Viral sensitizers compositions, methods and uses thereof

Abstract

The present application relates to viral sensitizers. More specifically, the present application relates to compounds of Formula (I), or a salt, solvate and / or prodrug thereof, as well as processes for their preparation and methods of using such compounds and compositions as viral sensitizers, specifically for increasing permissiveness of a cell to a virus.

Description

VIRAL SENSITIZERS COMPOSITIONS, METHODS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority of co-pending U.S. Provisional Patent Application No. 63 / 619,812, which was filed January 11 , 2024, the contents of which are incorporated herein by reference in their entiretyFIELD

[0002] The present application relates to viral sensitizers. More specifically, the present application relates to compounds, as well as processes for their preparation and methods of using such compounds, for example as viral sensitizers.BACKGROUND

[0003] Immunotherapy, in its many forms, is currently revolutionizing the treatment of cancer. Oncolytic viruses (OVs) have also made their way to the clinic, with the first OV approved for treatment of melanoma and many more in clinical development. Though their mechanism of action partially relies on oncolysis of tumor targets, OVs potently stimulate anti-tumor immunity. Cancer cells are more susceptible to infection by viruses because of their increased metabolism, resistance to apoptosis, and defective innate viral defenses. Nevertheless, hurdles still remain in achieving therapeutic efficacy when single agents are used for many tumor types. The development of “viral sensitizers” which synergistically amplify viral replication and spread within the tumor region may allow for more efficacious treatment regimens in solid tumors.

[0004] Outside of the direct treatment of disease, virus production remains a challenge in other manufacturing contexts, namely vaccine production. The replication capacity of the virus often represents a rate-determining step in the manufacturing process, limiting the final quantity of product. Finding new methods to improve the replicating yield of these viral vectors would prove valuable for improving the therapeutic efficacy of viral-based therapeutics and increasing costefficiency of viral-based manufacturing.

[0005] Viral sensitizing compounds are compounds that, for example, increase the production of viruses and viral vectors by increasing the infectivity of cells by suppressing their innate antiviral programmes.

[0006] Several compounds with viral sensitizing properties have been previously identified, most of which centrally operate by repressing the type 1 interferon response to increase viral infectivity of treated cells, see for example PCT / CA2010 / 001057, PCT / CA2014 / 050564, PCT / CA2016 / 050061 , PCT / CA2016 / 050062, PCT / CA2017 / 051176, PCT / CA2018 / 051492, and PCT / CA2022 / 050713. In combination with oncolytic viruses, some of these compounds have been demonstrated to increase anti-tumour activity across various in vivo mouse models of cancer. These compounds have also been successfully applied commercially to improve the production of viral-based products. While different viral sensitizing compounds can be effective in a broad range of applications; their efficacy can fluctuate depending on the context owing to differences in their physicochemical properties as well as their compoundspecific off-target effects. From a therapeutic standpoint in particular, the problem of low potency, side-effects, toxicity, and poor pharmacokinetics remain a primary obstacle to clinical translation.

[0007] As such, there is need to provide improved viral sensitizing compounds, for example, for viral-based gene therapies and viral vector production.SUMMARY

[0008] It has been shown herein that compounds of the present application are effective to increase permissiveness of a cell to a virus, and thus exhibit viral sensitizing activity, with high potency and versatility.

[0009] Accordingly, the present application includes a compound of Formula (I), or a salt, solvate and / or prodrug thereof:wherein:X is Ci-6alkylene;Cy1is selected from phenyl, 6-membered heteroaryl, benzofused 5- to 6- membered heteroaryl and benzofused 5- to 6-membered heterocycloalkyl, Cy1being unsubstituted or substituted with one to four substituents independently selected from halo, Ci ealkyl, Ci-ehaloalkyl, OR1, NR1R2, =0, SO2NR1R2, CO2R3, SR3, S(O)R3and SO2R3, and Cy1being optionally substituted with one Cy2;R1is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl, C(0)Ci-4alkyl and C(O)CHR4NR5R6;R2and R3are independently selected from H, Ci-4alkyl and Ci-4haloalkyl;R4is selected from H, NH2, Ci-4alkyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R5is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R6is selected from H, Ci-4alkyl and Ci-4haloalkyl;Cy2is selected from 5- to 6 membered heterocycloalkyl comprising at least one N-R7and optionally substituted with one to four substituents independently selected from halo, Ci ealkyl, Ci-ehaloalkyl, OR8, NR8R9, =0, SO2NR8R9, CO2R8, SR8, S(O)R8and SO2R8;R7is selected from H, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkylC(O)R12, C(O)CHR10NR11R12, 6-membered heteroarylR8and R9are independently selected from H, Ci-4alkyl and Ci-4haloalkyl; R10is selected from H, NH2, Ci-4alkyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R11is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl and a naturally occurring amino, the latter group being optionally substituted withone or more substituents independently selected from Ci-4alky I, halo, OH and OCi-4alkyl; andR12is selected from H, Ci-4alkyl and Ci-4haloalkyl; provided that, when Cy1is phenyl or 6-membered heteroaryl, Cy1is substituted with at least one of NR1R2, SO2NR1R2, CO2R3and Cy2.

[0010] The present application further includes a compound having the structure of Formula (IA), or a salt, solvate and / or prodrug thereof:wherein:X is Ci-6alkylene;Cy1is selected from phenyl and pyridyl, each of which is unsubstituted or substituted with one to four substituents independently selected from halo, Ci-4alkyl, NH2, N(Ci-4alkyl)(Ci-4alkyl), OCi-4alkyl, Ci-4haloalkyl and OC1- 4haloalkyl;R7is selected from H, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkyleneOR12, C(O)OR12,C(O) R12, C(O)CHR10NR11R12, 6-membered heteroarylR10is selected from H and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl;R11is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl; andR12is selected from H, Ci-4alkyl and Ci-4haloalkyl;R13is selected from halo, Ci-4alkyl and Ci-4haloalkyl;R14is =0; n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8; andm is 0, 1 or 2.

[0011] Also included is a composition comprising a compound of the present application and carrier.

[0012] Further included is a method of increasing permissiveness of a cell to a virus, comprising administering an effective amount of a compound of the present application to the cell.

[0013] The present application also includes a method of increasing permissiveness of a cell to genetic material encoding components of a virus, comprising administering an effective amount of a compound of the present application to the cell in combination with provision of the genetic material encoding components of a virus to the cell.

[0014] Also included is a method of treating a disease, disorder or condition by increasing permissiveness of a cell to a virus comprising administering a therapeutically effective amount of a compound of the present application and the virus or genetic material encoding the virus to a subject in need thereof.

[0015] The present application further includes a method of increasing the oncolytic activity of a virus comprising administering a therapeutically effective amount of a compound of the present application with an oncolytic virus to a subject or cell in need thereof.

[0016] Further included is a method of treating a disease, disorder or condition by gene therapy comprising administering a therapeutically effective amount of a compound of the present application and a gene therapy vector to a subject or cell in need thereof.

[0017] Also included is a method of increasing production of a virus by a cell comprising administering a compound of the present application to the cell.

[0018] The present application further includes a method of increasing transduction of a virus into a cell comprising administering a compound of the present application and the virus to the cell.

[0019] Also included is a method of increasing virally-encoded transgene expression comprising administering a compound of the present application and the virus to a cell.

[0020] Further included is a method of increasing virus growth and / or virus spread in cells comprising administering a compound of the present application to the cells in combination with provision of the virus to the cells.

[0021] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole.BRIEF DESCRIPTION OF DRAWINGS

[0022] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0023] FIG.1 is a graph showing simultaneous quantification of viral output and cytotoxicity at different concentrations of exemplary compound I-8 in MC38 murine colon carcinoma. The circles are associated with the right y-axis and represent GFP counts at each dose tested. The triangles represent cytotoxicity of the compound of the application alone whereas the squares indicate cytotoxicity of the compound of the application in combination with VSV.

[0024] FIG.2 is a graph showing simultaneous quantification of viral output and cytotoxicity at different concentrations of exemplary compound I-8 in CT2A murine glioma. The circles are associated with the right y-axis and represent GFP counts at each dose tested. The triangles represent cytotoxicity of the compound of the application alone whereas the squares indicate cytotoxicity of compound of the application in combination with VSV.

[0025] FIG.3 is a graph showing simultaneous quantification of viral output and cytotoxicity at different concentrations of exemplary compound I-8 in OVCA433 murine ovarian carcinoma. The circles are associated with the right y-axis and represent GFP counts at each dose tested. The triangles represent cytotoxicity of the compound of the application alone whereas the squares indicate cytotoxicity of compound of the application in combination with VSV.

[0026] FIG.4 is a graph showing simultaneous quantification of viral output and cytotoxicity at different concentrations of exemplary compound I-8 in (B16F10mouse melanoma. The circles are associated with the right y-axis and represent GFP counts at each dose tested. The triangles represent cytotoxicity of the compound of the application alone whereas the squares indicate cytotoxicity of compound of the application in combination with VSV.

[0027] FIG.5 is a graph showing simultaneous quantification of viral output and cytotoxicity at different concentrations of exemplary compound 1-8 in 4T1 mouse breast carcinoma. The circles are associated with the right y-axis and represent GFP counts at each dose tested. The triangles represent cytotoxicity of the compound of the application alone whereas the squares indicate cytotoxicity of compound of the application in combination with VSV.

[0028] FIG.6 is a graph showing VEU / ml and GFP foci or counts at different concentrations of exemplary compound I-8 tested in 786-0 cells. The diamonds are associated with the left y-axis and show GFP foci or counts while the circles are associated with the right y-axis and show VEU / ml at the same doses of compound I-8.

[0029] FIG.7A and FIG.7B are graphs showing enhancement of nonreplicating lentivirus encoding GFP (LV-GFP) transduction by exemplary compound I-8, with FIG.7A showing results on HT1080 connective tissue and FIG.7B showing results on HEPG2 hepatic cells.

[0030] FIG.8A and FIG.8B are graphs showing enhancement of adeno- associated virus serotype 2 encoding GFP (AAV2-GFP) transduction by exemplary compound I-8, with FIG.8 showing results on HT 1080 connective tissue and FIG.8B showing results on HEPG2 hepatic cells.

[0031] FIG.9 is a graph showing enhancement of non-replicating adeno virus type 5 encoding GFP (Ad5-GFP) transduction by exemplary compound I-8, on HEPG2 hepatic cells.DETAILED DESCRIPTIONI. Definitions

[0032] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0033] As used in this application and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0034] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0035] The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0036] The terms "about", “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0037] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0038] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0039] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “atleast one of” or “one or more” of the listed items is used or present. The term “and / or” with respect to prodrugs, salts and / or solvates thereof means that the compounds of the application exist as individual prodrugs, salts and hydrates, as well as a combination of, for example, a salt of a solvate of a compound of the application.

[0040] The term “compound of the application” or “compound of the present application” and the like as used herein refers to a compound of Formula (I), including compounds of Formula (l-A), as well as salts, solvates and / or prodrugs thereof.

[0041] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds of the application.

[0042] The term “suitable” as used herein means that the selection of the particular composition or conditions would depend on the specific steps to be performed, the identity of the components to be transformed and / or the specific use for the compositions, but the selection would be well within the skill of a person trained in the art.

[0043] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0044] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term Ci-walkyl means an alkyl group having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0045] The term “alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term C2-6alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.

[0046] The term “heterocyclyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. Heterocyclyl groups are either saturated or unsaturated (i.e. contain one or more double bonds).

[0047] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C

[0048] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.

[0049] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0050] The term “haloalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen. Thus, for example, “Ci-6haloalkyl” refers to a C1-6 linear or branched alkyl group as defined above with one or more halogen substituents.

[0051] The term “fluoroalkyl” refers to the replacement of one or more, including all, available hydrogens in an alkyl group with fluoro. Thus, for example, “Ci-efluoroalkyl” refers to a C1-6 linear or branched alkyl group as defined above with one or more fluoro substituents.

[0052] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0053] As used herein, the term “one or more” item includes a single item selected from the list as well as mixtures of two or more items selected from the list.

[0054] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0055] The term “naturally occurring amino acid” as used herein refers to an amino acid known to exist in nature, including the 22 known alpha amino acids thatare incorporated into polypeptides, 20 of which are encoded by the universal genetic code and the remaining 2, selenocysteine and pyrrolysine, are incorporated into proteins by unique synthetic mechanisms. The term “non-naturally or unnatural amino acids or unnaturally occurring amino acid” as used herein refers to a synthetic or semi-synthetic amino acid. See for example Narancic, T., Almahboub, S.A. & O’Connor, K.E. Unnatural amino acids: production and biotechnological potential. World J Microbiol Biotechnol 35, 67 (2019).

[0056] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0057] The term “subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0058] The term “pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.

[0059] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e. , a dosage form capable of administration to a subject.

[0060] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0061] The term “solvate” as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0062] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0063] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results.

[0064] “Palliating” a disease or disorder means that the extent and / or undesirable clinical manifestations of a disorder or a disease state are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0065] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition.

[0066] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell either in cell culture or in a subject.

[0067] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.

[0068] The term “cancer” as used herein refers to cellular-proliferative disease states.

[0069] The terms “sensitization” or “sensitizing” as used herein, in the context of a cell, refers to a decreased or altered cellular response to an outside agent such that the outside agent has an increased or altered effect on the cell. Where the outside agent is a virus, the terms “sensitization” or “sensitizing” (also referred to as “viral sensitization” or “viral sensitizing”) refers to a decreased or altered cellular response to the virus, thereby increasing the ability of the virus to infect and / or replicate in the cell.

[0070] The term “permissiveness” as used herein, in the context of a cell, refers to an increase in the uptake of an outside agent by the cell and / or an increase in the activity of the outside agent in the cell and / or a reduction in cellular defenses that would otherwise inhibit the expression, replication or stability of the outside agent in the cell. When the outside agent is a virus, “permissiveness” refers to the ability of a virus to infect and / or transduce a cell.

[0071] The term “genetic material encoding components of a virus” refers to a nucleic acid, and chemically modified variants thereof, that carry viral-likesequences of nucleotides. The sequences encode viral-like proteins and / or functional sequences for targeting, integration, promotion, etc.

[0072] The term “increase” or “increasing” as used herein refers to any detectable increase or enhancement in a function or characteristic in the presence of one or more test variables, compared to otherwise the same conditions except in the absence of the one or more test variables.

[0073] The term “decrease” or “decreasing” as used herein refers to any detectable decrease or reduction in a function or characteristic in the presence of one or more test variables, compared to otherwise the same conditions except in the absence of the one or more test variables.

[0074] The term “drug” as used herein, is intended to refer to any compound or mixture of compounds which is capable of exerting an effective or useful pharmacological effect.II. Compounds and Compositions of the Application

[0075] It has been shown herein that compounds of the application are effective to increase permissiveness of a cell to a virus, and thus exhibit viral sensitizing activity, with high potency and versatility.

[0076] Accordingly, the present application includes a compound of Formula I, or a salt, solvate and / or prodrug thereof, as well as a composition comprising a compound of Formula (I), or a salt, solvate and / or prodrug thereof, optionally with a pharmaceutically acceptable carrier or excipient, and optionally with a virus or genetic material encoding components of the virus.

[0077] In some embodiments, the compound of Formula (I) or a salt, solvate and / or prodrug thereof is:wherein:X is Ci-6alkylene;Cy1is selected from phenyl, 6-membered heteroaryl, benzofused 5- to 6-membered heteroaryl and benzofused 5- to 6-membered heterocycloalkyl, Cy1being unsubstituted or substituted with one to four substituents independently selected from halo, Ci-ealkyl, Ci-ehaloalkyl, OR1, NR1R2, =0, SO2NR1R2, CO2R3, SR3, S(O)R3and SO2R3, and Cy1being optionally substituted with one Cy2;R1is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl, C(0)Ci-4alkyl and C(O)CHR4NR5R6;R2and R3are independently selected from H, Ci-4alkyl and Ci-4haloalkyl;R4is selected from H, NH2, Ci-4al kyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH, 0Ci-4alkyl, and NR5R6;R5is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl, a naturally occurring amino acid the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R6is selected from H, Ci-4alkyl and Ci-4haloalkyl;Cy2is selected from 5- to 6 membered heterocycloalkyl comprising at least one N- R7and optionally substituted with one to four substituents independently selected from halo, Ci-ealkyl, Ci-ehaloalkyl, OR8, NR8R9, =0, SO2NR8R9, CO2R8, SR8, S(O)R8and SO2R8;R7is selected from H, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkyleneOR12, C(O)OR12,C(O)R12, C(O)CHR10NR11R12, 6-membered heteroarylR8and R9are independently selected from H, Ci-4alkyl and Ci-4haloalkyl;R10is selected from H, NH2, Ci-4alkyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R11is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl; and R12is selected from H, Ci-4alkyl and Ci-4haloalkyl; provided that, when Cy1is phenyl or 6-membered heteroaryl, Cy1is substituted with at least one of NR1R2, SO2NR1R2, CO2R3and Cy2.

[0078] In some embodiments, in the definition of Cy1, the 6-membered heteroaryl is selected from pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl. In some embodiments, in the definition of Cy1, the benzofused 5- to 6- membered heteroaryl is selected from indolinyl, benzoimidazolyl, benzoxazolyl, benzopyrazolyl, benzoxathiolyl, benzoisoxathiolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyridazinyl, benzopyrimidinyl, benzotriazolyl and benzotetrazolyl. In some embodiments, in the definition of Cy1, the benzofused 5- to 6-membered heterocycloalkyl is selected from benzopiperidinyl, benzopiperazinyl, benzotetrahydrofuranyl, benzotetrahydrothiophenyl, benzopyrrolidinyl, benzoimidazolidinyl, benzopyrazolidinyl, benzoisoxthiolidinyl, benzothiazolidinyl, benzoisothiazolidinyl, benzodioxolanyl, benzodithiolanyl, benzotetrahydropyranyl, benzomorpholinyl, benzothiomorpholinyl, benzodioxanyl and benzodithianyl.

[0079] In some embodiments, Cy1is selected from phenyl, pyridinyl, indolinyl, and benzodioxolanyl.

[0080] In some embodiments, Cy1is unsubstituted or substituted with one to four substituents independently selected from F, Ci-4alkyl, Ci-4fluoroalkyl, OCi-4alkyl, OCi-4fluoroalkyl, NH2, NHCi-4alkyl, N(Ci-4alkyl)2, NHC(O)Ci-4alkyl, NHC(O)CH2NH2, NHC(O)R5, =0, SO2NH2, SO2NHC(O)R5, and CO2H.

[0081] In some embodiments, Cy1is substituted with one to four substituents independently selected from F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, OCH3, OCF3, OCF2H, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, NH2, NHCH3, N(CH3)2, NHC(O)CH3, NHC(O)OtBu, NHC(O)CH2NH2, =0, SO2NH2, SO2NHC(O)CH(CH3)NHCH3, and CO2H.

[0082] In some embodiments, Cy1is substituted with one to three substituents. In some embodiments, Cy1is substituted with one to two substituents. In some embodiments, Cy1is substituted with one substituent.

[0083] In some embodiments, X is selected from Ci-3alkylene. In some embodiments, X is CH2.

[0084] In some embodiments, R1is selected from H, Ci-4fluoroalkyl and Ci- 4alkyl. In some embodiments, R1is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2and CH(CF3)2.

[0085] In some embodiments, R2is selected from H, Ci-4fluoroalkyl and Ci- 4alkyl. In some embodiments, R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0086] In some embodiments, R3is selected from H, Ci-4fluoroalkyl and C1- 4alkyl. In some embodiments, R3is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0087] In some embodiments, wherein R4is a side chain of a naturally occurring amino acid which is optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, glycine, proline, threonine and valine.

[0088] In some embodiments, R5is selected from H, Ci-4fluoroalkyl, Ci-4alkyl, and a naturally occurring amino acid, the latter group being optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl. In some embodiments, R5is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2. In some embodiments, R5is the naturally occurring amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, glycine, proline, threonine and valine.

[0089] In some embodiments, R6is selected from H, Ci-4fluoroalkyl and C1- 4alkyl. In some embodiments, R6is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0090] In some embodiments, Cy2is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, diazolidinyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, diazinanyl(e.g, piperazinyl), morpholinyl, and thiomorpholinyl, optionally substituted with one to four substituents as previously defined. In some embodiments, Cy2is selected from piperazinyl optionally substituted with one to four substituents as previously defined. In some embodiments, Cy2is substituted with one to four substituents independently selected from Ci ealkyl and =0;

[0091] In some embodiments, R7is selected from H, Ci-4fluoroalkyl, Ci-4alkyl, Ci-4alkyleneOH, C(O)OR12, C(O)R12, C(O)CHR10NR11R12, pyrimidinyl and

[0092] In some embodiments, R7is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu, C(O)CH3, C(O)CH2NH2, C(O)CH2N(CH3)2 C(O)CH(NH2)CH3C(O)NH2, C(O)CH(CH3)NHCH3, C(O)CH(CH3)N(CH3)C(O)OtBu, CH2CH2OH,C(O)CH(NH2)N(CH3)C(O)OtBu, pyrimidinyl,

[0093] In some embodiments, R8is selected from H, Ci-4fluoroalkyl and C1- 4alkyl. In some embodiments, R8is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0094] In some embodiments, R9is selected from H, Ci-4fluoroalkyl and C1- 4alkyl. In some embodiments, R9is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0095] In some embodiments, R10is a side chain of a naturally occurring amino acid which is optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, glycine, proline, threonine and valine.

[0096] In some embodiments, R11is selected from H, Ci-4fluoroalkyl, Ci- 4alkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or two substituents independently selected from Ci- 4alkyl, Cl, F, Br, OH and OCi-4alkyl. In some embodiments, R11is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, glycine, proline, threonine and valine.

[0097] In some embodiments, R12is selected from H, Ci-4fluoroalkyl and C1- 4alkyl. In some embodiments, R12is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0098] In some embodiments, the compound of the present application has the structure of Formula (I A) , or a salt, solvate and / or prodrug thereof:wherein:X is Ci-ealkylene;Cy1is selected from phenyl and pyridyl, each of which is unsubstituted or substituted with one to four substituents independently selected from halo, Ci-4al ky I , NH2, N(Ci-4alkyl)(Ci-4alkyl), OCi-4alkyl, Ci-4haloalkyl and OCi-4haloalkyl;R7is selected from H, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkyleneOR12, C(O)OR12,C(O)R12, C(O)CHR10NR11R12, 6-membered heteroarylR10is selected from H, NH2, Ci-4alkyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl;R11is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl; and R12is selected from H, Ci-4alkyl and Ci-4haloalkyl;R13is selected from halo, Ci-4alkyl and Ci-4haloalkyl;R14is =0; n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8; and m is 0, 1 or 2.

[0099] In some embodiments, Cy1in Formula l-A is unsubstituted or substituted with one to four substituents independently selected from F, Ci-4alkyl, Ci-4fluoroalkyl, OCi-4alkyl, OCi-4fluoroalkyl, NH2, and NHCi-4alkyl.

[0100] In some embodiments, Cy1is substituted with one to four substituents independently selected from F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, NH2, and NHCH3.

[0101] In some embodiments, X in Formula l-A is selected from Ci-3alkylene. In some embodiments, X is -CH2-.

[0102] In some embodiments, R7in Formula l-A is selected from H, C1-4fluoroalkyl, Ci-4alkyl, Ci-4alkyleneOH, C(O)OR12, C(O)R12, C(O)CHR10NR11R12,

[0103] In some embodiments, R10in Formula l-A is a side chain of a naturally occurring amino acid, which is optionally substituted with one or two substituentsindependently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, glycine, proline, threonine and valine.

[0104] In some embodiments, R11in Formula l-A is selected from H, Ci- 4fluoroalkyl, Ci-4alkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl. In some embodiments, R11in Formula l-A is H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, the naturally occurring amino acid is selected from alanine, arginine, asparagine, glycine, proline, threonine and valine.

[0105] In some embodiments, R12in Formula l-A is selected from H, C1- 4fluoroalkyl and Ci-4al kyl . In some embodiments, R12in Formula l-A is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0106] In some embodiments, R13in Formula l-A is selected from F, C1- 4fluoroalkyl and Ci-4al kyl . In some embodiments, R13in Formula l-A is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

[0107] In some embodiments, m in Formula l-A is 0 or 1 .

[0108] In some embodiments, n in Formula l-A is 0 or 1 .

[0109] In some embodiments, the compound of Formula (I) is selected from a compound in Table 1.Table 1 : Compounds of Formula (I)or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0110] In some embodiments, the salt of a compound of the application is an acid addition salt or a base addition salt. In some embodiments, for pharmaceutical methods and uses on human or animal subjects, the salt is a pharmaceutically acceptable salt. The selection of a suitable salt may be made by a person skilled in the art. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compoundsare discussed, for example, by P. Stahl et al, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0111] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p- toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. In some embodiments, the mono- or di-acid salts are formed and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application forlaboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0112] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, Abutyl amine, choline and salts with amino acids such as arginine, lysine and the like. Basic nitrogen containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts) and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol groupbeing present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0113] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the application and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the application. In addition, when a compound of the application contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds of the application may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the application.

[0114] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0115] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0116] It is understood and appreciated that in some embodiments, compounds of the present application may have at least one chiral center and therefore can exist as enantiomers and / or diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that anyoptical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0117] In some embodiments, the compounds of the present application can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0118] The compounds of the present application may further exist in varying amorphous and polymorphic forms and it is contemplated that any amorphous forms, polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0119] In the compounds of general Formula I and pharmaceutically acceptable salts, solvates and / or prodrugs thereof, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present application is meant to include all suitable isotopic variations of the compounds of application. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H) and tritium (3H). Protium is the predominant hydrogen isotope found in nature. In some embodiments, the compounds of the application comprise one of more deuterium atoms.

[0120] The compounds of the present application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application. Therefore, the compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure.

[0121] In some embodiments, the compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers, optionally in combination with one or more viruses. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The present application also includesa composition comprising one or more compounds of the application, one or more viruses and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier as well as a pharmaceutical composition comprising one or more compounds of the application, one or more viruses and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.

[0122] The compositions of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a composition of the application is formulated for administration by oral, inhalation, parenteral, buccal, sublingual, insufflation, epidurally, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0123] Parenteral administration includes systemic delivery routes other than the gastrointestinal (Gl) tract and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0124] In some embodiments, a composition of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewinggum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions and the like. In the case of tablets, carriers that are used include lactose, com starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), or solvents (e.g. medium chain triglycerides, ethanol, water). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled- release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers, solvents or diluents include lactose, medium chain triglycerides, ethanol and dried com starch.

[0125] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phasethat is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium chain triglycerides, almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p- hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0126] It is also possible to freeze-dry the compositions of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0127] In some embodiments, a composition of the application is administered parenterally. For example, solutions are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions are usually prepared, and the pH's of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiments, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0128] In some embodiments, a composition of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, withan added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compositions of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0129] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compositions of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active components. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0130] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein a composition of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0131] Suppository forms of the compositions of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0132] In some embodiments a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0133] The compositions of the application are particularly amenable to administration with the aid of nano-carrier systems, such as liposomes, micelles, nanoparticles, nano-emulsions, lipidic nano-systems and the like (see for example, Bhat, M. et al. Chem. and Phys, of Lipids, 2021 , 236, 105053). Accordingly, the present application includes a composition comprising one or more compounds of the application, optionally one or more viruses and one or more components of a nano-carrier system.

[0134] Depending on the mode of administration, a pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient (compound(s) of the application and optionally one or more viruses) and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[0135] In some embodiments, the compositions of the application comprise an additional therapeutic agent. Therefore, the present application also includes a pharmaceutical composition comprising one of more compounds of the application, optionally one or more viruses and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is an anticancer drug.

[0136] Also included is a kit comprising the compound of the application and a) a virus, suitably an attenuated or genetically modified virus or an oncolytic virus; b) one or more cancer cells; c) a pharmaceutically acceptable carrier, diluent or excipient; d) non-cancer cells; e) cell culture media; f) one or more cancer therapeutics, g) a cell culture plate or multi-well dish; h) an apparatus to deliver the viral sensitizing compound to a cell, medium or to a subject; i) instructions for using the viral sensitizing agent; or j) a carrier diluent or excipient, or any combination of a)-j).

[0137] In some embodiments, which are not meant to be limiting in any manner, included is a kit comprising a compound of the application and a medium for growing, culturing or infecting cells with a virus and optionally, one or more cells which are capable of being infected by the virus. In a further embodiment, the cells are immortalized cells, cancer cells or tumor cells. In an alternate embodiment, the cells are MDCK, HEK293, Vero, HeLa or PER.C6 cells.

[0138] In some embodiments, the kit comprises instructions for using any component or combination of components and / or practicing any method as described herein.

[0139] In the above, the term "a compound" also includes embodiments wherein one or more compounds are referenced.III. Methods and Uses of the Application

[0140] The application also provides uses and methods relating to the compounds and compositions described herein.

[0141] The compounds and compositions of the application have been shown to increase permissiveness of a cell to a virus, and thus exhibit viral sensitizing activity, with high potency and versatility. Accordingly, the compounds and compositions of the application are useful for increasing permissiveness of a cell to a virus and for treating diseases, disorders or conditions by increasing permissiveness of a cell to a virus. The compounds and compositions of the application are also useful for increasing the oncolytic activity of a virus, treating a disease, disorder or condition by gene therapy, increasing virus production, increasing transduction, increasing virally-encoded transgene expression and increasing virus growth and / or spread. In some embodiments the cell is in vitro. In some embodiments, the cell is ex vivo. In some embodiments, the cells is in vivo (i.e. in a subject).Methods and uses of increasing permissiveness of a cell to a virus

[0142] The present application includes a method of increasing permissiveness of a cell or a subject to a virus, comprising administering an effective amount of a compound of the application, or a salt, solvate and / or prodrug thereof, (i.e. a compound of the application) to the cell or the subject.

[0143] Also provided is use of a compound of the application to increase permissiveness of a cell or a subject to a virus. In another embodiment, a compound of the application is used in the manufacture of a medicament to increase permissiveness of a cell or a subject to a virus. In yet another embodiment, a compound of the application is for use in increasing permissiveness of a cell or a subject to a virus.

[0144] In some embodiments, the compound of the application is administered to the cell before, after and / or concurrently with the virus. In some embodiments, the compound of the application is administered to the cell before the virus is administered to the cell.

[0145] In some embodiments, permissiveness of the cell to the virus is increased 1 .1 fold or more, 1 .2 fold or more, 1 .5 fold or more, 2 fold or more, 2.5 foldor more, 3 fold or more, 5 fold or more, or 10 fold or more, e.g., compared to permissiveness of the cell, or a comparable cell prior to the method or in the absence of the method. In some cases, the method includes measuring the increase in permissiveness to viral infection.

[0146] In some embodiments, the virus is a therapeutic virus.

[0147] In some embodiments, the virus is an interferon (IFN)-sensitive virus.

[0148] In some embodiments, the virus is an attenuated virus, a genetically modified virus, a non-replicating virus, or an oncolytic virus.

[0149] In some embodiments, the virus is a non-replicating viral vector, optionally an adenovirus (Ad), an adeno-associated virus (AAV) or lentivirus (LV).

[0150] In some, embodiments, the virus is a herpes simplex virus (HSV) viral vector.

[0151] In some embodiments, the virus is a gene therapy vector. As used herein, the term “gene therapy vector” is used to refer to a viral vector designed to deliver therapeutic genetic material to a cell or subject. Examples of gene therapy vectors include, but are not limited to human Ad5, Ad3, Ad11 , Ad35, canine Ad2, chimp Ad26, chimp AdOx1 , or recombinant serotypes therein, AAV serotypes 1 -9 or recombinant serotypes therein, Lentivirus, gamma-retrovirus, Annellovirus, or Baculovirus.

[0152] In some embodiments, the virus is a component of a vaccine. For example, but not limited to, a live attenuated vaccine such as, measles, mumps, rubella, rotavirus, chickenpox, yellow fever or a viral vector vaccine encoding a vaccine antigen transgene such as rVSVAG-ZEBOV-GP (Ervebo) or ChadOx1-S (Vaxzevria).

[0153] In some embodiments, the virus is a rhabdovirus, a togavirus, or an orthomyxovirus.

[0154] In some embodiments, the rhabdovirus is vesicular stomatitis virus (VSV), engineered mutants of VSV (VSVA51), an oncolytic non-VSV rhabdovirus, or a recombinant oncolytic non-VSV rhabdovirus encoding one or more of rhabdoviral N, P, M, G and / or L protein, or variant thereof including chimeras and fusion proteins thereof, having an amino acid identity of at least or at most 20, 30,40, 50, 60, 65, 70, 75, 80, 85, 90, 92, 94, 96, 98, 99, 100%, including all ranges and percentages there between, to the N, P, M, G and / or L protein of Arajas virus, Chandipura virus, Cocal virus, Isfahan virus, Maraba virus, Piry virus, Vesicular stomatitis Alagoas virus, BeAn 157575 virus, Boteke virus, Calchaqui virus, Eel virus American, Gray Lodge virus, Jurona virus, Klamath virus, Kwatta virus, La Joya virus, Malpais Spring virus, Mount Elgon bat virus, Perinet virus, Tupaia virus, Farmington, Bahia Grande virus, Muir Springs virus, Reed Ranch virus, Hart Park virus, Flanders virus, Kamese virus, Mosqueiro virus, Mossuril virus, Barur virus, Fukuoka virus, Kern Canyon virus, Nkolbisson virus, Le Dantec virus, Keuraliba virus, Connecticut virus, New Minto virus, Sawgrass virus, Chaco virus, Sena Madureira virus, Timbo virus, Almpiwar virus, Aruac virus, Bangoran virus, Bimbo virus, Bivens Arm virus, Blue crab virus, Charleville virus, Coastal Plains virus, DakArK 7292 virus, Entamoeba virus, Garba virus, Gossas virus, Humpty Doo virus, Joinjakaka virus, Kannamangalam virus, Kolongo virus, Koolpinyah virus, Kotonkon virus, Landjia virus, Manitoba virus, Marco virus, Nasoule virus, Navarro virus, Ngaingan virus, Oak-Vale virus, Obodhiang virus, Oita virus, Quango virus, Parry Creek virus, Rio Grande cichlid virus, Sandjimba virus, Sigma virus, Sripur virus, Sweetwater Branch virus, Tibrogargan virus, Xiburema virus, Yata virus, Rhode Island, Adelaide River virus, Berrimah virus, Kimberley virus, or Bovine ephemeral fever virus.

[0155] In some embodiments, the togavirus is sindbis, semliki forest virus or M1 virus.

[0156] In some embodiments, the orthomyxovirus is influenza A, influenza B, influenza C, influenza D, isavirus, thogotovirus or quanranjavirus.

[0157] In some embodiments, the cell is a eukaryotic cell, for example a human or other mammalian cell. In some embodiments, the cell is a prokaryotic cell.

[0158] The cell is optionally in vivo, ex vivo or in vitro. In some embodiments, the cell is a cell in subject (i.e. in vivo). In some embodiments, the cell is a cell in vitro, for example a cell line or a cell culture.Methods and uses of increasing permissiveness of a cell to genetic material encoding components of a virus

[0159] The present application includes a method of increasing permissiveness of a cell to genetic material encoding components of a virus, comprising administering an effective amount of a compound of the application, or a salt, solvate and / or prodrug thereof, (i.e. a compound of the application) to the cell prior, concurrent with, or after provision of the said genetic material to the cell using a carrier or method commonly known to a person skilled in the art. In no way limiting, this includes transfection using PEI or lipid-based reagents, electroporation, and nanoparticles, as is generally known in the art.

[0160] The term “genetic material encoding components of a virus” refers to nucleic acids, and chemically modified variants thereof, that comprise or consist of viral and / or viral-like sequences. The sequences can encode viral proteins, viral- like proteins and / or functional sequences for targeting, integration, promotion, etc.

[0161] Delivery of such genetic material to a cell is generally described as transfection. T ransfection efficiency refers to the degree to which a supplied source of genetic material is taken up and functional for its intended purpose in a cell.

[0162] Such genetic material may be delivered to the cell directly, or it may be provided in a carrier to enhance delivery and uptake by the cell. Examples of carriers include diverse polymers known in the art, which may be designed in a variety of nanoparticle formats, either loosely organized or more precision designed. Common carriers of genetic material are described, for example, in Cullis and Hope (2017) and in Mitchell et al. (2021 ).

[0163] In some embodiments, the genetic material is comprised in a plasmid.

[0164] In one example, lentivirus, gamma-Retrovirus, or AAV are produced following transfection of plasmids encoding lentivirus, gamma-Retrovirus, or AAV viral or viral-like sequences into a cell.Methods and uses of treating diseases, disorders or conditions

[0165] Compounds and compositions of the application are useful for treating diseases, disorders or conditions by increasing permissiveness of a cell to a virus. Therefore, the compounds and compositions of the present application are useful as medicaments and the application also includes a compound or composition of the application for use as a medicament in combination with a virus.

[0166] Accordingly, the present application includes a method of treating a disease, disorder or condition by increasing permissiveness of a cell to a virus comprising administering a therapeutically effective amount of a compound of the application and the virus or genetic material encoding the virus to a subject in need thereof. Also provided is use of a compound of the application and a virus or genetic material encoding a virus to treat a disease, disorder or condition. In another embodiment, a compound of the application is used in the manufacture of a medicament for treating a disease, disorder or condition in combination with a virus or genetic material encoding a virus.

[0167] In some embodiments, the compound of the application is administered to the cell before, after and / or concurrently with a virus that treats the disease, disorder or condition or genetic material encoding a virus that treats the disease, disorder or condition. In further embodiment, the compound of the application is for use before, after and / or concurrently with use of a virus that treats the disease, disorder or condition or genetic material encoding a virus that treats the disease, disorder or condition. In yet another embodiment, a compound of the application is for use before, after and / or concurrently with use of a virus that treats the disease, disorder or condition or genetic material encoding a virus that treats the disease, disorder or condition.

[0168] In some embodiments, the compound of the application allows a lower amount of the virus to be used to treat the disease, disorder or condition and / or increases the therapeutic efficacy of the virus.

[0169] In some embodiments, the virus is a therapeutic virus, for example a gene therapy vector.

[0170] In some embodiments, the disease, disorder or condition is cancer or tumor. In such embodiments, the virus is optionally an oncolytic virus. As used herein, an oncolytic virus is a virus that preferentially infects and lyses cancer or tumor cells as compared to non-cancer or normal cells. Oncolytic viruses can be natural or engineered.

[0171] In some embodiment, the cancer is a tumor.

[0172] In some embodiments, the cancer is lymphoblastic leukemia, myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma,anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain stem glioma, brain tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, craniopharyngioma, ependymoblastoma, medulloblastoma, pineal parenchymal tumors of intermediate differentiation, supratentorial primitive neuroectodermal tumors and pineoblastoma, visual pathway and hypothalamic glioma, spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, central nervous system lymphoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumors, extracranial, extragonadal, ovarian, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (Liver) cancer, histiocytosis, Langerhans cell cancer, Hodgkin lymphoma, hypopharyngeal cancer, islet cell tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, lymphocytic leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, malignant fibrous histiocytoma of bone and osteosarcoma, medulloblastoma, medulloepithelioma, melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter cancer, transitional cell cancer, respiratory tract carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine sarcoma, skincancer, Merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach (Gastric) cancer, supratentorial primitive neuroectodermal tumors, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, trophoblastic tumor, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms tumor.

[0173] In some embodiments, the cancer is colon cancer, breast cancer, rectal cancer, lung cancer, a leukemia, cervical cancer, sarcoma, melanoma, pancreatic cancer and / or ovarian cancer.

[0174] In some embodiments, the oncolytic virus is talimogene laherparepvec (T-VEC), Delytact, Maraba MG-1 , or vesicular stomatitis virus (VSVA51). In some embodiments, the oncolytic virus is a Newcastle Disease Virus (NDV), measles virus, (MeV), parvovirus H1 (ParvOryx), M1 virus, poliovirus, reovirus, Myxomavirus, or Sindbis virus (SinV).

[0175] In some embodiments, the subject is a mammal. In another embodiment, the subject is human.

[0176] In some embodiments, the cell is a cancer cell, a tumor cell or an immortalized cell. In some embodiments, the cells are cancer cells or tumor cells in vivo, or in vitro. In some embodiments, the cell is one or more types of immortalized cells in vitro or in vivo from any cell, cell line, tissue or organism, not limited to, human, rat, mouse, cat, dog, pig, primate, horse and the like, for example, without limitation: Vero, HEK-293 cells, VPC 1.0, VPC 2.0, EB-66 cells, EbX cells, PER. C6 cells, AGE1.CR, Agel.O S, Agel.HN, Agel.RO, Q0R2 / 2E11 , UMNSAH-DF1 , CHO, hybridoma cells, sf9 cells, or R4 cells. In some embodiments, the cell is cancer or tumor cells in vitro or in v / vo from any cell, cell line, tissue or organism, for example, but not limited to human, rat, mouse, cat, dog, pig, primate, horse and the like, for example tumor forming cells such as, but not limited to 293-T cells, BHK21 cells, or MDCK cells, or cells and tumor cells from cancer and tumor listed in the application.

[0177] In some embodiments, the term “treatment” refers to beneficial or desired clinical results which can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread ofdisease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations.

[0178] In some embodiments, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject or species. In some embodiments, the amount of a given composition that will correspond to an effective amount will vary depending upon factors, such as the given drug(s), compound(s) and / or viruses, the pharmaceutical formulation, the route of administration, the schedule of administration, the type of condition, disease or disorder, the identity of the subject being treated and the like, but can nevertheless be routinely determined by one skilled in the art.Methods and uses of increasing oncolytic activity of a virus

[0179] The present application also includes a method of increasing the oncolytic activity of a virus comprising administering a therapeutically effective amount of a compound of the application with an oncolytic virus to a subject or cell in need thereof. Also provided is use of a compound of the application for increasing the oncolytic activity of an oncolytic virus. In another embodiment, a compound of the application is used in the manufacture of a medicament for increasing the oncolytic activity of an oncolytic virus. In yet another embodiment, a compound of the application is for use in for increasing the oncolytic activity of an oncolytic virus.

[0180] As used herein, the expression “oncolytic activity” refers to the ability of the virus to infect and kill a cancer cell.

[0181] In some embodiments, the oncolytic activity of the virus is increased 1.1 fold or more, 1 .2 fold or more, 1.5 fold or more, 2 fold or more, 2.5 fold or more, 3 fold or more, 5 fold or more, or 10 fold or more, e.g., compared to the oncolyticactivity of the virus, or a comparable virus prior to the method or in the absence of the method. In some cases, the method includes measuring the increase in oncolytic activity of the virus.Methods and uses of treating a disease, disorder or condition by gene therapy

[0182] The present application also includes a method of treating a disease, disorder or condition by gene therapy comprising administering a therapeutically effective amount of a compound of the application and a gene therapy vector to a subject or cell in need thereof. Gene therapy vectors are understood to be viral or non-viral, where non-viral may include genetic material encoding a virus as described elsewhere herein. Also included is use of a compound of the application for treating a disease, disorder or condition by gene therapy, wherein the compound is for use in combination with a gene therapy vector, as well as a use of a compound of the application in the manufacture of a medicament for treating a disease, disorder or condition by gene therapy, wherein the compound is for use in combination with a gene therapy vector. The application also includes, a compound of the application for use in treating a disease, disorder or condition by gene therapy, wherein the compound is for use in combination with a gene therapy vector.

[0183] In some embodiments, the gene therapy vector comprises a therapeutic gene for treating said disease, disorder or condition. In such an embodiment, the compound of the application increases permissiveness of the cell to the gene therapy vector to increase the amount of virally-encoded therapeutic gene incorporated into the cell. The therapeutic gene may be incorporated into the genome of the cell or may stay episomal.Methods and uses of increasing production of viruses

[0184] The present application also includes a method, optionally an in vitro method, of increasing production of a virus by a cell comprising administering a compound of the application to the cell. Also included is a use of a compound of the application for increasing production of a virus by a cell, as well as a compound of the application for use in increasing production of a virus by a cell.

[0185] In some embodiments, the method comprises growing the virus in an appropriate medium in the presence of a compound of the application.

[0186] In some embodiments, the cell is a viral production cell, namely a cell that is used to produce a virus. Examples of viral production cells include, but are not limited to, Vero, HEK-293, VPC 1 .0, VPC 2.0, EB-66, EbX, PER, C6, AGE1 .CR, UMNSAH-DF1 , CEF, MRC-5, WI-38, BHK21 , Hela, A549 and sf9 cells.

[0187] In some embodiments, the virus produced by the cell is an oncolytic virus, gene therapy vector or a vaccine.

[0188] In some embodiments, production of the virus increased 1.1 fold or more, 1.2 fold or more, 1.5 fold or more, 2 fold or more, 2.5 fold or more, 3 fold or more, 5 fold or more, or 10 fold or more, e.g., compared to production of the virus by the cell, or a comparable cell, prior to the method or in the absence of the method. In some cases, the method includes measuring the increase in production of the virus, for example by determining the level of the virus in the cell and / or in the cell culture medium. Methods for determining virus production are known in the art and include, but are not limited to plaque assays, TCID50, PCR, ddPCR, ELISA, SRID and HPLC.Methods and uses of increasing transduction

[0189] The present application also includes a method, optionally an in vitro method, of increasing transduction of a virus into a cell comprising administering a compound of the application and the virus to the cell. Also included is a use of a compound of the application for increasing transduction of a virus into a cell, as well as a compound of the application for use in increasing transduction of a virus into a cell.

[0190] “Transduction” or “transducing” as used herein, refers to the introduction of a virus containing an exogenous gene into a cell leading to expression of the gene, e.g., the transgene in the cell. The gene is optionally a therapeutic gene.

[0191] As used herein, the expression “increasing transduction” includes increasing transduction efficiency.

[0192] In some embodiments, transduction of the virus is increased 1.1 fold or more, 1.2 fold or more, 1.5 fold or more, 2 fold or more, 2.5 fold or more, 3 fold or more, 5 fold or more, or 10 fold or more, e.g., compared to transduction of the virus by the cell, or a comparable cell, prior to the method or in the absence of themethod. In some cases, the method includes measuring the increase transduction of the virus, for example by determining the level of the virus in the cell. Methods of measuring transduction efficiency are known in the art and include, but are not limited to Fluorescence imaging, in vitro and in vivo luminometry, immunohistochemistry, PCR, ddPCR and flow cytometry.

[0193] In some embodiments, the virus is a non-replicating viral vector, optionally an adenovirus (Ad), an adeno-associated virus (AAV) or lentivirus (LV).Methods and uses of increasing virally-encoded transgene expression

[0194] The present application also includes a method, optionally an in vitro method, of increasing virally-encoded transgene expression comprising administering a compound of the application and the virus to a cell. Also included is a use of a compound of the application for increasing virally-encoded transgene expression, as well as a compound of the application for use in increasing virally- encoded transgene expression. Optionally, the virally-encoded transgene is a therapeutic gene.

[0195] In some embodiments, expression of the transgene is increased 1.1 fold or more, 1.2 fold or more, 1.5 fold or more, 2 fold or more, 2.5 fold or more, 3 fold or more, 5 fold or more, or 10 fold or more, e.g., compared to expression of the transgene, prior to the method or in the absence of the method. In some cases, the method includes measuring the expression of the transgene. Measuring expression levels of a transgene can be done by any method known in the art, including but not limited to measuring levels of nucleic acid expression or expression levels of protein encoded by the transgene.Methods and uses of increasing virus growth and / or virus spread

[0196] The present application also includes a method, optionally an in vitro method, of increasing virus growth and / or virus spread in cells comprising administering a compound of the application to the cells prior to, after or concurrently with the virus. Also included is a use of a compound of the application for increasing virus growth and / or virus spread, as well as a compound of the application for use in increasing virally-encoded transgene expression for increasing virus growth and / or virus spread.

[0197] In some embodiments, virus growth and / or virus spread is increased 1.1 fold or more, 1 .2 fold or more, 1.5 fold or more, 2 fold or more, 2.5 fold or more, 3 fold or more, 5 fold or more, or 10 fold or more, e.g., compared to virus growth and / or virus spread, prior to the method or in the absence of the method. In some cases, the method includes measuring virus growth and / or virus spread.

[0198] To be clear, in the above methods and uses, the term “a compound of the application” also includes embodiments wherein one or more compounds of the application are referenced or formulated in a composition as described herein.IV. Methods of Preparing the Compounds and Compositions of the Application

[0199] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of the application is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources or may be extracted from cells, plants, animals or fungi. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0200] The compounds of Formula (I) generally can be prepared according to the processes illustrated in the Schemes below. In the structural formulae shown below the variables are as defined in Formula (I) unless otherwise stated. A person skilled in the art would appreciate that many of the reactions depicted in the Schemes below would be sensitive to oxygen and water and would know to perform the reaction under an anhydrous, inert atmosphere if needed. Reaction temperatures and times are presented for illustrative purposes only and may be varied to optimize yield as would be understood by a person skilled in the art.

[0201] Accordingly, in an embodiment, the compounds of Formula (I) are prepared as shown in Scheme A.Scheme A

[0202] Accordingly, starting material 3,4-dichloro-5-hydroxyfuran-2(5H)-one is halogenated at the 2-position to generate intermediate 1 A, which is reacted with an amine RA-NH2 under suitable conditions to give compound 2A. In some embodiments, RAfrom the reacting amine RA-NH2 represents -X-Cy1of the compound of Formula (I), or a protected form thereof. In some embodiments, RAfrom the reacting amine RA-NH2 partially represents -X-Cy1of the compound of Formula (I) on which further reactions may be conducted to arrive at the compound of Formula (I). For example, in the case of compound of Formula (IA), RAfrom the reacting amine RA-NH2 represents the portion -X-Cy1-piperazine to give compound (IB) on which R7may be introduced. In some embodiments R7is introduced by reacting an acyl chloride, an ester or a carboxylic acid thereof with amine (IB). Various suitable coupling reactions would be known to those skilled in the art.

[0203] Salts of the compounds of the application are generally formed by dissolving the neutral compound in an inert organic solvent and adding either the desired acid or base and isolating the resulting salt by eitherfiltration or other known means.

[0204] The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped underambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”.

[0205] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0206] Throughout the processes, it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill(1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.EXAMPLES

[0207] The following non-limiting examples are illustrative of the present application.General Methods1AScheme 1

[0208] Compound 1A (3,4,5-trichloro-furan-2(5H)-one) was prepared from 3,4-dichloro-5-hydroxyfuran-2(5H)-one using known procedures, for example as disclosed in Diallo et al. (PCT Int. Appl., 2016119051 , 04 Aug 2016). Commercially available compound 1 may also be used.General procedure A for the synthesis of compound 2AScheme 2

[0209] A mixture of compound 1 A (1 .0 mmol) and the corresponding amine RNH2 (1 .0 - 2.0 mmol) in dioxane (8.0 mL) was stirred at room temperature for 20 h and then concentrated. The residue was purified by either normal phase, reverse phase chromatography or by preparative HPLC to the desired adduct 2A.General procedure AA for the synthesis of compound 2BScheme 3

[0210] A mixture of compound 1A (1.0 mmol), NaOAc (2.1 mmol) and the corresponding amine RNH2 (1.1 mmol) in dioxane (2.5 mL) and DMSO (1.25 mL) was stirred at room temperature for 1 -4 days and then filtered. The filtrate was purified by either reverse phase chromatography or by preparative HPLC to give the desired adduct 2B.General Method B: Boc Deprotection with TFA / DCM / H2O

[0211] A mixture of N-Boc amine (5.5 mmol) in TFA / DCM / H2O (19 mL / 19 mL / 2 mL) was stirred at room temperature for 1-2 h and then concentrated. The residue was purified by either reverse phase chromatography or by preparative HPLC to give the desired amine.General Method BB: Boc Deprotection with TFA / DCM

[0212] A mixture of N-Boc amine (2.0 mmol) and / or / V-trityl amide (2.0 mmol) in TFA / DCM (5 mL / 10 mL) was stirred at room temperature for 1-2 h and then concentrated. The residue was purified by either reverse phase chromatography or by preparative HPLC to give the desired amine.General Method C: Coupling of an Amine with an NHS-ester

[0213] A mixture of an amine (1 .0 mmol), NHS-ester (1.1 mmol) and DIPEA (5.0 mmol) in DMF (10 mL) was stirred for 2h and then purified preparative HPLC (ACN / H2O with 0.1 %TFA) to give the desired amide adduct.General Method D: Coupling of an Amine with an Acyl Chloride

[0214] A mixture of an amine (1.0 mmol), acyl chloride (1 .1 mmol) and DIPEA (4.0 mmol) in CH2CI2 (10 mL) was stirred for 2h and then purified by one of flash chromatography, reverse phase chromatography or preparative HPLC to give the desired amide adduct.Scheme 4

[0215] General Method E: HATU Coupling of an Amine with a Carboxylic Acid

[0216] A mixture the corresponding amine (1.0 mmol), the corresponding carboxylic acid (1 .2 mmol), HATU (1 .2 mmol) and DIPEA (4.6 mmol) in DMF (9 mL) was stirred for 20 h. The reaction mixture was filtered and the filtrate was purified by one of flash chromatography, reverse phase chromatography or preparative HPLC to give the desired amide adduct.1-(Benzo[d][1,3]dioxol-5-ylmethyl)-3,4-dichloro-5-hydroxy-1,5-dihydro-2H- pyrrol-2-one (compound 1-1)

[0217] Prepared using general method A with benzo[d][1 ,3]dioxol-5- ylmethanamine. The crude product was purified by trituration in CH2CI2 to give an off-white solid (yield = 37%).1H NMR (400 MHz, DMSO-cfe) 5 7.19 (d, J = 9.3 Hz, 1 H), 6.90 - 6.83 (m, 2H), 6.77 (dd, J = 7.9, 1.8 Hz, 1 H), 6.00 (s, 2H), 5.33 (d, J = 9.3 Hz, 1 H), 4.62 (d, J = 15.3 Hz, 1 H), 4.22 (d, J = 15.3 Hz, 1 H). Mass calculated for (C12H9CI2NO4-H)- 300.0, found 299.9.4-((3,4-Dichloro-2-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzoic acid (compound 1-2)

[0218] Prepared using general method A with 4-(aminomethyl)benzoic acid. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give a yellow solid (yield = 5%).1H NMR (400 MHz, DMSO-cfe) 5 12.91 (s, 1 H), 7.94 - 7.86 (m, 2H), 7.44 - 7.37 (m, 2H), 7.24 (d, J = 9.3 Hz, 1 H), 5.41 (d, J = 9.2 Hz, 1 H), 4.74 (d, J = 16.0 Hz, 1 H), 4.45 (d, J = 16.1 Hz, 1 H). Mass calculated for (Ci2HgCl2NO4-H)_300.0, found 300.0.3,4-Dichloro-1-(4-(dimethylamino)benzyl)-5-hydroxy-1,5-dihydro-2H-pyrrol-2- one (compound 1-3)

[0219] Prepared using general method A with 4-(aminomethyl)- / V, / \ / - dimethylaniline. The crude product was purified by flash chromatography (EtOAc / Hex) to give an off-white solid (yield = 58%).1H NMR (400 MHz, DMSO- cfe) 5 7.17 (d, J = 9.3 Hz, 1 H), 7.14 - 7.08 (m, 2H), 6.76 - 6.64 (m, 2H), 5.24 (d, J = 9.3 Hz, 1 H), 4.65 (d, J = 15.0 Hz, 1 H), 4.13 (d, J = 15.0 Hz, 1 H), 2.87 (s, 5H). Mass calculated for (Ci3Hi4Cl2N2O2+H)+301 .0, found 301 .5. tert-Butyl (4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro-1 H-pyrrol-1 - yl)methyl)phenyl)carbamate (compound 1-4)

[0220] Prepared using general method A with te / Y-butyl (4-(aminomethyl)phenyl)carbamate. The crude product was purified by flash chromatography (EtOAc / Hex) to give a yellow solid (yield = 66%).1H NMR (400MHz, DMSO-cfe) 5 9.32 (s, 1 H), 7.40 (d, J = 8.2 Hz, 2H), 7.17 (dd, J = 8.9, 5.3 Hz,3H), 5.29 (d, J = 9.3 Hz, 1 H), 4.66 (d, J = 15.3 Hz, 1 H), 4.22 (d, J = 15.3 Hz, 1 H), 1 .47 (s, 9H). Mass calculated for (Ci6HisCl2N2O4+Na)+395.1 , found 395.1 .1-(4-Aminobenzyl)-3,4-dichloro-5-hydroxy-1,5-dihydro-2H-pyrrol-2-one(compound 1-5)

[0221] Prepared using general method BB with compound I-4. The crude product was purified by flash chromatography (EtOAc / Hex) to give a yellow solid (yield = 74%).1H NMR (400 MHz, DMSO-cfe) 5 7.16 (d, J = 9.4 Hz, 1 H), 7.02 (d, J = 7.9 Hz, 2H), 6.64 (d, J = 7.8 Hz, 2H), 6.08 (s, 2H), 5.25 (d, J = 8.7 Hz, 1 H), 4.62 (d, J = 15.1 Hz, 1 H), 4.11 (d, J = 15.0 Hz, 1 H). Mass calculated for (CiiHioCl2N202+H)+273.0, found 273.0.N-(4-((3,4-Dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1- yl)methyl)phenyl)acetamide (compound 1-6)

[0222] Prepared using general method E with compound I-5 and acetic acid. The crude product was purified by trituration in CH2CI2 to give an off-white solid (yield = 61 %).1H NMR (400 MHz, DMSO-cfe) 5 9.93 (s, 1 H), 7.57 - 7.49 (m, 2H), 7.24 - 7.11 (m, 3H), 5.31 (d, J = 8.2 Hz, 1 H), 4.67 (d, J = 15.4 Hz, 1 H), 4.25 (d, J = 15.5 Hz, 1 H), 2.03 (s, 3H). Mass calculated for (Ci3Hi2Cl2N2O3+Na)+337.0, found 337.0.tert- Butyl 4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1 - yl)methyl)phenyl)piperazine-1-carboxylate (compound 1-7)

[0223] Prepared using general method A with tert-butyl 4-(4- (aminomethyl)phenyl)piperazine-1 -carboxylate. The crude product was purified by flash chromatography (EtOAc / Hex) to give a yellow solid (yield = 58%).1H NMR (400 MHz, DMSO-cfe) 5 7.17 (dd, J = 11 .7, 8.9 Hz, 3H), 6.95 - 6.91 (m, 2H), 5.27 (d, J = 9.3 Hz, 1 H), 4.64 (d, J = 15.2 Hz, 1 H), 4.19 (d, J = 15.2 Hz, 1 H), 3.45 (t, J = 5.2 Hz, 4H), 3.07 (t, J = 5.2 Hz, 4H), 1.42 (s, 9H). Mass calculated for (C2oH25Cl2N304+H)+442.1 , found 442.1.3,4-Dichloro-5-hydroxy-1-(4-(piperazin-1-yl)benzyl)-1,5-dihydro-2H-pyrrol-2- one (compound 1-8)

[0224] Prepared using general method BB with compound 1-7. The crude product was purified by flash chromatography (MeOH / CH2Cl2) to give a yellow solid (yield = 99%).1H NMR (400 MHz, DMSO-cfe) 5 8.69 (s, 2H), 7.26 - 7.10 (m, 3H), 7.01 - 6.90 (m, 2H), 5.29 (d, J = 9.3 Hz, 1 H), 4.64 (d, J = 15.2 Hz, 1 H), 4.22 (d, J = 15.3 Hz, 1 H), 3.31 - 3.27 (m, 4H), 3.21 (dd, J = 6.6, 3.5 Hz, 4H). Mass calculated for (Ci5Hi7Cl2N3O2+H)+342.1 , found 342.1.1-(4-(4-Acetylpiperazin-1-yl)benzyl)-3,4-dichloro-5-hydroxy-1,5-dihydro-2H- pyrrol-2-one (compound 1-9)

[0225] Prepared using general method C with compound I-8 and 2,5- dioxopyrrolidin-1-yl acetate. The crude product was purified by flash chromatography (MeOH / CH2Cl2) to give a yellow solid (yield = 57%).1H NMR (400 MHz, DMSO-cfe) 5 7.17 (dd, J = 11 .0, 8.9 Hz, 3H), 6.96 - 6.87 (m, 2H), 5.28 (d, J = 9.3 Hz, 1 H), 4.65 (d, J = 15.2 Hz, 1 H), 4.19 (d, J = 15.2 Hz, 1 H), 3.56 (p, J = 3.1 Hz, 4H), 3.10 (dt, J = 26.3, 5.3 Hz, 4H), 2.04 (s, 3H). Mass calculated for (Ci7Hi9Cl2N3O3+H)+384.1 , found 384.3.3,4-Dichloro-1-(4-(4-glycylpiperazin-1-yl)benzyl)-5-hydroxy-1,5-dihydro-2H- pyrrol-2-one (compound 1-10)

[0226] Prepared using general methods C and BB with compound I-8 and (te / Y-butoxycarbonyl)glycine. The crude product was purified by flash chromatography (MeOH / CH2Cl2) to give a yellow solid (yield = 59%).1H NMR (400 MHz, DMSO-cfe) 5 7.25 - 7.14 (m, 3H), 6.96 - 6.86 (m, 2H), 5.81 (s, 3H), 5.28 (d, J = 8.9 Hz, 1 H), 4.64 (d, J = 15.2 Hz, 1 H), 4.20 (d, J = 15.2 Hz, 1 H), 3.68 (s, 2H), 3.65 - 3.57 (m, 2H), 3.50 (d, J = 5.6 Hz, 2H), 3.13 (dt, J = 16.4, 5.4 Hz, 4H). Mass calculated for (Ci?H2oCl2N403+H)+399.1 , found 399.2.2-Amino-N-(4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1- yl)methyl)phenyl)acetamide (compound 1-11)

[0227] Prepared using general methods E and BB with compound I-5 and (te / Y-butoxycarbonyl)glycine. The crude product was purified by flash chromatography (MeOH / CH2Cl2) to give a yellow solid (yield = 86%).1H NMR (400 MHz, DMSO-cfe) 5 10.49 (s, 1 H), 8.13 (s, 3H) 7.62 - 7.51 (m, 2H), 7.27 (dd, J = 8.8, 6.3 Hz, 3H), 5.35 (d, J = 9.2 Hz, 1 H), 4.67 (d, J = 15.6 Hz, 1 H), 4.30 (d, J = 15.6 Hz, 1 H), 3.78 (s, 2H). Mass calculated for (Ci3Hi3Cl2N3O3+H)+330.0, found 330.3.(2S,3R)-2-Amlno-N-(4-((3,4-dlchloro-2-hydroxy-5-oxo-2,5-dlhydro-1H-pyrrol- 1-yl)methyl)phenyl)-3-hydroxybutanamide (compound 1-12)

[0228] Prepared using general methods E and BB with compound I-5 and (te / Y-butoxycarbonyl)-L-threonine. The crude product was purified by flash chromatography (MeOH / CH2Cl2) to give a yellow solid (yield = 68%).1H NMR (400 MHz, DMSO-cfe) 5 10.54 (d, J = 5.0 Hz, 1 H), 8.24 - 8.19 (m, 3H)7.57 (d, J = 8.3 Hz, 2H), 7.27 (dd, J = 12.6, 8.7 Hz, 3H), 5.67 (d, J = 5.1 Hz, 1 H), 5.34 (d, J = 9.2 Hz, 1 H), 4.68 (d, J = 15.6 Hz, 1 H), 4.31 (d, J = 15.6 Hz, 1 H), 4.02 (q, J = 5.9 Hz, 1 H), 3.73 (d, J = 6.0 Hz, 1 H), 1.20 (d, J = 6.4 Hz, 3H). Mass calculated for (Ci5Hi7Cl2N3O4+H)+374.1 , found 374.4.1-(4-(4-(L-Threonyl)piperazin-1-yl)benzyl)-3,4-dichloro-5-hydroxy-1,5- dihydro-2H-pyrrol-2-one (compound 1-13)

[0229] Prepared using general methods E and BB with compound I-8 and (te / Y-butoxycarbonyl)-L-threonine. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1%TFA) to give an off-white solid (yield = 44%).1H NMR (400 MHz, DMSO-cfe) 58.02 (d, J = 5.3 Hz, 3H), 7.21 - 7.14 (m, 2H), 6.99 - 6.91 (m, 2H), 5.53 (s, 1 H), 5.31 - 5.25 (m, 1 H), 4.64 (d, J = 15.2 Hz, 1 H), 4.33 (t, J=5.1 Hz, 1H), 4.21 (d, J=15.2 Hz, 1H), 4.00-3.90 (m, 1H), 3.81 -3.66 (m,4H), 3.23 - 3.18 (m, 3H), 3.11 - 3.07 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H). Mass calculated for (Ci9H24CI2N4O4+H)+443.1, found 443.3.(3S)-3-Amino-4-(4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dlhydro-1 H-pyrrol-1 - yl)methyl)phenyl)piperazin-1-yl)-4-oxobutanamide (compound 1-14)

[0230] Prepared using general methods E and BB with compound I-8 and ^-(te / Y-butoxycarbonyO-A / rityl-L-asparagine. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1%TFA) to give an off-white solid (yield = 23%).1H NMR (400 MHz, DMSO-cfe) 58.12 (d, J = 5.1 Hz, 3H) 7.66 (s, 1H), 7.28 (s, 1H), 7.21 -7.14 (m, 2H), 6.98-6.91 (m, 2H), 5.28 (d, J =6.5 Hz, 1H), 4.68-4.60 (m, 2H), 4.21 (d, J= 15.3 Hz, 1H), 3.83-3.56 (m, 6H), 3.29-3.01 (m, 4H), 2.67 - 2.59 (m, 1H). Mass calculated for (Ci9H23Cl2N5O4+H)+456.1, found 456.2.1 -(4-(4-(L-Prolyl)piperazin-1 -yl)benzyl)-3,4-dichloro-5-hydroxy-1, 5-dihydro- 2H-pyrrol-2-one (compound 1-15)

[0231] Prepared using general methods E and BB with compound I-8 and (te / Y-butoxycarbonyl)-L-proline. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give an off-white solid (yield = 67%).1H NMR (400 MHz, DMSO-cfe) 5 7.22 - 7.14 (m, 2H), 6.99 - 6.91 (m, 2H), 5.28 (s, 1 H), 4.69 - 4.60 (m, 2H), 4.21 (d, J = 15.2 Hz, 1 H), 3.78 - 3.53 (m, 5H), 3.32 - 3.24 (m, 1 H), 3.24 - 3.03 (m, 5H), 2.47 - 2.29 (m, 1 H), 2.00 - 1.74 (m, 3H). Mass calculated for (C2oH24Cl2N403+H)+439.1 , found 439.3.3,4-Dichloro-5-hydroxy-1-(4-(4-(methyl-L-alanyl)piperazin-1-yl)benzyl)-1,5- dihydro-2H-pyrrol-2-one (compound 1-16)

[0232] Prepared using general methods E and BB with compound I-8 and / V-(tert-butoxycarbonyl)- / \ / -methyl-L-alanine. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give an off-white solid (yield = 55%).1H NMR (400 MHz, DMSO-cfe) 7.23 - 7.14 (m, 2H), 6.98 - 6.92 (m, 2H), 5.28 (s, 1 H), 4.64 (d, J = 15.2 Hz, 1 H), 4.45 (q, J = 6.4 Hz, 1 H), 4.21 (d, J = 15.2 Hz, 1 H), 3.81 - 3.71 (m, 2H), 3.69 - 3.52 (m, 3H), 3.30 - 3.00 (m, 4H), 2.56 - 2.52 (m, 3H), 1.36 (d, J = 6.9 Hz, 3H). Mass calculated for (Ci9H24Cl2N4O3+H)+427.1 , found 427.4.1-(4-(4-(Butyryl-L-prolyl)piperazin-1-yl)benzyl)-3,4-dichloro-5-hydroxy-1,5- dihydro-2H-pyrrol-2-one (compound 1-17)

[0233] Prepared using general method D with compound 1-15 and butyryl chloride. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1%TFA) to give a white solid (yield = 50%).1H NMR (400 MHz, DMSO-cfe) 5 7.17 (d, J = 8.2 Hz, 3H), 6.94 (dd, J = 8.8, 2.6 Hz, 2H), 5.28 (s, 1 H), 4.99 (dd, J = 8.8, 2.8 Hz, 4.65 (d, J = 15.2 Hz, 1 H), 4.20 (dd, J = 15.3, 2.2 Hz, 1 H), 3.73 (d, J= 34.4 Hz, 3H), 3.21 (d, J = 13.5 Hz, 2H), 3.15 - 3.06 (m, 3H), 2.29 - 2.19 (m, 2H), 2.12 (dq, J = 11.0, 7.7, 7.1 Hz, 2H), 1.98 - 1.68 (m, 4H), 1.49 (dt, J = 15.2, 7.6 Hz, 2H), 0.89 (t, J = 7.4 Hz, 2H), 0.82 (t, J = 7.4 Hz, 1 H). Mass calculated for (C24H3OCI2N404+H)+509.2, found 509.1.N-((2S)-1-(4-(4-((3, 4-Dlchloro-2-hydroxy-5-oxo-2, 5-dihydro- 1 H-pyrrol- 1 - yl)methyl)phenyl)piperazin-1-yl)-1-oxopropan-2-yl)-N-methylbutyramide (compound 1-18)

[0234] Prepared using general method D with compound 1-16 and butyryl chloride. The crude product was purified by flash chromatography (EtOAc / Hex)) to give a white solid (yield = 50%).1H NMR (400 MHz, DMSO-cfe) 57.17 (dd, J= 13.6, 8.9 Hz, 3H), 6.92 (d, J = 8.5 Hz, 2H), 5.40 (q, J = 6.8 Hz, 1 H), 5.27 (dd, J = 9.3, 1.1 Hz, 1 H), 4.64 (d, J = 15.1 Hz, 1 H), 4.19 (d, J = 15.2 Hz, 1 H), 3.72 (s, 1 H), 3.45 (d,J = 25.4 Hz, 3H), 3.18 (s, 2H), 3.05 - 2.86 (m, 2H), 2.79 (s, 2H), 2.73 - 2.63 (m, 1 H), 2.34 - 2.21 (m, 2H), 1 .59 - 1 .43 (m, 2H), 1 .26 (d, J = 11 .0 Hz, 1 H), 1 .11 (d, J = 6.7 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). Mass calculated for (C23H3oCI2N404+H)+497.2, found 497.2.3,4-Dichloro-5-hydroxy-1-(4-(4-methylpiperazin-1-yl)benzyl)-1,5-dihydro-2H-

[0235] Prepared using general method A with (4-(4-methylpiperazin-1- yl)phenyl)methanamine. The crude product was purified by flash chromatography (DCM / (MeOH with 5% aqueous NH4OH)) to give pale brown solid (yield = 39%).1H NMR (400 MHz, DMSO-cfe) 5 7.19 (d, J = 9.3 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.27 (d, J = 9.3 Hz, 1 H), 4.64 (d, J = 15.1 Hz, 1 H), 4.18 (d, J = 15.1 Hz, 1 H), 3.15 - 3.11 (m, 4H), 2.57 - 2.52 (m, 4H), 2.29 (s, 3H).13C NMR (101 MHz, DMSO) 5 161.89, 150.64, 144.79, 129.26, 127.51 , 125.13, 115.87, 81.58, 54.76, 48.23, 45.78, 43.15. Mass calculated for (Ci6Hi9Cl2N3O2+H)+356.1 , found 356.1.3,4-Dichloro-5-hydroxy-1-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)-1,5- dihydro-2H-pyrrol-2-one (compound 1-31)

[0236] Prepared using general method A with (6-(4-methylpiperazin-1- yl)pyridin-3-yl)methanamine. The crude product was purified by flash chromatography (DCM / (MeOH with 5% aqueous NH4OH)) to give pale brown solid(yield = 32%).1H NMR (400 MHZ, DMSO-cfe) 6 8.06 (d, J = 2.4 Hz, 1 H), 7.47 (dd, J = 8.8, 2.5 Hz, 1 H), 7.19 (d, J = 9.3 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 5.34 (d, J = 9.3 Hz, 1 H), 4.56 (d, J = 15.2 Hz, 1 H), 4.21 (d, J = 15.2 Hz, 1 H), 3.55 - 3.42 (m, 4H), 2.48 - 2.42 (m, 4H), 2.26 (s, 3H).13C NMR (101 MHz, DMSO) 5 161 .96, 158.89, 147.81 , 144.86, 138.31 , 125.05, 121.79, 107.38, 81.80, 54.64, 46.75, 44.87, 41.09. Mass calculated for (Ci5HisClzN40z+H)+357.1 , found 357.1 .3,4-Dichloro-1-(3-(dimethylamino)benzyl)-5-hydroxy-1,5-dihydro-2H-pyrrol-2- one (compound 1-27)

[0237] Prepared using general method A with 3-(aminomethyl)- / V, / \ / - dimethylaniline. The crude product was purified by flash chromatography (EtOAc / Hex) and then recrystallized with EtOAc / Hex to give pale yellow solid (yield = 26%).1H NMR (400 MHz, DMSO-cfe) 5 7.21 (d, J = 9.3 Hz, 1 H), 7.18 - 7.09 (m, 1 H), 6.66 - 6.60 (m, 2H), 6.55 (d, J = 7.5 Hz, 1 H), 5.30 (d, J = 9.3 Hz, 1 H), 4.69 (d, J= 15.3 Hz, 1 H), 4.21 (d, J= 15.3 Hz, 1 H), 2.88 (s, 6H).13C NMR (101 MHz, DMSO) 5 162.02, 151.06, 144.87, 137.90, 129.58, 125.13, 115.90, 112.19, 111.94, 81.74, 44.10, 40.57. Mass calculated for (Ci3Hi4ClzNzOz+H)+301.0, found 301.0.3,4-Dichloro-1-(2-(dimethylamino)benzyl)-5-hydroxy-1,5-dihydro-2H-pyrrol-2- one (compound 1-26)

[0238] Prepared using general method A with 2-(aminomethyl)- / V, / \ / - dimethylaniline. The crude product was purified by flash chromatography (EtOAc / Hex) to give pale yellow syrup (yield = 17%).1H NMR (400 MHz, DMSO-cfe)6 7.24 (td, J = 7.6, 1 .7 Hz, 1 H), 7.20 - 7.08 (m, 3H), 7.02 (t, J = 6.7 Hz, 1 H), 5.32 (d, J = 9.0 Hz, 1 H), 4.69 (d, J = 16.3 Hz, 1 H), 4.56 (d, J = 16.2 Hz, 1 H), 2.64 (s, 6H).13C NMR (101 MHz, DMSO) 5 162.50, 152.45, 144.99, 131.18, 128.32, 128.09, 125.17, 123.64, 119.77, 82.18, 45.11 , 39.75. Mass calculated for (Ci3Hi4Cl2N2O2+H)+301 .0, found 301 .1 .1 -((1 H-lndol-5-yl)methyl)-3,4-dichloro-5-hydroxy-1 ,5-dihydro-2H-pyrrol-2-one (compound 1-25)

[0239] Prepared using general method A with (1 / 7-indol-5-yl)methanamine. The crude product was purified by flash chromatography (EtOAc / Hex) and then recrystallized with EtOAc / Hex to give colorless solid (yield = 24%).1H NMR (400 MHz, DMSO-cfe) 5 11 .08 (s, 1 H), 7.46 (s, 1 H), 7.39 - 7.31 (m, 2H), 7.21 (d, J = 9.3 Hz, 1 H), 7.02 (dd, J = 8.4, 1 .7 Hz, 1 H), 6.43 - 6.37 (m, 1 H), 5.26 (d, J = 9.3 Hz, 1 H), 4.87 (d, J= 14.9 Hz, 1 H), 4.30 (d, J= 14.9 Hz, 1 H).13C NMR (101 MHz, DMSO) 5 161.84, 144.78, 135.73, 128.13, 127.50, 126.29, 125.16, 121.73, 120.04, 112.00, 101 .51 , 81 .38, 44.08. Mass calculated for (Ci3HioCl2N202+H)+297.0, found 297.1 .3,4-Dichloro-5-hydroxy-1-(4-(methylamino)benzyl)-1,5-dihydro-2H-pyrrol-2- one (compound 1-45)

[0240] Prepared using general method AA with 4-(aminomethyl)- / V- methylaniline hydrochloride. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give brown solid (yield = 17%).1H NMR (400 MHz, Methanol-c ) 5 7.45 (d, J = 8.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 5.28 (s, 1 H), 4.84(d, J = 15.4 Hz, 1 H), 4.46 (d, J = 15.4 Hz, 1 H), 3.01 (s, 3H).13C NMR (101 MHz, MeOD) 5 162.83, 144.69, 139.44, 135.45, 129.59, 125.12, 119.69, 81.80, 42.93, 34.68. Mass calculated for (Ci2Hi2Cl2N2O2+H)+287.0, found 287.0.3,4-Dichloro-5-hydroxy-1-(3-(methylamino)benzyl)-1,5-dihydro-2H-pyrrol-2- one (compound 1-46)

[0241] Prepared using general method AA with 3-(aminomethyl)- / V- methylaniline hydrochloride. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give pale yellow solid (yield = 6%).1H NMR (400 MHz, Methanol-c ) 5 7.46 (t, J = 7.8 Hz, 1 H), 7.30 - 7.17 (m, 3H), 5.32 (s, 1 H), 4.86 (d, J = 15.5 Hz, 1 H), 4.48 (d, J = 15.5 Hz, 1 H), 3.00 (s, 3H).13C NMR (101 MHz, MeOD) 5 162.92, 144.80, 139.17, 130.15, 125.60, 125.14, 118.74, 118.35, 81.89, 43.19, 34.46. Mass calculated for (Ci2Hi2Cl2N2O2+H)+287.0, found 287.0.3,4-Dichloro-5-hydroxy-1-(2-(methylamino)benzyl)-1,5-dihydro-2H-pyrrol-2- one (compound 1-44)1.TFA

[0242] Prepared using general method AA with 2-(aminomethyl)- / V- methylaniline hydrochloride. The crude product was purified by preparative HPLC (ACN / H2O with 0.1%TFA) to give brown solid (yield = 7%).1H NMR (400 MHz, Methanol-cU) 5 7.38 - 7.27 (m, 2H), 7.00 - 6.91 (m, 2H), 5.25 (s, 1 H), 4.81 (d, J = 15.4 Hz, 1 H), 4.43 (d, J = 15.4 Hz, 1 H), 2.95 (s, 3H).13C NMR (101 MHz, MeOD) 5163.31 , 145.01 , 130.81 , 129.56, 124.77, 122.74, 120.49, 113.78, 81.64, 39.78, 31 .57. Mass calculated for (Ci2Hi2Cl2N2O2+H)+287.0, found 287.0.Synthesis of Intermediate 3Scheme 5 tert- Butyl 4-(4-cyano-2-nitrophenyl)piperazine-1-carboxylate (intermediate 2)

[0243] A mixture of 4-fluoro-3-nitrobenzonitrile 1 (1 .64 g, 9.9 mmol), tert-butyl piperazine-1 -carboxylate (2.22 g, 11.9 mmol) and K2CO3 (2.6 g, 18.8 mmol) in DMSO (10 mL) was heated at 100°C for 18h and then cooled to rt. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was recrystallized with EtOAc and Hex to give yellow fully solid intermediate 2 (3.06 g, 93%).1H NMR (400 MHz, DMSO-cfe) 5 8.35 (d, J = 2.1 Hz, 1 H), 7.93 (dd, J = 8.8, 2.1 Hz, 1 H), 7.38 (d, J = 8.9 Hz, 1 H), 3.49 - 3.42 (m, 4H), 3.23 - 3.16 (m, 4H), 1.42 (s, 9H). Mass calculated for (Ci6H2oN404+H)+333.2, found 333.1. tert-Butyl 4-(2-amino-4-(aminomethyl)phenyl)piperazine-1 -carboxylate (intermediate 3)

[0244] A solution of compound 2 (1 .01 g, 3.04 mmol), NH4OH (30% aqueous solution, 2 mL), Raney Ni (half spatula) in MeOH (100 mL) was agitated with a Parr shaker at 35 PSI with H2 for 4 d. The mixture was filtered through a pad of Celite™ and then concentrated. The residue was purified by flash chromatography (DCM / (MeOH with 5% aqueous NH4OH)) to give colorless syrup intermediate 3 (767 mg, 82%).1H NMR (400 MHz, DMSO-cfe) 5 6.81 (d, J = 7.9 Hz, 1 H), 6.64 (d, J = 2.0 Hz, 1 H), 6.49 (dd, J = 8.0, 2.0 Hz, 1 H), 4.75 (s, 2H), 3.56 - 3.26 (m, 6H), 2.77 - 2.60 (m, 4H), 1.42 (s, 9H). Mass calculated for (Ci6H26N4O2+H)+307.2, found 307.3.tert- Butyl 4-(2-amino-4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol- 1 -yl) methyl) phenyl)piperazine-1 -carboxylate (compound 1-47)

[0245] Prepared using general method AA from intermediate 3. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give pale yellow solid (yield = 35%).1H NMR (400 MHz, Methanol-cU) 5 7.33 (d, J = 8.0 Hz, 1 H), 7.26 - 7.19 (m, 2H), 5.28 (s, 1 H), 4.82 (d, J = 15.4 Hz, 1 H), 4.41 (d, J = 15.4 Hz, 1 H), 3.64 - 3.60 (m, 4H), 2.89 - 2.82 (m, 4H), 1.50 (s, 9H).13C NMR (101 MHz, MeOD) 5 162.80, 155.02, 144.71 , 143.75, 134.84, 126.06, 125.15, 122.39, 120.49, 81.76, 80.06, 51.89, 42.85, 27.24. Mass calculated for (C2OH26CI2N404+H)+457.1 , found 457.2.Synthesis of intermediate 6Scheme 6 tert-Butyl 4-(4-cyano-2-methoxyphenyl)piperazine-1 -carboxylate(intermediate 5)

[0246] A mixture of 4-fluoro-3-methoxybenzonitrile 4 (1 .50 g, 9.9 mmol), tert- butyl piperazine-1 -carboxylate (2.22 g, 11.9 mmol) and K2CO3 (2.6 g, 18.8 mmol) in DMSO (10 mL) was heated at 100°C for 18h and then cooled to rt. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by flash chromatography ( EtOAc / Hex) to give off-white solid intermediate 5 (1 .86 g, 59%).1H NMR (400 MHz, DMSO-cfe) 5 7.39 - 7.32 (m, 2H),6.99 (d, J = 8.7 Hz, 1 H), 3.85 (s, 3H), 3.47 - 3.42 (m, 4H), 3.07 - 3.00 (m, 4H), 1 .42 (s, 9H). Mass calculated for (Ci7H23N3O3+H)+318.2, found 318.2. tert-Butyl 4-(4-(aminomethyl)-2-methoxyphenyl)piperazine-1-carboxylate (intermediate 6)

[0247] A solution of intermediate 5 (1.85 g, 5.83 mmol), NH4OH (30% aqueous solution, 3 mL), Raney Ni (half spatula) in MeOH (120 mL) was agitated with a Parr shaker at 35 PSI with H2 for 21 h. The mixture was filtered through a pad of celite and then concentrated. The residue was purified by flash chromatography (DCM / (MeOH with 5% aqueous NH4OH)) to give colorless syrup intermediate 6 (1.71 g, 91 %).1H NMR (400 MHz, DMSO-cfe) 5 6.95 (s, 1 H), 6.83 - 6.79 (m, 2H), 3.78 (s, 3H), 3.63 (s, 2H), 3.52 - 3.39 (m, 4H), 2.89 - 2.82 (m, 4H), 1.42 (s, 9H). Mass calculated for (Ci7H27N3O3+H)+322.2, found 322.3. tert-Butyl 4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1 - yl)methyl)-2-methoxyphenyl)piperazine-1-carboxylate (compound 1-48)

[0248] Prepared using general method AA from intermediate 6. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give off-white solid (yield = 11 %).1H NMR (400 MHz, Methanol-cU) 5 7.31 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 1 .8 Hz, 1 H), 7.02 (dd, J = 8.2, 1 .8 Hz, 1 H), 5.29 (s, 1 H), 4.84 (d, J = 15.8 Hz, 1 H), 4.44 (d, J = 15.3 Hz, 1 H), 3.98 (s, 3H), 3.81 - 3.72 (m, 4H), 3.38 - 3.34 (m, 4H), 1.51 (s, 9H).13C NMR (101 MHz, MeOD) 5 162.87, 154.54, 152.11 , 144.70, 136.70, 134.25, 125.15, 120.70, 119.82, 112.09, 81.82, 80.56, 55.23, 52.02, 43.25, 27.16. Mass calculated for (C2iH27Cl2N3O5+H)+472.1 , found 472.1.Scheme 7 tert-Butyl 4-(4-cyano-2-(methylamino)phenyl)piperazine-1 -carboxylate(intermediate 7)

[0249] A mixture of intermediate 2 (1 .95 g, 5.9 mmol), bis(pinacolato)diboron (4.6 g, 18.1 mmol) and tBuOK (790 mg, 7.0 mmol) in / PrOH (25 mL) was heated at 110°C for 2.5h and then cooled to rt. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated to give intermediate 7 as a pale yellow syrup (3.1g). The residue (1.0g) was dissolved in MeOH (50 mL) and then cooled to 0°C. Paraformaldehyde (100 mg, 3.3 mmol) was added and the mixture was stirred at 0°C for 30 min followed by the addition of NaBHaCN (210 mg, 3.3 mmol). The resulting mixture was stirred at rt for 1d. More paraformaldehyde (100 mg, 3.3 mmol) and NaBHaCN (210 mg, 3.3 mmol) was added and the mixture was stirred for an additional 5d. The reaction mixture was partitioned between DCM and 2M aqueous NaOH. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by flash chromatography (EtOAc / Hex) to give white foam (533 mg, 53%).1H NMR (400 MHz, DMSO-cfe) 6 7.06 - 6.97 (m, 2H), 6.81 (d, J = 1.5 Hz, 1 H), 5.39 (q, J = 5.1 Hz, 1 H), 3.63 - 3.44 (m, 4H), 2.81 - 2.73 (m, 7H), 1 .43 (s, 9H). tert-Butyl 4-(4-(aminomethyl)-2-(methylamino)phenyl)piperazine-1- carboxylate (intermediate 8)

[0250] A solution of intermediate 7 (550 mg, 1.74 mmol), NH4OH (30% aqueous solution, 2 mL), Raney Ni (half spatula) in MeOH (70 mL) was agitated with a Parr shaker at 35 PSI with H2 for 17 h. The mixture was filtered through a pad of celite and then concentrated. The residue was purified by flash chromatography (DCM / (MeOH with 5% aqueous NH4OH)) to give colorless syrupof intermediate 8 (394 mg, 71 %).1H NMR (400 MHz, DMSO-cfe) 6 6.84 (d, J = 8.3 Hz, 1 H), 6.54 - 6.48 (m, 2H), 5.03 (q, J = 5.3 Hz, 1 H), 3.61 (s, 2H), 3.53 - 3.22 (m, 4H), 2.75 (d, J = 5.3 Hz, 2H), 2.70 - 2.66 (m, 4H), 1 .43 (s, 9H). Mass calculated for (Ci7H28N4O2+H)+321 .2, found 321 .3. tert- Butyl 4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1 - yl)methyl)-2-(methylamino)phenyl)piperazine-1-carboxylate (compound 1-60)1.TFABoc

[0251] Prepared using general method AA from intermediate 8. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give pale brown solid (yield = 71 %).1H NMR (400 MHz, Methanol-c ) 5 7.31 - 7.25 (m, 1 H), 7.09 - 7.02 (m, 2H), 5.27 (s, 1 H), 4.84 (d, J = 15.3 Hz, 1 H), 4.39 (d, J = 15.2 Hz, 1 H), 3.75 - 3.48 (m, 4H), 2.97 (s, 3H), 2.87 - 2.80 (m, 4H), 1 .50 (s, 9H).13C NMR (101 MHz, MeOD) 5 162.82, 155.06, 144.69, 141.74, 135.15, 125.16, 122.96, 122.09, 115.37, 91.71 , 81.68, 80.01 , 52.03, 43.22, 32.68, 27.25, 18.83. Mass calculated for (C2iH2sCl2N4O4+H)+471.2, found 471 .1. tert- Butyl 4-(5-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1 - yl)methyl)pyridin-2-yl)piperazine-1-carboxylate (compound 1-24)Scheme 8

[0252] A mixture of compound 1A (179 mg, 0.96 mmol), tert-butyl 4-(5-(aminomethyl)pyridin-2-yl)piperazine-1 -carboxylate (280 mg, 0.96 mmol) indioxane (5.0 mL) and DMSO (1 mL) was stirred at rt for 2.5 h. DIPEA (100 pL, 0.57 mmol) and additional tert-butyl 4-(5-(aminomethyl)pyridin-2-yl)piperazine-1- carboxylate (80 mg, 0.27 mmol) was added and the mixture was stirred for 19h and then concentration. The residue was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) and then by flash chromatography (DCM / (MeOH with 5% aqueous NH4OH)) to the desired adduct I-24 as a white solid (210 mg, 50%).1H NMR (400 MHz, DMSO-cfe) 5 8.07 (d, J = 2.4 Hz, 1 H), 7.49 (dd, J = 8.8, 2.5 Hz, 1 H), 7.18 (d, J = 9.3 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 5.34 (d, J = 9.3 Hz, 1 H), 4.57 (d, J = 15.2 Hz, 1 H), 4.22 (d, J = 15.2 Hz, 1 H), 3.49 - 3.37 (m, 8H), 1.42 (s, 9H).13C NMR (101 MHz, DMSO) 5 161.98, 158.66, 154.42, 147.72, 144.88, 138.45, 125.06, 122.04, 107.58, 81.83, 79.48, 44.97, 41.09, 28.55. Mass calculated for (Ci9H24CI2N4O4+H)+443.1 , found 443.1.3,4-Dichloro-5-hydroxy-1-((6-(piperazin-1-yl)pyridin-3-yl)methyl)-1,5-dihydro- 2H-pyrrol-2-one (compound 1-23)

[0253] Prepared using general method BB from compound 1-24. The crude product was triturated in Et2O and the pale yellow solid was collected, (yield = 98%).1H NMR (400 MHz, DMSO-cfe) 5 8.87 (s, 2H), 8.11 (d, J = 2.4 Hz, 1 H), 7.60 (dd, J = 8.8, 2.4 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 5.37 (s, 1 H), 4.57 (d, J = 15.3 Hz, 1 H), 4.28 (d, J = 15.3 Hz, 1 H), 3.74 - 3.67 (m, 4H), 3.24 - 3.13 (m, 4H).13C NMR (101 MHz, DMSO) 5 162.06, 157.53, 146.80, 144.90, 139.12, 125.07, 123.07, 108.37, 82.00, 42.90, 42.47, 41.07. Mass calculated for (Ci4Hi6CI2N4O2+H)+343.1 , found 343.1.3,4-Dichloro-5-hydroxy-1-(3-methoxy-4-(piperazin-1-yl)benzyl)-1, 5-dihydro-2H-pyrrol-2-one (compound 1-49)

[0254] Prepared using general method BB from compound 1-48. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give off-white solid (yield = 64%).1H NMR (400 MHz, Methanol-cU) 5 7.01 - 6.94 (m, 2H), 6.91 (dd, J = 8.1 , 1.8 Hz, 1 H), 5.23 (s, 1 H), 4.83 (d, J = 15.1 Hz, 1 H), 4.34 (d, J = 15.1 Hz, 1 H), 3.88 (s, 3H), 3.41 - 3.34 (m, 4H), 3.30 - 3.23 (m, 4H).13C NMR (101 MHz, MeOD) 5 162.75, 152.71 , 144.57, 139.21 , 132.78, 125.15, 120.51 , 118.62, 111.63, 81.54, 54.70, 47.43, 43.74, 43.19. Mass calculated for (Ci6Hi9Cl2N3O3+H)+372.1 , found 372.2.1-(3-Amino-4-(piperazin-1-yl)benzyl)-3,4-dichloro-5-hydroxy-1,5-dihydro-2H- pyrrol-2-one (compound 1-50)

[0255] Prepared using general method BB from compound 1-47. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give pale yellow solid (yield = 86%).1H NMR (400 MHz, Methanol-cU) 5 7.18 (d, J = 8.1 Hz, 1 H), 7.02 - 6.92 (m, 2H), 5.24 (s, 1 H), 4.82 (d, J = 15.3 Hz, 1 H), 4.31 (d, J = 15.3 Hz, 1 H), 3.45 - 3.38 (m, 4H), 3.17 - 3.10 (m, 4H).13C NMR (101 MHz, MeOD) 5 162.76, 144.63, 139.64, 137.31 , 134.76, 125.15, 121.59, 121.01 , 117.68, 81.53, 48.40, 43.86, 42.89. Mass calculated for (Ci5Hi8CI2N4O2+H)+357.1 , found 357.1.3,4-Dichloro-5-hydroxy-1-((6-(4-(methyl-L-alanyl)piperazin-1-yl)pyrdin-3- yl)methyl)-1,5-dihydro-2H-pyrrol-2-one (compound 1-22)

[0256] Prepared using general method E with compound 1-23 and Boc-N- Me-Ala-OH, followed by general method B to give the desired adduct as a colorless syrup (16%).1H NMR (400 MHz, Methanol-cU) 58.07 (d, J= 2.3 Hz, 1H), 7.93 (dd, J= 9.2, 2.3 Hz, 1H), 7.22 (d, J =9.2 Hz, 1H), 5.38 (s, 1H), 4.67 (d, J= 15.5 Hz, 1H), 4.50 (d, J = 15.5 Hz, 1H), 4.46 - 4.39 (m, 1H), 3.96 - 3.59 (m, 8H), 2.72 (s, 3H), 1.53 (d, J = 6.9 Hz, 3H).13C NMR (101 MHz, MeOD) 5167.59, 162.98, 154.27, 144.86, 142.51, 139.69, 125.11, 122.93, 111.00, 82.19, 54.83, 45.25, 44.83, 43.68, 41.07, 40.33, 30.42, 14.03. Mass calculated for (Ci8H23Cl2N5O3+H)+428.1, found 428.1.1-((6-(4-(L-Prolyl)piperazin-1-yl)pyridin-3-yl)methyl)-3,4-dichloro-5-hydroxy- 1 ,5-dihydro-2 / 7-pyrrol-2-one (compound 1-21)

[0257] Prepared using general method E with compound I-23 and Boc-L- proline, followed by general method B to give the desired adduct as a pale brown solid (22%).1H NMR (400 MHz, Methanol-cU) 58.09 (d, J= 2.3 Hz, 1H), 7.84 (dd, J= 9.1, 2.4 Hz, 1H), 7.13 (d, J= 9.1 Hz, 1H), 5.34 (s, 1H), 4.73 (dd, J=8.9, 6.9 Hz, 1H), 4.68 (d, J= 15.4 Hz, 1H), 4.46 (d, J= 15.4 Hz, 1H), 3.92-3.81 (m, 1H), 3.81- 3.62 (m, 7H), 3.52 - 3.41 (m, 1 H), 3.41 - 3.34 (m, 1 H), 2.62 - 2.49 (m, 1 H), 2.16- 1.92 (m, 3H). Mass calculated for (Ci9H23Cl2N5O3+H)+440.1 , found 440.1.tert-Butyl ((2S)-1-(4-(2-amino-4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro- 1H-pyrrol-1-yl)methyl)phenyl)piperazin-1-yl)-1-oxopropan-2- yl)(methyl)carbamate (compound 1-51)

[0259] Prepared using general method E with compound I-50 and Boc-N- Me-Ala-OH. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give off-white (yield = 40%). Mass calculated for (C24H33Cl2NsO5+H)+542.2, found 542.2. tert-Butyl (2S)-2-(4-(2-amino-4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro- 1 H-pyrrol-1-yl)methyl)phenyl)piperazine-1 -carbonyl)pyrrolidine-1- carboxylate (compound 1-52)

[0260] Prepared using general method E with compound 1-50 and Boc-L- proline. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give off-white (yield = 36%). Mass calculated for (C25H33Cl2NsO5+H)+554.2, found 554.1. tert-Butyl (2R)-2-(4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol- 1 -yl)methyl)-2-methoxyphenyl)piperazine-1-carbonyl)pyrrolidine-1- carboxylate (compound 1-53)

[0261] Prepared using general method E with compound I-49 and Boc-L- proline. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give white (yield = 93%).1H NMR (400 MHz, Methanol-cU) 5 7.42 - 6.77 (m, 3H), 5.28 (s, 1 H), 4.84 - 4.73 (m, 2H), 4.44 (d, J = 15.4 Hz, 1 H), 4.09 - 3.71 (m, 7H), 3.64 - 3.36 (m, 3H), 3.28 - 3.12 (m, 2H), 2.40 - 2.23 (m, 1 H), 2.05 - 1.85 (m, 3H), 1.47 (s, 9H).. Mass calculated for (C26H34Cl2N4Oe+H)+569.2, found 569.3. tert-Butyl ((2S)-1 -(4-(4-((3,4-dlchloro-2-hydroxy-5-oxo-2, 5-dlhydro-1 H-pyrrol- 1-yl)methyl)-2-methoxyphenyl)piperazin-1-yl)-1-oxopropan-2- yl)(methyl)carbamate (compound 1-54)

[0262] Prepared using general method E with compound I-49 and Boc-N- Me-Ala-OH. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give pale yellow solid (yield = 73%).1H NMR (400 MHz, Methanol-cU) 5 7.27 - 6.92 (m, 3H), 5.28 (s, 1 H), 5.14 - 5.05 (m, 1 H), 4.84 (d, J = 15.3 Hz, 1 H), 4.42 (d, J = 15.1 Hz, 1 H), 4.11 - 3.66 (m, 7H), 3.42 - 3.14 (m, 4H), 2.82 (s, 3H), 1.49 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H). Mass calculated for (C25H34CI2N4O6+H)+557.2, found 557.2.1-(3-Amino-4-(4-(methyl-L-alanyl)piperazin-1-yl)benzyl)-3,4-dichloro-5- hydroxy-1,5-dihydro-2H-pyrrol-2-one (compound 1-55)

[0263] Prepared using general method BB from compound 1-51. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give white solid (yield = 52%).1H NMR (400 MHz, Methanol-cU) 57.19 (d, J = 8.1 Hz, 1 H), 7.07 - 6.97 (m, 2H), 5.25 (s, 1 H), 4.83 (d, J = 15.3 Hz, 1 H), 4.43 (q, J = 7.Q Hz, 1 H), 4.33 (d, J = 15.3 Hz, 1 H), 3.97 - 3.58 (m, 4H), 3.00 - 2.88 (m, 4H), 2.72 (s, 3H), 1 .53 (d, J = 6.9 Hz, 3H).13C NMR (101 MHz, MeOD) 5 167.16, 162.77, 144.65, 141.05, 134.42, 125.16, 122.61 , 121.37, 118.23, 81.56, 54.84, 51.56, 51.20, 45.44, 42.89, 42.40, 30.41 , 14.18. Mass calculated for (Ci9H25Cl2N5O3+H)+442.1 , found 442.0.1 -(4-(4-(L-Prolyl)piperazin-1 -yl)-3-aminobenzyl)-3,4-dichloro-5-hydroxy-1, 5- dihydro-2H-pyrrol-2-one (compound 1-56)

[0264] Prepared using general method BB from compound I-52. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give pale yellow solid (yield = 73%).1H NMR (400 MHz, Methanol-cU) 5 7.18 (d, J = 8.1 Hz, 1 H), 7.05 - 6.96 (m, 2H), 5.25 (s, 1 H), 4.82 (d, J = 15.1 Hz, 1 H), 4.72 (dd, J = 8.8, 7.0 Hz, 1 H), 4.32 (d, J = 15.2 Hz, 1 H), 3.93 - 3.63 (m, 4H), 3.47 (dt, J = 11 .5, 7.0 Hz, 1 H), 3.37 (dt, J = 8.7, 5.7 Hz, 1 H), 2.99 - 2.88 (m, 4H), 2.56 (ddd, J = 15.8, 12.8, 7.0 Hz, 1 H), 2.19 - 1.93 (m, 3H).13C NMR (101 MHz, MeOD) 5 166.63,162.78, 144.65, 140.90, 137.58, 134.35, 125.17, 122.33, 121.31 , 118.03, 81.55, 58.45, 51.37, 51.10, 46.05, 45.44, 42.90, 42.71 , 28.93, 23.82. Mass calculated for (C2oH25Cl2N503+H)+454.1 , found 454.0.1-(4-(4-(L-Prolyl)piperazin-1-yl)-3-methoxybenzyl)-3,4-dichloro-5-hydroxy-1 ,5-dihydro-2H-pyrrol-2-one (compound 1-57)

[0265] Prepared using general method BB from compound 1-53. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give white solid (yield = 57%).1H NMR (400 MHz, Methanol-cU) 5 7.01 - 6.96 (m, 2H), 6.90 (dd, J = 8.1 , 1.9 Hz, 1 H), 5.23 (s, 1 H), 4.85 (d, J = 15.1 Hz, 1 H), 4.70 (dd, J = 8.8, 7.0 Hz, 1 H), 4.33 (d, J = 15.1 Hz, 1 H), 3.89 (s, 3H), 3.86 - 3.64 (m, 4H), 3.51 - 3.34 (m, 2H), 3.14 - 3.04 (m, 4H), 2.55 (ddt, J = 13.1 , 9.0, 6.9 Hz, 1 H), 2.16 - 1.93 (m, 3H).13C NMR (101 MHz, MeOD) 5 166.56, 162.77, 152.64, 144.59, 139.63, 132.51 , 125.16, 120.55, 118.57, 111.63, 81.52, 58.44, 54.72, 50.54, 50.18, 46.04, 45.10, 43.19, 42.35, 28.90, 23.81. Mass calculated for (C2iH26CI2N4O4+H)+469.1 , found 469.1.3,4-Dichloro-5-hydroxy-1-(3-methoxy-4-(4-(methyl-L-alanyl)piperazin-1- yl)benzyl)-1,5-dihydro-2H-pyrrol-2-one (compound 1-58)

[0266] Prepared using general method BB from compound 1-54. The crude product was purified by preparative HPLC (ACN / H2O with 0.1 %TFA) to give white solid (yield = 57%).1H NMR (400 MHz, Methanol-cU) 5 7.01 - 6.94 (m, 2H), 6.90(dd, J = 8.1 , 1.9 Hz, 1 H), 5.23 (s, 1 H), 4.83 (d, = 15.1 Hz, 1 H), 4.41 (q, J = 6.9 Hz, 1 H), 4.33 (d, J = 15.1 Hz, 1 H), 3.90 (s, 3H), 3.87 - 3.62 (m, 4H), 3.16 - 3.02 (m, 4H), 2.71 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H).13C NMR (101 MHz, MeOD) 5 167.08, 162.77, 152.64, 144.58, 139.63, 132.50, 125.16, 120.55, 118.55, 111.63, 81.52, 54.83, 54.72, 50.69, 50.23, 45.14, 43.19, 42.08, 30.40, 14.16. Mass calculated for (C2OH26CI2N404+H)+457.1 , found 457.0.3,4-Dichloro-5-hydroxy-1-(3-(methylamino)-4-(piperazin-1-yl)benzyl)-1,5- dihydro-2H-pyrrol-2-one (compound 1-61)

[0267] Prepared using general method BB from compound I-60. The crude product was purified by reverse phase chromatography (ACN / H2O with 0.1 %TFA) to give off-white solid (yield = 68%).1H NMR (400 MHz, Methanol-cU) 5 7.11 (d, J = 8.6 Hz, 1 H), 6.82 - 6.76 (m, 2H), 5.23 (s, 1 H), 4.84 (d, J = 15.1 Hz, 1 H), 4.31 (d, J = 15.1 Hz, 1 H), 3.45 - 3.38 (m, 4H), 3.13 - 3.03 (m, 4H), 2.89 (s, 3H).13C NMR (101 MHz, MeOD) 5 162.75, 144.58, 142.61 , 138.14, 134.81 , 125.15, 120.17, 118.32, 111.66, 81.45, 48.41 , 43.92, 43.35, 30.36. Mass calculated for (Ci6H2oCl2N402+H)+371 .1 , found 371 .2.4-(5-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-di hydro- 1 H-pyrrol- 1 - yl)methyl)pyridin-2-yl)piperazin-2-one (compound 1-38)

[0268] Prepared from 4-[5-(aminomethyl)-2-pyridinyl]-2-piperazinone through general procedure A to yield 80 mg (42%).1H NMR (400 MHz, DMSO-cfe)6 8.18 (s, 1 H), 8.05 (d, J = 2.3 Hz, 1 H), 7.66 (dd, J = 8.9, 2.4 Hz, 1 H), 6.99 (d, J = 8.9 Hz, 1 H), 5.38 (s, 1 H), 4.57 (d, J = 15.3 Hz, 1 H), 4.30 (d, J = 15.3 Hz, 1 H), 4.03 (s, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.34 - 3.29 (m, 2H).13C NMR (101 MHz, DMSO) 5 166.94, 162.13, 158.49, 155.43, 144.96, 140.39, 125.04, 122.27, 109.01 , 82.04, 49.32, 42.19, 40.92, 39.56. m / z found: 357.1 ; (C14H14CI2N4O3) [M+H]+calcd. = 357.0.3,4-dichloro-5-hydroxy-1-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3- yl)methyl)-1,5-dihydro-2H-pyrrol-2-one (compound 1-37)

[0269] Prepared from 2-{4-[5-(aminomethyl)-2-pyridinyl]-1-piperazinyl}-1- ethanol through general procedure A to yield 98 mg (37%).1H NMR (400 MHz, DMSO-cfe) 5 9.80 (s, 1 H), 8.12 (d, J = 2.4 Hz, 1 H), 7.59 (dd, J = 8.8, 2.5 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 5.37 (s, 1 H), 4.57 (d, J = 15.3 Hz, 1 H), 4.38 - 4.24 (m, 3H), 3.81 - 3.74 (m, 2H), 3.67 - 3.45 (m, 2H), 3.35 - 2.93 (m, 6H).13C NMR (101 MHz, DMSO) 5 162.05, 157.57, 147.20, 144.90, 138.95, 125.08, 123.18, 108.27, 82.00, 57.97, 55.22, 51.21 , 42.35, 41.10. m / z found: 387.2; (C16H20CI2N4O3) [M+H]+calcd. = 387.1.5-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-1,3- dihydro-2H-benzo[d]imidazol-2-one (compound 1-36)

[0270] Prepared from 5-aminomethyl-1 ,3-dihydrobenzoimidazol-2-one HCI salt through general procedure A with 1.0 eq DIPEA to neutralize HCI salt to yield59 mg (35%).1H NMR (400 MHz, DMSO-cfe) 5 10.58 (s, 1 H), 10.57 (s, 1 H), 7.23 (d, J = 9.2 Hz, 1 H), 6.89 - 6.85 (m, 3H), 5.28 (d, J = 9.2 Hz, 1 H), 4.72 (d, J = 15.1 Hz, 1 H), 4.24 (d, J = 15.1 Hz, 1 H).13C NMR (101 MHz, DMSO) 5 161.94, 155.86, 144.90, 130.36, 129.59, 129.54, 125.08, 120.85, 108.76, 108.74, 81.57, 43.88. m / z found: 314.1 ; (C12H9CI2N3O3) [M+H]+calcd. = 313.0.3,4-dichloro-5-hydroxy-1-((6-methoxybenzo[d][1,3]dioxol-5-yl)methyl)-1,5- dihydro-2H-pyrrol-2-one (compound 1-35)

[0271] Prepared from (6-methoxybenzo[d][1 ,3]dioxol-5-yl)methanamine through general procedure A to yield 12.9 mg (36%).1H NMR (400 MHz, Chloroform-d) 5 6.85 (s, 1 H), 6.57 (s, 1 H), 6.00 - 5.91 (m, 2H), 5.21 (d, J = 5.4 Hz, 1 H), 4.74 (d, J = 14.6 Hz, 1 H), 4.43 (d, J = 14.6 Hz, 1 H), 3.87 (s, 3H).13C NMR (101 MHz, CDCI3) 5 162.25, 152.46, 148.42, 142.40, 141.79, 126.98, 116.21 , 110.81 , 101 .50, 94.98, 81 .54, 57.04, 38.72. m / z found: 332.1 ; (C13H11CI2NO5) [M+H]+calcd. = 332.0.3.4-dichloro-1-(3-fluoro-4-(4-(pyrimidin-2-yl)piperazin-1-yl)benzyl)-5-hydroxy-1.5-dihydro-2H-pyrrol-2-one (compound 1-34)

[0272] Prepared from (3-fluoro-4-(4-(pyrimidin-2-yl)piperazin-1- yl)phenyl)methanamine through general procedure A to yield 27.4 mg (59%).1H NMR (400 MHz, DMSO-cfe) 5 8.39 (d, J = 4.8 Hz, 2H), 7.21 (d, J = 9.2 Hz, 1 H), 7.11(d, J= 13.6 Hz, 1H), 7.07-6.99 (m, 2H), 6.66 (t, J = 4.7 Hz, 1H), 5.38 (d, J = 9.2 Hz, 1H), 4.29 (d, J= 15.6 Hz, 1H), 3.92 - 3.86 (m, 4H), 3.08-3.01 (m, 4H).13C NMR (101 MHz, DMSO) 5162.12, 161.63, 158.46, 154.16, 144.98, 132.21, 125.08, 124.63, 119.93, 116.06, 115.85, 110.81, 82.01, 66.82, 50.57, 43.80, 42.99. m / z found: 438.1; (C19H18CI2FN5O2) [M+H]+calcd. = 438.1.4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-3- methylphenyl)piperazin-2-one (compound 1-33)

[0273] Prepared from 4-(4-(aminomethyl)-3-methylphenyl)piperazin-2-one through general procedure A to yield 8.0 mg (20%).1H NMR (400 MHz, DMSO-cfe) 58.02 (s, 1 H), 7.09 (d, J = 9.5 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.77 (d, J = 2.6 Hz, 1H), 6.71 (dd, J= 8.4, 2.6 Hz, 1H), 5.15 (d, J= 9.6 Hz, 1H), 4.69 (d, J= 15.2 Hz, 1H), 4.18 (d, J= 15.2 Hz, 1H), 3.68 (s, 2H), 3.41 - 3.34 (m, 2H), 3.30 - 3.27 (m, 2H), 2.25 (s, 3H).13C NMR (101 MHz, DMSO) 5167.67, 161.75, 148.98, 144.85, 137.24, 130.11, 125.17, 124.98, 116.86, 112.53,81.52,52.25, 44.77,40.89, 19.66. m / z found: 370.1; (C16H17CI2N3O3) [M+H]+calcd. = 370.1.4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-di hydro- 1 H-pyrrol- 1 - yl)methyl)phenyl)piperazin-2-one (compound 1-30)

[0274] Prepared from 4-(4-(aminomethyl)phenyl)piperazin-2-one through general procedure AAto yield 5.7 mg (10%).1H NMR (400 MHz, DMSO-cfe) 58.03 (s, 1H), 7.16 (d, J= 8.7 Hz, 2H), 6.89 (d, J= 8.7 Hz, 2H), 5.27 (s, 1H), 4.65 (d, J =15.1 Hz, 1 H), 4.19 (d, J = 15.2 Hz, 1 H), 3.69 (s, 2H), 3.41 - 3.32 (m, 2H), 3.32 - 3.27 (m, 2H).13C NMR (101 MHz, DMSO) 5 167.61 , 161.89, 148.94, 144.79, 129.41 , 127.38, 125.12, 115.05, 81.58, 52.23, 44.78, 43.14. m / z found: 356.2; (C15H15CI2N3O3) [M+H]+calcd. = 356.1 .4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-2- fluorophenyl)piperazin-2-one (compound 1-29)

[0275] Prepared from 4-(4-(aminomethyl)-2-fluorophenyl)piperazin-2-one through general procedure AA to yield 19.6 mg (33%).1H NMR (400 MHz, DMSO- cfe) 6 7.97 (s, 1 H), 7.15 - 6.96 (m, 3H), 5.37 (s, 1 H), 4.62 (d, J = 15.6 Hz, 1 H), 4.29 (d, J = 15.6 Hz, 1 H), 3.57 (s, 2H), 3.31 - 3.18 (m, 4H).13C NMR (101 MHz, DMSO) 5 167.42, 162.13, 156.17, 153.74, 144.99, 137.56, 137.48, 132.40, 132.33, 125.09, 124.67, 124.64, 119.80, 119.77, 116.18, 115.97, 82.02, 53.96, 47.36, 42.97, 40.64. m / z found: 374.1 ; (C15H14CI2FN3O3) [M+H]+calcd. = 374.0.4-((3,4-dichloro-2-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1- yl)methyl)benzenesulfonamide (compound 1-28)

[0276] Prepared from 4-(aminomethyl)benzenesulfonamide through general procedure AA to yield 87 mg (32%).1H NMR (400 MHz, DMSO-cfe) 5 7.78 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.34 (s, 2H), 7.25 (s, 1 H), 5.42 (s, 1 H), 4.72 (d, J= 16.1 Hz, 1 H), 4.47 (d, J= 16.0 Hz, 1 H).13C NMR (101 MHz, DMSO) 5 165.05, 145.63, 143.54, 141.51 , 128.45, 126.29, 124.79, 82.32, 43.59.tert-butyl 4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1 - yl)methyl)-3-methylphenyl)piperazine-1-carboxylate (compound 1-20)

[0277] The tert-butyl 4-(4-(aminomethyl)-3-methylphenyl)piperazine-1- carboxylate was prepared through Raney nickel reduction as follows: the nitrile (810 mg, 2.69 mmol, 1.0 eq) was taken up in MeOH (100 mL), then Raney Ni (1 small spatula, ~ 200 mg) was added, then cone, ammonium hydroxide solution (12 M, 1.12 mL, 13.4 mmol, 5.0 eq) was added. The reaction was purged then pressurized with 40 psi hydrogen gas. After 22 h, pressure was released, the solution was filtered through celite, then concentrated in vacuo to a wet oil. After 1x coevaporation with MeOH, the remaining oil was left on high-vacuum overnight to yield 791 mg (96%) of the intermediate amine as a white solid.1H NMR (400 MHz, DMSO-cfe) 5 7.16 (d, J = 8.1 Hz, 1 H), 6.77 - 6.69 (m, 2H), 3.60 (s, 2H), 3.48 - 3.41 (m, 4H), 3.06 - 2.99 (m, 4H), 2.23 (s, 3H), 1 .42 (s, 9H).

[0278] Next, the title compound was prepared from the intermediate amine through general procedure AA to yield 19.6 mg (33%).1H NMR (400 MHz, DMSO- cfe) 5 7.09 (d, J = 9.6 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 6.81 - 6.71 (m, 2H), 5.16 (d, J = 9.6 Hz, 1 H), 4.69 (d, J = 15.3 Hz, 1 H), 3.46 - 3.41 (m, 4H), 3.10 - 3.03 (m, 4H), 2.00 (s, 3H), 1.42 (s, 9H).13C NMR (101 MHz, DMSO) 5 161.77, 154.33, 150.71 ,144.85, 137.05, 129.92, 125.79, 124.99, 118.26, 113.86, 81.55, 79.44, 55.38,48.85, 40.91 , 28.53, 19.65. m / z found: 456.3; (C21H27CI2N3O4) [M+H]+ealed. = 456.1.3,4-dichloro-5-hydroxy-1-(2-methyl-4-(piperazin-1-yl)benzyl)-1,5-dihydro-2H- pyrrol-2-one (compound 1-19)

[0279] Prepared from compound I-20 through general method BB to yield 680 mg (99%) after trituration with Et20.1H NMR (400 MHz, DMSO-cfe) 58.76 (s, 2H), 7.07 (d, J= 8.4 Hz, 1H), 6.83 (s, 1H), 6.78 (d, J= 8.6 Hz, 1H), 5.18 (s, 1H), 4.68 (d, J= 15.3 Hz, 1H), 4.21 (d, J= 15.3 Hz, 5H), 3.37 - 3.13 (m, 8H), 2.26 (s, 3H).13C NMR (101 MHz, DMSO) 5161.83, 149.77, 144.86, 137.21, 129.89, 126.57, 125.04, 118.29, 113.95, 81.67, 46.06, 43.21, 40.94, 19.63. m / z found: 356.3; (C16H19CI2N3O2) [M+H]+calcd. = 356.1. tert-butyl ((2S)-1 -(4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol- 1 -yl)methyl)-3-methylphenyl)piperazin-1-yl)-1-oxopropan-2- yl)(methyl)carbamate (compound 1-39)

[0280] Prepared from compound 1-19 and Boc-N-Me-Ala-OH through general method E to yield 112 mg (82%).1H NMR (400 MHz, Chloroform-d) 57.18(d, J= 8.2 Hz, 1H), 6.76-6.68 (m, 2H), 5.22 - 5.10 (m, 1H), 5.06 (d, J= 9.9 Hz, 1H), 4.97 (d, J= 14.8 Hz, 1H), 4.29 (d, J= 14.7 Hz, 1H), 3.99-3.90 (m, 1H), 3.84 -3.73 (m, 1H), 3.69-3.52 (m, 2H), 3.30-3.17 (m, 2H), 3.11 -2.94 (m, 3H), 2.75 (s, 3H), 2.33 (s, 3H), 1.50 (s, 9H), 1.31 (d, J = 7.7 Hz, 3H). m / z found: 541.1; (C25H34CI2N4O5) [M+H]+calcd. = 541.2.tert-butyl (2S)-2-(4-(4-((3,4-dichloro-2-hydroxy-5-oxo-2, 5-dihydro-1 H-pyrrol-1 - yl)methyl)-3-methylphenyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (compound 1-40)

[0281] Prepared from compound 1-19 and Boc-Pro-OH through general method E to yield 130 mg (94%).1H NMR (400 MHz, Methanol-cU) 5 8.00 (s, 1 H), 7.15 (d, J = 8.3 Hz, 1 H), 6.86 (d, J = 2.5 Hz, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 5.07 (s, 1 H), 4.91 (d, J = 14.9 Hz, 1 H), 4.80 - 4.71 (m, 1 H), 4.29 (d, J = 14.8 Hz, 1 H), 3.90- 3.60 (m, 4H), 3.59 - 3.42 (m, 2H), 3.26 - 3.09 (m, 4H), 2.38 - 2.24 (m, 4H), 2.02- 1.79 (m, 3H), 1.48 (s, 3H), 1.42 (s, 6H).13C NMR (101 MHz, MeOD) 5 171.85, 171.54, 163.48, 162.42, 154.45, 150.83, 150.75, 144.55, 137.30, 129.98, 125.81 , 125.66, 124.99, 118.32, 113.94, 113.89, 81.18, 79.80, 79.73, 57.03, 56.74, 49.41 , 49.20, 49.03, 48.87, 48.47, 46.75, 46.37, 45.00, 44.89, 41.87, 40.50, 37.50, 35.56, 30.21 , 29.61 , 27.40, 27.38, 23.83, 23.17, 18.29. m / z found: 553.2; (C26H34CI2N4O5) [M+H]+calcd. = 553.2.3,4-dichloro-1-(4-(4-(dimethylglycyl)piperazin-1-yl)-2-methylbenzyl)-5- hydroxy-1,5-dihydro-2H-pyrrol-2-one (compound 1-41)

[0282] Prepared from compound 1-19 and Me2-Gly-OH through general method E to yield 83 mg (75%).1H NMR (400 MHz, Methanol-^) 5 7.15 (d, J = 8.3Hz, 1 H), 6.88 - 6.79 (m, 2H), 5.06 (s, 1 H), 4.91 (d, J = 15.0 Hz, 1 H), 4.30 (d, J = 15.0 Hz, 1 H), 3.95 (s, 2H), 3.79 - 3.74 (m, 2H), 3.65 - 3.59 (m, 2H), 3.26 - 3.17 (m, 4H), 2.75 (s, 6H), 2.32 (s, 3H).13C NMR (101 MHz, MeOD) 5 164.72, 162.42, 150.71 , 144.53, 137.29, 129.95, 125.84, 1 18.40, 114.00, 81.20, 58.60, 49.13, 48.83, 44.50, 43.80, 41 .63, 40.49, 18.26. m / z found: 441 .1 ; (C20H26CI2N4O3) [M+H]+calcd. = 441.1.3,4-dichloro-5-hydroxy-1-(2-methyl-4-(4-(methyl-L-alanyl)piperazin-1- yl)benzyl)-1,5-dihydro-2H-pyrrol-2-one (compound 1-42)

[0283] Prepared from compound 1-39 through general method BB to yield 63 mg (51 %) after trituration with Et2O.1H NMR (400 MHz, DMSO-cfe) 5 8.93 (s, 1 H), 8.73 (s, 1 H), 7.11 (s, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 6.81 (s, 1 H), 6.77 (d, J = 8.8 Hz, 1 H), 5.17 (s, 1 H), 4.68 (d, J = 15.2 Hz, 1 H), 4.45 (s, 1 H), 4.20 (d, J = 15.2 Hz, 1 H), 3.82 - 3.43 (m, 7H), 3.27 - 2.98 (m, 4H), 2.25 (s, 3H), 1 .36 (d, J = 6.8 Hz, 3H).13C NMR (101 MHz, DMSO) 5 167.69, 161.80, 150.33, 144.84, 137.10, 129.88, 126.07, 125.03, 118.27, 113.88, 81.62, 54.16, 49.05, 48.69, 45.00, 41.97, 40.94, 31.25, 19.65, 15.28. m / z found: 441.1 ; (C20H26CI2N4O3) [M+H]+calcd. = 441 .1 .1-(4-(4-(L-prolyl)piperazin-1-yl)-2-methylbenzyl)-3,4-dichloro-5-hydroxy-1,5- dihydro-2H-pyrrol-2-one (compound 1-43)

[0284] Prepared from compound 1-40 through general method BB to yield 32.4 mg (26%) after trituration with Et2O.1H NMR (400 MHz, DMSO-cfe) 5 9.36 (s, 1 H), 8.51 (s, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 6.82 (d, J = 2.5 Hz, 1 H), 6.77 (dd, J = 8.5, 2.6 Hz, 1 H), 5.17 (s, 1 H), 4.73 - 4.64 (m, 2H), 4.20 (d, J = 15.3 Hz, 1 H), 3.81 - 3.50 (m, 4H), 3.33 - 3.07 (m, 6H), 2.47 - 2.34 (m, 1 H), 2.26 (s, 3H), 2.02 - 1 .74 (m, 3H).13C NMR (101 MHz, DMSO) 5 167.04, 161.80, 150.32, 144.85, 137.11 , 129.88, 126.11 , 125.02, 118.30, 113.93, 81.62, 58.15, 48.95, 48.65, 46.28, 44.92, 42.21 , 40.93, 29.07, 24.12, 19.65. m / z found: 453.1 ; (C21H26CI2N4O3) [M+H]+calcd. = 453.1.Viral sensitizing activity of compounds in 786-0 cells

[0285] 786-0 cells were seeded in 96 well dishes at 4E4 cells per well. Stock preparations of compounds of the application in DMSO at 100 mM were used to treat confluent monolayers of 786-0 cells. These stocks were first diluted in 5% DMSO (in water) and then in cell culture media to obtain the dose range tested. Vehicle alone (DMSO) was used as a negative control. 4h after treatment with the compounds of the application, cells were infected with VSVA51 at MOI (multiplicity of infection) 0.05. 24h after infection GFP counts were obtained following high content imaging and quantification using the Cellomics Arrayscan. Compounds of the application were evaluated fortheir viral sensitizer activity on VSV in 786-0 cells, which is reported as Peak Fold Change in GFP counts normalized to vehicle control (DMSO). Results are reported in Table 2. The Dose at Peak represents a particularly effective dose for each compound of the application at which the peak fold change was recorded.Table 2Viral sensitizing activity of Compound 1-8 in various cancer cell linesMethods

[0286] Cell lines: Cell lines: 786-0 (human renal carcinoma), B16-F10 (murine melanoma), 4T1 (murine mammary carcinoma), MC38 (murine colon carcinoma), CT2A (murine glioma) and OVCA433 (human ovarian carcinoma) cells were obtained from the American Type Culture Collection and maintained in Dulbecco's Modified Eagle's Medium or Roswell Park Memorial Institute (RPMI) supplemented with 10% fetal bovine serum and buffered with 30 mM Hepes. All cell lines were incubated at 37°C with 5% CO2.

[0287] Viruses: VSVA51 is a recombinant variant of the Indiana serotype of VSV harbouring a deletion of the 51st methionine in the M protein. VSVA51 expressing green fluorescent protein (GFP) or firefly luciferase (FLuc) are recombinant derivatives of VSVdelta51 . All virus stocks were propagated in Vero cells, purified on Optiprep™ gradient and titered on Vero cells as described in (Diallo et al. Methods Mol Biol. 2012;797:127-40).

[0288] Compound screening: Cell lines were seeded in 96well dishes at 3- 4E4 cells per well. Stock preparations of compounds in DMSO at 100m M were used to treat confluent monolayers of cells. These stocks were first diluted in 5% DMSO(in water) and then in cell culture media to obtain the dose range tested. Vehicle alone (DMSO) was used as a negative control. 4h after treatment with the compounds, cells were infected with VSVA51 expressing GFP at MOI 0.005-0.05. 24h after infection GFP counts were obtained following high content imaging and quantification using the Cellomics Arrayscan. Compounds were evaluated for their viral sensitizer activity on VSV in 786-0, which is reported as Peak Fold Change in GFP counts normalized to vehicle control (DMSO). The Dose at Peak represents a particularly effective dose for each compound at which the peak fold change was recorded. For high throughput virus quantification, cells were infected with VSVA51 expressing firefly luciferase, and output was measured as described in (Garcia V et al., J Vis Exp. 2014 Sep19;(91 ):51890). To generate a standard curve, known amounts of virus (in plaque forming units, or pfu) were added to Vero cells at the same time as transfer of supernatant. Upon measurement of bioluminescence, input pfu was plotted against mean relative light units. Four-parameter non-linear regression analysis generates a standard curve for each cell line from which viral expression units (VEUs) were interpolated. Resazurin assay was used to determine cell metabolic activity (viability) relative to an untreated or virus-only treated control.

[0289] More specifically, a standard curve was generated where known amounts of virus (in plaque forming units, or pfu) were added to Vero cells at the same time as transfer of supernatant. Upon measurement of bioluminescence, input pfu was plotted against mean relative light units. Four-parameter non-linear regression analysis generates a standard curve for each cell line from which viral expression units (VEUs) were interpolated. Graphs show simultaneous quantification of viral output (GFP foci or counts) and cytotoxicity for compound I-8 in various cell lines including MC38 murine colon carcinoma (FIG.1), CT2A murine glioma (FIG.2), OVCA433 murine ovarian carcinoma (FIG.3), B16F10 mouse melanoma (FIG.4) and 4T1 mouse breast carcinoma (FIG.5). In these graphs, the circles are associated with the right y-axis and represent GFP counts at each dose tested. The dotted lines (triangles and squares) indicate relative metabolic activity in 786-0 cells as determined using resazurin dye (1 means 100% viable) and are associated with the left y-axis. The triangles represent cytotoxicity of the compound of the application alone whereas the squares indicate cytotoxicity of compound of the application in combination with VSV. In FIG.6, the circles are associated withthe right y-axis and show VEU / ml while the diamonds are associated with the left y- axis and show GFP foci or counts at the same doses of compound 1-8 tested in 786- 0.Increased permissiveness to non-replicating viral vectors by Compound 1-8Lentivirus

[0290] A representative compound of the application, compound 1-8, was selected for further testing for its viral sensitizing activity and ability to increase permissiveness of various cells to various non-replicating viral vectors. Initial tests were carried out in the context of non-replicating Lentivirus. In FIG.7A and FIG.7B cells were seeded in 96-well plates and pretreated for 4h with 1-8 at indicated concentrations in triplicate. HT1080 connective tissue or HEPG2 hepatic (FIG.7A, FIG.7B) cells were transduced with lentivirus encoding GFP (LV-GFP) at an MOI of 10. At 70 hours post transduction, plates were imaged for GFP using the Cellomics Arrayscan and mean fluorescence per well determined using the Agilent Biotek Cytation5TM. GFP mean intensity was quantified and plotted (n=3, fold-change compared to DMSO treated control in hashed line). Alternatively, for Jurkat T-cells (Table 3), different MOIs (0.1 , 1 , 10) of LV-GFP were used as indicated and flow cytometry was used to determine mean fluorescence intensity (MFI). The fold change in MFI relative to the DMSO control is shown in Table 3. Altogether, these data show varying dose ranges leading to enhanced transduction as measured by increased expression of GFP using non-replicating LV-GFP across cell types, with peak enhancement between 20-40 pM depending on the cell type.Table 3: Enhancement of LV-GFP in Jurkat T-cellsMOIAdeno-Associated Virus

[0291] Additional tests were carried out in the context of non-replicating Adeno-Associated Virus serotype 2 (AAV2). In FIG.8A and FIG.8B, Cells were seeded in 96well plates and pretreated for 4h with compound I-8 at indicated concentrations in triplicate. HT1080 connective tissue or HEPG2 hepatic (FIG.8A, FIG.8B) cells were transduced with AAV2 encoding GFP (AAV2-GFP) at an MOI of 5000. At 70 hours post transduction, plates were imaged for GFP using the Cellomics Arrayscan and mean fluorescence per well determined using the Agilent Biotek Cytation5. GFP mean intensity was quantified and plotted (n=3, fold-change compared to DMSO treated control in hashed line). Altogether, these data show varying dose ranges of I-8 lead to enhanced transduction of non-replicating AAV2- GFP across cell types, with peak enhancement between 20-40 pM depending on the cell type.Adenovirus

[0292] Further tests were carried out in the context of non-replicating Adenovirus type 5 (Ad5). In FIG.9, Cells were seeded in 96well plates and pretreated for4h with compound I-8 at indicated concentrations in triplicate. HEPG2hepatic cells were transduced with non-replicating human Ad5 encoding GFP (Ad5- GFP) at an MOI of 5. At 70 hours post transduction, plates were imaged for GFP using the Cellomics Arrayscan and mean fluorescence per well determined using the Agilent Biotek Cytation5. GFP mean intensity was quantified and plotted (n=3, fold-change compared to DMSO treated control in hashed line). Altogether, these data show varying dose ranges of 1-8 lead to enhanced transduction of nonreplicating Ad5-GFP, with peak enhancement between 20-40 pM in HEPG2 cells.

[0293] While the applicant's teachings described herein are in conjunction with various embodiments for illustrative purposes, it is not intended that the applicant's teachings be limited to such embodiments as the embodiments described herein are intended to be examples. On the contrary, the applicant's teachings described and illustrated herein encompass various alternatives, modifications, and equivalents, without departing from the embodiments described herein, the general scope of which is defined in the appended claims.

Claims

CLAIMS1 . A compound of Formula (I), or a salt, solvate and / or prodrug thereof:wherein:X is Ci-6alkylene;Cy1is selected from phenyl, 6-membered heteroaryl, benzofused 5- to 6- membered heteroaryl and benzofused 5- to 6-membered heterocycloalkyl, Cy1being unsubstituted or substituted with one to four substituents independently selected from halo, Ci ealkyl, Ci-ehaloalkyl, OR1, NR1R2, =0, SO2NR1R2, CO2R3, SR3, S(O)R3and SO2R3, and Cy1being optionally substituted with one Cy2;R1is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl, C(0)Ci-4alkyl and C(O)CHR4NR5R6;R2and R3are independently selected from H, Ci-4alkyl and Ci-4haloalkyl;R4is selected from H, NH2, Ci-4alkyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R5is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(0)0Ci-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and 0Ci-4alkyl;R6is selected from H, Ci-4alkyl and Ci-4haloalkyl;Cy2is selected from 5- to 6 membered heterocycloalkyl comprising at least one N-R7and optionally substituted with one to four substituents independently selected from halo, Ci-ealkyl, Ci-ehaloalkyl, OR8, NR8R9, =0, SO2NR8R9, CO2R8, SR8, S(O)R8and SO2R8;R7is selected from H, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkylC(O)R12, C(O)CHR10NR11R12, 6-membered heteroarylR8and R9are independently selected from H, Ci-4alkyl and Ci-4haloalkyl; R10is selected from H, NH2, Ci-4alkyl and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl;R11is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(O)OCi-4alkyl and a naturally occurring amino, the latter group being optionally substituted with one or more substituents independently selected from Chalky I, halo, OH and OCi-4alkyl; andR12is selected from H, Ci-4alkyl and Ci-4haloalkyl; provided that, when Cy1is phenyl or 6-membered heteroaryl, Cy1is substituted with at least one of NR1R2, SO2NR1R2, CO2R3and Cy2.

2. The compound of claim 1 , wherein Cy1is selected from phenyl, pyridyl, indolyl, and benzodioxolanyl, and Cy1being unsubstituted or substituted with one to four substituents as defined in claim 1 .

3. The compound of claim 1 or 2, wherein Cy1is substituted with one to four substituents independently selected from F, Ci-4alkyl, Ci-4fluoroalkyl, OC1- 4alkyl, OCi-4fluoroalkyl, NH2, NHCi-4alkyl, N(Ci-4alkyl)2, NHC(O)Ci-4alkyl, NHC(O)CH2NH2, NHC(O)R5, =0, SO2NH2, SO2NHC(O)R5, and CO2H.

4. The compound of any one of claims 1 to 3, wherein Cy1is substituted with one to four substituents independently selected from F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, OCH3, OCF3, OCF2H, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, NH2, NHCH3, N(CH3)2, NHC(O)CH3, NHC(O)OtBu, NHC(O)CH2NH2, =0, SO2NH2, SO2NHC(O)CH(CH3)NHCH3, and CO2H.

5. The compound of any one of claims 1 to 4, wherein X is selected from Ci- salkylene.

6. The compound of any one of claims 1 to 5, wherein X is CH2.

7. The compound of any one of claims 1 to 6, wherein R1is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

8. The compound of any one of claims 1 to 7, wherein R1is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

9. The compound of any one of claims 1 to 8, wherein R2is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

10. The compound of any one of claims 1 to 9, wherein R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)211.The compound of any one of claims 1 to 10, wherein R3is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

12. The compound of any one of claims 1 to 11 , wherein R3is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

13. The compound of any one of claims 1 to 12, wherein R4is a side chain of a naturally occurring amino acid which optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OC1- 4alkyl.

14. The compound of any one of claims 1 to 13, wherein R5is selected from H, Ci-4alkyl, Ci-4fluoroalkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl.

15. The compound of any one of claims 1 to 14, wherein R5is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

16. The compound of any one of claims 1 to 15, wherein R6is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

17. The compound of any one of claims 1 to 15, wherein Cy2is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, diazolidinyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, diazinanyl, morpholinyl, and thiomorpholinyl, optionally substituted with one to four substituents as defined in claim 1 .

18. The compound of any one of claims 1 to 17, wherein Cy2is selected from piperazinyl optionally substituted with one to four substituents as defined in claim 1.

19. The compound of any one of claims 1 to 18, wherein Cy2is substituted with one to four substituents independently selected from Ci -ealkyl and =0.

20. The compound of any one of claims 1 to 19, wherein R7is selected from H,Ci-4alkyl, Ci-4fluoroalkyl, Ci-4alkyleneOH, C(O)OR12, C(O)R12,C(O)CHR10NR11R12, pyrimidinyl21. The compound of any one of claims 1 to 20, wherein R7is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu, C(O)CH3, C(O)CH2NH2, C(O)CH2N(CH3)2C(O)CH(NH2)CH3C(O)NH2, C(O)CH(CH3)NHCH3,C(O)CH(CH3)N(CH3)C(O)OtBu, CH2CH2OH,C(O)CH(NH2)N(CH3)C(O)OtBu, pyrimidinyl,22. The compound of any one of claims 1 to 21 , wherein R8is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

23. The compound of any one of claims 1 to 22, wherein R8is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

24. The compound of any one of claims 1 to 23, wherein R9is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

25. The compound of any one of claims 1 to 24, wherein R9is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

26. The compound of any one of claims 1 to 25, wherein R10is a side chain of a naturally occurring amino acid which is optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OC1- 4alkyl.

27. The compound of any one of claims 1 to 26, wherein R11is selected from H, Ci-4fluoroalkyl, Ci-4alkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl.

28. The compound of any one of claims 1 to 27, wherein R11is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu.

29. The compound of any one of claims 1 to 28, wherein R12is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

30. The compound of any one of claims 1 to 29, wherein R12is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

31. The compound of claim 1 having the structure of Formula (IA), or a salt, solvate and / or prodrug thereof: ci, ciwherein:X is Ci-6alkylene;Cy1is selected from phenyl and pyridyl, each of which is unsubstituted or substituted with one to four substituents independently selected from halo, Ci-4alkyl, NH2, N(Ci-4alkyl)(Ci-4alkyl), OCi-4alkyl, Ci-4haloalkyl and OC1- 4haloalkyl;R7is selected from H, Ci-4alkyl, Ci-4haloalkyl, Ci-4alkyleneC(O) R12, C(O)CHR10NR11R12, 6-membered heteroaryl anR10is selected from H and a side chain of a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl;R11is selected from H, Ci-4alkyl, Ci-4haloalkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or more substituents independently selected from Ci-4alkyl, halo, OH and OCi-4alkyl; andR12is selected from H, Ci-4alkyl and Ci-4haloalkyl;R13is selected from halo, Ci-4alkyl and Ci-4haloalkyl;R14is =0; n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8; and m is 0, 1 or 2.

32. The compound of claim 31 , wherein Cy1is substituted with one to four substituents as defined in claim 31 .

33. The compound of claim 31 or 32, wherein Cy1is substituted with one to four substituents independently selected from F, Ci-4alkyl, Ci-4fluoroalkyl, OCi- 4alkyl, OCi-4fluoroalkyl, NH2 and NHCi-4alkyl.

34. The compound of any one of claims 31 to 33, wherein Cy1is substituted with one to four substituents independently selected from F, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, NH2, and NHCH3.

35. The compound of any one of claims 31 to 34, wherein X is selected from Cisalkylene.

36. The compound of any one of claims 31 to 35, wherein X is CH2.

37. The compound of any one of claims 31 to 36, wherein R7is selected from H,Ci-4alkyl, Ci-4fluoroalkyl, Ci-4alkyleneOH, C(O)OR12, C(O)R12,C(O)CHR10NR11R12, pyrimidinyl38. The compound of any one of claims 31 to 37, wherein R7is selected from H,CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu, C(O)CH3, C(O)CH2NH2, C(O)CH2N(CH3)2 C(O)CH(NH2)CH3C(O)NH2, C(O)CH(CH3)NHCH3,C(O)CH(CH3)N(CH3)C(O)OtBu, CH2CH2OH,C(O)CH(NH2)N(CH3)C(O)OtBu, pyrimidinyl,39. The compound of any one of claims 31 to 38, wherein R10is a side chain of a naturally occurring amino acid which is optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl.

40. The compound of any one of claims 31 to 39, wherein R11is selected from H, Ci-4alkyl, Ci-4fluoroalkyl, C(O)OCi-4alkyl and a naturally occurring amino acid, the latter group being optionally substituted with one or two substituents independently selected from Ci-4alkyl, Cl, F, Br, OH and OCi-4alkyl.41 . The compound of any one of claims 31 to 40, wherein R11is H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(O)OtBu.

42. The compound of any one of claims 31 to 41 , wherein R12is selected from H, Ci-4fluoroalkyl and Ci-4alkyl.

43. The compound of any one of claims 31 to 42, wherein R12is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

44. The compound of any one of claims 31 to 43, wherein R13is F, Ci-4alkyl and Ci-4fluoroalkyl.

45. The compound of any one of claims 31 to 44, wherein R13is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CF2H, CH2CF2H, CH2CF3, CH2CFH2 and CH(CF3)2.

46. The compound of any one of claims 31 to 45, wherein m is 0 or 1 .

47. The compound of any one of claims 31 to 46, wherein n is 0 or 1 .

48. The compound of claim 1 selected from:or a salt, solvate and / or prodrug thereof.

49. The compound of claim 1 , selected fromor a salt, solvate and / or prodrug thereof.

50. A composition comprising a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, and carrier.

51. The composition of claim 50, further comprising a virus or genetic material encoding components of a virus.

52. The composition of claim 50 or 51 , wherein the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.

53. A method of increasing permissiveness of a cell to a virus, comprising administering an effective amount of a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, to the cell.

54. The method of claim 53, wherein the compound, or salt, solvate and / or prodrug thereof, is administered to the cell before, after and / or concurrently with the virus.

55. The method of claim 53, wherein the compound, or salt, solvate and / or prodrug thereof, is administered to the cell before the virus is administered to the cell.

56. The method of any one of claims 53 to 55, wherein the permissiveness of the cell to the virus is increased 1.1 fold or more compared to permissiveness of the cell, or a comparable cell prior to the method or in the absence of the method.

57. The method of any one of claims 53 to 56, wherein the virus is a therapeutic virus.

58. The method of any one of claims 53 to 57, wherein the virus is an interferon (IFN)-sensitive virus.

59. The method of any one of claims 53 to 58, wherein the virus is an attenuated virus, a genetically modified virus, a non-replicating virus, a gene therapy vector, or an oncolytic virus.

60. The method of any one of claims 53 to 58, wherein the virus is a herpes simplex virus (HSV) viral vector.61 . The method of any one of claims 53 to 58, wherein the virus is an adenovirus.

62. The method of claim 59, wherein the gene therapy viral vector is Ad5, Ad3, Ad11 , Ad35, canine Ad2, chimp Ad26, chimp AdOx1 , or recombinant serotypes therein, AAV serotypes 1-9 or recombinant serotypes therein, Lentivirus, gamma-retrovirus, Annellovirus, or Baculovirus.

63. The method of any one of claims 53 to 59, wherein the virus is a rhabdovirus, a togavirus, or an orthomyxovirus.

64. The method of claim 63, wherein the rhabdovirus is vesicular stomatitis virus (VSV), engineered mutants of VSV (VSVA51), an oncolytic non-VSV rhabdovirus, or a recombinant oncolytic non-VSV rhabdovirus encoding one or more of rhabdoviral N, P, M, G and / or L protein, or variant thereof including chimeras and fusion proteins thereof, having an amino acid identity of at least or at most 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 92, 94, 96, 98, 99, 100%, including all ranges and percentages there between, to the N, P, M, G and / or L protein of Arajas virus, Chandipura virus, Cocal virus, Isfahan virus, Maraba virus, Piry virus, Vesicular stomatitis Alagoas virus, BeAn 157575 virus, Boteke virus, Calchaqui virus, Eel virus American, Gray Lodge virus, Jurona virus, Klamath virus, Kwatta virus, La Joya virus, Malpais Spring virus, Mount Elgon bat virus, Perinet virus, Tupaia virus, Farmington, Bahia Grande virus, Muir Springs virus, Reed Ranch virus, Hart Park virus, Flanders virus, Kamese virus, Mosqueiro virus, Mossuril virus, Barur virus, Fukuoka virus, Kern Canyon virus, Nkolbisson virus, Le Dantec virus, Keuraliba virus, Connecticut virus, New Minto virus, Sawgrass virus, Chaco virus, Sena Madureira virus, Timbo virus, Almpiwar virus, Aruac virus, Bangoran virus, Bimbo virus, Bivens Arm virus, Blue crab virus, Charleville virus, Coastal Plains virus, DakArK 7292 virus, Entamoeba virus, Garba virus, Gossas virus, Humpty Doo virus, Joinjakaka virus, Kannamangalam virus, Kolongo virus, Koolpinyah virus, Kotonkon virus, Landjia virus, Manitoba virus, Marco virus, Nasoule virus, Navarro virus, Ngaingan virus, Oak-Vale virus, Obodhiang virus, Oita virus, Quango virus, Parry Creek virus, Rio Grande cichlid virus, Sandjimba virus, Sigma virus, Sripur virus, Sweetwater Branch virus, Tibrogargan virus, Xiburema virus, Yata virus, Rhode Island, Adelaide River virus, Berrimah virus, Kimberley virus, or Bovine ephemeral fever virus.

65. The method of claim 63, wherein the togavirus is sindbis, semliki forest virus or M1 virus.

66. The method of claim 63, wherein the orthomyxovirus is influenza A, influenza B, influenza C, influenza D, isavirus, thogotovirus or quanranjavirus.

67. The method of claim 59, wherein the virus is a component of a vaccine.

68. The method of claim 67, wherein the component of the vaccine is a live attenuated vaccine selected from measles, mumps, rubella, rotavirus, chickenpox, and yellow fever, or a viral vector vaccine encoding a vaccine antigen transgene selected from rVSVAG-ZEBOV-GP (Ervebo) and ChadOx1-S (Vaxzevria).

69. The method of any one of claims 53 to 58, wherein the virus comprises a non-replicating viral vector.

70. The method of claim 69, wherein the viral vector is an adenovirus (Ad), an adeno-associated virus (AAV) or lentivirus (LV).

71. The method of any one of claims 53 to 70, wherein the cell is a eukaryotic cell or a prokaryotic cell.

72. The method of any one of claims 53 to 70, wherein the cell is a human cell or a mammalian cell.

73. The method of any one of claims 53 to 71 , wherein the cell is in vivo, ex vivo or in vitro.

74. The method of any one of claims 53 to 71 , wherein the cell is a cell in subject.

75. The method of any one of claims 53 to 71 , wherein the cell is a cell line or a cell culture.

76. A method of increasing permissiveness of a cell to genetic material encoding components of a virus, comprising administering an effective amount of a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, to the cell in combination with provision of the genetic material encoding components of a virus to the cell.

77. The method of claim 76, wherein the provision of the genetic material encoding components of a virus to the cell is prior, concurrent with or after administration of the effective amount of the compound.

78. The method of claim 76 or 77, the genetic material encoding components of a virus are nucleic acids, or chemically modified variants thereof, comprising viral and / or viral-like sequences.

79. The method of any one of claims 76 to 78, wherein the genetic material encoding components of a virus encode viral proteins, viral-like proteins and / or functional sequences.

80. The method of any one of claims 76 to 79, wherein the genetic material encoding components of a virus is delivered directly to the cell or is delivered in a carrier.

81. The method of any one of claims 76 to 80, wherein the genetic material encoding components of a virus is comprised in a plasmid.

82. The method of claim 81 , wherein a lentivirus, gamma-Retrovirus, or AAV is produced following transfection of the plasmid encoding lentivirus, gammaRetrovirus, or AAV viral or viral-like sequences into the cell.

83. A method of treating a disease, disorder or condition by increasing permissiveness of a cell to a virus comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, and the virus or genetic material encoding the virus to a subject in need thereof.

84. The method of claim 83, wherein the compound is administered to the cell before, after and / or concurrently with the virus that treats the disease, disorder or condition or genetic material encoding the virus that treats the disease, disorder or condition.

85. The method of claim 83 or 84, wherein the compound allows a lower amount of the virus or genetic material encoding components to be used to treat the disease, disorder or condition.

86. The method of any one of claims 83 to 85, wherein the disease, disorder or condition is cancer or a tumor.

87. The method of any one of claims 83 to 86, wherein the virus is an oncolytic virus.

88. The method of claim 87, wherein the oncolytic virus is a virus that preferentially infects and lyses cancer or tumor cells as compared to noncancer or normal cells.

89. The method of claim 87 or 88, wherein the oncolytic virus is talimogene laherparepvec (T-VEC), Delytact, Maraba MG-1 , or vesicular stomatitis virus (VSVA51). In some embodiments, the oncolytic virus is a Newcastle Disease Virus (NDV), measles virus, (MeV), parvovirus H1 (ParvOryx), M1 virus, poliovirus, reovirus, Myxomavirus, or Sindbis virus (SinV).

90. The method of any one of claims 86 to 89, wherein the cancer is lymphoblastic leukemia, myeloid leukemia, adrenocortical carcinoma, AIDS- related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain stem glioma, brain tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, craniopharyngioma, ependymoblastoma, medulloblastoma, pineal parenchymal tumors of intermediate differentiation, supratentorial primitive neuroectodermal tumors and pineoblastoma, visual pathway and hypothalamic glioma, spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, central nervous system lymphoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma,esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumors, extracranial, extragonadal, ovarian, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (Liver) cancer, histiocytosis, Langerhans cell cancer, Hodgkin lymphoma, hypopharyngeal cancer, islet cell tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, lymphocytic leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, nonsmall cell lung cancer, small cell lung cancer, Hodgkin lymphoma, nonHodgkin lymphoma, malignant fibrous histiocytoma of bone and osteosarcoma, medulloblastoma, medulloepithelioma, melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumors, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, renal pelvis and ureter cancer, transitional cell cancer, respiratory tract carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine sarcoma, skin cancer, Merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach (Gastric) cancer, supratentorial primitive neuroectodermal tumors, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, trophoblastic tumor, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms tumor.

91. The method of any one of claims 86 to 90, wherein the cancer is colon cancer, breast cancer, rectal cancer, lung cancer, a leukemia, cervical cancer, sarcoma, melanoma, pancreatic cancer and / or ovarian cancer.

92. The method of any one of claims 86 to 91 , wherein the subject is a mammal.

93. The method of any one of claims 86 to 92, wherein the subject is a human.

94. The method of any one of claims 86 to 93, wherein the cell is a cancer cell, a tumor cell or an immortalized cell.

95. The method of any one of claims 86 to 94, wherein the cell is one or more types of immortalized cells in vitro or in vivo from a cell, cell line, tissue or organism selected from human, rat, mouse, cat, dog, pig, primate, horse, Vero, HEK-293 cells, VPC 1.0, VPC 2.0, EB-66 cells, EbX cells, PER. C6 cells, AGE1.CR, Agel.O S, Agel.HN, Agel.RO, Q0R2 / 2E11 , UMNSAH-DF1 , CHO, hybridoma cells, sf9 cells, or R4 cells.

96. The method of any one of claims 86 to 95, wherein the cell is a tumor forming cells selected from 293-T cells, BHK21 cells, and MDCK cells.

97. A method of increasing the oncolytic activity of a virus comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, with an oncolytic virus to a subject or cell in need thereof.

98. A method of treating a disease, disorder or condition by gene therapy comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, and a gene therapy vector to a subject or cell in need thereof.

99. A method of increasing production of a virus by a cell comprising administering a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, to the cell.

100. The method of claim 99, comprising growing the virus in an appropriate medium in the presence of the compound.

101. The method of claim 99 or 100, wherein the cell is a viral production cell.

102. The method of claim 101 , wherein the viral production cell is Vero, HEK-293, VPC 1.0, VPC 2.0, EB-66, EbX, PER, C6, AGE1.CR, UMNSAH-DF1 , CEF, MRC-5, WI-38, BHK21 , Hela, A549 or sf9 cells.

103. The method of any one of claims 99 to 102, wherein the virus produced by the cell is an oncolytic virus, gene therapy vector or a vaccine.

104. A method of increasing transduction of a virus into a cell comprising administering a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, and the virus to the cell.

105. A method of increasing virally-encoded transgene expression comprising administering a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, and the virus to a cell.

106. A method of increasing virus growth and / or virus spread in cells comprising administering a compound of any one of claims 1 to 48, or a salt, solvate and / or prodrug thereof, to the cells in combination with provision of the virus to the cells.

107. The method of claim 106, wherein the provision of the virus to the cells is prior, concurrent with or after administration of the compound, or a salt, solvate and / or prodrug thereof.

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