VPS4 inhibitors

Abstract

This invention relates to novel VPS4 inhibitors and uses thereof for treatment of cancers or solid or hematological tumors, which are characterized by the loss of VPS4A or VPS4B.

Description

VPS4 INHIBITORSFIELD OF THE INVENTION

[0001] This invention relates to novel VPS4 inhibitors and uses thereof for treatment of cancers or solid or hematological tumors, which are characterized by the loss of VPS4A or VPS4B.BACKGROUND OF THE INVENTION

[0002] The vacuolar protein sorting 4 (VPS4) protein is a member of the AAA ATPase protein family associated with a variety of cellular activities. Many important cellular processes including DNA replication, nuclear-cytoplasmic transport, organelle biogenesis, vesicular trafficking, protein degradation, and oncogenic transformation rely on one or more members of the AAA ATPase subfamily.

[0003] The paralogs VPS4A and VPS4B are selective genetic vulnerabilities for tumors harboring genomic loss of SMAD4 or CDH1 because of co-deletion of VPS4B or VPS4A, respectively. Targeting VPS4A and / or VPS4B in cancer cells is considered an effective advance in the treatment of cancers.SUMMARY OF THE INVENTION

[0004] In one aspect, the invention provides a compound represented by formula (I) whereinR1is aryl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, - NRmRn, CN, and NO2;R2and R3are each independently H or C1-C3alkyl, or together with the carbon atom they are attached to form a C3-C7cycloalkyl group;Xis CHRb or NRb;Y is 0, S, or NRb;Z is N or CRb;R4is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRcRd, CN, or NO2;Ra, Rm, and Rn are each independently H or C1-C3alkyl;Rb is H, C1-C3alkyl, -SOsRa, -COORa, or -CONRcRd; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2, and* represents R or S configuration, wherein said C1-C3alkyl, C1-C6alkyl, and C3-C7cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of halo, NRmRn, CN, -ORa, -COORa, and -CONRmRn, or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the compound of formula (I) is represented by formula (IA)whereinR1is aryl or heteroaiyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2;R2and R3are each independently H or C1-C3alkyl;Xis CHRb or NRb;Y is 0, S, or NRb; andZis N.

[0006] In some embodiments, the compound is represented by

[0007] In another aspect, the present invention provides a compound represented by formula (II)whereinR1is aiyl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2;R2is substituted aryl or heteroaryl.

[0008] In another aspect, the present invention provides a compound represented by formula (IIA)wherein R = C1-C6alkyl, halo, C1-C3haloalkyl, -0Ra, -NRmRn, CN, or NO2; and substitution can be anywhere on the ring;R2is substituted aryl or heteroaryl.

[0009] In another aspect, the present invention provides a compound represented by formula (IIB)whereinR1 is aryl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2;R2is substituted aryl or heteroaryl.

[0010] In another aspect, the present invention provides a compound represented by formula (III)

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of the invention as described herein. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the compound is a VPS4A inhibitor and / or a VPS4B inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings.

[0014] Figure 1A depicts that CHAMP-003 strongly induced the inflammatory cytokines IFN-β and CXCL10 in A549 NSCLC cells.

[0015] Figure IB depicts that CHAMP-002 weakly induced the inflammatory cytokine CXCL10 in A549 NSCLC cells.

[0016] Figure 2A depicts that CHAMP-003 potently induced the inflammatory cytokines IFN-β and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA-damage.

[0017] Figure 2B depicts that CHAMP-002 had no effect on the secretion of inflammatory cytokines IFN-β and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA- damage.

[0018] Figure 3A. depicts that treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with genetic knockdown of VPS4.

[0019] Figure 3B depicts that treatment of A549 NSCLC cells with CHAMP-002 weakly induced a transcriptomic profile associated with genetic knockdown of VPS4.

[0020] Figure 4A depicts that treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with chemical inhibition of VPS4.

[0021] Figure 4B depicts that treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with the chemical inhibition of VPS4.

[0022] Figure 5A depicts that treatment of A549 NSCLC cells with CHAMP-003 weakly induced a transcriptomic profile associated with activation of the pro-inflammatory interferon pathway.

[0023] Figure 5B depicts that treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with activation of the pro-inflammatory interferon pathway.

[0024] Figure 6A depicts that CHAMP-003 potently induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatory DNA- damage.

[0025] Figure 6B depicts that CHAMP-002 induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatory DNA-damage.

[0026] Figure 7A depicts that CHAMP-003 had minimal effect on the short-term viability of A549 NSCLC cells in the presence or absence of pro-inflammatory DNA-damage.

[0027] Figure 7B depicts that CHAMP-002 had minimal effect on the short-term viability of A549 NSCLC cells in the presence or absence of pro-inflammatory DNA-damage.

[0028] Figure 8A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly reduced cell viability.

[0029] Figure 8B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly reduced cell viability.

[0030] Figure 9A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly reduced cell viability with low micromolar potency.

[0031] Figure 9B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly reduced cell viability with potentially moderate micromolar potency.

[0032] Figure 10A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly induced interferon regulatory factor (IRF) activity.

[0033] Figure 10B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly induced interferon regulatoiy factor (IRF) activity.

[0034] Figure 11A depicts that prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly induced interferon regulatoiy factor (IRF) activity with potentially moderate micromolar potency.

[0035] Figure 11B depicts that prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly induced interferon regulatory factor (IRF) activity with potentially high micromolar potency.

[0036] Figure 12A depicts that CHAMP-003 bound to and stabilized VPS4B protein, causing a small shift in its melting curve profile.

[0037] Figure 12B depicts that CHAMP-002 bound to and stabilized VPS4B protein, causing a large shift in its melting curve profile.

[0038] Figure 13A depicts that CHAMP-003 bound to and stabilized VPS4B protein, causing a small increase in melting temperature (Tm).

[0039] Figure 13B depicts that CHAMP-002 bound to and stabilized VPS4B protein, causing a large increase in melting temperature (Tm).

[0040] Figure 14 depicts that CHAMP-002 directly prevented the ATPase activity of VPS4B from being stimulated.

[0041] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0042] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0043] The present invention relates to novel VPS4 inhibitors that are useful in the treatment of cancers or solid or hematological tumors characterized by the loss of VPS4A or VPS4B.

[0044] In one aspect, the invention provides a compound represented by formula (I),whereinR1is aryl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -0Ra, - NRmRn, CN, and NO2;R2and R3are each independently H or C1-C3alkyl, or together with the carbon atom they are attached to form a C3-C7cycloalkyl group;Xis CHRb or NRb;Y is 0, S, or NRb;Z is N or CRb;R4is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRcRd, CN, or NO2;Ra, Rm, and Rn are each independently H or C1-C3alkyl;Rb is H, C1-C3alkyl, -SO3Ra, -COORa, or -CONRcRa; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2, and* represents R or S configuration, wherein said C1-C3alkyl, C1-C6alkyl, and C3-C7cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of halo, NRmRn, CN, -ORa, -COORa, and -CONRmRn, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, R1is aryl. In some embodiments, R1is phenyl.

[0046] In some embodiments, X is NRb. In some embodiments, X is NH.

[0047] In some embodiments, Y is NRb. In some embodiments, Y is 0 or S. In certain embodiments, Y is 0.

[0048] In some embodiments, R2and R3are H. In some embodiments, R2and R3are C1-C3alkyl. In some embodiments, R2and R3are methyl. In other embodiments, R2and R3are ethyl, isopropyl, or n-propyl.

[0049] In some embodiments, R2is H and R3is C1-C3alkyl. In some embodiments, R2is H and R3is methyl. In certain embodiments, R2is H and R3is ethyl, isopropyl, or n-propyl.

[0050] In some embodiments, m is 0. In other embodiments, m is 1 or 2.

[0051] In some embodiments, R4is halo, C1-C3haloalkyl, -ORa, -NRcRa, CN, or NO2. In some embodiments, R4is halo. In other embodiments, R4is C1-C3haloalkyl. In some embodiments, R4is -ORa. In certain embodiments, R4is OH.

[0052] In some embodiments, * represents S configuration.

[0053] In some embodiments, the compound of formula (I) is represented by formula (IA)whereinR1is aryl or heteroaiyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -0Ra, -NRmRn, CN, and NO2;R2and R3are each independently H or C1-C3alkyl;Xis CHRb or NRb;Y is 0, S, or NRb; andZ is N.

[0054] In some embodiments, R1is aryl. In some embodiments, R1is phenyl.

[0055] In some embodiments, X is NRb. In some embodiments, X is NH.

[0056] In some embodiments, Y is NRb. In some embodiments, Y is 0 or S. In certain embodiments, Y is 0.

[0057] In some embodiments, R2and R3are H. In some embodiments, R2and R3are C1-C3alkyl. In some embodiments, R2and R3are methyl. In other embodiments, R2and R3are ethyl, isopropyl, or n-propyl.

[0058] In some embodiments, R2is H and R3is C1-C3alkyl. In some embodiments, R2is H and R3is methyl. In certain embodiments, R2is H and R3is ethyl, isopropyl, or n-propyl.

[0059] In some embodiments, m is 0. In other embodiments, m is 1 or 2.

[0060] In some embodiments, R4is halo, C1-C3haloalkyl, -ORa, -NRcRa, CN, or NO2. In some embodiments, R4is halo. In other embodiments, R4is C1-C3haloalkyl. In some embodiments, R4is -ORa. In certain embodiments, R4is OH.

[0061] In some embodiments, * represents S configuration.

[0062] In some embodiments, the compound of formula (I) is represented by formula (IB) whereinR5is C1-C6alkyl, halo, C1-C3haloalkyl, -0Ra, -NRmRn, CN, and NO2; and p is 0, 1, 2, 3, or 4.

[0063] In some embodiments, the compound of formula (I) is represented by formula (IC)whereinR5is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; and p is 0, 1, 2, 3, or 4.

[0064] In some embodiments, the compound of formula (I) is represented by formula (ID)whereinR5is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; and p is 0, 1, 2, 3, or 4.

[0065] In some embodiments of the compound of the invention as described above, R5is halo. In some embodiments, R5is F or Cl. In some embodiments, p is 0. In other embodiments, p is 1.

[0066] In some embodiments, the compound of the invention is represented by

[0067] In some embodiments, the present invention provides a compound represented by formula (II)whereinR1is aryl, heteroaiyl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2;R2is substituted aryl or heteroaryl.

[0068] Examples of compounds with formula II include, but are not limited to:

[0069] In some embodiments, the present invention provides a compound represented by formula (IIA)whereinR = C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, or NO2; and substitution can be anywhere on the ring;R2is substituted aryl or heteroaryl.

[0070] Example of compounds with formula IIA includes, but is not limited to:

[0071] In some embodiments, the present invention provides a compound represented by formula (IIB)whereinR1 is aryl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2;R2is substituted aryl or heteroaryl.

[0072] Example of compounds with formula IIB includes, but is not limited to:

[0073] In another aspect, the present invention provides a compound represented by formula (III)

[0074] In some embodiments, the compound of the invention is a VPS4A inhibitor and / or a VPS4B inhibitor.

[0075] The compounds of the invention can be prepared based on the methods known in the art and the examples as described herein.

[0076] It is another aspect of the invention to provide processes for the preparation of compounds of the invention as described herein.

[0077] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art

[0078] As used herein, in some embodiments, the term "alkyl" refers to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g, n-propyl and isopropyl), butyl e.g, n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

[0079] In some embodiments, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has from 6 to about 20 carbon atoms. In some embodiments, "aryl" may be optionally substituted at any one or more positions.

[0080] In some embodiments, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include without limitation, pyridyl, N -oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, "heteroaryl" may be optionally substituted at any one or more positions capable of bearing a hydrogen atom.

[0081] The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0082] In some embodiments, “halo" or "halogen” includes fluoro, chloro, bromo, and iodo. A "halogen-substitution" or "halo" substitution designates replacement of one or more hydrogen atoms with F, CI, Br or I.

[0083] In some embodiments, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, and the like.

[0084] It is understood that each of alkyl, aryl, and heteroaryl may be optionally substituted with independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof, including esters, amides, and nitrites, hydroxy, alkyloxy, acyloxy, amino, alky and dialkylamino, acylamino, thio, and the like, and combinations thereof.

[0085] In some embodiments, the term "substituted" refers to the replacement of a hydrogen moiety with a non-hydrogen moiety in a molecule or group. It can refer to "monosubstituted" or "poly-substituted." The term "mono-substituted" or "poly-substituted" means substituted with one or more than one substituent up to the valence of the substituted group. For example, a mono-substituted group can be substituted with 1 substituent, and a poly-substituted group can be substituted with 2, 3, 4, or 5 substituents. When a list of possible substituents is provided, the substituents can be independently selected from that group.

[0086] The term "optionally substituted," in some embodiments, refers to that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, CN, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl, CH, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid is optionally substituted. In some embodiments, the functional groups are the substituents described herein for any one of variables. Furthermore, when using the terms "independently," "independently are," and "independently selected from" mean that the groups in question may be the same or different Certain of the herein defined terms may occur more than once in the structure, and upon such occurrence each term shall be defined independently of the other.

[0087] Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0088] In each of the foregoing and each of the following embodiments, it is to be understood that the formulas also include any and all hydrates and / or solvates of the compound formulas. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and / or coordination compounds with water and / or various solvents, in the various physical forms of the compounds. Accordingly, the above formulas are to be understood to include and represent those various hydrates and / or solvates.

[0089] As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. If the solvent is water, the solvate is referred to as "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that, for example, may include from 1 to about 100, or from 1 to about 10, or from one to about 2.3 or 4 molecules of water or a solvent In some embodiments, the hydrate may be a channel hydrate. It should be understood that the term "compound" in this application covers the compound and solvates of the compound, as well as mixtures thereof.

[0090] In some embodiments, the term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like.

[0091] The compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0092] The compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0093] The compounds of the invention as described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible optical isomers, diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. In some embodiments, a compound of the invention is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

[0094] In some embodiments, 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.

[0095] The present invention also includes "pharmaceutically acceptable salts" of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the compound of the invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compound of the invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. In some embodiments, the solvent is a nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

[0096] The pharmaceutically acceptable salts of the compound of the invention can be formed by conventional means, such as by reacting the free base or free acid form of theproduct with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ionexchange resin.

[0097] Possible pharmaceutically acceptable salts are well known in the art For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977; incorporated herein by reference.

[0098] A pharmaceutically acceptable salt form of a compound of the invention can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base functionality with a suitable organic or inorganic acid. Suitable acids for preparation of the pharmaceutically acceptable salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.

[0099] Other pharmaceutically acceptable salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0100] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0101] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calciumhydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, lH-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)- pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl)-l,3-propanediol, and tromethamine.

[0102] The invention further includes derivatives of the compound of the invention. The term "derivatives" includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.

[0103] The invention further includes metabolites of the compound of the invention. The term "metabolite" means any substance produced from another substance by metabolism or a metabolic process.

[0104] The invention further includes pharmaceutical products of the compound of the invention. The term "pharmaceutical product' means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.

[0105] The invention further includes prodrugs of the compound of the invention. The term "prodrug" means a substance which can be converted in vivointo a biologically active agent by such reactions as hydrolysis, esterification, de-esterification, activation, salt formation and the like.

[0106] This invention further includes crystals of the compound of the invention. Further, this invention provides polymorphs of the compound of the invention. The term "crystal" means a substance in a crystalline state. The term "polymorph" refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.

[0107] As noted herein, the compounds of the invention are inhibitors of VPS4 proteins. In some embodiments, the compound is a VPS4A inhibitor. In some embodiments, the compound is a VPS4B inhibitor. In some embodiments, the compound is an inhibitor of both VPS4A and VPS4B. In some embodiments, the compound inhibits the activity of VPS4A, VPS4B, or both VPS4A and VPS4B in cancer cells.

[0108] The biological activity of the compounds of the invention as VPS4 inhibitors can be readily assessed in any of a number of in vitro and in vivo assays, for example, as described in Examples IA-14 as described herein.

[0109] Cell lines representing a wide variety of cancers have been noted to rely on one of the two VPS4 genes for their survival, including pediatric rhabdomyosarcoma and bile duct, bladder, breast, colorectal, esophageal, gastric, liver, lung, ovarian, and pancreatic cancers. More than 40% of pancreatic cancer and pediatric rhabdomyosarcoma (RMS) cancer cell lines demonstrate robust dependence on VPS4A. VPS4A is also essential in a substantial fraction of bladder, bile duct, lung, ovarian, colon, and esophageal cancer cell lines. For VPS4B, more than 25% of ovarian, breast, pancreatic, liver, gastric, and bile duct cancer cell lines demonstrate strong dependency (Neggers etal, 2020, Cell Reports 33, 108493).

[0110] It is one aspect of the present invention that the compounds of the invention are used for treatment of cancer. In some embodiments, the cancer depends on VPS4A and / or VPS4B for survival. In some embodiments, the cancer is characterized by the loss of VPS4A or by the loss of VPS4B. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer. In one embodiment, the compound of the invention suppresses the growth of cancer cells in vitro or in vivo.

[0111] In some embodiments, the compounds of the invention are used for treatment of a cancer that depends on VPS4A and / or VPS4B for survival. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In someembodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0112] In some embodiments, the compounds of the invention are used for treatment of a cancer that is characterized by the loss of VPS4A or by the loss of VPS4B. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0113] The present invention further provides a method for treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer depends on VPS4A and / or VPS4B for survival. In some embodiments, the cancer is characterized by the loss of VPS4A or by the loss of VPS4B. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the canceris bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0114] The present invention further provides a method for treating a cancer, which depends on VPS4A for survival, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0115] The present invention further provides a method for treating a cancer, which depends on VPS4B for survival, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments,the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0116] The present invention further provides a method for treating a cancer, which depends on both VPS4A and VPS4B for survival, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0117] The present invention further provides a method for treating a cancer, which is characterized by the loss of VPS4A, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In someembodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0118] The present invention further provides a method for treating a cancer, which is characterized by the loss of VPS4B, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma. In some embodiments, the cancer is non-small cell lung cancer.

[0119] In some embodiments, the cancer that can be treated by the compound of the invention includes but is not limited to cancerous and precancerous conditions, including, for example, premalignant and malignant hyperproliferative diseases. In another embodiment, the compounds of the invention are used to prevent and / or treat premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above. Such uses are indicated in conditions known to precede or suspected of preceding progression to neoplasia or cancer.

[0120] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0121] A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given indication and administration regimen.

[0122] As used herein, a "pharmaceutically acceptable carrier" is well known to those skilled in the art The carrier may be a solid carrier for solid formulations, a liquid carrier or diluent for liquid formulations, or mixtures thereof. In addition, the pharmaceutical compositions of the invention may further include one or more ingredient selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. The formulations may be of immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.

[0123] The invention further provides a pharmaceutical composition comprising a compound of the invention as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use in treating a cancer in a subject in need thereof. In some embodiments, the cancer depends on VPS4A and / or VPS4B for survival. In some embodiments, the cancer is characterized by the loss of VPS4A or by the loss of VPS4B. In some embodiments, the cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor. In some embodiments, the cancer is bile duct cancer. In other embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is pediatric rhabdomyosarcoma.

[0124] The compound of the invention as described herein and a pharmaceutical composition comprising the same can be administered to a subject by any method known to a person skilled in the art. These methods include, but are not limited to, orally, parenterally, intravascularly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, intraventricularly, intracranially, intravaginally, by inhalation, rectally, or intratumorally. These methods include any means in which the compound or the pharmaceutical composition comprising the same can be delivered to tissue e.g., needle or catheter). Alternatively, a topical administration may be desired for application to dermal, ocular, or mucosal surfaces. Another method of administration is via aspiration or aerosol formulation. The compound or the pharmaceutical composition may be administered topically to body surfaces and are thus formulated in a form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, dropsand the like. For topical administrations, the compositions are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

[0125] In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. For solid oral preparations such as, powders, capsules, and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. For parenteral formulations, the carrier will usually comprise sterile water, though other ingredients may be included, such as ingredients that aid solubility or for preservation. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed. In some applications, it may be advantageous to utilize the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.

[0126] Methods of treatment using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient Optionally, a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught

[0127] A tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.

[0128] A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative,agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

[0129] Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which, in some embodiments, is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

[0130] Parenteral administration may comprise any suitable form of systemic delivery. Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be carried out by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.

[0131] Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.

[0132] For administration to mammals, and particularly humans, it is expected that the physician will determine the actual dosage and duration of treatment, which will be most suitable for an individual and can vary with the age, weight, genetics and / or response of the particular individual. In some embodiments, the subject is a mammal (e.g., a human or nonhuman mammal). In some embodiments, the subject is a human.

[0133] The methods of the invention comprise administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, at a therapeutically effective amount The therapeutically effective amount may include various dosages.

[0134] A dosage unit of the compounds used in the present invention may comprise a single compound or mixtures thereof with additional therapeutic agents. A "dose" or "dosage unit' or "unit dosage” of a compound of the invention as measured in milligrams refers to the milligrams of the compound of the invention present in a composition, regardless of the form of the composition.

[0135] In some embodiments, a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, liquid suspensions, and granules.

[0136] In some embodiments, a compound of the invention is administered at a dosage of 1-3000 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1-1000 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 1-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 10-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 50-500 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 5-250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 10-250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 20-250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-250 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-200 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-150 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-125 mg per day. In some embodiments, a compound of the invention as described herein is administered at a dosage of 25-100 mg per day.

[0137] In other embodiments, a compound of the invention is administered at a dose of 1- 10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 10-26 mg per day, 10-100 mg per day, 15-60 mg per day, 15-100 mg per day, 25-100 mg per day, 50-100 mg per day, 50-200 mg per day, 100-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mg per day, 500-1000 mg per day, 200-1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 125-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day.

[0138] The methods may comprise administering a compound at various dosages. For example, the compound may be administered per day at a dosage of 3 mg, 10 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 125 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg.

[0139] Alternatively, the compound may be administered at a dosage of 0.1 mg / kg / day. The compound may be administered at a dosage between 0.2 to 30 mg / kg / day, or 0.2 mg / kg / day, 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 mg / kg / day, 30 mg / kg / day, 50 mg / kg / day or 100 mg / kg / day.

[0140] In some embodiments, the compound of the invention is prepared for once daily administration. In another embodiment, the compound of the invention is prepared for more than once daily administration, for example, twice daily, three times daily, four times daily, etc.

[0141] In some embodiments, the compound or the pharmaceutical composition of the invention is administered in the form of a capsule, a tablet, or a liquid suspension. In other embodiments, the compound or the pharmaceutical composition of the invention is administered in an oral dosage unit form.

[0142] The methods of treatment of the present invention can additionally include administering to the subject one or more additional therapeutic agents for a combination therapy. Such additional therapeutic agents may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with a compound or composition of the present invention.

[0143] The term "combination therapy" means the administration of two or more therapeutic agents to treat a cancer described in the present invention. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein.

[0144] As used herein, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise.

[0145] The terms "subject" and "patient" are used interchangeably herein when referencing, for example, a mammalian subject In some embodiments, the subject in the method of the invention is a human patient

[0146] The term "treatment" or "treating" as used herein refers to the administering of a therapeutically effective amount of the compound of the invention to ameliorate undesired symptoms associated with the cancer, to prevent the manifestation of such symptomsbefore they occur, to slow down the progression of the cancer, slow down the deterioration of symptoms, to slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above.

[0147] It is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. When a range of values is expressed, another embodiment 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 embodiment All ranges are inclusive and combinable. Further, reference to values stated in ranges includes each and every value within that range. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects may also be provided in combination in a single aspect Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0148] The following examples are presented in order to more fully illustrate the embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.Example I: Preparation of Compounds of Invention

[0149] The compounds in the invention can be synthesized by any of the protocols known in the art and generally described below:Protocol A:

[0150] Substituted dihydropyrimidine analogs of structure I can be prepared by a 3- component condensation of an aldehyde, a substituted guanidine, and a 1,3 dicarbonyl compound to form the dihydropyrimidine ring as described in patent W02013043192A1 and the publication Chemistry of Heterocyclic Compounds, Vol. 42, No. 10, 2006, as illustrated below:Protocol B:

[0151] Substituted tetrahydro-lH-pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione analogs of structure III can be prepared by a 3-component condensation of an aldehyde, a 3-amino-l- substituted-lH-pyrazol-5-ol and a 1,3-dicarbonyl compound to form the tetrahydro-lH- pyrazolo[3,4-b]quinoline-3,5(2H,6H)-dione ring as illustrated below:Protocol C:

[0152] 5-Substituted-N-[lH-pyrazol-3-yl] carboxamide analogs of structure II can be prepared by condensation of a substituted lH-pyrazol-3-amine with an aryl carboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:Protocol D:

[0153] 5-substituted-N-[lH-l,2,4-triazol-3-yl] carboxamide analogs of structure Ila can be prepared by condensation of a 5-substituted lH-l,2,4-triazol-3-amines with an arylcarboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:Protocol E:

[0154] 3-substituted-N-(l,2-oxazol-5-yl) carboxamide analogs of structure lib can be prepared by condensation of a 3-substituted-l,2-oxazol-5-amines with an aryl carboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:Protocol F:

[0155] Substituted-3-amino indazole carboxamide analogs of structure lie can be prepared by condensation of a substituted-3-amino indazole with an aryl carboxylic acid or carboxylic acid chloride, or with a suitable coupling agent to form the desired carboxamide compounds as illustrated below:TABLE 1 - Synthetic Procedures and Characterization DataExample II: Biological ActivityExample 1A: Effects on inflammatory cytokine CXCL10Materials and Methods

[0156] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM. Double-stranded poly(deoxyadenylic-deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and the secretion of cytokines, was added at 100 ng / ml as an assay positive control. After treatment, cytokine levels were evaluated using a Luminex assay. The results depict fold changes in the levels of IFN-β and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.Results and Discussion

[0157] As demonstrated in Figure 1A, CHAMP-003 strongly induced the inflammatory cytokines IFN-β and CXCL10 in A549 NSCLC cells.Example 1B: Effects on inflammatory cytokine CXCL10Materials and Methods

[0158] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM. Double-stranded poly(deoxyadenylic-deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and the secretion of cytokines, was added at 100 ng / ml as an assay positive control (not shown, off axes scale). After treatment, cytokine levels were evaluated using a Luminex assay. The results depict fold changes in the levels of IFN-β and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.Results and Discussion

[0159] CHAMP-002 weakly induced the inflammatory cytokine CXCL10 in A549 NSCLC cells (Figure IB).Example 2A: Effects on the secretion of inflammatory cytokines IFN-β and CXCL10Materials and Methods

[0160] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 |iM and the DNA-damaging chemotherapeutic doxorubicin at 0.5 |1M. Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and the secretion of cytokines, was added at 100 ng / ml as an assay positive control. After treatment, cytokine levels were evaluated using a Luminex® assay. The results depict fold changes in the levels of IFN-β and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.Results and Discussion

[0161] CHAMP-003 potently induced the inflammatory cytokines IFN-β and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA-damage (Figure 2A).Example 2B: Effects on the secretion of inflammatory cytokines IFN-β and CXCL10Materials and Methods

[0162] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM and the DNA-damaging chemotherapeutic doxorubicin at 0.5 pM. Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and the secretion of cytokines, was added at 100 ng / ml as an assay positive control (not shown, off axis scale). After treatment, cytokine levels were evaluated using a Luminex® assay. The results depict fold changes in the levels of IFN-β and CXCL10 detected in the media relative to cells treated with the vehicle control, DMSO.Results and Discussion

[0163] CHAMP-002 had no effect on the secretion of inflammatory cytokines IFN-P and CXCL10 in A549 NSCLC cells in the presence of pro-inflammatory DNA-damage (Figure 2B).Example 3A: Treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0164] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 |1M. The archetypal VPS4 inhibitor MSC 1094308 (Pohler, 2018) was added as a positive control, also at 10 |1M. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated using RNASeq and correlated to the transcriptomic pattern in A549 cells in which both VPS4A and VPS4B had been knocked down using siRNA technology. The results depict rank- ordered Pearson’s correlation coefficients for all test agents with the position of CHAMP- 003 shown.Results and Discussion

[0165] Treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with genetic knockdown of VPS4 (Figure 3A).Example 3B: Treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0166] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 jiM. The archetypal VPS4 inhibitor MSC 1094308 (Pohler, 2018) was added as a positive control, also at 10 iM. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated using RNASeq and correlated to the transcriptomic pattern in A549 cells in which both VPS4A and VPS4B had been knocked down using siRNA technology. The results depict rank- ordered Pearson's correlation coefficients for all test agents with the position of CHAMP- 002 shown.Results and Discussion

[0167] Treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with genetic knockdown of VPS4 (Figure 3B).Example 4A: Treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0168] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 iM. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated usingRNASeq and correlated to the transcriptomic pattern in A549 cells treated with 10 pM of the published VPS4B inhibitor, MSC1094308 (Pbhler, 2018). The results depict rank- ordered Pearson's correlation coefficients for all test agents with the position of CHAMP- 003 shown.Results and Discussion

[0169] Treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with chemical inhibition of VPS4 (Figure 4A).Example 4B: Treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0170] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated using RNASeq and correlated to the transcriptomic pattern in A549 cells treated with 10 pM of the published VPS4B inhibitor, MSC1094308 (Pbhler, 2018). The results depict rank- ordered Pearson's correlation coefficients for all test agents with the position of CHAMP- 002 shown.Results and Discussion

[0171] Treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with the chemical inhibition of VPS4 (Figure 4B)Example 5A: Treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0172] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM. The archetypal VPS4 inhibitor MSC 1094308 (Pbhler, 2018) was added as a positive control, also at 10 pM. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated using RNASeq and correlated to the known transcriptomic profile for activation of the interferon pathway. The results depict rank-ordered Pearson's correlation coefficients for all test agents with the position of CHAMP-003 shown.Results and Discussion

[0173] Treatment of A549 NSCLC cells with CHAMP-003 induced a transcriptomic profile associated with activation of the pro-inflammatory interferon pathway (Figure 5A).Example 5B: Treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0174] A549 NSCLC cells were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 p.M. The archetypal VPS4 inhibitor MSC 1094308 (Pohler, 2018) was added as a positive control, also at 10 pM. After treatment, cells were harvested, and poly-A RNA prepared. Gene expression patterns were evaluated using RNASeq and correlated to the known transcriptomic profile for activation of the interferon pathway. The results depict rank-ordered Pearson’s correlation coefficients for all test agents with the position of CHAMP-002 shown.Results and Discussion

[0175] Treatment of A549 NSCLC cells with CHAMP-002 induced a transcriptomic profile associated with activation of the pro-inflammatory interferon pathway (Figure 5B).Example 6A: Compounds of Invention induced interferon regulatory factor activityMaterials and Methods

[0176] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 pM, in the presence or absence of the DNA- damaging chemotherapeutic doxorubicin at 0.5 pM. Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and IRF activity, was added at 100 ng / ml as an assay positive control. After treatment, IRF activity was evaluated using a luminometer. The results depict fold changes in IRF activity relative to cells treated with the vehicle control, DMSO, and normalized for cell viability (as measured using the Cell Titer Gio® luminescent assay). The level of IRF activity induced by CHAMP- 003 is shown.Results and Discussion

[0177] CHAMP-003 potently induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatoiy DNA-damage (Figure 6A).Example 6B: Compounds of Invention induced interferon regulatory factor activityMaterials and Methods

[0178] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 |1M, in the presence or absence of the DNA- damaging chemotherapeutic doxorubicin 0.5 |1M. Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and IRF activity, was added at 100 ng / ml as an assay positive control. After treatment, IRF activity was evaluated using a luminometer. The results depict fold changes in IRF activity relative to cells treated with the vehicle control, DMSO, and normalized for cell viability (as measured using the Cell Titer Gio® luminescent assay). The level of IRF activity induced by CHAMP- 002 is shown.Results and Discussion

[0179] CHAMP-002 induced interferon regulatory factor (IRF) activity in A549 NSCLC cells in the presence and absence of pro-inflammatory DNA-damage (Figure 6B)Example 7A: Effects on the short-term viability of A549 NSCLC cellsMaterials and Methods

[0180] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 iM, in the presence or absence of the DNA- damaging chemotherapeutic doxorubicin 0.5 |1M. Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and IRF activity, was added at 100 ng / ml as an assay positive control. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict fold changes in cell viability relative to cells treated with the vehicle control, DMSO. The viability of cells in the presence of CHAMP-003 is shown.Results and Discussion

[0181] CHAMP-003 had minimal effect on the short-term viability of A549 NSCLC cells in the presence or absence of pro-inflammatory DNA-damage (Figure 7A).Example 7B: effects on the short-term viability of A549 NSCLC cellsMaterials and Methods

[0182] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 24 hours with a series of test agents targeting VPS4 at 10 |1M, in the presence or absence of the DNA- damaging chemotherapeutic doxorubicin 0.5 |1M. Double-stranded poly(deoxyadenylic- deoxythymidylic) (polydAdT), a known stimulant triggering inflammation and IRF activity, was added at 100 ng / ml as an assay positive control. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict fold changes in cell viability relative to cells treated with the vehicle control, DMSO. The viability of cells in the presence of CHAMP-002 is shown.Results and Discussion

[0183] CHAMP-002 had minimal effect on the short-term viability of A549 NSCLC cells in the presence or absence of pro-inflammatory DNA-damage (Figure 7B).Example 8A: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0184] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-003 at concentrations ranging from 0.10 to 20 gM. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict fold changes in cell viability relative to cells treated with the vehicle control, DMSO. Bars show mean + SD for n=3 wells from a single experiment Results and Discussion

[0185] Prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly reduced cell viability (Figure 8A)Example 8B: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0186] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-002 at concentrations ranging from 0.10 to 20 |1M. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict fold changesin cell viability relative to cells treated with the vehicle control, DMSO. Bars show mean ± SD for n=3 wells from a single experimentResults and Discussion

[0187] Prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly reduced cell viability (Figure 8B).Example 9A: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0188] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-003 at concentrations ranging from 0.10 to 20 pM. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict changes in cell viability relative to cells treated with the vehicle control, DMSO. Circles show mean ± SD for n=3 wells from a single experiment For the purposes of calculating an ICso value, the DMSO control was assigned a "concentration" of 0.01 pM. The estimated ICso value for CHAMP-003 is 4.1 pM.Results and Discussion

[0189] Prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly reduced cell viability with low micromolar potency (Figure 9A).Example 9B: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0190] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-002 at concentrations ranging from 0.10 to 20 pM. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict changes in cell viability relative to cells treated with the vehicle control, DMSO. Circles show mean + SD for n=3 wells from a single experiment For the purposes of calculating an ICso value, the DMSO control was assigned a "concentration" of 0.01 pM. An ICso value for CHAMP-002 could not be accurately estimated because of the non-sigmoidal nature of the dose-response curve. Results and Discussion

[0191] Prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly reduced cell viability with potentially moderate micromolar potency (Figure 9B).Figure 10A: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0192] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-003 at concentrations ranging from 0.10 to 20 pM. After treatment, IRF activity was evaluated using a luminometer. The results depict fold changes in IRF activity relative to cells treated with the vehicle control, DMSO, and normalized for cell viability (as measured using the Cell Titer Gio® luminescent assay). Bars show mean ± SD for n=3 wells from a single experimentResults and Discussion

[0193] Prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly induced interferon regulatory factor (IRF) activity (Figure 10A).Example 10B: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0194] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-002 at concentrations ranging from 0.10 to 20 pM. After treatment, IRF activity was evaluated using a luminometer. The results depict fold changes in IRF activity relative to cells treated with the vehicle control, DMSO, and normalized for cell viability (as measured using the Cell Titer Gio® luminescent assay). Bars show mean + SD for n=3 wells from a single experimentResults and Discussion

[0195] Prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly induced interferon regulatory factor (IRF) activity (Figure 10B).Example 11A: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0196] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-003 at concentrations ranging from 0.10 to 20 |1M. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict changes in cellviability relative to cells treated with the vehicle control, DMSO. Circles show mean ± SD for n=3 wells from a single experiment For the purposes of calculating an ICso value, the DMSO control was assigned a “concentration" of 0.0 lpM. An ECso value for CHAMP-003 could not be accurately estimated because of the non-sigmoidal nature of the dose-response curve. Results and Discussion

[0197] Prolonged treatment of A549 NSCLC cells with CHAMP-003 strongly induced interferon regulatory factor (IRF) activity with potentially moderate micromolar potency (Figure 11 A).Example 11B: treatment of A549 NSCLC cells with Compounds of InventionMaterials and Methods

[0198] A549 NSCLC cells stably transfected with a reporter construct responsive to IRF activity were seeded, allowed to attach overnight, and then treated for 72 hours with CHAMP-002 at concentrations ranging from 0.10 to 20 pM. After treatment, cell viability was evaluated using the Cell Titer Gio® luminescent assay. The results depict changes in cell viability relative to cells treated with the vehicle control, DMSO. Bars show mean + SD for n=2-3 wells from a single experiment For the purposes of calculating an ICso value, the DMSO control was assigned a "concentration" of 0.01 pM. An ECso value for CHAMP-002 could not be accurately estimated because of the non-sigmoidal nature of the dose-response curve.Results and Discussion

[0199] Prolonged treatment of A549 NSCLC cells with CHAMP-002 strongly induced interferon regulatory factor (IRF) activity with potentially high micromolar potency (Figure 11B).Example 12A: Compounds of Invention bound to and stabilized VPS4B proteinMaterials and Methods

[0200] Melt curve for soluble VPS4B protein (2 pM) treated with 30 pM CHAMP-003. Thermal stability (protein unfolding) was evaluated by differential scanning fluorimetry using the Invitrogen Thermal Shift Assay®. Compound binding stabilized VPS4B, causing an increase in the temperature at which it begins unfolding, as evidenced by a right-shift in the protein melting temperature profile (curve relative to the DMSO control curve).Results and Discussion

[0201] CHAMP-003 bound to and stabilized VPS4B protein, causing a small shift in its melting curve profile (Figure 12A).Example 12B: Compounds of Invention bound to and stabilized VPS4B proteinMaterials and Methods

[0202] Melt curve for soluble VPS4B protein (2 iM) treated with either 36 or 100 |1M CHAMP-002. Thermal stability (protein unfolding) was evaluated by differential scanning fluorimetry using the Invitrogen Thermal Shift Assay®. Compound binding stabilized VPS4B at both concentrations, causing an increase in the temperature at which it begins unfolding, as evidenced by a right-shift in the protein melting temperature profile (curves relative to the DMSO control curve).Results and Discussion

[0203] CHAMP-002 bound to and stabilized VPS4B protein, causing a large shift in its melting curve profile (Figure 12B).Example 13A: Compounds of Invention bound to and stabilized VPS4B proteinMaterials and Methods

[0204] Melt peak for soluble VPS4B protein (2 |iM) treated with 30 |1M CHAMP-003. Thermal stability (protein unfolding) was evaluated by differential scanning fluorimetry using the Invitrogen Thermal Shift Assay®. Compound binding stabilized VPS4B, causing a 2 °C increase in the temperature at which it begins unfolding, as evidenced by a right-shift in the protein melt peak (curve relative to the DMSO control curve).Results and Discussion

[0205] CHAMP-003 bound to and stabilized VPS4B protein, causing a small increase in melting temperature (Tm) (Figure 13A).Example 13B: Compounds of Invention bound to and stabilized VPS4B proteinMaterials and Methods

[0206] Melt peak for soluble VPS4B protein (2 p.M) treated with either 36 or 100 |1M CHAMP-002. Thermal stability (protein unfolding) was evaluated by differential scanning fluorimetry using the Invitrogen Thermal Shift Assay®. Compound binding at both concentrations stabilized VPS4B, causing a 4 °C and 9 °C increase respectively in thetemperature at which it begins unfolding, as evidenced by a right-shift in the protein melt peak (curves relative to the DMSO control curve).Results and Discussion

[0207] CHAMP-002 bound to and stabilized VPS4B protein, causing a large increase in melting temperature (Tm) (Figure 13B).Example 14: Effects on ATPase activity of VPS4BMaterials and Methods

[0208] Soluble SUMO-tagged VPS4B (0.8 pM) was pre-incubated with 50 |1M CHAMP-002 (or DMSO control) before the biological activator VTA1 (8 iM) and chemical stimulant poly- L-lysine (PLL; 8 piM) were added, along with 250 p,M of ATP substrate, to initiate the ATPase reaction. The level of ATP conversion to ADP was quantitated using the ADP-Glo® assay kit (Promega). The results depict the amount of luminescence relative to inactive VPS4B preincubated with DMSO (far left bar). Bars show mean + SD for n=2-3 wells from a single experiment Addition of VTA1 and PLL stimulated VPS4B activity relative to VPS4B alone (****; p<0.0001), whilst pre-incubation with CHAMP-002 prevented VPS4B from being activated by VTA1 and PLL to the same degree (####; p<0.0001).Results and Discussion

[0209] CHAMP-002 directly prevented the ATPase activity of VPS4B from being stimulated (Figure 14).

[0210] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

CLAIMSWhat is claimed is:

1. A compound represented by formula (I),whereinR1is aryl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -0Ra, -NRmRn, CN, and NO2;R2and R3are each independently H or C1-C3alkyl, or together with the carbon atom they are attached to form a C3-C7cycloalkyl group;Xis CHRb or NRb;Yis 0, S, or NRb;Z is N or CRb;R4is C1-C6alkyl, halo, C1-C3haloalkyl, -0Ra, -NRcRd, CN, or NO2;R3, Rm, and Rn are each independently H or C1-C3alkyl;Rb is H, C1-C3alkyl, -S03Ra, -COORa, or -CONRcRa; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2, and* represents R or S configuration, wherein said C1-C3alkyl, C1-C6alkyl, and C3-C7cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of halo, NRmRn, CN, -ORa, -COORa, and -CONRmRn, or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1-9, wherein R2and R3are H.

11. The compound according to any one of claims 1-9, R2and R3are C1-C3alkyl.

12. The compound according to claim 11, wherein R2and R3are methyl.

13. The compound according to claim 11, wherein R2and R3are ethyl, isopropyl, or n-propyl.

14. The compound according to any one of claims 1-9, R2is H and R3is C1-C3alkyl.

15. The compound according to any one of claims 1-9, R2is H and R3is methyl.

16. The compound according to any one of claims 1-9, R2is H and R3is ethyl, isopropyl, or n-propyl.

17. The compound according to any one of claims 1-16, wherein m is 0.

18. The compound according to any one of claims 1-16, wherein m is 1 or 2.

19. The compound according to any one of claims 1-18, wherein R4is halo, C1-C3haloalkyl, -ORa, -NRcRd, CN, or NO2.

20. The compound according to any one of claims 1-19, wherein * represents S configuration.

21. The compound according to claim 1, wherein said compound of formula (I) is represented by formula (IB)2. The compound according to claim 1, wherein said compound of formula (I) is represented by formula (IA)whereinR1is aryl or heteroaryl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2;R2and R3are each independently H or C1-C3alkyl;X is CHRb or NRb;Y is 0, S, or NRb; andZ is N.

3. The compound according to claim 1 or claim 2, R1is aryl.

4. The compound according to claim 3, R1is phenyl.

5. The compound according to any one of claims 1-4, wherein X is NRb.

6. The compound according to claim 5, wherein X is NH.

7. The compound according to any one of claims 1-6, wherein Y is NRb.

8. The compound according to any one of claims 1-6, wherein Y is 0 or S.

9. The compound according to any one of claims 1-6, wherein Y is 0.whereinR5is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; and p is 0, 1, 2, 3, or 4.

22. The compound according to claim 1, wherein said compound of formula (I) is represented by formula (IC)whereinR5is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; and p is 0, 1, 2, 3, or 4.

23. The compound according to claim 1, wherein said compound of formula (I) is represented by formula (ID)whereinR5is C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; and p is 0, 1, 2, 3, or 4.

24. The compound according to any one of claims 21-23, wherein R5is halo.

25. The compound according to any one of claims 21-23, wherein R5is F or Cl.

26. The compound according to any one of claims 21-23, wherein p is 0.

27. The compound according to any one of claims 21-23, wherein p is 1.

28. The compound according to claim 1, wherein said compound is represented(7), or29. A compound represented by formula (II)whereinR1is aiyl, heteroaiyl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; andR2is substituted aryl or heteroaryl.

30. The compound according to claim 29, wherein said compound is represented bywhereinR = C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, or NO2; and substitution can be anywhere on the ring; andR2is substituted aryl or heteroaryl.

32. The compound according to claim 31, wherein said compound is represented byCHAMP-001333. A compound represented by formula (IIB)whereinR1 is aryl, heteroaryl, or C3-C7cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of C1-C6alkyl, halo, C1-C3haloalkyl, -ORa, -NRmRn, CN, and NO2; andR2is substituted aryl or heteroaiyl.

34. The compound according to claim 33, wherein said compound is represented byCHAMP-003135. A compound represented by formula (III)36. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-35.

37. The method according to claim 36, wherein said cancer is lung cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, or any other solid or hematological tumor.

38. The method according to claim 36, wherein said compound is a VPS4A inhibitor.

39. The method according to claim 36, wherein said compound is a VPS4B inhibitor.

40. The method according to claim 36, wherein said compound is an inhibitor of both VPS4A and VPS4B.

41. The method according to claim 36, wherein said compound inhibits the activity of VPS4A, VPS4B, or both VPS4A and VPS4B in said cancer's cells.

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