WO2025043065A1

WO2025043065A1 - Modulators of myc family proto-oncogene protein

Info

Publication number: WO2025043065A1
Application number: PCT/US2024/043367
Authority: WO
Inventors: William Greenlee; Stephen J. Shuttleworth; Keith Wilson
Original assignee: Nalo Therapeutics Inc
Current assignee: Nalo Therapeutics Inc
Priority date: 2023-08-24
Filing date: 2024-08-22
Publication date: 2025-02-27
Anticipated expiration: 2026-02-24

Abstract

Disclosed herein are compounds and compositions having potency in the modulation of Myc family proteins. Such compounds and compositions can be used in the treatment of proliferative diseases, such as cancer, or in the treatment of disease where modulation of Myc family proteins is desired. Also disclosed herein are methods of using said compounds and compositions.

Description

Attorney Docket No. NAL-008WO MODULATORS OF MYC FAMILY PROTO-ONCOGENE PROTEIN CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] For example, amplification and overexpression of N-Myc can lead to tumorigenesis.

[0004] C-Myc can also be constitutively expressed in various cancers such as cervix, colon,

outcomes. However, strategies for direct modulation of Myc proteins remain elusive, as the Myc proteins are not easily targeted. [0006] Therefore, an ongoing need exists for small-molecule therapeutic modulators of Myc proteins for the treatment of various ailments, diseases and disorders, e.g., cancer. IPTS/128670292.1 Attorney Docket No. NAL-008WO SUMMARY [0007] The present disclosure provides compounds and compositions that are useful as Myc protein modulators, and methods of using the same. Furthermore, the present disclosure contemplates using disclosed compounds and compositions as direct modulators of Myc proteins in the treatment of proliferative disease, such as cancer, or in the treatment of diseases where modulation of Myc family proteins is desired. [0008] For example, provided herein is a compound represented by Formula I:

(Formula I) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH₃, O, S, CH₂, CF₂, CH(CH₃),

ring X is 5-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl (optionally substituted by one or two C₁-C₄ alkyl), provided that ring X is not

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C₁-C₄ alkyl (optionally substituted by one, two or three halogens), oxo, C₁-C₄ alkoxy, and cyano; L¹ is bond or C₁-C₆ alkylene (optionally substituted by one, two or three R⁴); R³ is OR’; IPTS/128670292.1 Attorney Docket No. NAL-008WO R⁴ is each independently selected from the group consisting of halogen and C₁-C₆ alkyl (optionally substituted by one, two or three halogens), or two R⁴ together with the carbon to which the R⁴ are attached form a C₃-C₅ carbocyclyl; R’ is each independently selected from the group consisting of H and C₁-C₆ alkyl (optionally substituted by one, two or three halogens); R¹ is selected from the group consisting of C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, heteroaryl, cyano, halo, C₁-C₄alkyl, and H; wherein C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens); and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. [0009] Also provided herein is a compound represented by Formula II:

(Formula II) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH₃, O, S, CH₂, CF₂, CH(CH₃),

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; IPTS/128670292.1 Attorney Docket No. NAL-008WO ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C₁-C₄ alkyl (optionally substituted by one, two or three halogens), oxo, C₁-C₄ alkoxy, and cyano; L¹ is bond or C₁-C₆ alkylene (optionally substituted by one, two or three R⁴); R³ is OR’; R⁴ is each independently selected from the group consisting of halogen and C₁-C₆ alkyl (optionally substituted by one, two or three halogens), or two R⁴ together with the carbon to which the R⁴ are attached form a C₃-C₅ carbocyclyl; R’ is each independently selected from the group consisting of H and C₁-C₆ alkyl (optionally substituted by one, two or three halogens); R¹ is selected from the group consisting of C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, heteroaryl, cyano, halo, C₁-C₄alkyl, and H; wherein C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens); and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. [0010] Pharmaceutical compositions comprising a disclosed compound or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, as described herein, for example a disclosed pharmaceutical composition may include least one or more pharmaceutically acceptable carriers, diluents, stabilizers, excipients, dispersing agents, suspending agents, and/or thickening agents. The present disclosure also provides a method of manufacturing of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. [0011] A method of modulating the amount and activity of a Myc family protein (i.e., C- Myc, N-Myc, L-Myc, or human Myc) is also provided, for example, an activity of a Myc family IPTS/128670292.1 Attorney Docket No. NAL-008WO protein may be modulated in a cell by contacting a cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. [0012] The present disclosure also provides a method of treating a Myc family protein associated disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, including embodiments in any examples, tables, or figures. In some embodiments, the subject is a human subject and the disease is a proliferative disease, such as cancer. DETAILED DESCRIPTION Definitions [0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. [0014] It is understood that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may fall within the definition of more than one term. [0015] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C_1-6alkoxy, and C_2-6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc. [0016] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C_1-6alkyl, C_1-4alkyl, and C_1- ₃alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. 5 IPTS/128670292.1 Attorney Docket No. NAL-008WO [0017] As used herein, the term “alkylene” refers to a di-radical alkyl group. Examples include, methylene (–CH₂–), ethylene (–CH₂CH₂–), propylene (–CH₂CH₂CH₂–), 2- methylpropylene (–CH₂–CH(CH₃) –CH₂–), hexylene (–(CH₂)₆–) and the like. [0018] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C_2-6alkenyl, and C_3-4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc. [0019] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C_2-6alkynyl, and C_3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc. [0020] As used herein, the terms “alkenylene,” “alkynylene,” “arylene,” “arylalkylene,” and “alkylarylene” refer to di-radical alkenyl, alkynyl, aryl, arylalkyl, and alkylaryl groups, respectively. [0021] As used herein, the term “azido” refers to group –N₃. [0022] As used herein, the term “carboxyl,” “carboxy” or “carboxylate” refers to –CO₂H or salts thereof. [0023] As used herein, the term “carbamoyl” refers to the group NH₂CO–. [0024] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-10, 3-6, or 4-6 carbons, referred to herein as C_3-10cycloalkyl , or C_4-6cycloalkyl, respectively, and which may be monocyclic or bicyclic ring structures, e.g.4-9 or 4-6 membered saturated ring structures, including bridged, fused or spirocyclic rings. Exemplary cycloalkyl groups include, but are not limited to, adamantanyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclopropyl, and indanyl. [0025] As used herein, the groups

are

interchangeably and refer to a cyclohexyl group. [0026] As used herein, the term “cyano” and “carbonitrile” refer to the group –CN. IPTS/128670292.1 Attorney Docket No. NAL-008WO [0027] As used herein, the term “formyl” refers to the group –C(O)H. [0028] As used herein, the term “guanidino” refers to the group –NHC(=NH)NH₂. [0029] As used herein, the terms “halo” and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. [0030] As used herein, the terms “hydroxy” and “hydroxyl” refer to the group -OH. [0031] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc. [0032] The terms “heterocyclyl” or “heterocyclic group” are art-recognized and refer to e.g. saturated or partially unsaturated, 4-10 membered monocyclic or bicyclic ring structures, or e.g. 4-9 or 4-6 membered saturated ring structures, including bridged, fused or spirocyclic rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc. [0033] As used herein, the term “nitro” refers to the group –NO₂. [0034] As used herein, the term “oxo” refers to the group (=O) or (O). [0035] As used herein, the term “isomers” refers to compounds comprising the same numbers and types of atoms or components, but with different structural arrangement and connectivity of the atoms. [0036] As used herein, the term “tautomer” refers to one of two or more structural isomers which readily convert from one isomeric form to another and which exist in equilibrium. [0037] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “

“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The IPTS/128670292.1 Attorney Docket No. NAL-008WO present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. [0038] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z”

configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. [0039] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring may be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.” [0040] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. IPTS/128670292.1 Attorney Docket No. NAL-008WO Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. [0041] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present disclosure embrace both solvated and unsolvated forms. In one embodiment, a disclosed compound is amorphous. In one embodiment, a disclosed compound is a single polymorph. In another embodiment, a disclosed compound is a mixture of polymorphs. In another embodiment, a disclosed compound is in a crystalline form. [0042] The present disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. [0043] Certain isotopically-labeled disclosed compounds

those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated

³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent [0044] As used herein, singular articles such as “a,” “an” and “the” and similar referents in the context of describing the elements are to be construed to cover both the singular and the IPTS/128670292.1 Attorney Docket No. NAL-008WO plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the upper and lower bounds of the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (i.e.,“such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. [0045] In some embodiments, where the use of the term "about" is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context. [0046] Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context. [0047] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0048] As used herein, a dash (“–”) that is not between two letters or symbols refers to a point of bonding or attachment for a substituent. For example, –NH₂ is attached through the nitrogen atom. [0049] As used herein, the terms “active agent,” “drug,” “pharmacologically active agent” and “active pharmaceutical ingredient” are used interchangeably to refer to a compound or composition which, when administered to a subject, induces a desired pharmacologic or physiologic effect by local or systemic action or both. [0050] As used herein, the term “prodrug” refers to compounds that are transformed in vivo to provide a compound or pharmaceutically acceptable salt, hydrate or solvate of the compound IPTS/128670292.1 Attorney Docket No. NAL-008WO described herein. The transformation can occur by various mechanisms (i.e., esterase, amidase, phosphatase, oxidative and/or reductive metabolism) in various locations (i.e., in the intestinal lumen or upon transit into the intestine, blood, or liver). [0051] As used herein, the term “modulator” refers to a compound or composition that increases or decreases the level of a target or the function of a target, which may be, but is not limited to, a Myc family protein, such as c-Myc, N-Myc, L-Myc and human Myc. [0052] As used herein, the term “degrader” refers to a compound or composition that decreases the amount of a target or the activity of a target. In some embodiments, the target may be, but is not limited to, a Myc family protein comprising c-Myc, N-Myc, L-Myc and human Myc. [0053] As used herein, the term “degrading” refers to a method or process that decreases the amount of a target or the activity of a target. In some embodiments, the target may be, but is not limited to, a Myc family protein comprising c-Myc, N-Myc, L-Myc and human Myc. [0054] As used herein, the term “Myc family protein” refers to any one of the proteins c- Myc, N-Myc, or L-Myc as described herein. In some embodiments, a Myc protein is a c-Myc protein. In some embodiments, a Myc protein is a N-Myc protein. In some embodiments, a Myc protein is a L-Myc protein. In some embodiments, a Myc protein is a human c-Myc protein. In some embodiments, a Myc protein is a human N-Myc protein. In some embodiments, a Myc protein is a human L-Myc protein. In some embodiments, a Myc family protein is a human Myc family protein. [0055] As used herein, the terms “N-Myc” and “MycN” can be used interchangeably and refer to the protein “V-Myc myelocytomatosis viral related oncogene, neuroblastoma derived” and include the wildtype and mutant forms of the protein. In some embodiments, MycN refers to the protein associated with one or more of database entries of Entrez Gene 4613, OMIM 164840, UniProt P04198, and RegSeq NP_005369. [0056] As used herein, the term “c-Myc” refers to the protein “V-Myc myelocytomatosis viral oncogene” and include the wildtype and mutant forms of the protein. In some embodiments, c-Myc refers to the protein associated with one or more of database entries of Entrez Gene 4609, OMIM 190080, UniProt P01106, and RegSeq NP_002458. [0057] As used herein, the term “L-Myc” refers to the protein “V-Myc myelocytomatosis viral oncogene homolog, lung carcinoma derived” and include the wildtype and mutant forms of IPTS/128670292.1 Attorney Docket No. NAL-008WO the protein. In some embodiments, L-Myc refers to the protein associated with one or more of database entries of Entrez Gene 4610, OMIM 164850, UniProt P12524, and RegSeq NP_001028253. [0058] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to an animal, including, but not limited to, human and non-human primates, including simians and humans; rodents, including rats and mice; bovines; equines; ovines; felines; canines; and the like. "Mammal" means a member or members of any mammalian species, and includes, by way of example, canines, felines, equines, bovines, ovines, rodentia, etc. and primates, i.e., non-human primates, and humans. Non-human animal models, i.e., mammals, non-human primates, murines, lagomorpha, etc. may be used for experimental investigations. [0059] As used herein, the terms “treating,” “treatment,” and the like, refer to obtaining a desired pharmacologic and/or physiologic effect, such as reduction of tumor burden. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (i.e., including diseases that may be associated with or caused by a primary disease); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease (i.e., reduction in of tumor burden). In some embodiments, certain methods described herein treat cancer associated with the signaling pathway of a Myc family protein, such as c-Myc, N-Myc, L-Myc or human Myc. [0060] As used herein, the term “pharmaceutically acceptable salt” refers to a salt which is acceptable for administration to a subject. It is understood that such salts, with counter ions, will have acceptable mammalian safety for a given dosage regime. Such salts can also be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, and may comprise organic and inorganic counter ions. The neutral forms of the compounds described herein may be converted to the corresponding salt forms by contacting the compound with a base or acid and isolating the resulting salts. IPTS/128670292.1 Attorney Docket No. NAL-008WO [0061] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. [0062] Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as N⁺, NH₄ ⁺, and NW₄ ⁺ (where W can be a C₁-C₈ alkyl group), and the like. For therapeutic use, salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0063] Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2- hydroxy-3-naphthoate )) salts. [0064] Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. [0065] Compounds included in the present compositions that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic IPTS/128670292.1 Attorney Docket No. NAL-008WO acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. [0066] As used herein, the terms “determining,” “measuring,” “assessing,” and “assaying” are used interchangeably and include both quantitative and qualitative determinations. [0067] As used herein, the phrase “signaling pathway” refers to a series of interactions between cellular components, both intracellular and extracellular, that conveys a change to one or more other components in a living organism, which may cause a subsequent change to additional component. Optionally, the changes conveyed by one signaling pathway may propagate to other signaling pathway components. Examples of cellular components include, but are not limited to, proteins, nucleic acids, peptides, lipids and small molecules. [0068] As used herein, the terms “effective amount” and “therapeutically effective amount” are used interchangeably and refer to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to affect such treatment for the disease, condition, or disorder. The “effective amount” or "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. [0069] As used herein, the terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” refer to an excipient, diluent, carrier, and adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use. The phrase “a pharmaceutically acceptable excipient, diluent, carrier and adjuvant” as used in the specification and claims includes both one and more than one such excipient, diluent, carrier, and adjuvant. [0070] As used herein, the term “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general a “pharmaceutical composition” is sterile, and free of contaminants that are capable of eliciting an undesirable response within the subject (i.e., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of IPTS/128670292.1 Attorney Docket No. NAL-008WO administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, intramuscular, subcutaneous, and the like. [0071] Generally, reference to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, ¹⁴C, ³²P and ³⁵S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein. [0072] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures of (R)-enantiomer and (S)-enantiomer, and enantio-enriched stereomeric mixtures comprising of (R)- and (S)-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology. [0073] The compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry. [0074] As described herein, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology. Compounds IPTS/128670292.1 Attorney Docket No. NAL-008WO [0075] The disclosure is generally directed to compounds that modulate (e.g., degrade) MycN and/or MycC, and may therefore have significant antineoplastic properties. The disclosed compounds and pharmaceutical compositions thereof find use in a variety of applications in which the modulation of the amount and activity of a Myc protein is desired, including use as potent antineoplastic agents. [0076] Thus, provided herein, in part, is a compound of Formula I:

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C1-C4 alkyl; ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C₁-C₄ alkyl (optionally substituted by one, two or three halogens), oxo, C₁-C₄ alkoxy, and cyano; L¹ is bond or C₁-C₆ alkylene (optionally substituted by one, two or three R⁴); R³ is OR’; IPTS/128670292.1 Attorney Docket No. NAL-008WO R⁴ is each independently selected from the group consisting of halogen and C₁-C₆ alkyl (optionally substituted by one, two or three halogens), or two R⁴ together with the carbon to which the R⁴ are attached form a C₃-C₅ carbocyclyl; R’ is each independently selected from the group consisting of H and C₁-C₆ alkyl (optionally substituted by one, two or three halogens); R¹ is selected from the group consisting of C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, heteroaryl, cyano, halo, C₁-C₄alkyl, and H; wherein C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens); and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. [0077] In some embodiments, Y is NH, N-CH₃, O, S, CH₂, CF₂, CH(CH₃), or C(CH₃)₂,

[0078] In some embodiments, W is C-H or C-F. In other embodiments, W is N. For example, W is N and Y is NH, and the compound is represented by the Formula Ia:

(Formula Ia) or a pharmaceutically acceptable salt, stereoisomer and/or N-oxide thereof. [0079] In some embodiments, R¹ is a 5-6 membered heterocyclyl or C₃-C₆ cycloalkyl. In some embodiments, R¹ is C₃-C₆ cycloalkyl optionally substituted by one or two substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens). In some embodiments, R¹ is a C₃-C₆ cycloalkyl. For example, R¹ is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R¹ is cyclopropyl or cyclopentyl. In some embodiments, R¹ is cyclopropyl. In some embodiments, R¹ is cyclopentyl. [0080] In some embodiments, ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic IPTS/128670292.1 Attorney Docket No. NAL-008WO heterocycle, and 6-10 membered bridged heterocycle. In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocyclyl, and 6-10 membered bridged heterocycle. In other embodiments, ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle and 6-10 membered bridged heterocycle. For example, ring Z is selected from the group consisting of:

. [0081] In some embodiments, ring Z is selected from the group consisting of:

. [0082] In some embodiments, ring Z is selected from the group consisting of:

. [0083] Exemplary contemplated compounds are represented by Formula Ib:

(Formula Ib) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. [0084] Also contemplated herein are compounds represented by Formula Ic:

(Formula Ic) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. [0085] In other embodiments, contemplated compounds are represented by Formula Id: IPTS/128670292.1 Attorney Docket No. NAL-008WO

(Formula Id) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. [0086] In some embodiments, the compound is a compound of Formula Ie:

(Formula Ie) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0087] In some embodiments, ring X is selected from the group consisting of 6-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by C₁-C₄ alkyl). In some embodiments, ring X is selected from the group consisting of 6 membered monocyclic heterocyclyl (optionally substituted by oxo), 8- 10 membered bicyclic heterocyclyl, or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by methyl). In some embodiments, ring X is selected from the group consisting of 6 membered monocyclic heterocyclyl substituted by oxo, 8-10 membered bicyclic heterocyclyl containing at least two nitrogens, or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by methyl). [0088] In some embodiments, ring X is selected from the group consisting of: IPTS/128670292.1 Attorney Docket No. NAL-008WO

, wherein * indicates attachment to Y and ** indicates attachment to R¹. [0089] In some embodiments, L¹ is C₁-C₆ alkylene substituted by one or two R⁴. For example, L¹ may be methylene substituted by one or two R⁴. In some embodiments, R⁴ is C₁-C₄ alkyl (optionally substituted by one, two or three halogens). For example, R⁴ may be methyl, ethyl, or propyl. In other embodiments, two R⁴s together with the carbon to which the R⁴ are attached form a C₃-C₄ carbocyclyl. For example, two R⁴s together with the carbon to which the R⁴ are attached may form a cyclopropyl. [0090] In some embodiments, R³ is selected from the group consisting of OH, O-methyl, O- ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl. [0091] In some embodiments, R² is H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O-methyl, or -O- ethyl. In some embodiments, R² is H, F, or -O-methyl. In some embodiments, R² is H or F. In some embodiments, R² is H. [0092] Also provided herein is a compound of Formula II:

(Formula II) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; IPTS/128670292.1 Attorney Docket No. NAL-008WO Y is selected from the group consisting of NH, N-CH₃, O, S, CH₂, CF₂, CH(CH₃),

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C₁-C₄ alkyl (optionally substituted by one, two or three halogens), oxo, C₁-C₄ alkoxy, and cyano; L¹ is bond or C₁-C₆ alkylene (optionally substituted by one, two or three R⁴); R³ is OR’; R⁴ is each independently selected from the group consisting of halogen and C₁-C₆ alkyl (optionally substituted by one, two or three halogens), or two R⁴ together with the carbon to which the R⁴ are attached form a C₃-C₅ carbocyclyl; R’ is each independently selected from the group consisting of H and C₁-C₆ alkyl (optionally substituted by one, two or three halogens); R¹ is selected from the group consisting of C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, heteroaryl, cyano, halo, C₁-C₄alkyl, and H; wherein C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens); and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. [0093] In some embodiments, Y is NH, N-CH₃, O, S, CH₂, CF₂, CH(CH₃), or C(CH₃)₂,

IPTS/128670292.1 Attorney Docket No. NAL-008WO [0094] In some embodiments, W is C-H or C-F. In other embodiments, W is N. For example, when W is N and Y is NH, the compound may be represented by Formula IIa:

(Formula IIa) or a pharmaceutically acceptable salt, stereoisomer and/or N-oxide thereof. [0095] In some embodiments, R¹ is a 5-6 membered heterocyclyl or C₃-C₆ cycloalkyl. In some embodiments, R¹ is C₃-C₆ cycloalkyl optionally substituted by one or two substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens). In some embodiments, R¹ is a C₃-C₆ cycloalkyl. For example, R¹ is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R¹ is cyclopropyl or cyclopentyl. In some embodiments, R¹ is cyclopropyl. In some embodiments, R¹ is cyclopentyl. [0096] In some embodiments, ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle. In some embodiments, ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle and 6-10 membered bridged heterocycle. For example, ring Z may be selected from the group consisting of:

. [0097] In some embodiments, ring Z is selected from the group consisting of:

. [0098] In some embodiments, ring X is selected from the group consisting of 6-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by C₁-C₄ alkyl). In some embodiments, ring X is selected from the group consisting of 6 membered monocyclic heterocyclyl (optionally substituted by oxo), 8- 10 membered bicyclic heterocyclyl, or 5-6 membered heteroaryl containing at least one nitrogen IPTS/128670292.1 Attorney Docket No. NAL-008WO (optionally substituted by methyl). In some embodiments, ring X is selected from the group consisting of 6 membered monocyclic heterocyclyl substituted by oxo, 8-10 membered bicyclic heterocyclyl containing at least two nitrogens, or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by methyl). [0099] In some embodiments, ring X is selected from the group consisting of:

, wherein * indicates attachment to Y and ** indicates attachment to R¹. [00100] In some embodiments, L¹ is C₁-C₆ alkylene substituted by one or two R⁴. For example, L¹ may be methylene substituted by one or two R⁴. In some embodiments, R⁴ is C₁-C₄ alkyl (optionally substituted by one, two or three halogens). For example, R⁴ may be methyl, ethyl, or propyl. In other embodiments, two R⁴s together with the carbon to which the R⁴ are attached form a C₃-C₄ carbocyclyl. For example, two R⁴s together with the carbon to which the R⁴ are attached may form a cyclopropyl. [00101] In some embodiments, R³ is selected from the group consisting of OH, O-methyl, O- ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl. [00102] In some embodiments, R² is H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O-methyl, or -O- ethyl. In some embodiments, R² is H, F, or O-methyl. In some embodiments, R² is H or F. In some embodiments, R² is H. [00103] In some embodiments, the compound is selected from the group consisting of: IPTS/128670292.1 Attorney Docket No. NAL-008WO

IPTS/128670292.1 Attorney Docket No. NAL-008WO

and pharmaceutically acceptable salts, stereoisomers, and/or N-oxides thereof. [00104] Also provided herein, in some embodiments, is a compound represented by Formula III: IPTS/128670292.1 Attorney Docket No. NAL-008WO

(Formula III) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein: R¹¹ is H or CH₃; L¹ is methylene or ethylene; R³ is OR”; R” is H or C₁-C₆ alkyl (optionally substituted by one, two or three halogens); ring X is 5-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl (optionally substituted by one or two C₁-C₄ alkyl), provided that ring X is not

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. [00105] In some embodiments, R² is H or F. In some embodiments, R² is H. [00106] Also provided herein, in some embodiments, is a compound represented by Formula IV:

(Formula IV) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein: R¹¹ is H or CH₃; L¹ is methylene or ethylene; IPTS/128670292.1 Attorney Docket No. NAL-008WO R³ is OR”; R” is H or C₁-C₆ alkyl (optionally substituted by one, two or three halogens); ring X is 5-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl (optionally substituted by one or two C₁-C₄ alkyl), provided that ring X is not

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. [00107] In some embodiments, R² is H or F. In some embodiments, R² is H. Pharmaceutical Compositions and Formulations [00108] The compounds, prodrugs, and compositions described herein can be useful as pharmaceutical compositions for administration to a subject in need thereof. [00109] Accordingly, pharmaceutical compositions are presented that can comprise at least a compound described herein, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carriers, diluent, stabilizers, excipients, dispersing agents, suspending agents, or thickening agents. For example, a disclosed pharmaceutical compositions may include one or more of the disclosed compounds, pharmaceutically acceptable salts, or prodrugs described herein. Contemplated compositions may include a compound, a pharmaceutically acceptable salt thereof, or a prodrug thereof in a therapeutically effective amount, for example, a disclosed pharmaceutical composition may be formulated for parenteral administration to a subject in need thereof, formulated for intravenous administration to a subject in need thereof, or formulated for subcutaneous administration to a subject in need thereof. Methods of Treatment [00110] As described above, embodiments of the present disclosure include the use of compounds, prodrugs, and pharmaceutical compositions described herein to treat a Myc protein associated proliferative disease in a subject in need thereof. Such proliferative diseases include cancer, for example, a cancer selected from a group consisting of head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, lung/mediastinum cancer, breast cancer, esophageal IPTS/128670292.1 Attorney Docket No. NAL-008WO cancer, stomach cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, large bowel cancer, colorectal cancer, gynecological cancer, genito-urinary cancer, ovarian cancer, thyroid gland cancer, adrenal gland cancer, skin cancer, melanoma, bone sarcoma, soft tissue sarcoma, pediatric malignancy, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site. [00111] In some embodiments, a contemplated method of treating includes treating a cancer that is a Myc protein associated cancer, e.g., wherein the Myc protein is selected from the group consisting of a N-Myc protein, a c-MYc protein, a L-Myc protein, a human N-Myc protein, a human c-Myc protein, and a human L-Myc protein. [00112] For example, provided herein is a method of treating a cancer selected from the group consisting of neuroblastoma, small cell lung carcinoma, breast cancer or a hematopoietic cancer. [00113] In some embodiments, a disclosed method to treat cancer further comprises a second therapy, wherein the secondary therapy is an antineoplastic therapy, e.g., a contemplated method may further comprise administering an antineoplastic therapy such as one or more agents selected from a DNA topoisomerase I or II inhibitor, a DNA damaging agent, an immunotherapeutic agent (e.g., an antibody, cytokine, immune checkpoint inhibitor or cancer vaccine), an antimetabolite or a thymidylate synthase (TS) inhibitor, a microtubule targeted agent, ionizing radiation, an inhibitor of a mitosis regulator or a mitotic checkpoint regulator, an inhibitor of a DNA damage signal transducer, and an inhibitor of a DNA damage repair enzyme. For example, additional antineoplastic therapy may be selected from the group consisting of immunotherapy (e.g., immuno-oncologic therapy), radiation therapy, photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), gene therapy, and controlled diets. [00114] The present disclosure also contemplates the use of compounds, prodrugs, and pharmaceutical compositions described herein to modulate the amount and activity of a Myc protein (in vitro or in a patient), where the Myc protein may be for example a N-Myc protein, a c-MYc protein, a L-Myc protein, a human N-Myc protein, a human c-Myc protein, and/or a human L-Myc protein. [00115] For example, the disclosure provides a method of modulating the amount (e.g., the concentration) and/or activity of a Myc protein such as (e.g. degrading a Myc protein, or modulating the rate of degradation of a Myc protein) that comprises contacting a Myc protein IPTS/128670292.1 Attorney Docket No. NAL-008WO with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, including embodiments or from any examples, tables or figures. [00116] Contemplated methods include methods of modulating the protein-protein interactions of the Myc family protein, or a method of decreasing the amount and decreasing the level of activity of a Myc protein. [00117] A disclosed method of modulating the amount and activity of a Myc protein may include co-administering a compound described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second agent, e.g., therapeutic agent. EXAMPLES [00118] Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (i.e., amounts, temperatures, etc.), but some experimental error and deviation should be allowed for. Abbreviations aq Aqueous Boc tert-butyloxycarbonyl Cbz Benzyloxycarbonyl DCM Dichloromethane DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide eq Equivalent(s) EtOAc Ethyl acetate h Hour(s) HPLC High-performance liquid chromatography IPA Isopropanol MeCN Acetonitrile IPTS/128670292.1 Attorney Docket No. NAL-008WO NMR Nuclear magnetic resonance r.t. Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran UPLC-MS Ultra-performance liquid chromatography-mass spectrometry General Experimental [00119] ¹H and ¹³C NMR spectra were recorded in CDCl₃ (residual internal standard CHCl₃ = į^^^^^^^^'062-d₆ (residual internal standard CD₃SOCD₂+^ ^į^^^^^^^^methanol-d₄ (residual internal standard CD₂HOD = į 3.20), or acetone-d₆ (residual internal standard CD₃COCD₂+^ ^į^ ^^^^^^^7KH^FKHPLFDO^VKLIWV^^į^^UHSRUWHG^DUH^JLYHQ^LQ^SDUWV^SHU^million (ppm) and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = pentuplet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, tt = triplet of triplet, and m = multiplet. [00120] UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using aa Acquity QDa detector (mass scanning from 100–1250 Da; positive and negative modes simultaneously). A Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm) was used to separate the analytes. [00121] Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% (v/v) MeCN in water. The resulting solutions were then filtered through a 0.2 mm syringe filter before submitting for analysis. All of the solvents, including formic acid and 36% ammonia solution, were purchased as the HPLC grade. Conditions (Acidic 2 min): 0.1% v/v Formic acid in water [Eluent A]; 0.1% v/v Formic acid in MeCN [Eluent B]; Flow rate 0.8mL/min; injection volume 2mL and 1.5 min equilibration time between samples. Conditions (Acidic 4 min): 0.1% v/v formic acid in water [Eluent A]; 0.1% v/v formic acid in MeCN [Eluent B]; Flow rate 0.8mL/min; injection volume 2mL and 1.5 min equilibration time between samples. Conditions (Basic 2 min): 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; Flow IPTS/128670292.1 Attorney Docket No. NAL-008WO rate 0.8mL/min; injection volume 2mL and 1.5 min equilibration time between samples. Conditions (Basic 4 min): 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; Flow rate 0.8mL/min; injection volume 2mL and 1.5 min equilibration time between samples. General Synthetic Schemes

A1 Formula I Scheme 1 [00122] In certain embodiments, a compound of Formula I is prepared according to Scheme 1. Intermediate A1 (e.g., disclosed herein) is reacted with amine B1 (e.g., amines disclosed herein) in the presence of a base (e.g., N,N-diisopropylethylamine) to produce a compound of Formula I. In certain embodiments, amine B1 may comprise a protecting group (e.g., tert- butyloxycarbonyl (Boc), benzyl carbamate (Cbz)). In certain embodiments, when amine B1 comprises a protecting group (e.g., tert-butyloxycarbonyl (Boc), benzyl carbamate (Cbz)), the intermediate produced from the reaction thereof with intermediate A1 in the presence of a base may further be reacted to deprotect the protecting group (e.g., in the presence of reducing agents such as hydrogen (e.g., with Pd/C as catalyst) or LiAlH₄ or acid such as TFA or HBr) to produce a compound of Formula I.

C1 A1 Scheme 2 [00123] In certain embodiments, intermediate A1 is prepared according to Scheme 2. Compound C1 (e.g., disclosed herein), wherein Z is a halogen such as Br or Cl, is reacted with IPTS/128670292.1 Attorney Docket No. NAL-008WO amine D1 (e.g., amines disclosed herein), wherein R^x is H or C_1-4 alkyl, in the presence of a base (e.g., N,N-diisopropylethylamine) to produce intermediate A1. Example 1: Synthesis of [2-[4-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyridin-2- ylamino)pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 1)

N-(2-Chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-amine [00124] To 4H,5H,6H,7H-tetrahydropyrazolo[1,5-a]pyridin-2-amine (83 mg, 0.60 mmol) in DMSO (4 mL) was added N,N-diisopropylethylamine (0.32 mL, 1.8 mmol) then 2,4- dichloropyrimidine (90 mg, 0.60 mmol) and the reaction mixture heated at 60 °C for 18 hours. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (20 mL). The organic layer was washed with water (2 x 20 mL) and a saturated aqueous brine solution (20 mL). The organic layer was separated, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude residue was purified by automated flash column chromatography, over silica gel (12 g cartridge) eluting with MeOH (0% to 10%) in CH₂Cl₂ to give the title compound (86 mg, 0.34 mmol, 57%) as a solid. [00125] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^W^^J = 6.1 Hz, 2H), 2.72 (t, J = 6.3 Hz, 2H), 1.95 (td, J = 7.1, 4.5 Hz, 2H), 1.81 – 1.71 (m, 2H). [00126] UPLC-MS (Basic method, 2 min): rt = 0.92 min, m/z = 250.1 [M+H]⁺. [2-[4-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyridin-2-ylamino)pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptan-4-yl]methanol [00127] To N-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-amine (86 mg, 0.34 mmol) in 1-butanol (4 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) and 2-azabicyclo[2.2.1]heptan-4-ylmethanol (53 mg, 0.41 mmol) and the reaction mixture stirred at reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and diluted IPTS/128670292.1 Attorney Docket No. NAL-008WO with EtOAc (20 mL). The organic phase was washed with water (20 mL) then a saturated aqueous brine solution (20 mL). The organic layer was separated, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The crude residue was purified by automated flash column chromatography on silica gel (12 g cartridge) eluting with 3:1 EtOAc/EtOH (v/v) with 0.5% NH₃ (0% to 80%) in iso-hexane to give the title compound (78 mg, 0.23 mmol, 66%) as a solid. [00128] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^V^^^+^^^^^^^^^G^^-^ ^5.7 Hz, 1H), 6.24 – 6.20 ^P^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^W^^-^ ^^^^^+]^^^+^^^^^^^^^V^^^+^^^^^^^^– 3.26 (m, 1H), 3.12 – ^^^^^^P^^^+^^^^^^^^^W^^-^ ^^^^ Hz, 2H), 1.99 – 1.89 (m, 2H), 1.80 – 1.69 (m, 3H), 1.64 – 1.51 (m, 3H), 1.36 (s, 2H). [00129] UPLC-MS (Basic method, 4 min): rt = 1.29 min, m/z = 341.1 [M+H]⁺. Example 2: Synthesis of [2-[4-[(5-Cyclopropyl-2-methyl-pyrazol-3-yl)-methyl- amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 2)

2-Chloro-N-(5-cyclopropyl-2-methyl-pyrazol-3-yl)-N-methyl-pyrimidin-4-amine [00130] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (700 mg, 2.97 mmol) in dry DMF (6 mL) was added potassium carbonate 325 mesh (821 mg, 5.94 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 °C and methyl iodide (0.17 mL, 2.67 mmol) was added dropwise, then the reaction mixture was allowed to warm to room temperature and was stirred for 20 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by reverse phase basic prepHPLC to afford the title compound as an oil (105 mg, 0.40 mmol, 13%). [00131]

= 6.0 Hz, 1H), 6.04 (d, J = 5.9 Hz, 1H), 5.79 (s, 1H), 3.54 (s, 3H), 3.36 (s, 3H), 1.93 – 1.82 (m, 1H), 0.96 – 0.85 (m, 2H), 0.75 – 0.64 (m, 2H). [00132] UPLC-MS: (basic, 6 min): rt = 2.52 min, m/z = 264.1 [M+H]⁺. IPTS/128670292.1 Attorney Docket No. NAL-008WO [2-[4-[(5-Cyclopropyl-2-methyl-pyrazol-3-yl)-methyl-amino]pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptan-4-yl]methanol [00133] To a solution of 2-azabicyclo[2.2.1]heptan-4-ylmethanol (61 mg, 0.48 mmol) and 2- chloro-N-(5-cyclopropyl-2-methyl-pyrazol-3-yl)-N-methyl-pyrimidin-4-amine (105 mg, 0.398 mmol) in 1-butanol (2.5 mL) was added N,N-diisopropylethylamine (DIPEA) (0.21 mL, 1.19 mmol). The reaction mixture was heated to reflux and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature then diluted with EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL), the organics separated, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified on silica by automated flash column chromatography (Teledyne ISCO, 12 g cartridge) eluting with MeOH (0% to 3%) in CH₂Cl₂ to give the title compound as a solid (132 mg, 0.37 mmol, 91%). [00134] ¹H NMR (400 MHz, DMSO-d₆) į 7.80 (s, 1H), 5.90 (s, 1H), 5.43 – 5.24 (m, 1H), 4.73 – 4.66 (m, 1H), 4.53 (s, 1H), 3.64 – 3.57 (m, 2H), 3.45 (s, 3H), 3.23 (s, 3H), 3.14 – 3.04 (m, 1H), 1.87 – 1.76 (m, 1H), 1.71 (d, J = 12.2 Hz, 1H), 1.64 – 1.58 (m, 2H), 1.58 – 1.49 (m, 2H), 1.41 – 1.30 (m, 2H), 0.90 – 0.77 (m, 2H), 0.67 – 0.59 (m, 2H). [00135] UPLC-MS: (basic, 4 min): rt = 1.51 min, m/z = 355.4 [M+H]⁺. Example 3: Synthesis of [2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (Compound 3)

2-Chloro-N-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)pyrimidin-4-amine [00136] To a solution of 2,4-dichloropyrimidine (200 mg, 1.34 mmol) and 5-cyclopropyl-4H- 1,2,4-triazol-3-amine (250 mg, 2.01 mmol) in DMSO (10 mL) was added N,N- diisopropylethylamine (0.47 mL, 2.69 mmol), and the solution was heated to 60 °C and stirred for 18 hours. The reaction mixture was diluted with EtOAc (25 mL), and washed consecutively with water (5 × 20 mL) and saturated aqueous brine solution (20 mL). The organic phase was dried over Na₂SO₄, filtered and the volatiles removed under reduced IPTS/128670292.1 Attorney Docket No. NAL-008WO pressure to afford a yellow oil, which was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (20% to 90%) in iso-hexane to afford the title compound as a powder (47 mg, 0.167 mmol, 12%). [00137] UPLC-MS (basic method, 2 min): rt = 0.88 min, m/z = 237.2 [M+H]⁺. [00138] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^G^^J = 5.6 Hz, 1H), 8.71 (d, J = 5.7 Hz, 1H), 7.65 (d, J = 5.7 Hz, 1H), 7.60 (d, J = 4.1 Hz, 1H), 1.88 (tt, J = 8.2, 4.8 Hz, 1H), 0.97 – 0.88 (m, 2H), 0.86 – 0.77 (m, 2H). [2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]methanol [00139] To a solution of 2-chloro-N-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)pyrimidin-4-amine (44 mg, 0.19 mmol) and 2-azabicyclo[2.2.1]heptan-4-ylmethanol (47 mg, 0.37 mmol) in n- butanol (5 mL) was added N,N-diisopropylethylamine (0.097 mL, 0.56 mmol), and the reaction mixture was heated to 110 °C and stirred for 16 hours. The reaction mixture was allowed to cool to ambient temperature, and the volatiles were removed under reduced pressure. This combined crude was then triturated with methanol, which left a solid in a solution which was filtered, and the solid dried under reduced pressure to afford the title compound as a solid (25 mg, 0.076 mmol, 41%). [00140] UPLC-MS (basic method, 4 min): rt = 1.29 min, m/z = 328.3 [M+H]⁺. [00141] ¹H NMR (400 MHz, DMSO-

5.4 Hz, 1H), 7.31 (s, 2H), 6.78 (d, J = 5.4 Hz, 1H), 4.58 (s, 1H), 4.39 (s, 1H), 3.67 (d, J = 3.6 Hz, 2H), 3.42 (dd, J = 9.5, 2.9 Hz, 1H), 3.19 – 3.11 (m, 1H), 1.90 – 1.74 (m, 2H), 1.73 – 1.61 (m, 3H), 1.49 – 1.42 (m, 2H), 0.92 – 0.78 (m, 4H). Example 4: Synthesis of [2-[4-[(5-Cyclopropyl-4-methyl-1H-pyrazol-3-yl)amino]pyrimidin- 2-yl]-2-azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 4)

IPTS/128670292.1 Attorney Docket No. NAL-008WO 2-Chloro-N-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine [00142] To a solution of 2,4-dichloropyrimidine (100 mg, 0.67 mmol) and 3-cyclopropyl-4- methyl-1H-pyrazol-5-amine (92 mg, 0.67 mmol) in DMSO (4 mL) was added N,N- diisopropylethylamine (0.35 mL, 2.0 mmol), and the solution was heated to 60 °C and stirred for 18 hours. The reaction mixture was diluted with EtOAc (20 mL), and the organic phase was washed with water (20 mL). The aqueous was extracted with EtOAc (2 x 20 mL) and the combined organics washed with a saturated aqueous brine solution (40 mL). The organic phase was dried (Na₂SO₄), filtered concentrated under reduced pressure. The residue was purified on silica by flash column chromatography (12 g cartridge) eluting with MeOH (0% to 20%) in CH₂Cl₂ to afford the title compound as a solid (50 mg, 0.20 mmol, 30%). [00143] UPLC-MS (basic method, 2 min): rt = 0.91 min, m/z = 250.2 [M+H]⁺. [00144] ¹H NMR (400 MHz, DMSO-d₆^^į^11.97 (s, 1H), 9.65 (s, 1H), 8.08 (d, J = 6.0 Hz, 1H), 6.90 (s, 1H), 1.84 (s, 3H), 1.77 (td, J = 8.6, 4.4 Hz, 1H), 0.90 – 0.80 (m, 2H), 0.74 – 0.66 (m, 2H).

[00145] To a solution of 2-chloro-N-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)pyrimidin-4- amine (50 mg, 0.20 mmol) in n-butanol (4 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.60 mmol) and 2-azabicyclo[2.2.1]heptan-4-ylmethanol (28 mg, 0.22 mmol). The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (15 mL) and washed with water (20 mL) then a saturated aqueous brine solution (20 mL). The organic phase was separated, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (12 g cartridge) eluting with 3:1 EtOAc:EtOH + 0.5% NH₃ (0% to 80%) in iso-hexane to give the title compound as a solid (40 mg, 0.12 mmol, 60%). [00146] UPLC-MS (basic method, 4 min): rt = 1.34 min, m/z = 341.1 [M+H]⁺. [00147] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^G^^-^ ^^^^^+]^^ ^+^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^G^^-^ ^^^^^+]^^^+^^^^^^^^^G^^-^ ^^^^^+]^^^+^^^ ^^^^^^G^^-^ ^^^^^+]^^^+^^^^^^^^^V^^^+^^^^^^^^– 1.65 (m, 2H), 1.64 – 1.54 (m, 2H), 1.54 – 1.48 (m, 1H), 1.39 – 1.29 (m, 2H), 0.90 – 0.81 (m, 2H), 0.77 – 0.67 (m, 2H). IPTS/128670292.1 Attorney Docket No. NAL-008WO Example 5: Synthesis of [2-[4-[(5-cyclopropylpyrazin-2-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 5)

N-(5-Cyclopropylpyrazin-2-yl)-2-methylsulfanyl-pyrimidin-4-amine [00148] A solution of 2-methylthio-4-chloropyrimidine (70 ^L, 0.62 mmol), 5- cyclopropylpyrazin-2-amine (101 mg, 0.75 mmol) in 1,4-dioxane (5 mL) was sparged with nitrogen for 10 min. To that were added cesium carbonate (609 mg, 1.87 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (36 mg, 0.060 mmol) and bis(dibenzylideneacetone)palladium(0) (36 mg, 0.06 mmol) and the reaction mixture was heated to reflux for 2.5 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude residue which was purified by column chromatography over silica gel eluting with a gradient of 3:1 EtOAc:EtOH (0% to 60%) in iso-hexane to afford the title compound as a solid (134 mg, 0.51 mmol, 81%). [00149] UPLC-MS (basic method, 2 mins): rt: 1.03 min, m/z = 260.0 [M+H]⁺. [00150] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^G^^J = 1.5 Hz, 1H), 8.26 (d, J = 5.8 Hz, 1H), 7.18 (d, J = 5.8 Hz, 1H), 2.20 – 2.09 (m, 1H), 1.00 – 0.95 (m, 2H), 0.91 – 0.86 (m, 2H). 3H singlet obscured by solvent peak. N-(5-Cyclopropylpyrazin-2-yl)-2-methylsulfonyl-pyrimidin-4-amine IPTS/128670292.1 Attorney Docket No. NAL-008WO [00151] To a stirred solution of N-(5-cyclopropylpyrazin-2-yl)-2-methylsulfanyl-pyrimidin-4- amine (130 mg, 0.50 mmol) in DCM (5 mL) at 0 °C was added 3-chloroperoxybenzoic acid (260 mg, 1.50 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was quenched with a 1 M aqueous sodium thiosulphate solution (5 mL) and treated with a saturated aqueous solution of NaHCO₃ (10 mL) followed by extraction with 9:1 DCM/MeOH (2 x 20 mL). The organic phase was washed with water (3 x 10 mL), then a saturated aqueous brine solution (10 mL). The organic phase was dried over Na₂SO₄, then concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel eluting with a gradient of 3:1 EtOAcEtOH (0% to 50%) in iso-hexane to afford the title compound as a solid (50 mg, 0.17 mmol, 33%). [00152] UPLC-MS (acidic method, 2 mins): rt: 0.87 min, m/z = 292.1 [M+H]⁺. [00153] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^G^^J = 5.9 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 7.72 (s, 1H), 3.35 (s, 3H), 2.23 – 2.12 (m, 1H), 1.01 – 0.97 (m, 2H), 0.93 – 0.88 (m, 2H). [2-[4-[(5-cyclopropylpyrazin-2-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4- yl]methanol [00154] A suspension of N-(5-cyclopropylpyrazin-2-yl)-2-methylsulfonyl-pyrimidin-4-amine (45 mg, 0.15 mmol), 2-azabicyclo[2.2.1]heptan-4-ylmethanol (27 mg, 0.18 mmol) and N,N- diisopropylethylamine (0.081 mL, 0.46 mmol) in n-butanol (1 mL) was heated to reflux and stirred for 3 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (28 mg, 0.080 mmol, 54%). [00155] UPLC-MS (basic method, 4 mins): rt: 1.43 min, m/z = 339.1 [M+H]⁺. [00156] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^V^^^+^^^^^^^^^P^^^+^^^^^^^^^G^^-^ ^^^^^+]^^ 1H), 7.98 – 7.92 (m, 1H), 6.53 – 6.31 (m, 1H), 4.71 (s, 1H), 4.53 (s, 1H), 3.66 – 3.59 (m, 2H), 3.41 (s, 1H), 3.18 – 3.08 (m, 1H), 2.17 – 2.05 (m, 1H), 1.84 – 1.69 (m, 1H), 1.64 – 1.55 (m, 3H), 1.44 – 1.33 (m, 2H), 0.97 – 0.90 (m, 2H), 0.89 – 0.84 (m, 2H). Example 6: Synthesis of [2-[4-[(5-Cyclopropylthiazol-2-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 6) IPTS/128670292.1 Attorney Docket No. NAL-008WO

[00157] To a suspension of 2,4-dichloropyrimidine (159 mg, 1.07 mmol) and 5-cyclopropyl- thiazol-2-ylamine (100 mg, 0.71 mmol) in IPA (3 mL) was added N,N-diisopropylethylamine (0.25 mL, 1.43 mmol) and it was heated to reflux for 24 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (10 mL) then it was extracted with DCM (2 x 10 mL). The combined organic extracts were dried over Na₂SO₄, then concentrated to dryness under reduced pressure. The crude residue was purified by column chromatography over silica gel eluting with a gradient of EtOAc (0% to 50%) in iso-hexane to afford the title compound as a solid (36 mg, 0.14 mmol, 20%). [00158] UPLC-MS (basic method, 2 min): rt = 1.12 min, m/z = 253.0 [M+H]⁺. [00159] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^V^^^+^^^^^^^^^G^^J = 5.8 Hz, 1H), 8.65 (d, J = 5.8 Hz, 1H), 7.41 (s, 1H), 1.95 – 1.84 (m, 1H), 0.89 – 0.82 (m, 2H), 0.63 – 0.58 (m, 2H). [2-[4-[(5-Cyclopropylthiazol-2-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4- yl]methanol [00160] A suspension of N-(2-chloropyrimidin-4-yl)-5-cyclopropyl-thiazol-2-amine (35 mg, 0.14 mmol), 2-azabicyclo[2.2.1]heptan-4-ylmethanol (22 mg, 0.15 mmol), N,N- diisopropylethylamine (0.072 mL, 0.41 mmol) in n-butanol (1 mL) was heated to 100 °C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to afford the crude which was purified by column chromatography over silica gel eluting with a gradient of EtOAc (0% to 100%; v/v) in iso-hexane followed by MeOH (0% to 5%; v/v) in EtOAc to afford the title compound as a solid (17 mg, 0.050 mmol, 35%). [00161] UPLC-MS (basic method, 4 mins): rt: 1.57 min, m/z = 344.1 [M+H]⁺. [00162] ¹H NMR (400 MHz, DMSO-d₆^^į^^^^^^^V^^^+^^^^^^^^^G^^-^ ^^^^^+]^^^+^^^^^^^^– 7.83 (m, 1H), 7.48 (d, J = 15.9 Hz, 1H), 4.73 – 4.67 (m, 1H), 4.63 – 4.56 (s, 1H), 3.63 (m, 2H), 3.12 (d, J = 9.8 Hz, 1H), 1.82 – 1.75 (m, 2H), 1.63 – 1.55 (m, 4H), 1.41 – 1.34 (m, 2H), 1.26 – 1.20 (m, 1H), 0.86 – 0.81 (m, 2H), 0.55 – 0.53 (m, 1H). IPTS/128670292.1 Attorney Docket No. NAL-008WO Example 7: Degradation of MycC/MycN Protein [00163] For L363 cells (suspension), 1E6 cells are plated into each well of a 6 well plate. For SK-N-BE(2) cells (adherent), 5E5 cells are plated into each well of a 6 well dish. Cells are cultured for 24 hrs then treated with exemplary compounds at 0.1, 0.25, 0.5, 1.0, 3.0 and 6.0 mM final assay concentrations plus DMSO control. All compounds are diluted to 10 mM in DMSO. Cells are treated with the compound for 24 hrs, then for both cell types, media containing cells are removed from wells into a 15ml centrifuge tube, and remaining adherent SK-N-BE(2) cells are also scraped from the wells into the appropriate tubes. Tubes are centrifuged, cells are washed with PBS then re-centrifuged to pellet cells. A RIPA buffer cocktail are added to the cells on ice for 5 mins. Cell lysates are clarified by centrifugation and stored at -80 degrees until required. BCA assay is performed on each lysate to determine the protein concentration. [00164] For validation studies of antibodies, lysates and antibodies are used at a number of concentrations (Lysates: 2, 1, 0.2mg/ml; Antibodies: 1 in 50, 1 in 200 dilution). Once an appropriate lysate concentration and antibody concentration is determined, samples are screened LQ^WKH^-(66^WHFKQRORJ\^^3URWHLQ^6LPSOH^^6DQ^-RVH^^&$^- https://www.proteinsimple.com/jess.html). [00165] Target protein antibodies (n-myc and c-myc) are detected in the chemi-luminescence channel and loading controls (tubulin and GAPDH) are detected using a Near Infra Red (NIR) labeled secondary antibody. Cell proliferation/viability measures [00166] For SK-N-EB2 adherent cells, 5E5 cells in 1.9mls media are plated into 6 well dishes and incubated for 24hrs. Exemplary compounds are added (100ul, 1 in 20 dilution in media) to each well (final assay concentration 6, 3, 1 and 0.5mM) together with DMSO control wells and incubated for 24hrs. Cells are scrapped off the plate, centrifuged, washed with PBS, centrifuged, then a RIPA buffer cocktail added to the cells (100ul), centrifuged and stored at -80 for later analysis. For L363 suspension cells, 1E6 cells are plated into 24 well dishes (950ul media) and incubated for 24hrs. Exemplary compounds are added (50ul, 1 in 20 dilution in media) to each well (final assay concentration 6, 3, 1 and 0.5 mM) together with DMSO control wells and incubated for 24hrs. Cells are aspirated into tubes, centrifuged, washed with PBS, centrifuged, then a RIPA buffer cocktail added to the cells (100ul), centrifuged and stored at -80 for later analysis. IPTS/128670292.1 Attorney Docket No. NAL-008WO [00167] For Western blot, a BCA (total protein) assay is run on all samples, these are then run in batches of 5 compounds plus control (DMSO) on each Western blot run – n-myc and c-myc are run in separate experiments in the chemiluminescence channel. Both tubulin and GAPDH are run as loading controls in all lanes in the near infrared channel. [00168] For cytotox, both SK-N-EB2 or L363 cells are run in 384 well format. For SK-N-EB2 cells, 5000 cells per well (in 30ul media) are incubated for 24hrs prior to the addition of compounds (10ul, 1 in 4 dilution, 10mM top final concentration, 1 in 2 dilutions) for 24hrs. For L363 cells, 2000 cells per well (30ul media) are incubated for 24hrs prior to the addition of compounds (10ul, 10mM 1 in 2 dilutions) for 24hrs. In both cases Promega Cell Titer GLO is added according to the manufacturer’s instructions and the plates are read immediately in the luminometer. Table 1. Percent Degradation of MycC/MycN Protein by Various Compounds

Key: ****: degradation 80-100% ***: degradation 50-79% **: degradation 20-49% *: degradation <20% ND – No Degradation [00169] It will be appreciated that compounds reported as a salt form (e.g., a TFA salt) may or may not have a 1:1 stoichiometry, and/or for example, reported potency concentrations or other assay results may be, e.g., slightly higher or lower. [00170] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of organic chemistry, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. While the disclosure has been particularly shown and described with reference to a preferred embodiment and various alternate IPTS/128670292.1 Attorney Docket No. NAL-008WO embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the disclosure. [00171] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes. IPTS/128670292.1

Claims

Attorney Docket No. NAL-008WO CLAIMS 1. A compound of Formula I:

ring X is 5-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl (optionally substituted by one or two C1-C4 alkyl), provided that ring X is not

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C₁-C₄ alkyl (optionally substituted by one, two or three halogens), oxo, C₁-C₄ alkoxy, and cyano; L¹ is bond or C₁-C₆ alkylene (optionally substituted by one, two or three R⁴); R³ is OR’; R⁴ is each independently selected from the group consisting of halogen and C₁-C₆ alkyl (optionally substituted by one, two or three halogens), or two R⁴ together with the carbon to which the R⁴ are attached form a C₃-C₅ carbocyclyl; R’ is each independently selected from the group consisting of H and C₁-C₆ alkyl (optionally substituted by one, two or three halogens); IPTS/128670292.1 Attorney Docket No. NAL-008WO R¹ is selected from the group consisting of C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, heteroaryl, cyano, halo, C₁-C₄alkyl, and H; wherein C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens); and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. 2. The compound of claim 1, wherein W is N and Y is NH, and having the Formula Ia:

(Formula Ia) or a pharmaceutically acceptable salt, stereoisomer and/or N-oxide thereof. 3. The compound of claim 1 or 2, wherein R¹ is a 5-6 membered heterocyclyl or C₃-C₆ cycloalkyl. 4. The compound of any one of claims 1-3, wherein R¹ is a C₃-C₆ cycloalkyl. 5. The compound of any one of claims 1-4, wherein R¹ is cyclopropyl. 6. The compound of any one of claims 1-4, wherein R¹ is cyclopentyl. 7. The compound of any one of claims 1-6, wherein ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle. 8. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocyclyl, and 6-10 membered bridged heterocycle. 9. The compound of any one of claims 1-8, wherein ring Z is 6-10 membered bridged heterocycle. 10. The compound of any one of claims 1-9, wherein ring Z is selected from the group consisting of: IPTS/128670292.1 Attorney Docket No. NAL-008WO

. 11. The compound of any one of claims 1-10, wherein ring Z is selected from the group consisting of:

. 12. The compound of any one of claims 1-11, represented by Formula Ib:

(Formula Ib) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. 13. The compound of any one of claims 1-11, represented by Formula Ic:

(Formula Ic) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. 14. The compound of any one of claims 1-11, represented by Formula Id:

(Formula Id) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof. IPTS/128670292.1 Attorney Docket No. NAL-008WO 15. The compound of any one of claims 1-14, wherein ring X is selected from the group consisting of 6-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by C₁-C₄ alkyl). 16. The compound of any one of claims 1-15, wherein ring X is selected from the group consisting of:

, wherein * indicates attachment to Y and ** indicates attachment to R¹. 17. The compound of any one of claims 1-16, wherein L¹ is C₁-C₄ alkylene. 18. The compound of claim 17, wherein L¹ is methylene. 19. The compound of any one of claims 1-18, wherein R³ is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl. 20. The compound of any one of claims 1-19, wherein R³ is OH. 21. The compound of any one of claims 1-20, wherein R² is H or F. 22. The compound of any one of claims 1-21, wherein R² is H. 23. A compound selected from the group consisting of:

IPTS/128670292.1 Attorney Docket No. NAL-008WO

Attorney Docket No. NAL-008WO

and pharmaceutically acceptable salts, stereoisomers, and/or N-oxides thereof. 24. A compound of Formula II:

(Formula II) or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, wherein: IPTS/128670292.1 Attorney Docket No. NAL-008WO W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH₃, O, S,

wherein * indicates attachment to Y and ** indicates attachment to R¹ and R^H is H or C₁-C₄ alkyl; ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C₁-C₄ alkyl (optionally substituted by one, two or three halogens), oxo, C₁-C₄ alkoxy, and cyano; L¹ is bond or C₁-C₆ alkylene (optionally substituted by one, two or three R⁴); R³ is OR’; R⁴ is each independently selected from the group consisting of halogen and C1-C6 alkyl (optionally substituted by one, two or three halogens), or two R⁴ together with the carbon to which the R⁴ are attached form a C₃-C₅ carbocyclyl; R’ is each independently selected from the group consisting of H and C₁-C₆ alkyl (optionally substituted by one, two or three halogens); R¹ is selected from the group consisting of C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, heteroaryl, cyano, halo, C₁-C₄alkyl, and H; wherein C₃-C₁₀ cycloalkyl, spiro C₅-C₁₀ bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C₁-C₄alkyl (optionally substituted by one, two or three halogens); and R² is selected from the group consisting of H, F, CF₃, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C₃-C₇ cycloalkyl, and heterocyclyl. IPTS/128670292.1 Attorney Docket No. NAL-008WO 25. The compound of claim 24, wherein W is N and Y is NH, and having the Formula IIa:

(Formula IIa) or a pharmaceutically acceptable salt, stereoisomer and/or N-oxide thereof. 26. The compound of claim 23 or 24, wherein R¹ is a 5-6 membered heterocyclyl or C₃-C₆ cycloalkyl. 27. The compound of any one of claims 23-25, wherein R¹ is a C₃-C₆ cycloalkyl. 28. The compound of any one of claims 23-26, wherein R¹ is cyclopropyl. 29. The compound of any one of claims 23-26 wherein R¹ is cyclopentyl. 30. The compound of any one of claims 23-29, wherein ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle. 31. The compound of any one of claims 23-30, wherein ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle and 6-10 membered bridged heterocycle. 32. The compound of any one of claims 23-31, wherein ring Z is selected from the group consisting of:

. 33. The compound of any one of claims 23-32, wherein ring X is selected from the group consisting of 6-10 membered heterocyclic (optionally substituted by oxo) or 5-6 membered heteroaryl containing at least one nitrogen (optionally substituted by C₁-C₄ alkyl). 34. The compound of any one of claims 23-33, wherein ring X is selected from the group consisting of: IPTS/128670292.1 Attorney Docket No. NAL-008WO

, wherein * indicates attachment to Y and ** indicates attachment to R¹. 35. The compound of any one of claims 23-24, wherein L¹ is C₁-C₄ alkylene. 36. The compound of claim 35, wherein L¹ is methylene. 37. The compound of any one of claims 23-36, wherein R³ is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl. 38. The compound of any one of claims 23-37, wherein wherein R³ is OH. 39. The compound of any one of claims 23-38, wherein R² is H or F. 40. The compound of any one of claims 23-39, wherein R² is H. 41. A pharmaceutical composition comprising a compound according to any one of claims 1- 40, or a pharmaceutically acceptable salt, stereoisomer, and/or N-oxide thereof, and at least one pharmaceutically acceptable carrier or diluent. 42. The pharmaceutical composition of claim 41, wherein the composition is formulated for parenteral administration. 43. The pharmaceutical composition of claim 41, wherein the composition is formulated for intravenous administration. 44. The pharmaceutical composition of claim 41, wherein the composition is formulated for subcutaneous administration. 45. A method of treating a proliferative disease, comprising: administering to a subject with a proliferative disease a therapeutically effective amount of a compound according to any one of IPTS/128670292.1 Attorney Docket No. NAL-008WO claims 1-40, or a pharmaceutically acceptable salt, stereoisomer and/or N-oxide thereof, or a therapeutically effective amount of the pharmaceutical composition of any one of claims 41-44. 46. The method of claim 45, wherein the proliferative disease is cancer. 47. The method of claim 46, wherein the cancer is selected from the group consisting of head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, lung/mediastinum cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, large bowel cancer, colorectal cancer, gynecological cancer, genito- urinary cancer, ovarian cancer, thyroid gland cancer, adrenal gland cancer, skin cancer, melanoma, bone sarcoma, soft tissue sarcoma, pediatric malignancy, Hodgkin's disease, non- Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site. 48. A method of modulating MycN in cells of a subject in need thereof, comprising: administering to a subject in need thereof an amount of a compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, stereoisomer and/or N-oxide thereof, or a pharmaceutical composition according to any one of claims 41-44, that is effective to cause MycN modulation in cells of the subject. 49. The method of any one of claims 45-48, further comprising administering to the subject a second therapy. 50. The method of claim 49, wherein the second therapy is an antineoplastic therapy. 51. The method of claim 50, wherein the antineoplastic therapy is administration of one or more agents selected from a DNA topoisomerase I or II inhibitor, a DNA damaging agent, an immunotherapeutic agent, an antimetabolite or a thymidylate synthase (TS) inhibitor, a microtubule targeted agent, ionising radiation, an inhibitor of a mitosis regulator or a mitotic checkpoint regulator, an inhibitor of a DNA damage signal transducer, and an inhibitor of a DNA damage repair enzyme. 52. The method of claim 50, wherein the antineoplastic therapy is selected from the group consisting of immunotherapy, radiation therapy, photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), gene therapy, and controlled diets. IPTS/128670292.1