight for an extended period.^1-3 [0004] The inositol pyrophosphate (PP-IP) biosynthetic pathway has been identified as a target in metabolic diseases, osteoporosis, thromboembolism, infection, cancer metastasis and aging.^{11- 22} Inositol pyrophosphates are conserved eukaryotic messenger molecules with functionally significant and highly “energetic” diphosphate groups.^23-24 They play crucial roles in diverse cellular functions including insulin secretion and signaling,^{12, 25-26} ATP production,²⁷ DNA damage sensing²⁸ and repair.²⁹ Many of these effects contribute to an over-arching role for PP-IPs in regulating bioenergetic homeostasis.^{23-24, 30} The initial and primary reaction in the PP-IP synthetic pathway is the phosphorylation of inositol hexakisphosphate (InsP6) to 5-diphosphoinositol pentakisphosphate (5-InsP₇) by a family of small molecule kinases known as IP6K1, IP6K2 and IP6K3. [0005] IP6K1 and IP6K2 are expressed in most tissues while IP6K3 is mainly expressed in the heart, skeletal muscle, and brain.^{16, 20} IP6K1 regulates metabolism in vivo by several mechanisms.^{14, 20} This isoform promotes insulin secretion from pancreatic β cells,²⁵ but attenuates certain aspects of insulin signaling.¹² Moreover, IP6K1 reduces whole-body energy expenditure by inhibiting adipocyte thermogenesis.^{11, 15} Consequently, whole-body and adipocyte specific IP6K1-KO mice display increased insulin sensitivity and energy expenditure and are protected from high fat diet (HFD)-induced obesity, hyperinsulinemia, and insulin resistance.^{11-12, 15} Furthermore, whole-body or hepatocyte-specific IP6K1 deletion ameliorates NAFLD and NASH in mice.²² IP6K2 deletion in mice decreases cancer cell migration, invasion, and tumor metastasis.²¹ Deletion of IP6K3 protects mice from age-induced fat accumulation and insulin resistance.¹⁶ [0006] These observations suggest that it would be useful to develop IP6K degraders to dissect the alternate biological functions of each isoform,³¹ and potentially to further develop drug candidates, particularly to target obesity and obesity-induced metabolic and other diseases.¹⁴ Thus, the IP6Ks are potential targets for mediation of diseases and disorders associated with IP6K function. For example, inositol hexakisphosphate 5-kinase 1 (IP6K1) is a potential target for NAFLD/NASH treatment due to its pleiotropic effects on metabolic parameters.³² [0007] Recent publications also demonstrated the applications of IP6K inhibitors in hyperphosphataemia³³ and IPMK inhibitors in fungal infection.³⁴ [0008] The presently disclosed subject matter provides heterocyclic compounds having IP6K and IPMK degradation action useful as a prophylactic or therapeutic agents for the treatment of diseases such as NAFLD/NASH, hyperphosphatemia, fungal infection, glioblastoma, and coronavirus. These and other aspects are addressed by the disclosures herein. SUMMARY [0009] In accordance with the purpose(s) of the currently disclosed subject matter, as embodied and broadly described herein, in one aspect relates to a compound of Formula I: or a pharmaceutically acceptable salt or

hereof, wherein X is aryl or heteroaryl; R¹ is –OR³-L-M, wherein R³ is selected from alkyl, aryl, heteroaryl, and heterocycloalkyl; O O O R² is heteroaryl ;

L is a linker selected from the group consisting of -E-F- ,

,

, , -CH₂CH₂OCH₂CH₂- ,

weren s seected rom te group consstng o a bond, -C(=O)-,-CH₂CH₂OCH₂CH₂-, ,

,

ting of 0, 1, 2, 3, 4, and 5, and A and B are independently selected from a bond, –CH₂-, -CH₂CH₂O-, - CH₂CH₂NH-, -CH₂CH₂C(=O)NH-, -C(=O)-, -C(=O)NH-, -NHC(=O)-, and a – ne,

pyrrolidine, and triazole; and M is a moiety selected from the group consisting of

, .

maceutical composition comprising a compound of Formula I in a pharmaceutically acceptable carrier or excipient. [0011] In another aspect, the subject matter described herein is directed to a method of preventing or treating a disease or disorder mediated by IP6K and/or IPMK, the method comprising administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof. In an embodiment, the disease or disorder is NAFLD, NASH, glioblastoma, or coronavirus. [0012] In another aspect, the subject matter described herein is directed to a kit for treating a disease or disorder mediated by IP6K and/or IPMK, the kit comprising: 1) a pharmaceutical composition comprising a compound of Formula I, and 2) instructions for use. [0013] In another aspect, the subject matter described herein includes a compound of Formula I for use as a medicament, and for use in treating a disease or disorder mediated by IP6K and/or IPMK. In another aspect, the subject matter described herein includes the use of a compound of Formula I in the manufacture of a medicament for the treatment of a disease or disorder mediated by IP6K and/or IPMK. In some embodiments, the disease or disorder is selected from the group consisting of obesity, obesity related diseases, hyperphosphatemia, fungal infections, cancer, and viral infections. In some embodiments, the obesity related disorders include, but are not limited to, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the disease or disorder is NAFLD, NASH, glioblastoma, or coronavirus. In some embodiments, the cancer is glioblastoma, but is not limited thereto. In some embodiments, the viral infection is coronavirus, but is not limited thereto. In some embodiments, the fungal infection is caused by a yeast strain. Exemplary yeast strains include, but are not limited to, Cryptococcus neoformans and Candida albicans. [0014] These and other aspects are disclosed in further detail below. BRIEF DESCRIPTION OF THE FIGURES [0015] FIG.1 shows immunoblotting used to detect and identify proteins of interest for IP6K degraders. IP6K1 siRNA was used to confirm the band of IP6K1. DETAILED DESCRIPTION [0016] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein. [0017] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. 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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described. [0018] The presently disclosed subject matter provides heterocyclic compounds having IP6K and/or IPMK degradation action useful as a prophylactic or therapeutic agents for the treatment of diseases and disorders mediated by the IP6Ks, such as NAFLD/NASH or hyperphosphatemia and by IPMK such as fungal infection, glioblastoma or coronavirus. In some embodiments, the heterocyclic compounds disclosed herein have a structure of Formula I, wherein X, R¹, and R² are defined as described herein.

[0019] While aspects of the present invention 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 invention can be described and claimed in any statutory class. 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 in 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. A. DEFINITIONS [0020] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group. [0021] 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 “an alkyl group” or “a phenyl” includes mixtures of two or more such alkyl groups or phenyls. [0022] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. 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. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. Further, unless specified by the term “integer,” the number specified includes fractions or numbers with decimals. For example, the range of “from about 1 to about 5” includes numbers such as 1, 1.1, 1.5, 2.0, 2.2, and so on. As used herein, the term “integer” refers to a number that is a whole number, and not a fraction. [0023] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denote the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing two parts by weight of component X and five parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compositions. [0024] A weight percent (wt%) of a component, unless specifically stated to the contrary, is based on the total weight of the vehicle or composition in which the component is included. [0025] As used herein, the terms “optional” and “optionally” mean 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. [0026] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. It is understood that embodiments described herein include “consisting of” and/or “consisting essentially of” embodiments. [0027] As used herein, the terms “increase,” “increases,” “increased,” “increasing”, “improve”, “enhance”, and similar terms indicate an elevation in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more. [0028] As used herein, the terms “reduce,” “reduces,” “reduced,” “reduction”, “inhibit”, and similar terms refer to a decrease in the specified parameter of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%. [0029] As used herein, the “contacting” refers to reagents in close proximity so that a reaction may occur. [0030] As used herein, “ambient temperature” or “room temperature” refers to a temperature in the range of about 20 °C to about 25 °C. [0031] As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, and the like. These groups may be substituted with groups selected from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, ester, amide, nitro, or cyano. [0032] The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some degree of unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. [0033] As used herein, the term “heterocycloalkyl” refers to a nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system is completely saturated. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, tetrahydrofuryl, tetrahydrothienyl, thienyl, and the like. [0034] As used herein, the term “heteroaryl” or “heteroaromatic” refers to a monovalent aromatic radical of 5- or 6-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5-20 atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4- hydroxypyrimidinyl), pyrazolyl, triazolyl (including, for example, 3-amino-1,2-4-triazole or 3- mercapto-1,2,4-triazole), pyrazinyl (including, for example, aminopyrazine), tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, oxazol-2(3H)-onyl, and furopyridinyl. The heteroaryl groups are thus, in some embodiments, monocyclic or bicyclic. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. [0035] As used herein, the term “aryl” refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. [0036] It will be understood that the structures provided herein and any recitation of “substitution” or “substituted with” includes the implicit proviso that such structures and substitution are in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. [0037] As used herein, the term “stereoisomer” refers to compounds which have identical chemical constitution, but differ with regards to the arrangement of the atoms or groups in space. These “stereoisomers” have a “stereogenic center” which may be a chiral center. [0038] As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. [0039] As used herein, the term “diastereomers” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. [0040] As used herein, the term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wiley, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. [0041] As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with a condition. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disease is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable. The term “treatment” of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment). [0042] As used herein, the term “pharmaceutical composition” refers to the active agent in combination with a pharmaceutically acceptable carrier, e.g. a carrier commonly used in the pharmaceutical industry. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and/or ointment. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier that the active ingredient would not be found to occur in nature. [0043] Use of the word “degrader” herein is meant to mean a molecule that degrades activity of an enzyme, such as IP6K. “Degrade” herein is meant to decrease the activity of the target enzyme, as compared to the activity of that enzyme in the absence of the inhibitor. In some embodiments, the term “degrade” means a decrease in IP6K activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibit means a decrease in IP6K activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibit means a decrease in IP6K activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro degradation assays. [0044] The term “administration” or “administering” includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal. [0045] The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the inhibitor compound are outweighed by the therapeutically beneficial effects. [0046] The phrases “systemic administration,” “administered systemically”, “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes. [0047] The phrase “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. [0048] The term “subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human. B. ARYLBENZOISOXAZOLE-CONTAINING COMPOUNDS [0049] As described herein are compounds of Formula I. In some embodiments, the compounds of Formulae II, III, IV, Iva and IVb are degraders of IP6Ks and/or IPMK. As such, as embodied and broadly described herein, in one aspect relates to a compound of Formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is aryl or heteroaryl; R¹ is –OR³-L-M, wherein R³ is selected from alkyl, aryl, heteroaryl, and heterocycloalkyl; O O O R² is heteroaryl ;

L is a linker selected from the group consisting of -E-F- ,

- , -, - , ,

f 0, 1, 2, 3, 4, and 5, and A and B are independently selected from a bond, –CH₂-, -CH₂CH₂O-, - CH₂CH₂NH-, -CH₂CH₂C(=O)NH-, -C(=O)-, -C(=O)NH-, -NHC(=O)-, and a – ne,

pyrrolidine, and triazole; and M is a moiety selected from the group consisting of , .

[0050] As in any embodiment above, a compound wherein X is aryl. In some embodiments, X is phenyl. In some embodiments, X is unsubstituted phenyl. [0051] As in any embodiments above, R in each instance is a hydrogen or a halogen. [0052] As in any embodiment above, R² is a heteroaryl selected from the group consisting of .e.,

. In some embodiments, R² is a 1,2,4-oxadiazol-5(4H)-one, i. .

[0053] As in any embodiment above, a compound wherein X is aryl

selected from the group consisting of . As in any embodiment above,

a compound wherein X is aryl and R² is selected from the group consisting and

.

[005 ] In some embodiments, the compounds disclosed herein comprise a compound of Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, and R² is the same as described in Formula I. [0055] In some embodiments, the compounds disclosed herein comprise a compound of Formula II, wherein R² is –OR³-L-M; and R³ is selected from alkyl, aryl, heteroaryl, and heterocycloalkyl. [0056] As in any embodiment above, a compound wherein R³ is heterocycloalkyl. In some embodiments, R³ is a heterocycloalkyl selected from the group consisting of piperidinone, piperidinyl, morpholino, azetidinyl, and pyrrolidinyl, any one of which may be substituted. In some embodiments, R³ is piperidinyl. [0057] In some embodiments, the compounds disclosed herein comprise a compound of Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L and M are the same as already described above for Formula I. [0058] In some embodiments, the compounds disclosed herein comprise a compound of Formula IV:

or a pharmaceutically acceptable sal

ereof, wherein L and M are the same as described above for Formula I. [0059] In some embodiments, the compounds disclosed herein comprise a compound of Formula IVa or IVb:

ormu a a ormu a or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L and M are the same as described above for Formula I.

[0060] In some embodiments, M is a moiety selected from the group consisting of ,

[0061] In some embodiments, L i or -E-F-, wherein p is an integer selected from the group consisting of

nd B are independently selected from bond, –CH₂-, -CH₂CH₂O-, -CH₂CH₂NH-, -CH₂CH₂C(=O)NH-, -C(=O)-, -C(=O)NH-, -NHC(=O)- , , wherein E is selected from the group consisting of -CH₂-, -C(=O),

F is , ,

[0062] In some embodiments, M is a moiety selected from the group consisting of and

[0064] In some embodiments, L is selected from the group consisting

or -E-F-, wherein E is selected from the group consisting of -CH₂-, -C(=O)-

, , wherein F is selected from the

group consisting of a bond, C(=O), ,

,

me the is f - nd E s - is

and L is -E-F-, wherein E is selected from the group consisting and

[0066] F-, wherein E is

selected from the group consisting of and ; and F is

selected from the group consisting of , and

-F-,

is

is is

, wherein A is -C(=O)-. In some embodiments, M is

s a ,

me is F-,

, y g g of N a_nd

[0071] In some embodiments, R is hydrogen or flourine. [0072] In some embodiments, L is -E-F-, wherein E is selected from the group consisting of - CH₂- and and wherein F is selected

rom t e group cons stng o a bond, , , ,

. or is

is H₂- is

me is

n such embodiments, R is fluorine.

[0074] In some embodiments, , wherein R is hydrogen or

fluorine; and L is -E-F-, wherein E is . In some embodiments, M is

, wherein R is hydrogen or fluorine; and L is -E-F-, wherein E is

. In some embodiments, M is

E is

[0075] In some embodiments, , wherein R is hydrogen or

fluorine; and L is -E-F-, wherei .

[0076] In some embodiments, , wherein R is hydrogen or

fluorine; and L is -E-F-, wherei .

[0077] In some embodiments, , wherein R is hydrogen or

fluorine; and L is -E-F- wherein E is and F is . m_e is .

is is

In .

and L is -E-F-. In some

embodiments, F-, wherein E is selected from the

In om ,

and F is selected from the group consisting of a bond ,

is F-, is is is is ein

E is or -CH₂- and F is . In some embodiments, M is

is

of and

, of N n_d

n.

[0085] In some embodiments, R is hydrogen or flourine. [0086] In some embodiments, L is -E-F-, wherein E is selected from the group consisting of - CH₂- and , and F is selected from the group consisting of

,

[0087] In some embodiments F-, wherein E is

and F is selected from the group consisting of and

n some embodiments F-, wherein

. In some embodiments, M is

is

[0088] In some embodiments is -

CH₂- or and F is selected from the group consisting of a bond,

is In F is

is

[0090] In some embodiments F-, wherein E is selected

from the group consisting of , and F is selected from

the group consisting is

is ein s - nd E is is

is

ted from the compounds listed in the table disclosed herein. Entry Structure

5

11

17 18

23

30

36

41

48

53

57 [0093

] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and/or recrystallization or by the forming diastereomers and separation thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art. In some embodiments, the compounds disclosed herein are enantiomers having an enantiomeric excess (% ee) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are diastereomers having a diastereomeric excess (% de) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are present as enantiomeric or diastereomeric mixtures. [0094] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. [0095] The compounds disclosed herein may be in the form of a salt. Non-limiting examples thereof include metal salts, an ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; an aluminum salt, and the like. Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N’-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene- sulfonic acid and the like. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. [0096] Among the salts, a pharmaceutically acceptable salt is preferable. For example, when a compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt etc.) and the like, ammonium salt, etc., and when a compound has a basic functional group, examples thereof include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. [0097] In some embodiments, the compounds disclosed herein are selective degraders. As used herein, the term “selective degrader” refers to compounds which display an increased selectivity for degrading a particular IP6K (such as IP6K1) when compared to degrading other IP6Ks or IPMK. In some embodiments, the compounds disclosed herein are pan-degraders. As used herein, the term “pan-degrader” refers to compounds that degrade two or more IP6Ks in a similar potency range. [0098] In some embodiments, the compounds disclosed herein associate and/or bind to an E3 ligase. In some embodiments, such an E3 ligases includes, but is not limited to, CRBN, VHL, IAP, MDM2, RNF114, RNF116, RNF4, DCAF16, DCAF15, DCAF11, KEAP1, FEM1B and AhR. C. PHARMACEUTICAL COMPOSITIONS [0099] The presently disclosed compounds can be formulated into pharmaceutical compositions along with a pharmaceutically acceptable carrier. Compounds as disclosed herein can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect, there is provided a pharmaceutical composition comprising a compound as disclosed herein in association with a pharmaceutically acceptable diluent, carrier, or excipient. [0100] A typical formulation is prepared by mixing a compound as disclosed herein and a carrier, diluent, or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound as disclosed herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). [0101] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound as disclosed herein or stabilized form of the compound), such as a complex with a cyclodextrin derivative or other known complexation agent, is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. [0102] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. [0103] Pharmaceutical formulations may be prepared for various routes and types of administration. For example, a compound as disclosed herein having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington’s Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are nontoxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment. [0104] The compounds can be sterile. In particular, formulations to be used for in vivo administration should be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes. The compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution. [0105] The pharmaceutical compositions comprising a compound as disclosed herein can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “therapeutically effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the coagulation factor mediated disorder. Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to bleeding. [0106] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). [0107] Sustained-release preparations of compounds may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound as disclosed herein, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid. [0108] The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. [0109] Formulations of a compound as disclosed herein suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound. [0110] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. [0111] Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of compounds as disclosed herein intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. [0112] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. [0113] If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. [0114] The oily phase of the emulsions may be constituted from known ingredients in a known manner. While the phase may comprise solely an emulsifier, it may also comprise a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. A hydrophilic emulsifier included together with a lipophilic emulsifier may act as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. [0115] Aqueous suspensions of compounds contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. [0116] The pharmaceutical compositions of compounds may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such 1,3-butanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. [0117] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 1 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 10 mL/hr to about 50 mL/hr can occur. [0118] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. [0119] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w. [0120] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. [0121] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. [0122] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments of microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below. [0123] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. [0124] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. [0125] The subject matter further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. [0126] In particular embodiments, the pharmaceutical composition comprising the presently disclosed compounds further comprise a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapeutic agent. [0127] Administration of the compounds of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, inhalation and rectal administration. [0128] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. [0129] A dose may be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamics properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy. [0130] The active compound may be applied as a sole therapy or in combination with one or more therapeutic agents. Such treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment. D. ARTICLES OF MANUFACTURE [0131] In another embodiment of the presently disclosed subject matter is an article of manufacture, or “kit,” containing materials useful for the treatment of the diseases and disorders described herein. The kit comprises a container comprising a compound of Formulae I, II, III, IV, Via and/or IVb. The kit may further comprise a label or package insert, on or associated with the container. The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of Formulae I, II, III, IV, Via and/or IVb or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper able to be pierced by a hypodermic injection needle). At least one active agent in the composition is a compound of Formulae I, II, III, IV, Via and/or IVb. The label or package insert indicates that the composition is used for treating the condition of choice, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is one having a disorder such as NAFLD or NASH. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate- buffered saline, Ringer’s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. [0132] The kit may further comprise directions for the administration of the compound of Formulae I, II, III, IV, Via and/or IVb and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of Formulae I, II, III, IV, Via and/or IVb, and a second pharmaceutical formulation, the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof. [0133] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formulae I, II, III, IV, Via and/or IVb, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a “blister pack”. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. [0134] According to one embodiment, a kit may comprise (a) a first container with a compound of Formulae I, II, III, IV, Via and/or IVb contained therein; and optionally (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound. Alternatively, or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. [0135] In certain other embodiments wherein the kit comprises a composition of Formulae I, II, III, IV, Via and/or IVb and a second therapeutic agent, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet; however, the separate compositions may also be contained within a single, undivided container. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. E. METHODS OF PREPARING [0136] Compounds disclosed herein may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources or are readily prepared using method well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents/or Organic Synthesis, v.1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). [0137] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing Formulae I, II, III, IV, Via and/or IVb compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G .M. Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. [0138] The General Procedures and Examples provide exemplary methods for preparing Formulae I, II, III, IV, Via and/or IVb compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and discussed in the Figures, General Procedures, and Examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. [0139] In preparing compounds, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. F. METHODS OF USE [0140] The compounds and compositions disclosed herein can also be used in methods for treating various diseases and/or disorders that have been identified as being associated with any members of the IP6K family. [0141] The diseases and disorders to be treated include, but are not limited to, degenerative disorders, cancer, diabetes, autoimmune disorders, cardiovascular disorders, clotting disorders, diseases of the eye, infectious disease, and diseases caused by mutations in one or more genes. [0142] More particularly, the diseases and disorders may include diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, obese diabetes), cardiovascular disease (e.g., cardiac failure, arrhythmia, ischemic cardiac diseases, heart valvular disease, arteriosclerosis), obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity etc.), non-alcoholic fatty liver diseases (NAFLD), non-alcoholic steatohepatitis (NASH), hyperphagia, hyperlipidemia/dyslipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL- cholesterolemia, hypo HDL-cholesterolemia, postprandial hyperlipemia), hyperphosphatemia, hypophosphatemia, hyperkalemia, hypertension, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia hypacusis, hypacusis, cerebrovascular diseases, peripheral blood circulation disorder], metabolic syndrome (pathology with not less than 3 selected from hyper-triglycerid(TG)emia, hypo HDL cholesterol(HDL-C)emia, hyper tension, abdomen obesity and impaired glucose tolerance), sarcopenia, emotional disorder, sexual dysfunction, depression, anxiety, neurosis, arteriosclerosis, gonitis, acute renopathy, glaucoma, ischemic disease, myocardial infarction, cerebral apoplexy, dementia, Neurodegenerative dis- eases [e.g., amyotrophic lateral sclerosis], mitochondria disease, Retinitis pigmentosa, glaucoma, osteoporosis, fungal infections and the like. [0143] In accordance with the purpose(s) of the currently disclosed subject matter, as embodied and broadly described herein, in one aspect relates to a method of preventing or treating a disease or disorder mediated by IP6K, the method comprising administering a therapeutically effective amount of a compound of Formula I, II, III, IV, IVa, or IVb to a subject in need thereof. G. EXAMPLES [0144] The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative. [0145] General Information: Microwave reactions were carried out using a CEM Discover-S reactor with a vertically-focused IR external temperature sensor and an Explorer 72 autosampler. The dynamic mode was used to set up the desired temperature and hold time with the following fixed parameters: PreStirring, 1 min; Pressure, 200 psi; Power, 200 W; PowerMax, off; Stirring, high. Sonication was carried out on Branson 3510 Ultrasonic Cell. Centrifugation was carried out on Eppendorf Centrifuge 5418. Flash chromatography was carried out on Teledyne ISCO Combi Flash^® R_f 200 with pre-packed silica gel disposable columns or pre-packed reverse phase C18 columns. Analytical HPLC was performed with prominence diode array detector (SPD-M20A). Samples were injected onto a 3.6 µm PEPTIDE XB-C18100 Å, 150 x 4.6 mm LC column at room temperature. The flow rate was 1.0 mL/min. Various linear gradients were used with A being H₂O + 0.1% TFA and B being acetonitrile + 0.1% TFA. Analytical thin-layer chromatography (TLC) was performed with silica gel 60 F254, 0.25 mm pre-coated TLC plates. TLC plates were visualized using UV₂₅₄ and phosphomolybdic acid with charring. All ¹H NMR spectra were obtained with a 400 or 500 MHz spectrometer using CDCl₃ (7.26 ppm), D

SO- d⁶ (2.50 ppm, quintet) or CD₃OD (3.31 ppm, quintet) as an internal reference. Signals are reported as m (multiplet), s (singlet), d (doublet), t (triplet), q (quartet), and bs (broad singlet), and coupling constants are reported in hertz (Hz). ¹³C NMR spectra were obtained with a 100 or 125 MHz spectrometer using CDCl₃ (77.2 ppm, triplet), DMSO-d⁶ (39.5 ppm, septet), or CD3OD (49.3 ppm, septet) as the internal standard. LC/MS was performed using an analytical instrument with the UV detector set to 220 nm, 254 nm, and 280 nm, and a single quadrupole mass spectrometer using electrospray ionization (ESI) source. Samples were injected (2 μL) onto a 4.6 x 50 mm, 1.8 μM, C18 column at room temperature. A linear gradient from 10% to 100% B (MeOH + 0.1% acetic Acid) in 5.0 min was followed by pumping 100% B for another 2 or 4 min with A being H₂O + 0.1% acetic acid. The flow rate was 1.0 mL/min. High-resolution (positive ion) mass spectra (HRMS) were acquired using a LCMS- TOF mass spectrometer. Purity of all final compounds (>95%) was determined by LC-MS. [0146] Example 1: 4-((2-(3-(4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

o a solution of PPh3 (5.91 g, 22.5 mmol), 2-(3-hydroxyphenyl)acetonitrile (2.00 g, 15.0 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (3.63 g, 18.0 mmol) in THF (200 mL) at 0 ℃. The reaction mixture was stirred at rt for 16 h and then quenched with water. The resulting suspension was diluted saturated brine and extracted with EtOAc (3X, 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by normal phase ISCO to afford tert-butyl 4-(3- (cyanomethyl)phenoxy)piperidine-1-carboxylate as colorless oil (3.90 g, 82% yield). ¹H NMR (400 MHz, CDCl3) δ 7.32 – 7.24 (m, 1H), 6.93 – 6.82 (m, 3H), 4.48 (tt, J = 7.1, 3.5 Hz, 1H), 3.74 – 3.64 (m, 4H), 3.35 (ddd, J = 13.5, 7.7, 3.8 Hz, 2H), 1.97 – 1.85 (m, 2H), 1.82 – 1.67 (m, 2H), 1.47 (s, 9H). MS (ESI) m/z calcd for C₁₈H₂₄N₂NaO₃: 339.17 [M + Na]⁺; found 339.20. [0148] Newly grinded NaOH powder (6.28 g, 157 mmol) was added to i-PrOH (100 mL) and the suspension was sonicated for 1h.5-(4-nitrophenyl)-2H-tetrazole (3.00 g, 15.7 mmol) was then added and the mixture was stirred at rt for another 30 min before the addition of a solution of butyl 4-(3-(cyanomethyl)phenoxy)piperidine-1-carboxylate (6.46 g, 20.4 mmol) in i-PrOH (20 mL). The reaction was stirred at rt for 24 h, quenched with water, and acidified with 1.0 N HCl aqueous solution to pH 4. The resulting suspension was diluted with saturated brine and extracted with EtOAc (3X, 100 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure. The resulting residue was purified by normal phase ISCO to afford tert-butyl 4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidine-1- carboxylate as yellow solid (4.72 g, 65% yield).¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.08 (dd, J = 9.4, 1.4 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.30 (dd, J = 7.9, 2.3 Hz, 1H), 4.77 (tt, J = 7.3, 3.9 Hz, 1H), 3.72 (dt, J = 13.2, 4.8 Hz, 2H), 3.30 – 3.09 (m, 2H), 2.02 – 1.94 (m, 2H), 1.64 – 1.50 (m, 2H), 1.41 (s, 9H). MS (ESI) m/z calcd for C₂₄H₂₇N₆O₄: 463.21 [M + H]⁺; found 463.20. [0149] A solution of tert-butyl 4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidine-1-carboxylate (2.00 g, 4.32 mmol) in methanol (15 mL) was added a 4.0 N HCl solution in dioxane (10 mL). The reaction mixture was stirred at rt for 2h, then concentrated under reduced pressure to yield 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5- yl)benzo[c]isoxazole hydrogen chloride salt as white solid that was used directly in the next step without further purification. MS (ESI) m/z calcd for C₂₄H₂₇N₆O₄: 363.16 [M + H]⁺; found 363.10. [0150] To a solution of tert-butyl 3-(2-aminoethoxy)propanoate (72 mg, 380 μmol) and 2-(2,6- dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (100.0 mg, 362 μmol) in DMAc (5 mL) was added DIEA (189 μL, 1.09 mmol). The reaction mixture was heated at 90 ℃ for 2h, quenched with water, diluted with saturated brine, and extracted with EtOAc (3X, 20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by normal phase ISCO to afford tert-butyl 3-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoate as yellow oil (132 mg, 82% yield).¹H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 5.7 Hz, 1H), 4.91 (dd, J = 12.0, 5.3 Hz, 1H), 3.72 (t, J = 6.5 Hz, 2H), 3.66 (t, J = 5.4 Hz, 2H), 3.44 (q, J = 5.4 Hz, 2H), 3.01 – 2.64 (m, 3H), 2.50 (t, J = 6.5 Hz, 2H), 2.15 – 2.04 (m, 1H), 1.43 (s, 9H). MS (ESI) m/z calcd for C₂₂H₂₈N₃O₇: 446.19 [M + H]⁺; found 446.20. [0151] A solution of tert-butyl 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoate (60 mg, 135 μmol) in CH₂Cl₂ (5 mL) was added TFA (1.0 mL). The reaction mixture was stirred at rt for 1h and concentrated to yield 3-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid TFA salt as yellow oil that was used directly in the next step without further purification. MS (ESI) m/z calcd for C₁₈H₂₀N₃O₇: 376.15 [M + H]⁺; found 376.20. [0152] General procedure A (Amide Coupling Reaction): To a suspension of 3-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic TFA salt, 3-(3-(piperidin- 4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (56 mg, 141 μmol), and HATU (56 mg, 148 μmol) in DMF (5.0 mL) was added DIEA (117 μL, 673 μmol). The resulting mixture was stirred at rt for 2 h, then purified by prep-HPLC (with MeCN and water containing 0.5% TFA as eluents) to afford the title compound as a yellow solid (73 mg, 74% yield over two steps).¹H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.71 (s, 1H), 8.06 (dd, J = 9.4, 1.4 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.65 – 7.62 (m, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.56 (dd, J = 8.6, 7.1 Hz, 1H), 7.27 (dd, J = 8.3, 2.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.58 (s, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.80 (tt, J = 8.0, 3.7 Hz, 1H), 3.98 – 3.72 (m, 2H), 3.70 (t, J = 6.6 Hz, 2H), 3.61 (t, J = 5.4 Hz, 2H), 3.51 – 3.42 (m, 2H), 3.42 – 3.22 (m, 2H), 2.86 (ddd, J = 17.2, 13.9, 5.4 Hz, 1H), 2.62 (t, J = 6.6 Hz, 2H), 2.60 – 2.43 (m, 2H), 2.05 – 1.89 (m, 3H), 1.74 – 1.50 (m, 2H). MS (ESI) m/z calcd for C37H36N9O8: 734.27 [M + H]⁺; found 734.30. [0153] Table 1 describes compounds prepared following procedures described in Example 1 using appropriate reagents. Compound Structure Physical Data

1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.82 (tt, J 5 8 = 0 /z d s, z, 8 8 8 z, 4 7 = ), S + s, z, J J ), 6 ), 0, 0 z, ), or . = 9 z, z, J

= 8.3, 1.9 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H),

p - - - - - - --y -- yl)phenoxy)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[0155 4 mmol) and 2-

(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (300 mg, 1.09 mmo) in DMAc (10 mL) was added DIEA (540 μL, 3.26 mmol). The reaction mixture was heated at 90 ℃ for 2 h, quenched with water at rt, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford 2-(2,6-dioxopiperidin-3-yl)-4-((1-phenyl-2,6,9,12- tetraoxatetradecan-14-yl)amino)isoindoline-1,3-dione (429 mg, 84%) as yellow solid. ¹H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.09 (d, J = 7.1 Hz,

), 6.92 (d, J = 8.5 Hz, 1H), 6.50 (s, 1H), 4.95 – 4.86 (m, 1H), 3.80 – 3.41 (m, 20H), 2.94 – 2.66 (m, 3H), 2.17 – 2.07 (m, 1H). MS (ESI) m/z calcd for C₂₃H₃₂N₃O₉: 494.21 [M + H]⁺; found 494.20. [0156] General procedure B (Dess-Martin Oxidation): To a solution of 2-(2,6-dioxopiperidin- 3-yl)-4-((14-hydroxy-3,6,9,12-tetraoxatetradecyl) amino)isoindoline-1,3-dione (110 mg, 223 μmol) in CH₂Cl₂ (20 mL) was added Dess-Martin periodinane (DMP, 123 mg, 290 μmol). The reaction mixture was stirred at rt for 10 h, then added a saturated aqueous sodium carbonate solution (10 mL) and stirred vigorously at rt for another 30 min. The mixture was extracted with CH₂Cl2 (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was used in the next step without further purification. MS (ESI) m/z calcd for C23H30N3O9: 492.20 [M + H]⁺; found 492.20. [0157] General procedure C (Reductive Amination): To a suspension of KOAc (24 mg, 0.25 mmol), 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxatetradecanal (49 mg, 99 μmol) and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5- yl)benzo[c]isoxazole HCl salt (30 mg, 83 μmol) in DMF (5 mL) was added NaBH(OAc)3 (35 mg, 0.17 mmol). The reaction mixture was stirred at rt for 6 h and was added TFA (0.2 mL). The mixture was directly purified by a reverse ISCO silica gel column to afford 4-((14-(4-(3-(5-(1H- tetrazol-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (32 mg, 46 %).¹H NMR (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.74 (s, 1H), 8.07 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 9.3 Hz, 1H), 7.81 – 7.76 (m, 1H), 7.75 – 7.61 (m, 2H), 7.54 (dd, J = 8.6, 7.1 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.54 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.97 (s, 1H), 4.77 (br, 1H), 3.83 – 3.12 (m, 24H), 2.88 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.66 – 2.42 (m, 2H), 2.38 – 2.27 (m, 1H), 2.12 (br, 2H), 2.07 – 1.96 (m, 1H), 1.96 – 1.84 (m, 1H). MS (ESI) m/z calcd for C42H48N9O10: 838.35 [M + H]⁺; found 838.50. [0158] Table 2 describes compounds prepared following procedures described in Example 2 using appropriate reagents. Compoun Structure Physical Data (s, ), ), z, .6 = ), m, ), 12 m, 10:

9 ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H) 873 (s 1H) 810 – 804 (m 1H) 791

yl)phenoxy)piperidin-1-yl)ethoxy)piperidin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

mg,

2.90 mmol) and 1-(2,2-diethoxyethyl)piperazine (703 mg, 3.48 mmol) in DMSO (10 mL) was added DIPEA (1.51 mL, 8.69 mmol). The reaction mixture was heated under nitrogen at 90 ℃ for 3 h, quenched with water at rt, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford 5-(4-(2,2-diethoxyethyl)piperazin-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.10 g, 2.40 mmol) as yellow solids in 83% yields.¹H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 4.93 (dd, J = 12.2, 5.2 Hz, 1H), 4.68 (t, J = 5.2 Hz, 1H), 3.70 (dq, J = 9.4, 7.1 Hz, 2H), 3.56 (dq, J = 9.4, 7.1 Hz, 2H), 3.47 – 3.38 (m, 4H), 2.93 – 2.74 (m, 3H), 2.74 – 2.67 (m, 4H), 2.61 (d, J = 5.2 Hz, 2H), 2.17 – 2.08 (m, 1H), 1.23 (t, J = 7.1 Hz, 6H). MS (ESI) m/z calcd for C23H31N4O6: 459.22 [M + H]⁺; found 459.20. [0161] 5-(4-(2,2-Diethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (200 mg, 436 μmol) was added a mixture of 4 N HCl in dioxane and water (5 mL/5 mL). The reaction mixture was heated at 50 ℃ for 16 h and neutralized by a saturated aqueous sodium carbonate solution to pH 8 at rt. The mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to yield the desired product 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin- 1-yl)acetaldehyde as a yellow solid that was used in the next step without further purification.¹H NMR (400 MHz, CDCl3) δ 9.73 (t, J = 1.3 Hz, 1H), 8.21 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.5, 2.4 Hz, 1H), 5.00 – 4.87 (m, 1H), 3.52 – 3.46 (m, 4H), 3.29 (d, J = 1.3 Hz, 2H), 2.96 – 2.74 (m, 3H), 2.74 – 2.63 (m, 4H), 2.22 – 2.07 (m, 1H). MS (ESI) m/z calcd for C19H21N4O5: 385.15 [M + H]⁺; found 385.20. [0162] tert-Butyl 4-(2-oxoethoxy)piperidine-1-carboxylate (340 mg, 64%) was prepared according to general procedure B from tert-butyl 4-(2-ydroxyethoxy)piperidine-1-carboxylate (530 mg, 2.16 mmol) and DMP (1.37 g, 3.24 mmol) as colorless oil.¹H NMR (400 MHz, CDCl₃) δ 9.72 (t, J = 1.0 Hz, 1H), 4.10 (d, J = 1.0 Hz, 2H), 3.92 – 3.67 (m, 2H), 3.60 – 3.47 (m, 1H), 3.08 (ddd, J = 13.2, 9.1, 3.5 Hz, 2H), 1.92 – 1.76 (m, 2H), 1.64 – 1.49 (m, 2H), 1.44 (s, 9H). [0163] tert-Butyl 4-(2-(4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin-1- yl)ethoxy)piperidine-1-carboxylate (310 mg, 64%) was prepared according to general procedure C from 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (300 mg, 828 μmol) and tert-butyl 4-(2-oxoethoxy)piperidine-1-carboxylate (242 mg, 993 μmol) as a light yellow solid.¹H NMR (400 MHz, CD3OD) δ 8.68 (t, J = 1.3 Hz, 1H), 8.16 (dd, J = 9.4, 1.3 Hz, 1H), 7.74 (dt, J = 7.7, 1.2 Hz, 1H), 7.69 (dd, J = 9.4, 1.0 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.2, 2.5 Hz, 1H), 4.77 – 4.58 (m, 1H), 3.81 – 3.63 (m, 4H), 3.54 (tt, J = 8.1, 3.7 Hz, 1H), 3.17 – 3.00 (m, 4H), 2.84 (t, J = 5.6 Hz, 2H), 2.77 – 2.65 (m, 2H), 2.21 – 2.06 (m, 2H), 2.03 – 1.77 (m, 4H), 1.54 – 1.40 (m, 11H). MS (ESI) m/z calcd for C31H40N7O5: 590.31 [M + H]⁺; found 590.20. [0164] To a solution of tert-butyl 4-(2-(4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)ethoxy)piperidine-1-carboxylate (300 mg, 509 μmol) in methanol (20 mL) was added a 4.0 N HCl solution in dioxane (15 mL). The reaction mixture was stirred at rt for 6.0 h and concentrated under reduced pressure to yield 3-(3-((1-(2-(piperidin-4- yloxy)ethyl)piperidin-4-yl)oxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt as a yellow solid that was used in the next step without further purification. MS (ESI) m/z calcd for C₂₆H₃₂N₇O₃: 490.26 [M + H]⁺; found 490.30. [0165] The title compound (20 mg, 39%) was prepared according general procedure C from 3- (3-((1-(2-(piperidin-4-yloxy)ethyl)piperidin-4-yl)oxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c] isoxazole HCl salt (35 mg, 67 μmol) and 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)acetaldehyde (26 mg, 67μmol) as a yellow solid.¹H NMR (400 MHz, DMSO- d6) δ 11.09 (s, 1H), 8.75 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.84 – 7.60 (m, 4H), 7.45 (d, J = 2.2 Hz, 1H), 7.39 – 7.28 (m, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.99 (s, 1H), 4.86 – 4.75 (m, 1H), 4.69 – 2.97 (m, 25H), 2.89 (ddd, J = 17.9, 14.1, 5.5 Hz, 1H), 2.64 – 2.48 (m, 2H), 2.42 – 2.30 (m, 1H), 2.24 – 1.72 (m, 8H). MS (ESI) m/z calcd for C45H52N11O7: 858.41 [M + H]⁺; found 858.45. [0166] Table 3 describes compounds prepared following procedures described in Example 3 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 11 ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H),

8.75 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.84 – 7.60 (m, 4H), 7.45 (d, J = 2.2 Hz, 1H), 7.39 – 7.28 (m, 2H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.99 (s, 1H), 4.86 – 4.75 (m, 1H), 4.69 – 2.97 (m, 25H), 2.89 (ddd, J = 17.9, 14.1, 5.5 Hz, 1H), 2.64 – 2.48 (m, 2H), 2.42 – 2.30 (m, 1H), 2.24 – 1.72 (m, 8H). MS (ESI) m/z calcd for C₄₅H₅₂N₁₁O₇: 858.41 [M + H]⁺; found 858.45. 12 ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.73 (s, 1H), 8.07 (dd, J = 9.3, 1.3 Hz, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.74 – 7.62 (m, 2H), 7.59 (d, J = 11.2 Hz, 1H), 7.33 (ddd, J = 11.8, 8.3, 2.5 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 5.01 – 4.97 (m, 1H), 4.79 (s, 1H), 4.04 (s, 2H), 3.92 (s, 2H), 3.64 (d, J = 11.9 Hz, 1H), 3.54 – 3.35 (m, 3H), 3.30 – 2.78 (m, 9H), 2.63 – 2.43 (m, 2H), 2.38 – 2.27 (m, 1H), 2.24 – 2.07 (m, 4H), 2.07 – 1.90 (m, 4H), 1.91 – 1.68 (m, 6H), 1.11 – 0.92 (m, 4H). MS (ESI) m/z calcd for C47H52FN10O6: 871.41 [M + H]⁺; found 871.30. 13 ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.73 (t, J = 1.3 Hz, 1H), 8.07 (dd, J = 9.4, 1.4 83 – 39 – 1H), 3.54 (m, 2H), 1.50 for 30. 14 1H), 7.91 7.75 38 – 1H), 3.41 (m, 0H), MS M + 15 1H), 7.91 7.75 7.38 5.06 Hz, 3 (s, 12.0 J = 2H), 2.06 J = ESI) H]⁺;

16 ¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.75 (s, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.93 (d, J H 1H H 1H 77 – 8 – (dd, 4.76

(m, 1H), 3.91 – 3.47 (m, 4H), 3.46 – 3.08 (m, 6H), 2.94 – 2.84 (m, 1H), 2.84 – 2.74 (m, 1H), 2.67 – 2.45 (m, 2H), 2.42 – 2.30 (m, 1H), 2.27 – 2.06 (m, 3H), 2.07 – 1.86 (m, 2H), 1.85 – 1.72 (m, 1H). MS (ESI) m/z calcd for C₃₇H₃₅FN₉O₆: 720.27 [M + H]⁺; found 720.20. 17 ¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.72 (s, 1H), 8.06 (dd, J = 9.4, 1.4 Hz, 1H), 7.90 Hz, Hz, Hz,

0 (s, 1H), 4.87 – 4.75 (m, 1H), 3.89 – 3.46 (m, 4H), 3.45 – 3.11 (m, 6H), 2.88 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.84 – 2.74 (m, 1H), 2.65 – 2.45 (m, 2H), 2.43 – 2.30 (m, 1H), 2.28 – 2.08 (m, 3H), 2.06 – 1.86 (m, 2H), 1.84 – 1.73 (m, 1H). MS (ESI) m/z calcd for C₃₇H₃₅FN₉O₆: 720.27 [M + H]⁺; found 720.20. 18 ¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.74 (s, 1H), 8.08 (dd, J = 9.3, 1.4 Hz, 1H), 7.92 75 – 38 – (dd,

J = 12.9, 5.4 Hz, 1H), 5.00 (s, 1H), 4.86 – 4.75 (m, 1H), 3.79 (t, J = 8.7 Hz, 1H), 3.75 – 3.43 (m, 6H), 3.42 – 3.04 (m, 8H), 3.01 – 2.83 (m, 3H), 2.82 – 2.71 (m, 1H), 2.66 – 2.45 (m, 2H), 2.42 – 2.29 (m, 1H), 2.25 – 2.08 (m, 4H), 2.07 – 1.86 (m, 4H), 1.82 – 1.71 (m, 1H), 1.52 (q, J = 13.1 Hz, 2H). MS (ESI) m/z calcd for C₄₃H₄₆FN₁₀O₆: 817.36 [M + H]⁺; found 817.20. 19 ¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (s, 1H), 8.73 (s, 1H), 8.07 (dd, J = 9.3, 1.4 Hz, 1H), 7.90 74 – 37 – (dd, 4.76 3.43 (m, (m, 4H), 1.53 for .20. 2H), J = 7.62 2H), 5.4 3.79 2.82 (m, 6H), MS M +

[0167] Example 4: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(4-((4-((4-(3-(5-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin-1-yl)methyl)piperidin-1- yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

0 mg, 1.36 mmol) and piperidin-4-ylmethanol (164 mg, 1.43 mmol) in DMSO (15 mL) was added DIPEA (710 μL, 4.08 mmol). The reaction mixture was heated under nitrogen atmosphere at 100 ℃ for 2 h, quenched with water at rt, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 2-(2,6- dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (430 mg, 81%) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.70 (d, J = 11.5 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 4.50 (s, 1H), 3.61 (d, J = 11.9 Hz, 2H), 2.95 – 2.81 (m, 3H), 2.63 – 2.45 (m, 4H), 2.09 – 1.98 (m, 1H), 1.81 – 1.74 (m, 2H), 1.68 – 1.48 (m, 1H), 1.29 (qd, J = 12.4, 4.0 Hz, 2H). MS (ESI) m/z calcd for C₁₉H₂₁FN₃O₅: 390.15 [M + H]⁺; found 390.10. [0169] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1- yl)isoindoline-1,3-dione (370 mg, 950 μmol) and Et₃N (397 μL, 2.85 mmol) in CH₂Cl₂ (30 mL) was added TsCl (272 mg, 1.43 mmol) and DMAP (23 mg, 190 μmol). The reaction mixture was stirred at rt for 12 h, then was added silica gel. The solvent was removed under reduced pressure. The residue was purified by a normal phase ISCO silica gel column to afford the desired product (1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl 4- methylbenzenesulfonate (350 mg, 68%) as a yellow solid. ¹H NMR (400 MHz, D2O) δ 8.04 (s, 1H), 7.82 – 7.78 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 10.9 Hz, 1H), 7.39 – 7.34 (m, 2H), 4.93 (dd, J = 12.3, 5.3 Hz, 1H), 3.93 (d, J = 6.5 Hz, 2H), 3.67 – 3.60 (m, 2H), 2.95 – 2.66 (m, 5H), 2.46 (s, 3H), 2.18 – 2.07 (m, 1H), 1.99 – 1.76 (m, 3H), 1.51 (qd, J = 12.4, 3.9 Hz, 2H). MS (ESI) m/z calcd for C26H27FN3O7S: 544.16 [M + H]⁺; found 544.10. [0170] To a solution of (1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (285 mg, 524 μmol), 4- (dimethoxymethyl)piperidine (167 mg, 1.05 mmol) and DIPEA (274 μL, 1.57 mmol) in DMF (10 mL) was added NaI (79 mg, 524 μmol). The reaction was heated under nitrogen atmosphere at 90 ℃ for 18 h, quenched with water at rt, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 5-(4- ((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- fluoroisoindoline-1,3-dione (150 mg, 54%) as a yellow solid. MS (ESI) m/z calcd for C27H36FN4O6: 531.26 [M + H]⁺; found 531.20. [0171] To a solution of 5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2- (2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (150 mg, 283 μmol) in a mixture of MeCN (9.0 mL) and water (3.0 mL) was added TFA (1.0 mL). The reaction was stirred at rt for 36 h, quenched with a saturated aqueous Na2CO3 solution, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperidine-4-carbaldehyde (100 mg, 73%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.60 (s, 1H), 7.59 (d, J = 12.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 3.75 – 3.48 (m, 4H), 3.46 – 3.13 (m, 6H), 2.88 (ddd, J = 17.2, 14.0, 5.4 Hz, 1H), 2.64 – 2.43 (m, 2H), 2.32 – 2.18 (m, 1H), 2.17 – 2.07 (m, 1H), 2.06 – 1.89 (m, 3H), 1.88 – 1.34 (m, 6H). MS (ESI) m/z calcd for C₂₅H₃₀FN₄O₅: 485.22 [M + H]⁺; found 485.10. [0172] The title compound (23 mg, 38%) was prepared according to general procedure C from 3-(3-(3-(piperidin-4-yloxy)phenyl)benzo[c]isoxazol-5-yl)-1,2,4-oxadiazol-5(4H)-one HCl salt (33 mg, 79 μmol) and 1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (35 mg, 72 μmol) as a yellow solid.¹H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.55 (s, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.74 – 7.62 (m, 2H), 7.60 (d, J = 12.5 Hz, 1H), 7.39 – 7.32 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 5.00 (s, 1H), 4.85 – 4.74 (m, 1H), 3.75 – 3.42 (m, 6H), 3.36 – 3.02 (m, 8H), 2.99 – 2.82 (m, 3H), 2.64 – 2.45 (m, 2H), 2.38 – 2.31 (m, 1H), 2.30 – 2.21 (m, 1H), 2.20 – 2.07 (m, 4H), 2.06 – 1.73 (m, 6H), 1.70 – 1.59 (m, 1H), 1.54 – 1.40 (m, 2H). MS (ESI) m/z calcd for C₄₅H₄₈FN₈O₈: 847.36 [M + H]⁺; found 847.40. [0173] Table 4 describes compounds prepared following procedures described in Example 4 using appropriate reagents. C_{ompound Structure} ^{Physical Data 1}HNMR and MS m/z (M+1) 21 ¹H NMR (500 MHz, DMSO-d6) δ 11.08 (s,

1H), 8.55 (s, 1H), 7.86 (d, J = 9.4 Hz, 1H), 7.82 – 7.75 (m, 2H), 7.74 – 7.62 (m, 2H), 7.60 (d, J = 12.5 Hz, 1H), 7.39 – 7.32 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 5.00 (s, 1H), 4.85 – 4.74 (m, 1H), 3.75 – 3.42 (m, 6H), 3.36 – 3.02 (m, 8H), 2.99 – 2.82 (m, 3H), 2.64 – 2.45 (m, 2H), 2.38 – 2.31 (m, 1H), 2.30 – 2.21 (m, 1H), 2.20 – 2.07 (m, 4H), 2.06 – 1.73 (m, 6H), 1.70 – 1.59 (m, 1H), 1.54 – 1.40 (m, 2H). MS (ESI) m/z calcd for C₄₅H₄₈FN₈O₈: 847.36 [M + H]⁺; found 847.40. 22 ¹H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H) 11.09 (s 1H) 8.76 (s 1H) 7.93 – 7.82 (m, (m, J =

12.9, 5.4 Hz, 1H), 5.00 (s, 1H), 4.89 – 4.79 (m, 1H), 3.76 – 3.05 (m, 17H), 2.96 – 2.83 (m, 3H), 2.67 – 2.46 (m, 2H), 2.43 – 2.33 (m, 1H), 2.33 – 2.22 (m, 1H), 2.21 – 2.07 (m, 4H), 2.06 – 1.74 (m, 5H), 1.72 – 1.61 (m, 1H), 1.51 – 1.38 (m, 2H). MS (ESI) m/z calcd for C₄₅H₅₁FN₇O₉S: 884.35 [M + H]⁺; found 884.40. 23 ¹H NMR (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.74 – 8.67 (m, 1H), 8.51 (t, J = 1.3 Hz, 1H), 7.87 (dd J = 9.3 1.4 Hz 1H) 7.85 – 7.80 (m 1H) 7.76 (m, , 5.4 1H), 65 – (m, 1.72 m/z H]⁺;

[0174] Example 5: 3-(5-((4-((trans-4-((4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione [0175

.71 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.14 g, 7.43 mmol) and K3PO4 (2.36 g, 11.1 mmol) in a mixture of MeCN (36 mL) and water (4.0 mL) was added Pd(dppf)Cl2 (163 mg, 223 μmol). The reaction mixture was degassed (3x) and then heated under nitrogen at 90 ℃ for 1.0 h, quenched with water at rt, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 3-(1-oxo-5- vinylisoindolin-2-yl)piperidine-2,6-dione (740 mg, 74%) as a white solid. ¹H NMR (400 MHz,

DMSO-d6) δ 10.99 (s, 1H), 7.74 – 7.66 (m, 2H), 7.62 (dd, J = 7.9, 1.4 Hz, 1H), 6.87 (dd, J = 17.6, 11.0 Hz, 1H), 6.00 (d, J = 17.7 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 2.91 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.65 – 2.55 (m, 1H), 2.40 (qd, J = 13.3, 4.5 Hz, 1H), 2.06 – 1.95 (m, 1H). MS (ESI) m/z calcd for C15H15N2O: 271.11 [M + H]⁺; found 271.10. [0176] To a solution of 3-(1-oxo-5-vinylisoindolin-2-yl)piperidine-2,6-dione (520 mg, 1.92 mmol) and 2,6-lutidine (412 mg, 3.85 mmol) in a mixture of dioxane (20 mL) and water (5.0 mL) was added NaIO4 (1.65 g, 7.70 mmol) and a solution of OsO4 (25 mg, 96 μmol) in t-BuOH (0.5 mL). The reaction mixture was stirred at rt for 12 h, quenched with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5- carbaldehyde (460 mg, 88%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.15 (s, 1H), 8.15 (d, J = 1.3 Hz, 1H), 8.06 (dd, J = 7.8, 1.3 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 5.16 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 17.6 Hz, 1H), 4.45 (d, J = 17.6 Hz, 1H), 2.92 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.67 – 2.56 (m, 1H), 2.42 (qd, J = 13.3, 4.6 Hz, 1H), 2.09 – 1.99 (m, 1H). MS (ESI) m/z calcd for C₁₄H₁₃N₂O₄: 273.09 [M + H]⁺; found 273.10. [0177] tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazine-1- carboxylate (81 mg, 25%) was prepared according to general procedure C from 2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde (200 mg, 735 μmol) and tert-butyl piperazine-1-carboxylate (178 mg, 955 μmol) as a white solid.¹H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.47 – 7.38 (m, 2H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.31 (d, J = 16.0 Hz, 1H), 3.58 (s, 2H), 3.42 (t, J = 5.0 Hz, 4H), 3.06 – 2.66 (m, 2H), 2.47 – 2.26 (m, 5H), 2.25 – 2.11 (m, 1H), 1.44 (s, 9H). MS (ESI) m/z calcd for C23H31N4O5: 443.23 [M + H]⁺; found 443.10. [0178] General procedure D (Boc Deprotection): To a solution of tert-butyl 4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazine-1-carboxylate (30 mg, 68 μmol) in CH₂Cl2 (5.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at rt for 3 h, then concentrated under reduced pressure to yield the desired product 3-(1-oxo-5-(piperazin-1- ylmethyl)isoindolin-2-yl)piperidine-2,6-dione TFA salt that was used directly in the next step without further purification. MS (ESI) m/z calcd for C18H23N4O3: 343.18 [M + H]⁺; found 343.20. [0179] The title compound (29 mg, 52%) was prepared according to general procedure C from crude 3-(1-oxo-5-(piperazin-1-ylmethyl)isoindolin-2-yl)piperidine-2,6-dione and trans-4-((4-(3- (5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin-1-yl)methyl) cyclohexane-1- carbaldehyde (33 mg, 68 μmol) as a light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.75 (t, J = 1.2 Hz, 1H), 8.08 (dt, J = 9.4, 1.3 Hz, 1H), 7.92 (dt, J = 9.4, 0.9 Hz, 1H), 7.83 – 7.76 (m, 2H), 7.75 – 7.61 (m, 3H), 7.58 (d, J = 7.8 Hz, 1H), 7.33 (ddd, J = 11.6, 8.1, 2.4 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 5.03 – 4.95 (m, 1H), 4.85 – 4.73 (m, 1H), 4.48 (d, J = 17.5 Hz, 1H), 4.36 (d, J = 17.5 Hz, 1H), 4.16 (s, 2H), 3.62 (d, J = 12.4 Hz, 1H), 3.43 (d, J = 11.9 Hz, 2H), 3.36 – 2.80 (m, 15H), 2.67 – 2.55 (m, 1H), 2.42 (qd, J = 13.3, 4.6 Hz, 1H), 2.36 – 2.26 (m, 1H), 2.13 (s, 2H), 2.05 – 1.62 (m, 8H), 1.09 – 0.89 (m, 4H). MS (ESI) m/z calcd for C45H53N10O5: 813.42 [M + H]⁺; found 813.30. [0180] Table 5 describes compounds prepared following procedures described in Example 5 using appropriate reagents. C_{ompound Structure} ^{Physical Data 1}HNMR and MS m/z (M+1) 24 ¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H),

8.75 (t, J = 1.2 Hz, 1H), 8.08 (dt, J = 9.4, 1.3 Hz, 1H), 7.92 (dt, J = 9.4, 0.9 Hz, 1H), 7.83 – 7.76 (m, 2H), 7.75 – 7.61 (m, 3H), 7.58 (d, J = 7.8 Hz, 1H), 7.33 (ddd, J = 11.6, 8.1, 2.4 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 5.03 – 4.95 (m, 1H), 4.85 – 4.73 (m, 1H), 4.48 (d, J = 17.5 Hz, 1H), 4.36 (d, J = 17.5 Hz, 1H), 4.16 (s, 2H), 3.62 (d, J = 12.4 Hz, 1H), 3.43 (d, J = 11.9 Hz, 2H), 3.36 – 2.80 (m, 15H), 2.67 – 2.55 (m, 1H), 2.42 (qd, J = 13.3, 4.6 Hz, 1H), 2.36 – 2.26 (m, 1H), 2.13 (s, 2H), 2.05 – 1.62 (m, 8H), 1.09 – 0.89 (m, 4H). MS (ESI) m/z calcd for C45H53N10O5: 813.42 [M + H]⁺; found 813.30.

[0181] Example 6: 3-(5-((4-((4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)methyl)piperidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione [0182

ng to general procedures C, D, and C from 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbaldehyde (70 mg, 257 μmol), 4-(dimethoxymethyl)piperidine (61 mg, 386 μmol), TFA (1.0 mL), and 3-(3- (piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (30 mg, 80 μmol) as a light yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.75 (t, J = 1.3 Hz, 1H), 8.09 (dd, J = 9.3, 1.4 Hz, 1H), 7.93 (dd, J = 9.4, 1.0 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.83 – 7.75 (m, 2H), 7.75 – 7.61 (m, 3H), 7.38 – 7.32 (m, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 5.00 (s, 1H), 4.86 – 4.74 (m, 1H), 4.52 (d, J = 17.7 Hz, 1H), 4.46 (s, 2H), 4.40 (d, J = 17.7 Hz, 1H), 3.73 – 3.59 (m, 1H), 3.57 – 3.39 (m, 3H), 3.38 – 2.85 (m, 7H), 2.68 – 2.57 (m, 1H), 2.50 – 2.27 (m, 2H), 2.24 – 1.81 (m, 7H), 1.57 – 1.38 (m, 2H). MS (ESI) m/z calcd for C₃₉H₄₂N₉O₅: 716.33 [M + H]⁺; found 716.30. [0183] Table 6 describes compounds prepared following procedures described in Example 6 using appropriate reagents. C_{ompound Structure} ^{Physical Data 1}HNMR and MS m/z (M+1) 25 ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.75 (t, J = 1.3 Hz, 1H), 8.09 (dd, J = 9.3, 1.4 Hz, 7.8 3H), 1H), 17.7 1H), 8 – (m, MS H]⁺;

[0184] Example 7: 3-(5-((1-((trans-4-((4-(3-(5-(2H-tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0185] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol) and Et3N (2.08 ml, 14.9 mmol) in CH₂Cl2 (50 mL) was added TsCl (1.23 g, 6.46 mmol) and DMAP (61 mg, 497 μmol). The reaction mixture was stirred at rt for 6 h, then was added Silica gel. The solvent was removed under reduced pressure. The residue was purified by a normal phase ISCO silica gel column to afford the desired product tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (1.40 g, 79%) as colorless oil.¹H NMR (400 MHz, CDCl₃) δ 7.83 – 7.76 (m, 2H), 7.38 – 7.31 (m, 2H), 4.67 (tt, J = 7.5, 3.8 Hz, 1H), 3.59 (ddd, J = 13.7, 7.4, 4.0 Hz, 2H), 3.25 (ddd, J = 13.7, 7.6, 4.0 Hz, 2H), 2.45 (s, 3H), 1.83 – 1.61 (m, 4H), 1.43 (s, 9H). [0186] To a solution of 3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 384 μmol) and tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (178 mg, 500 μmol) in DMF (10 mL) was added potassium carbonate (106 mg, 768 μmol). The reaction mixture was heated under nitrogen atmosphere at 90 ℃ for 16 h, quenched with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1- carboxylate (135 mg, 79%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.4, 2.2 Hz, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.73 – 4.66 (m, 1H), 4.38 (d, J = 17.1 Hz, 1H), 4.26 (d, J = 17.1 Hz, 1H), 3.67 (dt, J = 13.9, 4.8 Hz, 2H), 3.32 – 3.08 (m, 2H), 2.90 (ddd, J = 18.1, 13.5, 5.3 Hz, 1H), 2.63 – 2.54 (m, 1H), 2.38 (qd, J = 13.2, 4.4 Hz, 1H), 2.03 – 1.90 (m, 3H), 1.65 – 1.47 (m, 2H), 1.41 (s, 9H). MS (ESI) m/z calcd for C23H30N3O6: 444.21 [M + H]⁺; found 444.20. [0187] The title compound (40 mg, 60% over 2 steps) was prepared according to general procedures D&C from tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)oxy)piperidine-1-carboxylate (40 mg, 90 μmol) and trans-4-((4-(3-(5-(1H-tetrazol-5- yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin-1-yl)methyl)cyclohexane-1-carbaldehyde (40 mg, 82 μmol) as a light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.73 (s, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.76 (t, J = 7.1 Hz, 1H), 7.73 – 7.55 (m, 3H), 7.31 (t, J = 10.5 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7.12 (dd, J = 15.1, 8.4 Hz, 1H), 5.07 (dd, J = 13.2, 5.0 Hz, 1H), 4.98 (s, 1H), 4.88 (s, 1H), 4.84 – 4.73 (m, 1H), 4.73 – 4.62 (m, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 3.61 (t, J = 10.3 Hz, 2H), 3.42 (t, J = 9.0 Hz, 2H), 3.31 – 2.81 (m, 9H), 2.63 – 2.55 (

1H), 2.45 – 2.22 (m, 3H), 2.22 – 2.03 (m, 4H), 2.02 – 1.65 (m, 9H), 1.11 – 0.89 (m, 4H). MS (ESI) m/z calcd for C₄₅H₅₂N₉O₆: 814.40 [M + H]⁺; found 814.40. [0188] Table 7 describes compounds prepared following procedures described in Example 7 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 26 ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.73 (s, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.76 (t, J = 7.1 Hz, 1H), 7.73 – 7.55 (m, 3H), 7.31 (t, J = 10.5 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7.12 (dd, J =

15.1, 8.4 Hz, 1H), 5.07 (dd, J = 13.2, 5.0 Hz, 1H), 4.98 (s, 1H), 4.88 (s, 1H), 4.84 – 4.73 (m, 1H), 4.73 – 4.62 (m, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 3.61 (t, J = 10.3 Hz, 2H), 3.42 (t, J = 9.0 Hz, 2H), 3.31 – 2.81 (m, 9H), 2.63 – 2.55 (m, 1H), 2.45 – 2.22 (m, 3H), 2.22 – 2.03 (m, 4H), 2.02 – 1.65 (m, 9H), 1.11 – 0.89 (m, 4H). MS (ESI) m/z calcd for C45H52N9O6: 814.40 [M + H]⁺; found 814.40. [0189] Example 8: 3-(5-(3-(2-(2-(2-(4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)ethoxy)ethoxy)ethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

-1- oxoisoindolin-2-yl)piperidine-2,6-dione (400 mg, 1.24 mmol) in a mixture of DMF and Et3N (18 mL/6mL) was added Pd(PPh₃)₂Cl₂ (87 mg, 124 μmol) and CuI (47 mg, 248 μmol). The reaction mixture was heated under nitrogen at 85 ℃ for 16 h, quenched with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 3-(5-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)prop-1-yn-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (220 mg, 1.24 mmol) as colorless oil in 74% yields. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.64 – 7.46 (m, 2H), 5.20 (dd, J = 13.3, 5.2 Hz, 1H), 4.53 – 4.40 (m, 3H), 4.31 (d, J = 16.2 Hz, 1H), 3.82 – 3.75 (m, 2H), 3.75 – 3.64 (m, 8H), 3.64 – 3.58 (m, 2H), 2.96 – 2.74 (m, 2H), 2.34 (qd, J = 13.0, 5.1 Hz, 1H), 2.26 – 2.15 (m, 1H). MS (ESI) m/z calcd for C₂₂H₂₇N₂O₇: 431.18 [M + H]⁺; found 431.10. [0191] The title compound (23 mg, 42 % over 2 steps) was prepared according to general procedures B&C from 3-(5-(3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)prop-1-yn-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, 186 μmol), DMP (118 mg, 279 μmol), and 3-(3- (piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (29 mg, 74 μmol) as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.73 (t, J = 1.2 Hz, 1H), 8.07 (d, J = 9.3 Hz, 1H), 7.92 (dd, J = 9.4, 1.0 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.74 – 7.60 (m, 4H), 7.52 (dd, J = 7.9, 2.9 Hz, 1H), 7.36 – 7.25 (m, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.96 (s, 1H), 4.84 – 4.68 (m, 1H), 4.46 – 4.37 (m, 3H), 4.30 (d, J = 17.5 Hz, 1H), 3.79 (t, J = 5.2 Hz, 2H), 3.72 – 3.54 (m, 10H), 3.52 – 3.12 (m, 4H), 2.90 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.44 – 2.29 (m, 2H), 2.13 (br, 2H), 2.05 – 1.82 (m, 2H). MS (ESI) m/z calcd for C₄₁H₄₃N₈O₈: 775.32 [M + H]⁺; found 775.30. [0192] Table 8 describes compounds prepared following procedures described in Example 8 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 27 ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s,

1H), 8.73 (t, J = 1.2 Hz, 1H), 8.07 (d, J = 9.3 Hz, 1H), 7.92 (dd, J = 9.4, 1.0 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.74 – 7.60 (m, 4H), 7.52 (dd, J = 7.9, 2.9 Hz, 1H), 7.36 – 7.25 (m, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.96 (s, 1H), 4.84 – 4.68 (m, 1H), 4.46 – 4.37 (m, 3H), 4.30 (d, J = 17.5 Hz, 1H), 3.79 (t, J = 5.2 Hz, 2H), 3.72 – 3.54 (m, 10H), 3.52 – 3.12 (m, 4H), 2.90 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.44 – 2.29 (m, 2H), 2.13 (br, 2H), 2.05 – 1.82 (m, 2H). MS (ESI) m/z calcd for C41H43N8O8: 775.32 [M + H]⁺; found 775.30. 28 ¹H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 9.2 Hz, 3H), Hz, 2H), Hz,

1H), 3.87 (t, J = 4.8 Hz, 2H), 3.84 – 3.71 (m, 3H), 3.69 – 3.26 (m, 8H), 3.25 – 3.08 (m, 3H), 3.06 – 2.96 (m, 1H), 2.85 (ddd, J = 17.5, 13.6, 5.4 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.45 – 2.29 (m, 2H), 2.16 (br, 3H), 2.09 – 1.87 (m, 4H), 1.83 – 1.60 (m, 1H). MS (ESI) m/z calcd for C44H48N9O7: 814.37 [M + H]⁺; found 814.35. 29 ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.74 (s, 1H), 8.09 (dd, J = 9.4, 1.3 Hz, 1H), 7.92 (d, J = 9.4 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.75 – 7.60 (m, 4H), 7.56 (d, J = 7.9

Hz, 1H), 7.41 – 7.23 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.96 (s, 1H), 4.89 – 4.74 (m, 1H), 4.43 (d, J = 17.5 Hz, 1H), 4.33 (d, J = 17.5 Hz, 1H), 3.93 – 3.73 (m, 6H), 3.61 – 3.13 (m, 13H), 3.06 – 2.83 (m, 4H), 2.68 – 2.55 (m, 1H), 2.47 – 2.29 (m, 2H), 2.24 – 2.08 (m, 2H), 2.06 – 1.83 (m, 2H). MS (ESI) m/z calcd for C₄₃H₄₇N₁₀O₆: 799.37 [M + H]⁺; found 799.35. 30 ¹H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H) 873 (d J = 11 Hz 1H) 807 (dd J = 9.4, 7.75 (m,

9 (s, 1H), 4.88 – 4.75 (m, 1H), 4.49 (d, J = 17.7 Hz, 1H), 4.42 (s, 2H), 4.37 (d, J = 17.7 Hz, 1H), 3.78 – 3.39 (m, 6H), 3.39 – 2.98 (m, 8H), 2.99 – 2.78 (m, 3H), 2.66 – 2.56 (m, 1H), 2.48 – 2.29 (m, 2H), 2.27 – 1.86 (m, 10H), 1.61 – 1.47 (m, 4H). MS (ESI) m/z calcd for C47H53N10O5: 837.42 [M + H]⁺; found 837.40. 31 ¹H NMR (400 MHz DMSO-d₆) δ 11.01 (s, 9.3, 9 (t, 68 – 7.33

, J = 13.2, 5.1 Hz, 1H), 4.99 (t, J = 3.4 Hz, 1H), 4.85 – 4.73 (m, 1H), 4.51 (s, 2H), 4.47 (d, J = 17.7 Hz, 1H), 4.34 (d, J = 17.7 Hz, 1H), 3.96 (t, J = 3.5 Hz, 1H), 3.83 – 3.70 (m, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 11.7 Hz, 1H), 3.37 (d, J = 11.7 Hz, 1H), 3.30 – 2.79 (m, 9H), 2.66 – 2.55 (m, 1H), 2.40 (qd, J = 13.3, 4.4 Hz, 1H), 2.31 (br, 1H), 2.25 – 2.08 (m, 3H), 2.06 – 1.91 (m, 4H), 1.90 – 1.65 (m, 7H), 1.01 (s, 4H). MS (ESI) m/z calcd for C48H54N9O6: 852.42 [M + H]⁺; found 852.30. 32 0 (s, 1H), Hz, 2H), 1.4, 9 (t, (dd, 3.9 (m, (m, (m, 9O₅: 33 1 (s, 9.3, 1H), 7.38 1H), J =

17.7 Hz, 1H), 4.43 (s, 2H), 4.36 (d, J = 17.7 Hz, 1H), 3.78 – 3.59 (m, 3H), 3.57 – 3.43 (m, 1H), 3.38 – 3.00 (m, 6H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.65 – 2.56 (m, 1H), 2.48 – 2.27 (m, 2H), 2.26 – 1.87 (m, 7H), 1.64 – 1.39 (m, 2H). MS (ESI) m/z calcd for C41H42N9O5: 740.33 [M + H]⁺; found 740.40. 34 ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.75 (t, J = 1.3 Hz, 1H), 8.08 (dd, J = 9.4, 1H), 7.38 7.26 Hz,

1H), 5.42 (dd, J = 12.8, 5.4 Hz, 1H), 5.00 (s, 1H), 4.89 – 4.70 (m, 1H), 4.36 (s, 2H), 3.76 – 3.42 (m, 6H), 3.36 (s, 3H), 3.33 – 2.97 (m, 8H), 2.97 – 2.84 (m, 3H), 2.80 – 2.58 (m, 2H), 2.44 – 2.27 (m, 1H), 2.24 – 1.85 (m, 10H), 1.64 – 1.39 (m, 4H). MS (ESI) m/z calcd for C₄₇H₅₄N₁₁O₅: 852.43 [M + H]⁺; found 852.40. 35 ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.75 (s, 1H), 8.08 (d, J = 9.4 Hz, 1H), Hz, 2H), Hz, 0 (s, J = (m, (m, Hz, 1O5: 36 (s, 1H), 83 – J = 0 (s, 1 (s, (m,

6H), 3.39 – 2.83 (m, 10H), 2.77 (t, J = 6.6 Hz, 2H), 2.43 – 2.28 (m, 1H), 2.26 – 1.86 (m, 9H), 1.54 (m, 4H). MS (ESI) m/z calcd for C46H53N12O4: 837.43 [M + H]⁺; found 837.35. 37 ¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.78 (s, 1H), 8.11 (dd, J = 9.4, 1.4 Hz, (m, 3.1, 1H), 3.13 (m, alcd und

[0193] Example 9: 4-(3-(2-(4-(2-(4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)ethoxy)piperidin-1-yl)ethoxy)propyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione

[ ] -( , - oxopper n- -y)- -( -( - y roxye oxy)prop- -yn- -y)isoindoline-1,3- dione (310 mg, 59%) was prepared according to general procedure E from 3-(5-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.48 mmol) and 2-(prop-2-yn-1-yloxy)ethan-1- ol (223 mg, 2.22 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 7.96 – 7.82 (m, 3H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 4.50 (s, 2H), 3.65 – 3.53 (m, 4H), 2.89 (m, 1H), 2.65 – 2.46 (m, 2H), 2.12 – 2.01 (m, 1H). MS (ESI) m/z calcd for C18H17N2O6: 357.11 [M + H]⁺; found 357.10. [0195] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)prop-1-yn-1- yl)isoindoline-1,3-dione (200 mg, 561 μmol) in a mixture of THF (20 mL) and dioxane (10 mL) was added 10% Pd/C (10 mg, 5%) and Pd(OH)2/C (10 mg, 5%). The reaction mixture was then stirred under hydrogen atmosphere at rt for 12 h, then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to yield the desired product 2-(2,6-dioxopiperidin-3-yl)- 4-(3-(2-hydroxyethoxy)propyl)isoindoline-1,3-dione that was used in the next step without further purification. MS (ESI) m/z calcd for C₁₈H₂₁N₂O₆: 361.14 [M + H]⁺; found 361.20. [0196] The title compound (22 mg, 39 %) was prepared according to general procedures B&C from 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)propyl)isoindoline-1,3-dione (60 mg, 167 μmol), DMP (245 mg, 577 μmol), and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5- yl)benzo[c]isoxazole HCl salt (66 mg, 167 μmol) as a yellow solid.¹H NMR (400 MHz, DMSO- d6) δ 11.13 (s, 1H), 8.74 (s, 1H), 8.08 (dd, J = 9.4, 1.4 Hz, 1H), 7.92 (dd, J = 9.3, 0.9 Hz, 1H), 7.85 – 7.57 (m, 6H), 7.39 – 7.26 (m, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.99 (s, 1H), 4.79 (br, 1H), 3.86 – 2.97 (m, 21H), 2.89 (ddd, J = 16.9, 13.7, 5.4 Hz, 1H), 2.69 – 2.44 (m, 2H), 2.42 – 2.26 (m, 1H), 2.26 – 1.76 (m, 9H), 1.73 – 1.58 (m, 1H). MS (ESI) m/z calcd for C44H50N9O8: 832.38 [M + H]⁺; found 832.35. [0197] Table 9 describes compounds prepared following procedures described in Example 9 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 38 ¹H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 874 1H 808 dd J 94 14 H 1H 792 H), z, m, 69 76 cd 5.

[0198] Example 10: (2S,4R)-1-((S)-2-(4-(4-(3-(5-(2H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [

0 99] suspens on o ( S,4 )- -((S)- -am no-3,3-dmet y butanoy )- - ydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide HCl salt (100 mg, 214 μmol) and 4-(tert- butoxy)-4-oxobutanoic acid (41 mg, 236 μmol) in DMF (10 mL) was added HATU (90 mg, 236 μmol) and DIEA (149 μL, 856 μmol). The resulting mixture was stirred at rt for 3h, quenched with water, diluted with saturated brine, and extracted with EtOAc (3X, 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure. The resulting residue was purified by normal phase ISCO silica gel column to afford the desired product tert-butyl 4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl -1-oxobutan-2-yl)amino)-4-oxobutanoate as colorless oil (108 mg, 86%).¹H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.44 (t, J = 6.0 Hz, 1H), 7.39 – 7.29 (m, 4H), 6.54 (d

= 8.6 Hz, 1H), 4.73 (t, J = 8.0 Hz, 1H), 4.58 – 4.45 (m, 3H), 4.33 (dd, J = 15.0, 5.3 Hz, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.59 (dd, J = 11.4, 3.6 Hz, 1H), 2.60 – 2.32 (m, 8H), 2.19 – 2.06 (m, 1H), 1.41 (s, 9H), 0.92 (s, 9H). MS (ESI) m/z calcd for C30H43N4O6S: 587.29 [M + H]⁺; found 587.30. [0200] The title compound (42 mg, 63% over 2 steps) was prepared according to general procedures D&A from tert-butyl 4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoate (45 mg, 77 μmol) and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (34 mg, 84 μmol) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.72 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.07 (dd, J = 9.4, 1.4 Hz, 1H), 7.95 – 7.87 (m, 2H), 7.74 (dt, J = 7.8, 1.1 Hz, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.45 – 7.35 (m, 4H), 7.31 (dd, J = 8.0, 2.4 Hz, 1H), 4.93 – 4.76 (m, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.47 – 4.39 (m, 2H), 4.38 – 4.31 (m, 1H), 4.22 (dd, J = 15.9, 5.5 Hz, 1H), 3.98 – 3.72 (m, 2H), 3.71 – 3.58 (m, 2H), 3.44 – 3.19 (m, 2H), 2.65 – 2.35 (m, 7H), 2.14 – 1.82 (m, 4H), 1.76 – 1.47 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z calcd for C45H51N10O7S: 875.37 [M + H]⁺; found 875.40. [0201] Table 10 describes compounds prepared following procedures described in Example 10 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 39 ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.72 (s, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.07 (dd, J dt, H), H), m, m, 5.5 m, H), 94 7S: H), , J dt, H), H), .7, 37 .9, m, H),

2.14 – 1.81 (m, 4H), 1.78 – 1.48 (m, 2H), 0.93 (s, 9H). MS (ESI) m/z calcd for C47H55N10O8S: 1 M H ⁺ f 1 4 41 1H), d, J (dt, 1H), 4H), 8.0, 4.38 5.8, (m, 7H), 0.93 O₉S: 42 1H), d, J (dt, 1H),

7.61 (t, J = 8.0 Hz, 1H), 7.45 – 7.34 (m, 4H), 7.29 (dd, J = 8.3, 1.9 Hz, 1H), 4.82 (tt, J = 7.8, 3.7 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.48 – 4.38 (m, 2H), 4.38 – 4.31 (m, 1H), 4.21 (dd, J = 15.9, 5.5 Hz, 1H), 3.98 – 3.71 (m, 2H), 3.70 – 3.43 (m, 14H), 3.43 – 3.20 (m, 2H), 2.72 – 2.28 (m, 7H), 2.11 – 1.82 (m, 4H), 1.77 – 1.50 (m, 2H), 0.93 (s, 9H). MS (ESI) m/z calcd for C₅₁H₆₃N₁₀O₁₀S: 1007.44 [M + H]⁺; found 1007.50. 43 ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.71 (t, J = 1.3 Hz, 1H), 8.55 (t, J = 6.1 Hz, 1H), 8.06 (dd, J = 9.4, 1.4 Hz, 1H), 7.94 – 7.85 (m,

2H), 7.73 (dt, J = 7.7, 1.3 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.45 – 7.35 (m, 4H), 7.29 (dd, J = 8.3, 1.9 Hz, 1H), 4.82 (tt, J = 7.8, 3.7 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.47 – 4.38 (m, 2H), 4.38 – 4.32 (m, 1H), 4.21 (dd, J = 15.9, 5.5 Hz, 1H), 3.99 – 3.71 (m, 2H), 3.71 – 3.43 (m, 18H), 3.43 – 3.23 (m, 2H), 2.66 – 2.29 (m, 7H), 2.09 – 1.84 (m, 4H), 1.74 – 1.49 (m, 2H), 0.93 (s, 9H). MS (ESI) m/z calcd for C54H68N9O11S: 1051.47 [M + H]⁺; found 1051.30. 44 ¹H NMR (500 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.71 (t, J = 1.3 Hz, 1H), 8.62 (t, J = 6.1 Hz, 1H), 8.06 (dd, J = 9.3, 1.4 Hz, 1H), 7.93 – 7.87 (m, 2H), 7.73 (dt, J = 7.8, 1.1 Hz, 1H), 7.65 (t, J = 2.1 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.43 – 7.33

(m, 4H), 7.31 – 7.25 (m, 1H), 4.82 (tt, J = 7.9, 3.7 Hz, 1H), 4.48 (d, J = 9.0 Hz, 1H), 4.44 (dd, J = 15.8, 6.7 Hz, 1H), 4.37 (dd, J = 8.7, 6.0 Hz, 1H), 4.26 (dd, J = 15.8, 5.6 Hz, 1H), 4.21 (t, J = 5.6 Hz, 1H), 3.97 – 3.89 (m, 2H), 3.81 – 3.72 (m, 1H), 3.66 – 3.54 (m, 5H), 3.51 – 3.42 (m, 5H), 3.42 – 3.34 (m, 1H), 3.33 – 3.21 (m, 1H), 2.60 (t, J = 6.6 Hz, 2H), 2.58 – 2.47 (m, 1H), 2.43 (s, 3H), 2.40 – 2.28 (m, 2H), 2.09 – 1.91 (m, 3H), 1.75 (dt, J = 12.3, 5.9 Hz, 1H), 1.72 – 1.63 (m, 1H), 1.62 – 1.52 (m, 1H), 0.94 (s, 9H). MS (ESI) m/z calcd for C₄₉H₅₉N₁₀O₉S: 963.42 [M + H]⁺; found 963.40. [0202] Example 11: (2S,4R)-1-((S)-2-(3-(2-(2-(4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)ethoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0203] tert-Butyl 3-(2-(2-oxoethoxy)ethoxy)propanoate (250 mg, 84%) was prepared according to general procedure B from DMP (815 mg, 1.92 mmol) and tert-butyl 3-(2-(2- hydroxyethoxy)ethoxy)propanoate (300 mg, 1.28 mmol) as colorless oil ¹H NMR (400 MHz, CDCl3) δ 9.72 (t, J = 0.9 Hz, 1H), 4.14 (d, J = 0.9 Hz, 2H), 3.75 – 3.69 (m, 4H), 3.69 – 3.64 (m,

2H), 2.50 (t, J = 6.5 Hz, 2H), 1.44 (s, 9H). [0204] tert-Butyl 3-(2-(2-(4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3-yl)phenoxy)piperidin- 1-yl)ethoxy)ethoxy)propanoate (90 mg, 41%) was prepared according to general procedure C from NaBH(OAc)₃ (239 mg, 1.13 mmol), tert-butyl 3-(2-(2-oxoethoxy)ethoxy)propanoate (175 mg, 752 μmol), and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (150 mg, 376 μmol) as a light yellow solid. ¹H NMR (400 MHz, CD3OD) δ 8.63 (t, J = 1.2 Hz, 1H), 8.14 (dd, J = 9.4, 1.2 Hz, 1H), 7.74 – 7.61 (m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.15 – 7.11 (m, 1H), 4.88 – 4.81 (m, 1H), 3.83 (t, J = 5.1 Hz, 2H), 3.69 – 3.63 (m, 4H), 3.63 – 3.57 (m, 2H), 3.54 – 3.43 (m, 2H), 3.41 – 3.32 (m, 4H), 2.44 (t, J = 6.1 Hz, 2H), 2.31 – 2.07 (m, 4H), 1.39 (s, 9H). MS (ESI) m/z calcd for C30H39N6O6: 579.29 [M + H]⁺; found 579.30. [0205] The title compound (38 mg, 68% over 2 steps) was prepared according to general procedures D&A from tert-butyl 3-(2-(4-(2-(4-(3-(5-(1H-tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)ethyl)piperidin-1-yl)ethoxy)propanoate (35 mg, 60 μmol) and (2S,4R)- 1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide HCl salt (28 mg, 60 μmol) as a light yellow solid.¹H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.74 (t, J = 1.2 Hz, 1H), 8.56 (t, J = 6.1 Hz, 1H), 8.08 (dt, J = 9.3, 1.4 Hz, 1H), 7.96 – 7.88 (m, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.75 – 7.59 (m, 2H), 7.43 – 7.29 (m, 5H), 4.98 (t, J = 3.4 Hz, 1H), 4.86 – 4.71 (m, 1H), 4.55 (dd, J = 9.4, 3.5 Hz, 1H), 4.46 – 4.38 (m, 2H), 4.38 – 4.31 (m, 1H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 3.81 – 3.73 (m, 2H), 3.70 – 3.49 (m, 9H), 3.49 – 3.11 (m, 6H), 2.62 – 2.48 (m, 1H), 2.43 (s, 3H), 2.41 – 2.30 (m, 1H), 2.19 – 2.09 (m, 2H), 2.08 – 2.01 (m, 1H), 1.98 – 1.82 (m, 2H), 0.92 (s, 9H). MS (ESI) m/z calcd for C₄₈H₅₉N₁₀O₈S: 935.42 [M + H]⁺; found 935.30. [0206] Table 11 describes compounds prepared following procedures described in Example 11 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 45 ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.74 (t, J = 1.2 Hz, 1H), 8.56 (t, J = 6.1 Hz, 1H), 8.08 (dt, J = 9.3, 1.4 Hz, 1H), 7.96 – 7.88 (m, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.75 – 7.59 (m, 2H), 7.43 – 7.29 (m, 5H), 4.98 (t, J =

3.4 Hz, 1H), 4.86 – 4.71 (m, 1H), 4.55 (dd, J = 9.4, 3.5 Hz, 1H), 4.46 – 4.38 (m, 2H), 4.38 – 4.31 (m, 1H), 4.22 (dd, J = 15.8, 5.4 Hz, 1H), 3.81 – 3.73 (m, 2H), 3.70 – 3.49 (m, 9H), 3.49 – 3.11 (m, 6H), 2.62 – 2.48 (m, 1H), 2.43 (s, 3H), 2.41 – 2.30 (m, 1H), 2.19 – 2.09 (m, 2H), 2.08 – 2.01 (m, 1H), 1.98 – 1.82 (m, 2H), 0.92 (s, 9H). MS (ESI) m/z calcd for C48H59N10O8S: 935.42 [M + H]⁺; found 935.30. 46 ¹H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.75 (t, J = 1.2 Hz, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.13 – 8.05 (m, 1H), 7.93 (dd, J = 9.4, 1.0 Hz, 2H), 7.80 (t, J = 7.5 Hz, 1H), 7.76

– 7.61 (m, 2H), 7.46 – 7.37 (m, 4H), 7.34 (td, J = 8.6, 2.5 Hz, 1H), 4.99 (t, J = 3.3 Hz, 1H), 4.86 – 4.73 (m, 1H), 4.57 (dd, J = 9.5, 1.4 Hz, 1H), 4.49 – 4.40 (m, 2H), 4.40 – 4.34 (m, 1H), 4.23 (dd, J = 15.9, 5.5 Hz, 1H), 3.85 – 3.76 (m, 2H), 3.73 – 3.13 (m, 18H), 2.63 – 2.49 (m, 1H), 2.45 (s, 3H), 2.42 – 2.30 (m, 2H), 2.21 – 2.10 (m, 2H), 2.10 – 2.01 (m, 1H), 2.00 – 1.86 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z calcd for C50H63N10O9S: 979.45 [M + H]⁺; found 979.40. 47 ¹H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H 875 J = 13 H 1H 862 – 854 (m, Hz, (m, Hz, Hz, 1H), 3.57 2 (q, 49 –

2.41 (m, 4H), 2.40 – 2.30 (m, 1H), 2.21 – 2.00 (m, 3H), 1.99 – 1.71 (m, 4H), 1.70 – 1.50 (m, 3H), 1.50 – 1.33 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z calcd for C53H68N11O7S: 1002.50 [M + H]⁺; found 1002.35. [0207] Example 12: (2S,4R)-N-(2-(2-(2-(3-(4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)- 2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamide S S HO N O O O N O O

[0208] To a suspension of K₂CO₃ (47 mg, 0.34 mmol) and (2S,4R)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (60 mg, 0.11 mmol) in DMF (10 mL) was added a solution of tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propanoate (130 mg, 0.45 mmol) in DMF (1.0 mL) and NaI (8.0 mg, 56 μmol). The reaction mixture was heated at 70 ℃ for 16 h, quenched with water, and extracted with EtOAc (3X, 20 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated under reduced pressure. The resulting residue was purified by normal phase ISCO silica gel column to afford the desired product tert-butyl 3-(2- (2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethoxy)ethoxy) propanoate (58 mg, 70%) as a white solid. MS (ESI) m/z calcd for C₃₇H₅₄FN₄O₉S: 749.36 [M + H]⁺; found 749.30. [0209] The title compound (42 mg, 76% over 2 steps) was prepared according to general procedures D&A from 3-(2-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5- yl)phenoxy)ethoxy)ethoxy) propanoate (40 mg, 53 μmol) and (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide HCl salt (21 mg, 53 μmol) as a light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.70 (t, J = 1.3 Hz, 1H), 8.48 (t, J = 6.0 Hz, 1H), 8.05 (dd, J = 9.4, 1.4 Hz, 1H), 7.88 (dd, J = 9.4, 1.0 Hz, 1H), 7.71 (dt, J = 7.8, 1.2 Hz, 1H), 7.62 (t, J = 2.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.03 (d, J = 1.7 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 4.79 (tt, J = 7.9, 3.7 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.52 (t, J = 8.2 Hz, 1H), 4.39 – 4.27 (m, 2H), 4.26 – 4.15 (m, 3H), 3.92 (dt, J = 11.3, 4.7 Hz, 1H), 3.83 – 3.71 (m, 3H), 3.70 – 3.57 (m, 6H), 3.57 – 3.51 (m, 2H), 3.42 – 3.32 (m, 1H), 3.32 – 3.21 (m, 1H), 2.59 (t, J = 6.7 Hz, 2H), 2.44 (s, 3H), 2.14 – 2.06 (m, 1H), 2.06 – 1.87 (m, 3H), 1.74 – 1.49 (m, 2H), 1.42 – 1.27 (m, 2H), 1.26 – 1.14 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z calcd for C52H62FN10O10S: 1037.44 [M + H]⁺; found 1037.40. [0210] Table 12 describes compounds prepared following procedures described in Example 12 using appropriate reagents. C_{ompound Structure} ^{Physical Data 1}HNMR and MS m/z (M+1) 48 ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H),

1 H 1H 4 Hz, 1H), 8.05 (dd, J = 9.4, 1.4 Hz, 1H), 7.88 (dd, J = 9.4, 1.0 Hz, 1H), 7.71 (dt, J = 7.8, 1.2 Hz, 1H), 7.62 (t, J = 2.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.03 (d, J = 1.7 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 4.79 (tt, J = 7.9, 3.7 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.52 (t, J = 8.2 Hz, 1H), 4.39 – 4.27 (m, 2H), 4.26 – 4.15 (m, 3H), 3.92 (dt, J = 11.3, 4.7 Hz, 1H), 3.83 – 3.71 (m, 3H), 3.70 – 3.57 (m, 6H), 3.57 – 3.51 (m, 2H), 3.42 – 3.32 (m, 1H), 3.32 – 3.21 (m, 1H), 2.59 (t, J = 6.7 Hz, 2H), 2.44 (s, 3H), 2.14 – 2.06 (m, 1H), 2.06 – 1.87 (m, 3H), 1.74 – 1.49 (m, 2H), 1.42 – 1.27 (m, 2H), 1.26 – 1.14 (m, 2H), 0.94 (s, 9H). MS (ESI) m/z calcd for C52H62FN10O10S: 1037.44 [M + H]⁺; found 1037.40. 49 ¹H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.64 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.01 (dd, Hz, (m, 9.3, 7.02 Hz, 8.3 (m,

5H), 3.67 – 3.55 (m, 2H), 3.42 – 3.32 (m, 1H), 3.33 – 3.22 (m, 1H), 2.63 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.14 – 2.04 (m, 1H), 2.03 – 1.84 (m, 3H), 1.70 – 1.49 (m, 2H), 1.40 – 1.24 (m, 2H), 1.24 – 1.14 (m, 2H), 0.92 (s, 9H). MS (ESI) m/z calcd for C50H58FN10O9S: 993.41 [M + H]⁺; found 993.30. [0211] Example 13: (2S,4R)-N-((S)-3-((2-(3-(4-(3-(5-(2H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-1-(4-(4-methylthiazol-5-yl)phenyl)-3- oxopropyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4- hydroxypyrrolidine-2-carboxamide

O OH O OH O O O O F N N H H ₂N N N O_H ^F H _N O O

p g, p p p g general procedures A, D, and A from (S)-3-((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-(4-methylthiazol-5-yl)phenyl) propanoic acid (50 mg, 87 μmol), tert-butyl 3-(2-aminoethoxy)propanoate (21 mg, 0.11 mmol), TFA (1.0 mL), and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (26 mg, 64 μmol) as a light yellow solid.¹H NMR (500 MHz, DMSO-d₆) δ 9.04 – 8.98 (m, 1H), 8.73 – 8.67 (m, 1H), 8.54 (dd, J = 7.9, 2.0 Hz, 1H), 8.08 – 8.01 (m, 1H), 7.94 (t, J = 5.7 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.76 – 7.68 (m, 1H), 7.66 – 7.57 (m, 2H), 7.43 – 7.39 (m, 2H), 7.40 – 7.30 (m, 2H), 7.30 – 7.22 (m, 2H), 5.23 – 5.12 (m, 1H), 4.85 – 4.76 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.49 – 4.39 (m, 1H), 4.30 – 4.24 (m, 1H), 3.95 – 3.87 (m, 1H), 3.76 – 3.68 (m, 1H), 3.64 – 3.50 (m, 4H), 3.47 – 3.22 (m, 4H), 3.22 – 3.07 (m, 2H), 2.66 – 2.59 (m, 2H), 2.55 (t, J = 6.5 Hz, 2H), 2.44 (s, 3H), 2.11 – 1.91 (m, 3H), 1.79 – 1.71 (m, 1H), 1.70 – 1.61 (m, 1H), 1.61 – 1.51 (m, 1H), 1.40 – 1.25 (m, 2H), 1.24 – 1.15 (m, 2H), 0.96 (s, 9H). MS (ESI) m/z calcd for C₅₂H₆₁FN₁₁O₉S: 1034.44 [M + H]⁺; found 1034.40. [0213] Table 13 describes compounds prepared following procedures described in Example 13 using appropriate reagents. C_{ompound Structure} ^{Physical Data 1}HNMR and MS m/z (M+1) 50 ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 – 8.98 (m, 1H), 8.73 – 8.67 (m, 1H), 8.54 (dd, J = 7.9, J = 7.68 (m, 2H),

5.23 – 5.12 (m, 1H), 4.85 – 4.76 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.49 – 4.39 (m, 1H), 4.30 – 4.24 (m, 1H), 3.95 – 3.87 (m, 1H), 3.76 – 3.68 (m, 1H), 3.64 – 3.50 (m, 4H), 3.47 – 3.22 (m, 4H), 3.22 – 3.07 (m, 2H), 2.66 – 2.59 (m, 2H), 2.55 (t, J = 6.5 Hz, 2H), 2.44 (s, 3H), 2.11 – 1.91 (m, 3H), 1.79 – 1.71 (m, 1H), 1.70 – 1.61 (m, 1H), 1.61 – 1.51 (m, 1H), 1.40 – 1.25 (m, 2H), 1.24 – 1.15 (m, 2H), 0.96 (s, 9H). MS (ESI) m/z calcd for C52H61FN11O9S: 1034.44 [M + H]⁺; found 1034.40. 51 ¹H NMR (500 MHz, DMSO-d6) δ 9.05 – 8.97 (m, 1H), 8.72 – 8.65 (m, 1H), 8.53 (dd, J = 7.9, J = 7.67 (m,

2H), 7.38 – 7.31 (m, 2H), 7.28 (dd, J = 8.5, 2.5 Hz, 1H), 7.24 (dd, J = 9.5, 2.8 Hz, 1H), 5.22 – 5.13 (m, 1H), 4.85 – 4.76 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.49 – 4.40 (m, 1H), 4.30 – 4.25 (m, 1H), 3.95 – 3.87 (m, 1H), 3.79 – 3.70 (m, 1H), 3.65 – 3.51 (m, 4H), 3.50 – 3.22 (m, 8H), 3.21 – 3.06 (m, 2H), 2.66 – 2.54 (m, 4H), 2.44 (s, 3H), 2.10 – 1.92 (m, 3H), 1.80 – 1.71 (m, 1H), 1.71 – 1.61 (m, 1H), 1.61 – 1.51 (m, 1H), 1.41 – 1.27 (m, 2H), 1.26 – 1.14 (m, 2H), 0.96 (s, 9H). MS (ESI) m/z calcd for C₅₄H₆₅FN₁₁O₁₀S: 1078.46 [M + H]⁺; found 1078.35. 52 ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 – 8.98 7.9, J = 7.69 (m,

2H), 7.39 – 7.33 (m, 2H), 7.30 (dd, J = 8.1, 2.5 Hz, 1H), 7.25 (dd, J = 9.3, 2.8 Hz, 1H), 5.23 – 5.13 (m, 1H), 4.87 – 4.78 (m, 1H), 4.58 (d, J = 9.2 Hz, 1H), 4.49 – 4.40 (m, 1H), 4.31 – 4.25 (m, 1H), 3.97 – 3.89 (m, 1H), 3.81 – 3.73 (m, 1H), 3.67 – 3.53 (m, 4H), 3.53 – 3.22 (m, 12H), 3.22 – 3.06 (m, 2H), 2.67 – 2.55 (m, 4H), 2.45 (s, 3H), 2.11 – 1.92 (m, 3H), 1.80 – 1.72 (m, 1H), 1.72 – 1.62 (m, 1H), 1.62 – 1.52 (m, 1H), 1.42 – 1.28 (m, 2H), 1.26 – 1.17 (m, 2H), 0.97 (s, 9H). MS (ESI) m/z calcd for C56H69FN11O11S: 1122.49 [M + H]⁺; found 1122.40. 53 ¹H NMR (500 MHz, DMSO-d6) δ 9.02 – 8.94 (m, 1H), 8.73 (s, 1H), 8.51 (d, J = 8.8 Hz, 1H), 9.3 7.60 (m, 1H), 4.58 Hz, Hz,

), . – . (m, ), . – . (m, 7H), 2.50 – 2.43 (m, 4H), 2.39 – 2.28 (m, 1H), 2.21 – 1.98 (m, 4H), 1.94 – 1.72 (m, 2H), 1.70 – 1.42 (m, 5H), 1.42 – 1.29 (m, 2H), 1.26 – 1.13 (m, 2H), 0.97 (s, 9H). MS (ESI) m/z calcd for C₅₄H₆₅FN₁₁O₇S: 1030.48 [M + H]⁺; found 1030.40.

54 _HN ^{N 1}H NMR (500 MHz, DMSO-d₆) δ 9.01 (s, 1H), N N 8.75 (s, 1H), 8.51 (dd, J = 10.5, 8.0 Hz, 1H), H 1H Hz, (m, H), 5.02 d, J 39 – 70 – 2.52 2.23 3 – 1.12 for und 1H), (d, (d, 7.75 7 –

. , , . . , , . 5.11 (m, 1H), 5.00 – 4.93 (m, 1H), 4.82 – 4.72 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.44 (t, J = 8.3 Hz, 1H), 4.29 – 4.24 (m, 1H), 3.78 – 3.71 (m, 2H), 3.66 – 3.07 (m, 16H), 2.65 – 2.53 (m, 2H), 2.43 (s, 3H), 2.38 – 2.29 (m, 1H), 2.20 – 2.01 (m, 3H), 1.98 – 1.81 (m, 1H), 1.77 – 1.69 (m, 1H), 1.41 – 1.27 (m, 2H), 1.27 – 1.13 (m, 2H), 0.96 (s, 9H). MS (ESI) m/z calcd for C53H65FN11O9S: 1050.47 [M + H]⁺; found 1050.40. [0214] Example 14: N-(2-(3-(4-(3-(5-(2H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)-3-oxopropoxy)ethyl)-2-(adamantan-1-yl)acetamide

[ ] tert- uy -( -( -(a aman an- -y )ace am o)e oxy)propanoa e ( mg, 465 μmol) was prepared according to general procedure A from tert-butyl 3-(2-aminoethoxy)propanoate (100 mg, 528 μmol), 2-(adamantan-2-yl)acetic acid (123 mg, 634 μmol), HATU (241 mg, 634 μmol) and DIPEA (276 μL, 1.59 mmol) as colorless oil in 88% yields. ¹H NMR (400 MHz, CDCl₃) δ 6.14 (br, 1H), 3.66 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 5.1 Hz, 2H), 3.42 (q, J = 5.1 Hz, 2H), 2.47 (t, J = 6.0 Hz, 2H), 2.02 – 1.90 (m, 5H), 1.75 – 1.56 (m, 12H), 1.45 (s, 9H). [0216] The title compound (46 mg, 84% over 2 steps) was prepared according to general procedures D&A from tert-butyl 3-(2-(2-(adamantan-2-yl)acetamido)ethoxy)propanoate (45 mg, 0.12 mmol) and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H-tetrazol-5-yl)benzo[c]isoxazole HCl salt (45 mg, 0.11 mmol) as a light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t, J = 1.2 Hz, 1H), 8.03 (dd, J = 9.3, 1.4 Hz, 1H), 7.87 (dd, J = 9.3, 1.0 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.64 – 7.54 (m, 2H), 7.28 (dd, J = 7.6, 2.5 Hz, 1H), 4.82 (tt, J = 7.8, 3.7 Hz, 1H), 4.00 – 3.87 (m, 1H), 3.84 – 3.70 (m, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.46 – 3.34 (m, 3H), 3.29 (ddd, J = 12.7, 8.8, 3.4 Hz, 1H), 3.17 (q, J = 5.8 Hz, 2H), 2.63 – 2.56 (m, 2H), 2.10 – 1.92 (m, 2H), 1.86 (t, J = 3.1 Hz, 3H), 1.81 (s, 2H), 1.73 – 1.46 (m, 14H). MS (ESI) m/z calcd for C36H44N7O5: 654.34 [M + H]⁺; found 654.40. [0217] Table 14 describes compounds prepared following procedures described in Example 14 using appropriate reagents. Compound Structure Physical Data ¹HNMR and MS m/z (M+1) 56 ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t, J = 1.2 Hz, 1H), 8.03 (dd, J = 9.3, 1.4 Hz, 1H),

7.87 (dd, J = 9.3, 1.0 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.64 – 7.54 (m, 2H), 7.28 (dd, J = 7.6, 2.5 Hz, 1H), 4.82 (tt, J = 7.8, 3.7 Hz, 1H), 4.00 – 3.87 (m, 1H), 3.84 – 3.70 (m, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.46 – 3.34 (m, 3H), 3.29 (ddd, J = 12.7, 8.8, 3.4 Hz, 1H), 3.17 (q, J = 5.8 Hz, 2H), 2.63 – 2.56 (m, 2H), 2.10 – 1.92 (m, 2H), 1.86 (t, J = 3.1 Hz, 3H), 1.81 (s, 2H), 1.73 – 1.46 (m, 14H). MS (ESI) m/z calcd for C36H44N7O5: 654.34 [M + H]⁺; found 654.40. 57 ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (t, J = 1.2 Hz, 1H), 8.02 (dd, J = 9.3, 1.4 Hz, 1H), 7.85 (dd, J = 9.3, 1.0 Hz, 1H), 7.72 – 7.63 (m, 2H), 7.63 – 7.54 (m, 2H), 7.26 (dd, J = 8.0, 2.4 Hz, 1H), 4.82 (tt, J = 7.9, 3.6 Hz, 1H), 3.99 – 3.89 (m, 1H), 3.79 – 3.68 (m, 1H), 3.36 (ddd, J = 13.0, 8.8, 3.2 Hz, 1H), 3.31 – 3.18 (m, 3H), 2.09 – 1.92 (m, 2H), 1.87 (t, J = 3.1 Hz, 3H), 1.79 (d, J = 2.8 Hz, 2H), 1.71 – 1.44 (m, 14H). MS (ESI) m/z calcd for C₃₄H₄₀N₇O₄: 610.31 [M + H]⁺; found 610.20. [0218] Example 15: N-(3-(4-(3-(5-(1H-Tetrazol-5-yl)benzo[c]isoxazol-3- yl)phenoxy)piperidin-1-yl)-3-oxopropyl)-2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetamide

[0219] To a solution of 1,2,3,4-tetrahydroquinolin-6-ol (1.00 g, 6.70 mmol) and Et3N (3.74 mL, 26.8 mmol) in THF was added 2-chloroacetyl chloride (2.27 g, 20.1 mmol). The reaction mixture was stirred at rt for 5 h, then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by a normal phase ISCO silica gel column to afford the desired product 1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl 2-chloroacetate (1.68 g, 83%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.36 (br, 1H), 7.12 – 6.86 (m, 2H), 4.30 (s, 2H), 4.21 (s, 2H), 3.82 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.02 (p, J = 6.7 Hz, 2H). [0220] A suspension of 1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl 2-chloroacetate (1.00 g, 1.31 mmol) in a mixture of dioxane (10 ml) and 2.0 N aqueous NaOH solution (10 mL) was stirred at rt for 3 h, quenched by water, neutalized with acetic acid to pH 7, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product 2-chloro-1-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)ethan- 1-one (635 mg, 85%) as a white solid. [0221] To a suspension of Cs2CO3 (3.32 g, 10.2 mmol) and 2-chloro-1-(6-hydroxy-3,4- dihydroquinolin-1(2H)-yl)ethan-1-one (1.15 g, 5.10 mmol) in DMF (30 mL) was added a solution of tert-butyl 2-bromoacetate (1.49 g, 7.64 mmol) in DMF (3 mL). The reaction mixture was stirred at rt for 6 h, quenched with water, and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by normal phase ISCO silica gel column to afford the desired product tert-butyl 2- ((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (1.20 g, 68%) as a white solid. [0222] tert-Butyl 3-(2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetamido) propanoate (82 mg, 68% over 2 steps) was prepared according to general procedures D&A from tert-butyl 2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetate (100 mg, 294 μmol) and tert-butyl 3-aminopropanoate (51 mg, 353 μmol) as a white solid.¹H NMR (400 MHz, CDCl3) δ 7.22 – 6.99 (m, 2H), 6.86 – 6.52 (m, 2H), 4.45 (s, 2H), 4.17 (s, 2H), 3.78 (t, J = 6.6 Hz, 2H), 3.57 (q, J = 6.1 Hz, 2H), 2.74 (br, 2H), 2.47 (t, J = 6.1 Hz, 2H), 2.13 – 1.80 (m, 2H), 1.43 (s, 9H). MS (ESI) m/z calcd for C16H20ClN2O5: 355.11 [M – isobutene + H]⁺; found 355.10. [0223] The title compound (55 mg, 65% over 2 steps) was prepared according to general procedures D&A from tert-butyl 3-(2-((1-(2-chloroacetyl)-1,2,3,4-tetrahydroquinolin-6- yl)oxy)acetamido)propanoate (60 mg, 146 μmol) and 3-(3-(piperidin-4-yloxy)phenyl)-5-(1H- tetrazol-5-yl)benzo[c]isoxazole HCl salt (49 mg, 122 μmol) as a light yellow solid.¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.85 (br, 1H), 7.75 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.15 (br, 1H), 7.06 (dd, J = 8.3, 2.4 Hz, 1H), 6.85 – 6.62 (m, 2H), 4.73 – 4.64 (m, 1H), 4.58 (s, 2H), 4.26 (s, 2H), 3.94 – 3.60 (m, 7H), 3.59 – 3.42 (m, 1H), 2.76 (t, J = 5.8 Hz, 2H), 2.69 (br, 2H), 2.14 – 1.80 (m, 6H). MS (ESI) m/z calcd for C₃₅H₃₆ClN₈O₆: 699.24 [M + H]⁺; found 699.30. [0224] Table 15 describes compounds prepared following procedures described in Example 15 using appropriate reagents. Compound Structure Physical Data 1HNMR and MS m/z (M+1) 58 ¹H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.85 (br, 1H), 7.75 (d, J = 9.3 H 1H 768 d J = 77 H 1H 756 1H 748 .3, m, H), 69 cd 30. 10 H), 46 br, 39 H), for 09 H), H), = H), H), – for

[0225] Example 16: IP6K degradation assays: [0226] Fully confluent HEK293 cells were treated with DMSO or indicated concentrations of the IP6K degraders in 6-well plates. After six hours, cells were washed with PBS, lysed with a lysis buffer (20 mM Tris-HCl, pH 7.4; 1% Triton X-100, 150 mM NaCl and protease and phosphatase inhibitors). After centrifugation, the supernatant, containing soluble proteins, were taken, and protein concentrations estimated by the BCA assay method. SDS-PAGE analysis was done to detect the proteins of interest. Fifty μg of total proteins were loaded on each lane. Levels of IP6K1-3 and GAPDH were detected by immunoblotting. IP6K1 siRNA was used to confirm the band of IP6K1 in the immunoblot experiment. See FIG.1. [0227] Table 16. Degradation activity. ((Note: +++ means > 50% degradation below 30 nM; ++ means >50 % degradation below 1 uM, + means >50% degradation below 10 uM; - means inactive.) C_ompound ^IP6K1 IP6K2 degradation degradation 1 - 2 - 3 - 4 ^{+ +} 5 ⁺ 6 - 7 ⁺ 8 - 9 ⁺ 1₀ ⁺ 1₁ ⁺ 1₂ ^{+++ +} 1₃ ⁺⁺⁺ 1₄ ^{+++ +++} 1₅ ⁺⁺⁺ 1₆ ^{- -} ₁₇ ^{++ -} ₁₈ ^{+++ ++} _{19 20 21 22}

_{23 24} ⁺⁺ ₂₅ ^{+++ +++} ₂₆ ^{+++ +++} ₂₇ - ₂₈ - ₂₉ - ₃₀ ⁺⁺ _{31 32 33 34 35 36 37 38 39 40 41}

₄₂ -

_{43 44} - 4₅ ^{+ -} 4₆ ^{- -} 4₇ ^{- -} 4₈ ^{++ -} 4₉ ^{++ +} 5₀ ^{- -} 5₁ ^{- -} 5₂ ^{- -} 5₃ ^{+ -} 5₄ ^{++ -} 5₅ ^{+ -} 5₆ - 5₇ - 5₈ - 5₉ ⁺ 6₀ ⁺ [0228] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other aspects of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. [0001] References 1. Montesi, L.; El Ghoch, M.; Brodosi, L.; Calugi, S.; Marchesini, G.; Dalle Grave, R., Long- term weight loss maintenance for obesity: a multidisciplinary approach. Diabetes, metabolic syndrome and obesity: targets and therapy 2016, 9, 37. 2. 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Claims

What is claimed is: A compound of Formula I: N O R²

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is aryl or heteroaryl; R¹ is –OR³-L-M, wherein R³ is selected from alkyl, aryl, heteroaryl, and heterocycloalkyl; O O O O N R² is heteroaryl, ;

H O N L is a linker selected from the group consisting of -E-F-, , O

O O O ,

, , -CH₂CH₂OCH₂CH₂- N N _O ^N ,

w eren F s seected rom t e group consstng o a bond, -C(=O)-,-CH₂CH₂OCH₂CH₂-, N N N , ,

,

group consisting of 0, 1, 2, 3, 4, and 5, and A and B are independently selected from a bond, –CH₂-, -CH₂CH₂O-, - CH₂CH₂NH-, -CH₂CH₂C(=O)NH-, -C(=O)-, -C(=O)NH-, -NHC(=O)-, and a – ne,

pyrrolidine, and triazole; and M is a moiety selected from the group consisting of , ,

, , .

2. The compound of claim 1, wherein X is phenyl. 3. The compound of claim 1 or claim 2, wherein R² is selected from the group consisting of .

5. The compound of claim 3, wherein R² is . 6. The compound of claim 4, wherein the compound is a compound of Formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ is –OR³-L-M, R³ is selected from alkyl, aryl, heteroaryl, and heterocycloalkyl. 7. The compound of claim 6, wherein R³ is a heterocycloalkyl selected from the group consisting of piperidinone, piperidinyl, morpholino, azetidinyl, and pyrrolidinyl. 8. The compound of claim 7, wherein R³ is piperidinyl. 9. The compound of claim 6, wherein the compound is a compound of Formula IV:

or a pharmaceutically acceptable sal

eof, wherein or -E-F-, wherein p is an integer selected from the group consist

nd B are independently selected from a bond, –CH₂-, -CH₂CH₂O- , -CH₂CH₂NH-, -CH₂CH₂C(=O)NH-, -C(=O)-, -C(=O)NH-, -NHC(=O)-, , wherein

E is selected from the group consisting of -CH₂-, -C(=O), ,

, wherein F is selected from the

, ,

M is a moiety selected from the group consistin ,

10. The compound of claim 9, wherein R is hydrogen or fluorine. 11. The compound of claim 10, wherein M is a moiety selected from the group consisting of N n_d

12. The compound of claim 11, wherei F-, wherein

E is and F is selected from the group consisting of and

13. The compound of claim 12, wherei F-, wherein

E i F i ein

15. The compound of claim 11, wherei F-, wherein

nd

16. The compound of claim 15, wherei F-, wherein

E is and F is a bond.

17. The compound of claim 15, wherei F-, wherein

H a_{nd the linker is -E-F-, wherein}

.

19. The compound of claim 11, wherei F-, wherein E is

selected from the group consisting of d F is

20. The compound of claim 19, wherei F-, wherein E is

.

21. The compound of claim 19, wherein M i F-, wherein E is

.

22. The compound of claim 11, wherei F-, wherein

, and F is selected from the group consisting and

23. The compound of claim 22, wherei F-, wherein

24. The compound of claims 22, wherein M i F-, wherein

E is and F is .

compound is present in at least a 95% enantiomeric excess (% ee). 26. The compound of claim 1, wherein the compound is present in at least 95% diastereomeric excess (% de). 27. A compound having one of the following structures: , , ,

, , or

28. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier or excipient. 29. A method of preventing or treating a disease or disorder mediated by IP6K and/or IPMK, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof. 30. The method of claim 29, wherein the disease or disorder is selected from obesity, obesity related diseases, hyperphosphatemia, fungal infections, cancer, and viral infections. 31. The method of claim 30, wherein the obesity related diseases are non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). 32. The method of claim 30, wherein the cancer is glioblastoma. 33. The method of claim 30, wherein the viral infection is coronavirus. 34. The method of claim 30, wherein the disorder is hyperphosphatemia. 35. The method of claim 30, wherein the fungal infection is caused by a yeast strain. 36. The method of claim 35, wherein the yeast strain is selected from Cryptococcus neoformans and Candida albicans. 37. A kit for treating a disease or disorder mediated by IP6K and/or IPMK, the kit comprising: 1) a pharmaceutical composition comprising a compound of Formula I, and 2) instructions for use. 38. A compound of claim 1 for use as a medicament, and for use in treating a disease or disorder mediated by IP6K and/or IPMK. 39. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier or excipient. 40. A method of preventing or treating a disease or disorder mediated by IP6K and/or IPMK, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.